key: cord- -jz hoxk authors: song, lili; ouyang, menglu; sun, lingli; chen, chen; anderson, craig s. title: impact of covid- on patient behavior to stroke symptoms in china date: - - journal: cerebrovasc dis doi: . / sha: doc_id: cord_uid: jz hoxk nan dear editor, the covid- outbreak has had a major impact across the whole of china, affecting all aspects of people's daily lives and triggered psychological problems of anxiety and panic [ ] . during the peak period of the outbreak in february and march , the implementation of national policies to avoid social gatherings and travel to high-risk areas [ ] resulted in hospitals reducing outpatient clinics and many services were restricted to urgent cases. consequently, clinical research abruptly ceased, hospitals suspended ethics committee submissions and their review, and few in-person participant assessments were conducted. china is now emerging from this difficult period, but the shadow of covid- continues, as we have encountered during initiation of the intensive ambulance-delivered blood pressure reduction in hyper-acute stroke trial (interact ) (clinicaltrials.gov nct , and chinese trial registry chictr- ). as the effectiveness of reperfusion therapy in highly time-dependent, public health strategies encourage patients to urgently call an ambulance, so that they can present rapidly to hospital after the onset of symptoms suggestive of acute stroke, most popularly defined by the face symmetry, arm weakness, speech slurring, and time to call (fast) tool. we wish to highlight how co-vid- has jeopardized this approach by adversely influencing the behavior of patients with suspected stroke. interact is a multicenter, prospective, randomized, open, blinded outcome assessed, trial of prehospital, ambulance-administered, intensive blood pressure-lowering treatment in patients with fast-positive presumed acute stroke within h from last known well. we launched the study on march , , and the first patient was enrolled weeks later. until may , , patients have met the eligibility criteria from patients screened across hospitals in expanding research networks in shanghai and chengdu. this screened eligibility rate ( % [ / ]) in the emergency department of the project lead hospital in shanghai is much lower than that recorded ( % [ / ]) in the period before the pandemic ( april to july , ). the main reason that patients were song/ouyang/sun/chen/anderson cerebrovasc dis doi: . / excluded according to the ambulance screening logs is "delayed time from symptom onset" (> h [n = ]). the percentage of exceeding the time window among excluded patients during the pandemic ( % [ / ]) is higher than that recorded in a similar period before the pandemic ( % [ / ]) at the lead hospital. these patients (or their family members) indicated that they postponed calling the emergency hotline due to concerns of "getting infected" from being exposed at a "high-risk" hospital, and their first reaction was to wait and hope that the symptom(s) would mitigate or disappear. moreover, parallel screening logs at participating hospitals indicate that many patients with mild stroke-related deficits chose to travel to hospital in their own vehicle, again to reduce a perceived high risk of infection via the ambulance. although "time is brain" is critical for effective reperfusion therapy, covid- has clearly impacted the behavior of patients in china, as inferred elsewhere [ ] , with the likelihood that this will have flow-on adverse effects in reducing the potential for recovery from stroke and increasing the impact of subsequent disability on families and society. although various clinical guidelines for the management of stroke during the covid- pandemic have been released [ ] , additional efforts are needed to reassure the population and encourage people to seek rapid access to stroke services in order to receive essential interventions. a nationwide survey of psychological distress among chinese people in the covid- epidemic: implications and policy recommendations novel coronavirus pneumonia prevention guidance for public (in chinese) collateral effect of covid- on stroke evaluation in the united states clinical guide for the management of stroke patients during the coronavirus pandemic c.s.a. holds a senior investigator fellowship of the national health and medical research council of australia and reports honoraria and travel reimbursement and grants from takeda, china. the other authors have no conflicts of interest to declare. no funding sources to report for the manuscript. c.s.a. and l.s. contributed to the concept and rationale for the study. m.o. and l.s. wrote the first draft of the manuscript with inputs from c.s.a. all authors commented upon and approved the final version of the manuscript for publication. key: cord- -kl ccmz authors: de jonge, jeroen c.; woodhouse, lisa j.; reinink, hendrik; van der worp, h. bart; bath, philip m. title: precious: prevention of complications to improve outcome in elderly patients with acute stroke—statistical analysis plan of a randomised, open, phase iii, clinical trial with blinded outcome assessment date: - - journal: trials doi: . /s - - - sha: doc_id: cord_uid: kl ccmz rationale: aspiration, infections, and fever are common in the first days after stroke, especially in older patients. the occurrence of these complications has been associated with an increased risk of death or dependency. aims and design: prevention of complications to improve outcome in elderly patients with acute stroke (precious) is an international, multi-centre, × factorial, randomised, controlled, open-label clinical trial with blinded outcome assessment, which will assess whether prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, respectively, or any combination of these in the first days after stroke onset improves functional outcome at days in elderly patients with acute stroke. discussion: this statistical analysis plan provides a technical description of the statistical methodology and unpopulated tables and figures. the paper is written prior to data lock and unblinding of treatment allocation. trial registration: isrctn registry isrctn . registered on september . the trial was prospectively registered. in the first days after stroke, about half of all patients develop one or more complications, including aspiration, infections, or fever. the risk of developing these events is greater in patients of higher age or with more severe stroke [ ] [ ] [ ] . these complications can impede functional recovery, prolong hospital admissions, and are independently associated with an increased risk of death or longterm dependency [ , , [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . the risk of developing these complications can be reduced by very simple, safe, and inexpensive measures, such as metoclopramide for the management of dysphagia, antibiotics for the prevention of infections, and paracetamol for the prevention of fever, but it is uncertain whether these measures also improve functional outcome [ ] [ ] [ ] [ ] . in some generally small, randomised trials, preventive treatment with these drugs not only convincingly reduced the risks of aspiration, infections, or fever by one third to one half, but was also associated with clear trends towards a lower risk of death or poor outcome [ ] [ ] [ ] [ ] . however, in two large randomised clinical trials, preventive treatment with antibiotics did not improve functional outcomes [ , ] . guidelines of the european stroke organisation concluded that there is insufficient evidence from randomised trials to make strong recommendations on whether, when, and to whom preventive antibiotic or antipyretic treatment should be given after ischaemic stroke or intracerebral haemorrhage [ , ] . the prevention of complications to improve outcome in elderly patients with acute stroke (precious) trial will assess whether prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first days after stroke onset improves functional outcome at days in older patients with acute stroke. the current paper describes the statistical analysis plan (sap) of the trial and conforms to the guidelines set by gamble et al. [ ] . the details of the study protocol of the precious trial have been published earlier [ ] . precious has received funding from the european union's horizon research and innovation programme under grant agreement no. . precious is an international, multi-centre, multifactorial, randomised, controlled, phase iii, open-label clinical trial with blinded outcome assessment (probe). the primary objective is to assess whether prevention of aspiration, infections, or fever with metoclopramide, ceftriaxone, paracetamol, or any combination of these in the first days after stroke onset improves functional outcome at days in older patients with acute stroke. patients will be randomly allocated in a × × factorial design to any combination of open-label oral, rectal, or intravenous metoclopramide ( mg thrice daily); intravenous ceftriaxone ( mg once daily); oral, rectal, or intravenous paracetamol ( mg four times daily); or usual care, started within h after symptom onset and continued for days or until complete recovery or discharge from hospital, if earlier. in patients with moderate to severe renal impairment or with severe hepatic impairment, the dose of metoclopramide is reduced to mg thrice daily, and in patients with end-stage renal disease to . mg thrice daily. patients will be stratified according to country (estonia, germany, greece, hungary, italy, the netherlands, norway, poland, uk), and there will be minimisation factors: age ( - years; > years), sex (male vs. female), stroke type (ischaemic stroke vs. intracerebral haemorrhage), stroke severity (nihss - vs. > ), and diabetes mellitus (yes vs. no).a total of patients will be recruited, based on the sample size calculation described in the previously published protocol [ ] . an independent data and safety monitoring board (dsmb) will conduct unblinded interim analyses after , , , , and patients have completed follow-up to assess the safety of the interventions in the trial. with respect to efficacy, the dsmb will conduct unblinded interim analyses after patients had their final follow-up. dsmb members will receive listings of all sae reports as well as unblinded aggregate summaries of data by treatment groups for review in closed meetings. the results of these interim analyses are confidential and limited to the members of dsmb. this statistical analysis plan (sap) will be signed off by the trial steering committee and then submitted for publication prior to data lock and final analysis. the final statistical analysis will be performed once recruitment has ceased, final follow-up and final outcome adjudication have been completed, final data have been checked and any errors corrected, and the database has been locked. the analyses will be carried out according to the current statistical analysis plan. the statistical analyses will be performed by the nottingham stroke trial unit (nstu) at the university of nottingham (unott) in collaboration with the umc utrecht. the study population will consist of patients aged years or older who are hospitalised with moderately severe to severe (national institutes of health stroke scale (nihss) ≥ ) acute ischaemic stroke or intracerebral haemorrhage. patients will only be included if treatment can be started within h of stroke onset. for a complete overview of the inclusion and exclusion criteria, we refer to the study protocol [ ] . patients are planned to be recruited in about hospitals in european countries over a period of about years. to increase the generalisability of the findings, these countries are distributed across europe and include estonia, germany, greece, hungary, italy, the netherlands, norway, poland, and the uk. for the same reason, the trial will recruit patients both in academic and regional hospitals ( table , fig. ). the primary outcome measure is the score on the modified rankin scale (mrs) at days (± days). the mrs is an ordinal scale ranging from to [ ] . the mrs assessment at days will be during a hospital/home visit or by telephone, and the assessment or a report thereof will be recorded using a digital video camera. three blinded raters will view the videotape and adjudicate a score on the mrs. pre-stroke method of food intake oral softened food or fluids only paracetamol acute stroke treatment (%) data are n (%) or median [iqr] . mrs modified rankin scale, nihss national institutes of health stroke scale, bp blood pressure for each patient, a median mrs score will be calculated from the three mrs scores obtained through centralised adjudications by raters who are blinded to treatment allocation. the use of three scores increases the precision in scoring and statistical power as compared to a single mrs assessment [ ] . the primary effect estimate will be the difference in the mrs scores between the active treatment group and controls assessed using ordinal logistic regression, and will be expressed as an odds ratio with % confidence interval [ ] . the primary analysis will be performed on all randomised patients with a valid mrs score at days. the distribution of the mrs scores will be shown as a figure (fig. ). three separate primary analyses will be performed for each intervention vs. their respective controls (e.g. metoclopramide vs. non- the primary analyses will be adjusted for stratification (country), minimisation (age, sex, stroke type, stroke severity, diabetes), and other baseline prognostic (e.g. premorbid mrs, atrial fibrillation, reperfusion treatment [alteplase and/or thrombectomy], time from onset to randomisation) factors, and treatment allocation for the other two strata of the trial (table ) . comparison of the effect of the three intervention groups vs. their respective controls on the primary outcome will be performed in the following pre-specified subgroups (assuming sufficient numbers in each subgroup) with assessment of interaction between treatment and the minimisation factors (these subgroup analyses are considered hypothesis-generating) ( table ) : age (≤ , > years); sex (male, female); stroke type (ischaemic stroke, intracerebral haemorrhage); stroke severity (nihss - , > ); diabetes mellitus (yes, no). in addition, the interaction between treatment and other baseline factors will be assessed: presence of atrial fibrillation (yes, no); pre-stroke mrs score ( , > ); reperfusion treatment (alteplase and/or mechanical thrombectomy); time to treatment (< , ≥ h < h, ≥ h); treatment allocation for the other two trial strata (paracetamol-active, control; ceftriaxone-active, control; metoclopramide-active, control). since the study is not powered to detect interactions between the three interventions, these interactions will be investigated in secondary analyses. four sensitivity analyses of the mrs will also be performed: unadjusted ordinal logistic regression, adjusted analysis of mrs following regression imputation of missing data, multiple linear regression on the mean mrs score for each participant, and binary logistic regression on mrs > . the following secondary outcomes will be assessed at days (± day) or at discharge, if earlier: infections in the first days (± day; frequency, type, and clostridium difficile infections). infections will be categorised as diagnosed by the clinician and as judged by an independent adjudication committee (masked to treatment allocation); third generation cephalosporin resistance in the first days (± day), detected as part of routine clinical practice; antimicrobial use during the first days, converted to units of defined daily doses according to the classification of the who anatomical therapeutic chemical classification system with defined daily doses index; serious adverse events (saes) in the first days; in a subgroup of patients: presence of extended-spectrum beta-lactamase (esbl)-producing bacteria as detected by pcr in a rectal swab at day (± day, or at discharge, if earlier). the following secondary outcomes will be assessed at days (± days) ( table ): death; unfavourable functional outcome, defined as mrs to ; disability assessed with the score on the barthel index (bi); cognition assessed with the montreal cognitive assessment (moca); quality of life assessed with the euroqol d- l (eq- d- l) and eq-visual analogue scale (eq-vas); home time: the number of nights among the first since stroke onset that are spent in the patient's own home or a relative's home. resource use will be censored at days. where final follow-up occurs earlier, the last known placement will be extrapolated to days; patient location over first days (± days): hospital, rehabilitation service, chronic nursing facility, and home. binary logistic regression will be used for binary outcomes (e.g. mrs > ). cox proportional hazards regression will be used for time to events (e.g. death). ordinal logistic regression will be used for ordered categorical data (e.g. mrs). multiple linear regression will be used for continuous outcomes (e.g. bi, eq-vas). patients with missing outcome data will be excluded from the analysis. patients without a primary outcome assessment at ± days will be considered as a lost to follow-up. the total amount of patients who are lost to follow-up will be recorded and calculated for each treatment arm. the primary analysis will be performed on all randomised patients with a valid mrs score at days. in a sensitivity analysis, missing mrs data will be imputed using multiple regression-based imputation. for the secondary outcome measures (barthel index, moca, eq- d- l, eq-vas), patients who die will be assigned a value one unit worse than any living value. this way, patients who die cannot be given a score similar to the worst score of patients who are alive, and it ensures that all patients will be included in the analysis. potential scores, with worst with dead added, are as follows: -modified rankin scale (mrs), to with death = ; -barthel index (bi), to with death = − ; -euroqol d- l (eq- d- l), − . to with death = ; -euroqol visual analogue scale (eq-vas), to with death = − ; -montreal cognitive assessment (moca), to with death = − . in the first days after randomisation, all saes will be reported and described by duration (start and stop dates), severity, outcome, treatment, and relation to the investigational medical product (imp), or if unrelated, the cause. all saes will be tabulated per treatment stratum. in addition, any sae occurring between day and the end of follow-up on day (± days) for which a causal relationship between the imp and the sae is considered at least a reasonable possibility (i.e. sars and susars) should be reported as other saes. the presence of any treatment restriction will be recorded at baseline and during the hospital phase, and classified as ( ) do not resuscitate, ( ) do not intubate and ventilate, ( ) withhold other treatments that may prolong life, ( ) withhold food, ( ) withhold fluids, and ( ) palliation (e.g. with morphine or a benzodiazepine). any combination of these strategies is possible. the primary study will report on the frequency of each treatment restriction, and further analyses on this topic will be published in future subgroup analyses. precious is an open-label clinical trial, and both patients and treating physicians are therefore aware of the assigned treatment. knowledge of treatment allocation can influence outcome assessment, and unblinded trials like precious are therefore at risk of detection bias. in addition, despite its apparent simplicity, assessment of the score on the mrs has been associated with considerable inter-observer variability, especially in multicentre studies, and may therefore affect trial power and treatment effect size. in precious, these two major issues are minimised through ( ) online training and certification of outcome assessors via a link on the precious website and ( ) central outcome assessment by three blinded adjudicators based on digital video recordings of the -day outcome interviews. this central adjudication by trained adjudicators offers several benefits [ ] : . blinding is assured; . standardisation is possible across multiple regions and cultures; . statistical power is enhanced through the use of three repeated assessments; . the estimate of treatment effect size is restored (since statistical noise leads to underestimation); . it provides independent validation of the information that is collected, thereby minimising the risk of fraud; . site staff perform to a higher standard when aware that there will be review or audit of their activity. in addition, the risk of bias is reduced by performing the statistical analyses according to the intention-totreat principle and adjusting for the minimisation factors, other relevant baseline characteristics, and treatment allocation for the other two strata of the trial. analyses will be two-sided p < . with % confidence intervals presented. the trial is testing the effect of the interventions on mrs, and analyses in subgroups and on other outcomes are considered hypothesis-generating. hence, no adjustment will be made for multiplicity of testing. the data monitoring committee performs safety assessments using the haybittle-peto boundary rule (p < . ); hence, no significant spending of alpha will occur during the trial. all analyses will be two-tailed, and p values of < . will denote statistical significance; % confidence intervals will be provided. adjustment for multiple comparisons will not be performed, but all contrasts will be declared. compliance with allocated treatment will be tabulated. for each of the three study drugs, the number of received dosages will be calculated (maximum of four for ceftriaxone, twelve for metoclopramide, and sixteen for paracetamol). the number of patients who received the first dosage within the time window of h will also be presented; if the dosage was not given within h, the reason will be given (withdrawn informed consent, death, human error, other reason). all efficacy analyses will be performed on the intentionto-treat population. the robustness of the primary and key secondary analyses will be assessed in the perprotocol population. safety analyses will be performed on the safety population. the following population definitions will be used: ▪ intention-to-treat in primary efficacy analysis: all randomised participants who received any study medication and with a valid mrs score recorded at days. ▪ intention-to-treat in primary safety analysis: all randomised participants with a vital status recorded at days. ▪ per-protocol: all participants in the intention-to-treat population who are deemed to have no major protocol violations that could interfere with the objectives of the study. patients with protocol violations in trial eligibility will be included in the intention-to-treat population, but excluded in the per-protocol analysis. patients who withdrew informed consent before initiating treatment will be excluded from analysis. if (per accident) multiple randomisations are performed for a single patient, the result of the first randomisation will be used. the trial received approval from the central medical ethics committee of the university medical center utrecht, the netherlands, on february . the dutch national competent authority (centrale commissie mensgebonden onderzoek (ccmo)) declared to have no objection against the execution of the clinical trial within the netherlands on november . in addition, the national (and local, if applicable) medical ethical committees and competent authorities of the other participating countries have approved the trial. the first patient was included in may . the analysis and reporting of the trial will be in accordance with consort guidelines. after publication of the trial, to promote the independent re-use of precious data, a coded dataset will be made available in a public data repository within months of the final follow-up of the last patient. coded data will also be included in the virtual international stroke trials archive (vista). supplementary information accompanies this paper at https://doi.org/ . /s - - - . additional file : table s . protocol violations in eligibility. data are n (%). mrs, modified rankin scale. additional file : table s . compliance and cross-over in first days. data are n (%). comparisons made by binary logistic regression. additional file : table s . secondary outcomes and treatment restrictions at days. mrs, modified rankin scale. data are n (%) or median [iqr] . aor: adjusted odds ratio. comparison by adjusted ordinal logistic regression (aolr) or binary logistic regression (ablr). * converted to units of defined daily doses according to the classification of the who anatomical therapeutic chemical classification system with defined daily doses (ddd) index. additional file : table s . overview of safety. data are n (%). sae, severe adverse event; sar, severe adverse reaction; susar, severe unexpected serious adverse reaction. comparisons made by binary logistic regression. medical complications after stroke characteristic adverse events and their incidence among patients participating in acute ischemic stroke trials development and internal validation of a prediction rule for post-stroke infection and poststroke pneumonia in acute stroke patients post-stroke infection: a systematic review and meta-analysis therapeutic hypothermia in acute ischemic stroke impact of fever on outcome in patients with stroke and neurologic injury: a comprehensive meta-analysis effect of hyperthermia on prognosis after acute ischemic stroke dysphagia after stroke: incidence, diagnosis, and pulmonary complications temporal profile of body temperature in acute ischemic stroke: relation to infarct size and outcome poststroke dysphagia: a review and design considerations for future trials route of feeding as a proxy for dysphagia after stroke and the effect of transdermal glyceryl trinitrate: data from the efficacy of nitric oxide in stroke randomised controlled trial an early rise in body temperature is related to unfavorable outcome after stroke: data from the pais study antibiotic therapy for preventing infections in patients with acute stroke the paracetamol (acetaminophen) in stroke (pais) trial: a multicentre, randomised, placebo-controlled, phase iii trial safety and effect of metoclopramide to prevent pneumonia in patients with stroke fed via nasogastric tubes trial the preventive antibiotics in stroke study (pass): a pragmatic randomised open-label masked endpoint clinical trial prophylactic antibiotics after acute stroke for reducing pneumonia in patients with dysphagia (stroke-inf): a prospective, cluster-randomised, open-label, masked endpoint, controlled clinical trial european stroke organisation (eso) guidelines for the management of spontaneous intracerebral hemorrhage european stroke organisation (eso) guidelines for the management of temperature in patients with acute ischemic stroke guidelines for the content of statistical analysis plans in clinical trials precious: prevention of complications to improve outcome in elderly patients with acute stroke. rationale and design of a randomised, open, phase iii, clinical trial with blinded outcome assessment contemporary outcome measures in acute stroke research improving the efficiency of stroke trials statistical analysis of the primary outcome in acute stroke trials publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations none. hbvdw is the precious coordinating investigator. all authors contributed to the design of the statistical analysis. jdj wrote the first draft of the manuscript, and all authors reviewed the manuscript carefully. all authors read and approved the final version of the manuscript. the details of the study protocol have been published earlier [ ] . after publication of the trial, to promote the independent re-use of precious data, a coded dataset will be made available in a public data repository within months of the final follow-up of the last patient. coded data will also be included in vista. the primary ethics approval for the precious trial has been provided by the medical ethics committee of the university medical center utrecht, utrecht, the netherlands (nl . . ). we have obtained informed consent from all participants in the study. key: cord- -vfr g kp authors: lee, meng; chen, chi-hsin sally; ovbiagele, bruce title: covert covid- complications: continuing the use of evidence-based drugs to minimize potentially lethal indirect effects of the pandemic in stroke patients date: - - journal: j neurol sci doi: . /j.jns. . sha: doc_id: cord_uid: vfr g kp nan stroke and cardiovascular diseases are the world's biggest killers, globally accounting for over million deaths each year (https://www.who.int/news-room/fact-sheets/detail/the-top- -causes-of-death). since the coronavirus disease (covid- ) outbreak in wuhan, china and its rapid spread to other countries, as of april , there were about million cases with over deaths worldwide. however, actual situation might be even more dire, since such statistics likely do not fully display the entire impact of covid- , especially with regard to its influence on patients with a history of stroke who need to take cardiovascular drugs regularly to prevent recurrent vascular events. although there is currently a lack of definitive data, it is conceivable that several of these patients are unable to receive their cardiovascular preventive medications, especially if they live in most covid- ravaged areas with medical systems overwhelmed, and/or are restricted to their homes. most stroke patients with atrial fibrillation need to take an oral anticoagulant regularly. clinical trial evidence shows that stroke patients with atrial fibrillation assigned to apixaban, a novel oral anticoagulant, compared with aspirin, had a substantially lower risk of recurrent stroke or systemic embolism ( . % vs . % per year, hazard ratio . , % confidence interval [ci] . to . ). the safety advantage for novel oral anticoagulants over warfarin may be even larger during the j o u r n a l p r e -p r o o f journal pre-proof covid- pandemic, because it will be challenging for stroke patients with atrial fibrillation who take warfarin to receive regular blood tests to monitor international normalized ratios, and therefore it may be prudent to prescribe novel oral anticoagulants instead of warfarin to stroke patients with atrial fibrillation during this crisis period. on the other hand, a large cohort study showed that discontinuation of aspirin was associated with a % increase in the risk of ischemic stroke compared with continuation of therapy in people taking aspirin for the secondary prevention of cardiovascular or cerebrovascular events. it would be a disaster if stroke patients cannot continuously take their prescribed antithrombotic agent during this pandemic. an italian cohort study showed that in first-ever ischemic stroke patients who were to years, discontinuation of antihypertensive drugs was independent predictors of recurrent cardiovascular events. a taiwan nationwide cohort study showed that discontinuation of statin therapy during chronic stage of an index ischemic stroke was associated with a higher risk of recurrent stroke (adjusted hazard ratio . , % ci . to . ) within year after statin discontinuation. discontinuation of antihypertensive drugs or statin therapy in stroke patients is likely to be associated with the increased risk of future cardiovascular events and should be avoid in any circumstance. based on currently available information, there is about a . -fold increase in j o u r n a l p r e -p r o o f journal pre-proof as the u.s. centers for disease control and prevention are advising high risk patient groups to take precautions, including requests for extra supplies and mail-order options from their healthcare providers, in case they must stay home for a prolonged period. local pharmacies may provide delivery services, drive-through services, or authorization forms that allow family members to pick up prescribed medication. these are examples of steps that could be taken to prevent discontinuation of vascular drug treatment in case of quarantine or city lockdown. government efforts in securing the supply and dispensing necessary medications generally, but especially for those with a history of stroke who are at higher risk for severe illness or dying with and without covid- than the general population, need to be escalated to properly mitigate the potentially looming threat of drug shortages, and associated poor clinical outcomes. apixaban versus aspirin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a predefined subgroup analysis from averroes, a randomised trial increased risk of stroke after discontinuation of acetylsalicylic acid: a uk primary care study predictors of long-term recurrent vascular events after ischemic stroke at young age: the italian project on stroke in young adults utilization of statins beyond the initial period after stroke and -year risk of recurrent stroke key: cord- -fwz chzf authors: myserlis, pavlos; radmanesh, farid; anderson, christopher d. title: translational genomics in neurocritical care: a review date: - - journal: neurotherapeutics doi: . /s - - - sha: doc_id: cord_uid: fwz chzf translational genomics represents a broad field of study that combines genome and transcriptome-wide studies in humans and model systems to refine our understanding of human biology and ultimately identify new ways to treat and prevent disease. the approaches to translational genomics can be broadly grouped into two methodologies, forward and reverse genomic translation. traditional (forward) genomic translation begins with model systems and aims at using unbiased genetic associations in these models to derive insight into biological mechanisms that may also be relevant in human disease. reverse genomic translation begins with observations made through human genomic studies and refines these observations through follow-up studies using model systems. the ultimate goal of these approaches is to clarify intervenable processes as targets for therapeutic development. in this review, we describe some of the approaches being taken to apply translational genomics to the study of diseases commonly encountered in the neurocritical care setting, including hemorrhagic and ischemic stroke, traumatic brain injury, subarachnoid hemorrhage, and status epilepticus, utilizing both forward and reverse genomic translational techniques. further, we highlight approaches in the field that could be applied in neurocritical care to improve our ability to identify new treatment modalities as well as to provide important information to patients about risk and prognosis. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. translational genomics represents a diverse collection of research approaches that leverage human genomics and model systems to identify new approaches to treat and prevent disease and improve healthcare ( , ) . rooted by the central dogma of dna to rna to protein, genomic research examines the entire genome concurrently, and may include analyses of dna variants in association with traits of interest as well as the impact of genomic variation on gene transcription and translation. genomic research has been enabled by technological advances to accurately and cost-effectively study variation across the genome at scale, as well as computational techniques to store and analyze genomic data quickly and efficiently ( ) . while translational research is often defined in terms of the traditional "bench to bedside" techniques that advance discoveries from model systems through biomarkers and mechanisms ultimately to clinical applications, genomic research offers a strong use-case for an alternative approach. termed "reverse translation," this approach starts with humans as the model system, utilizing genomic associations to derive new information about biological mechanisms that can be in turn studied further in vitro and in animal models for target refinement (fig. ) . both of these approaches possess advantages and drawbacks ( , ) . forward translation depends on the relevance of the model system to human disease, both in terms of the physiologic responses to disease or insult, as well as the approach taken to perturb the system. for instance, the human applicability of genomic studies of the response to traumatic brain injury (tbi) in a mouse model require that the mouse's response to tbi is analogous to a human's, and that the approach taken to pavlos myserlis and farid radmanesh contributed equally to this work. create a tbi in the mouse provokes a similar pattern of injury seen in human tbi ( ) ( ) ( ) ( ) . as such, a great deal of careful work is required to demonstrate the validity of these model systems before the results arising from them can be judged relevant to human disease. the challenges of bridging this divide are illustrated by the universal failure of neuroprotection mechanisms that reached human trials in the last several decades, essentially all of which had promising model system data in preclinical development ( ) ( ) ( ) ( ) ( ) . reverse genomic translation, in contrast, begins with humans ( fig. ). as such, there are few concerns as to the relevance of the system for discovery of biomarkers and mechanisms of disease. however, this approach carries a new series of challenges in study design and data acquisition ( ) . compared to isogenic cell lines or carefully bred animals in a controlled setting, humans are highly variable in both their environmental and genetic exposures. this is advantageous in identifying genetic susceptibility to disease risk and outcomes, but teasing out these small genetic effects from highly variable non-genetic exposures requires both careful computational techniques as well as large sample sizes. furthermore, because genomic data is both identifiable and can potentially lead to discrimination, human genomic studies require complex consent and data management procedures ( ) . in neurocritical care, the relative rarity of many of the diseases we encounter, coupled with the challenges of critical illness and surrogate consent make human genomic studies all the more difficult to execute effectively ( ) ( ) ( ) ( ) . neurointensivists routinely encounter diseases and complications for which there are a dearth of effective treatments, or even foundational knowledge of their underlying pathophysiologic mechanisms ( , ) . in this review, we will highlight some of the approaches being taken to apply translational genomics to the study of diseases commonly found in neurocritical care, utilizing both forward and reverse genomic translational techniques. further, we will highlight some of the best practices in the field that could be applied in neurocritical care to improve our ability to identify new treatment modalities as well as risk and prognosis information to patients and their families. in advance of the human genome project and the hapmap consortium, genetic studies were confined to the study of candidate genes and lower-resolution genome-wide techniques such as categorization of restriction fragment length polymorphisms (rflp), tandem repeats, and microsatellites ( ) . these genomic features enabled early efforts to perform linkage analyses in families with related traits and disorders, as well as selected populations of unrelated individuals. careful work in this arena led to validated discoveries that have survived replication in the common era, such as chromosome in late-onset alzheimer disease (ad), ultimately mapped to the apoe locus that has become a target for a great deal of genetic research in ad, as well as many other diseases including tbi and intracerebral hemorrhage (ich) ( ) ( ) ( ) ( ) . still, much of the pregwas era was characterized by candidate gene studies that suffered from low statistical power and multiple sources of confounding that led to a failure to replicate many reported associations in the gwas era that followed ( , ) . the most substantial source of confounding in candidate gene analyses is population stratification, in which differences in allele frequency due to ancestral imbalance between cases and controls introduces spurious associations (positive or negative) between genotype and trait based solely on these cryptic ancestral imbalances ( , ) . even in studies of apoe in european ancestry populations, uncontrolled variation in the percentages of individuals of northern vs. southern european ancestry between cases and controls can mask true associations between apoe and ich, for instance ( ) . the gwas era, in which variants across the genome could be reliably genotyped and mapped to a common reference template by chromosomal location, ushered in a new system of best practices that could minimize the contribution of many of the sources of confounding in describing associations between genomic variation and traits or diseases. the international hapmap consortium obtained genotypes on individuals across ancestral populations around the globe, creating a resource that described the patterns of allele frequency variation across diverse populations ( ) . with these breakthroughs and a number of landmark evolutions that followed, case/control and population-based gwas have led to the identification of over , associations with human diseases and other traits (https://www.ebi.ac.uk/gwas/). obviously there is an enormous disconnect between the discovery of genetic loci and leveraging of this information for human benefit, which is where the translational genomic work that serves as the topic of the present review becomes relevant ( ) . post-gwas, in addition to functional and translational efforts, the movement has been towards so-called "next-generation sequencing" methodologies consisting of whole exome sequencing (wes) and whole genome sequencing (wgs). using these approaches, each nucleotide in the exome or genome is ascertained with high reliability, permitting the identification of rare and de novo variants that escape detection in traditional gwas ( ) . wes captures within-gene coding variation only, offering detection of variants that may more directly impact protein structure and function than non-coding variation detected by wgs ( ) . because the coding exome is only~ % of the overall genome, it is more cost-effective than wgs, but debate continues as to which is the more appropriate tool for large-scale study of the human genome ( ) . regardless, both wes and wgs remain orders of magnitude more expensive than traditional gwas approaches at this time, and as such well-powered sequencing studies remain unreachable for many diseases in the current pricing models. less common diseases and conditions that one may find in a neurocritical care unit are doubly disadvantaged, as even larger sample sizes are required for sequencing analyses than gwas, due to the need for many observations to identify rare exonic or intronic variants associated with disease ( , ) . as pricing models improve and larger and larger community or hospital-based cohorts receive sequencing through clinical or biobanking efforts, it is hoped that even uncommon conditions such as subarachnoid hemorrhage or status epilepticus will benefit from the insights achievable through sequencing analysis, where case/control and smaller sequencing studies have shown promise ( , ) . obviously genomic research need not be limited solely to human studies. a wealth of information about disease pathogenesis and response to injury can be gleaned from model systems of human conditions using genomic and transcriptomic approaches. because animal models and isogenic tissue cultures are specifically designed to limit genetic differences between individual animals or plated cells, dna-based association tests typically do not offer insight in the same way that they do in humans. as such, many model system studies start with rna, examining how the genome responds to perturbation through the transcriptome. however, there are substantial genomic differences between model systems and humans, as coding sequences are not necessarily conserved, promoter and enhancer control of gene expression can vary, and in the case of immortalized tissue and cell-based assays, the chromosomal architecture itself can be quite different from the organism from which it was derived ( , ) . these differences can be highly relevant when determining whether observed transcriptomic and proteomic results from model systems are likely to be shared in humans. with those caveats, the dynamic nature of the transcriptome in model systems offers opportunities to assess the way in which the genome responds to noxious insults or drug exposures, and in animal models this can even be done across specific organs or tissues of interest ( ) . as one example, traumatic brain injury researchers have obtained insight into both the initial injury cascade as well as brain response to potential injury modulators such as valproate using animal models and transcriptional microarrays, in which rna expression patterns in brain tissue can be rapidly and replicably assessed across the transcriptome ( ) . using more recent technological advancements such as drop-seq, rna expression can be assessed in single cells, as has been done in individual hippocampal neurons in a mouse model of tbi ( ) . at a minimum, these elegant studies can help to identify relevant cell types important in the response to injury, highlighting testable hypotheses that may be important in human conditions, all with access to tissues and control over experimental conditions that would never be possible in human-based research. given that diseases common to the neurocritical care population so rarely afford access to brain tissue for pathologic or genomic analysis antemortem, model system genomic studies offer an important adjunct for translational research. forward genomic translation begins with model systems with the goal of using the measured associations in these models to derive insight into biological mechanisms that may also be relevant in human disease. forward translation requires wellcharacterized models that are often designed to mimic the human exposures of interest as closely as possible. this is often challenging given the natural differences between humans and many of the animals chosen to serve as models. in this section, we will highlight several model systems in current use for translational genomics relevant to neurocritical care, but the field of translational modeling in neurologic disease is suitably large to prevent an exhaustive review herein. malignant cerebral edema is a highly lethal complication of ischemic stroke, with mortality of - % ( ) . currently, hemicraniectomy is the only available option to prevent death and yet it does not address the underlying pathophysiology. hyperosmolar therapy is potentially useful as a bridge to surgery. preclinical data based on a forward translation approach has been useful in highlighting mechanisms underlying postinfarct edema as potential targets for therapeutic manipulation. the sulfonylurea receptor (sur ) is encoded by the abcc gene that is upregulated after cns injury, forming an ion channel in association with transient receptor potential melastatin (trpm ). continuous activation of this complex can lead to cytotoxic edema and neuronal cell death, which has been demonstrated in both animal and human models ( , ) . sur is also found in pancreatic beta cells, constituting the target for the oral hypoglycemic agent, glyburide. studies of rodent and porcine stroke models demonstrated that in the first few hours after an ischemic insult, both sur and trpm are upregulated ( , ) . limited case series of human postmortem specimens also demonstrated upregulation of sur in infarcted tissue ( ) . therefore, intravenous glyburide has been proposed for treatment of malignant cerebral edema. targeting sur in rat models of ischemia have consistently resulted in reduced edema and better outcomes ( ) . in particular, glyburide infusion starting h after complete middle cerebral artery occlusion resulted in decreased swelling by two thirds and % reduction in mortality ( ) . one desirable characteristic of glyburide is that it cannot penetrate intact blood-brain barrier, but that is facilitated following brain injury ( ) . the effect of glyburide for treatment of cerebral edema has also been studied in tbi with promising data obtained from animal studies ( ) . limited randomized trials in human using oral glyburide have shown promising results; however, use of oral formulation and study design limitations prohibit generalizability of results ( , ) . building on this preclinical data, the phase randomized clinical trial (games-rp) showed that the iv preparation of glyburide, glibenclamide, is associated with reduction in edema-related deaths, less midline shift, and reduced rate of nih stroke scale deterioration. however, it did not significantly affect the proportion of patients developing malignant edema ( ) . the phase charm trial, sponsored by biogen, is currently enrolling patients with large hemispheric infarction to determine whether iv glibenclamide improves -day modified rankin scale scores. if this trial proves successful, this vignette will represent a dramatic success story for the forward translation paradigm in genomic research. in the light of recent advances in revascularization therapy, the national institute of neurological disorders and stroke has supported an initiative aiming to develop neuroprotective agents to be used as adjunctive therapy to extend the time window for reperfusion and to improve long-term functional outcome. this stroke preclinical assessment network (span) supports late-stage preclinical studies of putative neuroprotectants to be administered prior to or at the time of reperfusion, with long-term outcomes and comorbidities constituting the endpoint. the goal is to determine if an intervention can improve outcome as compared to reperfusion alone and/or extend the therapeutic window for reperfusion. span directly applies to forward translation efforts in preclinical models of neuroprotection after stroke and is an outstanding opportunity to stimulate research efforts in a field more remembered for its past failures than the promise it holds for the future of therapeutic development in the area. other societies have also begun to endorse more comprehensive modeling approaches in areas with few therapeutic options with the hope of implementing a paradigm shift. for example, the neurocritical care society has initiated "curing coma" campaign with the -to -year mission to improve the understanding of the mechanisms and to ultimately develop preventative and therapeutic measures. traumatic brain injury (tbi) is among the leading causes of disability and death worldwide, particularly in the young. the type of tbi is in part determined by the attributes of mechanical forces, including objects or blasts striking the head, rapid acceleration-deceleration forces, or rotational impacts. following the primary injury, an intricate cascade of neurometabolic and physiological processes initiates that can cause secondary or additional injury ( , ) . intensive care management has improved the prognosis of tbi patients; however, specific targeted treatments informed by pathophysiology could have a tremendous impact on recovery. the period of secondary tissue injury is the window of opportunity when patients would potentially benefit from targeted interventions, given that in tbi, the primary injury cannot be intervened upon by the neurologist or intensivist. the goal of therapy is therefore to reduce secondary damage and enhance neuroplasticity. the utility of animal models of tbi primarily depends on the research question, as each model emulates specific aspects of injury and has selective advantages and disadvantages. these include biomechanics of initial injury, molecular mechanisms of tissue response, and suitability for high-throughput testing of therapeutic agents, to name a few. although phylogenetically higher species are likely more representative models for human tbi, rodent models are more commonly used given the feasibility to generate and measure outcomes, as well as ethical and financial limitations of higher-order models. table summarizes some common and representative tbi models [ table ]. in contrast with the rodent models described in table , other model systems in tbi have been selected specifically to study other aspects of the physiologic response to tbi. for example, a swine model of controlled cortical impact offers the opportunity to readily monitor systemic physiologic parameters such as tissue oxygen and acid-base status while investigating therapeutic interventions, which is argued to provide greater insight into human response to injury ( ) . translation of preclinical studies using these animal tbi models to humans is inherently challenging. differences in brain structure, including geometry, craniospinal angle, gyral complexity, and white-gray matter ratio, particularly in the rodent models, can result in different responses to trauma ( ) . the limitation of extrapolating animal studies to human is also manifested at the genetic level, as differences in gene structure, function, and expression levels may suggest genetic mechanisms that are incompletely correlated with humans. as an example, female sex may be associated with better outcome through the neuroprotective effect of progesterone in animal models, but these observations did not carry over to humans in the protect-iii trial ( , ) . variable outcome measures, including neurobehavioral functional tests, glasgow outcome scale correlates, and high-resolution mri have been used in attempts to correlate animal responses to injury with those of humans. the lack of a large cache of standardized tools further limits comparison or pooling the results of different studies that use variable models of tbi or outcome measurement. transcriptomics, a genomic technique in which global rna expression is quantified through either expression microarrays or rna sequencing, has been employed to characterize specific inflammatory states following tbi. many studies have assessed the transcriptome in the acute post-tbi interval within - days after injury, with some showing upregulation of inflammation and apoptosis genes. gene ontology analysis at months post-tbi have shown similar changes, with upregulation of inflammatory and immune-related genes ( ) . importantly, late downregulation of ion channel expression in the peri-lesional cortex and thalamus suggests that this delayed examination of the transcriptome could be valuable for revealing mechanisms relevant to chronic tbi morbidities, including epileptogenesis and prolonged cognitive impairment ( ) . in addition, tissue-specific analysis of gene diffuse axonal injury reproduces human tbi needs standardization, e.g., location of animal within shock tube and heard immobilization ( ) expression across cell types in brain could provide useful insight into cell-specific pathways. for example, temporal trending of microglial expression profile indicates a biphasic inflammatory pattern that transitions from downregulation of homeostasis genes in the early stages to a mixed proinflammatory and anti-inflammatory states at subacute and chronic phases ( ) . the list of antiepileptic drugs has expanded significantly in the past decade, reflecting substantial investment in the search for new therapeutics with better efficacy and tolerability. however, the list of options with demonstrated efficacy in status epilepticus (se) has remained limited. the utility of benzodiazepines, often deployed in the field as a first-line agent, decreases with increasing duration of se. in addition, - % of patients with se develop refractory se when they fail to respond to first-and second-line therapy, posing a significant management and prognostic challenge ( ) . the development of aeds has relied substantially on preclinical animal models to establish efficacy and safety prior to proceeding to human trials. different epilepsy models exist that are each useful for different aspects of drug development and no model is suitable for all purposes. the majority of animal models induce epilepsy using electroshock or chemical seizure induction. nearly all recent aeds have been discovered by the same conventional models, and the reliance on these common screening models has been implicated as one of the reasons for the low yield of drugs with efficacy in refractory epilepsy ( ) . the pros and cons for each epilepsy model are discussed in detail in several excellent reviews ( , ) . some of the chemicals used include kainic acid, pilocarpine, lithium, organophosphates, and flurothyl ( ) . sustained electrical stimulation to specific sites, including the perforant path, the ventral hippocampus, the anterior piriform cortex can induce se ( ) . the latency, length, and mortality of convulsive se are more variable in chemoconvulsant as compared to electrical models, which are in turn determined by the drug and route of administration, species, sex, age, strain, and genetic background among other factors ( ) . it should also be noted that the presence of behavioral convulsion does not correlate fully with the electrographic data and vice versa. this can have c r i t i c a l i m p l i c a t i o n s w h e n s t u d y i n g d r u g s f o r pharmacoresistant se. therefore, it has been suggested that electroencephalographic quantification be used to measure the severity of se ( ) . furthermore, the genetic background and expressivity of animals can have a significant effect on seizure susceptibility, even between batches of inbred mice ( ) . proteomic and transcriptomic approaches have been utilized for assessment of alterations in expression profile following se, demonstrating that certain subsets of genes are upregulated at each timepoint following the onset of se. specifically, upregulation of genes regulating synaptic physiology and transcription, homeostasis and metabolism and, cell excitability and morphogenesis occur at immediate, early, and delayed timepoints. in addition, related studies have demonstrated changes in expression of micrornas related to epileptogenesis, including mirna- and mi-rna- following se ( , ) . selective rna editing post-transcription is yet another potential source of proteomic diversity in preclinical models of se, and merits further investigation as a modulator of protein levels that may be less closely tethered to gene expression ( ) . aneurysmal subarachnoid hemorrhage (sah) has an earlier age of onset and is associated with higher morbidity compared with other stroke subtypes. the pathophysiology of insult has traditionally been studied under two time-intervals, early brain injury (ebi) and, cerebral vasospasm (cv) and delayed cerebral ischemia (dci). the prime goal of translational research in this arena is to identify the mechanisms and targets related to the risk, severity, evolution and outcome. about % of patients die immediately following sah ( ) . thereafter, early brain injury within the first days, followed by dci are the most feared complications. cv is the phenomenon with strongest association with the development of dci, which - % of patients experience between day to ( ) . the underlying mechanisms leading to cv remain poorly understood and have therefore been a prime focus of preclinical studies. the majority have used rodent models, but primate, swine, and dog models have also been employed ( ) . cerebral aneurysms are difficult to model and hence two common approaches to modeling sah use alternative strategies. the first is direct injection of blood into the subarachnoid space, specifically into either the prechiasmatic cistern or cisterna magna, to generate sah predominantly in the anterior or posterior circulation territories, respectively ( ) . the second model, endovascular suture, passes a suture or filament through the internal carotid artery, creating a hole in one of the major branches resulting in egress of variable amount of blood into the subarachnoid space ( ) . variations in some parameters of the first method, including injected blood volume, csf removal prior to injection to prevent egress of blood into the spinal canal, and replenishing intravascular volume to keep cerebral perfusion pressure constant through maintenance of mean arterial pressure, as well as the rapidity of injection have raised questions about comparability and biofidelity of the results ( ) ( ) ( ) ( ) . the latter model appears to remove some of the mentioned confounding factors, as the hemorrhage occurs at physiologic mean arterial pressure (map) and intracranial pressure (icp), but is limited by variable puncture site and ultimate hemorrhage volume. another potential drawback is the period of ischemia caused by the intraluminal suture, although the occlusion period is typically not judged to be long enough to cause significant ischemia. the missing element in these models is the absence of aneurysm formation and rupture, and consequently the vascular processes intrinsic to the aneurysm itself that influence dci. as such, some studies have used combinations of interventions to generate aneurysms, including induced hypertension via unilateral nephrectomy and administration of angiotension ii or deoxycorticosterone acetate, as well as elastase injection. the downside of these models is that the timing of aneurysm rupture cannot be reliably predicted, which limits close monitoring and physiologic assessments in the early phase following sah, blurring the timing of dci ( ) ( ) ( ) . the immediate hemodynamic changes following the hemorrhage are monitored via a variety of methods. regardless of the method chosen, reports on the direction and range of values of cpp, cbf, and map can be quite variable, both within the same model and between different models. a common technique to measure blood flow is laser doppler flowmetry that provides a continuous measure of cortical perfusion. although it does not measure global cerebral blood flow and has spatial limitation, it appears to be relatively reliable and technically reproducible. other methods of flow measurement include radiolabeling methods and mri with the latter has the advantage of capturing the dynamic nature of the condition, as well as global and region-specific blood flows. as noted, cv and dci are responsible for delayed morbidity and mortality. given that these manifestations typically occur while patients are inpatient for care of their sah, therapeutic interventions are more feasible compared to the hyperacute phase when the processes leading to initial damage may have already occurred. however, monitoring for cv in animal models is not straightforward. one method of identifying cv is measuring the intraluminal diameter of vessels on histological samples. in addition to being an end-measure and therefore precluding measurements at different time points in the same animal, varying degrees of tissue desiccation among samples may yield numbers different from actual in vivo values. digital subtraction angiography and magnetic resonance angiography can provide a real-time evaluation, but the severity of cvand its timing, as well as neuronal cell death varies depending on the model and the affected vessels ( ) . the foundational molecular pathways that orchestrate cv are complex and remain incompletely elucidated. however, translational research using many of the above models has demonstrated that endothelin- , nitric oxide, and an inflammatory cascade ignited by breakdown of blood products play predominant roles. endothelin- is a potent vasoconstrictor produced by infiltrated leukocytes, and based on this notion, clazosentan was developed as an endothelin- receptor antagonist to combat cv. in human trials, clazosentan was found to significantly reduce the incidence of the dci without improving the functional outcome, and this or a related approach could ultimately prove beneficial if off-target drug effects, including pulmonary complications, hypotension, and anemia can be mitigated ( , ) . hemoglobin and its degradation products are also a strong stimulus for cv through direct oxidative stress on arterial smooth muscle, decreased nitric oxide production and, increasing endothelin and free radical production ( ) . this suggests that facilitating clearance of hemoglobin degradation products from the csf may be a potential therapeutic target. modulating the intense inflammatory response is also intuitive and while preclinical results support this notion in general, the evidence has thus far not been judged adequate to justify clinical trials. for example, il- receptor antagonist (il- ra) reduces blood-brain barrier (bbb) breakdown, a biomarker that is itself correlated with the severity of brain injury, and work continues to determine whether this or related pathways mediating bbb permeability might have therapeutic promise ( ) . given these numerous and likely interconnected mechanisms of delayed brain injury, further research is needed to understand their relative applicability to humans, and whether targeting a single pathway or a number of pathways simultaneously is likely to be the most adaptive strategy to reduce cv and dci in humans. the results of genome-wide rna sequencing analysis have supported the primary role of neuroinflammation in the pathogenesis of early brain injury. some studies have specifically found a key role for long non-coding rna (lncrna), a type of rna without protein-coding potential that are particularly abundant in the brain, in modulating the inflammatory behaviors of microglial cells ( ) . high-throughput mass spectrometry has also been utilized in demonstration of differential expression of proteins in the cerebral vessels after sah, as well as for monitoring the effect of experimental therapeutics ( ). we will not cover these proteomic studies in detail here, as they typically fall outside the rubric of what is classically considered "genomics", but their approach, which leverages global protein signatures rather than restricting observations to specific compounds, shares many similarities with genomics. as mentioned above, reverse genomic translation refers to an approach to the study of a disease by starting with humans using either cohort-based or case/control genomic studies. the observations made through the course of these studies then inform on the best approach for target validation and refinement to prioritize candidate mechanisms and related endophenotypes for therapeutic development. it has been shown that candidate compounds with independent confirmation of their therapeutic target via human genomics are more than twice as likely to prove effective in clinical trials ( ) . therefore, the reverse translation approach would seem an adaptive strategy to identify disease-associated mechanisms and therapeutic targets with the best chance of impacting clinical care in the near term. however, the approach to reverse translation requires large sample sizes with well-characterized patient data in order to achieve a statistically confident result. these large sample sizes raise the issue of variability in risk and treatment exposures between participants, which could impact patient outcomes independently of genomic effects and therefore erode power to detect genetic risk. the utility of reverse translation in target refinement and mechanism exploration in model systems can be highlighted using an example from the stroke community. recent gwas and subsequent meta-analyses of ischemic stroke and stroke subtypes in very large case/control datasets have validated the histone deacetylase (hdac ) region in chromosome p . as a major risk locus for stroke due to large artery atheroembolism (laa). this locus was also previously discovered in association with coronary artery disease (cad) ( , ) . based on these findings, azghandi et al. sought to investigate the role of the leading single nucleotide polymorphism (snp) in this genomic region (rs ) in increasing laa stroke risk ( ) . they found that rs , both in heterozygotes as well as in homozygote human carriers, is associated with increased expression of hdac in peripheral blood mononuclear cells on a dose-dependent manner, suggesting that the effect of this locus in stroke risk may be mediated by increased hdac expression. additionally, they demonstrated that hdac deficiency in mice is associated with smaller and less advanced atherosclerotic lesions in the aortic valves, curvature, and branching arteries, suggesting that hdac may increase atherogenesis and therefore represents a novel target for atherosclerosis and laa stroke prevention. notably, recent studies have suggested that both nonspecific (e.g. sodium valproate) as well as specific hdac inhibitors can have a positive impact on both stroke recurrence risk, as well as other phenotypes, including cancer. this highlights the central role that reverse translation can have in therapeutic target investigation and refinement, with potential beneficial off-target properties ( , ) . while acute stroke care is a vital component of neurocritical care at many institutions, reverse genomic translation successes in other relevant traits also merit mention. acute respiratory distress syndrome (ards) is a frequent complication of severe neurologic injury due to sah or neurotrauma. in a recent gwas by bime et al., variation in the selectin p ligand gene (selpg), encoding p-selectin glycoprotein ligand (psgl- ) was found to be associated with increased susceptibility to ards ( ) . the most significant snp in this locus, rs , which results in a missense mutation, has been successfully replicated in independent cohorts. further functional analyses have demonstrated that selpg expression was significantly increased in mice with ventilator (vili)-and lipoprotein (lps)-induced lung injury, and that psgl- inhibition with a neutralizing polyclonal antibody led to an attenuation of inflammatory response and lung injury. in selpg knockout mice, inflammatory response as well as lung injury scores were significantly reduced compared to wild-type mice ( ) . these results highlight the value of reverse genomic translation in first identifying human-relevant genetic risk factors for disease, and using model systems to understand the pathways impacted by their introduction to select rationally-informed modalities for potential treatment. intracranial aneurysms (ia) are commonly encountered in the neurocritical care setting, albeit most commonly after rupture. even so, inroads leading to a better understanding of aneurysm formation may ultimately reveal opportunities for treatments to prevent acute re-rupture or prevent future aneurysm formation after sah. the strongest associations with ia have been reported in the region near cdkn a/cdkn b in p . as well as in a nearby intragenic region known as cdkn bas or anril ( , ). anril is a long noncoding region responsible for the regulation of cdkn a and cdkn b and has also been implicated in the pathogenesis of cad and atherosclerosis, among other traits ( ) . overexpression of anril in mouse models of cad has been associated with negative atherosclerosis outcomes including increased atherosclerosis index, unfavorable lipid profiles, thrombus formation, endothelial cell injury, overexpression of inflammatory factors in vascular endothelial cells, increased apoptosis of endothelial cells, and upregulation of apoptosis-related genes. notably, reduced anril expression has been associated with reduced inflammatory, biochemical and molecular markers of atherosclerosis, indicating a potential target for atherosclerosis and ia prevention ( ) . when utilizing the reverse translation approach in genomic studies, the aforementioned examples highlight two distinct but equally important considerations for a successful implementation of such approaches. the first major consideration is that large populations of well-characterized individuals must be selected to ensure adequate statistical power to detect meaningful associations. thorough and standardized phenotyping of study subjects is one of the main predictors of the success of a gwas ( , ) . careful assignment of cases based on strict phenotypic criteria permits well-executed gwas even in diseases with heterogeneous presentations and multiple pathogenic features, such as multiple sclerosis (ms) and stroke ( ) . in neurocritical care populations where subtle characteristics of disease presentation and intermediate outcomes may represent important phenotypes for genomic investigation, such as sah, these traits should be closely defined and recorded to the greatest degree possible in all participants. this initial step is critically important in the greater scheme of reverse translational genomics, as these associations with subclasses and endophenotypes of disease often provide the biological insights needed to continue translational efforts using model systems tailored to refine observations. the second major consideration is that the execution of genomic studies needs to be comprehensive and thorough so as to permit association testing in a hypothesis-free environment. at the moment, gwas array-based studies seem to remain a favorable option of the genome, considering the lower cost associated with their utilization and proven track record in discovery, but over time, wes and wgs studies will become reachable even on more modest research budgets. for the transcriptome, rna sequencing and rna microarrays both offer unbiased surveys of global transcriptional variation, but because gene expression varies substantially by tissue it is critical that rational choices are made regarding the suitability of specific tissues for specific conditions. in uncommon conditions with necessarily small sample sizes, including neurocritical care-relevant diseases like se, sah, and ards, external validation studies can strengthen associations from an initial small discovery dataset, and in many cases these follow-up studies can make use of freely available resources. for example, in a recent expression-based gwas (egwas), microarray data for ards from the gene expression omnibus (geo) were collected and combined in an effort to identify novel genetic targets ( ) . the study not only validated previously known lung injury-and ardsrelated genes, but also discovered new candidate genes that may prove to be useful in future translational work. identifying loci, variants, expression patterns, and genenetworks with the use of human genomic studies is only the initial step in the reverse translation process. these discoveries must inform and guide the research to further understand and refine the phenotypic effects of these variants in model systems, including some of those described above. there are several techniques with which we can utilize the discoveries made from case/control genomic studies to build or modify model systems. one approach is transgenesis, in which a larger dna sequence including a human gene containing a mutation of interest, called a transgene, is injected into the pronucleus of a mouse fertilized egg. the fertilized egg is then inserted into the oviduct of a pseudopregnant female mouse, which is a female who has been mated with vasectomized male in order to achieve the hormonal profile of a pregnancy state. the offspring produced from this female can create an animal line that contains the human gene and allele of interest ( ) . however, because the transgene is inserted randomly at one or more genetic locations as either one or more copies, the level of expression and regulatory influences of the gene of interest may not initially be well-controlled across animals. as such, there are several intermediate steps that can allow more specific genetic alteration using transgenesis, involving embryonic stem cells (escs). the first step is the introduction of regulatory sequences (such as expression cassettes) into escs. then, by injecting the transgene first into these modified escs, gene expression can be more closely controlled. the escs with the transgene can then be inserted into blastocysts and give rise to new strains, using the same methods previously described ( ) . there are multiple variations on the transgenic approach which are uniquely suited to the model system being employed and can give rise to models that express transgenes in response to a particular stimulus, or in particular tissues of interest. a newer method utilizing programmable endonucleases has allowed researchers to bypass more traditional escbased methods for direct and precise gene editing. endonucleases are enzymes that cause double stranded dna (dsdna) breaks that can further be repaired either with non-homologous end-joining (nhej), an imprecise method for rejoining the dna breaks that involves various enzymes and may result in inactivating mutations, or with homologydirected repair (hdr), in which the dna breaks are repaired based on a co-injected template. four categories of programmable endonucleases have been used for direct and precise gene editing: homing endonucleases (he), zinc-finger nucleases (zfns), transcription activator-like effector nucleases (talens) and the clustered regularly interspaced short palindromic repeats/crispr-associated (crispr/cas ) system. the common characteristic of these enzymes is that they possess sequence-specific nuclease activity, allowing researchers to cleave dsdna at desired, pre-specified sites. the crispr/ cas system has proven to be the most successful so far, in terms of efficiency, cost, and simplicity of use. perhaps the most important advantage of this approach is that programmable endonucleases do not require the use of escs and can directly be inserted into one-or two-cell stage embryos, thus allowing more specific and direct gene-editing in a single step ( ) . drawbacks include enzymatic limitations as to where dna breaks can be reliably introduced, as well as off-target endonuclease activity at other sites across the genome which can disrupt gene activity in unintended ways. work is ongoing to refine these tools, improving the number of sites where gene editing can occur while also improving the specificity of the system ( ). one illustrative example of human genomic studies being used to refine models to understand disease processes is the case of human ich-associated mutations in col a and col a . col a and col a are the most abundant proteins in basement membranes. they form heterotrimers consisting of one col a and two col a peptides and are produced and modified in the endoplasmic reticulum (er). after their production, they are packaged into vesicles in the golgi apparatus and transferred to vascular endothelial basement membranes ( ) ( ) ( ) . the initial identification of mutations in this region in familial forms of cerebral small vessel disease, coupled with the subsequent detection of common col a /col a variants associated with sporadic deep ich led to the development of animal model systems to explore their effects ( ) ( ) ( ) ( ) . through mouse models, representative col a /col a mutations were found to recapitulate human disease phenotypes, with multifocal ich in subcortical regions of the forebrain and the cerebellum, as well as porencephaly, small vessel disease, recurrent intraparenchymal and intraventricular hemorrhages, agerelated ich, and macro-angiopathy ( , ) . using cellular assays and tissue derived from mouse models, mutations in col a /col a have been associated with decreased ratio of intracellular to extracellular col a , retention of abnormal collagen proteins in the er, er stress, and activation of the unfolded protein response ( ) ( ) ( ) , suggesting that the intracellular accumulation and er-stress could be an important molecular mechanism underlying ich related to col a and col a mutations. notably, treatment with the molecular chaperone sodium -phenylbutyrate resulted in decreased intracellular accumulation and significant decrease of ich severity in vivo, which could point the way towards eventual forms of treatment for both familial and sporadic col a and col a -associated ich ( ) . another recent example of model system refinement for neurocritical care-relevant disorders is status epilepticus (se). pyridoxal phosphate binding protein (plpbp) variants have been associated with a rare form of b -dependent epilepsy, which, if left untreated can lead to se. in a recent study, johnstone et al. utilized crispr/cas to create a zebrafish model lacking its encoded protein ( ) . they observed that plpbp-deficient zebrafish experienced significantly increased epileptic activity compared to their wild type counterparts, in terms of physical activity (high-speed movements), biochemistry (c-fos expression) and electrophysiologicallyrecorded neuronal activity. additionally, treatment of plpbp −/ − larvae with plp and pyridoxine led to an increase in their lifespan, and a decrease in their epileptic movements and neuronal activity. lastly, in these plpbp-deficient zebrafish, systemic concentrations of plp and pyridoxine were significantly reduced, as well as concentrations of plp-dependent neurotransmitters. collectively, these results provide insights for biomarker development and preclinical target refinement in b -dependent epilepsy. understanding how novel treatments might impact rare disease presentations could ultimately lead to new insights for common forms of disease as well, just as the discovery of rare pcsk variants in patients with very low cholesterol ultimately led to pcsk -inhibitors to treat more common forms of familial hypercholesterolemia. however, the use of animal models is not always the ideal approach to describing the effects of genetic variation, as the phenotypic alterations may be too subtle to observe or require impractical prolonged observation in late-life animals to ultimately exhibit relevant phenotypes. in these cases, tissuebased systems can provide a useful tool to study these effects. for example, ia formation, as previously described, has been associated with variants in anril. although the direct impact of these variants in human tissue or animal models is difficult to discern, work with mutations of anril in endothelial models have provided valuable insight. specifically, upregulation of anril has been associated with increased expression of inflammatory and oxidative markers in the vascular tissue such as il- , il- , nf-κb, tnf-a, inos, icam- , vcam- , and cox- ( , ) . these observations provide vital information about cellular mechanisms impacted by human disease-associated genetic risk factors without requiring the expense and time investment of creating, validating, and studying animal models. ultimately such models may still be required, but prior knowledge about cellular phenotypes associated with genetic variation may be highly valuable in choosing the right model system and selecting efficient approaches to validate these systems. the aforementioned examples highlight significant contributions of the field of translational genomics in identifying novel therapeutic targets, developing biomarkers of disease severity and elucidating disease-relevant pathophysiology. undoubtedly, these contributions are valuable in application to existing model systems of disease, or through refinement of models informed by the reverse translation process. given that many of our current models have proven to be ineffective in many cases, the reverse translation approach offers a significant advantage in that the translational discoveries arising in established or refined model systems have already been proven to be relevant to human disease. this advantage provides us with reasonable expectation that observed effects in model systems will also remain relevant to human disease, providing a substrate for therapeutic development. certainly, the ultimate goal of translational genomics is to be able to transfer the discoveries found from experimental models into clinically useful information in order to improve human health. this aim, with regard to the translational genomic approach, can be satisfied with two distinct approaches. one is concerned with improving our understanding of the mechanisms of disease, providing novel targets for therapeutic development. the other is concerned with leveraging the conclusions of translational genomics through more direct applications to clinical care. we will discuss these in order. once genomic discovery and translational exploration have confirmed the mechanism and relevance of a particular genomic association, translational genomics offers the opportunity to use these same translational approaches to derive highthroughput assays for screening of compound libraries, which are collections of small molecules useful for early-stage drug-discovery ( ) . the same in vitro assays used to identify cellular phenotypes associated with genetic risk factors can be tested for amelioration or "rescue" of wild-type features after exposure to library compounds. this is particularly advantageous for the reverse genomic translation approach, as these assays are often critical components of the overall discovery cycle, and with optimization to provide ideal readouts, screening can proceed quickly. an example of success here is the identification of molecular chaperones that can ameliorate the unfolded protein response detrimental to cell survival in col a -mediated cerebrovascular disease ( ) . identifying hits in these assays has the potential to accelerate drug-discovery, provided that the mechanism can be targeted by a small molecule and not a designed biologic entity such as a monoclonal antibody. while screening can be performed using novel compound libraries, it can also be accomplished using libraries containing already-approved drugs, providing an innovative way for compound repurposing based on genetic interactions. numerous tools already exist for in silico evaluation of existing compounds based on known mechanisms, so this step can begin even in the genomic discovery phase prior to translational validation ( ) . the second approach in which translational genomics has proven to be of great potential is the rapidly evolving and highly anticipated field of precision medicine. the observations arising from translational genomics, even when not informing us about the specific mechanisms associated with the phenotype in question, may be of predictive value. this finds application in two relevant translational genomics tools: polygenic risk scores (prs) and biomarker development based on rna expression profiles. while common genetic variation can provide valuable information about disease-relevant mechanisms and help refine disease models, they are relatively weak in explaining a significant proportion of the genetic basis of complex polygenic disorders, such as cad, diabetes, stroke, or sah ( ) . by summarizing the impact of many variants of small effect across the genome simultaneously, a polygenic risk score (prs) can be developed which explains far more of the genetic risk of a disease than any common variant can individually (fig. ) . application of these prs in independent clinical populations as a predictive tool represents a novel translational approach. in a recent study examining stroke, a prs combining snps associated with atrial fibrillation (af) was found to be significantly associated with cardioembolic (ce) stroke risk and no other stroke subtypes, paving the way for a potentially useful tool to discriminate ce stroke from other etiologies without reliance on expert adjudication or longitudinal monitoring ( ) . another recent study compiled a prs of cad, demonstrating that individuals in the highest quantiles of the prs exhibited cad risk on par with known mendelian cardiac diseases ( ) . these studies highlight the potential uses of prs as a genetic biomarker of disease, capturing orthogonal risk information compared to clinical risk factors alone. much work is still needed in this arena, ranging from derivation of readily accessible clinical genomic testing, dissemination of prs results in an interpretable format, disclosure of off-target results that may be clinically meaningful in their own right, and, critically, the validation of prs in ancestrally-diverse populations ( ) . despite these challenges, utilization of polygenic risk data to directly inform patient risk independent of our understanding of the underlying mechanisms is an exciting and rapidly evolving use-case for translational genomics. development of biomarkers is another approach in translational genomics that focuses more on predictive utilization than on elucidating mechanisms, and critical care has seen some early potential applications of this approach. in sepsis, where clinical prs percentile across the population distribution. plotting percentiles by disease risk, patients in higher prs percentiles (red dots) are at correspondingly highest risk for the disease outcomes are highly heterogenous, tools that might identify patients who are more likely to respond to certain treatments or identify individuals at highest risk for morbidity and mortality would be highly useful. in a recent study by scicluna et al., the authors categorized sepsis patients based on peripheral bloodderived genome-wide expression profiles and identified four distinct molecular endotypes (mars - ) ( ) . the mars expression profile was the only category that was significantly associated with -day and -year mortality. in addition, combination of the apache iv clinical score with this genetic scoring system resulted in significant improvement in -day mortality risk prediction, compared to apache iv alone. to further aid translation to clinical application, the authors used expression ratios of combinations of genes to stratify patients to the four molecular endotypes. bisphosphoglycerate mutase (bpgm): transporter , atp binding cassette subfamily b member (tap ) ratio reliably stratified patients to mars endotype; while other protein ratios were able to assign individuals to the other three mars categories. using this approach, not only could bpgm and tap transcripts potentially be used to identify patients with increased risk of mortality, but if these categorizations can be demonstrated to be causal, these molecular pathways could also be explored for therapeutic target identification and validation. further work is required to extend these findings across clinical populations, but this approach could ultimately yield new tools for prognostication in sepsis. in ischemic stroke, tissue plasminogen activator (t-pa) response and risk for hemorrhagic transformation (ht) are highly correlated with functional outcomes, and biomarkers to predict each of these would have obvious clinical utility. in a recent study, del rio-espinola et al. found that two genetic variations (rs and rs ) were associated with increased risk for ht and mortality after t-pa administration in stroke patients ( ) . specifically, rs in a m was associated with ht and rs was associated with in-hospital mortality. in a subsequent validation study, researchers created a genetic-clinical regression score that was successfully used to stratify stroke patients treated with t-pa based on risk for ht and parenchymal hemorrhage (ph) ( ) . while in the current clinical landscape the vast majority of patients do not have readily accessible genome-wide genotypes prior to events like acute stroke, increasing uptake of clinical genomics and genomically-enabled electronic health record systems could soon enable real-time risk prediction calculations incorporating both clinical and genetic information, providing more accurate tools for clinicians to incorporate into medical decision-making. a separate set of tools that could potentially become diagnostically useful in the clinical setting is the transcriptomic approaches to identify biomarkers, using array-based screening or rna sequencing. in a recent systematic review, a total of mirnas were reported to be differentially expressed in the blood cells of patients with acute ischemic stroke within h after stroke ( ) . some studies reported the area under the curve (auc) ranging from . to . , indicating a potential for clinical utility as early diagnostic markers when neuroimaging is not immediately available or is limited by feasibility. subsequent studies were able to partially replicate these findings, showing three mirnas (mir- a- p, mir- b- p, and mir- - p) that were upregulated in the acute poststroke period, an effect independent of stroke pathophysiology and infarct volume ( ) . these transcripts were associated with an auc of . in differentiating ischemic stroke and healthy controls, a metric that significantly outperformed computed tomography, as well as previously reported bloodbased biomarkers. in ich, a recent report identified up to and transcripts from whole blood that are differentially expressed between ich and controls and, ich and ischemic stroke, respectively ( ) . when comparing ich and ischemic stroke transcriptomes in the first h, and transcripts were differentially expressed compared to controls, respectively. ich transcriptome was over-represented by t cell receptor genes compared to none for ischemic stroke and underrepresented by non-coding and antisense transcripts. t cell receptor expression successfully differentiated between ich, ischemic stroke, and controls. similarly, rna-seq of whole blood rna successfully differentiated between not only ich, ischemic stroke and controls, but also between different stroke subtypes ( ). the list of genetic mutations that can cause se is extensive with most genes are associated with infantile-onset or childhood epilepsy syndromes. only a minority are seen in adultonset status epilepticus ( ) . the patients in the former group usually have accompanying intellectual disability related to their epilepsy syndromes. however, the evidence supporting a genetic etiology in the latter group may be absent, posing a diagnostic challenge. the available options include gene panel sequencing, whole exome sequencing, or whole genome sequencing. sequencing a pre-selected panel of genes is more common, but with decreasing cost, exome and genome sequencing are being used with increasing frequency. bioinformatic filtering and genotype-phenotype correlation are the main challenges, particularly with the large number of genetic variants identified during whole exome or genome sequencing. the yield of sequencing studies depends on pretest probability that is determined by early age of onset, consanguinity, or affected siblings. as such, to date, only a few genes associated with adult-onset se have been identified, posing a practical limitation that predominantly limits next-generation sequencing to pediatric patients at present ( ) . as clinical tools for determination of putative functional significance and deleteriousness of variants identified through sequencing are refined, it is hoped that sequencing approaches find a home in the armamentarium of the clinicians treating refractory or recurrent se in the neurocritical care unit. translational genomics undoubtedly represents an important component to overall efforts to improve our understanding of the diseases we treat, and in principle should improve our ability to identify therapeutic approaches to improve outcomes and, in some cases, prevent disease altogether. given the inherent complexity and inaccessibility of the human brain and its tissues, combined with the relative infrequency of the conditions we treat at the overall population level, progress has been modest when compared to conditions such as hyperlipidemia ( ) , coronary artery disease ( ) , or atrial fibrillation ( ) . nevertheless, the observation-based, hypothesisfree experimental process inherent to translational genomics lends itself well to conditions such as stroke and tbi in which the search for the "master regulator" that governs response to injury has remained elusive despite carefully designed and executed hypothesis-driven studies. an important component to future translational genomic studies in neurocritical care is the pressing need for collaboration across centers with access to large, well-characterized patient populations. the success of the international stroke genetics consortium, and the track-tbi and center-tbi consortia in amassing large human populations with stroke and traumatic brain injury, respectively, is a proven model to accelerate the human genomic studies that serve as the basis for reverse genomic translational research ( , ( ) ( ) ( ) . similar efforts through the critical care eeg monitoring research consortium and other partners could lead to biorepositories of specific conditions relevant to neurocritical care that could provide sample sizes sufficient to drive unbiased genomic discoveries ( ) . close alliances with model systems researchers are another critical component to accelerating translational genomics in neurocritical care. as characterization of human disease through multimodal and continuous physiological monitoring, electrophysiology, medical imaging, and biomarker sampling continues to evolve, it is imperative that this information is shared and explored with allied model systems researchers to ensure that models are re-evaluated for their correlation with these endophenotypes, and potentially for dedicated exploration of how these human-derived phenotypes inform on the utility of specific model systems to investigate disease. finally, building relationships with biotechnology and pharmaceutical industry partners will be essential to efforts to extend therapeutic targets arising from translational genomic discoveries towards drug development ( ) . while repurposing existing drug compounds for new indications is an important consideration, small molecule and biologic targets are likely to require extensive research and development in the preclinical and clinical space, and industry partners are often optimized for these phases of the therapeutic development process ( , ) . relatedly, development of polygenic risk scores for assessment of risk, prognosis, or treatment response will also require commercial investment and infrastructure, as few academic environments exist that can manage cliacertified genotyping, quality control, and result reporting and interpretation for on-target and clinically relevant secondary results ( , ) . particularly in rarer or particularly challenging disease indications like those commonly encountered in neurocritical care populations, academic-industry partnerships are important to raise awareness of and interest in important clinical indications where investment could yield a large impact on a relatively small population of patients. translational genomics, in which genomic associations with risk, outcome, or treatment response are systematically identified and explored for functional relevance in humans or model systems of disease, is a valuable tool for identification of mechanisms, risk factors, therapeutic targets, and risk estimates in multiple diseases that are highly relevant to clinicians and scientists operating in the neurocritical care space. while there are undoubtedly challenges to studying some of the most complex diseases that affect the most complex organ in the body, translational genomic approaches may be uniquely suited to this task. coordinated investments in the collaborations, consortia, and infrastructures that enable these studies are likely to contribute to the novel treatments and biomarkers that are so sorely needed in the highly morbid and often poorly understood conditions in the patient populations we serve. translational genomics reengineering translational science: the time is right human genome project: twenty-five years of big biology it's time to reverse 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statement of the american college of medical genetics and genomics publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations key: cord- -l vkq j authors: mohamed, sherif; abd el-mohsen, seham; abo el-hassan, osama; abdelhaffez, azza; abd el-aziz, nashwa title: incidence and pathophysiologic mechanisms of stroke in the covid- pandemic: the dilemma date: - - journal: egypt j bronchol doi: . /s - - -y sha: doc_id: cord_uid: l vkq j background: while covid- pandemic affected more than million people worldwide, still, the definite link between covid- and incidence of stroke remains to be re-evaluated. main body: many pathophysiologic and immunologic mechanisms have been implicated in stroke occurring among patients with covid- . the covid- pandemic has, in different ways, negative impacts on care of stroke patients worldwide, and still, many challenges are faced by neurologists to improve care of stroke patients during such crisis. in this brief report, we try to discuss these issues. conclusions: although the control of covid- is of crucial importance, at the same time, the management of stroke must not be neglected. therefore, introducing care for critical conditions such as stroke, and providing strategies to ensure this proceeds, is a priority even at the time of the pandemic. the coronavirus infection covid- first presented as an outbreak of atypical pneumonia in wuhan, china, on december , . since then, it has spread globally to infect over million people [ ] . the definite link between covid- and the prevalence of stroke remains to be determined. many pathophysiologic and immunologic mechanisms have been implicated in stroke occurring among patients with covid- . in this minireview, we will discuss the links between covid- and stroke. incidence of stroke at the time of covid- pandemic: increased or decreased? despite the worldwide spread of covid- , the true relationship between it and the incidence of stroke remains to be elucidated. it has been suggested that covid- infection, by itself, may lead to stroke. in an interesting study from wuhan, china, . % of covid- patients had symptoms of neurological affection, which were more encountered in those with severe disease [ ] . among those neurological disorders, stroke was a complication of covid- infection in . % of patients. characteristically, patients with stroke were older, had more severe pneumonia, and more cardiovascular comorbidities [ ] . in comparison to influenza virus, a recent study has reported that . % of patients with emergency department visits or hospitalizations with covid- experienced ischemic stroke, a rate . -fold higher than in patients with influenza [ ] . mechanisms by which covid- might increase the risk of stroke have been addressed. these mechanisms may include hypercoagulability status due to critical illness and intracardiac thrombosis and pulmonary embolism from sars-cov- -related coagulopathy. as the obligate receptor for the virus, human angiotensin-converting enzyme (ace- ) is expressed in epithelial cells throughout the body, including in the central nervous system (cns); this raises the probability of a direct role in viral infection [ , ] . on the contrary, at the onset of the covid- era, there was an apparent reduction in the number of stroke cases in many parts of the world. reports pulled out from multiple countries showed a marked drop in the number of stroke-related hospitalizations [ ] . in a retrospective cohort study of consecutive patients with ischemic stroke who were hospitalized between march , , and april , , within a major health system in new york, yaghi and coworkers found that, out of hospitalized patients with diagnosis of covid- infection, patients ( . %) had imaging-proven ischemic stroke. cryptogenic stroke was more common in patients with covid- ( . %) as compared to contemporary controls ( . %, p = . ) and historical controls ( . %, p < . ) [ ] . many explanations for these reduced numbers of stroke cases were considered. patients with milder stroke may have reduced rates of admissions; some patients have fears of getting infected if they were referred to the hospital during times of the pandemic. in a recent report from italy, other mechanisms were claimed [ ] . first, il- plays a controversial role in stroke. while high levels of serum markers for thrombosis and inflammation have been reported in covid- -affected patients, as well as increased levels of inflammatory cytokines (interleukin [il]- r, il- , and tumor necrosis factor-α) [ ] . indeed, there were debates if high il- levels have a negative influence on the volume of brain infarct and/or long-term outcomes [ ] . on the contrary, there was supportive evidence that il- may have a protective effect and helps in the improvement of the angiogenesis process in patients with ischemic stroke [ , ] . second, a possible explanation is related to the observation that most covid- patients have thrombocytopenia [ ] . some authors wondered if thrombocytopenia was related to the reduction in the incidence of large vessel occlusion (lvo) strokes. third, the burden of chronic persistent infections rather than one single current pandemic could be associated with risk for cerebrovascular disease [ ] . another explanation may come from the observation that air pollution is associated with an increased risk of cardiovascular disease; we had seen a strikingly reduced air pollution during the pandemic secondary to lockdown; this phenomenon could have a protective effect against stroke [ ] . is stroke a risk factor for covid- or is covid- a risk factor for stroke? from our experience, it was observed that the presence of cerebrovascular disease (cvd) in patients with sars-cov- or mers-cov was associated with worse outcomes. still, we do not know whether cvd predicts outcomes of patients with sars-cov- or not. a pooled analysis has showed an~ . -fold increase in odds of severe covid- in patients with a history of cvd, but there was no association with mortality [ ] . on the other hand, in patients with stroke, the presence of covid- infection itself was thought to be a potential factor in the genesis or worsening of cerebrovascular stroke. the virus causing covid- can enter the cns through two different pathways: retrograde neuronal diffusion and via the blood-brain barrier. also, the spread of covid- through the cribriform plaque of the ethmoid bone can lead to brain involvement. this could happen during the initial phase or at subsequent infection. notably, the presence of ace- receptors on both neuronal and capillary endothelial cells could give rise to the subsequent spread and damage to the cerebral nervous system, characteristically without substantial inflammatory load [ , ] . oxley et al. [ ] reported five cases of large vessel stroke over days in covid- patients aged under years. remarkably, all cases had either no or mild covid- symptoms. interestingly, this observation represents a sevenfold increase in what would normally be noticed. the covid- pandemic has both direct and indirect major implications for stroke care. a minority of countries did manage to maintain a full range of coverage for stroke services. however, the other majority has experienced significant service shortage and/or reorganization. the latter faced problems. first, reallocation of neurology care beds including those of the icu to manage covid- patients necessitated moving of stroke units to a less optimal situation. second, the crisis needed redeployment of stroke physicians, nurses, and other stroke facilities to look after covid- patients [ ] . at the best services, intravenous thrombolysis is under threat because of pressures and delays resulted from managing potentially infected patients. this has resulted in missing the therapeutic window at the worst stroke patients. adding to this dilemma, there were delays in hospitalizations for stroke, or even patients preferring not to be hospitalized at all. the impact on developing countries was eventually worse. many have not only much less-developed stroke services but also lessdeveloped usual care for managing covid- patients, including the major challenge of shortage of ventilators in the intensive care units [ ] . best practice guidelines had to offer guidelines for the best way(s) to manage stroke in the context of the current pandemic while keeping in mind the safety of the healthcare workers. telemedicine was found to offer many solutions during this pandemic. stroke has led the way in telemedicine for proper assessment for thrombolysis, which continues to be of crucial importance for stroke care particularly in rural settings. utilizing telemedicine had avoided the use of excessive protection, allowed a reasonable stroke evaluation, and reduced the risk of exposure for the stroke-managing team [ , , ] . although the control of covid- is of crucial importance, at the same time, the management of stroke must not be neglected. therefore, introducing care for critical conditions such as stroke, and providing strategies to ensure this proceeds, is a priority even at the time of the pandemic. world health organization. who coronavirus disease (covid- ) dashboard neurologic manifestations of hospitalized patients with coronavirus disease risk of ischemic stroke in patients with coronavirus disease (covid- ) vs patients with influenza express: covid- and stroke-a global world stroke organization perspective the neuroinvasive potential of sars-cov may play a role in the respiratory failure of covid- patients sars-cov- and stroke in a new york healthcare system the baffling case of ischemic stroke disappearance from the casualty department in the covid- era anticytokine agents targeting interleukin signaling pathways for the treatment of atherothrombosis thrombocytopenia is associated with severe coronavirus disease (covid- ) infections: a meta-analysis cerebrovascular disease is associated with an increased disease severity in patients with coronavirus disease (covid- ): a pooled analysis of published literature large-vessel stroke as a presenting feature of covid- in the young management of acute ischemic stroke in patients with covid- infection: insights from an international panel on being a neurologist in italy at the time of the covid- outbreak publisher's note springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations not applicable availability of data and materials not applicable ethics approval and consent to participate not applicable. not applicable. author details department of chest diseases and tuberculosis, faculty of medicine, assiut key: cord- -ynfb pq authors: tang, yaohui title: modification of bone marrow stem cells for homing and survival during cerebral ischemia date: - - journal: bone marrow stem cell therapy for stroke doi: . / - - - - _ sha: doc_id: cord_uid: ynfb pq over the last decade, major advances have been made in stem cell-based therapy for ischemic stroke, which is one of the leading causes of death and disability worldwide. various stem cells from bone marrow, such as mesenchymal stem cells (mscs), hematopoietic stem cells (hscs), and endothelial progenitor cells (epcs), have shown therapeutic potential for stroke. concomitant with these exciting findings are some fundamental bottlenecks that must be overcome in order to accelerate their clinical translation, including the low survival and engraftment caused by the harsh microenvironment after transplantation. in this chapter, strategies such as gene modification, hypoxia/growth factor preconditioning, and biomaterial-based methods to improve cell survival and homing are summarized, and the potential strategies for their future application are also discussed. stroke is the third leading cause of mortality and the leading cause of long-term disability in the united states. approximately , , people suffer a stroke, and more than , people die each year. ischemic stroke accounts for over % of total stroke patients [ ] . though extensive neuroprotection and regenerative studies have been performed, only tissue plasminogen activator (tpa) has been proven to be effective. however, due to its narrow therapeutic time window (less than . h) and hemorrhagic complication, fewer than % of stroke patients are able to benefit from tpa, and even among those, only % return to independent living [ ] . epc medium could also promote angiogenesis [ ] , or differentiate into endothelial cells to replace/repair injured ecs and integrate into endogenous blood vessels, which is detected by histological studies [ ] . these results support that epcs have great therapeutic potential for stroke, most possibly through both directly integrating into blood vessels and secreting trophic factors. in , ratajczak's group first discovered a nonhematopoietic population that expresses neural lineage markers (gfap, nestin, olig , olig , sox , and musashi- ) and resides in the nonhematopoietic cxcr +/sca- +/lin-/cd -bm mononuclear cell fraction, named as very small embryonic-like cells (vsels) [ ] . the number of circulating vsels in pb increases in mice after experimental stroke [ ] and in stroke patients [ ] , suggesting that vsels residing in adult tissues or mobilized into pb are a potent source of adult tissue-derived stem cells that can be used for regenerative medicine, particularly for neural repair after stroke. ratajczak et al. observed increased gene expression of both pluripotent and nsc markers in pb-borne nucleated cells in stroke patients, resembling what they previously noted in murine stroke model. further analyses using computer tomography imaging revealed differences in vsel mobilization between patients with posterior circulation infarcts and patients with partial anterior circulation infarcts [ ] . in addition, the observation that murine vsels are capable of differentiating into neurons, oligodendrocytes, and microglia further encourages us to use these cells as donor grafts for regeneration of a damaged cns. however, a limitation for clinical application is the small number of vsels that could be harvested, requiring ex vivo expansion strategy, especially to generate enough supply of vsels for stroke therapy in clinical setting. although stem cell transplantation appears to be very promising for stroke, a number of problems remain unresolved and need specific attention in order to improve therapeutic efficacy for further successful clinical translation, including low survival and engraftment of transplanted cells in the brain subjected to multiple insults including ischemia, reactive oxygen species (ros) generation, inflammatory response, apoptotic cascade activation, and so on. accumulating evidence demonstrates that less than % of transplanted stem cells could survive in the lesion site after transplantation as they are exposed in hostile environment, and cell death is initiated via multiple mechanisms [ ] . it's reported that more cells survive when they are transplanted into sham animals (no brain injury) compared to injured animals [ ] , indicating that factors in the lesion y. tang site induce death of the transplanted cells. these factors include but not limited to time after injury [ ] , distance from the transplantation site to the lesion site [ ] , state of the cells transplanted (differentiated or undifferentiated) [ ] , aging of the cells transplanted [ ] , host immune response [ ] , and phagocytic response of host [ ] . subsequent evidence shows that delivery time is the major determinant of the survival of transplanted stem cells. it is reported that npc survival was significantly reduced following delayed cell delivery [ ] , which was mediated by the inflammatory milieu. cell death is initiated even prior to transplantation, explained by two main mechanisms: detachment of cells from adherent surface and the removal of growth factor, during the procedure of trypsinization and suspension. inhibition of cell adhesioninduced cell death was first reported in by frisch and francis. they found that when epithelial cells were seeded in medium with the addition of soluble peptide-grgdsp, which prevented cell attachment by blocking integrins, it resulted in increased apoptosis [ ] . this kind of cell death is termed anoikis, which can be rescued by culturing cells on ecm-coated surfaces to promote cell adhesion. for example, oligodendrocyte progenitor cells cultured on glass coverslips coated with fibronectin or laminin showed greater viability compared to those cultured on noncoated surfaces [ ] . in vitro study demonstrated that addition of laminin to neural progenitor cells increased the number of neurospheres and reduced cell death in comparison to control groups, while blocking the beta integrin inhibited the effect of laminin, suggesting this is beta integrin mediated [ ] . one proposed explanation for detachment-induced cell death is that bmf released from actin in terms of cytoskeleton stabilization is reduced after cell detachment. bmf binds to bcl- in mitochondria and neutralizes its antiapoptotic effect, which activates caspase- , further releasing bcl- from the mitochondria to induce cell death [ ] . in addition to detachment-mediated cell death, removal of growth factors also induces apoptosis. typically, c-jun amino-terminal kinase (jnk) signaling pathway is activated when trophic support is removed, mediates c-jun phosphorylation, thus induces the expression of proapoptotic factor-bcl- family (dp /hrk). it further demonstrates that dp activates a proapoptotic member of the bcl- family-bax, causes mitochondrial damage, and releases cytochrome c, leading to the formation of apoptotic protease-activating factor (apaf- )/caspase- complex, which activates caspase- resulting in cell apoptosis [ ] . therefore, cell-ecm interactions are reduced, and apoptosis is initiated even prior to transplantation when stem cells are trypsinized as single cells, cell survival is further reduced by needle insertion, and growth factors withdraw during the injection process, as well as hostile environment they confront in the lesion site after transplantation, given the generation of reactive oxygen species (ros) and inflammatory response mediators in brain postischemia. it is highly accepted that cerebral ischemia caused excessive ros would induce the apoptosis of the transplanted cells [ ] . our study showed that more than % of grafted cells died within h after administration [ ] , and our in vitro studies also suggested that exposure of stem cells to culture conditions which mimic the hostile environment in vivo (such as oxygen-glucose deprivation and h o stimulation) led to the apoptosis mediated by ros [ ] . modification of bone marrow stem cells for homing and survival… both basic studies and clinical evidence strongly support that bmscs could serve as a promising restorative therapy for stroke. however, as stated above, high stem cell death rate is the main hurdle that hinders the therapy. scientists in the field propose several strategies to conquer this challenge, including gene modification, preconditioning, and biomaterial-based methods. after cerebral ischemia, both intrinsic and extrinsic apoptosis pathways are activated [ ] . more than % of stem cells died after their transplantation, which is mainly caused by the activation of proapoptotic signals. thus, downregulation of proapoptotic or upregulation of antiapoptotic cues by manipulating gene expression of stem cells posttransplantation may ameliorate the microenvironment and further enhance their survival. indeed, overexpressing of bcl- in embryonic stem cells (escs) increased their survival after injection into ischemic rat brain, as well as enhanced their neuronal differentiation, and improved functional outcome [ ] . in addition to regulate apoptotic-related genes, amounting evidence shows that modification of trophic genes in stem cells also has significant impacts on their survival and therapeutic efficacy (table . ). mscs overexpressing bdnf or gdnf after injection into ischemic rats showed more cell survival, promoted functional recovery, and reduced ischemic damage at and days following mcao, while rats that received cntf-or nt -transfected mscs showed neither functional recovery nor ischemic damage reduction [ ] . liu et al. found that intravenously administered hmscs overexpressing pigf could accumulate in the ischemic lesions, further reduced lesion volume, enhanced angiogenesis, and elicited functional improvement [ ] . fgf- -modified mscs with hsv- greatly reduced infarct volume and improved functional recovery at days after stroke [ ] . when surviving, a new apoptosis-inhibiting protein was overexpressed in mscs and promoted mscs' survival by . -fold at days and . -fold higher at days posttransplantation, which results in reduced infarct volume and improved neurological function [ ] . besides bmscs, lots of studies from dr. kim's group showed that transplantation of human nscs overexpressing bdnf [ ] , vegf [ ] , or akt- [ ] could produce a two-to threefold increase in cell survival at weeks and weeks posttransplantation, as well as reduce infarct volume and improve functional recovery [ ] . transduction of npcs with tat-hsp led to increased number of grafted npcs, reduced bbb disruption, enhanced postischemic neurogenesis, and increased neurotrophic factor secretion [ ] . during the last decade, micrornas (mirs), a group of short rna molecules that involve in posttranscriptional downregulation, have gained extensive attention in modulating cell survival. it is reported that mir- and mir- exert significant y. tang antiapoptotic effects in bmscs by targeting caspase- -associated protein- and programmed cell death- [ ] . pharmacological agents, including diazoxide [ ] , can induce protective mirs expression. besides mirs, a recent investigation elucidated that preconditioning of mscs with specific cell-free dnas (cfdnas) increased cell survival via toll-like receptor (tlr ) and translocation of nuclear factor-kappa b (nfkb) [ ] . this evidence highlights the possibility that mirs and cfdnas may be potential new targets to promote stem cell survival after transplantation. collectively, these exciting results suggest that gene modification is a promising strategy to increase cell survival after transplantation, and these enhanced cell survivals could contribute to reduced infarcts and improved behavioral recovery through neuronal differentiation and promoted trophic factor secretion. gene modification takes the risk that uncontrolled expression of introducing gene may have adverse effects and induce tumor formation on normal brain. recent studies show that precondition strategy including hypoxia preconditioning, growth factor preconditioning, and antiapoptosis drug preconditioning could be a safe and efficient method [ ] . up to now, a number of sublethal insults including hypoxia [ ] , anoxia [ ] , hydrogen sulfide (h s) [ ] , hydrogen peroxide (h o ) [ ] , as well as growth factors, such as erythropoietin (epo) [ ] , stromal-derived factor- (sdf- ) [ ] , insulin-like growth factor- (igf- ) [ ] , heat shock proteins (hsps) [ ] , or pharmacological agents such as melatonin [ ] , minocycline [ ] , isoflurane [ ] , and lipopolysaccharide (lps) [ ] , have been tested in stem cells (table . ). sublethal hypoxia preconditioning applied to stem cells have shown to activate protective signals including hypoxia-inducible factor- (hif- ), growth factors, akt, and erk signals to further enhance their resistance to apoptosis/necrosis cues by increasing survival signals [ ] . dr. wei's group has performed extensive studies related to hypoxia preconditioning. in these studies they demonstrated that transplantation of hypoxia preconditioning mscs improves infarcted heart function [ ] and ischemic brain function [ ] recovery via enhanced survival of implanted cells and angiogenesis. also they found hypoxic precondition reduced es-npcs apoptosis by - % in serum-free medium via upregulation of erythropoietin (epo), bcl- , and hif- alpha [ ] . one study from dr. yang's group demonstrated that melatonin pretreatment increased mscs' survival and proangiogenic activity through erk / signaling pathway [ ] , which is consistent with other studies that melatonin treatment enhanced adipose-derived mesenchymal stem cells (admscs) survival and therapy for lung ischemia injury [ ] and reduced grafted eepc apoptosis/necrosis as well as increased their outgrowth in injured kidney [ ] . for minocycline, sakata et al. showed that transplantation of minocycline-preconditioned nscs protected their survival from ischemic reperfusion injury via upregulation of nrf and nrf regulated antioxidant genes, increased their paracrine factors releasing, attenuated infarct size, and improved neurological performance [ ] , and doxycycline has the similar protective effects [ ] . additionally, low lps pretreatment was found to protect mscs against oxidative stress-induced apoptosis and increase cell engraftment after transplantation into ischemic heart [ ] . a recent study showed that epo pretreatment could also suppress mscs' apoptosis in response to hydrogen peroxide stimuli [ ] . the development of biomaterials has evolved from the first-generation, materialbased approach that focused on mechanical strength, durability, and biocompatibility to the third-generation, bio-functional materials that try to integrate biological cues to modulate cellular functions by modifying with extracellular matrix (ecm) related to signaling molecules. in recent years, biomaterials have been proven to be an effective strategy for regulating cellular behavior, including promoting cell survival, directing cell differentiation. advances in biomaterials engineering enable promoting grafted cell survival and engraftment and have generated much attention in stroke therapy. with regard to injecting stem cells which are encapsulated within biomaterials into ischemic brain, the infarct cavity is always an ideal location. first, it is more clinical relevant since the transplantation procedure is not initiated until infarct cav-y. tang table ity is formed, which is already - weeks after the onset of stroke; second, cavity is adjacent to the highly plastic peri-infarct region, and injection of stem cells into the cavity shows to achieve best outcome. third, injection into the cavity will not damage normal brain tissues. although directly injecting stem cells into infarct cavity shows its merit in reduced infarct volume, enhanced behavioral recovery, and increased angiogenesis and neurogenesis, low cell survival is still a major problem that hinders its clinical application. for instance, only % of the grafted nspc transplanted cells survived weeks posttransplantation in mongolian gerbils after focal ischemia [ ] . in another study, approximately % of grafted npcs survived at weeks posttransplantation [ ] . previous experimental studies showed that using matrigel, fibrin glue gels, particles, and other scaffolds as matrices could improve the survival of stem cells in the infarct cavity posttransplantation (table . ). matrigel is an extracellular matrix comprised of ecm proteins and growth factor mixtures, including collagen, laminin, epidermal growth factor (egf), and fibroblast growth factor (fgf- ). jin et al. injected npcs encapsulated with matrigel into the infarct cavity in both young and aged rats. compared to control group, more cells were detected at the infarct site, and best functional recovery was achieved in the npcs+matrigel group [ , ] . however, matrigel is derived from a mouse sarcoma that raises a serious concern for its clinical application. the functions of biodegradable polymers such as pga and plga are also extensively investigated in stem cell-based therapy in stroke. for instance, park et al. implanted nscs seeded on polyglycolic acid (pga), a high biocompatible scaffold into the infarct cavity, and found infarct volume was greatly reduced as well as establishment of neuronal connections between exogenous transplanted nscs and endogenous neurons [ ] . modo's group demonstrated plga could act as a structural support for nscs in infarct cavity to improve cell survival and function [ ] . in their further study, they loaded vegf into the plga microparticles and transplanted nscs which were seeded on the vegf-releasing plga particles into the cavity. their results showed that vegf-releasing plga not only provides structural support but also attracts ecs into the cavity to induce neurovascular formation [ ] . hyaluronan (ha), a glycosaminoglycan that naturally and abundantly exist in the brain, could involve in brain development and influence cell adhesion, migration, angiogenesis, and axon growth. thus it is reasonable to choose ha as protective matrices to encapsulate cells for transplantation into the brain to maintain a hydrated and porous environment [ ] . recently, experimental studies from dr. thomas carmichael's group proved that hydrogel composed of cross-linked hyaluronan and heparin sulfate significantly promoted npcs' survival after transplantation into the infarct cavity, accompanied by reduced inflammation [ ] . in their further study, they proposed to modify hyaluronic acid hydrogel with cell adhesion peptide rgd and cross-linked with either mmp degradable peptides or non-mmp degradable peptides through a michael addition reaction to produce two hydrogel formulations with two different stiffness moduli ( pa in mmp ha and pa in non-mmp ha). npcs derived from induced pluripotent stem cells (ips-npc) were encapsulated in the hydrogel matrix and delivered to the infarct cavity of stroke y. tang migration and homing of administered cells to the ischemic regions are clinically relevant and very critical to their therapeutic efficacy. a detailed analysis of the biological responses to brain injury would not only give us insight into the mechanism of stem cell homing but also give us important clues about how we can improve their homing capacity. now it is clear that following brain injury, homing molecular cues, including chemokines, growth factors, and adhesion molecules, originating from the inflammatory zone in the injured brain, are activated and upregulated to cause bmsc homing. chemokines such as g-csf and sdf- have been demonstrated to be an important stem cell homing mediator that mobilizes stem cells from bone marrow into the pb. g-csf treatment enhances tissue regeneration and improves recovery after stroke by mobilizing bmscs from bone marrow into peripheral blood [ ] . previous studies showed that subcutaneous injection of g-csf for days after cerebral ischemia promotes bmsc migration to the lesion area, reduces infarcts, and enhances functional recovery in stroke rats [ ] . g-csf treatment is also demonstrated to facilitate neurogenesis in svz by increasing the infiltration of bmsc into the brain [ ] . bmscs exert their benefits on cerebral ischemic injuries through promoting neuronal repair and recovery of brain function, which provides a basis for the development of a noninvasive autologous therapy for cerebral ischemia. some pilot clinical trials demonstrated that g-csf could mobilize bmscs in patients after acute stroke safely and provide better neurological outcome compared to conventional treatment [ ] . sdf- is another important homing factor, which is secreted primarily by bone marrow fibroblasts and is required for bmsc homing/retention in the bone marrow microenvironment. sdf- and its receptors cxcr and cxcr were found upregulated after early focal cerebral ischemia [ ] and showed beneficial for the adhesion and migration of bmscs both to bone marrow and to ischemic tissue through activation of specific integrin molecules. given that cxcr and cxcr are present on bone marrow stem cells [ ] , upregulation of sdf- in the local ischemic damage after injury may be related to stem cell homing and engraftment toward the injured tissue. during cerebral ischemia, sdf- was found primarily co-localized with endothelial cells and closely interacted with infiltrated bmscs from bone marrow in the ischemic penumbra region, suggesting that sdf- may mediate trafficking of transplanted bmscs to ischemically damaged tissue. indeed, overexpression of sdf- in ischemic tissues has recently been found to augment epc-induced vasculogenesis in hind-limb ischemic mice, as well as enhanced recovery of blood perfusion, increased capillary density, and induced partial incorporation of epcs y. tang into the microvessels [ ] . our previous studies have highlighted biphasic function of sdf- in stroke mice in a time-dependent manner. one study demonstrated that injection of cxcr inhibitor amd into ischemic mice during acute phase significantly suppressed inflammatory response and reduced blood-brain barrier disruption via inhibiting leukocyte migration and infiltration [ ] ; however, another study showed that overexpression of sdf- in mice brain during post-acute phase promoted neurovascular recovery, neurogenesis, and angiogenesis through enhancing migration of neural progenitor cells and endothelial cells, while amd reversed protective effects of sdf- [ ] . in addition to chemokines, growth factors, inflammatory cytokines, and adhesionrelated molecules also play important roles in stem cell homing. for instance, pdgf and vegf are demonstrated to act as chemoattractants to induce migration of mscs [ ] ; il- , (tgf)-β , interleukin (il)- β, and tumor necrosis factor (tnf)-α stimulate chemotactic migration through matrix metalloproteinases (mmps) secreted by the mscs [ ] . during the transmigration process of mscs through the vascular endothelium, integrins and adhesion molecules are involved. based on the fact that mscs express α β integrin and vascular cell adhesion molecule- (vcam- ), it is proposed that mscs roll along the vascular endothelium may share the same mechanism as white blood cells and hscs to move through the blood vessels. indeed, ip et al. identified that β integrins are important for the intramyocardial traffic of mscs by developing a functional genomics approach [ ] . moreover, the adhesion of rat mscs to endothelial cells of microvessels is reduced by anti-vcam- antibody [ ] . different administration routes will result in different homing, distribution, and engraftment. experimental studies demonstrated that intracerebral [], intra-arterial, intravenous, and intracisternal injection of mscs result in reduced infarct volume and enhanced behavioral functional recovery, irrespective of pros and cons existing in each injection method [ ] . intracerebral injection delivers and had the highest cell retention in a desired location compared to other methods [ ] , but it also induces adverse effects involving seizures and transient motor function impairment given its invasive procedure. intraventricular transplantation is less invasive but achieves less therapeutic efficacy as intraventricularly injected human nscs into ischemic rat brain did not show improvement [ ] . intravenous delivery is safer and more feasible, but only few cells could localize to the infarct region [ ] . intraarterial administration contributes to more cells retaining in the brain than intravenous delivery and is beneficial for behavioral recovery [ ] . however, intra-arterial transplantation leads to high mortality (about %) and morbidity due to cell accumulation and microemboli, especially when large-sized stem cells (e.g., mscs) were transplanted intra-arterially [ ] , which is a major concern for its clinical translation. in order to determine stem cell migration and in vivo distribution, noninvasive and real-time imaging modalities are developed in recent years. several multifunctional nanoprobes with high mr sensitivity are developed by our group to label stem cells and allow us to longitudinally track them after injection by mri in terms of its high spatial resolution. in one study we labeled mscs [ ] and nscs [ ] with high mr sensitivity fluorescent-magnetite-nanocluster (fmnc) and tracked them by mri and fluorescent imaging after injection into the contralateral hemisphere of the ischemic mice brain. mscs were detected to migrate toward the perifocal region of the ipsilateral hemisphere through the corpus callosum. we further developed a trifunctional nanoprobe by adding iodine- to superparamagnetic iron oxide nanoparticles, which allows us to quantitatively track mscs injected into the brain by micro-spect/ct and mri. using this method we found % of intracerebrally grafted mscs migrated from the injection hemisphere to the lesion area, and intravenously injection induced more than % of mscs migrated and accumulated in the lung, while no cells were found in the brain ( fig. . ) [ ] . however, one major limitation of spio-based imaging strategy is that survival and dead cells cannot be distinguished. signals from survival and dead cells are all captured by mri and micro-spect. to resolve this problem, bioluminescence imaging (bli) is developed and widely used to track the migration and survival of transplanted cells which are modified with a firefly or renilla luciferase (luc) enzyme [ ] . however, the spatial resolution and the penetration depth of bli are limited, which hinder its clinical application at current stage. recently, radionuclide probes for pet imaging were designed, as f-fluorodeoxyglucose ([ f]-fdg) is the most popular one. several studies have reported direct imaging of transplanted cells with f-fdg [ , ] . to track survival of grafted cells, the herpes simplex virus type -derived thymidine kinase (hsv- -tk), which could exclusively phosphorylate substrates composed of acycloguanosines, is employed and routinely used to monitor human escs and c . nscs in the rodent brain [ , ] . stem cell homing is a multistep process involving cell attachment, adhesion to the vascular endothelium, and migration through the tissue stromal, which are mediated by different factors, including chemokines, growth factors, integrins, and adhesion molecules. understanding the mechanism of homing could help us to develop novel strategies to improve their homing ability and further increase the therapeutic efficacy. in principle, those methods that used to increase stem cell survival could also apply to improving stem cell homing. y. tang we and others demonstrated that genetic modification of the target tissue or the stem cells with homing genes is feasible to stimulate their homing ability and further improve behavioral recovery after stroke (table . ). by stereotactic injection of adeno-associated virus (aav) carrying sdf- α gene into ischemic mice brain, li et al. found that migration of endogenous neural stem cells and opcs from subventricular zone to the peri-infarct region was enhanced and induced increased neurogenesis and oligodendrogenesis, reduced brain atrophy, as well as improved white matter and behavioral recovery [ , ] . in addition to sdf- α, yu and coworkers demonstrated its receptor cxcr also plays a pivotal role in stem cell homing. by transducing mscs with cxcr by lentivirus and injecting them via the femoral vein following mcao, they found that cxcr overexpression promoted mscs' migration to the infarct region and enhanced neuroprotection via increased angiogenesis [ ] . besides stroke, mscs overexpressing cxcr was also proved to migrate into the cardiac infarct area in a cardiac infarct animal model, leading to a significant improvement in cardiac func- [ ] mscs myocardial infarction increased accumulation of bmscs in the lesion area and an improvement in cardiac function ccr [ ] msc myocardium infarct ccr -mscs accumulated in the infarcted myocardium at significantly higher levels. ccr -msc-injected hearts exhibited a significant reduction in infarct size, reduced cardiomyocyte apoptosis, and increased capillary density ace [ ] epc cerebral ischemia ace overexpression improved the abilities of epc migration and tube formation, reduced cerebral infarct volume and neurologic deficits, increased cerebral microvascular density and angiogenesis hgf sirna [ ] asc transduced asc-shhgf secreted > % less hgf, which led to a reduced ability to promote survival, proliferation, and migration of mature and progenitor endothelial cells in vitro igf- [ ] msc permanent coronary artery occlusion igf- transgene expression induced massive stem cell mobilization via sdf- α signaling and culminated in extensive angiomyogenesis in the infarcted heart gdnf [ ] npc stroke more nspc-gdnf cells migrated toward the ischemic core, reduced infarct volume, and improved behavioral recovery scf [ ] nspcs normal mice recombinant scf induces potent nspc migration in vitro and in vivo through the activation of c-kit on nspcs microrna [ ] hesc-derived neural progenitors stroke hnpcs without mir- activity also showed enhanced migration y. tang tion [ ] . additionally, growth factors also show their capacity to enhance stem cell migration posttransplantation. haider et al. demonstrated that igf- overexpression promoted msc recruitment through paracrine activation of sdf- α and enhanced myocardial repair [ ] . when npcs overexpressing gdnf were injected into ischemic rat brain, more cells were found accumulated in the lesion area [ ] . for epc it was reported that overexpression of angiotensin-converting enzyme (ace ) improved the epc migration and tube formation, and injection of lentivirus-ace transfected epcs reduced cerebral infarct volume and neurological deficits, which was driven by enos [ ] . recently, mirnas were demonstrated to play an important role in stem cell migration. one study from delaloy et al. for the first time identified mir- as a novel regulator that coordinates the proliferation and migration of hnpcs. they found that hnpcs without mir- activity showed enhanced migration when transplanted into mouse embryonic or adult brains in a stroke mouse model [ ] . other mirnas such as mir- b and mir- have been also proven to play an important role in cell migration [ , ] . as we discussed above, although overexpression of homing genes in both grafted stem cells and local brain tissues improves stem cell homing, several disadvantages exist in this strategy. for instance, uncontrolled expression of introducing genes raises the safety issue, and the risk of tumorigenicity such as leukemia also limits its application. recently, upregulation of homing genes in mscs under stress conditions including hypoxia has been confirmed, which may be mediated by hif- alpha [ ] . it is reported that hypoxia induces cxcr and cxcr expression in bmscs via upregulated hif- α [ ] , and hypoxia preconditioning enhances migration of mscs via increased expression of cmet [ ] , which hints at the possibility that hypoxia preconditioning could enhance mobilization of stem cells to lesion sites in ischemic brain. in addition to hypoxia preconditioning, h o preconditioning could increase the migration of mscs through upregulation of cxcr and activation of extracellular signal-regulated kinase (erk) [ ] , and pretreatment of hscs with sdf- or dextran sulfate enhances their homing to bone marrow, which is involved in several genes including cxcr and mmp- [ ] . accumulating evidence shows that pretreatment with growth factors also increases mscs' mobilization (table . ). in previous investigations, igf- as well as vegf increased msc migratory responses via cxcr chemokine receptor signaling which is pi /akt dependent [ , ] . early studies have demonstrated that statins increased epc number and function through activating the akt/enos pathway [ ] . likewise, enhancement of enos enhancers improves the stem cell homing. in particular, pretreatment with enos enhancers significantly increased the homing of the intravenously infused epcs or bmcs and led to increased exercise capacity in a hind-limb ischemia model [ ] . [ , , ] ; es-npcs [ ] h o msc [ , ] myocardial infarction with the rapid development of tissue engineering, many state-of-the-art biomaterials have been developed to combine stem cells to treat cerebrovascular diseases, with the ultimate goal of repairing organs and tissue. in past two decades, many protein-based, polysaccharide-based, polymer-based, peptide-based, and ceramicbased scaffolds that have been proven to promote the viability, differentiation, and migration of stem cells are well designed [ ] . both natural and synthetic biomaterials have been developed and combined with stem cell-based therapy to promote cell survival and migration posttransplantation (table . ). fibrin gel is ranked as the first biomaterial to prevent bleeding and promote wound healing in terms of the abundance of fibrinogen, ease fabrication, controllable gelation time, and tunable mechanical property. fibrin gel is able to exclusively enhance the migration of the transplanted cells toward the lesion boundary zone, even it disappears completely weeks after transplantation [ ] . in one study performed by lee and coworkers, they designed a vegf-releasing gel that could attract nsc migration [ ] . it is also reported that pegylated fibrin patch controlled the release of sdf- α at the infarct site and increased the rate of c-kit+ stem [ ] cortical injury fibrin matrix enhanced the retention of the transplanted cells within the lesion, migration toward the lesion boundary zone, and differentiation into the neurons and perivascular cells c . cell line [ ] myocardial ischemia the cells migrated toward the fibrin gel, with the total migration distance of . ± . μm over days (pegylated) fibrin patch [ ] the myocardial recruitment of c-kit+ cells was significantly higher in the group treated with the sdf- a pegylated fibrin patch alginate microspheres bone marrowderived progenitor cells [ ] hind-limb ischemia increased mobilization of bone marrow-derived progenitor cells and also improved recruitment of angiogenic cells expressing cxcr from bone marrow and local tissue hmscs [ ] myocardial ischemia rgd-modified alginate improved cell attachment and growth and increased angiogenic growth factor expression starpeg-heparin hydrogels epcs [ ] in vitro higher migration rates were achieved gtn-hpa hydrogels and pcns npcs [ ] in vitro gtn-hpa/sdf- -pcn hydrogels promoted hemotactic recruitment to enhance infiltration of anpcs by -to -fold relative to hydrogels that lacked sdf- collagen microgel hmscs [ ] hind-limb ischemia optimized hmsc embedded microgels were shown to induce vascular repair and functional improvement by increasing sdf- expression ha epcs [ ] myocardial ischemia induced continuous homing of epcs and improved left ventricular function in a rat model of myocardial infarction sdf- [ ] injection of biomimetic hydrogels containing sdf- and ac-sdkp increased stem cell homing and significantly improved left ventricle function, increased angiogenesis, decreased infarct size and great (continued) y. tang cell recruitment and offered potential therapeutic benefits in the myocardium ischemic mice [ ] . this body of work suggests that migration of stem cells can be monitored by fibrin scaffolds. recently, scaffolds fabricated from gelatin [ ] , collagen [ ] , alginate [ ] , and hyaluronic acid (ha) [ ] have been developed for the controlled release of growth factors, which could provide homing signals to enhance stem cell migration. kuraitis et al. found encapsulating sdf- into alginate microspheres led to increased mobilization of bone marrow-derived cxcr + progenitor cells and restoring perfusion to ischemic tissues via neovascularization [ ] . further studies demonstrated hmscs encapsulated in rgd-modified alginate microspheres are capable of facilitating myocardial repair [ ] . baumann et al. reported that encapsulating sdf- α with starpeg-heparin hydrogels enhanced migration of epcs in vitro [ ] . lim et al. [ , ] in vitro released sdf- α caused significant migration of mscs throughout the duration of release from the microspheres threefold increase of the host-derived stem cell migration at the interface for up to weeks pcl mscs [ ] bone tissue engineering model mscs were shown to migrate within a polycaprolactone scaffold in response to sdf- pleof [ ] bmscs in vitro the migration of bms cells in response to time-released sdf- alpha closely followed the protein release kinetics from the hydrogels puasm [ ] sdf- mcao systemic administration of sdf- αloaded copolymer into ischemic rat resulted in enhanced angiogenesis and neurogenesis spions combined with exterior magnet epcs [ ] mcao spion-labeled epc homing was greatly increased in ischemic hemisphere with magnetic field treatment mscs [ ] balloon angioplasty in a rabbit model magnetic targeting of mesenchymal stem cells gives rise to a sixfold increase in cell retention following balloon angioplasty in a rabbit model hnscs [ ] magnet treated rats had a larger number and greater distribution of ferumoxide-labeled nscs as compared with controls modification of bone marrow stem cells for homing and survival… developed a multifunctional biomaterial comprising injectable gelatinhydroxyphenylpropionic acid (gtn-hpa) hydrogels and dextran sulfate/chitosan polyelectrolyte complex nanoparticles (pcns) to carry sdf- to promote infiltration of npcs through mmp- [ ] . in particular, an interesting study fabricated and optimized a shape-controlled d type-i collagen-based microgel platform to modulate sdf- expression of hmscs, and hmscs embedded in the microgels were shown to induce vascular repair and functional improvement in hind-limb ischemic mouse [ ] . currently, ha is gaining its popularity as a biomaterial for tissue regeneration [ ] . by chemically modifying ha with hydroxyethyl methacrylate, controlled release of sdf- was achieved after its encapsulation into ha, and enhanced endothelial progenitor cell chemotaxis was identified [ ] . it is also reported that loading sdf- and angiogenic peptides (ac-sdkp) to ha-based hydrogel promoted regeneration of cardiac function through increasing stem cell homing and angiogenesis [ ] . poly lactic-co-glycolic acid (plga) is an fda-approved polymer and the most attractive polymeric drug/protein carrier among those synthetic materials as its high biocompatibility, biodegradability, and tunable mechanical property. plga has been extensively designed for controlled release of small molecule drugs, proteins, and other macromolecules in commercial use and in research. double-emulsion solvent extraction/evaporation is a routine technique to load proteins to biodegradable plga microspheres. using this strategy, cross et al. loaded sdf-lα into plga microspheres for releasing sdf- α over days without affecting its bioactivity, and significant migration of mscs throughout the duration of release from the microspheres was observed [ ] . thevenot and colleagues fabricated plga saltleached scaffolds to carry sdf- and implanted in the subcutaneous cavity of balb/c mice. they found this strategy enhanced host-derived stem cell engraftment by threefold compared to conventional mini-osmotic pump delivery for up to weeks with limited inflammatory response [ ] . in addition to plga, polycaprolactone (pcl) and poly (lactide ethylene oxide fumarate) hydrogel (pleof) have also been used to achieve msc recruitment. schantz et al. have developed acellular pcl scaffolds that allowed sequential delivery of vegf, sdf- , and bone morphogenetic protein- (bmp- ) in the rat and increased mscs infiltrating into the scaffold, with concomitant angiogenesis [ ] . in another study, he et al. synthesized sdf- -loaded pleof hydrogel with poly(llactide) (pla) fractions. a pronounced burst release followed by a period of sustained release was achieved, and mscs showed migration to sdf- in a dose-dependent manner [ ] . recently, kim et al. synthesized a dual ph-sensitive copolymer-poly (urethane amino sulfamethazine) (puasm)-based random copolymer for controlled release of sdf- in stroke. this copolymer showed high protein encapsulation efficiency at ph . , and at ph . , it could release protein rapidly. systemic administration of sdf- α-loaded copolymer into ischemic rat resulted in enhanced angiogenesis and neurogenesis [ ] . recent studies have highlighted the role of superparamagnetic iron oxide nanoparticles in targeted cell delivery. experimental studies from dr. yang's lab showed that intravenous injection of spion-labeled epcs into ischemic mice and y. tang followed by magnetic field treatment promoted their migration to the infarcts, further reduced brain atrophic volume, and improved neurobehavioral outcomes [ ] . other studies with this method also showed that magnetic targeting of mscs or hnscs led to increased cell retention following their injection [ , ] . an interesting study reported that small direct current (dc) electric fields induced significant directional migration of hnscs toward the cathode independent of cxcr signal [ ] . bone marrow-derived stem cells have been demonstrated as promising sources of adult stem cells for regeneration and repair of neurological disorders, including ischemic stroke. on the other hand, many experimental studies make us recognize many fundamental questions related to the cell survival, homing, and engraftment that contribute to the limited efficacy of bm-derived stem cell transplantation in the clinic. we and other groups have proposed many strategies such as gene modification, preconditioning treatment, and biomaterial-based method to overcome these limitations. strategies to improve cell survival and homing would enhance their therapeutic efficacy and strengthen the application potential of stem cell therapy. in summary, stem cell-based therapy for ischemic stroke in humans is still in its infancy. further basic and translational studies are required before it becomes a scientifically proven strategy in clinical setting. isolation of putative progenitor endothelial cells for angiogenesis delayed post-ischaemic neuroprotection following systemic neural stem cell transplantation involves multiple mechanisms caspasemediated cell death predominates following engraftment of neural progenitor cells into traumatically injured rat brain intra-arterial immunoselected cd + stem cells for acute ischemic stroke transplantation of human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and endogenous neurogenesis after cerebral ischemia in rats modification of bone marrow stem cells for homing and survival… a novel, biased-like sdf- derivative acts synergistically with starpeg-based heparin hydrogels and improves eepc migration in vitro the support of neural stem cells transplanted into stroke-induced brain cavities by plga particles neo-vascularization of the stroke cavity by implantation of human neural stem cells on vegf-releasing plga microparticles myocardial substrate and route of administration determine acute cardiac retention and lung bio-distribution of cardiosphere-derived cells bone marrow stem cell mobilization in stroke: a 'bonehead' may be good after all! leukemia the great migration of bone marrow-derived stem cells toward the ischemic brain: therapeutic implications for stroke and other neurological disorders transplantation of bone marrow mesenchymal stem cells decreases oxidative stress, apoptosis, and hippocampal damage in brain of a spontaneous stroke model mesenchymal stem cells the sdf- /cxcr axis in stem cell preconditioning therapeutic benefit of intravenous administration of bone marrow stromal cells after cerebral ischemia in rats angiotensin-converting enzyme priming enhances the function of endothelial progenitor cells and their therapeutic efficacy targeted migration of mesenchymal stem cells modified with cxcr gene to infarcted myocardium improves cardiac performance selective migration and engraftment of bone marrow mesenchymal stem cells in rat lumbar dorsal root ganglia after sciatic nerve constriction stromal-derived factor- alpha-loaded plga microspheres for stem cell recruitment survival, migration and neuronal differentiation of human fetal striatal and cortical neural stem cells grafted in stroke-damaged rat striatum microrna- coordinates proliferation and migration of human embryonic stem cell-derived neural progenitors hmg-coa reductase inhibitors (statins) increase endothelial progenitor cells via the pi -kinase/akt pathway transduction of neural precursor cells with tat-heat shock protein chaperone: therapeutic potential against ischemic stroke after intrastriatal and systemic transplantation the effect of hypoxia on mesenchymal stem cell biology in vitro protection of adipose tissue-derived mesenchymal stem cells by erythropoietin endothelial progenitor cell transplantation improves long-term stroke outcome in mice guided migration of neural stem cells derived from human embryonic stem cells by an electric field disruption of epithelial cell-matrix interactions induces apoptosis anoikis mechanisms preconditioning and stem cell survival igf- -overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of sdf- alpha/ cxcr signaling to promote myocardial repair ffrench-constant c. laminin enhances the growth of human neural stem cells in defined culture media dextran sulfate and stromal cell derived factor- promote cxcr expression and improve bone marrow homing efficiency of infused hematopoietic stem cells migration of marrow stromal cells in response to sustained release of stromal-derived factor- alpha from poly(lactide ethylene oxide fumarate) hydrogels labeled schwann cell transplantation: cell loss, host schwann cell replacement, and strategies to enhance survival heparin-functionalized chitosan-alginate scaffolds for controlled release of growth factor effects of extracellular matrix molecules on the growth properties of oligodendrocyte progenitor cells in vitro transplantation of hypoxiapreconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis modification of bone marrow stem cells for homing and survival… cxcr antagonist amd protects blood-brain barrier integrity and reduces inflammatory response after focal ischemia in mice bone marrow stromal cells that enhanced fibroblast growth factor- secretion by herpes simplex virus vector improve neurological outcome after transient focal cerebral ischemia in rats genomic loss of tumor suppressor mirna- promotes cancer cell migration and invasion by activating akt/mtor/rac signaling and actin reorganization mesenchymal stem cells use integrin beta not cxc chemokine receptor for myocardial migration and engraftment human neural stem/progenitor cells, expanded in longterm neurosphere culture, promote functional recovery after focal ischemia in mongolian gerbils cell size and velocity of injection are major determinants of the safety of intracarotid stem cell transplantation transplantation of human neural precursor cells in matrigel scaffolding improves outcome from focal cerebral ischemia after delayed postischemic treatment in rats delayed transplantation of human neural precursor cells improves outcome from focal cerebral ischemia in aged rats time of transplantation and cell preparation determine neural stem cell survival in a mouse model of huntington's disease human fetal cortical and striatal neural stem cells generate region-specific neurons in vitro and differentiate extensively to neurons after intrastriatal transplantation in neonatal rats adult neural stem and progenitor cells modified to secrete gdnf can protect, migrate and integrate after intracerebral transplantation in rats with transient forebrain ischemia niche-to-niche migration of bone-marrow-derived cells enhancing neurogenesis and angiogenesis with target delivery of stromal cell derived factor- alpha using a dual ionic ph-sensitive copolymer isoflurane decreases death of human embryonic stem cell-derived, transcriptional marker nkx . (+) cardiac progenitor cells marrow-derived stromal cells express genes encoding a broad spectrum of arteriogenic cytokines and promote in vitro and in vivo arteriogenesis through paracrine mechanisms extracellular gc-rich dna activates tlr -and nf-kb-dependent signaling pathways in human adipose-derived mesenchymal stem cells (hamscs) cells enriched in markers of neural tissue-committed stem cells reside in the bone marrow and are mobilized into the peripheral blood following stroke a stromal cell-derived factor- releasing matrix enhances the progenitor cell response and blood vessel growth in ischaemic skeletal muscle mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model delivery of ips-npcs to the stroke cavity within a hyaluronic acid matrix promotes the differentiation of transplanted cells improving the survival of human cns precursorderived neurons after transplantation human neural stem cells over-expressing vegf provide neuroprotection, angiogenesis and functional recovery in mouse stroke model human neural stem cells genetically modified to overexpress akt provide neuroprotection and functional improvement in mouse stroke model the spreading, migration and proliferation of mouse mesenchymal stem cells cultured inside hyaluronic acid hydrogels transplantation of marrow stromal cells restores cerebral blood flow and reduces cerebral atrophy in rats with traumatic brain injury: in vivo mri study silicacoated superparamagnetic iron oxide nanoparticles targeting of epcs in ischemic brain injury oxidative preconditioning promotes bone marrow mesenchymal stem cells migration and prevents apoptosis postacute stromal cell-derived factor- alpha expression promotes neurovascular recovery in ischemic mice the role of astrocytes in mediating exogenous cell-based restorative therapy for stroke erythropoietin-induced neurovascular protection, angiogenesis, and cerebral blood flow restoration after focal ischemia in mice modification of bone marrow stem cells for homing and survival… cxcl gene therapy ameliorates ischemia-induced white matter injury in mouse brain insulin-like growth factor enhances the migratory capacity of mesenchymal stem cells endothelial progenitor cells in ischemic stroke: an exploration from hypothesis to therapy mir- b is overexpressed in hepatocellular carcinoma and promotes cell proliferation, migration and invasion through rhoc, upar and mmps chemotactic recruitment of adult neural progenitor cells into multifunctional hydrogels providing sustained sdf- alpha release and compatible structural support neuroprotection by plgf gene-modified human mesenchymal stem cells after cerebral ischaemia hypoxic preconditioning advances cxcr and cxcr expression by activating hif- alpha in mscs effects of transplantation with bone marrow-derived mesenchymal stem cells modified by survivin on experimental stroke in rats cell based therapies for ischemic stroke: from basic science to bedside insulin-like growth factor- preconditioning accentuates intrinsic survival mechanism in stem cells to resist ischemic injury by orchestrating protein kinase calpha-erk / activation sustained release of engineered stromal cell-derived factor -alpha from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction doxycycline can stimulate cytoprotection in neural stem cells with oxygen-glucose deprivation-reoxygenation injury: a potential approach to enhance effectiveness of cell transplantation therapy microrna partly inhibits endothelial progenitor cells differentiation via hif- beta safety of thrombolysis in acute ischemic stroke: a review of complications, risk factors, and newer technologies hyaluronan, neural stem cells and tissue reconstruction after acute ischemic stroke pharmacologically preconditioned skeletal myoblasts are resistant to oxidative stress and promote angiomyogenesis via release of paracrine factors in the infarcted heart the injured brain interacts reciprocally with neural stem cells supported by scaffolds to reconstitute lost tissue transplantation of adult rat spinal cord stem/progenitor cells for spinal cord injury the hormone melatonin stimulates renoprotective effects of "early outgrowth" endothelial progenitor cells in acute ischemic kidney injury controlled release of vascular endothelial growth factor from spray-dried alginate microparticles in collagen-hydroxyapatite scaffolds for promoting vascularization and bone repair innate immunity as orchestrator of stem cell mobilization very small embryonic-like stem cells (vsels) represent a real challenge in stem cell biology: recent pros and cons in the midst of a lively debate stem cell recruitment after injury: lessons for regenerative medicine superparamagnetic iron oxide nanoparticle targeting of mscs in vascular injury hypoxic preconditioning results in increased motility and improved therapeutic potential of human mesenchymal stem cells minocycline-preconditioned neural stem cells enhance neuroprotection after ischemic stroke in rats ex vivo pretreatment of bone marrow mononuclear cells with endothelial no synthase enhancer ave enhances their functional activity for cell therapy cell therapy for stroke cell guidance in tissue engineering: sdf- mediates sitedirected homing of mesenchymal stem cells within three-dimensional polycaprolactone scaffolds mesenchymal stem cell adhesion to cardiac microvascular endothelium: activators and mechanisms potentiation of neurogenesis and angiogenesis by g-csf after focal cerebral ischemia in rats intracerebral peripheral blood stem cell (cd +) implantation induces neuroplasticity by enhancing beta integrin-mediated angiogenesis in chronic stroke rats modification of bone marrow stem cells for homing and survival… granulocyte colony-stimulating factor for acute ischemic stroke: a randomized controlled trial implantation site and lesion topology determine efficacy of a human neural stem cell line in a rat model of chronic stroke regeneration of chronic myocardial infarction by injectable hydrogels containing stem cell homing factor sdf- and angiogenic peptide ac-sdkp using a neodymium magnet to target delivery of ferumoxide-labeled human neural stem cells in a rat model of focal cerebral ischemia inflammation and tumor microenvironments: defining the migratory itinerary of mesenchymal stem cells long term non-invasive imaging of embryonic stem cells using reporter genes administration of cd + cells after stroke enhances neurogenesis via angiogenesis in a mouse model embryonic neural stem cells transplanted in middle cerebral artery occlusion model of rats demonstrated potent therapeutic effects, compared to adult neural stem cells vascular endothelial growth factor promotes cardiac stem cell migration via the pi k/akt pathway melatonin pretreatment improves the survival and function of transplanted mesenchymal stem cells after focal cerebral ischemia mri/spect/fluorescent tri-modal probe for evaluating the homing and therapeutic efficacy of transplanted mesenchymal stem cells in a rat ischemic stroke model opportunities and challenges: stem cellbased therapy for the treatment of ischemic stroke noninvasive quantification and optimization of acute cell retention by in vivo positron emission tomography after intramyocardial cardiac-derived stem cell delivery in vitro hypoxic preconditioning of embryonic stem cells as a strategy of promoting cell survival and functional benefits after transplantation into the ischemic rat brain the effect of incorporation of sdf- alpha into plga scaffolds on stem cell recruitment and the inflammatory response a shape-controlled tuneable microgel platform to modulate angiogenic paracrine responses in stem cells the in vitro preconditioning of myoblasts to enhance subsequent survival in an in vivo tissue engineering chamber model multimodal imaging of neural progenitor cell fate in rodents anoxic preconditioning: a way to enhance the cardioprotection of mesenchymal stem cells therapeutic applications of bone marrow-derived stem cells in ischemic stroke roles of chemokine cxcl and its receptors in ischemic stroke high mr sensitive fluorescent magnetite nanocluster for stem cell tracking in ischemic mouse brain transplantation of embryonic stem cells overexpressing bcl- promotes functional recovery after transient cerebral ischemia transplantation of hypoxia preconditioned bone marrow mesenchymal stem cells enhances angiogenesis and neurogenesis after cerebral ischemia in rats combining stem cells and biomaterial scaffolds for constructing tissues and cell delivery stroke statistics s. heart disease and stroke statistics - update: a report from the american heart association transplantation of mesenchymal stem cells preconditioned with hydrogen sulfide enhances repair of myocardial infarction in rats heparin-decorated, hyaluronic acid-based hydrogel particles for the controlled release of bone morphogenetic protein stromal cell-derived factor- effects on ex vivo expanded endothelial progenitor cell recruitment for ischemic neovascularization controlled release of growth factors based on biodegradation of gelatin hydrogel modification of bone marrow stem cells for homing and survival… hypoxic preconditioning improves survival of cardiac progenitor cells: role of stromal cell derived factor- alpha-cxcr axis lipopolysaccharide preconditioning enhances the efficacy of mesenchymal stem cells transplantation in a rat model of acute myocardial infarction effect of biodegradable fibrin scaffold on survival, migration, and differentiation of transplanted bone marrow stromal cells after cortical injury in rats melatonin treatment improves adipose-derived mesenchymal stem cell therapy for acute lung ischemia-reperfusion injury the use of human mesenchymal stem cells encapsulated in rgd modified alginate microspheres in the repair of myocardial infarction in the rat preconditioning strategy in stem cell transplantation therapy overexpression of cxcr in mesenchymal stem cells promotes migration, neuroprotection and angiogenesis in a rat model of stroke apoptosis in the nervous system ex vivo priming of endothelial progenitor cells with sdf- before transplantation could increase their proangiogenic potential controlled release of stromal cellderived factor- alpha in situ increases c-kit+ cell homing to the infarcted heart hydrogen peroxide preconditioning enhances the therapeutic efficacy of wharton's jelly mesenchymal stem cells after myocardial infarction high mri performance fluorescent mesoporous silica-coated magnetic nanoparticles for tracking neural progenitor cells in an ischemic mouse model comparison of imaging techniques for tracking cardiac stem cell therapy endothelial progenitor cells: therapeutic perspective for ischemic stroke hydrogel matrix to support stem cell survival after brain transplantation in stroke a novel, biased-like sdf- derivative acts synergistically with starpeg-based heparin hydrogels and improves eepc migration in vitro the support of neural stem cells transplanted into stroke-induced brain cavities by plga particles neo-vascularization of the stroke cavity by implantation of human neural stem cells on vegf-releasing plga microparticles suppression of hepatocyte growth factor production impairs the ability of adipose-derived stem cells to promote ischemic tissue revascularization angiotensin-converting enzyme priming enhances the function of endothelial progenitor cells and their therapeutic efficacy functional improvement of focal cerebral ischemia injury by subdural transplantation of induced pluripotent stem cells with fibrin glue stromal-derived factor- alpha-loaded plga microspheres for stem cell recruitment microrna- coordinates proliferation and migration of human embryonic stem cell-derived neural progenitors transduction of neural precursor cells with tat-heat shock protein chaperone: therapeutic potential against ischemic stroke after intrastriatal and systemic transplantation human embryonic stem cell neural differentiation and enhanced cell survival promoted by hypoxic preconditioning igf- -overexpressing mesenchymal stem cells accelerate bone marrow stem cell mobilization via paracrine activation of sdf- alpha/ cxcr signaling to promote myocardial repair migration of marrow stromal cells in response to sustained release of stromal-derived factor- alpha from poly(lactide ethylene oxide fumarate) hydrogels transplantation of hypoxiapreconditioned mesenchymal stem cells improves infarcted heart function via enhanced survival of implanted cells and angiogenesis genetic modification of mesenchymal stem cells overexpressing ccr increases cell viability, migration, engraftment, and capillary density in the injured myocardium bone marrow stromal cells that enhanced fibroblast growth factor- secretion by herpes simplex virus vector improve neurological outcome after transient focal cerebral ischemia in rats hypoxia-preconditioned mesenchymal stromal cells improve cardiac function in a swine model of chronic myocardial ischaemia modification of bone marrow stem cells for homing and survival… transplantation of human neural precursor cells in matrigel scaffolding improves outcome from focal cerebral ischemia after delayed postischemic treatment in rats adult neural stem and progenitor cells modified to secrete gdnf can protect, migrate and integrate after intracerebral transplantation in rats with transient forebrain ischemia enhancing neurogenesis and angiogenesis with target delivery of stromal cell derived factor- alpha using a dual ionic ph-sensitive copolymer a stromal cell-derived factor- releasing matrix enhances the progenitor cell response and blood vessel growth in ischaemic skeletal muscle mesenchymal stem cells that produce neurotrophic factors reduce ischemic damage in the rat middle cerebral artery occlusion model collagen matrices enhance survival of transplanted cardiomyoblasts and contribute to functional improvement of ischemic rat hearts delivery of ips-npcs to the stroke cavity within a hyaluronic acid matrix promotes the differentiation of transplanted cells human neural stem cells over-expressing vegf provide neuroprotection, angiogenesis and functional recovery in mouse stroke model human neural stem cells genetically modified to overexpress akt provide neuroprotection and functional improvement in mouse stroke model bio-printing of collagen and vegf-releasing fibrin gel scaffolds for neural stem cell culture improved anti-apoptotic and anti-remodeling potency of bone marrow mesenchymal stem cells by anoxic pre-conditioning in diabetic cardiomyopathy silicacoated superparamagnetic iron oxide nanoparticles targeting of epcs in ischemic brain injury chemotactic recruitment of adult neural progenitor cells into multifunctional hydrogels providing sustained sdf- alpha release and compatible structural support neuroprotection by plgf gene-modified human mesenchymal stem cells after cerebral ischaemia effects of transplantation with bone marrow-derived mesenchymal stem cells modified by survivin on experimental stroke in rats sustained release of engineered stromal cell-derived factor -alpha from injectable hydrogels effectively recruits endothelial progenitor cells and preserves ventricular function after myocardial infarction doxycycline can stimulate cytoprotection in neural stem cells with oxygen-glucose deprivation-reoxygenation injury: a potential approach to enhance effectiveness of cell transplantation therapy combined transplantation of bone marrow stromal cell-derived neural progenitor cells with a collagen sponge and basic fibroblast growth factor releasing microspheres enhances recovery after cerebral ischemia in rats mesenchymal stem cell survival in the infarcted heart is enhanced by lentivirus vector-mediated heat shock protein expression ex vivo pretreatment with melatonin improves survival, proangiogenic/mitogenic activity, and efficiency of mesenchymal stem cells injected into ischemic kidney mscbased vegf gene therapy in rat myocardial infarction model using facial amphipathic bile acid-conjugated polyethyleneimine hyaluronan, neural stem cells and tissue reconstruction after acute ischemic stroke therapeutic benefits by human mesenchymal stem cells (hmscs) and ang- gene-modified hmscs after cerebral ischemia superparamagnetic iron oxide nanoparticle targeting of mscs in vascular injury bdnf pretreatment of human embryonic-derived neural stem cells improves cell survival and functional recovery after transplantation in hypoxic-ischemic stroke enhancement of mesenchymal stem cell angiogenic capacity and stemness by a biomimetic hydrogel scaffold interleukin -preconditioned neural stem cells reduce ischaemic injury in stroke mice cell guidance in tissue engineering: sdf- mediates sitedirected homing of mesenchymal stem cells within three-dimensional polycaprolactone scaffolds minocycline protects oligodendroglial precursor cells against injury caused by oxygen-glucose deprivation modification of bone marrow stem cells for homing and survival… regeneration of chronic myocardial infarction by injectable hydrogels containing stem cell homing factor sdf- and angiogenic peptide ac-sdkp using a neodymium magnet to target delivery of ferumoxide-labeled human neural stem cells in a rat model of focal cerebral ischemia neuronally expressed stem cell factor induces neural stem cell migration to areas of brain injury melatonin pretreatment improves the survival and function of transplanted mesenchymal stem cells after focal cerebral ischemia in vitro hypoxic preconditioning of embryonic stem cells as a strategy of promoting cell survival and functional benefits after transplantation into the ischemic rat brain the effect of incorporation of sdf- alpha into plga scaffolds on stem cell recruitment and the inflammatory response a shape-controlled tuneable microgel platform to modulate angiogenic paracrine responses in stem cells mesenchymal stem cells primed with valproate and lithium robustly migrate to infarcted regions and facilitate recovery in a stroke model anoxic preconditioning: a way to enhance the cardioprotection of mesenchymal stem cells transplantation of embryonic stem cells overexpressing bcl- promotes functional recovery after transient cerebral ischemia delayed intranasal delivery of hypoxic-preconditioned bone marrow mesenchymal stem cells enhanced cell homing and therapeutic benefits after ischemic stroke in mice transplantation of mesenchymal stem cells preconditioned with hydrogen sulfide enhances repair of myocardial infarction in rats chitosan-collagen porous scaffold and bone marrow mesenchymal stem cell transplantation for ischemic stroke effect of biodegradable fibrin scaffold on survival, migration, and differentiation of transplanted bone marrow stromal cells after cortical injury in rats melatonin treatment improves adipose-derived mesenchymal stem cell therapy for acute lung ischemia-reperfusion injury combinated transplantation of neural stem cells and collagen type i promote functional recovery after cerebral ischemia in rats overexpression of cxcr in mesenchymal stem cells promotes migration, neuroprotection and angiogenesis in a rat model of stroke controlled release of stromal cellderived factor- alpha in situ increases c-kit+ cell homing to the infarcted heart novel therapeutic strategy for stroke in rats by bone marrow stromal cells and ex vivo hgf gene transfer with hsv- vector transplantation of vascular endothelial growth factor-transfected neural stem cells into the rat brain provides neuroprotection after transient focal cerebral ischemia key: cord- -baiqcoao authors: bersano, anna; pantoni, leonardo title: the impact of sars‐cov‐ pandemic on stroke care: a warning message date: - - journal: eur j neurol doi: . /ene. sha: doc_id: cord_uid: baiqcoao the recent coronavirus disease (covid‐ ) pandemic intensely impacted the health systems worldwide, which had to deal with the challenge of contemporarily answering to the needs of covid‐ patients and managing other life threatening disorders. several european countries such as italy, france and spain, particularly hit by the pandemic, had to deeply reorganize healthcare and to redistribute personnel, resources and beds to deal with the demands of the uncontrolled spreading of the covid‐ infection. reorganize healthcare and to redistribute personnel, resources and beds to deal with the demands of the uncontrolled spreading of the covid- infection ( ) . many stroke services and teams were closed or reallocated and different stroke care pathways were implemented in many countries, according to local health system resources and organization ( ) . overall, these conditions affected the standard stroke care including the delivery of time-dependent treatments and adequate diagnostic work-ups ( , ) . this article is protected by copyright. all rights reserved these two studies, although limited by a short observation time, are among the first to report data on stroke care quality changes in europe at the time of the covid- pandemic. although other observations on stroke care changes have been published, most of them lack of systemic information, due to the difficulty in data collection in this challenging time. a decreased number of acute stroke admissions was registered in many countries despite there is no reason to believe that the overall stroke incidence has been different. this phenomenon is still unexplained. one possible reason is that many patients with milder stroke remained at home for the fear of infection in the hospital or because symptoms were not clearly recognized because of social isolation and lockdown ( , , ( ) ( ) ( ) . in other cases, stroke signs could be misdiagnosed in patients with covid- severe respiratory problems or because protection measures and distancing limited or even prevented neurological consultations. although these two reports are related to restricted geographical areas of europe, these observations introduce a warning message on the negative impact that covid- had on quality of pre-hospital and in-hospital stroke care and hint at possible long-term consequences in terms of increased disability burden. because stroke is the second cause of mortality and the first of disability in western countries, the best stroke care should be ensured, also in any challenging time, in order to not vanish the excellent results achieved over the last years in improving stroke outcome ( , ) . on being a neurologist in italy at the time of the covid- outbreak neurology, in press express: covid- and stroke -a global world stroke organisation perspective atención al ictus en aragón" ischaemic stroke in the time of coronavirus disease impact of the covid- outbreak on acute stroke pathways -insights from the alsace region in france stroke care and the covid pandemic words from our president, www.world-stroke.org/news-and-blog/news/stroke-care-and-the-covid -pandemic acute stroke management pathway during coronavirus- pandemic the baffling case of ischemic stroke disappearance from the casualty department in the covid- era underutilization of healthcare for strokes during the covid- outbreak accepted article key: cord- -mkpn tz authors: requena, manuel; olivé, marta; muchada, marian; garcía-tornel, Álvaro; deck, matías; juega, jesús; boned, sandra; rodríguez-villatoro, noelia; piñana, carlos; pagola, jorge; rodríguez-luna, david; hernández, david; rubiera, marta; tomasello, alejandro; molina, carlos a.; ribo, marc title: covid- and stroke: incidence and etiological description in a high-volume center. date: - - journal: j stroke cerebrovasc dis doi: . /j.jstrokecerebrovasdis. . sha: doc_id: cord_uid: mkpn tz background: an increased rate of thrombotic events has been associated to coronavirus disease (covid- ) with a variable rate of acute stroke. our aim is to uncover the rate of acute stroke in covid- patients and identify those cases in which a possible causative relationship could exist. methods: we performed a single-center analysis of a prospective mandatory database. we studied all patients with confirmed covid- and stroke diagnoses from march (nd) to april (th). demographic, clinical, and imaging data were prospectively collected. final diagnosis was determined after full diagnostic work-up unless impossible due to death. results: of patients with confirmed sars-cov- infection, ( . %) presented an acute ischemic stroke and ( . %) suffered an intracranial hemorrhage. after the diagnostic work-up, in . % ischemic and all hemorrhagic strokes patients an etiology non-related with covid- was identified. only in patients the stroke cause was considered possibly related to covid- , all of them required mechanical ventilation before stroke onset. ten patients underwent endovascular treatment; compared with patients who underwent evt in the same period, covid- was an independent predictor of in-hospital mortality ( % versus %; odds ratio, . ; % ci, . - . ; p . ). conclusions: the presence of acute stroke in patients with covid- was below % and most of them previously presented established stroke risk factors. without other potential cause, stroke was an uncommon complication and exclusive of patients with a severe pulmonary injury. the presence of covid- in patients who underwent evt was an independent predictor of in-hospital mortality. in covid- hospitalized patients, acute stroke has been observed in % to . % of cases with high in-hospital mortality rate ( ) ( ) ( ) . although covid- pandemic has produced an enormous collateral damage over stroke systems of care leading to a drop of mild strokes admissions and late arrival of severe strokes, only incidental cases of large vessel occlusion (lvo) in young adults infected by sars-cov- have been reported without a clear causative relationship ( ) . the presence of antiphospholipid antibodies ( ) and the endothelial cell dysfunction ( ) have been proposed as possible mechanisms that could induce a stroke in covid- patients. an increased rate of thrombotic events ( , ) , mainly venous thromboembolism and acute pulmonary embolism have been associated with covid- . the infection may cause an hypercoagulable state supported by the presence of disseminated intravascular coagulation in most deaths ( ) and the results of autopsy reports ( ) . the presence of sars-cov- infection has been associated with worse functional outcome and higher mortality among patients with acute stroke ( ) ; in parallel, history of stroke has also been associated with more severe clinical symptoms and poorer outcomes in patients with covid- ( ) . our aim is to uncover the rate of acute stroke in covid- patients admitted in a highvolume center and identify those cases in which a possible causative relationship could exist. ethics approval was obtained from hospital universitari vall d'hebron institutional review board (pr(ag) / ). no specific investigational measures were applied for the purpose of this study. written informed consent was waived due the retrospective nature of the study. the data that support the findings of this study are available from the corresponding author on reasonable request. starting march nd , all patients admitted to our institution were clinically screened for covid- and a respiratory sample was obtained depending on clinical suspicion. we performed a single-center retrospective analysis of a prospective mandatory database that includes all stroke patients diagnosed in our institution. we studied all patients with confirmed covid- and stroke diagnoses from march nd to april th . demographic, clinical, and imaging data were prospectively collected. among stroke data, national institutes of health stroke scale (nihss) score and prestroke modified rankin scale (mrs) score were assigned by the stroke neurologist on call. final diagnosis and trial of org in acute stroke treatment (toast) classification was determined after full diagnostic work-up according to eso guidelines unless impossible due to death. the diagnostic work-up included a -lead ecg on admission, parenchymal and vascular neuroimaging (computed tomography or magnetic resonance imaging), continuous ecg monitoring for at least hours and transthoracic or transesophageal echocardiogram. we defined a stroke as cryptogenic when after full work-up there was no sufficient cause. recorded imaging variables included alberta stroke program early ct score (aspects), presence of a lvo (extracranial internal carotid artery, intracranial internal carotid artery, m and m segments of middle cerebral artery, basilar artery, a segment of anterior cerebral artery, p segment of posterior cerebral artery) and presence of an intracranial hemorrhage (ich); these variables were determined by the local neuroradiologist. workflow times including onset, arrival, imaging, and groin puncture were also recorded. patients received intravenous-tpa (tissue-type plasminogen activator) and endovascular treatment when indicated independently of covid- diagnosis according to current guidelines. endovascular procedures were performed by experienced interventionalists using commercially available stent retrievers and aspiration catheters. at the end of the procedure, recanalization was assessed according to modified thrombolysis in cerebral infarction (tici) ( ) ; successful recanalization was considered if the score was b or . we explored baseline and prognostic differences between patients who underwent evt in the same period in function of sars-cov- status. sars-cov- infection was considered when confirmed by real-time reverse transcription polymerase chain reaction (rt-pcr) assay on respiratory samples obtained in the two weeks prior to stroke onset or during hospital admission. covid- symptoms, clinical signs, laboratory findings, chest imaging (radiography or ct scan) findings were collected by trained physicians. severe covid- was defined as ( ) patients requiring icu admission, ( ) acute respiratory distress syndrome criteria defined as low oxygen saturation by pulseoximetry correlated to the inspired fraction of oxygen (spo /fio ratio < ) ( ) or death due to acute respiratory failure. we obtained descriptive and frequency statistical analyses using spss v. . software. shapiro-wilk test was used to assure normality of continuous variables. categorical variables were presented as absolute values and percentages and continuous variables as median (interquartile range (iqr)) or means (± standard deviation (sd)) as indicated. statistical significance for intergroup differences was assessed by pearson χ test or fisher exact test for categorical variables and by mann-whitney u test or student t test as indicated for continuous variables. multivariable logistic regression analyses were used to determine factors that could be considered as independent predictors of good functional outcomes. the analyses were adjusted using the variables that previously were shown statistical trends or differences between groups. the or along with its % confidence interval based on logistic regression was reported. a p-value < . was considered statistically significant. from march nd to april th , patients were admitted to our center with rt-pcr confirmed sars-cov- infection; of them ( . %) presented an acute ischemic stroke and ( . %) suffered an ich. demographic and clinical data are shown in table patients' data are shown in table . severe covid- condition ( % vs. . %, p= . ), icu admission ( . % vs. . %, p= . ) and the presence of covid- symptoms before stroke ( % vs. %, p= . ) were more frequent among patients in which stroke wasn't related to a usual stroke etiology. a logistic regression model adjusting for all these variables and age showed that severe covid- condition was an independent predictor of stroke without a usual etiology (or . , % ci, . - . ; p . ). overall, in-hospital mortality rate was % ( / ): ( %) lvo patients, ( . %) non-lvo ischemic stroke patients and ( %) ich patients died. of them, deaths were directly related with stroke severity ( ich and lvo), deaths were directly related with sars-cov- infection and presented possible causes (basilar artery occlusion successfully treated and severe hypoxemia). among patients with ischemic stroke, ( . %) received iv-tpa without any hemorrhagic transformation and ( . %) underwent evt with a median time from last seen well to groin puncture of . (iqr . - . ) minutes. among patients who underwent evt, presented intracranial lvo and two underwent acute extracranial stenting due to chronic carotid occlusion without intracranial lvo that became symptomatic in the context of severe hypoxemia. the median door-to-groin time was minutes (iqr - ) and in of the patients ( . %) with intracranial occlusion a successful recanalization was achieved. we did not find differences in baseline characteristics with patients who underwent evt during the same period in our center (table ) except a higher rate of unknown onset stroke and a longer last-time-seen-well to groin time among patients without covid- . in patients who underwent evt during the study period, covid- was an independent predictor of in-hospital mortality ( % versus %; odds ratio, . ; % ci, . - . ; p . ) and presented a trend to a higher median of nihss score at hours ( (iqr - ) vs. ( - ); p= . ). our study shows that the frequency of acute stroke in patients with covid- requiring hospital admission is low ( %) and in most cases a usual cause of stroke was identified. moreover, all patients with an acute stroke without a usual etiology presented a severe infection requiring mechanical ventilation. severe respiratory disease has been previously linked to neurological symptoms and in particular to stroke ( ) . neurological disorders were also described in patients affected by other coronavirus as middle east respiratory syndrome or sars-cov ( ) . cerebral ischemia associated with severe infections is not new to covid- ; the association of sepsis with intravascular coagulopathy and platelet activation is well known and has been described as a potential cause of stroke ( ) . recent bacterial and viral infections have been repeatedly reported as a risk factor for ischemic stroke ( ) ( ) ( ) ( ) . on the other hand, influenza vaccination, by reducing the infection rate, has been associated with a reduction in risk of stroke and myocardial infarction ( , ) . in all cases, stroke is an uncommon complication of the infectious disease and according to our observations sars-cov seems to follow the same pattern. therefore, among covid- patients, and mainly in the absence of severe symptoms, the stroke cause should not be directly attributed to sars-cov- , and an exhaustive diagnostic work-up must be completed. in the majority of patients in which stroke etiology was possibly related to sars-cov- infection elevated d-dimer and ferritin levels were found. high levels of d-dimer and inflammatory markers have been previously related to covid- severity( ). these laboratory findings, together with the fact that patients presented pres and deep vein thrombosis, suggest an inflammatory and coagulopathy state possibly associated to the ischemic brain injury ( ) . the infrequent but possible causal relation of sars-cov- and ischemic stroke observed in our study could not be confirmed for ich. during the study period we did not observe an increase in ich admissions and in all cases a usual ich cause was identified. moreover none of the patients receiving reperfusion therapies experienced a symptomatic hemorrhagic transformation, suggesting that covid- patients should not be excluded from these treatments for safety reasons. it is not possible to determine if covid- could act as a trigger in those patients with an identified usual stroke cause. severe covid- was less frequent among these stroke patients ( . %), this rate is not higher than in previously published series of covid patients admitted to a hospital ( , ) . in two of our cases, hypoxemia was considered the triggering stroke factor in patients with chronic extracranial carotid occlusion. therefore covid- patients with pre-existing vascular risk factors should undergo regular neurological exams. in conclusion, less than % of covid- patients admitted to our hospital presented an associated stroke. in most cases a usual stroke cause was identified. in patients without any other potential cause, stroke was an uncommon complication only seen in patients with a severe pulmonary injury. in stroke patients with lvo, the presence of covid- was a strong predictor of in-hospital mortality. marc ribó receives payment from philips as co-principal investigator of the we trust study and he has a consulting agreement with medtronic, stryker, cerenovus, cvaid, methinks, anaconda biomed and apta targets. the others authors reports no conflict. venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in milan, italy. thrombosis research sars-cov- and stroke in a new york healthcare system acute cerebrovascular events in hospitalized covid- patients large-vessel stroke as a presenting feature of covid- in the young. the new england journal of medicine antiphospholipid antibodies in patients with covid- cerebrovascular disease in patients with covid- : neuroimaging, histological and clinical description. brain : a journal of neurology pulmonary embolism in covid- patients: awareness of an increased prevalence. circulation acute pulmonary embolism associated with covid- pneumonia detected by pulmonary ct angiography abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia american journal of clinical pathology treatment of acute ischemic stroke due to large vessel occlusion with covid- clinical characteristics and outcomes of covid- patients with a history of stroke in wuhan recommendations on angiographic revascularization grading standards for acute ischemic stroke: a consensus statement posterior reversible encephalopathy syndrome: associated clinical and radiologic findings neurologic manifestations of hospitalized patients with coronavirus disease large artery ischaemic stroke in severe acute respiratory syndrome (sars) preceding infection as an important risk factor for ischaemic brain infarction in young and middle aged patients. british medical journal recent infection as a risk factor for cerebrovascular ischemia recent bacterial and viral infection is a risk factor for cerebrovascular ischemia: clinical and biochemical studies acute infection as a risk factor for ischemic stroke risk of myocardial infarction and stroke after acute infection or vaccination. the new england journal of medicine influenza vaccination is associated with a reduced risk of stroke risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease jama internal medicine the immunology of stroke: from mechanisms to translation nature medicine clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study the new england journal of medicine key: cord- -f sgobcz authors: metsker, oleg; igor, vozniuk; kopanitsa, georgy; morozova, elena; maria, prohorova title: stroke icu patient mortality day prediction date: - - journal: computational science - iccs doi: . / - - - - _ sha: doc_id: cord_uid: f sgobcz this article presents a study on development of methods for analysis of data reflecting the process of treatment of stroke inpatients to predict clinical outcomes at the emergency care unit. the aim of this work is to develop models for the creation of validated risk scales for early intravenous stroke with minimum number of parameters with maximum prognostic accuracy and possibility to calculate the time of “expected intravenous stroke mortality”. the study of experience in the development and use of medical information systems allows us to state the insufficient ability of existing models for adequate data analysis, weak formalization and lack of system approach in the collection of diagnostic data, insufficient personalization of diagnostic data on the factors determining early intravenous stroke mortality. in our study we divided patients into subgroups according to the time of death - up to day, to days, and to days. early mortality in each subgroup was associated with a number of demographic, clinical, and instrumental-laboratory characteristics based on the interpretation of the results of calculating the significance of predictors of binary classification models by machine learning methods from the scikit-learn library. the target classes in training were “mortality rate of day”, “mortality rate of – days”, “mortality rate from days”. auc roc of trained models reached % for the method of random forest. the results of interpretation of decision trees and calculation of significance of predictors of built-in methods of random forest coincide that can prove to correctness of calculations. stroke is the second most deadly cause of death worldwide. in russia, brain stroke is the second leading cause of death after myocardial infarction. every year around people suffer from stroke, in fact it is the population of a big city [ ] . the mortality rate in russia is times higher than in the usa and canada [ ] . among european countries, the mortality rate from cerebrovascular diseases is the highest in russia. according to the all-russian center for preventive medicine, in our country % of men and % of women die from cerebrovascular diseases. in the largest cities of the country the situation with this type of pathology is extremely unfavorable. in st. petersburg, for example, the frequency of stroke is about cases per , residents, while the mortality rate for ischemic stroke is %. it is necessary to emphasize the catastrophic consequences of ischemic stroke -up to - % of patients die or remain disabled and only - % of patients fully recover [ ] . according to the findings of a large-scale study of recent years, some modern epidemiological trends have been identified [ ] : in general, global statistics show a decline in stroke mortality over the past two decades due to the introduction of new treatments (thrombolysis, thrombectrosis), but the absolute number of people who have stroke is only increasing every year [ ] . this nosology is still the strong second leading cause of death from cardiovascular disease (cvd), remaining the undisputed leader among all nosologies leading to severe disability. hospital mortality remains one the most important quality indicator, which can be used to identify problems associated with the optimization of prehospital and hospital treatment process. it can be used to assess the effectiveness of primary and secondary care, routing, and the degree of implementation of modern diagnostic and treatment algorithms, including the quality of interaction between different levels of care [ ] . it is important to note that regional characteristics of the populations may significantly differ from the global ones, and the development of specialized care programs for patients with a stroke has its national and institutional characteristics. understanding the factors that contribute to the reduction of hospital mortality will allow us to develop a targeted strategy for the development of services providing care to patients with a stroke in russia and in the world. thus, development of personalized models and algorithms for planning of individual treatment tactics for the stroke patients can reduce mortality and increase the standard of life. the development of such models and algorithms will ensure better continuity and efficiency of medical care and help reducing the number of complications. the basis for such models can be the scales of calculation of patients' mortality risks in emergency units, which are also absent in russia at present. most statistics are accumulated in national stroke registries or national databases: china national stroke registry ii (cnsr ii) [ ] , the nationwide hospital discharge database (nhdd), berlin stroke register (bsr), german stroke register, the registry of the canadian stroke network (rcsn), national acute stroke israeli (nasis) registry, fleni stroke data bank, australian stroke clinical registry (auscr), national stroke register of ireland, the austrian stroke registy. the analysis of available literature revealed rather heterogeneous values of the share of hospital mortality of patients with stroke in different countries. at the same time, direct indicators of the share of hospital mortality had significant differences from , % in china [ ] to , % in ethiopia [ ] . significant differences in data can be explained both by the quality of care and by the nature of statistical data collection. in particular, most of the reports took into account only the ischemic type of stroke [ ] [ ] [ ] [ ] [ ] [ ] , different exclusion criteria were applied in a number of observations -daily mortality and stay exceeding days [ ] , inhospital stroke [ ] , patients in need of admission to the general intensive care unit [ ] or a general department. it should also be noted that samples are heterogeneous in terms of the number of patients: from [ ] to million patients [ ] . hospital mortality rates vary considerably between facilities within the same country. for example, the average hospital mortality rate in germany in was . % when stroke units were evaluated. [ ] , at the same time as in the german study of on this parameter was . % [ ] . in australia, hospital mortality also varies significantly (from % to %) depending on the level of the hospital. [ ] , in germany, there is a dependence on the size of the hospital -from % to % in small hospitals and from . % to . % in large hospitals. [ ] . only studies out of provide data that allow tracking the dynamics of changes in the indicator of intra-hospital mortality. the average rate of decline in this indicator was . % per year. rapid changes in this parameter are more typical of the ischemic type of stroke, and mainly the faster rate of decline was associated with the introduction and expansion of the vascular center network for stroke (with mandatory stroke unit). the most significant example of canada -where vascular center system was introduced, which led to the rate of change in the provinces was . % per year, while in the provinces without the introduction of the vascular center system, the rate changed only by . % per year [ ] . the availability of prognostic models and scales that are understandable to clinical staff and easy to operate, reduces hospital mortality and allows for a more targeted and individualized approach to therapy. such models should take into account locally established practices. models should be available that can predict a fatal scenario for the disease, considering all relevant factors. to date, the international medical community has made repeated attempts to create such a prognostic scale. in the review, c. counsell and m. dennis analyzed models with a total of prognostic factors, and the assessment resulted in only models meeting quality criteria [ ] . the databases have a huge number of parameters including various tests and indicators. in some cases, the use of a large number of features leads to lower rates of learning and forecasting, reduces the predictive accuracy of the model, and prevents the model from being interpreted, which is an important requirement for models used in medicine. thus, finding the best set of features in the context of our task is one of the key factors ensuring high quality of the predictive model. on the basis of the analysis of modern prognostic models from countries we can identify some of the most stable (main) predictors for the causes of intra-hospital mortality: age [ , [ ] [ ] [ ] [ ] [ ] ; type of stroke [ ] ; lesion location [ ] ; level of consciousness [ , , , , ] upon admission; nihss stroke severity [ , , , ] ; comorbidity [ , ] , charlson comorbidity index [ ] , atrial fibrillation [ , ] , case history transitor ischemic attack (tia) [ ]; hospital complications (high intracranial pressure) [ ] , pneumonia, seizures, anxiety/depression, infections, limb pains and constipation [ , ] . among the predictors related to the organization of care, the time of admission to hospital can be noted -in a japanese study, the -day mortality rate increased if the patient was admitted on weekends or holidays. [ ] , hospital delivery method had a predictive value as well [ ] , both these parameters are included in the gwtg-stroke program [ ] . in order to identify priority areas for improving the outcome of the disease it is necessary to divide the selected factors (predictors) into modifiable and unmodifiable, respectively. modifiable mortality predictors can be referred to: time and method of hospital delivery; qualifications of medical personnel; stroke care model; history of stroke or tia, atrial fibrillation, diabetes mellitus, comorbidity indexparameters to which primary prevention should be directed; intra-hospital complications (high intracranial pressure pneumonia, seizures, anxiety/ depression, infection, extremity pain and constipation). a special form of complications in the form of extracerebral pathology -polyorgan failure syndrome -is distinguished separately. special attention should be paid to the prevention of this syndrome. the unmodifiable factors of stroke mortality include: gender, age, type of stroke, localization of lesion. as for the assessment of the impact of comorbid diseases, it is important to consider not only the presence of individual pathologies, but also their combination. in particular, the following groups can be distinguished: arterial hypertension + atrial fibrillation, arterial hypertension + atrial fibrillation + coronary heart disease, atrial fibrillation + postinfarction cardiosclerosis, and, arterial hypertension + postinfarction cardiosclerosis + atrial fibrillation ma и + diabetes mellitus. only two studies presented clear prognostic scales containing a scoring system for rapid assessment of the risk (probability) of in hospital mortality [ , ] . the premise scale is simple, quick to calculate at > % of strokes and uses only variables that are available shortly after the onset of ischemic stroke when admitted to the stroke unit. it should be noted that the practical application of any analyzed scale above in different countries requires corrections to take into account regional peculiarities -social, geographical and medical and economic factors [ ] . the creation of such scales and models in russia would provide a tool to assess the efficiency of care. the goal of this work is to identify features for the creation of validated risk scales for early hospital mortality. the study includes data about episodes ( outpatient -inpatient patients -lethal patients patients who has international criteria for diagnosis icd i to i . ) and were treated in the almazov national research center from to . among the causes of admission: ischemic stroke, hemorrhagic stroke, embolic stroke, transitor attacks. as the initial data describing the condition the patient's examination data at the intake and use of clinical scales (nihss, mrs), conclusion of magnetic resonance imaging (mri), conclusion of ultrasound investigation, data from laboratory tests, data on treatment events from the medical information system. a separate more detailed analysis of the group of only deceased patients from people was carried out to identify differences and mortality factors in different time periods ( day, - days, - days) on the basis of data from the the saint petersburg research institute of emergency medicine n.a. i.i. dzhanelidze . the data of the medical information system of the operating specialized center of mri, ultrasound and other characteristics of the volume of cerebral and vascular stroke examination were compared with the data on the duration and outcomes and time of http://www.emergency.spb.ru/. death. information about hospital mortality was included in the study, if they met the following criteria: the fact of clinically confirmed diagnosis of acute cerebral circulation disorder (ischemic or hemorrhagic), with the presence of focal, general cerebral neurological syndromes, which lasted more than h from the beginning of the disease; hospitalization in connection with stroke in the first day of the disease; the entire period of hospitalization in connection with acute case of the patient spent in one institution; lethal outcome was associated with an acute period of stroke. information confirming lesions of the brain substance has been obtained from data from the ct scan and/or mri of the brain, which have been repeated if necessary. the extent of precerebral and cerebral artery lesions was assessed using ultrasound duplex scanning, ct scan, mri or cerebral angiography. to obtain the optimal set of features a combination of classical methods based on different correlation coefficients of features (pearson correlation coefficient and spearman correlation coefficient) were used. ensemble algorithms, including ensembles built on the basis of models with the use of decision trees, and random forest are used as prognostic models. a scikit-learn library was used to implement machine learning methods. in the process of definition of hyperparameters of machine learning models, cross-validation by k blocks was applied. precision and recall (accuracy and completeness), as well as their harmonic mean (f-score) were used as metrics at this stage. construction of the confusion matrix of multiclass classification allowed to analyze errors, improve data sampling used for model training and initialize the next iteration of model training. the data on treatment of real patients from the almazov center were used for validation of the final resulting models. the data of patients who did not participate in any stages of model training and adjustment of hyper-parameters were used. auc roc -the area under the error curve -was used as the result metrics. p-value was calculated using two methods. the essence of the first method is that for each sample of dead (< day, - days, - days) we have calculated p-value for every feature of the corresponding test. chi-square criterion was used for categorical features, kolmogorov-smirnov's test was used for continuous features. the essence of the second method of calculating p-value by one attribute (mortality period) for three groups of patients according to the severity and type of stroke (group : ich+pvh, is +ich; group : is+bilat atr, is-foc - hu; group : is- / < hu, sub tent icv). the analysis obtained a general model of mortality for all patients with stroke auc roc- % demonstrated random forest learned on the dataset with more than laboratory and personal patient observation features. three separate models have also been developed for patients with different lethality periods (up to day, from to days, and from to days) using decision trees that showed an auc roc of to %. for these models, the dataset consisted of more than specialized features, including a score on neurologic scales, brain examination data, assessment of the patient's consciousness and somatic state. the importance of features for different duration of lethality was also compared. moreover, a clinical interpretation of the comparison results is given below. the models were trained on the dataset describing patients who were treated as a binary classification models by machine learning methods from the scikit-learn library. the following parameters were used as features: patients age, male, pressure, area of brain damage, the size of the hematoma. moreover, the following laboratory tests were used as features: mchc-red blood cell index, endothelin, interleukin- , interleukin- , interleukin- , interleukin- , interleukin- -beta, inr, fibrogen, vitamin d, paratohormone, urine nitrites, urine bilirubin, urine, bld urine, leu urine, urine nit, urine ket, urine glucose, urine pro, urine ph, urine color, d-dimmer, albumin, lipids, triglyceride, total cholesterol, prothrombin index, fibrinogen by klaus, k+ (vienna), neutrophils, monocytes, lymphocytes, mpv average, platelet volume, pdw width of platelet distribution by volume, rdw width of red blood cell distribution by volume, mchc the average concentration of hemoglobin in eritr, mch is the average hemoglobin content in erythrocyte average volume of red blood cells, reactive protein, erythrocyte sedimentation rate, troponin, alt, ast, hgb hemoglobin, wbc white blood cells, rbc red blood cells, plt platelets, creatinine, bilirubin, hct hematocrit, glucose level. random forest demonstrated the best auc roc- %. the nine most importantly lethality features of the stroke patient further: systolic pressure ( . ), rbc red blood cells ( . ), interleukin- ( . ), hct hematocrit ( . ), diastolic pressure ( . ), age ( . ), mchc -red blood cell index( . ), ventricular damage( . ), hematoma volume ( . ). the following conclusions emerge from the general analysis of the overall data: . terms of mortality. all cases of death of patients, which were distributed within days, were estimated, with the greatest number of lethal outcomes occurring within days. . patients age to years (at least % out of dead) were most frequently encountered in the group of the deceased, the maximum frequency ( %) falls on the age of to years, in the same age group there is the maximum morbidity of stroke with their share is almost % of the number of diseased. . among the deceased, men prevailed (by more than %). . the proportion of deaths in the hemorrhagic stroke cohort was twice as high compared with the proportion of deaths in ischemic stroke patients. from the general analysis, several interlinked signs are evident indicating the likelihood of lethal outcomes in patients with cerebrovascular disease at an early stage: hemorrhagic type of stroke is most likely to be lethal in patients with acute cerebrovascular disease; stroke incidence and mortality are highest in patients aged to years; stroke with lethal outcomes are more likely in men; regardless of the type of stroke, lethal outcomes are most likely in patients aged to years. all patients were divided into subgroups according to the time of death -up to day, to days, and to days. early mortality in each subgroup was associated with a number of demographic, clinical, and instrumental-laboratory characteristics based on the interpretation of the results of calculating the significance of predictors of binary classification models by machine learning methods from the scikit-learn library . the target classes in training were "mortality rate of day", "mortality rate of - days", "mortality rate from days". auc roc of trained models reached % for the method of random forest. the results of interpretation of decision trees and calculation of significance of predictors of built-in methods of random forest coincide that can testify to correctness of calculations. as a result of the decision trees, the following conclusions were drawn regarding the time frame of death: . factors that cause patients to be lethal on the first day: patient's age over years; male sex; significant volume of brain lesions (more than / of the middle cerebral artery pool) hemispheric ischemic (or hemorrhagic with impregnation of the ischemic focus) stroke or patients with intracerebral hematoma (both less than ml and to ml) with a breakthrough into the ventricular system of the brain; more important was the combination of ischemic or hemorrhagic lesions with displacement of the medial structures due to perifocal edema; right hemispheric cerebral lesion; severe condition at entry (with severe neurological deficit, up to nihss points); unstable systemic hemodynamics, expressed by fluctuations in blood pressure, appearance of tachycardia and tachyarrhythmia, i.e., in the ventricular system.h. with sharp rise (> mm hg) or sharp decrease (< mm hg).) systolic and diastolic blood pressure and heart rhythm disorders (tachycardia and tachyarrhythmia); manifestations of decompensated hypersympathicotonia accompanied by hyperthermia and polyuria (densephalic syndrome, irritation of the densephalic region of the brain) and hemoconcentration (hypercoagulation); high degree of comorbidity (presence of significant number of concomitant diseases at the decompensation stage, comorbidity index > . ). . mortality in the group from to days is caused by the following factors: age over years old; male gender; consciousness impairment not lower than stun; presence of extensive hemispheric ischemic (more than / of the middle cerebral artery basin) or large intracerebral hematoma against the background of pronounced brain atrophy, in some cases with hemorrhagic saturation of the ischemic focus; the greatest importance was given to the combination of ischemic or hemorrhagic lesions with displacement of the medial structures due to perifocal edema; lesion of the right hemisphere; instability of system hemodynamics -with indicators of sharp decrease (< mm hg.st.) of systolic blood pressure, heart rate -with indicators of sharp decrease.st.) systolic blood pressure, heart rhythm disorders (bradiarrhythmia and tachycardia); or with a high degree of comorbidity (presence of a significant number of concomitant diseases at the decompensation stage, comorbidity index > . ); vivid manifestations of vegetative regulation decompensation (hypersympathicotonia), accompanied by hyperthermia and polyuria (diencephal syndrome, irritation of the diencephalic region of the brain) and hemoconcentration (hypercoagulation); phenomena of systemic inflammatory reaction and presence of signs of hemoconcentration in blood tests; . the largest contribution to the patients' mortality from to days was made by the following factors: age from to years (the largest group of patients aged - years); female gender; extensive hemispheric ischemic (more than / of the pool of the middle cerebral artery) in combination with severe hemispheric atrophy, or the presence of intracerebral hematoma (much more often less than ml), a breakthrough into the ventricles of the brain, the most important was the presence of dislocation, a combination of ischemic or hemorrhagic lesions with the displacement of medial structures due to general edema; conscious disturbance (stun, coma) or condition that required sedation (to provide prosthetics for breathing function); unstable systemic hemodynamics -with sharp rise (> mm hg) or (< mm hg) of systolic blood pressure; phenomena of moderate hemoconcentration and moderate systemic inflammatory response in blood tests; high degree of comorbidity (presence of a significant number of concomitant diseases at the decompensation stage, comorbidity index > ). at the same time, it should be noted that in contrast to patients with - day mortality, in this case the side of the brain lesion did not matter. three groups of patients were compared by the terms of mortality (mortality in the first day, mortality from to , lethality from to days) among themselves by means of standard t-test (non-parametric criterion chi) with thirty one parameter. the value p < . was considered significant. the results of the interpretation of the obtained test are presented in tables , and . the following calculation results have been obtained p-value using method : for the groups and p-value = . ; for the groups and p-value = . ; from the groups and p-value = . on the basis of the analysis calculations it is possible to draw a conclusion about a significant difference between the st and the rd group, where group : ich (intracerebral hemorrhage) +pvh (periventricular hyperintensity), is (ischemic stroke) +ich (intracranial hemorrhage); group : is+bilat atr, is-foc - hu; group : is- / < hu, sub tent icv (intracerebroventricular). feature < day p - days p - days p interpretation gender , , , gender showed the significance of differences between all subgroups, with the groups with mortality of - days dominated by women, and between the subgroups of mortality up to day and mortality of - days, with a general prevalence of incidence of men among deceased patients, the frequency of occurrence in the subgroups also significantly differed period of admission less than . the difference between subgroups of up to day and - days is insignificant, i.e. the fact of later hospitalization did not affect earlier mortality. the differences in subgroups - and - are significant, for lighter patients (with lower comorbidity index or with severe atrophy) the difference between the subgroups of up to day and - days is insignificant, i.e. the fact of edema affected earlier mortality. the differences in subgroups - and - are significant due to the fact that edema developed later as a factor affecting mortality or did not determine the mortality (e.g. in patients with severe atrophy, small foci) dislocation , , , the difference between the subgroups of up to day and - days is insignificant, i.e. the fact of edema influenced earlier mortality. the differences in subgroups - and - are significant due to the fact that the brain substance dislocation developed later as a factor influencing mortality or also did not determine the mortality (e.g. in patients with severe atrophy, small focus, cortical-subcortical focus, without affecting the central structures of the brain) (continued) the difference between subgroups of up to day and - days is insignificant, i.e. in each case the fact of hemorrhagic impregnation of the zone of brain matter ischemia affected mortality. in subgroups of - days and - days this difference is significant due to availability of reserve spaces due to brain atrophy and less probability of dislocation of brain substance amount of ischemia > / of the middle cerebral artery (mca) , , , the difference between subgroups of up to day and - days is insignificant, i.e. in each case the fact of extensive ischemic lesion had an impact on mortality in earlier periods. in subgroups of - days and - days this difference is significant due to availability of reserve spaces in connection with brain atrophy and less probability of threatening dislocation (constriction) of brain substance even in presence of a large focal point of ischemia and consequently edema and tissue swelling expressed atrophic changes in brain matter , , , the difference between subgroups of up to day and - days is insignificant, in the subgroups of - days and - days this difference is significant as the availability of reserve spaces due to brain atrophy reduces the probability of dislocation of brain matter even in the presence of a large focal point of ischemia or hemorrhage (large hematoma) a detailed study of electronic medical records data and combinations of clinical and laboratory characteristics of patients made it possible to reveal dependencies and develop descriptive models between the degree of lesion and the time of intra-hospital lethality of patients. further, based on a large array of correlated data, models were developed to identify major favorable and unfavorable patterns of early mortality of patients for control and correction of the treatment plan. decision-making models for predicting the outcome and duration of treatment of stroke patients have been developed using systems analysis, statistical analysis, mathematical modeling and machine learning methods. as a result, clinical and morphological predictors of early hospital stroke mortality have been identified. similar models can also be used to validate existing scales, to study the causes of mortality at the emergency stages and to develop clinical guidelines, including for the prevention, diagnosis and treatment of stroke. as a result of this study, descriptive and prognostic models of mortality in stroke patients have been developed. the significance of predictors was ranked using statistical and machine learning methods. clinical interpretation of the obtained results was made in the form of clear conclusions that can be used in the organization of continuity care for acute stroke patients, as well as the calculation of personal risks. provided that all standards of specialized medical care for patients with stroke are complied with, first of all, monitoring and intra-hospital logistics, completeness of the diagnostic scope, it is possible to make a prognostic assessment to identify predictors of early hospital lethality. a number of clinical, pathomorphological and instrumental parameters may indicate a high probability of early lethality, namely: charlson comorbidity index with a value greater than . ; six subtypes of stroke; for subtypes, combination with an extended intracellular cma clot, with an age greater than years and ind. ch- . b. for and subtypes the severity of lesion volume and presence of dislocation complications determine the high risk of mortality. for subtypes the greatest risk is associated with the combination of an acute focus in the deep parts of the temporal lobe with moderate perifocal ischemic oedema, compression of medial structures, with the age over years old and high and ind. ch- . b. for subtype , a significant contribution is made by global (diffuse atrophy or the presence of a fresh acute focus in the deep regions of the temporal lobe on the side of the opposite marked atrophy (including post-stroke). global, regional, and national burden of stroke, - : a systematic analysis for the global burden of disease study human mortality database global burden of stroke and risk factors in countries, during - : a systematic analysis for the global burden of disease study global and regional burden of stroke during - : findings from the global burden of disease study impact of microalbuminuria on incident stroke: a meta-analysis the china national stroke registry for patients with acute cerebrovascular events: design, rationale, and baseline patient characteristics gwtg risk model for all stroke types predicts in-hospital and -month mortality in chinese patients with acute stroke burden, clinical outcomes and predictors of time to in hospital mortality among adult patients admitted to stroke unit of jimma university medical center: a prospective cohort study analysis on geographic variations in hospital deaths and endovascular therapy in ischaemic stroke patients: an observational cross-sectional study in china in-hospital mortality among ischemic stroke patients in gondar university hospital: a retrospective cohort study predictors of in-hospital mortality and attributable risks of death after ischemic stroke the german stroke registers study group factors influencing in-hospital mortality and morbidity in patients treated on a stroke unit explaining the decrease of in-hospital mortality from ischemic stroke risk score for in-hospital ischemic stroke mortality derived and validated within the get with the guidelines-stroke program risk-adjusted hospital mortality rates for stroke: evidence from the australian stroke clinical registry (auscr) the quality of acute stroke units on a nation-wide level: the austrian stroke registry for acute stroke units recent trends in inpatient mortality and resource utilization for patients with stroke in the united states impact of atrial fibrillation on in-hospital mortality of ischemic stroke patients and identification of promoting factors of atrial thrombi-results from the german integrated systems of stroke care and reduction in -day mortality: a retrospective analysis predicting outcome after acute and subacute stroke: development and validation of new prognostic models predicting early mortality of acute ischemic stroke: score-based approach prediction of in-hospital stroke mortality in critical care unit derivation and validation of in-hospital mortality prediction models in ischaemic stroke patients using administrative data age and national institutes of health stroke scale score within hours after onset are accurate predictors of outcome after cerebral ischemia: development and external validation of prognostic models prediction of in-hospital mortality after first-ever stroke: the lausanne stroke registry a prognostic index for -day mortality after stroke trends in management and outcome of hospitalized patients with acute stroke and transient ischemic attack: the national acute stroke israeli (nasis) registry acknowledgements. this work was financially supported by the government of the russian federation through the itmo fellowship and professorship program. this work is financially supported by national center for cognitive research of itmo university. key: cord- - pfqm authors: szelenberger, rafal; saluk-bijak, joanna; bijak, michal title: ischemic stroke among the symptoms caused by the covid- infection date: - - journal: j clin med doi: . /jcm sha: doc_id: cord_uid: pfqm the global pandemic of coronavirus disease (covid- ) caused by the severe acute respiratory syndrome coronavirus (sars-cov- ) has been declared a public health emergency of international concern by the world health organization (who). the who recognized the spread of covid- as a pandemic on march . based on statistics from august , more than . million cases of covid- have been reported resulting in more than , deaths. this completely new coronavirus has spread worldwide in a short period, causing economic crises and healthcare system failures worldwide. initially, it was thought that the main health threat was associated with respiratory system failures, but since then, sars-cov- has been linked to a broad spectrum of symptoms indicating neurological manifestations, including ischemic stroke. current knowledge about sars-cov- and its complications is very limited because of its rapidly evolving character. however, further research is undoubtedly necessary to understand the causes of neurological abnormalities, including acute cerebrovascular disease. the viral infection is inextricably associated with the activation of the immune system and the release of pro-inflammatory factors, that can stimulate the host organism to defend itself. however, the body’s immune response is a double-edged sword that on one hand, destroys the virus but also disrupts the homeostasis leading to serious complications, including thrombosis. numerous studies have linked coagulopathies with covid- , however, there is great uncertainty regarding it functions on the molecular level. in this review, a detailed insight into the biological processes associated with ischemic stroke in covid- patients and suggest a possible explanation for this phenomenon is provided. coronavirus disease (covid- ) is a new infectious disease caused by the newly identified severe acute respiratory syndrome coronavirus (sars-cov- ), which was classified by the world health organization (who) as a pandemic on march . belonging to the orthocoronavirinae subfamily in the coronaviridae family, sars-cov- is the seventh member of all coronaviruses with the ability to infect humans [ ] . as regards its origin, there are few theories, the most probable one being that sars-cov- has a natural, zoonotic origin. it is closely related to bat coronaviruses, pangolin coronaviruses and sars-cov. the first diagnostic reports of an unusual respiratory disease appeared in december in the city of wuhan (hubei province), china and were linked to a cluster of wet markets processing bat meat and their guano [ ] . however, new reports from china suggest that a -year-old person from hubei may have been the first person infected on november . isolation and genome sequencing of the new virus led to the discovery of a new pathogen that primarily caused "pneumonia of an unknown etiology" [ ] . however, current knowledge about this virus is very limited and is mostly derived from previous coronaviruses. longitudinal serological and immunological studies are necessary to assess the efficiency of an immune response to sars-cov- [ ] . initially, sars-cov- was thought to cause fever, dyspnea, cough and fatigue via infection of the host's respiratory system [ ] . however, the ongoing scientific effort in order to profiling of covid- patients revealed that patients exhibit a broader range of atypical symptoms affecting the severity and disease progression, including headache, nasal congestion, diarrhea, loss of taste or smell, rash and conjunctivitis [ ] . furthermore, there is the onset of a wide range of symptoms, the presence of comorbidities and response to existing therapies failure, which may result in mild pneumonia that quickly develops into the acute respiratory syndrome sepsis, and even to multi-organ dysfunction within a short period of time [ ] . the vast majority of sars-cov- infections are asymptomatic at the time of testing. however, most of infected people developed symptoms later, which enhance the virus transmission. furthermore, the presence of flu-like symptoms with a prolonged viral incubation period may result in wrong diagnosis or the disease not being detected at all. not isolated and infected individuals are a vector for the rapid spread and advanced migration of sars-cov- . an estimation of the basic reproduction number (r ) for covid- in january showed that it may be about . (with a % confidence interval of . to . ). the low mortality threshold facilitates a host-to-host transfer, increasing the number of cases exponentially [ ] . according to the august who data, more than . million cases of covid- have been reported resulting in more than , deaths. this number will continue to grow unless an effective treatment or vaccine is developed. the appearing threat associated with covid- pandemic is related to the virus ability to induce microvascular, venous and arterial thrombosis, thus exacerbating the functionality of organs. many clinical studies have shown an association between sars-cov- infection and hypercoagulability diagnosed on the basis of abnormal coagulation parameters, including activated partial thromboplastin time, prothrombin time, fibrinogen, d-dimer and c-reactive protein level. furthermore, studies showed that ischemic events, including venous thromboembolism, were present in - % of patients with severe viral infection. statistics proved that patients with thrombotic complications have -fold augmented mortality. what is more, autopsy series on covid- non-survivors found not only macrovascular complications, but also microvascular thrombosis. small thrombi were found in over % samples of pulmonary vasculature. several groups reported also augmented rates of ischemic stroke in covid- patients admitted to hospital [ ] . all those evidence indicate that sars-cov- may contribute to a number of vascular disorders, indicating the necessity for detailed patients diagnoses in order to avoid further complications that significantly reduce life quality. in this review, the potential mechanism and the effect of the sars-cov- viral infection on the development of ischemic stroke in covid- patients were carefully studied. thrombosis is a pathological process associated with the blood clots formation in circulatory system. thrombosis may occur within the venous and arterial system and contribute to various medical complications, including stroke, myocardial infarction or pulmonary embolism [ ] . as mentioned above, many studies confirm the presence of thrombosis in patients diagnosed with covid- . although studies do not implicate sars-cov- to have procoagulant effect itself, scientists more likely assess covid- coagulopathy with profound inflammatory response [ ] . spreading the viral infection can contribute to the formation of many inflammatory foci in the human body in various places. the proliferation of the virus in the lungs causes diffuse interstitial and alveolar inflammatory exudation, which leads to edema and gas exchange disorders, resulting in hypoxia in the central nervous system (cns). thus increasing oxygen-free metabolism in the brain cells mitochondria [ , ] . what is more, rapidly progressing inflammation, activation of the coagulation system and an imbalance between pro-and anti-coagulant properties may lead to the formation of disseminated intravascular coagulation (dic) syndrome. moreover, a systematic disorder characterized by a widespread activation of the hemostatic system leading to excessive blood clot formation in small vessels with simultaneous, massive consumption of blood platelets and coagulation factors, resulting in hemorrhagic complications are observed [ , ] . the presence of dic was confirmed by the tang et al. study, in which most non-survivor covid- patients' ( . %) blood tests showed prolonged prothrombin time and an increased d-dimer levels, which indicated the state after activation of the plasma coagulation system [ ] . data from many studies showed a significant decrease in the platelet count, increased fibrinogen and d-dimer levels and prolonged prothrombin time, which was associated with severe covid- infections. thus indicating excessive activity of the coagulation system and the risk of dic development [ , [ ] [ ] [ ] . ranucci et al. besides the augmented level of fibrinogen and d-dimer levels, also presented a significant increase of il and antithrombin levels, prolonged coagulation indicator-activated partial thromboplastin time (aptt) and elevated parameters of blood viscoelasticity [ ] . coagulation changes were also proven by magro et al. in lung histopathological analysis and skin biopsies, which showed generalized microvascular thrombotic disorder [ ] . furthermore, in a study conducted by carsana et al. a pulmonary autopsy showed that small arterial vessel fibrin thrombus was observed in . % of examined, non-survived patients [ ] . stroke is a medical condition caused by a deficit of blood flow in the brain causing neurological dysfunctions [ ] . global epidemiologic reports ranked stroke as the second death cause globally, with a mortality rate of approximately . million per year. stroke survivors are at high risk of chronic disability leading to loss of their independence, work capacity, employment and material resources [ ] . a sudden loss of neurological function is caused by infarction or cerebral vessels hemorrhage, the spinal cord or retina. clinically, patients mostly experienced unilateral weakness, ataxia, altered speech, numbness and/or visual loss. however, atypical symptoms like amnesia, dysphagia, dysarthria, anosognosia, headache and confusion may occur simultaneously [ ] . the term "stroke" is not commonly used in clinical practice, because of its various etiology. the most common and generally diagnosed subtype of stroke is ischemic stroke, which constitutes % of all diagnosed cases. this subtype of stroke is caused by a partial or complete blockage of blood flow in the brain, which results in cerebral ischemia. a reduction in blood circulation to ml/ g of the brain tissue per minute may cause irreversible tissue damage within one hour. moreover, full occlusion and the absence of blood flow leads to the death of brain cells within to minutes [ ] . most commonly, ischemia is caused by local vessel injury as an effect of atherosclerosis. the formation of plaque in the vessel lumen begins with damaged endothelium, ongoing inflammation and activation of the coagulation system. along with the increased severity of pathological processes, plaque forms become thicker and fibrous. in the final step, a clot that forms may partially or completely limit the blood flow in the vessels, or break free, forming an embolus, which is able to travel through vessels and block the blood flow further on [ ] . a cerebral hemorrhage is the next subtype of stroke, caused by the rupture of a cerebral vessel, resulting in extravasation of blood within the brain [ ] . generally, hemorrhagic stroke is a complication of hypertension, cerebral amyloid angiopathy, anticoagulation therapy and/or vascular structural lesions [ ] . symptoms may vary between patients, depending on the anatomical site of the hemorrhage [ ] . the major risk factors for the stroke development are: modifiable and include hypertension, atrial fibrillation and atrial cardiopathy, dyslipidemia, obesity, lack of physical activity, diet, untreated co-morbidities and inflammation, alcohol consumption and smoking. mostly, they contribute to the elevation of blood pressure and the progression of atherosclerosis. health improvement associated with the elimination of behavioral and medical risk factors can significantly reduce the risk of stroke. however, non-modifiable risk factors including age, sex, genetics and ethnicity can also increase the chance of stroke development [ ] . identification of a stroke syndrome is usually easy to recognize because of visible neurologic deficits. however, symptoms differ among various regions of the brain and types of stroke. therefore, neuroimaging is a gold standard method for all stroke diagnostics. the vast majority of strokes may be recognized using fast acronym, which means facial droop, arm droop, speech disturbances and time. computed tomography (ct) is the first examination that can with almost % certainty confirm stroke and in over % accuracy assess the type of stroke. however, small-volume ischemia may not be detected in ct because of insufficient resolution. for higher resolution, magnetic resonance imagining (mri) is recommended. for all acute stroke syndromes, ct angiography is recommended due to the identification of ischemic area. the determination of occlusion and evaluation of extracranial vertebral and carotid, aortic arch and proximal great vessels is necessary for further management. although patients with acute coronary syndromes have helpful diagnostic biomarkers (i.e., serum troponin, electrocardiography), for stroke patients those tests are not available [ ] . despite the available clinical studies evaluating the potential role of hemostatis biomarkers (i.e., von willebrand factor (vwf), p-selectin, fibrinogen, thrombomodulin, tissue factor, d-dimer, etc.) in ischemic stroke patients, the value of studied biomarkers is still unproven and requires further investigation [ ] . ischemic stroke is a dynamic process that persists for more than h. an ischemic cascade is activated rapidly after lack of blood flow in the brain, resulting in an ionic imbalance, excitotoxicity, blood-brain barrier dysfunction, generation of nitrosative and oxidative stress and inflammation ( figure ). shortages in glucose and oxygen delivery, caused by the ischemic event, force the human body to use alternative biochemical pathways and substrates like glycogen, fatty acids or lactate. however, lack of oxygen leads to the reduction of adenosine triphosphate (atp) (inducing glycolytic metabolism), accumulation of lactate and protons and diminishment in intracellular ph. dysfunction in the activity of the electron transport chain in mitochondria causes a further reduction in atp concentration and disturbances in the functioning of ionic pumps. a loss of potassium ion concentration and an increase in sodium, chloride and calcium ion concentration leads to the depolarization of the cell membrane of astrocytes and neurons and to the secretion of neurotransmitters causing excitotoxicity [ ] . during the excitotoxicity process, neuronal cells are exposed to a high amount of glutamate. the augmented concentration of glutamate may occur after neuronal depolarization, which is excessively released after neuronal depolarization. increased exposition of brain tissue to glutamate induces neuronal death, mitochondria failure and apoptosis. an influx of calcium ions causes degeneration of organelles and disrupts the integrity of cellular membrane [ ] . removal of excess calcium ions is possible through atp-dependent mitochondria activity. however, this involves the production of reactive oxygen species (ros), thus inducing the peroxidation of lipids, activation of proteases, disruption of cell membrane integrity, dysfunction of mitochondria, stimulation of microglia and production of cytotoxic factors. during shortages of oxygen and glucose, mitochondria switches to anaerobic atp production, resulting in the formation of lactic acid and hydrogen ions, which provide a substrate for the conversion of superoxide anion into hydrogen peroxide or hydroxyl radical. along with nitrogen oxides, oxidative and nitrosative stress increase, thus enhancing brain tissue damage. ongoing ischemia and associated pathological processes cause necrotic cell death [ ] , which induces the release of damaged-associated molecular patterns (damps), endogenous biomolecules responsible for the activation of the innate immune system from dead cells [ ] . ischemic stroke also triggers the inflammation of the brain tissue as a result of oxidative and nitrosative stress and the formation of free radicals, hypoxia or necrotic cell death [ ] . the inflammatory response to ischemia causes the rapid activation of microglial cells, which induce the infiltration of circulating inflammatory cells. ischemic cell damage generates and releases pro-inflammatory mediators and ros, thus promoting transendothelial migration of circulating leukocytes and inducing the expression of adhesion molecules in endothelial brain cells. within hours and days, mobilized leukocytes release chemokines, cytokines and ros, which enhance the inflammatory response in brain tissue [ ] . circulating monocytes activated by cytokine storm and chemotactic factors roll from the central axis to the peripheral marginal bloodstream and bind with the endothelium surface. the rapidly repeating and overlapping processes of cytokine releasement, monocyte migration and its binding with endothelium cause excessive cell accumulation. trapped monocytes undergo a transformation process into macrophages, which intensively internalize and accumulate lipids, thus transforming into foam cells [ ] . oxidized low-density lipoproteins inhibit a tethered macrophages chemotaxis, thus preventing them from leaving the endothelium and amplifying the accumulation [ ] . the leukocytes sequential migration causes lymphocytopenia, which contributes to the increased risk of infection via immunodepression [ ] . the ongoing pathological state results in the expression of pro-inflammatory genes and the augmented production of pro-inflammatory factors via the nf-κb pathway. intra-and extracellular signaling pathways trigger the interaction among brain tissue, endothelial cells, immune cells and hemostatic cells, thus stimulating the release of cytotoxic molecules like matrix metalloproteinases (mmps), which initially, causes the disruption of blood-brain barrier (bbb) permeability, nitric oxide, which constitute an independent source of reactive nitrogen species and damps, which enhance the cells mobilization and migration. disruption of bbb permits the infiltration of leukocytes, neurotoxic substances, cytokines, chemokines and pathogens to enter the brain tissue, exaggerating the infarct zone and resulting in the microvascular occlusion [ , ] . figure . the brain ischemia pathway. brain ischemia causes shortages in the oxygen supply, brain tissue necrosis and release of cytokines and chemokines that cause an inflammatory response. lack of oxygen causes the dysregulation of mitochondria and induces the anaerobic production of adenosine triphosphate (atp), which generates the reactive oxygen species (ros). disorders in the concentration of ions cause excitotoxicity, which results in cell damage and brain tissue necrosis. necrotic cells release damaged-associated molecular patterns (damps), which induce the activation of microglia, resulting in a massive release of cytokines and chemokines. pro-inflammatory factors mobilize leukocytes to migrate into the infarct zone enhancing the release of inflammatory response molecules. cerebral endothelium is stimulated to express the adhesion molecules on its surface and accumulate the cells, narrowing the vessel lumen and elevating the formation of atherosclerotic plaque. the ongoing mobilization of leukocytes results in the immunodeficiency caused by lymphocytopenia, thus increasing the risk of infection, which complicates the stroke by increasing the activation of the immune system and its interaction with endothelial and neural cells. neuronal damage caused by brain injury may be monitored by some brain markers including s b protein and neuron-specific enolase (nse). s b belongs to the ca + binding protein family and is responsible for intracellular level of ca + ions regulation. the concentration of s b in cerebrospinal fluid and plasma is correlated with brain damage and disease severity. serum s b levels are -fold decreased in comparison to cerebrospinal fluid level, however, serum protein is significantly easier and less invasive to collect and measure. several studies concluded that serum s b level shows strong correlation with the volume of infarct and the size of neurological deficit [ ] . nse is an isoenzyme of the enolase found in neuron's cytoplasm and is considered as neuronal damage biomarker. nse is present in peripheral blood serum in negligible concentration and its level rise during cell death. the study conducted by bharosay et al. has shown that nse serum level increases significantly due to cerebrovascular stroke (p < . ) and is correlated with score and disability degree [ ] . both neuronal damage biomarkers have a potential to be use in the determination of the reason of brain damage (injury caused by sars-cov- , or injury caused by stroke). however, there are currently no studies that describe this association. the contribution of viral infection in atherogenesis has been discussed for many years. studies showed that viral infection can be associated with endothelial dysfunction, the progression of atherosclerosis and future cardiovascular mortality. pathogens residing in the vascular wall induce the response of the immune system and the endothelium dysfunction, promoting the inhibition of vasodilatation, elevating the expression of pro-inflammatory factors and reactive oxygen species (ros), as well as contributing to the rupturing of plaque caused by mmp activity. unfavorable features of an ongoing pathological state of viral infection devastate the host organism and may contribute to severe complications of the initial pneumonia [ ] . the formation of blood clots in the cerebral vessel as a complication of sars-cov- infection, has been reported in a significant number of research articles. in a study conducted by mao et al. of the patients diagnosed with covid- who enrolled for their study, had neurological disorders categorized into three categories: cns, which included headache, dizziness, impaired consciousness, ischemic stroke and cerebral hemorrhage; skeletal muscular injury defined as pain muscle or augmented level of serum creatine kinase (higher than u/i); and peripheral nervous system (pns), which included smell, taste or vision impairment, and/or nerve pain. cns symptoms were the most relevant among all the neurological manifestations in patients. of patients with diagnosed ischemic stroke, only one survived. the authors showed that patients with cns symptoms had lower platelet counts, lower lymphocyte levels and augmented blood urea nitrogen levels compared to patients without cns symptoms. what is more, patients with severe infections had augmented d-dimer levels [ ] . similar results were conducted by beyrouti et al. where the clinical characteristics of six patients were presented. the first patient, a -year-old man diagnosed with covid- and exhibiting symptoms like cough, fever, breathlessness, myalgia and poor appetite was admitted to the intensive care unit due to respiratory failure. during hospitalization, the patient developed mild left upper limb weakness and incoordination. magnetic resonance imaging (mri) showed acute left posterior inferior cerebellar artery territory infarct with petechial hemorrhage and intradural left vertebral artery occlusion. moreover, the patient had markedly elevated d-dimer levels (> , µg/l). the patient's deteriorating health revealed a bilateral pulmonary embolism and acute bilateral incoordination, high homonymous hemianopia and extensive acute posterior cerebral artery territory infarction diagnosed with mri. the second patient was a -year-old woman with valvular atrial fibrillation and confirmed covid- with cough, dyspnea, acute confusion, incoordination and drowsiness. a computed tomography (ct) scan showed acute large left cerebellar and right parieto-occipital infarcts. at the time of the stroke, there was an onset of symptoms: the patient had augmented d-dimer levels ( µg/l) and a prolonged prothrombin time with an international normalized ratio (inr) of . . cardiorespiratory deterioration and disease severity contributed to the patient's decease. the third patient, an -year-old man diagnosed with covid- and risk factors like hypertension, atrial fibrillation and ischemic heart disease, developed a left posterior cerebral artery occlusion and infarction confirmed with a ct scan. the d-dimer levels were also highly increased ( , µg/l). the fourth patient, a -year-old man admitted to the hospital with hypertension, a high body mass index and previous stroke history at the time of the medical interview, had acute right striatal infarct detected by a brain mri, and markedly elevated d-dimer levels ( , µg/l). during hospitalization, the patient developed respiratory symptoms with a pulmonary embolus confirmed with ct angiogram and was diagnosed with covid- . the fifth patient, an -year-old man diagnosed with covid- , diabetes, hypertension, smoking and alcohol consumption and ischemic heart disease, developed a thrombotic occlusion of proximal m branch of the right middle cerebral artery and infarct in the right insula. similarly to all patients, the d-dimer levels were augmented ( , µg/l). the final and sixth patient, a -year-old man with common covid- symptoms, was admitted to the hospital with dysphasia and right hemiparesis. an mri brain test confirmed bilateral p segment stenosis, thrombus in the basilar artery and multiple acute infarcts in the left pons, right thalamus, right cerebellar hemisphere and right occipital lobe. the d-dimer levels were µg/l and measured after intravenous thrombolysis. based on their observations, the authors suggest that ischemic stroke is a complication of covid- , and may have distinct characteristics. however, the mechanisms of this disorder are not yet understood [ ] . oxley et al. published a case report study, in which five patients younger than years of age, diagnosed with covid- , developed a large-vessel stroke. the first and second patients were a -year-old female and -year-old man, respectively, displayed no risk factors for stroke in their medical records. the female patient had mild covid- symptoms like cough, headache and chills. medical tests showed a partial infarction of the right middle cerebral artery with a partially occlusive thrombus in the right carotid artery at the cervical bifurcation, hemiplegia on the left side, dysarthria, sensory deficit, homonymous hemianopia and facial droop. the male patient, recently exposed to a sars-cov- infected family member, showed no symptoms of covid- . however, medical tests confirmed ischemia in a left middle cerebral artery, and stroke symptoms such as sensory deficit, dysarthria, hemiplegia on the right side, reduced consciousness and dysphasia. other patients, a -year-old man, a -year-old man and a -year-old man were diagnosed with ischemia in a right posterior cerebral artery, left middle cerebral artery and right middle cerebral artery respectively. patients had a burden of medical records with risk factors like hypertension, hyperlipidemia, diabetes or previous mild stroke, with various covid- symptoms (from none symptoms to lethargy). the authors suggest that vascular endothelial dysfunction and coagulopathy are a complication of the ongoing covid- disease. furthermore, before the world pandemic, the same hospital in the same -week period admitted . patients on average, in comparison to five admitted patients during the pandemic [ ] . the large disproportion in the number of patients admitted suggests that neurological manifestations, including ischemic stroke, are very serious complications of the ongoing sars-cov- virus infection and differential diagnoses should be implemented to hospitals to avoid delays in the diagnosis of concomitant complications. furthermore, the above-mentioned studies showed that patients with severe infections manifested neurologic symptoms more often. merkler %) were admitted because of cerebrovascular infarction. d-dimer levels and c-reactive protein were significantly augmented (with median values of ng/ml and ng/ml, respectively). the development of stroke with unknown etiology may be related with hypercoagulability caused by sars-cov- infection [ ] . in the study performed by qin et al. the clinical characteristics and outcomes of covid- patients with and without history of stroke were evaluated. authors showed that patients with a history of stroke presented more comorbidities, more coagulation disorders and more aggressive inflammatory response. moreover, those patients had poorer outcomes and higher risk of severe events. patients with history of stroke had elevated number of neutrophils and interleukin level, which may induce the cytokine storm and augmented, harmful immune system response. however, more severe course of the disease in patients with stroke history may not be associated with viral infection, but with enhanced risk factors and poorer health condition [ ] . genetically, sars-cov- shows about % similarity with sars-cov, and about % similarity with the middle-eastern respiratory syndrome coronavirus (mers-cov). studies showed that this new coronavirus enters the human cells by binding to the angiotensin-converting enzyme (ace ), such as sars-cov [ , ] . the parallels between those two viruses are very important in laboratory diagnostics, medical treatment, spreading prevention and clinical characteristics, because since its discovery, the virus has proved itself to be extremely harmful and highly contagious. however, very few studies have yielded any conclusive explanations regarding the virus properties. ace is mainly expressed in the human airway epithelia, lung parenchyma, kidney cells, heart, testis, vascular endothelial cells, intestinal epithelial cells and brain [ ] . hamming et al. carried out research based on immunohistochemistry testing on different human tissue organs, localized ace in endothelial cells from arteries and veins in all the studied samples, including the brain [ ] . these studies, published in and , demonstrated that sars-cov was found in the brain samples of infected patients. interestingly, virus particles were found mostly in the neurons [ ] [ ] [ ] . in order to find the means of virus neuroinvasion, netland et al. performed a study on transgenic mice, infected intranasally with sars-cov, and confirmed viral antigen distribution in the brain. thus suggesting that the virus can enter the brain via the olfactory nerve [ ] . there are currently no similar studies that could confirm sars-cov- brain infection through the olfactory system, however, the similarity between these viruses may suggest that this new coronavirus may invade the brain in the same way. ace is a part of the renin-angiotensin system (ras), which is very important in the cardiovascular functions regulation, through the degradation of angiotensin ii to angiotensin [ ] [ ] [ ] [ ] [ ] [ ] [ ] . experimental studies have shown that angiotensin ii induces myocardial hypertrophy, interstitial fibrosis, endothelial dysfunction, hypertension, vasoconstriction, oxidative stress, coagulation and enhances inflammation. the opposite role was shown in the case of angiotensin, which provides anti-inflammatory properties, thus reducing inflammation, fibrosis, migration and infiltration of cells. sars-cov- binding with the ace receptor leads to its down-regulation, increasing harmful and pathological state development in the host organism [ ] . in the cns, angiotensin ii increases blood pressure and releases vasopressin. moreover, in ace knockout mice models, gene deletion was correlated with the augmented level of superoxides [ ] . the severity and mortality of covid- are correlated with the body's immune response. in a study conducted by chen et al. most patients diagnosed with covid- had fewer lymphocytes and more c-reactive protein. furthermore, % of enrolled patients had an increased level of serum interleukin (il ) [ ] . huang et al. conducted a study, in which patients with severe infections, admitted to the intensive care unit, had elevated levels of plasma pro-inflammatory cytokines like il , il , il , granulocyte colony-stimulating factor (gscf), interferon γ-induced protein (ip ), monocyte chemoattractant protein- (mcp ), macrophage inflammatory protein- -α (mip a) and tumor necrosis factor α (tnfα). what is more, the concentration of platelet-derived growth factor (pdgf), vascular endothelial growth factor (vegf), il β, il , il and interferon γ (ifn-γ) were elevated in all diagnosed patients [ ] . in order to better understand all molecular processes ongoing during viral infection, the molecular mechanisms occurring in various cell types were described, maintaining the events chronology during the infection. a series of processes causing harmful body response to a viral infection leading to thromboembolic complications, begin with the endothelial cells. ace receptor located in endothelium allows the virus to connect and enter in the cells [ ] . although the adhesion of leukocytes and blood platelets to endothelium is normally prevented, localized pro-inflammatory mediators (cytokines and chemokines), clotting cascade factors, growth factors and nitric oxide effect the reduced barrier integrity [ ] . furthermore, experimental studies showed that tnf and il β, which are released from endothelial cells during viral infection, are able to activate endothelial cells via nfκb pathway, which finally induces the new genes expression associated with the inflammatory response, i.e., adhesion molecules like vascular cell adhesion protein (vcam- ) and intracellular adhesion molecule (icam- ) [ ] . furthermore, il and tnf have an ability to increase tissue factor (tf) and plasminogen activator inhibitor, increase the endothelium adhesivity for leukocytes and stimulate the secretion of pdgf. these effects tip the balance between pro-and anti-coagulant properties towards intravascular coagulation [ ] . ongoing inflammation in the endothelium causes changes in vascular permeability and leads to the cells death [ ] . release of damps from injured endothelial cells induces the migration of immune system cells, whose task is to eliminate the pathogen [ ] . a very important role in the viral infection response is played by neutrophils, which are the first cell population that migrates to the damaged area. to eliminate the threat, neutrophils are equipped with various biological features, including chemokines, ros and proteases (i.e., mpps). however, all the invasive and aggressive mechanisms responsible for the pathogens elimination also work efficiently with host cells, which can cause damage to the inflamed tissue [ ] . mobilization of macrophages, leukocytes and neutrophils (which constitute an innate immunity system) at the site of infection involves a massive release of cytokines and chemokines in damaged tissue. in the case of the brain tissue, mainly tnfα, il β and il were found to be associated with ischemic stroke [ , ] . cytokines and chemokines, which are released activate endothelium cell adhesion molecules that capture macrophages, leukocytes and neutrophils. the other pro-inflammatory molecule, ifn-γ, may increase the immune response by augmented infiltration of monocytes and lymphocyte into the damaged vessel. thus elevating the level of surface adhesion molecules and chemokines [ ] . released il possesses an ability to induce t-cell proliferation (which constitute an adaptive immune system) and regulates their development, function and survival, and induces the differentiation of t-helper cells [ ] . t-cell development is regulated also by released il , which shown the properties to stimulate the recruitment and adhesion of macrophages and monocytes to endothelial cells, and upregulated mcp in the endothelium, which is responsible for the antiviral immune response, and the migration and infiltration of monocytes and t-cells [ , ] . chemokines have a similar effect to mip a and ip [ , ] . migration of neutrophils and activation of mast cells are mainly provided by releasing il and il , respectively [ , ] . what is more, il may contribute to the augmented production of other pro-inflammatory cytokines in airways, resulting in its hyperresponsiveness [ ] . to increase the immune response, gcsf stimulates the generation of the granulocytes, mainly neutrophils, and their release into the bloodstream. however, gcsf has also shown to inhibit the production of tnf and il in monocytes, macrophages and neutrophils, and to induce the expression of il , anti-inflammatory cytokine, which enables the reduction of interaction between monocytes and endothelial cells resulting in decreased adhesiveness [ , ] . strengthening the inflammation as a result of the body's response to infection is caused by the rapid production of il , which is released by microglial, leukocytes, endothelial cells and astrocytes, and is responsible for the stimulation of production of c-reactive protein and fibrinogen. thus increasing the risk of a thrombotic event. furthermore, il may accelerate the migration of leukocytes as well as the production of adhesion molecules and chemokines. studies showed that il is associated with neurovascular dysfunction, neurodegeneration and inflammation of peripheral nerves [ ] . as a result of cell death, released damps activate astro-and microglia, thus amplifying the mobilization of immune response cells [ ] . the accumulation of immune cells in the vascular wall in response to the viral infection, especially among patients with ischemic risk factors, induces endothelial dysfunction, migration and proliferation of cells, activation of coagulation cascade and production of fibrous plaques. tf, which is activated by cytokines is the key initiator that triggers the coagulation cascade. blood platelets are the smallest nucleated blood morphotic elements, which are responsible for the maintaining a hemostasis process. in addition to that, platelets are the only cytoplasmic fragments of megakaryocytes, they are equipped with large number of receptors and biologically active compounds that interact with vascular microenvironment. under physiological conditions, platelets freely circulate in bloodstream without interacting with endothelium. this property is ensured by a glycoproteins layer and proteoglycans present between endothelium and blood, known as the glycocalyx [ ] . however, inflammatory mediators released during viral infection, such as tnfα and lipopolysaccharide (lps), can cause degradation of the glycocalyx, thus regulating the permeability of endothelium. the injured endothelium expose tf, which triggers the coagulation cascade. firstly, tf binds with serine protease factor viia, which further activates factor x and factor ix, resulting in thrombin generation in the final [ ] . the positive thrombin feedback brings a blood platelet activation. activated platelets change their shape in order to expose their adhesion receptors and to release granular content, pro-inflammatory cytokines and chemokines, and other activators (i.e., adp, vwf, thromboxane a ) that enhance thrombus formation [ ] . simultaneously, during the progression of the coagulation cascade, factor xiia cleaves plasma prekallikrein to form the active serine protease plasma kallikrein that generates bradykinin. its binding to endothelium resulting in the induction of glial activation, enhancing an inflammation and neuronal death, which in turn enhances the secretion of damps [ ] . activated blood platelets interact with leukocytes via glycoprotein p-selectin platelets and its ligand (p-selectin glycoprotein ligand- ; psgl- ) on leukocytes, and support their migration to inflamed endothelium [ ] . adhesive molecules on endothelium (e-selectin, p-selectin, vcam- ) trap the rolling leukocytes [ ] . during the accumulation of immune and hemostatic cells, thrombin generates the insoluble fibrin from fibrinogen [ ] . furthermore, this effect is enhanced by cytokines that stimulate the plasminogen activator inhibitor- (pai- ), that reduces the fibrinolysis efficiency and effectivity [ ] . the ongoing recruitment of platelets and successive infiltration of leukocytes, neutrophils and macrophages cause thickening of plaque that blocks the blood flow, resulting in the ischemic event ( figure ) [ , ] . severe acute respiratory syndrome coronavirus (sars-cov- ) infects human cells via the angiotensin-converting enzyme (ace ) receptor. neutrophils migrate to the infected area in order to eliminate the pathogen. release of biologically active compounds (i.e., chemokines, reactive oxygen species-ros) stimulates the inflammation, causing mobilization of other immune system cells. dead cells from the injured zone release damaged-associated molecular patterns (damps), which activate microglia, inducing the migration of macrophages, leukocytes and neutrophils. the ongoing endothelial dysfunction activates the coagulation cascade via tissue factor (tf). generated thrombin stimulates blood platelets activation and shape change. thus exposing adhesion receptors and secreting granular content, enhancing inflammation and coagulation. activated platelets interact with leukocytes and support their migration to the damaged area. the interaction among endothelium, immune system and hemostatic cells enhances the ischemia and inflammation, simultaneously reducing the fibrinolysis effectivity and efficiency. pharmacological treatment of stroke patients must be matched with the stroke type. that is why a detailed medical interview and examination have to be performed before drug supplementation. ischemic stroke patients mostly received thrombolytic therapy. clinical trials showed that recombinant tissue plasminogen activator (rt-pa, also named alteplase) administered in maximal . h after onset of symptoms, significantly reduce hypoxia and improve patients outcomes [ ] . according to the early management of patients with ischemic stroke guidelines, the combination of rt-pa with antiplatelet medicaments (excluding heparin, thrombin inhibitors, factor xa inhibitors and gpiib/iiia inhibitors) is recommended because of their beneficial character [ ] . due to the national institutes of health guidelines, hospitalized adult patients should be administered with venous thromboembolic events (vte) prophylaxis, if hematologic and coagulation parameters indicate the possibility of thrombotic complications, or patients are at high risk of thromboembolic event. what is more, patients receiving antiplatelet and anticoagulant therapies before covid- diagnosis should continue the treatment. however, available data are insufficient to recommend the use of thrombolytics and anticoagulant drugs. in the case of sars-cov- infection, there is no antiviral agent for covid- , however, several medicaments, including remdesivir, chloroquine, lopinavir, rotinavir and other hiv protease inhibitors, are evaluated as a potential antiviral drug (table ) . administration and selection of anticoagulant or antiplatelet drug for covid- patients should be always considered to potential drug-drug interactions. for this reason, the university of liverpool collated a list of drug interactions for medical personnel [ ] . table . potential antiviral drugs under evaluation for the treatment of coronavirus disease (covid- ) [ ] . intravenous prodrug responsible for inhibiting viral replication via binding to the viral rna polymerase. antimalarial drug, which inhibits the fusion of virus with host cell membranes. in vitro studies showed that both drugs may block the viral transport from endosomes to endolysosomes, thus regulating the releasement of viral genome. chloroquine has an ability to inhibits glycosylation of ace receptor, thus interfering the viral linkage. lopinavir/ritonavir lopinavir/ritonavir inhibits the activity of proteases responsible for replication of sars-cov- . numerous studies showed that covid- may cause thromboembolic complications, which lead to many vascular disorders, including ischemic stroke. the rapidly growing number of case-reports demonstrates the need for more detailed medical examination of patients, especially those with severe infections. oxygen and nutrient shortages caused by a viral infection, along 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covid- ) treatment guidelines. national institutes of health this article is an open access article distributed under the terms and conditions of the creative commons attribution (cc by) license the authors declare no conflict of interest. key: cord- -a sf f p authors: montaner, joan; barragán-prieto, ana; pérez-sánchez, soledad; escudero-martínez, irene; moniche, francisco; sánchez-miura, josé antonio; ruiz-bayo, lidia; gonzález, alejandro title: break in the stroke chain of survival due to covid- date: - - journal: stroke doi: . /strokeaha. . sha: doc_id: cord_uid: a sf f p background and purpose: emergency measures to treat patients with coronavirus (covid- ) and contain the outbreak is the main priority in each of our hospitals; however, these measures are likely to result in collateral damage among patients with other acute diseases. here, we investigate whether the covid- pandemic affects acute stroke care through interruptions in the stroke chain of survival. methods: a descriptive analysis of acute stroke care activity before and after the covid- outbreak is given for a stroke network in southern europe. to quantify the impact of the pandemic, the number of stroke code activations, ambulance transfers, consultations through telestroke, stroke unit admissions, and reperfusion therapy times and rates are described in temporal relationship with the rising number of covid- cases in the region. results: following confinement of the population, our stroke unit activity decreased sharply, with a % reduction in admitted cases (mean number of cases every days in previous months to cases in the days after the outbreak, p< . ). consultations to the telestroke network declined from every days before the outbreak to after the outbreak (p< . ). the increasing trend in the prehospital diagnosis of stroke activated by calls stopped abruptly in the region, regressing to levels. the mean number of stroke codes dispatched to hospitals decreased ( % versus %, p< . ). time of arrival from symptoms onset to stroke units was delayed > minutes, reperfusion therapy cases fell, and door-to-needle time started minutes later than usual. conclusions: the covid- pandemic is disruptive for acute stroke pathways. bottlenecks in the access and delivery of patients to our secured stroke centers are among the main challenges. it is critical to encourage patients to continue seeking emergency care if experiencing acute stroke symptoms and to ensure that emergency professionals continue to use stroke code activation and telestroke networks. t he international pandemic produced by coronavirus (covid- ) has already affected > . million patients and killed worldwide by the beginning of may, changing the rhythm of the planet in the last months. despite the emergency measures to treat patients with covid- and contain the outbreak being the main priority at each of our hospitals, it is also important to consider the collateral damage of this crisis on patients with other acute diseases. in fact, previous coronavirus outbreaks, such as south korea experienced in due to middle east respiratory syndrome, resulted in changes in emergency care utilization. in that situation, the number of emergency room visits during the peak of the middle east respiratory syndrome epidemic decreased by . % and was more pronounced for low-acuity diseases (eg, acute otitis media, . %) than for high-acuity diseases (eg, myocardial infarctions, . %; ischemic stroke, . %). similarly, the covid- outbreak has been shown to affect cardiovascular diseases, with an abnormally small number of patients with acute st-segment-elevation myocardial infarction seeking medical help after the establishment of infection control measures in hong kong. the authors of that report claim that people are reluctant to go to a hospital during the covid- outbreak, which explains the potential delays in seeking care; moreover, they also reported delays in evaluating patients with st-segment-elevation myocardial infarction after hospital arrival. we hypothesize that the covid- pandemic is disruptive for stroke care across the globe since several elements of the stroke chain of survival are likely to be interrupted. therefore, to better understand how the acute stroke care situation in the era of the covid pandemic crisis might be affected, we evaluated the number of stroke cases attending and treated at a south european region before and during the outbreak. all supporting data are available within the article and any data related with stroke during covid- pandemic in our region is also available from the corresponding author upon reasonable request. ethics approval was obtained from the local institutional review board that waived the need for patient consent (code -n- ). a descriptive analysis of the situation of acute stroke care before and after the covid- outbreak is given for a stroke network located in southern europe. seville is a province with . million inhabitants and has -stroke units at the large hospitals of seville city (hospital universitario virgen del rocío and hospital universitario virgen macarena). one of these hospitals is the reference thrombectomy center for sevilla and a close smaller province (huelva) with a total of . million inhabitants within its catchment area. the other hospital held the telestroke network for the whole region centro andaluz de tele-ictus according to a centralized hub and spoke model, with one neurologist supporting ( hours per day) the hospitals' network in the region. all data on the activity of both stroke units are prospectively recruited on a daily basis, and those on mechanical thrombectomy are obtained from the prospective a registry for thrombectomy in stroke therapy from andalusia registry maintained jointly by interventional neuroradiologists and vascular neurologists. centro andaluz de tele-ictus has its own registry for all andalusia, and data on the studied region (seville and huelva) have been used for this report. code stroke is activated by a unique coordinating center in there is suspicion following telephonic contact through the or numbers (local equivalents to ). the coordinating center allocates the closest properly equipped transport resources from the regional network of ambulances. all those code stroke activations are automatically recorded in the electronic medical records (diraya, hcm-d). to quantify the impact of the covid- outbreak, all figures on stroke activity at each link of the chain were compared across time from months before the outbreak until days after (march , ) and also compared with the same period last year for some of the explored variables. this was also compared with the number of covid- cases in the region in this period of time. times from symptoms onset to arrival to hospitals, reperfusion therapy times (door-to-needle and door-topuncture), and number of transient ischemic attacks attended at the emergency departments were also evaluated. all categorical variables are presented as number and frequency (%), while continuous variables are presented as mean±sd or median±interquartile range. in bivariate analysis, the χ test, fisher exact test, student t test, and mann-whitney u test, as appropriate, were used. all statistical analyses were performed using ibm spss statistics v. , ibm. a p< % indicated a statistically significant difference. spain, with covid- confirmed cases and deaths as of march , , has one of the highest burdens of covid- worldwide, and this picture probably underestimates the reality due to undertesting during the epidemic. in response, the government declared a national emergency and the alarm state, starting on march . in the area of seville, the first case of covid- was diagnosed on february , with cases by march , , and the situation beginning to stabilize in the coming days, reaching the peak and plateau phases ( figure ). regrettably, almost % of the confirmed covid- cases occurred among health care workers, especially those from emergency departments. following the confinement of the population, a clear decrease in the number of acute stroke cases attended and treated in our hospitals was seen, and also, the stroke activity outside of our hospitals (telestroke and ambulance transfers) decreased. the activity at both stroke units decreased sharply with a reduction of admitted cases of around %, going from a mean number of cases every days in the previous months to cases in the days after the outbreak (p< . ; figure ). ischemic strokes fell from a median of cases per days before covid- to cases during the days after the alarm (p< . ); this drop was not so important for hemorrhagic strokes with a medium of cases per days periods before and cases the days after the alarm (p= . ). the proportion of ischemic strokes was maintained in both periods of time ( % pre-covid- versus % post-covid- , p= . ). we also observed a % reduction intravenous tissue-type plasminogen activator in the number of patients with transient ischemic attack attending the emergency department. in fact, mean transient ischemic attack cases per days before covid- was . that fell to cases during the days after the alarm (p= . ). mean times of arrival to hospital from symptoms onset was delayed almost half an hour considering all code strokes ( minutes pre-covid- versus minutes post-covid- , p< . ). similarly, mean times of arrival from symptoms onset among those admitted to the stroke units were delayed more than half an hour ( minutes pre-covid- versus minutes post-covid- , p< . ). no differences in median national institutes of health stroke scale scores at admission was observed in both periods of time ( points pre-covid- versus points post-covid- , p= . ). regarding reperfusion therapies, thrombolytic therapy was also reduced (mean patients treated in days periods before and after the alarm: versus , p< . ) since fewer patients were attended. also, the mean global number of thrombectomies performed by the reference center was reduced from a mean of cases in days before the alarm compared with only cases after the alarm (p< . ). however, the proportion of treated patients with iv tpa (intravenous tissue-type plasminogen activator) remained stable ( % versus % p= . ). similarly, considering any reperfusion therapy offered to the ischemic stroke patients admitted in our stroke units, the proportion remained stable, with % before the outbreak and % after (p= . ; figure ) . unfortunately, iv tpa onset suffered also delays since door-to-needle time started minutes later than usual ( minutes pre-covid- versus minutes post-covid- , p< . ). no difference in median national institutes of health stroke scale scores was observed between patients that received mechanical thrombectomy in both periods of time ( points pre-covid- versus points post-covid- , p= . ). median alberta stroke program early ct score was also identical in both periods ( points pre-covid- versus points post-covid- , p= . ). surprisingly, mean times of arrival to thrombectomy reference center from symptoms onset improved during the pandemic ( minutes pre-covid- versus minutes post-covid- , p< . ). and also, door-to-puncture times improved accordingly ( minutes pre-covid- versus minutes post-covid- , p< . ). the consultations to our telestroke network also suffered a dramatic decrease (figure ). in fact, telestroke consultations declined from all smaller hospitals from seville and huelva covered by telestroke, from a mean of consultations in the periods of days before the outbreak to after the outbreak began (p< . ). the patients that get therapy using the system also declined, since among consultations received, % were given reperfusion therapies before the outbreak compared with only % after the outbreak (p= . ). a trend to increased stroke severity was observed among patients attended in the telestroke network the number of calls to increased dramatically during this time period, with almost million telephone calls to the system only in our region during the first weeks of the lockdown (source http://www.epes.es/). although the prehospital diagnosis of stroke had an increase in the region by around % as compared with the previous year, unfortunately, this number of activations during the days after the outbreak regressed to the level ( figure a) , and the expected increase in activations expected for this period as compared to the same period of the previous year did not occur. the mean number of stroke codes dispatched to hospitals decreased since in the days periods before the outbreak, % were dispatched to hospitals, and after the outbreak, only % of patients were dispatched to hospitals (p< . ; figure b ). we wondered how the measures aimed at covid- are changing the way stroke patients are treated and observed that the growing pandemic had produced a reduction in the number of acute stroke patients that come into our healthcare system. unfortunately, we observed a sharp decrease in the number of stroke code activations and ambulance transfers, a reduction in consultations through telestroke, the number of patients admitted to our stroke units, and treated with iv tpa or receiving thrombectomy, which had a clear temporal relationship with the rising number of covid- cases that crowded our hospitals. this reduction in stroke activity is seen despite patients with covid- perhaps being at increased risk of thromboembolism and that vascular inflammation might also contribute to the hypercoagulable state and endothelial dysfunction in such patients. there are reports of abnormal coagulation parameters in hospitalized patients with severe covid- , and elevated d-dimer levels are strongly associated with in-hospital death, and many of them are receiving low molecular weight heparins. in fact, some young strokes without vascular risk factors related to covid- are being reported. therefore, alternative hypothesis to explain reduced numbers of stroke such as less activity and stress, more sleep, or other changes during the lockdown seem less plausible. as the situation was rapidly worsening, we moved quickly to prepare to receive patients with stroke that might also be infected with covid- , putting protocols in place following key principles of minimizing exposure and maximizing resources. specifically, we modified local protocols for acute stroke management at emergency department arrival and for iv tpa. every code stroke patient is treated as potentially infected with a designated covid- scanner, and following head computed tomography, a chest computed tomography is done to all acute stroke cases to identify cases with lung infiltrates and shift them to the respiratory circuit of the hospital waiting for covid- confirmatory tests. also, for thrombectomy, the protection protocols were adapted, minimizing the use of anesthesia and intubation to avoid aerosols generation. similar recommendations , have been developed in many countries, and some protocols are even published and available, such as protected code stroke in the united states. however, these protocols will be useless if patients with stroke do not reach our hospitals or do so too late. so, where was the bottleneck? we think covid- telephone-specific helplines had long delays in some regions during the first days of the crisis, and most of the people were seeking help through the or numbers (our ) that probably collapsed at some moments. another concern that we are unable to evaluate is whether some patients with stroke or their relatives did not even seek care at all, preferring to stay at home with symptoms than taking the risk of getting infected at the hospitals. although our ambulance service decreased dispatches of patients to stroke designated hospitals, the transport system did not collapse. they were under huge assistance pressure and, in fact, had to adapt, with some of the ambulances dedicated to suspected patients with covid- . wearing the personal protection equipment takes some time that together with times lost in disinfecting ambulances has been probably responsible for generating some delays. prehospital diagnosis of stroke has been improving in the region in recent months and has increased by % compared with the previous year. this increase is largely due to several actions taken from the andalusian stroke plan; however, and unfortunately, these numbers have regressed to the level of last year due to the outbreak. in many cases, the medical staff from the ambulances before attending patients at home tried recalling patients to be sure whether they need to be transferred to the hospitals, probably precluding some patients to receive a full evaluation at the hospitals. it is possible that some minor strokes were included in that pool, where triage strategies might have been overly restrictive. in fact, a % reduction in the number of patients with transient ischemic attack attending the emergency departments of our hospitals occurred. another problem is that awareness of stroke signs and symptoms of alarm among our colleagues at emergency departments who should activate telestroke or call neurologists might be suboptimal due to overreplacement of staff in the frontline since there was many of them personally affected by covid- or at quarantines and had to be substituted by less experienced staff. this might also have been the case in smaller hospitals of the network since the telestroke activity was drastically reduced after the outbreak and fewer mild strokes were consulted. delays in reaching the hospital from the onset of stroke symptoms were observed both in the stroke units (delay of > minutes) and in the telestroke centers (delay of > hour). this could have an impact on the absolute reduction of reperfusion therapies administered during the pandemic. in fact, iv tpa was initiated minutes later than usual, likely in connection with overcrowded emergency departments and new for endovascular therapy, there were also reductions in the number of patients treated. similarly, preliminary data from china shows that the number of thrombectomies in shanghai decreased by % in the first month after the spring festival compared with the same period in . however, thrombectomies were performed at the reference center surprisingly fast, probably reflecting the absence of road traffic in the region during closure. additionally, the neuroradiologists canceled all scheduled activities and interventions and were only attending emergencies, so the team really focused on cases of acute stroke. in addition, patients who live at home by themselves may have less likelihood to be seen by family and friends until it is too late to get therapy and might even die from stroke without attending the hospitals. this could also have caused a reduction in the number of patients treated for stroke in our hospitals. a crisis such as this places pressure on all aspects of a healthcare system, and this is likely to be more pronounced in less equipped and organized systems. longterm underinvestment in health services, as seen in many countries following the financial crisis, impairs their ability to respond to surges in need for health care with sufficient health professionals, protective equipment, diagnostic test kits, and intensive care unit beds, and this is clearly the case of spain. an ongoing survey conducted by the european stroke organization and world stroke organization might identify whether differences in response to stroke care during the covid- pandemic exist among regions across the globe. we anticipate that the more robust and well-equipped public healthcare systems will be better able to maintain stroke management during the pandemic. our results show how public health emergencies can indirectly affect unrelated hospital areas, and the key question is how we maintain our stroke services throughout the pandemic. we and others propose some ideas or solutions to ensure appropriate acute stroke pathways continue working and offering the best treatment possible under these challenging conditions. these solutions might still be implemented for regions where the outbreak is ongoing, or in future disease outbreaks. stroke leaders and advocates, together with health authorities, should work with local mass media to encourage patients to continue seeking emergency care if experiencing acute stroke symptoms. a clear message about where to call and where to attend depending on covid- -related or -unrelated problems is critical to diminish the fear of the population, explaining that clean circuits are secured, and they will not get infected by attending the hospital seeking help for stroke or another acute severe disease. separate telephonic helplines for covid- and other conventional severe diseases would help avoid unnecessary delays in treating acute stroke. the lockdown time might be an opportunity to improve education, especially of those who are at high risk of stroke, helping them to recognize a stroke and call emergency medical services immediately. the establishment of centralized stroke centers where sufficient stroke care resources can be secured might help in some large cities with several fully equipped hospitals. it is important to remind the emergency medical system and the population that these centers will be protected and will remain fully operational. that decision should be taken according to the incidence of covid- cases in each region. the decision on when the stroke units should aim to remain covid- -free or become covid- positive also depends on the local incidence of the disease. continuous communication with the different levels of the hospital is critical to make that decision based on the availability of beds, respirators in the icu units, and available personnel. the use of rapid point-of-care tests to triage patients to our stroke units or even to aid in the administration of reperfusion therapies outside of the hospitals would be extremely helpful (when available) in this critical situation when hospitals are overcrowded. in conclusion, huge collateral damage to acute stroke patients is occurring during the covid- pandemic. we are initiating fewer emergency treatments or missing the therapeutic window due to delays in hospital admission or referrals or patients preferring not to enter the hospital at all. the investigated region, seville, is among the less affected areas of the country by covid- with times less cases than the spanish average incidence and times less cases than the areas with the highest incidence in the country such as madrid. therefore, our findings are likely to be repeated, with greater impact, in other regions in the country, where the situation was much more chaotic and in other countries deeply hit by covid- . in some regions, acute vascular diseases have probably killed more patients than covid- during this period. the duration of the drop in acute stroke activity in our stroke units and the morbimortality associated with this fact will have to be evaluated carefully in the near future. important lessons should be learned, and preparedness and innovation will help should there be similar outbreaks in the future. to ismael muñoz for fruitful discussions on the role of emergency primary care physicians in the crisis and wilfredo lopez for sharing data on coordinating center calls. to elvira, who personally suffered this dramatic situation. references . world health organization: coronavirus disease (covid- ) situation reports impact of the middle east respiratory syndrome outbreak on emergency care utilization and mortality in south korea impact of coronavirus disease (covid- ) outbreak on st-segment-elevation myocardial infarction care in hong kong cardiovascular considerations for patients, health care workers, and health systems during the covid- pandemic anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy emergency room neurology in times of covid- : malignant ischemic stroke and sars-cov infection temporary emergency guidance to us stroke centers during the covid- pandemic, on behalf of the aha/asa stroke council leadership management of acute ischemic stroke in patients with covid- infection: report of an international panel protected code stroke: hyperacute stroke management during the coronavirus disease (covid- ) pandemic the resilience of the spanish health system against the covid- pandemic challenges and potential solutions of stroke care during the coronavirus disease (covid- ) outbreak blood biomarkers for the early diagnosis of stroke: the stroke-chip study covid- in spain: geographical distribution to all the healthcare professionals working in the ambulances, emergency departments, stroke units, and cath labs at these very difficult times. to jesús rodríguez-baño from clinical unit for infectious diseases, microbiology and preventive medicine for his daily info on new covid- cases at the hospital and his help to establish safety protocols for our colleagues and stroke patients with suspicion of infection. to maría teresa diaz curiel from the analysis and evaluation service (virgen del rocio hospital) and josé e. arroyo izquierdo from the information and statistics systems unit (virgen macarena none. key: cord- -zsbmaieg authors: aguiar de sousa, diana; sandset, else charlotte; elkind, mitchell s. v. title: the curious case of the missing strokes during the covid- pandemic date: - - journal: stroke doi: . /strokeaha. . sha: doc_id: cord_uid: zsbmaieg nan d espite worldwide efforts, the incidence of coronavirus disease (covid- ) continues to increase. to address this ongoing public health emergency, most countries implemented strict social containment measures and reorganized health care systems. although these were necessary changes to contain the spread of disease and to deal with a rapidly rising number of severe cases that overwhelmed medical systems, the care of patients with other time-sensitive emergencies, such as stroke, has been impacted. globally, physicians have noted reduced admissions for stroke. , however, high-quality clinical registry data confirming this trend and exploring possible reasons has been lacking. the results of studies confirming these impressions are published in this issue of stroke. in these articles, colleagues from china and spain used data from stroke registries to compare the number of admissions during the pandemic surge and the corresponding period in the previous year, confirming a clear reduction in stroke admissions during this early phase of the covid- outbreak. they also compared aspects of stroke care before and during the pandemic. one study, based on data from a registry including stroke centers throughout china, reported a % drop in stroke admissions during the pandemic surge. no differences were found in the pattern of changes between hospitals designated for covid- and nondesignated hospitals. notably, the proportion of patients with stroke undergoing thrombolysis and thrombectomy remained stable, despite a % reduction in absolute numbers that is likely to be attributed to the drop in stroke admissions. unfortunately, although this registry includes a large network of certified stroke hospitals, the possibility that some missing patients with stroke were evaluated outside of these selected centers cannot be excluded. the second report focuses on the changes noted at a single comprehensive stroke center in barcelona, spain, a region that was strongly affected by covid- . in addition to finding a similar reduction in stroke admissions of %, the authors found an % decrease in the number of prehospital stroke codes, despite a % increment in the number of calls to emergency medical services during that period. there was also a fall in the number of stroke admissions without previous notification. impressively, in-hospital stroke care was maintained at a high level, including prehospital and in-hospital metrics, such as time from symptom onset-to-door, door-toneedle, or door-to-groin puncture; proportion of patients undergoing thrombectomy; and neurological and functional outcomes. what explains this curious decrease of stroke patients during the pandemic? there are likely several contributing reasons for these missing patients with stroke. first, strict instructions to stay at home and fear of infection in a medical facility may have led patients with milder strokes to remain at home. in barcelona, however, the median baseline national institutes of health stroke scale score was lower, albeit not significantly so, in march compared with march , suggesting that a relative decrease in milder strokes cannot fully explain the discrepancy. second, increased social isolation, especially among the elderly, could have contributed by making detection of stroke onset by family members less likely. this explanation is consistent with the finding that patients with stroke admitted during the pandemic were significantly younger. in addition, this theory is supported by data emerging from several countries suggesting a significant increase in mortality during the pandemic period that is unlikely to be explained by covid- cases alone. this excess mortality could be explained by undiagnosed covid- but may also reflect mortality due to other critical illnesses, including stroke, that went untreated, particularly among the elderly. third, as suggested by the analysis of the emergency calls in catalonia, the massive increase in requests to emergency medical services may have hindered the correct activation of the stroke code and limited the ability for emergency medical services to respond to calls. patients unaccounted for could have been taken to other centers outside of the usual stroke networks, a possibility that cannot be entirely excluded in either study. fourth, stroke symptoms could have been misinterpreted or not diagnosed properly in some patients with an acute respiratory infection, introducing misdiagnosis. finally, stroke incidence itself could have declined due to environmental or behavioral changes taking place during the period of reduced economic activity; lower levels of pollution and less physical or emotional strain at work, for example, may reduce stroke risk. , further research on these possibilities in the setting of the pandemic could lead to relevant discoveries about the mechanisms of stroke. taken together, observations from these studies show the ability to provide guideline-concordant stroke care in a pandemic with appropriate support from hospital administration and protected stroke pathways. while this is reassuring, it is concerning that during the covid- pandemic some missing stroke patients who would otherwise have been treated could have died or become disabled due to a failure to seek medical attention, as discussed in these reports. furthermore, the effect on stroke care and outcomes could be worse when hospital systems are completely overwhelmed, and admitted patients cannot get adequate care. in the barcelona hospital report, although % of hospital beds were allocated to patients with covid- , it does not appear that the stroke unit itself was adversely affected. the results, moreover, also raise questions. first, it is uncertain how generalizable these data are, and whether the impact of covid- on stroke depends on specific local or regional stroke systems of care or other features of health care systems. second, more data are needed on the types of stroke that are most affected by the pandemic. if the reductions in cases are primarily represented by an absence of minor strokes and transient ischemic attacks, we may expect an influx of stroke patients in the coming months due to lack of adequate secondary prophylaxis. third, increasing evidence suggests that covid- may itself lead to coagulopathy and vascular endothelial dysfunction, , potentially precipitating ischemic stroke, which makes the drop in stroke admissions even more striking. the potential association of covid- with stroke, though rare, requires further study. although it may be premature to conclude that a lack of stroke awareness played a major role in the decrease in hospital admissions, stroke professionals need to continue to educate the public and their patients that, even in a pandemic, stroke remains a disabling and potentially fatal illness. our stroke teams are ready to provide care, even if they require use of higher levels of protective equipment. it is also crucial to ensure that even in these trying times, stroke care remains a priority for health systems and among hospital administrators. meanwhile, further evaluation of epidemiological and clinical data can provide valuable insights into these trends that can be used to plan health care during future surges of covid- or other pandemics, thereby preventing the long-term impacts of suboptimal stroke treatment. none. dr aguiar de sousa reported nonfinancial support from boehringer ingelheim outside of the submitted work. dr sandset has received an honorarium from novartis and bayer outside the submitted work. dr elkind receives research support from the bms-pfizer alliance for eliquis and roche outside the submitted work. covid- and stroke -a global world stroke organization perspective collateral effect of covid- on stroke evaluation in the united states the impact of the covid- epidemic on stroke care and potential solutions acute stroke care is at risk in the era of covid- : experience at a comprehensive stroke center in barcelona estimating excess -year mortality associated with the covid- pandemic according to underlying conditions and age: a population-based cohort study short term exposure to air pollution and stroke: systematic review and meta-analysis ipd-work consortium. long working hours and risk of coronary heart disease and stroke: a systematic review and meta-analysis of published and unpublished data for , individuals clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study covid- and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up large-vessel stroke as a presenting feature of covid- in the young key: cord- -afq authors: ghanchi, hammad; patchana, tye; wiginton, james; browne, jonathan d; ohno, ai; farahmandian, ronit; duong, jason; cortez, vladimir; miulli, dan e title: racial disparity amongst stroke patients during the coronavirus disease pandemic date: - - journal: cureus doi: . /cureus. sha: doc_id: cord_uid: afq introduction the global coronavirus disease (covid- ) pandemic has had deleterious effects on our healthcare system. lockdown measures have decreased the number of patients presenting to the hospital for non-respiratory illnesses, such as strokes. moreover, there appears to be a racial disparity among those afflicted with the virus. we sought to assess whether this disparity also existed for patients presenting with strokes. methods the get with the guidelines national stroke database was reviewed to assess patients presenting with a final diagnosis of ischemic stroke, transient ischemic attack (tia), subarachnoid hemorrhage (sah), or spontaneous/nontraumatic intraparenchymal hemorrhage (iph). the period of february - may was chosen given the surge of patients affected with the virus and national shutdowns. data from this same time during was used as the control population. our hospital numbers and four additional regions were assessed (california hospitals, pacific state hospitals, western region hospitals, and all hospitals in the united states). patients were categorized by race (white, black/african american, asian, native american, hispanic) in each cohort. the primary endpoint of this study is to compare whether there was a significant difference in the proportion of patients in each reported racial category presenting with stroke during the covid- pandemic caused by severe acute respiratory syndrome coronavirus (sars-cov- ). results a downward trend in total number of patients was noted in all five regional cohorts assessed. a statistically significant increase in the number of black and hispanic patients presenting with strokes was noted in california, pacific hospitals, western hospitals, and all hospitals in the united states during various months studied comparing to . a statistically significant increase in the hispanic population was noted in february and march in all california hospitals (p= . and . , respectively) and pacific coast hospitals (p= . and . , respectively). the western region and all national hospitals noted a significant increase in strokes in the hispanic population in april (p= . and . , respectively). a statistically significant increase of strokes in the black population was noted in april in pacific hospitals, western region hospitals, and all national hospitals (p= . , . , and . , respectively). conclusion the covid- pandemic has adversely affected certain racial groups more than others. a similar increase is noted in patients presenting with strokes in these specific racial populations. moreover, lack of testing for the sars-cov- virus may be missing a possible link between racial disparity for patients infected with the virus and patients presenting with stroke. the authors advocate for widespread testing for all patients to further assess this correlation. the coronavirus disease pandemic, caused by the severe acute respiratory syndrome coronavirus (sars-cov- ), has affected many aspects of healthcare, including stroke care. significant racial disparities among populations affected by covid- have recently made headlines. some sources have also cited sars-cov- as a possible cause of stroke [ ] . nationally, hispanics and blacks are disproportionately represented among laboratory-confirmed covid- cases [ ] . as of june , age-adjusted covid- -associated hospitalization rates were highest among people who are non-hispanic american indian/alaska native, non-hispanic black, and hispanic/latino according to the covid- -associated hospitalization surveillance network (covid-net) [ ] . higher rates of covid- deaths were reported in counties with a high black population, especially in rural and small metro counties [ ] . this is not the first time in history that racial disparity has existed in medicine; surgeries on black women without anesthesia by dr. sims [ ] and the tuskegee syphilis study are two examples of racism and prejudice that have caused distrust towards the medical sciences among this population [ ] . there are no known unethical practices during the recent pandemic, however, this lingering mistrust can lead to delayed presentation in the setting of stroke and render black patients to be ineligible for receiving intravenous tissue plasminogen activator (iv-tpa) treatment [ ] . despite the national decline in the mortality rate from stroke, it remains the second leading cause of death in blacks [ ] . moreover, black individuals have been shown to have a higher mortality rate [ ] and a higher chance of experiencing disability [ ] following a stroke compared to whites. furthermore, the american heart association (aha) stroke council scientific oversight committee has reported a history of racial discrepancies in stroke risk factors, incidence, prevalence, and symptom recognition [ ] . given the recent pandemic and racial disparity among patients afflicted with sars-cov- and the possible link of this virus and cerebrovascular accidents (cva), we sought to analyze whether there was a disparity for stroke patients presenting to hospitals during this time using the get with the guidelines (gwtg) national stroke database. the primary endpoint of this study is to assess whether disparity exists at our own hospital. we also wanted to expand this scope to the regional and national levels to assess for any possible racial disparities. the gwtg stroke registry at our institution, a level primary stroke center certified by the healthcare facilities accreditation program, was retrospectively reviewed to assess the impact of the sars-cov- outbreak on the number of patients presenting with stroke to our hospital. demographics with regards to patients' race were collected. data were stratified by date and comparison was made between the covid- period (february -may ) and similar timeframe pre-covid- (february -may ). the months preceding the covid- period (october -janurary ) were avoided as a control as it is hard to know whether sars-cov- was propagating in the population during this time. the gwtg database was used to review records at our hospital, all california hospitals, west and pacific regions, and all hospitals nationally. patients presenting to these hospitals with a final diagnosis of ischemic stroke, transient ischemic attack (tia), subarachnoid hemorrhage (sah), or spontaneous/nontraumatic intraparenchymal hemorrhage (iph) were reviewed. after data was extracted from the database, the cohorts were stratified into five groups: (a) our hospital, (b) all california hospitals, (c) all pacific coast hospitals (alaska, washington, oregon, california, and hawaii), (d) all western hospitals (pacific plus montana, idaho, wyoming, nevada, utah, colorado, arizona, and new mexico), and (e) all hospitals in the united states that submit data to the registry. among these groups, the number and relative proportion of each reported race (white, black/african american, asian, native american, or hispanic) were reviewed each month during covid- and a similar time frame pre-covid- . proportions were chosen instead of volume of patients to limit any confounding decreases/changes in the number of patients in each time frame as recent data has suggested a decrease in total number of stroke patients presenting to the hospital during this time [ ] . the primary endpoint of this study is to compare whether there was a significant difference in the proportion of patients in each reported racial category presenting to our institution with stroke during the covid- pandemic caused by sars-cov- . the same analysis was conducted for the pacific hospitals, western hospitals, and all national hospitals. statistical analysis was performed using z-test to compare the proportions for all races for any significant difference month by month (i.e. february compared to february , march compared to march , etc.). there was an average of . patients per month in and patients per month in during the time frame studied at our hospital. this downward trend in compared to in total patients per month was echoed in all the groups studied (california, pacific, western region, and national). the total number of patients in each subgroup can be viewed in the appendix. to remove the confounding effect of decreased patient numbers, as this decrease became more evident on the regional and national levels (i.e. mean of , . patients nationally february through may versus , . patients during the same months in ) during the covid- months, the percentage of each race presenting to each hospital category was calculated (see appendix). looking at our hospital's local population, a significant difference in native hawaiian/pacific islander population was noted in february compared to (p= . ) but other racial cohorts remained similar ( table ) . data for asian and american indian or american native populations were insufficiently powered to perform statistical analysis. expanding the scope to include all california hospitals, a significant difference was noted again in the native hawaiian/pacific islander population in february compared to the prior year (p< . ). the hispanic population also showed a significant difference for the months of february and march (p= . and p= . , respectively). the remainder of racial cohorts in california remained stable during the studied time studied. racial disparities are well documented in all aspects of stroke as it relates to differences in stroke risk factors, incidence, prevalence, and symptom recognition in comparison to the white population [ ] . while disparity in stroke may partially be explained by geography [ ] , neighborhood socioeconomic status [ ] , or age [ ] , there is substantial evidence emphasizing racial predisposition to stroke. the first-stroke risk at age is . times higher in black individuals compared to white individuals, with black patients having higher rates of ischemic and hemorrhagic stroke [ ] . in one cohort study, black patients also had a % greater risk of recurrent stroke within two years compared to white patients, as well as higher prevalence of key vascular risk factors, including hypertension, diabetes mellitus, smoking, and high bmi [ ] . prevalence of underlying comorbidities and differences in leisure-time physical activity and diet may be contributing to the racial disparity among patients presenting with stroke prior to and during the covid- period. among patients hospitalized for covid- with data on underlying conditions, . % had at least one underlying condition according to the u.s. centers for disease control and prevention [ ] . these included preventable vascular risk factors related to poor diet and physical inactivity, such as hypertension, cardiovascular disease, obesity, and diabetes [ ] . relative to non-hispanic whites, blacks have historically been found to be less physically active [ ] and have poorer diets [ ] . this trend is consistent with the disproportionate increase in blacks presenting with stroke on a national level in march from the prior year. in contrast, hispanics have been found to have healthier diets than whites [ ] [ ] [ ] although poorer diets have been reported among those with high acculturation status [ ] . this interaction between acculturation status and dietary behavior may be contributing to the difference in trend seen among hispanic patients presenting with stroke at a regional versus national level. as of late june , age-adjusted covid- -associated hospitalization rates were highest among people who are non-hispanic american indian/alaska native, non-hispanic black, and hispanic/latino according to the covid- -associated hospitalization surveillance network (covid-net) [ it has previously been reported that covid- patients may present with ischemic stroke [ ] . influenza-like illnesses have also been linked to stroke [ ] . while yet to be proven, there are several proposals on how covid- may increase the risk of stroke. angiotensin converting enzyme (ace) ii receptor is a functional receptor and entry point for sars-cov and sars-cov- . involved in cardiovascular homeostasis, the receptor is expressed on several vital tissues, including vascular endothelium, arterial smooth muscle, and the brain [ ] . sars-cov infection appears to downregulate ace ii [ ] , which may contribute to increased stroke risk. cardiac embolism from virus-related cardiac injury [ ] , hypercoagulability exhibited by elevated d-dimer levels [ ] , and inflammatory reactions due to cytokine storm [ ] are other mechanisms in which covid- may lead to increased risk of stroke. stress from lockdowninduced isolation increases sympathetic release cytokines which affects the comorbidities of this end-organ disease. these factors amplify the effects of stroke in this population. furthermore, during the month of february , the data demonstrate an increase in the total number of patients presenting with strokes in all subgroups (appendix table ). given the possibility of sars-cov- causing vascular injury, this rise may be attributed to early stages of the covid- pandemic, i.e. sars-cov- was propagating in february in the united states possibly causing increase in stroke numbers. this rise in total numbers was then mitigated during the following months by the nationwide lockdowns and patient fears of contracting the infection. testing for sars-cov- was not being performed at this time, so this postulation is difficult to prove. moreover, given the possibility of carriers of this virus being asymptomatic from a respiratory standpoint, patients presenting with stroke may fall into this category. one major limitation of this study is the lack of widespread testing for sars-cov- . the cause for the increase in the number of strokes in february before lockdown measures is uncertain but given the virus was circulating during this time along with the vascular injury it causes make it a possible suspect. moreover, lack of widespread testing the months following also limits our ability to assess whether the increase in certain races being more adversely affected from the virus and increase in the number of strokes in the same ethic groups is related. thus, we hope to advocate for universal testing for sars-cov- for all patients presenting to the hospital to further isolate possible carriers who are asymptomatic from a respiratory standpoint. moreover, given the retrospective nature of this study, we are unable to retroactively implement these goals. the global covid- pandemic has had many devastating effects on not only our economy and lifestyles, but also our healthcare system. certain races are being more adversely affected than others from this virus due to the effects on the human physiology and the ability of the virus amplify the negative health effects of the comorbid conditions of stroke. the potential for this virus to cause strokes may be causing our observed increase in minority cerebrovascular accidents. increase in stroke numbers prior to lockdowns may be related to early propagation of the virus. further work is needed to assess this relationship as well as more widespread testing for sars-cov- to determine the true pathophysiology of this illness. human subjects: consent was obtained by all participants in this study. animal subjects: all authors have confirmed that this study did not involve animal subjects or tissue. conflicts of interest: in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. characteristics and outcomes of covid- patients in new york city's public hospital system coronavirus disease case surveillance -united states accessed assessing differential impacts of covid- on black communities the medical ethics of the "father of gynaecology disparities and distrust: the implications of psychological processes for understanding racial disparities in health and health care racial disparities in tissue plasminogen activator treatment rate for stroke: a population-based study stroke declines from third to fourth leading cause of death in the united states: historical perspective and challenges ahead reasons for geographic and racial differences in stroke (regards) investigators. ethnic disparities in stroke: the scope of the problem divergent poststroke outcomes for black patients: lower mortality, but greater disability racial-ethnic disparities in stroke care: the american experience: a statement for healthcare professionals from the american heart association/american stroke association effects of the covid- pandemic on stroke patients. cureus. racial disparities in stroke risk factors: the impact of socioeconomic status neighborhood socioeconomic index and stroke incidence in a national cohort of blacks and whites sex and race differences in the association of incident ischemic stroke with risk factors trends and racial differences in first hospitalization for stroke and -day mortality in the us medicare population from to association of black race with recurrent stroke risk hospitalization rates and characteristics of patients hospitalized with laboratory-confirmed coronavirus disease nutrition and health are closely related - - dietary guidelines racial/ethnic disparities in exercise and dietary behaviors of middleaged and older adults racial/ethnic disparities in dietary intake of u.s. children participating in wic racial/ethnic disparities in us adolescents' dietary quality and its modification by weight-related factors and physical activity higher fat intake and lower fruit and vegetables intakes are associated with greater acculturation among mexicans living in washington state covid- presenting as stroke influenza-like illness as a trigger for ischemic stroke severe acute respiratory syndrome coronavirus infection and ischemic stroke sars-coronavirus modulation of myocardial ace expression and inflammation in patients with sars covid- and the heart neurologic manifestations of hospitalized patients with coronavirus disease in wuhan, china influence of covid- on cerebrovascular disease and its possible mechanism key: cord- -zc ve le authors: leclerc, angela m.; riker, richard r.; brown, caitlin s.; may, teresa; nocella, kristina; cote, jennifer; eldridge, ashley; seder, david b.; gagnon, david j. title: amantadine and modafinil as neurostimulants following acute stroke: a retrospective study of intensive care unit patients date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: zc ve le background/objective: neurostimulants may improve or accelerate cognitive and functional recovery after intracerebral hemorrhage (ich), ischemic stroke (is), or subarachnoid hemorrhage (sah), but few studies have described their safety and effectiveness in the intensive care unit (icu). the objective of this study was to describe amantadine and modafinil administration practices during acute stroke care starting in the icu and to evaluate safety and effectiveness. methods: consecutive adult icu patients treated with amantadine and/or modafinil following acute non-traumatic is, ich, or sah were evaluated. neurostimulant administration data were extracted from the electronic medication administration record, including medication (amantadine, modafinil, or both), starting dose, time from stroke to initiation, and whether the neurostimulant was continued at hospital discharge. patients were considered responders if they met two of three criteria within days of neurostimulant initiation: increase in glasgow coma scale (gcs) score ≥ points from pre-treatment baseline, improved wakefulness or participation documented in caregiver notes, or clinical improvement documented in physical or occupational therapy notes. potential confounders of the effectiveness assessment and adverse drug effects were also recorded. results: a total of patients were evaluable during the . -year study period, including ( %) with ich, ( %) with is, and ( %) with sah. the initial neurostimulant administered was amantadine in ( %) patients, modafinil in ( %), or both in ( %) patients. neurostimulants were initiated a median of ( . , . ) days post-stroke (range – days) for somnolence ( %), not following commands ( %), lack of eye opening ( %), or low gcs ( %). the most common starting dose was mg twice daily for both amantadine ( %) and modafinil ( %). of the patients included in the effectiveness evaluation, ( %) were considered responders, including / ( %) receiving amantadine monotherapy and / ( %) receiving both amantadine and modafinil at the time they met the definition of a responder. no patient receiving modafinil monotherapy was considered a responder. the median time from initiation to response was ( , ) days. responders were more frequently discharged home or to acute rehabilitation compared to non-responders ( % vs %, p = . ). among survivors, / ( %) were prescribed a neurostimulant at hospital discharge. the most common potential adverse drug effect was sleep disruption ( %). conclusions: neurostimulant administration during acute stroke care may improve wakefulness. future controlled studies with a neurostimulant administration protocol, prospective evaluation, and discretely defined response and safety criteria are needed to confirm these encouraging findings. electronic supplementary material: the online version of this article ( . /s - - - ) contains supplementary material, which is available to authorized users. approximately , americans suffer a new or recurrent stroke each year, including % that are ischemic (is), % that are intracerebral hemorrhages (ich), and % that are subarachnoid hemorrhages (sah) [ ] . stroke is a leading cause of disability, with . % of noninstitutionalized adults reporting stroke-related disability, including - % reporting ≥ long-term comorbid medical conditions [ , ] . the national institute of neurological disorders and stroke recently identified early recovery after stroke as a research priority, highlighting specific interventions (including pharmacologic agents), for future investigation [ ] . early rehabilitation is a central component of poststroke care, with clinical practice guidelines recommending early mobilization and rehabilitation within - h [ ] and inpatient rehabilitation rather than skilled nursing care whenever possible [ ] . efforts to provide early rehabilitation following acute stroke can be compromised by a variety of conditions, including apathy and hypersomnia, which may occur in up to % and % of stroke survivors, respectively [ , ] . disordered consciousness after ischemic or hemorrhagic stroke can result from damage to many different structures, including bilateral cerebral cortical injury, pontine tegmentum, midbrain, basal forebrain, hypothalamus and central thalamus, putamen, caudate, and pallidum [ ] . strategies to circumvent these impairments and increase participation in early rehabilitation are needed. neurostimulants such as amantadine and modafinil promote wakefulness and may increase patient participation in early rehabilitation, with data largely extrapolated from patients with traumatic brain injury (tbi). although amantadine is commonly administered to patients with disorders of consciousness, its mechanism of action remains unclear. it may modulate dopamine activity by increasing its release, blocking its reuptake, and increasing postsynaptic dopamine receptors or altering their conformation and may also antagonize n-methyl-d-aspartate (nmda) receptors [ , ] . the mechanism of action of modafinil has been attributed to stimulation of alpha b noradrenergic receptors, reduced gamma-aminobutyric acid (gaba) release, increased glutamate or histamine release, or altered hypocretin activity [ ] . modafinil's effects appear independent of serotonin, dopamine, gaba, adenosine, histamine- , melatonin, and benzodiazepine receptors. compared to conventional neurostimulants, modafinil appears to be devoid of dopaminergic effects, which may be of significance as post-stroke dopaminergic system dysfunction has been recently described [ , ] . among the many neurostimulants available, amantadine has the strongest evidence supporting its administration. when started weeks post-tbi during acute rehabilitation, amantadine accelerates functional recovery [ ] . smaller controlled studies treating tbi patients with amantadine during their acute hospitalization have shown improved glasgow coma scale (gcs) and mini mental status examination (mmse) scores [ , ] , but whether similar benefits would occur during acute hospitalization after stroke is unknown. amantadine and modafinil are administered to patients following acute stroke in our intensive care unit (icu) on an ad hoc basis, but data supporting this practice are largely limited to delayed treatment in rehabilitation or outpatient facilities with very few reports during the acute care hospitalization [ ] [ ] [ ] . the primary purpose of this study was to describe amantadine and modafinil administration practices during acute stroke care in patients initially treated in an icu. we also sought to evaluate the safety and effectiveness of this practice. consecutive acute stroke patients treated in the -bed medical, surgical, and neurological icu and the -bed cardiac icu at maine medical center between december and july were evaluated in this retrospective cohort study. patients were included if they were ≥ years of age, admitted with an acute nontraumatic ich, is, or sah, and were treated with amantadine, modafinil, or both for at least h starting in an icu. the -h window was chosen based on our anecdotal observation that patients generally respond within acute rehabilitation compared to non-responders ( % vs %, p = . ). among survivors, / ( %) were prescribed a neurostimulant at hospital discharge. the most common potential adverse drug effect was sleep disruption ( %). conclusions: neurostimulant administration during acute stroke care may improve wakefulness. future controlled studies with a neurostimulant administration protocol, prospective evaluation, and discretely defined response and safety criteria are needed to confirm these encouraging findings. this time frame and shorter treatment intervals may be inadequate to assess response. patients were excluded if they were receiving amantadine or modafinil prior to hospitalization, were admitted with tbi, encephalopathy (including hypoxic ischemic encephalopathy after cardiac arrest), brain tumor, encephalitis, or had a history of seizures. patients were identified using a pharmacy-generated report. the institutional review board at maine medical center reviewed this study design and determined it was exempt from regulatory review. demographic information (age, gender, ethnicity), clinical characteristics including type of stroke (ich, is, or sah), stroke-specific severity grading (ich score for ich, hunt and hess scale for sah, and national institutes of health stroke scale [nihss] for is), laterality for ich and is, and presence or absence of an aneurysm for sah were recorded. descriptive clinical outcomes included icu and hospital length of stay, icu and hospital mortality, and discharge disposition (home, acute rehabilitation, skilled nursing facility, hospice, or death). all information was obtained from the electronic medical record, including notes entered by physicians, nurse practitioners, physician assistants, nurses, pharmacists, and occupational, speech, and physical therapists. a single pharmacist investigator (csb) extracted amantadine and modafinil administration data from the electronic medication administration record (mar), including specific neurostimulant(s) initiated (amantadine, modafinil, or both), starting dose, time from stroke to initiation, changes in dosing, and whether or not the neurostimulant was continued at hospital discharge. discharge prescriptions were assessed for dose taper instructions, no taper instructions, or no mention of the neurostimulant. no protocol for neurostimulant administration following acute stroke existed during the study. no single clinical effectiveness measure following neurostimulant administration after an acute stroke has been defined. accordingly, we adapted the approach used by studies evaluating acute administration of amantadine to tbi patients [ , ] . acute stroke patients were characterized as responders if they met two of the following three criteria on any one calendar day within days after neurostimulant initiation: increase in gcs score ≥ points from pre-treatment baseline, clinical improvement in wakefulness or responsiveness documented in caregiver notes, or clinical improvement in wakefulness or responsiveness documented in physical or occupational therapy notes. caregiver notes and gcs scores were assessed by a neurocritical care physician assistant (aml), and physical and occupational therapy notes were assessed by a doctor of physical therapy (kn) and a registered, licensed occupational therapist (jc). supplement describes the approach used by these chart reviewers. patients who did not meet the definition for responsiveness were classified as non-responders. if patients had an additional neurostimulant added or substituted, the timing of this change was considered when interpreting which drug the patient responded to or did not respond to. since there was no published literature to establish an expected duration of treatment prior to a response, if a patient responded after at least h of a new combination, we considered them a responder to the new regimen. potential confounders of the clinical effectiveness assessment were identified a priori, including hydrocephalus, intracranial pressure (icp) crisis, seizure, cerebral vasospasm or ischemia, craniotomy for hematoma evacuation, and receipt of a concomitant psychoactive medication (including sedation for mechanical ventilation). hydrocephalus was defined as placement of a cerebrospinal fluid (csf) shunting device with radiographic evidence of ventriculomegaly. intracranial pressure crisis was defined as an icp > mmhg and/or dilated pupils requiring decompressive surgery or hyperosmolar therapy. new seizures were defined as treatment (not prophylaxis) with an antiepileptic drug and/or electroencephalographic seizures beginning after neurostimulant initiation. radiographic cerebral vasospasm was present if diagnosed by transcranial doppler ultrasound, computed tomography angiography, or digital subtraction angiography. delayed cerebral ischemia was present if focal neurological deterioration requiring fluid bolus, vasopressors, or intraarterial vasodilators occurred. craniotomy for hematoma evacuation was identified by reviewing neurosurgical procedure notes. mechanical ventilation was identified by reviewing respiratory flow sheets and required an endotracheal tube or tracheostomy with use of a ventilator. administration of psychoactive medications (sedatives, opioids, antiepileptics, antipsychotics, or sleep aids) was identified by reviewing the electronic mar. supplement includes a list of the potential confounders encountered in this study and suggested approaches to account for them in future studies. potential adverse drug effects were selected based on published studies [ , ] , the prescribing information for amantadine and modafinil [ , ] , and our anecdotal experience. these included spasticity, confusion, sleep disruption, seizures, qtc prolongation (amantadine), agitation, and delirium. spasticity and confusion were identified by reviewing caregiver notes. sleep disruption was present if the patient received a new sleep medication after starting a neurostimulant, and for the other adverse events, the medical record was reviewed for the h prior to initiating neurostimulant therapy, and if the adverse event was not described prior to initiation but was identified afterward, we considered it possibly drug related. measurements of qtc were obtained from -lead electrocardiograms (ecg) and were considered prolonged if > ms after an initial ecg with a normal qtc. agitation and delirium were assessed using a previously published algorithm [ ] . the probability that an adverse reaction was related to neurostimulant administration was not assessed using grading scales (e.g., naranjo scale or bradford hill criteria) because of the numerous confounders present in icu patients, and the lack of demonstrated validity and reliability in critically ill patients. instead, as is standard with good clinical practice for research, we reported all potential adverse drug effects [ ] . continuous data are reported as median (interquartile range - %), and categorical or dichotomous variables as number and percentage. discharge status was grouped into two outcomes, either "home or acute rehabilitation, " or "skilled nursing facility, hospice or death. " response rates according to neurostimulant administered and discharge locations were compared using chi-square analysis or fisher's exact testing and p < . was statistically significant. if a patient transitioned to another neurostimulant for non-response or adverse event, they were counted in both medication categories. adverse events and responsiveness were assigned to the medication they were receiving at the time these were first detected. two hundred five patients received amantadine and/ or modafinil during the . year study period and patients were initially excluded: neurostimulant administered for an indication other than acute stroke (tbi [n = ], cardiac arrest [n = ], brain tumor [n = ], encephalitis [n = ], or encephalopathy [n = ]); neurostimulant prescribed prior to hospital admission (n = ) or administered for < h (n = ); or history of seizures (n = ). after our initial chart review of patients, inconsistent data prompted a second review in which patients were confirmed to have received drug for < h; these were excluded from the effectiveness analysis but maintained in the safety analysis. the final evaluable cohort for effectiveness included acute stroke patients. the median age was ( , ) years, and most patients were male (n = ; %) and caucasian (n = ; %) ( table ). the cohort included patients ( %) with an ich, ( %) with an is, and ( %) with a sah (all aneurysmal). at the time of neurostimulant initiation, ( %) patients were receiving mechanical ventilatory support. the hospital mortality rate was / ( %); no death was associated with neurostimulant administration, and most patients ( / ; %) were discharged to acute rehabilitation (table ) . the initial neurostimulant administered was amantadine in ( %) patients, modafinil in ( %), or both amantadine and modafinil simultaneously in ( %). neurostimulants were initiated a median of ( . , . ) days post-stroke (range - days). indications for neurostimulant administration in caregiver notes included somnolence ( %), not following commands ( %), lack of eye opening ( %), or low gcs ( %); more than one indication could be documented for each patient. time of day for neurostimulant administration was variable, but most twice daily doses were administered at : and : , and most daily doses were administered at : . the most common initial dose of amantadine in patients with an estimated creatinine clearance (crcl) > ml/min was mg twice daily (n = ; %), followed by mg once daily (n = ; %) or mg once daily (n = ; %). among three patients with impaired kidney function, the initial dose was mg once every other day (n = ; %, crcl = ml/min), or once weekly doses of mg or mg (one patient each) for two patients receiving hemodialysis. the amantadine dose was increased in ( %) patients a median of ( , ) days after initiation for persistent somnolence (n = ; %), not following commands (n = ; %), lack of eye opening (n = ; %), low gcs (n = ; %), aphasia (n = ; %), or an undocumented reason (n = ; %); more than one reason could be documented for each patient. the amantadine dose was decreased in ( %) patients a median of . ( , ) days after initiation due to delirium (n = ; %), agitation (n = ; %), or an unknown reason (n = ; %). modafinil was added to patients who initially received amantadine monotherapy a median of ( , ) days following amantadine initiation, with an initial modafinil dose of mg once daily in ( %), mg twice daily in ( %), and mg daily in ( %) patients. the most common initial dose of modafinil was mg twice daily (n = ; %), less frequently mg twice daily (n = ; %), mg once daily (n = ; %), or mg three times daily (n = ; %). the modafinil dose was increased in ( %) patients and days after modafinil initiation for somnolence or not following commands (n = each). the modafinil dose was decreased in ( %) patients and days after modafinil initiation for agitation (n = ) or an unknown reason (n = ). amantadine was added to ( %) patients who initially received modafinil monotherapy a median of ( , . ) days following modafinil initiation, with an initial amantadine dose of mg twice daily (n = ; %), mg once daily (n = ; %), or mg every h (n = ; %). in patients starting both amantadine and modafinil simultaneously, the initial dose of amantadine was mg twice daily (n = ; %) or mg twice daily (n = ; %) and for modafinil it was mg twice daily (n = ; %) or mg twice daily (n = ; %). the amantadine dose was increased from mg twice daily to mg twice daily days after initiation in ( %) patient because they were not following commands. with transitions to different medication groups, and including patients in every medication group they received, a total of patients received amantadine monotherapy, continuous variables are reported as median (iqr) and frequencies as number (%). responder denominators sum to more than patients because patients were included in multiple groups if they transitioned to different medications ich, intracerebral hemorrhage; icu, intensive care unit; sah, subarachnoid hemorrhage; snf, skilled nursing facility a from the enrolled subjects, were excluded from effectiveness analysis, including who died and who were transferred to rehabilitation or skilled nursing facilities b this single patient was discharged to hospice, expired h after transfer, and was counted as a death in fig. icu length of stay, days ( received combined amantadine/modafinil therapy, and received modafinil monotherapy at some time during their hospitalization. of the ( %) patients who survived to hospital discharge, ( %) patients had their neurostimulant stopped prior to discharge, and ( %) were provided neurostimulant prescriptions. amantadine prescriptions were provided to ( %) patients, ( %) received a modafinil prescription, and ( %) received a prescription for both neurostimulants. among the discharge neurostimulant prescriptions, ( %) included dosing without taper instructions, ( %) had taper instructions, and ( %) included no information about continuing or tapering the neurostimulant. among the patients included in the clinical effectiveness analysis, ( %) were considered responders, including / ( %) receiving amantadine monotherapy and / ( %) receiving both amantadine and modafinil at the time they first met the definition of a responder; no patient receiving modafinil monotherapy was a responder (p < . ; fig. , table ). the median time from neurostimulant initiation to responder status was ( , ) days (range - days). responders were more frequently discharged to home or acute rehabilitation compared to non-responders ( % vs %, p = . ; fig. ). many factors potentially confounded the effectiveness assessment. the most common was hydrocephalus (n = ; %), including / ( %) patients with ich, / ( %) with sah, and / ( %) with is. most of these patients (n = ; %) required csf diversion. supplement includes a complete list of confounders, their estimated impact on our assessments, and a recommended approach for future studies. among the patients included in the safety analysis, the most common potential adverse drug effect was sleep disruption requiring administration of a new sleep medication (n = ; %) (fig. ) . other potential adverse drug effects occurring after neurostimulant initiation included agitation (n = ; %), spasticity (n = ; %), and qtc prolongation (n = ; %) with amantadine. new onset seizures requiring antiepileptic drug administration occurred in ( %) patients (n = with ich and n = with is). amantadine was discontinued due to seizure in one is patient and continued in the other four. amantadine was discontinued in patients a median of ( , ) days after initiation. the decision to stop was made by clinical teams, and included sustained wakefulness after and days of treatment (n = ; %), or adverse drug effects including agitation (n = ; %), anxiety (n = ; %), delirium (n = ; %), seizures (n = ; %), qt prolongation without arrhythmia (n = ; %), and decision to transition to comfort measures only (cmo) (n = ; %). modafinil was discontinued in one patient days after initiation due to insomnia and agitation. participation in rehabilitation activities during acute stroke care and eventually in specialized rehabilitation settings is an important component of stroke recovery and is prioritized in stroke guidelines [ , ] . neurostimulants have proven beneficial for tbi patients when administered in rehabilitation units and, with weaker evidence, earlier in their recovery during acute care [ ] [ ] [ ] . this study represents the largest cohort of stroke patients treated with neurostimulants during their acute hospitalization, and suggests amantadine started in the first week after stroke may be associated with improved wakefulness or responsiveness in approximately half of treated patients. responders showed a promising trend with more frequent discharge to home or acute rehabilitation compared to non-responders, but these findings must be considered hypothesis-generating. early rehabilitation after stroke is recommended by the american heart association and american stroke association [ ] , and efforts to increase rehabilitation participation during acute stroke care with neurostimulants may be beneficial in somnolent or non-participatory patients. in our study, patients were started on neurostimulants a median of days after stroke, with a single patient starting in the first h. the best time to start neurostimulants is not known, and caution has been advised to avoid very early, high-intensity mobilization in the first h after acute stroke, since this has been associated with a reduction in favorable outcome at months [ , ] . several patients had neurostimulants started late in their hospital course and were either transferred or had support withdrawn prior to h of treatment. it is not clear if a longer duration of monitored dosing would have resulted in a response or not, but because of the short administration time, we excluded them from our effectiveness analysis. among our responders, the median time to response was days, providing some justification for this a priori threshold for minimal duration. no valid and reliable clinical effectiveness measure exists to assess response to neurostimulants in the acute adverse effects by neurosƟmulant administered amantadine modafinil both fig. potential adverse drug effects during neurostimulant administration. potential adverse drug effects were identified by reviewing provider progress notes, the medication administration record, electrocardiograms, and nursing flow sheets. causality assessments were not conducted due to the presence of confounding variables in this patient population. *qtc prolongation was only assessed in patients receiving amantadine care setting after stroke. studies describing amantadine administration to one rehabilitation and five acutely hospitalized stroke patients utilized the coma recovery scale-revised (crs-r) and disability rating scale (drs) [ , ] . a randomized study comparing modafinil and placebo administration within days of stroke reported the multidimensional fatigue inventory at , , and days post-stroke [ ] . the lack of consensus supporting a specific clinical effectiveness measure in the acute stroke setting and the retrospective nature of our study necessitated the development of a novel method. glasgow coma scale was shown to increase during acute administration of amantadine to and tbi patients [ , ] ; we utilized a similar approach. assessing the effectiveness of neurostimulant administration during acute stroke care is complicated by patient care needs, which often persist into the rehabilitation phase (e.g., mechanical ventilation or medications for sedation, analgesia, or seizures). even in the rehabilitation setting, medications confounded assessment of responsiveness in prior studies for up to a third of patients [ ] . the common sequelae of stroke (e.g., pain, seizures, vasospasm, hydrocephalus, and intracranial hypertension) also complicated our neurostimulant response assessments. for example, hydrocephalus (which required csf diversion % of the time) may have induced somnolence, while csf diversion or unclamping external drains may have induced wakening. similarly, intubated patients who are liberated from mechanical ventilation may become more interactive as their communication improves and sedation is reduced. a recent study of tbi patients treated acutely with neurostimulants in the icu encountered many of the same confounders [ ] . supplement includes a list of the potential confounders we encountered in this study and suggested approaches to them in future studies. the most common potential adverse drug effect was need for a new sleep medication, suggesting sleep disruption may have been occurring. our most common administration schedule of amantadine at : and : may alleviate this, but this remains unproven. two subjects were initially prescribed twice daily doses at : and : ; both had insomnia noted and the timing of doses was adjusted to : and : . the ideal dose and whether a predictable dose-response relationship exists for amantadine during acute stroke care is unclear. amantadine may increase the number of postsynaptic dopamine receptors or alter their conformation over several weeks, suggesting time of daily administration may not influence sleep [ ] . the most concerning potential adverse drug effect during amantadine therapy was seizures, though it was impossible to assess causality since seizures are not rare after the types of stroke we studied. amantadine has been safely administered to patients with epilepsy since the mid- 's [ ] , but caution is still required. many patients had multiple other reasons for potential adverse effects (i.e., confusion potentially caused by amantadine or modafinil, urinary tract infection, steroids, vasospasm, hydrocephalus, or hypernatremia). prior studies examining the accuracy of delirium screening following acute stroke using the cam-icu have suggested decreased accuracy results [ ] [ ] [ ] . the number of patients with delirium in our study was low but use of accurate screening tests after stroke in future studies may increase recognition. all adverse events identified have been previously reported, though it is possible other adverse drug effects occurred and were not identified in our retrospective study. several limitations of this study warrant comment. due to the paucity of published data for stroke patients treated with neurostimulants in the acute setting, no protocols or robust data were available to guide us or allow for a power calculation. we performed this retrospective evaluation to obtain baseline data and response estimates to help design future studies. reliance on caregiver notes was an additional limitation but prompted us to incorporate more consistent documentation regarding neurostimulant administration and response. it was not possible to control for changes in the quality of caregiver and pt/ot documentation over time as neurostimulants were more frequently administered. physical and occupational therapists used a semi-structured template including initial and subsequent evaluations, which differ in frequency and domains evaluated from patient-topatient. future studies in the acute care setting should utilize a clinical effectiveness measure that evaluates the indication for neurostimulant use and regularly assesses response. whether adding a second neurostimulant (if no improvement is observed from the initial neurostimulant) adds benefit, risk, neither, or both is unclear. herrold and colleagues retrospectively evaluated tbi patients treated with neurostimulants in a rehabilitation center, finding that those treated with multiple agents had no better outcome than those treated with a single medication [ ] . given the lack of an untreated control group in this retrospective study, we cannot be certain that any improvements resulted from the medications and it is possible they reflect the natural phase of recovery over time after stroke. not all patients were monitored for the full -day period after starting or changing a neurostimulant, due to transfers to rehabilitation or skilled nursing facilities or decisions to withdraw lifesustaining therapy. ideally, a consistent follow-up period would have been maintained for all patients. similarly, after a change in neurostimulant, a response within the first few days could be from the new regimen or a delayed response from the initial treatment. it is possible our approach to assign credit for a response to the new regimen if > h of drug had been given was incorrect. our results suggest modafinil may not be effective as monotherapy in the acute care setting, but larger, prospective studies are needed. in a non-randomized study, potential bias related to gender, comorbidities, severity of illness, or other factors must be considered. lack of response to modafinil in our study may have been the result of a mechanism of action separate from dopamine neurotransmission. pre-clinical and clinical data suggest dopamine activity is disturbed following acute stroke, and dopamine supplementation or augmentation may be of benefit, but this requires confirmation [ , ] . analysis by stroke type and location was not possible due to the small sample size. such an analysis may be important as previous studies have suggested stroke location may play a role in neurostimulant responsiveness [ ] . due to small numbers, we did not include patients who received other neurostimulants, such as dextroamphetamine or methylphenidate. prior data have been published for these agents [ , ] , and amantadine and modafinil were the two most prescribed stimulants in a recent acute tbi study [ ] . continuing medications started in the icu at the time of hospital discharge may be inappropriate in some settings [ ] , but in the case of neurostimulants, declines were seen when medication was stopped after weeks in tbi patients [ ] , suggesting continuation may be appropriate. initiation of neurostimulants during the acute care of patients admitted with is, ich, or sah is potentially associated with improved wakefulness. those who responded were more frequently discharged home or to acute rehabilitation, but we can neither confirm these improvements were medication related, nor that these outcomes are generalizable to other settings. these results are encouraging but must be considered hypothesis-generating given the uncontrolled nature of the study, and the many potential biases and confounders. further study using standard dosing and escalation strategies, prospective assessment of response and drug safety, and appropriate controls is needed. the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. author contributions aml, rrr, and djg contributed to study design, data collection and manuscript development. tm and dbs contributed to study design and manuscript development. csb, kn, and jc contributed to data collection. ae contributed to study design. all authors approved the final manuscript prior to submission. this research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors. heart disease and stroke statistics- update: a report from the prevalence and most common causes of disability among adults-united states multimorbidity in stroke stroke research priorities meeting steering committee and the national advisory neurological disorders and stroke council, national institute of neurological disorders and stroke. research priority setting: a summary of the early mobilization after stroke: early adoption but limited evidence american heart association stroke council, council on cardiovascular and stroke nursing, council on clinical cardiology, council on quality of care and outcomes research, et al. guidelines for adult stroke rehabilitation and recovery: a guideline for healthcare professionals from the 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antiepileptic drugs have failed routine use of the confusion assessment method for the intensive care unit: a multicenter study deconstructing poststroke delirium in a prospective cohort of patients with intracerebral hemorrhage in the middle of difficulty lies opportunity-albert einstein prescribing multiple neurostimulants during rehabilitation for severe brain injury dopamine for motor recovery after stroke: where to from here? effect of modafinil on subjective fatigue in multiple sclerosis and stroke patients effect of dextroamphetamine on poststroke motor recovery: a randomized clinical trial effect of methylphenidate and/or levodopa combined with physiotherapy on mood and cognition after stroke: a randomized, double-blind, placebo-controlled trial an analysis of psychoactive medications initiated in the icu but continued beyond discharge: a pilot study of stewardship the authors report no conflicts of interest. we adhered to ethical guidelines. the institutional review board at maine medical center reviewed this study design and determined it to represent exempt research. springer nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations. key: cord- -ixxk plf authors: akhtar, naveed; abid, fatma ben; kamran, saadat; singh, rajvir; imam, yahia; aljerdi, salman; almaslamani, muna; shuaib, ashfaq title: characteristics and comparison of covid- and non-covid- ischemic strokes and historical stroke patients. date: - - journal: j stroke cerebrovasc dis doi: . /j.jstrokecerebrovasdis. . sha: doc_id: cord_uid: ixxk plf introduction: : the presence of covid- infection may increase the risk of thrombotic events including ischemic strokes. whilst a number of recent reports suggest that covid- associated stroke tends to be severe, there is limited data on the effects of covid- in prospective registries. patient and methods: : to determine how covid- infection may affect cerebrovascular disease, we evaluated the ischemic stroke sub-types, clinical course and outcomes prior to and during the pandemic in qatar. the hamad general hospital (hgh) stroke database was interrogated for stroke admissions during the last months of and january-may . results: : in qatar the number of confirmed cases of covid- increased from only in february to in march, , in april and , in may. stroke admissions to hgh declined marginally from an average of /month for six pre-covid months to /month in march – may. there were strokes that were positive for covid- . when compared to non-covid- stroke during the three months of the pandemic, covid- patients were younger with significantly lower rates of hypertension, diabetes and dyslipidemia. covid- positive patients had more cortical strokes ( . % vs . %; p= . ), severe disease (nihss > : . % vs . %; p= . ) prolonged hospitalization and fewer with good recovery (mrs - : . % vs . %; p= . ). conclusions: : when compared to six pre-covid- months, the number of ischemic stroke admissions during the three months of the pandemic declined marginally. covid- positive patients were more likely to have a large cortical stroke with severe symptoms and poor outcome. the number of confirmed cases of covid- worldwide has exceeded , , with more than , confirmed deaths as of september , ( ). the virus mainly manifests through respiratory involvement with fever, cough, shortness of breath and other pulmonary symptoms ( ) . neurological symptoms, including headaches, dizziness, myalgias, alteration in levels of consciousness and altered mental status are common symptoms and may occur in more than % of hospitalized patients ( ) . in one recent study, acute stroke has been reported in . % of consecutive covid- related hospital admissions ( ) . whereas neuropathological examination reveals diffuse hypoxic injury in severe cases, likely related to the severe hypoxemia, there was no evidence for thrombosis, overt vasculitis or encephalitis in a series of autopsy cases ( ) . despite the lack of overt intracranial thrombosis in the autopsy study ( ) there is however evidence that covid- infection has profound effects on the cardiovascular system including an increased risk of venous thrombosis and pulmonary embolism ( ) , myocardial injury ( ) and stroke ( , , ; ) . in addition, an interesting report from new york suggests that during the covid- pandemic, there was a higher likelihood for imaging-confirmed acute ischemic stroke to harbor the virus during 'code-stroke' activation ( ) . another interesting observation from several centers across the globe have shown that transient ischemic stroke (tia) and stroke admissions have decreased significantly during the covid- pandemic ( , , , ) . there was a decrease in the number of strokes in piacenza (a city of , inhabitants), an important epicenter of the disease in northern italy ( ) . the monthly admissions decreased from an average of cases to only over a -week period ( ) . large studies from china ( ) , brazil ( , ) , and spain ( ) reported an approximately % decrease in ed admissions during the peak weeks of the pandemic. additional reports suggest an increase in covid- -related severe stroke, especially in younger patients ( ) . this may be related to a possible pro-coagulant state seen with covid- infection ( ) . a decrease in hospital admissions of cardiovascular disease and acute coronary syndromes has also been observed in eds during the recent covid- pandemic ( ) . the numbers of cardiac catheterization laboratory stemi activations decreased by % in the usa ( ) and % in spain ( ) as the pandemic spread in these countries. although a decrease in minor ailments and trauma-related visits may be related to a fear of exposure to the virus during visits to the ed, the actual reason for significant decreases in ed visits for more serious illnesses remain unclear. these reports unfortunately provide insufficient details on the relationship of covid- infection and stroke. prospective hospital-based or community registries are important to study the effects of pandemics on the types of vascular diseases ( ) . registries may also provide important insight about time-sensitive healthcare delivery metrics such as door-to-intervention times, as was recently documented from treatment delays of myocardial infarctions in hong kong ( ) . similarly, time-sensitive management of emergencies including thrombolysis in acute stroke may also be affected by the covid- pandemic. the main objective of the present study is to compare the types of ischemic strokes in patients with or without confirmed covid- infection to a busy tertiary care hospital during the pandemic. we also determined if there were any differences in the rates of complications during hospitalization and short-term prognosis between acute stroke patients with covid- infections and patients with acute stroke and no covid- infection. the qatar stroke database prospectively collects information on all acute stroke patients for the present study, we evaluated the monthly rates of confirmed ischemic stroke admissions to the hospital for the last months in , prior to the onset of covid- pandemic. we compared this to the first months of as the pandemic was being documented in china and europe (january-february) and as covid- cases began to be diagnosed in qatar (march-may). we documented all patients with ischemic stroke who also were diagnosed with covid- . any symptoms related to the viral infection (fever, cough, sore throat and severity of pulmonary illness) were documented. particular attention was given to where the patient was admitted (icu vs stroke ward), medical complications and treatment offered were all documented. where available, we also documented changes in the laboratory markers of inflammation in covid- subjects. descriptive statistics in the form of mean and standard deviations for continuous variables and frequency with percentages for categorical variables were performed. one-way anovas were performed to see significant mean level differences for all continuous variables according to pre-covid- ischemic stroke, covid- negative ischemic stroke and covid- positive categories. student t tests were applied for continuous variables to see significant mean level differences between subcortical strokes or small vessel disease (svd) vs cortical or large vessel disease (lvd), and "no evidence of pneumonia" on chest x-ray vs "bilateral pneumonia" on chest x-ray. chi-square tests were applied to see association of categorical variables according to pre-covid- ischemic stroke, covid- negative ischemic stroke and covid- positive cases, subcortical strokes or svd vs cortical or lvd; and "no evidence of pneumonia" on chest x-ray vs "bilateral pneumonia" on chest x-ray respectively. multivariate logistic regression analysis was used for the significant and important variables at univariate analysis to association of risk factors to covid- positive group. adjusted odds ratios with % c.i. and p values were presented in the tables. roc curve with c-statistics was used to see discriminate power of the model for the covid- positive cases. p value . (two tailed) was considered statistically significant level. the statistical tests were performed in ibm spss statistics ver. (ibm, armonk, usa). during the months of the study, there were patients [age; . ± . male/female ( %)/ ( %)] admitted to hgh with a diagnosis of acute ischemic stroke. the higher percentage of males reflects the demographics of qatar with a predominantly male expatriate population as has been previously reported ( , ) . there were admissions in the months prior to when covid- cases were confirmed in qatar (average monthly admissions to hgh (table ) . c-statistics was . with % c.i.: . - . , suggesting the model's good ability to discriminate for covid cases (figure ). to our knowledge, this is the first study that compares covid- patients to non-covid- patients within a prospectively collected stroke database. similar to previous case reports and case-controlled studies, from usa ( ), iran ( ), dubai ( ) , france ( ) and china ( ), a third of our covid- positive patients had severe disease, required icu admissions, stayed longer in hospital and had fewer subjects with good outcome. these patients likely represent a subset of stroke patients in whom the viral infection likely contributed to a prothrombotic state resulting in vascular occlusions and large strokes. in the remainder of patients, especially those presenting with small vessel disease, the viral infection was perhaps coincidental and did not influence the clinical course and outcome of the illness. we did not observe any delays in times from onset to hospital admission, or any differences in the rates of thrombolysis or thrombectomies in patients with or without covid- infection. the higher rates of admission to icu in covid- positive patients is likely related to the severity of illness at presentation. in patients with covid- infection, there is increasing evidence for activation of inflammatory and thrombosis pathways. case series suggest a high incidence of venous thrombosis despite anticoagulation treatment ( ), myocarditis ( ) and stroke ( ) ( ) ( ) . similar to our patients, covid- positive patients from other reports with acute stroke were younger, have fewer vascular risk factors and many had recurrent thrombi in the large cranial arteries ( - ). the longer hospitalization in our covid- positive patients was also likely related to more severe disease as evidenced by higher nihss scores and more cortical involvement. such patients were also less likely to have a favorable outcome on discharge despite longer length of hospitalization. in a recent study from europe, patients with covid- associated ischemic strokes were more severe with worse functional outcome and higher mortality than non-covid- ischemic strokes ( ) . an intriguing observation during the covid- pandemic is the decreasing number of stroke admissions reported from a number of countries ( , ( ) ( ) ( ) . the reason for the decrease in rates of cardiovascular disease remains unclear. perhaps the most important reason may be the fear of exposure to covid- in hospitals and thus opting for staying home to minimize the risk. this may explain the decrease in the number of "stroke mimics" admission to hospital in our study and fewer hospitalization of patients with tias and milder strokes in the study from brazil ( ) . there are strengths to our study. the qatar stroke database is very robust and has prospectively recorded stroke trends in the country for more than years. we did not document major changes in the admission of ischemic stroke sub-types during the months preceding and during the three months of the covid- pandemic. whereas other studies comprised of case reports or case series, we compare profiles of non-covid- acute stroke patients before and during the pandemic with acute stroke patients who were covid- positive. our study reveals that covid- positive patients were more likely to be sicker, had more cortical involvement and had prolonged hospitalization. in addition, fewer patients had a good recovery at discharge as measured with mrs. the study has some limitations. the study period was only three months and may not be sufficient to determine if these were related to covid- infections. we did not document the relationship of the illness to the severity of covid- -related laboratory abnormalities. we also do not have enough follow-up data on the patients seen during the pandemic to adequately document the changes in outcomes. the onset of covid- pandemic has been associated with a decrease in non-covid- associated admissions to hospitals in asia, europe and north america. we present data from a prospective stroke database showing that ischemic stroke decreased marginally during the covid- pandemic. we also review the presenting features and clinical course of covid- positive patients. our data suggests that in a third of acute stroke patients, the viral infection results in a more severe disease, whereas in the remainder, the covid- illness has very little effect on the course of the illness. in summary, we believe that the spectrum of acute stroke in the covid- includes three presentations; stroke and no covid- infection, stroke with incidental covid- infection and covid- induced prothrombotic ischemic stroke. . johns hopkins coronavirus recourse center https/coronavirus.jhu.edu/map.html) clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study neurological manifestations in hospitalized patients with covid- : the albacovid registry venous and arterial thrombotic complications in covid- patients admitted to an academic hospital in neuropathological features of covid- autopsy findings and venous thromboembolism in patients with covid- covid- and cardiovascular disease impact of the covid- epidemic on stroke care and potential solutions break in the stroke chain of survivial due to covid- large-vessel stroke as a presenting feature of covid_ in the young sars -cov- and stroke in new york healthcare system covid- is an independent risk factor for acute ischemic stroke the baffling case of ischemic stroke disappearance from casualty department in the covid- era decrease in hospital admissions for transient ischemic attacks, mild and moderate stroke during covid- era falling stroke rates during covid- pandemic at a comprehensive stroke center lupus anticoagulant and abnormal coagulation tests in patients with covid- covid- : a&e visits in england fall by % in week after lockdown reduction in st-segment elevation cardiac catheterization laboratory activations in the united states during covid- pandemic impacto de la pandemia de covid- sobre la actividad asistencial en cardiología ntervencionista en españa. rec interv cardiol role of data registries in the time of covid- . circulation: cardiovascular quality and outcomes impact of coronavirus (covid- ) outbreak on st-segment-elevation myocardial infarction care in hong kong beneficial effects of implementing stroke protocols require establishment of a geographically distinct unit ethnic variation in acute cerebrovascular disease: analyses from the qatar stroke registry classification of subtype of acute ischemic stroke. definitions for use in a multicenter clinical trial. toast. trial of org in acute stroke treatment classification and natural history of clinically identifiable subtypes of cerebral infarction coronavirus disease and stroke in iran: a case series and effects on stroke admissions covid- and acute stroke -a case series from dubai treatment of acute ischemic stroke due to large vessel occlusion with covid- collateral effect of covid- on stroke evaluation in the united states what happened to surgical emergencies in the era of covid- outbreak? considerations of surgeons working in an italian red zone. update in surgery key: cord- -houm zcu authors: guillan, marta; villacieros-alvarez, javier; bellido, sara; peremarch, concepcion perez-jorge; suarez-vega, victor m.; aragones-garcia, maria; cabrera-rojo, celina; fernandez-ferro, jose title: unusual simultaneous cerebral infarcts in multiple arterial territories in a covid- patient date: - - journal: thromb res doi: . /j.thromres. . . sha: doc_id: cord_uid: houm zcu • in the occurrence of new-onset neurological symptoms in covid- patients, we should suspect an acute ischemic stroke and not assume that it is secondary to the respiratory syndrome (hypoxia). acute ischaemic stroke continues to be a treatable medical emergency also during the sars-cov- pandemic. • arterial thrombotic events may not only occur as a complication in severe cases of covid- ; but can also appear in mild-moderate cases due to other mechanisms. • several pathogeneses may be behind ischemic strokes in covid- , in addition to the more evident coagulopathy associated with the severe infection. j o u r n a l p r e -p r o o f syndrome, neurological manifestations have been described in more than a third of patients, both in mild-moderate cases of the infection, as associated or as a complication in severe and critical cases. anosmia, ageusia, myalgias and headache have been widely described in patients with mild symptoms; while acute cerebrovascular disease, seizures, polyneuritis and encephalopathies have been observed in the most severe cases [ , ] . in this report, we present a patient who was admitted with a diagnosis of sars-cov- multilobar pneumonia who developed a complex cortical visual deficit consistent with a partial anton's syndrome plus simultagnosia. a -year-old man with a history of hypertension, heavy smoking, and harmful alcohol consumption was brought to the emergency department after being found dazed and confused by his neighbours. he lived alone. his medications included enalapril and acetylsalicylic acid. upon arrival at the emergency department, he reported a dry cough in the last five days without fever or chills as long as he could recall. on examination, hypoventilation was auscultated in both lungs, basal oxygen saturation was always higher than %, and he was afebrile and normotensive. a chest radiograph showed multilobar pneumonia and a nasopharyngeal swab reverse transcription-polymerase chain reaction (pcr) resulted positive for sars-cov- . consequently, he was admitted to the internal medicine department and treated with a combination of hydroxychloroquine, ceftriaxone and azithromycin. prophylactic anticoagulation with lmwh and conventional low-flow nasal cannula oxygen therapy was also prescribed. the patient responded positively, without pulmonary complications and with a resolution of the respiratory syndrome both clinically and radiologically. a daily analysis showed peak levels of white cell count in . x ³μl (lymphocytes . x ³μl), fibrinogen mg/dl, d-dimer μg/l, lactate dehydrogenase iu/l, highsensitivity c reactive protein . mg/dl, serum ferritin μg/l; all other parameters were found within normal ranges. after fifteen days, the neurology service was consulted because the patient remains confused and a significant gait ataxia of undetermined time was detected. neurological examination showed temporo-spatial disorientation, dysarthria, partial cortical blindness and anosognosia with visual confabulation, optic ataxia, difficulty in visual scanning, simultagnosia, and mild left hemihypoesthesia. an unenhanced brain ct we, therefore, present an unusual case of simultaneous multivessel cerebral infarctions, without known extracerebral thrombotic events, in a patient with a moderate covid- who did not develop acute respiratory distress syndrome or disseminated intravascular coagulation. the temporal association with the infectious disease covid- , and the lack of other common causes of stroke, lead us to consider that they are associated. so far, the majority of published cases linking ischaemic stroke to covid- were severe or critical covid- cases with significant hemodynamic and analytical disturbances, especially with d-dimer rates above ng/ml [ , ] . moreover, the csf-analysis, in this case, presented hyperproteinorraquia and lymphocytic pleocytosis greater than expected for an ischaemic stroke. previous studies carried out in stroke patients showed a variable range of reactive pleocytosis up to mpt/l cell and nonspecific proteins up to mg/l in csf [ ] . in cases describing higher concentrations of cells and proteins, such as our case, pathogens j o u r n a l p r e -p r o o f causing vascular damage were found. the ocb mirror pattern in csf (in which identical clones of igg proteins are present in csf and serum), suggests that the igg has entered the central nervous system (cns) from the systemic circulation, this passive filtration is facilitated by blood-brain barrier damage. this pattern only indicates systemic immune activation but it has been previously observed in cases of systemic viral infections with neurological involvement as cerebral vasculitis (the diagnosis of cns vasculitis is difficult, in many cases cerebral biopsy is required and it is not always possible to confirm the presence of multiple cerebral artery stenosis in the imaging exam) [ ] . it seems clear that patients with severe covid- may suffer an ischaemic stroke or cerebral venous thrombosis because of the hypercoagulability that coincides with the critical illness [ ] . but it seems reasonable too to consider that in milder covid- syndromes, other pathophysiological mechanisms may well explain the occurrence of cerebral infarctions. thereby in other viral infections that have been associated with a higher stroke risk, the vasculitis caused by a direct infection of the cerebral arteries; as well as sustained inflammation triggering instability of atherosclerotic plaque, and a transient thrombophilia have been proposed as the potential mechanisms lead to the cerebral ischaemia [ ] . further studies are needed to clarify the different pathogenic pathways by which covid- may cause strokes and to identify the factors that put covid patients at higher risk of suffering a stroke. the authors declare that there are no competing interests associated with the manuscript. the bottom row images depict axial t gradient echo sequences with blooming neurological manifestations of hospitalized patients with covid- in wuhan, china: a retrospective case series study covid- -associated acute hemorrhagic necrotizing encephalopathy: ct and mri features characteristics of ischaemic stroke associated with covid- venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in low diagnostic yield of routine cerebrospinal fluid analysis in juvenile stroke central nervous system vasculitis associated with hepatitis c virus infection: a brain mri-supported diagnosis confirmation of the high cumulative incidence of thrombotic complications in critically ill icu patients with covid- : an updated analysis infections causing stroke or strokelike syndromes all patients in the stroke unit have signed an informed consent to collect and use their anonymised data for research purposes. key: cord- - w wqy h authors: borhani-haghighi, afshin; bavarsad shahripour, reza; azarpazhooh, mahmoud reza title: time is brain: a call to action to support stroke centers in low- and middle-income countries during the covid- pandemic date: - - journal: eur neurol doi: . / sha: doc_id: cord_uid: w wqy h nan dear editor, covid- infections may affect other noncommunicable diseases, such as stroke, both directly and indirectly. stroke may increase the probability of severe infection and mortality in covid- infections. covid- may lead to cardiac injury, arrhythmia, myocarditis, coagulopathy, and consequently stroke [ ] . as an example, in iran, neurologists identified some stroke cases among covid- cases. given the health infrastructure differences, economic differences, and previous differences in the burden of stroke between low-and middle-income (lmics) versus high-income countries [ , ] , lmics, in particular, may face a considerable strain with a possible negative impact on the healthcare delivery system. while we are globally fighting covid- , we need to implement feasible approaches to prevent or at least minimize any breakdown in the previous preventive and treatment approaches. we here recommend some suggestions and a call to action in lmics. healthcare professionals are at a higher risk of cov-id- than the normal population [ ] . given the previous staff shortages in healthcare in many lmics, providing personal protection equipment should be prioritized. we encourage international organizations, such as the world federation of neurology (wfn) and world stroke organization (wso), to help provide personal protection equipment for lmics. social isolation does not mean lack of social interactions. we recommend health policymakers to authorize telemedicine technology in lmics. many important aspects of acute stroke management, from ems dispatch to the selection of eligible cases for intravenous thrombolysis or endovascular therapy, can be performed via telestroke [ ] . expensive telemedicine and telerehab programs are not appropriate for many lmic situations. low-priced, accessible, and secured cross-platform mobile applications can facilitate telemedicine/telerehab usage. institutions may explore with the ethics committee and institutional review board whether commercially available low-cost smartphone applications can substitute in locations where telestroke networks are not available. besides, the security and confidentiality of telemedicine systems should be assured and perhaps funded by social media companies. early supported discharge services should be organized in lmics [ ] . stroke centers need to practice / outpatient support using secured video-audio applications or at least telephone questionnaires to address vascular risk factors and assure medication compliance. important screening questions with simple preventive measures to reduce the chance of deep vein thrombosis, falls, urinary tract infections, and pneumonia could be sent using bluetooth/ email to patients or the next of kin instead of paper-based documents. based on anecdotal data, some crucial investigations such as formal swallowing assessments were reduced in some centers for fear of contagion. all unnecessary diagnostic activities should be summarized or merged for the sake of decreasing the rate of, or at least the fear of, covid- . if possible, it is crucial to separate ct units of covid- cases from all other cases. neurologists can send holter monitoring to selected patients along with installation instructions or a telephone call for installation and a prepaid envelope to mail it back. finally, stroke centers in the world need to support each other. worldwide prestigious neurology centers, for example, wso or wfn, can host a network of centers to share the best policies and experiences. lmics need to be supported to continue fighting against stroke. neurology is a big but close-knit family. potential effects of coronaviruses on the cardiovascular system: a review excessive incidence of stroke in iran: evidence from the mashhad stroke incidence study (msis), a population-based study of stroke in the middle east socioeconomic status and stroke incidence, prevalence, mortality, and worldwide burden: an ecological analysis from the global burden of disease study covid- : protecting healthcare workers telestroke: india's solution to a public health-care crisis early supported discharge services for people with acute stroke: a cochrane review summary the authors have no conflicts of interest to declare. the authors did not receive any funding. study concepts, study design, manuscript preparation, definition of intellectual content, manuscript editing, and manuscript revision/review: afshin borhani-haghighi, m. reza azarpazhooh, and reza bavarsad shahripour. key: cord- - yzalrri authors: esenwa, charles; parides, michael k.; labovitz, daniel l. title: the effect of covid- on stroke hospitalizations in new york city date: - - journal: j stroke cerebrovasc dis doi: . /j.jstrokecerebrovasdis. . sha: doc_id: cord_uid: yzalrri background: little is known about the effect of the coronavirus disease pandemic on stroke care and the impact of the epidemic on acute stroke hospitalizations has not been described. methods: we analyze the stroke admission rate in three hospitals in new york city from january , through april , , identifying all cases of acute ischemic stroke, intraparenchymal hemorrhage and subarachnoid hemorrhage. results: we confirmed cases of out-of-hospital stroke. during the baseline period up to february , , the daily stroke admission rate was stable, with the slope of the regression describing the number of admissions over time equal to - . (se = . ), not significantly different from (p = . ), with daily admissions averaging . during the pandemic period, the slope was - . (se = . ); i.e., the number of stroke admissions decreased an average of . per week, (p = . ), with weekly admissions averaging , a reduction of % versus baseline. this general result was not different by patient age, sex, or race/ethnicity. conclusions: the weekly stroke admission rate started declining two weeks prior to the local surge of coronavirus admissions. the consequences of lack of diagnosis and treatment of a large proportion of acute stroke patients are likely severe and lasting. acute stroke is a medical emergency with a yearly united states (us) incidence of nearly , . of these, approximately , will eventually die and even more will be left with life-altering physical or cognitive disability. reducing post-stroke morbidity and mortality depends on hospitalbased diagnosis and management, including disease-changing treatment with intravenous tissue plasminogen activator (tpa) or mechanical thrombectomy (mt), secondary stroke prevention through risk factor identification and mitigation, and therapy for stroke complications. little is known about the effect of the coronavirus disease (covid- ) pandemic on acute stroke care. since early march, , when covid- became recognized as a major public health threat in the us, there have been reports of decreased treatment for mi and acute stroke. a nine-center report on st-elevation myocardial infarction activations in the us found a % reduction in march versus the previous months and a survey of hospitals in spain reported a % reduction in intervention for stemi comparing the last week in february to the third week in march, . a recent correspondence reported a % nationwide decrease in rapid neuroimaging software use in late march compared to february, . this corroborates an earlier observation from italy, but cannot distinguish the time relationship between the start of a local pandemic and decrease in stroke hospitalizations, and further does not measure potentially valuable differences in race, stroke type and acute stroke treatment. herein we report weekly rates of hospitalization for acute ischemic stroke (is), intraparenchymal hemorrhage (iph) and subarachnoid hemorrhage (sah) starting before the covid- pandemic and running through its peak in three hospitals in the bronx, new york, a diverse, urban county which at the time of the study had one of the highest covid- attack rates in the world. we include proportion of cases treated with tpa or mt, and assess differences in admission rates by age, sex and race/ethnicity. we included all cases of acute is, iph or sah admitted to the three montefiore health system hospitals in the bronx, comprising a community hospital, a new york state-designated primary stroke center and a joint commission-certified comprehensive stroke center, between january , and april th , . potential cases were ascertained by any primary or secondary stroke icd discharge code (i .x, i .x or i .x) and transient ischemic attack (tia) discharge codes (g .x) from hospital administrative records or by identification of stroke by screening of daily patient logs derived from the hospital problem list in epic by stroke data analysts, including inpatients who had not yet been discharged by the end of the study period. difficult ischemic stroke cases and all iph, sah and tia cases were reviewed by a vascular neurologist. demographic data, covid- status, in-hospital deaths and transfer source were ascertained from hospital administrative data. race and ethnicity were categorized as hispanic if the patient self-identified as spanish, hispanic or latino, otherwise by race, categorized as white, black, other or unknown. tpa, mt and stroke onset location (inpatient versus community) were ascertained from medical record review. tpa treatment at other hospitals prior to transfer was not included. daily covid- census at the three hospitals was extracted from data released by montefiore medicine. we summarize acute stroke cases by age, sex, race/ethnicity. we also report covid- status, in-hospital mortality and the proportion of cases receiving tpa and/or mt. changes in the admission rates of acute stroke over time, described by week, are modeled using piecewise regression. two distinct linear regression models describing the number of acute strokes, one for each time period, were obtained by a single model with number of stroke cases as the dependent variable, week (from to ) and period (baseline or pandemic) as independent variables, and the interaction between week and period. the definition of period as baseline or pandemic was not pre-defined, but was empirically determined based on the definition that yielded the best-fitting model. all analyses were performed in microsoft excel and sas using -sided chi-square or piecewise regression, alpha . . this study was approved by the montefiore medical center institutional review board. we screened potential stroke cases and confirmed cases, of which occurred outside the hospital and are included in subsequent analysis. cohort characteristics are provided in table . the best fitting piecewise regression model defined the baseline period as the first weeks of (ending february ) and the pandemic period as weeks - . statistical significance of differing slopes during these periods was based on the statistical significance of the interaction term of the regression model described previously (p = . ), with weekly admissions averaging . during the baseline period, the weekly stroke admission rate was stable, with the slope of the regression describing the number of admissions over time equal to - . (se = . ) which does not significantly differ from (p = . ). during the pandemic period, the number of arriving acute strokes decreased an average of . per week (i.e., the slope was - . , with se = . ), which differs significantly from (p= . ), with weekly admissions averaging , a % reduction versus baseline. this general result was not fig. . tpa or mt was performed on patients, with treated prior to the admission rate inflection point ( % of is cases) and after ( %), p = . . transfers from other hospitals in the bronx and beyond did not decline significantly. the earliest admission tested for covid- arrived on march and the earliest admission who had a positive test arrived on march . assessment for covid- was completed in patients during hospitalization, of whom ( %) were diagnosed with covid- . hospitalization ended in death in a higher proportion of patients who were diagnosed with covid- ( / , %) versus patients in whom covid- was excluded or not tested ( / , %), p < . . starting in the last week of february we observed a rapid decline in the weekly stroke admission rate across the three montefiore medicine hospitals in the bronx. the % decline in weekly admissions occurred about two weeks before the first covid- admission to the hospital network on march , and admissions remained low as the number of covid- admissions surged. the decline spanned demographic categories and stroke types but was not associated with a decrease in the proportion of ischemic stroke patients treated with tpa or mt. patients admitted with stroke and covid- infection had a high risk of death. the decline in admissions most likely reflects a fear of exposure to coronavirus rather than a decrease in capacity to admit and treat stroke patients (we had no such change) or in stroke risk. decades of educational efforts to get people to come immediately to the hospital with symptoms of acute stroke were immediately overwhelmed and it is unclear how quickly stroke admission rates will recover. the fear crossed all demographic boundaries, equally affecting old and young, men and women, whites, blacks and hispanics. the consequences of lack of diagnosis and treatment of a large proportion of acute stroke patients are likely widespread, severe and lasting. heart disease and stroke statistics- update: a report from the american heart association reduction in st-segment elevation cardiac catheterization laboratory activations in the united states during covid- pandemic impacto de la pandemia de covid- sobre la actividad asistencial en cardiología intervencionista en españa collateral effect of covid- on stroke evaluation in the united states the baffling case of ischemic stroke disappearance for the casualty department in the covid- era daily stroke admissions and daily covid- census. stroke hospitalizations during the covid- surge key: cord- -kca rvz authors: south, kieron; mcculloch, laura; mccoll, barry w; elkind, mitchell sv; allan, stuart m; smith, craig j title: preceding infection and risk of stroke: an old concept revived by the covid- pandemic date: - - journal: int j stroke doi: . / sha: doc_id: cord_uid: kca rvz anecdotal reports and clinical observations have recently emerged suggesting a relationship between covid- disease and stroke, highlighting the possibility that infected individuals may be more susceptible to cerebrovascular events. in this review we draw on emerging studies of the current pandemic and data from earlier, viral epidemics, to describe possible mechanisms by which sars-cov- may influence the prevalence of stroke, with a focus on the thromboinflammatory pathways, which may be perturbed. some of these potential mechanisms are not novel but are, in fact, long-standing hypotheses linking stroke with preceding infection that are yet to be confirmed. the current pandemic may present a renewed opportunity to better understand the relationship between infection and stroke and possible underlying mechanisms. the sars-cov- global pandemic at the time of writing, the global number of confirmed severe acute respiratory syndrome coronavirus (sars-cov- ) cases is approaching million, with over , reported fatalities. the current novel coronavirus outbreak began to receive worldwide media attention in early january with the earliest cluster of cases traced back to december in the city of wuhan in china. by january the world health organization (who) declared the outbreak a ''public health emergency of international concern'' and, after cases were reported in countries, the outbreak was recognized by who as a pandemic on march . sars-cov- is a member of the betacoronavirus genus of the coronaviridae family of enveloped, singlestranded rna viruses, several of which are known to cause mild respiratory disease in humans. it was named because of its similarity to sars-cov, the virus responsible for an epidemic in - that infected approximately people with almost fatalities. both sars-cov and sars-cov- cause acute respiratory symptoms but due to enhanced rates of transmission derived from transmission from asymptomatic individuals and a high level of early viral shedding in the upper respiratory tract, this recent pandemic has attained a large global impact. angiotensin-converting enzyme (ace ), the ''receptor'' for host cell entry of sars-cov- , is most prominently expressed on the surface of lung alveolar epithelial cells, venous and arterial endothelial cells, arterial smooth muscle cells and enterocytes of the small intestine. notably, considering the possible the possible relationship between respiratory tract infection and the incidence of stroke, particularly ischemic stroke, is not a new concept. early case-control studies identified respiratory tract infections as a significant risk factor across all age groups despite adjusting for other known vascular risk factors. a large caseseries analysis of uk medical records identified a significant risk of either first stroke or recurrent stroke associated with a diagnosis of acute respiratory tract infection. this risk was highest in the first few days after infection, steadily declining thereafter but remaining elevated over baseline for some time. the incidence ratio of first stroke was found to be . ( % ci . to . ) within three days of infection and . ( % ci . to . ) within days. a later retrospective case-crossover study of administrative data in the us, focusing on respiratory tract infections defined using centers for disease control and prevention criteria as ''influenza-like illness'', identified a similar risk of ischemic stroke within days of infection (odds ratio . , % ci . to . ). large, systematically collated datasets are not yet available for the current sars-cov- pandemic and, as such reliable estimates of the associated risk of stroke have not yet been published. this is also true of the previous sars pandemic that only affected individuals. although, an approximate stroke incidence rate of per sars patients was determined from a small, retrospective single-center analysis. for now, assumptions on the prevalence of stroke among covid- patients are based on small, single center observational studies, which estimate an incidence rate of approximately % among the most severe cases. in a larger single center study of covid- patients the estimated stroke incidence rate was much lower at . %. it is likely that any estimation of stroke incidence will be confounded by under-reporting; both in severe infection with competing risk of mortality and milder infections (and strokes) not presenting to hospital or primary care. common features of covid- pathogenesis and early pathology of ischemic stroke as we begin to better understand covid- there are clearly aspects of its pathogenesis and disease course that are implicated in the initiation, or in the very early pathophysiology, of ischemic stroke. what follows herein is a detailed summary of the current literature surrounding covid- , encompassing the immune and inflammatory responses to infection, thrombotic manifestations and vascular consequences of infection with a focus on possible mechanisms by which these elements may contribute to acute stroke events. activation of type i interferon (ifn), production of pro-inflammatory cytokines (interleukin- (il- ), tumor necrosis factor (tnf)) and the induction of ifn-stimulated genes (figure ( ) ). the immediate immunomodulatory impact of type ifn (and the subsequent type ifn (ifn-c) response) manifests as an accumulation of pro-inflammatory monocytes and macrophages in the alveoli. recruited macrophages are themselves prominent sources of il- , monocyte chemoattractant protein- (ccl ), il- and ifn, thereby contributing to further influx of myeloid cells (figure ( )), including neutrophils, which are an indispensable component of the inflammatory response to infection but also a major contributor to lung pathology. extensive neutrophil extravasation into the alveolar space has been identified in post-mortem tissue of covid- patients and neutrophil activation has long been associated with disease pathologies involving ards, and correlates with the extent of lung damage and with cytokine levels (tnfa, il- and il- ). the release of pro-inflammatory cytokines (type i ifn and il- ) also aids the initiation of the adaptive immune response to viral infection, through the maturation of lung resident conventional or monocytederived dendritic cells (dcs). these dcs migrate to draining lymph nodes and elicit a robust activation and proliferation of naı¨ve, antigen-specific cd þ (''cytotoxic'') t cells and naive cd þ (''helper'') t cells. in a cohort of sars patient samples, a high frequency of cd þ t cells, th and th cd þ t cells and polyfunctional cd þ t cells were identified in blood from patients with severe disease. early indications from covid- patients suggest a similar clonal infection of the lower respiratory tract begins with the binding of sars-cov- to ace on the surface of type ii alveolar pneumocytes ( ). the immediate type i interferon response recruits macrophages, monocytes, and neutrophils to the alveoli. propagation of the innate immune response is directed by th and th cd þ t cells ( ) as neutrophils and pro-inflammatory monocytes are targeted to the site of infection ( ) . endothelial activation, by either the inflammatory environment or by direct viral infection, upregulates key cell adhesion molecules allowing further infiltration of pro-inflammatory monocytes, cytotoxic t cells and activated neutrophils ( ) . endothelial activation also elicits tissue factor release, endovascular recruitment of neutrophils releasing neutrophil extracellular traps (nets) ( ) and von willebrand factor (vwf) exocytosis from weibel palade bodies ( ) all of which contribute to the development of microvascular thrombosis. these local immune and pro-coagulant responses may result in systemic release of multiple cytokines and chemokines and ultra large vwf multimers, hyper-activation of circulating platelets and the embolization of vwf/platelet-rich thrombi ( ) . increased pro-inflammatory and pro-coagulant factors in the plasma could be sufficient for in situ thrombus formation in the cerebral vasculature ( ) and this may be exacerbated by infection and/or activation of the cerebral endothelium and local release of vwf and tissue factor ( ) . endothelial activation would be expected to facilitate recruitment of neutrophils, monocytes and macrophages to the vessel lumen and induce a local inflammatory response in the surrounding brain parenchyma thereby polarizing microglia ( ) . small vessel occlusion, by thromboemboli or by in situ thrombosis due to endothelial dysfunction, causes hypoperfusion of brain tissue ( ) . ultimately, this combination of tissue hypoperfusion and the pro-inflammatory action of infiltrating and brain resident immune cells is the origin of stroke brain injury ( ) . expansion of cd þ and cd þ t cells, and differentiation of th and th cells. a paradoxical, but common, characteristic of sars-cov- infection is the development of lymphopenia, observed also in the sars-cov, mers-cov and h n /h n influenza pandemics. in covid- patients, a marked decrease in the number of peripheral cd þ and cd þ t cells, accompanied by hyperactivity of these populations, has been suggested as an effective predictor of disease severity. it has been postulated that this may be the result of virus-mediated dysfunction of lymphatic tissues, cytokine-mediated lymphocyte apoptosis or the direct killing of lymphocytes by viral infection. it could also be, simply, the redistribution of lymphocytes to the infected tissue and/ or lymph nodes. the net result of lymphopenia, particularly in combination with enhanced granulocytosis, is an increase in the neutrophil to lymphocyte ratio (nlr). increased nlr is already evident in covid- cohorts and has been suggested as a potential prognostic marker of more severe illness and increased risk of mortality. this is an important observation given that nlr also has prognostic value for determining stroke risk. the exaggerated immune response (''the cytokine storm'') the cumulative consequence of leukocyte recruitment and activation is the accumulation of cytokines, both in the lung tissue and in the circulation. in severe covid- patients, this response is exaggerated, resulting in a ''cytokine storm'', in which aberrant cytokine expression and disproportionate inflammation results in persistent acute lung injury extending beyond the time of peak viral load. cell populations of particular relevance to the development of a cytokine storm are pro-inflammatory (cd þ , cd þ , il- hi ) monocytes and pathogenic (gm-csf þ , ifn-c þ ) th lymphocytes, which appear to predominate in the circulation of covid- patients in icu, and th lymphocytes which are prevalent in influenza. together these cells propagate a second wave of immune cell infiltration, polarization of lung-resident macrophages to a proinflammatory phenotype and cytokine production ( figure ( ) and ( )). macrophage polarization rapidly elevates the levels of circulating cytokines, most notably il- ( figure ( ) ). in all of the covid- cohorts included in a recent meta-analysis, il- levels were significantly elevated (approximately fold) in patients with complicated disease compared to those with non-complicated disease. in the largest of the individual studies (n ¼ ), the median plasma concentration of il- was . pg/ml, in line with levels observed in severe sars-cov and mers-cov infection. the exaggeration of peripheral immune responses and ensuing inflammation is likely to be one of the key aspects of covid- pathogenesis that could result in cerebrovascular events. this is highlighted by the observation that il- is a predictor of stroke risk. it is possible that hyperinflammation may contribute to the progression of two key stroke risk factors, atherosclerosis and atrial fibrillation (af). in the case of chronic atherosclerosis, viral infection is thought to drive the progression of atheromatous plaques through enhanced macrophage and t-cell responses within the developing lesion, although this may not occur within a timeframe that is relevant to covid- related stroke. however, the release of ifn-c, tnf-a and other destabilizing factors can then expose the plaque's thrombogenic core inducing plaque rupture which is more likely to be influenced by acute inflammatory conditions. there is also some evidence that plaque development and rupture is influenced directly by viral infection of vascular cells. similarly, peripheral immune responses to viral infections are thought to contribute to the pathogenesis of af through the release of reactive oxygen species and myeloperoxidases from neutrophils and the local release of tnf-a and il- b from macrophages. viral infection may also be an important factor in the development of non-valvular af through upregulation of monocyte tlr and il- release. covid- appears to share many aspects of its pathology with previous viral pandemics including the prevalence of thrombotic complications. during the h n influenza pandemic, the incidence of overt thrombotic manifestations (deep vein thrombosis (dvt) or pulmonary embolism (pe)) was approximately %. during the - sars pandemic, the incidence of dvt was estimated to be as high as % with a further % of patients developing pe. in a larger sars cohort, thrombotic abnormalities were identified in over % of patients. studies of aberrant coagulation in covid- patients are often reporting on small cohorts and conclusions have been conflicting. in a cohort of patients with severe covid- , hemostatic abnormalities were associated with fatality, with % of non-survivors meeting the criteria for disseminated intravascular coagulation (dic), including a progressive increase in pt and d-dimer. however, in a smaller cohort of icu patients a state of hypercoagulability, not consistent with overt dic (increased d-dimer without associated bleeding), was reported indicating extensive pulmonary vascular thrombosis. this is further supported by a small autopsy series which identified thrombotic microangiopathy that was completely restricted to the lungs. it is, therefore, still unclear if sars-cov- infection has a direct impact on hemostatic mechanisms or whether the thrombotic manifestations are purely the result of dic, secondary to systemic inflammation, or sepsis-induced coagulopathy. there is some emerging consensus regarding the rate of incidence of venous thrombosis (in the absence of overt dic) in covid- patients, and it is extraordinarily high. klok et al. recorded an incidence of total thrombotic complications of % ( %ci - %, n ¼ ), of which % were pe. the incidence of unspecified venous thrombosis in two smaller studies was % (n ¼ ) and % (n ¼ ). in a larger cohort of patients (n ¼ ), the incidence of thromboembolic events was . % in icu patients and . % across all covid- patients in general wards. in all of these studies the incidence of vte is despite all patients having received, at least, a prophylactic dose of anticoagulants. there is clear evidence, from post-mortem lung pathology, of extensive thrombosis in the alveolar capillaries and small vessels in response to covid- infection. the composition of these thrombi includes fibrin deposits, platelet aggregates, cd þ cell aggregates, and partially degenerated neutrophils (figure ( ) ). fibrin deposition in response to inflammation is initially driven by elevated c-reactive protein (crp) and inflammatory cytokines. , local tissue factor release, generating thrombin, coupled with elevated plasma concentrations of fibrinogen results in deposition of fibrin which persists due to the concomitant suppression of fibrinolysis by crp-mediated release of plasminogen activator inhibitor- and thrombin activatable fibrinolysis inhibitor. any other pro-coagulant and/or anti-coagulant factors that may be specifically influenced by sars-cov- , thereby further contributing to the hypercoagulable state, are not yet known and, as most are synthesized in the liver, it may be unlikely that infection will alter their transcription. a comprehensive analysis of the plasma concentrations of coagulation factors in patients with covid- , or indeed any viral infection, seems to be lacking at present from the literature. the presence of platelet-containing thrombi in the lungs of covid- patients indicates the involvement of other thromboinflammatory pathways that upregulate endothelial platelet recruitment and aggregation (figure ( ) ). this is likely to be initiated by an increase in il- , il- , and tnf-a which stimulate the exocytosis of von willebrand factor (vwf) from weibel-palade bodies. the vwf strings released unfold under rheological shear forces and capture platelets through the glycoprotein ib-ix-v complex, a process down-regulated by the protease adamts . the synthesis of adamts is known to be inhibited by ifnc, il- and tnf-a and, through an as yet unknown mechanism, il- inhibits adamts activity at the endothelium. , therefore, under inflammatory conditions, there is an amplification of vwf-mediated platelet capture. as an acute phase reactant, vwf (particularly ultra large vwf multimers) has long been associated with acute inflammation and acute viral infection of the respiratory tract. , it is also highly likely that vwf/adamts imbalance plays an important role in covid-induced thrombosis with some small studies already identifying vwf antigen and vwf activity in covid- patients as high as - % of the normal range. , notably, an imbalance in the vwf/adamts axis is an established risk factor for the incidence of ischemic stroke and is already implicated in stroke complicating other viral infections. the formation of platelet-rich thrombi could be further exacerbated by a local hyper-activation of platelets, the consumption of which would account for mild thrombocytopenia observed in many covid- patients and linked to higher rates of mortality. platelet activation and aggregation is likely to be induced by the action of locally generated thrombin through par /par signaling on platelets. the recruitment of platelets from the circulation may also be supplemented by local production of platelets by pulmonary megakaryocytes. these have been observed, in post-mortem lung pathology, actively producing platelets in the alveolar capillaries. the significance of platelets in covid- pathology is highlighted by the possible therapeutic benefit of anti-platelet therapies. importantly, platelet activation and subsequent degranulation may be an early contributor to the exacerbated immune/inflammatory response to sars-cov- infection through numerous mediators of leukocyte and endothelial function. platelet recruitment of leukocytes to the developing thrombus would explain the notable presence of cd þ t cell aggregates and neutrophil extracellular traps (nets), both of which further contribute to both the proinflammatory and pro-coagulant environment. recently it has become apparent that stroke-causing thrombi are often rich in vwf, platelets, leukocytes and nets and that this composition is associated with tissue plasminogen activator resistance. formation of thrombi with this composition requires the upregulation of multiple thromboinflammatory components, many of which (described above) are influenced by covid- . this, together with the incontrovertible role of hypercoagulation in ischemic stroke pathology, forms perhaps the strongest argument for a causative link between covid- and stroke. international journal of stroke, ( ) vasculitis and endothelial dysfunction emerging evidence suggests that covid- pathology may be considered, at least in part, a vascular disease and that the effects of sars-cov- on endothelial function may go beyond the release of tissue factor and vwf already described. ace is expressed in venous and arterial endothelial cells, arterial smooth muscle cells, and pericytes. a recent post-mortem case series has indicated that sars-cov- is capable of productively infecting and damaging endothelial cells across multiple tissue beds (figure ( ) and ( )), although, the authors concede that these observations are not conclusive. hyperactivation of the endothelium during viral infection is known to induce the loss of tight junctions, vessel permeability and, subsequently, pulmonary hemorrhage, and alveolar edema. in the later stages of covid- progression, as the disease becomes more severe, it is possible that complement activation may also contribute to vasculitis. this mechanism has been observed previously in animal models of coronavirus infection and pulmonary biopsies from a small number of covid- patients indicate the presence of complement activation. in addition to inflammation of the vessel wall, complement may contribute to vascular dysfunction through the initiation of microvascular thrombosis. all of these processes could be expected to occur in the endothelium of multiple organs, including the brain, where alterations of the vascular environment are a key contributor to the development of ischemic brain injury. the possibility of sars-cov- neurotropism is intriguing. many other viruses, including coronaviruses, are capable of infecting cns related cell types including neurons, microglia, astrocytes, and oligodendrocytes. in covid- patients, cns infection may account for the high incidence of neurological manifestations (as high as % of severe cases ) which include headaches, nausea, impaired consciousness, acute cerebrovascular disease, and seizures. conversely, these manifestations may simply reflect the remote effects of systemic inflammation. a likely route of cns infiltration is through peripheral nerve terminals, particularly the olfactory bulb. in a humanized mouse model of sars-cov- infection, nasal inoculation was followed by dissemination of the virus from the olfactory epithelium to the axons of the olfactory bulb, through the pyriform cortex to the brain stem. this may also explain the widespread incidence of anosmia occurring in covid- cohorts. there is a strong association between acute cns infection (e.g. meningitis) and the incidence of stroke thought to result from vasculitis and a related hypercoagulant state. in the case of systemic thrombosis, an important distinction yet to be made is whether all thrombotic events are originating in a pro-coagulant micro-environment within the lungs or if there is a systemic procoagulant state facilitating in situ thrombus formation in the brain or embolism to the brain from elsewhere, such as the peripheral arterial or venous system (e.g. via patent foramen ovale). the latter is certainly possible through the presence of highly reactive ultra-large vwf multimers, hyper-activated platelets and upregulated cell adhesion molecules (through activation of the endothelium), all of which would be expected in the vasculature of the brain (figure ( ) ). endothelial dysfunction, particularly vasoconstriction, may occur as a result of direct infection of either endothelial cells or smooth muscle cells (figure ( ) ) and may enhance the shear-dependent formation of vwf-platelet aggregates in the smaller vessels (figure ( ) ). neutrophils, circulating in high numbers and in an activated state, may contribute further to in situ thrombus formation in the brain through the formation of nets (figure ( ) ). the majority of strokes being reported in covid- patients are large vessel occlusions, which is indicative of a thromboembolic source; however, in situ thrombosis cannot be ruled out. given the high incidence of myocardial injury (myocarditis, ischemia, pericarditis, etc.) associated with severe covid- disease/treatment, secondary stroke in covid- patients may also have a cardioembolic source. is covid- directly contributing to stroke incidence? as approximately % of observed strokes in covid- patients are conventionally cryptogenic, it may be tempting to prematurely assume a relationship; however, it is very important to emphasize that there is no direct evidence for a causal link between covid- and stroke. standardized case reporting and the application of bradford hill criteria will be essential in defining causality. thrombotic and cerebrovascular complications are not uncommon in critically ill patients due to systemic inflammation, prolonged immobility, intermittent af, sedation, mechanical ventilation, and central catheter placement, but can be effectively prevented by international journal of stroke, ( ) prophylactic anti-coagulants. this is not the case in covid- (and the previous sars outbreak) and a recent retrospective cohort study has suggested an incidence of stroke - times higher in patients hospitalized with covid- infection compared with those hospitalized by influenza, supporting the possibility of a sars-cov- -driven hyper-coagulant state. platform trials of anticoagulant or immunomodulatory therapies in hospitalized patients with covid- present a unique opportunity for gaining insights into the causal role of inflammation and thrombosis in stroke risk. however, many of these trials focus on short-term outcomes and it is unclear whether there would be sufficient power to detect differences in stroke events, even if incident stroke was recorded as an a priori outcome measure. comorbidities that are common to both covid- and stroke (hypertension, diabetes, obesity, etc.) may explain, at least some, coincidence of the two pathologies. [ ] [ ] [ ] obesity, in particular, is emerging as a prominent risk factor in the development of severe covid- disease and is generally associated with increased incidence and increased severity of respiratory viral infection. , this is perhaps unsurprising given the existence of low grade inflammation in obese patients which undoubtedly contributes to the initiation of ards. notably, the cytokine il- is persistently elevated in obese individuals and is capable of stimulating endothelial cells to release pro-coagulant tissue factor which may expose them to more severe covid- disease and/or stroke. of course, not all covid- patients who go on to have strokes will have these comorbidities, and this is especially true of younger patients. it is in these apparently healthy, young individuals that a causal link between covid- and cerebrovascular complications may be the most logical explanation, particularly in asymptomatic individuals with significant and undiagnosed inflammation. up until this point, we have discussed the incidence of stroke complicating covid- only in the context of the most severe and often critical cases as it does appear to be a delayed complication. it could, however, be argued that the strongest case for a causal link would be the incidence of stroke in individuals with sub-clinical sars-cov- infection, which has been identified in a number of cases. the true extent of community infection is not known due to a failure, in most countries, to introduce widespread testing and contact tracing, although this is changing rapidly. it has been estimated that in china as many as % of cases were undocumented and this is likely to be echoed in other epicenters of the outbreak and will become apparent when a reliable serological test becomes widely implemented. asymptomatic or mildly symptomatic individuals are also highly unlikely to undergo any kind of medical examination, especially in light of the imposed lockdown measures. therefore, we do not yet know the extent of systemic inflammation or the likelihood of aberrant coagulation in these mild or asymptomatic patients and whether or not they are at increased risk of stroke. an interesting study of infected individuals aboard the diamond princess cruise ship, one of the earliest clusters outside of china, has given some insight into the extent of asymptomatic infection within an isolated, and comprehensively tested population. of the confirmed infections on board, almost half were asymptomatic. follow-up chest imaging, performed on of these asymptomatic individuals, revealed a % incidence of abnormal ct findings (mostly ground-glass opacities). this is not a trivial observation as such abnormalities are indicative of established infection and advanced inflammation. applied to the general population this could indicate that as many as % of all infected individuals may have undetected inflammation and may be at risk of thrombotic complications, including stroke. a proven, direct link between covid- and stroke may only arise when a vaccine is deployed which then results in a reduced stroke incidence in already at-risk groups, as is thought to be the case with the influenza vaccine. recent meta-analyses have shown influenza vaccination is associated with a reduced risk of stroke; however, further prospective studies, particularly large, multicenter randomized controlled trials, are required to definitively show this link. until then, the mere possibility of a causal link will undoubtedly require some adaptation of current clinical practices to better manage their coincidence. this is likely to include changes to neurovascular imaging protocols, thrombolytic administration, and the application of mechanical thrombectomy. some of these proposed changes have been outlined in an international panel report published recently in ijs. a better understanding of the mechanisms underlying a link between covid- and stroke will help to adapt these clinical practices further, particularly in regard to the use of thrombolytic, anticoagulant, and anti-platelet therapies. the sars-cov- pandemic is by no means the first viral infection to be linked to an increased incidence of stroke. research interest in this phenomenon has peaked upon the emergence of past epidemics, giving us some insight into possible mechanisms, but has dissipated as the threat is contained (as was the case with sars and mers). this represents a missed opportunity to gain valuable insight on the general link between infection and stroke. international journal of stroke, ( ) similarly, we may have missed the first opportunity to study the present pandemic as the number of new cases in the main epicenters of the outbreak begin to decline. studies of sars-cov- so far have been generated at a staggering rate, possibly at the expense of scientific rigor. many have been small, case series studies that could be viewed as less insightful than larger, collated clinical datasets. it is gradually becoming clear from the early epicenters of the outbreak (e.g., china, south korea) that sars-cov- has not yet been fully contained and, with any potential treatments or vaccine still months away, a second wave remains possible. in addition, the implications of any potential causal relationship between sars-cov- and stroke risk on the primary and secondary prevention of stroke is yet to be determined. finally, the impact of covid- combined with seasonal influenza on stroke risk remains uncertain. in the meantime, the research community should be preparing to employ large systematic clinical studies and establishing animal models of covid- to confirm the causative mechanisms by which stroke might occur. only then we will be prepared for the next viral threat and the cerebrovascular risk it may pose. searches were performed in pubmed using the search terms ''covid- '', ''sars-cov- '', ''covid- , stroke'', ''sars-cov- , stroke'', and ''viral infection, stroke''. searches were performed periodically from april to june . search results were screened for relevance by multiple authors. expedited publications and those on pre-print servers were scrutinized by multiple authors for scientific rigor before inclusion. the author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: msv elkind will receive royalties from uptodate for a chapter related to covid- and stroke. the author(s) disclosed receipt of the following financial support for the research, authorship, and/or publication of this article: this work was funded by medical research foundation fellowship (mrf- - -rg-sout-c ) awarded to k substantial undocumented infection facilitates the rapid dissemination of novel coronavirus (sars-cov- ) temporal dynamics in viral shedding and transmissibility of covid- sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor tissue distribution of ace 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receptors present on various locations such as the pulmonary alveolar epithelium and vascular endothelium. in covid- patients, the interaction of sars-cov- with these receptors in the cerebral blood vessels has been attributed to stroke. although the incidence of acute ischemic stroke is relatively low, ranging from % to %, the mortality associated with it is substantially high, reaching as high as %. this case series describes three distinct yet similar scenarios of covid- positive patients with several underlying comorbidities, wherein two of the patients presented to our hospital with sudden onset right-sided weakness, later diagnosed with ischemic stroke, and one patient who developed an acute intracerebral hemorrhage during his hospital stay. the patients were diagnosed with acute stroke as a complication of covid- infection. we also provide an insight into the possible mechanisms responsible for the life-threatening complication. physicians should have a low threshold for suspecting stroke in covid- patients, and close observation should be kept on such patients particularly those with clinical evidence of traditional risk factors. the novel coronavirus disease of (covid- ) caused by the severe acute respiratory syndrome coronavirus- (sars-cov- ) has infected more than million people causing more than , deaths worldwide as on august , [ ] . although the virus predominantly affects the lower respiratory tract, the extrapulmonary manifestations are not uncommon. the commonly involved systems are cardiovascular, gastrointestinal, hematological, hepatocellular, renal, and dermatological [ , ] . another equally concerning feature of covid- is the involvement of the central nervous system, which may vary from headaches, dizziness, hypogeusia, or encephalitis owing to direct viral invasion of neural tissue, to cerebrovascular disease or stroke [ , ] . the incidence of both acute ischemic stroke and hemorrhagic in covid- patients is reported to range from % to % [ ] [ ] [ ] [ ] [ ] [ ] . the acute brain infarction secondary to stroke is of particular importance because it not only substantially affects the prognosis of the patient but can also have long-term residual neurological deficits. in our case series, we present three relatively uncommon cases of covid- presenting with stroke. a -year-old woman with a past medical history of type-ii diabetes mellitus, chronic obstructive pulmonary disease (copd) on nocturnal l/min home oxygen, obstructive sleep apnea on bipap (bilevel positive airway pressure) at home, hypertension, and dyslipidemia was diagnosed with covid- infection eight days prior to her admission. she presented to the emergency department (ed) with a sudden onset of right-sided weakness and aphasia. the patient received thrombolysis therapy with tissue plasminogen activator (tpa) for ischemic stroke after a ct scan of the head was negative for hemorrhage. the patient was then transferred to our hospital for a higher level of care and evaluation for possible thrombectomy. in our ed, the patient had blood pressure (bp) and heart rate (hr) of / mmhg and beats/min, respectively, with % spo on l of oxygen through a nasal cannula. she was awake, alert, and following commands. a critical neurologic examination revealed severe global aphasia, dense right hemiparesis, and a left gaze preference, with an nih stroke score (nihss) of . her initial laboratory reports did not show any derangements. the patient underwent a ct angiogram of head and neck and ct perfusion scan of the brain, both of which did not reveal any major vessel occlusion or a perfusion defect. she was then admitted to the covid icu and was subsequently started on aspirin and statin, and intravenous medications to maintain systolic bp < / . she was also started on remdesivir for covid- related illness. mri of the brain was performed the next day that showed an acute/sub-acute infarct involving the left caudate nucleus and putamen ( figure ). on day of admission, she was observed to have worsening somnolence (nihss of ), for which another head ct scan was performed that did not reveal any new findings. over the course of the next three days, the patient continued to deteriorate with worsening lethargy and a progressive decline in her mental status. the patient was intubated for airway protection. despite appropriate treatment and mechanical ventilatory support, the patient's clinical condition continued to deteriorate. the patient's family was updated regarding her clinical prognosis, and after an adjudicated discussion, the patient's family decided that they no longer wish to subject her to further aggressive interventions, which were also in concordance with the patient's wishes. the following day she was compassionately extubated receiving comfort measures only. our patient expired six days into her hospital admission. a -year-old caucasian male with a past medical history of coronary artery disease with a two-vessel coronary artery bypass graft nine years ago, heart failure, hypertension, dyslipidemia, type diabetes mellitus, methamphetamine abuse, and tobacco abuse was brought to the ed after being found down at a friend's house. his last-known well time was the night prior to the presentation. the patient upon presentation was lethargic with severe aphasia with an hr of beats/min, bp of / mmhg, temperature of . °c, and oxygen saturation of % on room air. upon examination, he was noted to have right-sided hemiparesis, right-sided facial droop, expressive aphasia, severe dysarthria, and left gaze preference. while in the ed, the patient became more obtunded, requiring intubation for airway protection. the patient had a white blood cell count of , /µl, lactic acidosis of . mmol/l, and an elevated procalcitonin of . ng/ml. his chest x-ray showed bilateral patchy opacities. a ct angiogram of the head and neck revealed a moderate-sized subacute left middle cerebral artery (mca) branch infarct, which was primarily perisylvian with a corresponding perfusion defect (figure a) . there was no intracranial hemorrhage, mass effect, or any major vessel occlusion. the patient was not a candidate for thrombolysis and was started on aspirin and atorvastatin. his chest ct did not show pulmonary emboli but diffuse bilateral ground-glass consolidation ( figure ) . a nasopharyngeal swab for covid- pcr (polymerase chain reaction) was obtained, which came back negative. due to the concern for covid- pneumonia, a tracheal aspirate was sent for covid- pcr that returned positive. the patient was initiated on remdesivir and dexamethasone for covid- pneumonia. the pneumonia panel from tracheal aspirate showed methicillin-sensitive staphylococcus aureus, streptococcus agalactiae, and streptococcus pneumoniae for which he was initiated on appropriate antibiotics. his echocardiogram showed normal systolic function with an ejection fraction (ef) of %. mri of the brain showed an evolving moderate size subacute left mca branch infarct (figure b) . ekg did not reveal any cardiac arrhythmia. the patient improved from a respiratory standpoint and was extubated to high-flow nasal cannula on day of his hospital stay. the patient was awake, alert, and oriented; however, he continued to have right-sided hemiparesis and expressive aphasia. a -year-old hispanic male with a past medical history of hypertension and tobacco abuse presented to the ed with a two-day history of progressively worsening dyspnea and cough. his vitals upon presentation were as follows: hr of /min, bp of / mmhg, temperature of . °c, and spo of % on room air. he had a leukocyte count of , /µl, lactic acid level of . mmol/l, c-reactive protein of . mg/l, creatinine of . mg/dl, and an elevated procalcitonin of . ng/ml. ct scan of the chest showed bilateral nodular ground-glass opacities with a crazy-paving appearance. a nasopharyngeal swab for covid- pcr was positive. the patient was also initiated on antibiotics for concomitant bacterial pneumonia with a positive streptococcus pneumoniae urine antigen. his oxygen requirements gradually worsened requiring intubation on day of hospitalization and vasopressor support for shock. a pneumonia panel from tracheal aspirate detected streptococcus pneumoniae. he also developed worsening renal function requiring renal replacement therapy. the patient was noted to develop paraplegia on minimal sedation on day of hospitalization prompting a ct scan of the head, which showed a . -cm low-density area in the right occipital lobe consistent with a subacute ischemic stroke (figure a) . he was started on aspirin and atorvastatin. a transthoracic echocardiogram showed an ef of - % with no wall motion abnormalities. his mental status continued to deteriorate until he became unresponsive with bilaterally dilated pupils. a repeat ct scan of his head showed a new large . -cm right intraparenchymal hematoma with associated midline shift and transtentorial herniation with evidence of global hypoxic-ischemic injury and herniation-related infarction as well as scattered subarachnoid hemorrhage (figure b) . the patient was receiving subcutaneous heparin for deep vein thrombosis (dvt) prophylaxis but no therapeutic anticoagulation was given. in the best interest of the patient and in accordance with the patient's wishes, the family decided to transition his goals of care to comfort care only. the patient expired after a prolonged hospital stay of days. largely due to its multi-system involvement and a wide spectrum of clinical presentations, covid- continues to pose challenges affecting clinical prognosis, particularly among the elderly and those with underlying comorbidities, such as our patients. the clinical profiles of our patients are consistent with the findings of a recent meta-analysis by tan et al. who concluded that the mean duration of an acute ischemic stroke from the onset of covid- symptoms was ± days, with a mean age of . ± years [ ] . the precise mechanism responsible for causing acute ischemic stroke in covid- positive patients is currently unclear. however, proposed speculations suggest that the process may be multifactorial. the sars-cov- gains entry into the human body by attaching itself to the membrane-bound angiotensin-converting enzyme (ace ) receptors located on, but not limited to, pulmonary alveolar epithelial cells and vascular endothelium [ , ] . the viral interaction with ace receptors in blood vessels causes endothelial damage and induces a hyperimmune response: "cytokine storm" releasing inflammatory markers such as interleukin (il)- , il- , and tumor necrosis factor-alpha (tnf-a) that might predispose to stroke by causing vasculitis [ , , ] . moreover, covid- is also associated with hypercoagulability and hyperviscosity, which can immensely increase the risk of stroke [ , ] . lastly, the preexistence of traditional risk factors such as hypertension, dyslipidemia, diabetes, and atherosclerotic vascular disease (such as in our case) in the setting of extensive covid- infection may have a synergistic contribution in increasing patient predisposition to stroke by causing plaque disruption. the ace receptors also play a role in the pathogenesis of hemorrhagic stroke, wherein the downregulation of receptors coupled with elevated angiotensin ii and endothelial dysfunction in cerebral arteries increases bp, and thus the risk of hemorrhage [ ] . pre-existing hypertension is a potential risk factor for hemorrhagic stroke. stroke (both ischemic and hemorrhagic) occurring in the setting of covid- is reported to have a worse patient prognosis, with a substantially higher risk of in-hospital mortality [ ] . one study found that the risk of mortality among covid- patients with ischemic stroke was % [ ] . tan et al. also reported a similar finding in their meta-analysis, with a cumulative mortality risk of % [ ] . strategies that seem plausible in treating covid- patients with stroke include the use of tpa, but the role of other anticoagulants such as lowmolecular-weight heparin or unfractionated heparin is debatable and controversial. since sars-cov- binds to and depletes ace receptors, administration of exogenous ace in the form of human recombinant soluble ace (hrs ace ) might reduce the risk of acute stroke by replenishing ace in cerebral blood vessels [ , ] . interestingly, elevated serum levels of d-dimer, fibrinogen, and anti-phospholipid antibodies are implicated in covid- patients with ischemic stroke [ ] . periodic assaying of these biomarkers might help in identifying patients with increased stroke predisposition. workflow proposed by qureshi et al. seems promising as it lays down a step-by-step guide for the management of acute ischemic stroke for the physicians [ ] . another study involving patients with ischemic stroke reported that early intravenous thrombolysis and recanalization through mechanical thrombectomy had resulted in poor outcomes in their patient cohorts [ ] . moreover, stroke teams need to be extra cautious so as to minimize the risk of self-exposure with the proper use of protective equipment. both ischemic and hemorrhagic stroke are associated with covid- infection and carry a high risk of mortality. the ace receptors, circulating cytokines, and hypercoagulability are integral in the pathogenesis of stroke in covid- patients. further studies need to be conducted to understand the exact mechanism in covid- patients with stroke. however, treating physicians should have a low threshold for suspecting stroke in covid- patients, and close observation should be kept on such patients particularly those with clinical evidence of traditional risk factors. human subjects: consent was obtained by all participants in this study. in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. situation report - extrapulmonary manifestations of covid- covid- and the nervous system influence of covid- on cerebrovascular disease and its possible mechanism acute cerebrovascular disease following covid- : a single center, retrospective, observational study neurologic manifestations of hospitalized patients with coronavirus disease risk of ischemic stroke in patients with covid- versus patients with influenza covid- and ischemic stroke: a systematic review and meta-summary of the literature sars-cov- and stroke in a new york healthcare system . stroke. hemorrhagic stroke and anticoagulation in covid- sars-cov- cell entry depends on ace and tmprss and is blocked by a clinically proven protease inhibitor hlh across speciality collaboration uk: covid- : consider cytokine storm syndromes and immunosuppression covid- -related stroke covid- -associated hyperviscosity: a link between inflammation and thrombophilia? inhibition of sars-cov- infections in engineered human tissues using clinical-grade soluble human ace management of acute ischemic stroke in patients with covid- infection: insights from an international panel treatment of acute ischemic stroke due to large vessel occlusion with covid- : experience from paris key: cord- -y j x ne authors: lee, kai wei; yusof khan, abdul hanif khan; ching, siew mooi; chia, peck kee; loh, wei chao; abdul rashid, anna misya'il; baharin, janudin; inche mat, liyana najwa; wan sulaiman, wan aliaa; devaraj, navin kumar; sivaratnam, dhashani; basri, hamidon; hoo, fan kee title: stroke and novel coronavirus infection in humans: a systematic review and meta-analysis date: - - journal: front neurol doi: . /fneur. . sha: doc_id: cord_uid: y j x ne background: as the world witnessed the devastation caused by the coronavirus disease (covid- ) outbreak, a growing body of literature on covid- is also becoming increasingly available. stroke has increasingly been reported as a complication of covid- infection. however, a systematic synthesis of the available data has not been conducted. therefore, we performed a systematic review and meta-analysis of currently available epidemiological, clinical, and laboratory data related to both stroke and covid- infection. methods: we systematically searched medline, cinahl, and pubmed for studies related to stroke and covid- from inception up to june , . we selected cohort studies, case series, and case reports that reported the occurrence of stroke in covid- patients. a fixed-effects model was used to estimate the pooled frequency of stroke in covid- patients with a % confidence interval (ci). results: twenty-eight studies were included in the systematic review and seven studies for the meta-analysis. the pooled frequency of stroke in covid- patients was . % ( % ci: . , . ). the heterogeneity was low (i( ) = . %). even though the frequency of stroke among patients having covid- infection was low, those with concomitant covid- infection and stroke suffered from a more severe infection and eventually had a poorer prognosis with a higher mortality rate ( . %) than covid- alone. many covid- patients shared the common traditional risk factors for stroke. we noted that ischemic stroke involving the anterior circulation with large vessels occlusion is the most common type of stroke with more strokes seen in multi-territorial regions, suggesting systemic thromboembolism. an elevated level of d-dimers, c-reactive protein, ferritin, lactic acid dehydrogenase, troponin, esr, fibrinogen, and a positive antiphospholipid antibody were also noted in this review. conclusions: the occurrence of stroke in patients with covid- infection is uncommon, but it may pose as an important prognostic marker and indicator of severity of infection, by causing large vessels occlusion and exhibiting a thrombo-inflammatory vascular picture. physicians should be made aware and remain vigilant on the possible two-way relationship between stroke and covid- infection. the rate of stroke among patients with covid- infection may increase in the future as they share the common risk factors. in december , an outbreak of a novel respiratory infection was first detected in wuhan, china, linked to three cases of patients presenting with pneumonia ( , ) . the cause of the pneumonia was found to be a viral infection known as novel coronavirus disease , and by march , the world health organization (who) declared this disease as a pandemic caused by a virus known as sars-cov- (severe acute respiratory syndrome coronavirus ) ( , ) . the who stated in its report on the state of the world's health that humans are now facing a serious threat from covid- ( , ) , and it was now necessary to declare covid- as a public health emergency ( ) . covid- 's main presentation relates to the infection of the upper respiratory system, with clinical features such as fever, dry cough, myalgia, and malaise, and in more severe cases, patients may develop pneumonia that may proceed to the lifethreatening acute respiratory distress syndrome (ards) ( ) . patients infected with covid- will also experience several mild neurological symptoms such as headache, dizziness and anosmia, to severe symptoms like altered level of consciousness, acute cerebrovascular events, seizures, and ataxia ( , ) . in addition, covid- could also cause viral encephalitis and hemorrhagic necrosis in the mesial temporal lobes and thalamus ( ) ( ) ( ) . stroke is one of the more disabling neurological complications being reported, where the first retrospective cohort of covid- showed stroke occurrence in around % of the patients ( ) . the american stroke association indicated that the risk of stroke doubled every years after the age of , and therefore, stroke affects more older adults than younger ones ( , ) . however, due to covid- , literature has reported an increasing number of premature strokes in the younger generation ( ) . the pathophysiology for the development of stroke in patients with covid- is multifactorial. infection, in general, may increase the odds of stroke . -fold, particularly in the early convalescence phase, and this association may also be similarly expected among covid- patients ( ) . secondly, sars-cov- may potentially predispose to thrombogenesis and increase the risk of stroke by infecting the myocardium cells via ace (angiotensin-converting enzyme ii) receptor and causing vascular injury and inflammation ( ) . covid- has been shown to create a prothrombotic state as evidenced by high d-dimer titres that further propagate the risk of thrombosis ( ) . moreover, covid- patients appear to be in a hyper inflammation state or cytokine storm like condition, which resulted in secretion of high interleukin- (il- ) levels, which in turn translates to hyperviscosity and increases the risk for stroke propensity ( ) . apart from the increased thrombotic potential in large vessels in patients with covid- , the patient may also be susceptible to spontaneous intracerebral hemorrhage and micro thrombosis of small penetrating vessels owing to the potential risk of vascular endothelial damage ( ) . there is growing evidence of the development of thromboembolic complications among patients with covid- , the occurrence of stroke. several case studies have also shown that patients with pre-existing cerebrovascular disease may be at a higher risk for a poor outcome if they become infected with covid- ( ) ( ) ( ) . given the worldwide covid- cases are now over nine million as updated on june , , and still rising in an exponential manner ( ) , the understanding of the association between stroke and covid- is essential in order to prevent debilitating sequelae associated with stroke and to aid in the prevention and management in these groups of patients. due to the novelty of the virus and the relatively short duration of the current covid- outbreak, only a limited and scattered body of scientific evidence on the neurological complications of covid- is currently available. furthermore, the possible twoway association between covid- and stroke has not yet been elucidated, and currently there are only limited data available on stroke co-occurrence and characterization in patients with covid- , which urgently needs further investigation and analysis to ensure a better outcome for this group of patients. therefore, it is vital to perform this review in order to determine the frequency of stroke among covid- patients and stroke characterization, as this may impact future management. we, therefore, performed a systematic review and metaanalysis involving the epidemiological, clinical presentation, imaging characteristics, and laboratory finding related to both stroke and covid- infection. this systematic review study was registered with the medical research and ethics committee, ministry of health malaysia (registration number: nmrr- - - ) and was conducted according to preferred reporting items for systematic reviews and meta-analyses (prisma) ( ) (appendix ). two investigators (ahkyk and jb) independently searched the medline, cinahl, and pubmed databases for potential studies that were published in peer-reviewed journals from inception to june , . we used the following search terms: (cerebrovascular accident or cva or stroke) and (covid- or coronavirus or -ncov) with limiters of english and human. the search strategies with the boolean or phrase operators are shown in appendix . subsequently, we removed duplications using endnote r before the next process of screening the title and abstracts for suitability. finally, the selected articles with their full text were assessed for their eligibility to be recruited into this systematic review and meta-analysis. all relevant articles identified through the above comprehensive databases were imported into the endnote r programme version x . initially, we performed de-duplication. title and abstracts were then reviewed for their relevance and articles highlighting cases of covid- and its relevance to stroke were reviewed in full text by four investigators (ahkyk, jb, pkc, and wcl) who are clinical neurologists with not < years of experience in the field of clinical neurology. studies were selected based on inclusion criteria that these studies have data on the frequency of stroke in cases of covid- or possess any data relevant to the relative risk of covid- and stroke. studies were excluded if they are a review paper, or there is no required data for both these conditions. we also excluded any study with patients who developed stroke prior to covid- infection. any disagreements between the investigators were resolved through discussions and consultations with another two senior investigators (smc and fkh) before the final consensus for quantitative analysis was reached. the participants should be those (age > years) with or without a confirmed diagnosis of stroke. exposure was referred to as exposure to covid- disease, whereby there were no limitations in severity criteria. comparator was referred to as non-covid- disease and covid- patients without stroke. the main outcomes we examined in this review were percentage or frequency of stroke that occurs after covid- infection, whereby the stroke incidence could be an ischemic and hemorrhagic stroke, venous stroke due to venous sinus thrombosis, or transient ischemic attack. the secondary outcomes were clinical presentation, the subtype of stroke, imaging characteristics, and laboratory finding related to both stroke and covid- infection. four investigators were paired into two groups (group : ahkyk and jb; group : pkc and wcl) to perform the data extraction independently. the following data were extracted from every study: the last name of the first author, year of publication, country, severity status, study design, patient characteristics (ethnicity composition, gender, and mean age), comorbidities (diabetes, hyperlipidemia, hypertension, ischemic heart disease, heart failure, previous stroke, chronic kidney disease/end-stage renal disease, number of stroke patients per overall participants, any information relevant to strokes such as the location of stroke [arterial or venous]), types of stroke (ischemic or haemorrhagic), classification of stroke, mortality rate, and blood parameters. another two investigators (amar and lnim) performed proofreading to ensure no errors and bias in the data extraction. pooled frequency of stroke among covid- patients was estimated using meta-analysis, and the data required for this was the number of patients with stroke and covid- infection (nominator) divided by the total number of patients with covid- infection (denominator). a synthesis of the findings in the aspect of clinical presentation, imaging characteristics, and laboratory finding extracted from included studies were summarized in tables. pertaining to clinical presentation, we classified stroke based on vessels occlusion and toast, whereby data were presented either in n value or ultimate decisionmaker (yes/no). the ultimate decision, either yes or no, was used because the particular study had only one patient with stroke. classification of stroke was based on imaging finding such as arterial vs. venous; ischemic vs. hemorrhagic; location of stroke (anterior circulation, posterior circulation, or multiple territories), whereby data were presented either in n value or ultimate decision-maker (yes/no). laboratory findings with clinical importance to inflammation due to stroke or viral infection were also examined, which include erythrocyte sedimentation rate, c-reactive protein, ferritin, d-dimer, lactic acid dehydrogenase, fibrinogen, antiphospholipid, procalcitonin, interleukin , troponin, platelet, and prothrombin time. blood parameters were presented in mean ± standard deviation or range. the quality of the individual studies pertaining to cohort studies was determined using the checklist strengthening the reporting of observational studies in epidemiology (strobe), which has items that assess components in observational studies ( ) . a " " was given if that item was not reported; " " was awarded if that item was sufficiently shown in the article. each article's quality was graded as "good" if strobe scores ≥ / or graded as "poor" if strobe score < / ( ) . nevertheless, studies would have been included in this review regardless of the strobe grading. we used a quality appraisal checklist for case series studies developed by the institute of health economics, which appraises over items. this is a three-options checklist with yes/partial/unclear/no depending on the clarity of items presented in case series ( ) (appendix ). a fixed-effect (dersimonian and laird method) meta-analysis method was employed to calculate the pooled frequency from these related studies, and it was reported with a % confidence interval (ci). i index was used to assess the study's heterogeneity (i.e., low is < %, moderate - %, and high > %) that indicated the total percent of discrepancy due to variation in the included studies ( ) . we also examined publication bias by begg's test and egger's test for studies which entered metaanalysis ( ) . a sensitivity analysis was conducted using leaveone-out meta-analysis to examine how individual studies affect the overall estimation of the rest of the studies. for statistical analysis, open meta(analyst) r software was used, and this software can be accessed and downloaded from http://www. cebm.brown.edu/openmeta/index.html ( ) . we identified manuscripts in the initial screening, as shown in figure . after removal of duplicate articles (n = ), a total of studies were retrieved for further assessment. after screening for its suitability through the individual title and abstract, studies fulfilled both our inclusion and exclusion criteria. after careful evaluation, articles were finally included for the systematic review and seven studies for the meta-analysis. the main characteristics of the included studies are shown in table . a total sample of , participants was included in the systematic review. these studies were conducted in many countries worldwide including in china ( , , ) , france ( , , , ) , india ( ) , iran ( ), italy ( , , ) , the netherlands ( ), philippines ( ), spain ( , ) , turkey ( ), uk ( , ) , and the usa ( , , , , , , , , ) . out of studies, eight studies were of retrospective cohort study design, were case series, and nine were case reports. the mean age of the participants ranged from to years old, giving a grand mean age of participants from the included studies of . ± . years, with more than half of them being males ( . %). the overall mortality rate among stroke patients ranged from . to . %; the average mortality rate for stroke patients with covid- and non-covid- infection were . and . %, respectively. a majority of the respondents were diagnosed with covid- using the reverse transcriptasepolymerase chain reaction (rt-pcr) tests conducted on samples collected either from the nasopharyngeal or oropharyngeal swab, and some also had concurrent confirmation by the antibody serology test. eight studies had reported data eligible for the estimation of the pooled frequency of stroke among patients with covid- , and therefore the pooled frequency using the fixed-effect model is presented below in figure . however, we decided to exclude the article by benussi et al. in the final analysis due to its high heterogeneity. the pooled frequency of stroke among patients with covid- as derived from the final seven studies was . % ( % ci: . , . ) and had a low degree of heterogeneity (i = . %, p = . ) if the article by benussi et al. ( ) was excluded from the meta-analysis. the pooled frequency increased to . % and heterogeneity was also extremely high (i = . , p < . ) if the article by benussi et al. ( ) was included in the metaanalysis. egger's test and begg's test (p < . ) suggested that there was publication bias; sensitivity analysis also identified all seven studies in the meta-analysis had substantial influences on the pooled frequency of stroke among covid- patients, which cause variation in a pooled frequency ranging from . to . . the data on stroke patients in different groups of severe vs. table . among the seven retrospective studies, two studies provided the number of patients having a stroke in the different groups of severe and non-severe covid- infection ( , ) . one study reported the number of patients having a stroke in the different groups of with or without covid- infection ( ) . among patients who suffered from a stroke and classified according to the severity of the infection, the majority were placed in the severe covid- infection group, whereby patients were classified as severe compared to in the non-severe group. among patients who suffered from a stroke, patients had covid- infection, whereas patients had no covid- infection. the average days to develop stroke among patients after the onset of covid- infection was . ± . days. regarding the severity stratification for covid- infection, we observed that multiple stratification approaches were used across studies such as severe and non-severe infections that were based on admission to intensive care unit vs. general ward, the presentation of respiratory failure warranting intubation and ventilation, ards criteria, and according to guidelines from american thoracic society for community-acquired pneumonia as per table . the imaging findings in covid- patients are summarized in table . majority of strokes seen among covid- patients were arterial stroke ( . %) while venous stroke was seen only in three patients ( . %). ischemic stroke was the predominant stroke, and it was observed in . % of stroke cases as compared to . % patients presenting with hemorrhagic stroke. more than half of stroke happened in anterior circulation ( . %), followed by the multiple territories ( . %) and posterior circulation ( . %). among the cases of stroke involving the anterior circulation, cases occurred in middle cerebral artery (mca) region, and only two cases involved the anterior cerebral artery (aca) region. table summarized the stroke classification based on large vessels occlusion (lvo) and the toast (trial of org in acute stroke treatment) classification ( ) in patients with covid- . the numbers of stroke were almost equal for lvo ( stroke cases in studies) and non-lvo ( cases in studies). location of lvos involved were m vessels ( , , , , , , , , ) , m vessel ( , , , , , ) , internal carotid ( , , , , , ) , multiteritorial ( , ) , posterior cerebral ( , ) , basilar ( ), aca ( , ) , and the vertebral artery ( ) . according to the classification of stroke based on the toast criteria, we found that large vessels and cryptogenic were the most common type of stroke ( . %), followed by cardioembolic ( . %), small vessels ( . %), and others ( . %). a majority of the studies did not classify their stroke type with the toast classification. table shows the data on comorbidities among participants in the included studies. hypertension ( . %) was found to be the highest in percentage among the comorbidities, followed by diabetes ( . %), atrial fibrillation ( . %), hyperlipidaemia ( . %), history of ischemic heart disease ( . %), smoking ( . %), previous stroke ( . %), malignancy ( . %), chronic kidney disease or end-stage renal disease ( . %), and finally heart failure ( . %). daa on the blood parameters are shown in table . functions of each of the blood tests and its normal range are summarized in a majority of the studies included had an elevated mean for the d-dimer test, which ranged from . to . mg/l except for the study done by lodigiani et al. ( ) , in which the mean of ddimer was . on day - among the survivors, and an elevated d-dimer of . was reported among the non-survivors. for the fibrinogen test, a majority of studies reported that the mean for fibrinogen was out of the normal range ( - mg/dl), in which they ranged from . to , mg/dl, except for the study done by valderrama et al., which had a normal level ( mg/dl) ( ) . similarly, a majority of the studies did not capture information on the presence of antiphospholipid, except the studies by ) reported the absence of antiphospholipid antibodies. for the procalcitonin titres, three studies had a blood test result of below . mg/ml, which ranged from . to . ng/ml ( , , ) , with the highest mean for procalcitonin concentration reported in the study by avula et al. ( . ng/ml) ( ) . we observed that only three studies captured information on interleukin- (il- ) levels among patients with covid- and stroke, which ranged from to . pg/ml, which are the studies by avula et al. ( ) , barios lopez et al. ( ) , and yaghi et al. ( ) . data of all these studies reported a normal reading for il- levels. for the troponin test, seven studies reported data on the troponin concentration ( , - , , ) . three out of the seven studies reported an ( ) . for the platelet level, the mean ranged from to × , and the levels were all within the normal range in the included studies, except for the study done by christian oliver et al. ( ) , which had a slightly elevated level ( × ). the normal range for clotting time (prothrombin test) is - . s ( ). among the included studies, six studies reported a normal mean for the prothrombin time, and these studies included the studies by benussi et al. the aim of this current study is to perform a systematic review and meta-analysis concerning the epidemiological, clinical presentation, imaging characteristics, and laboratory findings related to both stroke and covid- infection. coronaviruses are divided into four genera, in which the new coronavirus (sars-cov- ) is classified into the beta genus, which includes viruses causing sars and mers (middle east respiratory syndrome) as well ( ) . there are now at least seven human coronaviruses, including sars-cov- , sars-cov- , mers-cov, hcov-oc , hcov- e, hcov-nl- , and hcov-hku ( ) . studies on previous human coronaviruses infections indicated that the virus does not remain confined to the respiratory system and may also disseminate to other organs, including the central nervous system via the angiotensinconverting enzyme type receptor (ace- ) ( , ) . the possibility of neurological complications may stem from the neurotropic and neurovirulent property of sars-cov- , which are also seen in other human coronaviruses ( ) . the association of stroke with viral infection is wellestablished, albeit uncommon. in general, viral infection, particularly those in the early convalescence phase, increases the odds of stroke by . -folds ( ) . a previous study amongst sars-cov- patients showed that lvo occurred in a small percentage of patients ( . %) that were infected in which the two patients had cardiac dysfunction, disseminated intravascular coagulation, and significant hypotension before the onset of stroke ( ) . a similar trend among mers patients also showed that only a small number of patients developed stroke associated with preceding disseminated intravascular coagulation in one of the patients ( ) . in this current review, the pooled frequency of stroke was . %. we decided to remove benussi et al. ( ) in the final result as the study was conducted in a stroke hub for covid- in italy, which explained the high frequency of stroke ( . %) among patients with covid- . we found that overall, patients with covid- exhibited a lower percentage of stroke, which was . % of patients with covid- . this is similar to the worldwide prevalence of stroke ( . %) ( ) but much lower as compared to the prevalence of stroke in the united states ( . %) and in china ( . %) ( , ) . the association of stroke seen in patients with covid- may be attributed to the shared traditional risk factors for stroke also seen in covid- patients. literature reported that the traditional risk factors for stroke are diabetes, hypertension, hyperlipidemia, smoking, atrial fibrillation, previous stroke, ischemic heart disease, and family history of stroke, in which the estimated relative risk for total stroke associated with hypertension was . ( ), . for diabetes ( ), . for obesity ( ), . for atrial fibrillation ( ), and . for chronic kidney disease ( ) . our finding is consistent with the literature that reported that more than half of covid- patients with stroke had comorbidities of hypertension, followed by diabetes, atrial fibrillation, hyperlipidaemia, and/or history of ischemic heart disease. ischemic stroke is the most common type of stroke seen in this review as compared to less frequently occurring haemorrhagic and transient ischemic stroke. hypertension, diabetes, and cardiovascular disease are known risk factors for ischemic stroke ( ) . in addition, the risk factors of hemorrhagic and ischemic strokes were also relatively similar (interstroke study). a recent review showed that all infections increase the risk of acute ischemic stroke, although its pathophysiology is not adequately explained ( ) . anterior circulation is the most common site for stroke, with more than half of the strokes occurring in the middle cerebral artery, followed by the multiple territories. interestingly in our review, a quarter of the stroke was multi-territorial. this may be due to the propensity of systemic embolisation and microvascular thrombosis that typically occurs in covid- infection due to the excessive production of prothrombotic factors and dysregulation of the anti-thrombotic properties ( ) , whereas strokes are less commonly seen in the posterior and anterior cerebral arteries ( ) . this observation is similar to the non-covid- related stroke. a recent report pointed out the propensity of lvo to occur in patients with covid- and its tendency to occur in the younger age group ( ) . in our review of the currently available literature, half of the reported stroke cases were due to an lvo as compared to non-large vessel occlusion. this rate is much higher as compared to the general population where lvo usually occurs in around one-third of the patients ( ) . furthermore, among studies that used the toast classification, one-third reported stroke types as cryptogenic and others that indicate that there are other underlying pathologies apart from the traditional risk factors that contribute to the occurrence of stroke in patients with covid- . apart from the possible neuropathic property of sars-cov- that causes direct endothelial injury via the ace-type receptor ( ) and sharing of the common traditional risk factors for stroke, the pathophysiology of stroke in covid- patients could also be attributed to the pro-inflammatory and hypercoagulable state predisposing to thrombosis. the thrombo-inflammatory nature of sars-cov- was noted as to be associated with elevated levels of d-dimer, fibrinogen, platelet, and il- ( ). furthermore, the excessive systemic immune response that may be seen in this novel infection may be due to immunopathogenicity in which the over-stimulation of the immune system by this virus leads to attacks to one's own immune system ( ) . cytokine storm may also occur as our immune system goes into an overdrive, leading to a massive influx of sars-related inflammatory cytokine such as interleukin- β, il , il , interferon-γ, inducible protein− , and monocyte chemoattractant protein- ( , ) . these excessive inflammatory cascades may lead to two main sequelae [i.e., production of prothrombotic factors and endothelium damage due to dysregulation of antithrombotic properties, subsequently leading to microvascular thrombosis with potential for systemic embolization ( , ) ]. moreover, inflammatory markers [e.g., c-reactive protein and fibrinogen, are independent risk factors for ischemic stroke and may also predispose to atherosclerosis and endothelial dysfunction that can be further exacerbated by infection ( , ) ]. hypercoagulable state, on the other hand, as demonstrated by elevated d-dimer levels, abnormality in clotting variables, and hyperferritinemia, not only increases the risk of a thromboembolic event but is also an independent predictor for poor prognosis and mortality ( , ) . the role of other thrombotic markers such as the antiphospholipid antibodies, albeit their role in covid- , are also uncertain but may also contribute to the hypercoagulable state ( ) . in our review, several markers are commonly used to identify the thrombo-inflammatory nature of covid- (e.g., d-dimers, crp, ferritin, fibrinogen, antiphospholipid antibodies, ldh, and troponin). based on our observation, crp was the most commonly used biomarker, followed by d-dimer, ldh, troponin, and antiphospholipid tests. in this review, stroke patients with covid- consistently presented with an elevated level of d dimers, crp, ferritin, ldh, troponin, esr, fibrinogen, and with positive antiphospholipid antibodies reported in some studies. il- and pro-calcitonin were only reported in a few studies and were not found to be elevated. although the mean age of patients with covid- and stroke in our review was . years, many case series and case reports have shown that those in the younger age group or those with no comorbidities more commonly presented with stroke ( , , , , , , ) . furthermore, stroke is shown to occur early in the illness with mean onset at . days, with reports even showing that patients may present with stroke and at the same time have asymptomatic covid- infection ( , ) . unfortunately, patients with covid- and stroke had a more severe covid- infection and a poorer prognosis with a higher mortality rate as shown by this current review. the mean mortality rate among stroke patients with covid- infection was . % compared to only . % among those without covid- infection, and this could be attributed to the severity of infections in patients concurrently having neurological complications ( , , , ) . a subgroup analysis was done among the population cohorts of the benussi although covid- may predominantly present with respiratory symptoms, this review may create awareness among clinicians on potential presentation of stroke in those having this infection, especially for those with severe infection. as many of the patients share similar traditional risk factors for stroke, the presentation of a patient with stroke to the emergency department in this current pandemic must be reviewed cautiously and treated with high suspicion of the potential presence of sars-cov- infection in order to prevent further dissemination and deterioration. the role of specific blood tests as a potential thrombo-inflammatory marker can be a guide to predict the possible thromboembolic occurrence and disease severity, hence providing muchneeded guidance for physicians in taking necessary preventative measures. this is the first systematic review summarizing the findings in relation to both covid- and stroke. we found a high incidence of stroke among patients with covid- . the majority are ischemic stroke, involve large vessels occlusion, and occurs predominantly in the middle cerebral artery. we also found hypertension as the most common comorbidity among this study participants. most of the laboratory tests except for il- and procalcitonin appeared to be useful for indicating the presence of inflammation and the prothrombotic state as a predictor for stroke, although results varied between the studies. this review has several limitations. first, the majority of studies did not provide data based on the severity of the infection, and therefore meta-synthesis for severe cases of covid- and the risk of stroke cannot be performed with the existing studies. similarly, it is impossible to meta-synthesize the risk of stroke associated with covid- infection for all studies due to the lack of data on stroke characteristics among non-covid- patients. second, due to the lack of data of comorbidities for participants in the control group, analysis of the associated factors for stroke cannot be performed for this review. third, we also found that many varied types of blood tests were used for identifying inflammation and hypercoagulable state; thus, the usefulness of laboratory tests results in identifying patients with high risk for stroke could not be determined with the existing literature. future research with bigger sample size is needed to rectify these important issues. the occurrence of stroke in patients with covid- infection is uncommon but poses as an important prognostic marker and severity indicator. this brief review suggests that ischemic stroke may occur early in the course of the illness, and may also affect patients in the younger age groups with no comorbidities, causing large vessel occlusion and exhibiting thrombo-inflammatory vascular picture. given that many patients with covid- share the common traditional risk factors for stroke, physicians must be vigilant in the future for an increase in the number of strokes in patients with covid- as the pandemic continues and to take appropriate preventive measures. the continuing -ncov epidemic threat of novel coronaviruses to global 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inflammatory cytokines and chemokines in severe acute respiratory syndrome neurological manifestations of covid- : a review inflammatory risk factors, biomarkers and associated therapy in ischaemic stroke this research received its funding from the universiti putra malaysia under putra grant initiative (upm/ - / /geran putra). the funder had no role in study design, data collection and analysis, preparation of the manuscript, or decision to publish. we would like to thank the director general of health malaysia for his permission to publish this article. the supplementary material for this article can be found online at: https://www.frontiersin.org/articles/ . /fneur. . /full#supplementary-material conflict of interest: the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © lee, yusof khan, ching, chia, loh, abdul rashid, baharin, inche mat, wan sulaiman, devaraj, sivaratnam, basri and hoo. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -cpis l u authors: barrios-lópez, j. m.; rego-garcía, i.; muñoz martínez, c.; romero-fábrega, j. c.; rivero rodríguez, m.; ruiz giménez, j. a.; escamilla-sevilla, f.; mínguez-castellanos, a.; fernández pérez, m. d. title: ischaemic stroke and sars-cov- infection: a causal or incidental association? date: - - journal: nan doi: . /j.nrleng. . . sha: doc_id: cord_uid: cpis l u abstract introduction ischaemic stroke has been reported in patients with covid- , particularly in more severe cases. however, it is unclear to what extent this is linked to systemic inflammation and hypercoagulability secondary to the infection. materials and methods we describe the cases of patients with ischaemic stroke and covid- who were attended at our hospital. patients are classified according to the likelihood of a causal relationship between the hypercoagulable state and ischaemic stroke. we also conducted a review of studies addressing the possible mechanisms involved in the aetiopathogenesis of ischaemic stroke in these patients. results the association between covid- and stroke was probably causal in patients, who presented cortical infarcts and had no relevant arterial or cardioembolic disease, but did show signs of hypercoagulability and systemic inflammation in laboratory analyses. the other patients were of advanced age and presented cardioembolic ischaemic stroke; the association in these patients was probably incidental. conclusions systemic inflammation and the potential direct action of the virus may cause endothelial dysfunction, resulting in a hypercoagulable state that could be considered a potential cause of ischaemic stroke. however, stroke involves multiple pathophysiological mechanisms; studies with larger samples are therefore needed to confirm our hypothesis. the management protocol for patients with stroke and covid- should include a complete aetiological study, with the appropriate safety precautions always being observed. correos electrónicos: josemariabarrioslopez@gmail.com / iago.rego.garcia@gmail.com / claudia @gmail.com / juaromfab@gmail.com / jesusruizgimenez@hotmail.com / adolfo.minguez@sen.es / fescamilla@hotmail.com / marriver @gmail.com / lofepez@yahoo.es josé maría barrios lópez. correo electrónico: josemariabarrioslopez@gmail.com introducción: se ha comunicado la asociación de ictus isquémico y covid- , con mayor frecuencia en aquellos pacientes más graves. sin embargo, se desconoce en qué medida j o u r n a l p r e -p r o o f podría estar en relación con la inflamación sistémica e hipercoagulabilidad producidas en el contexto de la infección. métodos: descripción de cuatro pacientes atendidos en nuestro centro por ictus isquémico y diagnóstico de covid- , clasificándolos según el grado de probabilidad causal entre el estado de hipercoagulabilidad y el ictus isquémico. revisión de la literatura sobre los posibles mecanismos implicados en la etiopatogenia del ictus isquémico en este contexto. resultados: dos pacientes se consideraron con alta probabilidad causal: presentaban infartos corticales, sin patología cardioembólica ni arterial significativa, con parámetros de inflamación sistémica e hipercoagulabilidad; las otras dos pacientes eran de edad avanzada y el ictus isquémico se consideró cardioembólico, con una probable asociación casual de covid- . conclusiones: la inflamación sistémica, junto con la posible acción directa del virus, provocaría disfunción endotelial, generando un estado de hipercoagulabilidad que podría considerarse una causa potencial de ictus isquémico. sin embargo, puesto que los mecanismos del ictus pueden ser múltiples, se precisan estudios más amplios que evalúen esta hipótesis. mientras tanto, el estudio etiológico del ictus en pacientes con covid- debe ser sistemático atendiendo a los protocolos vigentes, con las adaptaciones necesarias en relación con las circunstancias clínicas y epidemiológicas de la actual pandemia. palabras clave: alteraciones neurológicas; covid- ; covid- ; hipercoagulabilidad; ictus isquémico; respuesta hiperinflamatoria; sars; sars-cov- ; sars -cov title: ischaemic stroke and sars-cov- infection: a causal or incidental association? introduction: ischaemic stroke has been reported in patients with covid- , particularly in more severe cases. however, it is unclear to what extent this is linked to systemic inflammation and hypercoagulability secondary to the infection. materials and methods: we describe the cases of patients with ischaemic stroke and covid- who were attended at our hospital. patients are classified according to the likelihood of a causal relationship between the hypercoagulable state and ischaemic stroke. we also conducted a review of studies addressing the possible mechanisms involved in the aetiopathogenesis of ischaemic stroke in these patients. results: the association between covid- and stroke was probably causal in patients, who presented cortical infarcts and had no relevant arterial or cardioembolic disease, but did show signs of hypercoagulability and systemic inflammation in laboratory analyses. the other patients were of advanced age and presented cardioembolic ischaemic stroke; the association in these patients was probably incidental. conclusions: systemic inflammation and the potential direct action of the virus may cause endothelial dysfunction, resulting in a hypercoagulable state that could be considered a potential cause of ischaemic stroke. however, stroke involves multiple pathophysiological mechanisms; studies with larger samples are therefore needed to confirm our hypothesis. the management protocol for patients with stroke and covid- should include a complete aetiological study, with the appropriate safety precautions always being observed. numerous neurological manifestations, including ischaemic stroke, have been described in patients with coronavirus disease (covid- ). [ ] [ ] [ ] in a series of hospitalised patients with covid- from the chinese city of wuhan, ischaemic stroke was reported in . % of patients, rising to . % in the subgroup of patients with severe covid- (n = ). these patients showed significantly higher d-dimer levels, which suggests that hypercoagulability may have caused stroke in these patients. according to data from the covid- registry created by the spanish society of neurology, ischaemic stroke is the second most frequent neurological disorder in these patients ( . %), following confusional syndrome ( . %). a recent study described the cases of patients with covid- who presented ischaemic stroke and antiphospholipid antibodies, in addition to elevated d-dimer levels and laboratory markers of systemic inflammation. insufficient evidence is available to determine whether determine whether hypercoagulability secondary to covid- presents a causal association with ischaemic stroke. to help clarify this matter, we describe patients attended at our hospital due to ischaemic stroke and covid- and present a literature review on the subject. we describe consecutive patients with ischaemic stroke and covid- who were attended between march and april at a reference centre. the study was approved by the clinical research ethics committee of the spanish province of granada. due to the current sars-cov- pandemic, patients and/or their legal representatives were informed about the study and gave informed consent by telephone. we gathered the following data: demographic variables, clinical data at admission, covid- related clinical variables at admission, stroke-related variables, laboratory data at the time of stroke, and data on clinical progression. stroke aetiology was determined using the toast classification criteria. patients were classified according to the likelihood of a causal relationship between hypercoagulability secondary to covid- and ischaemic stroke. we also conducted a review of studies addressing the possible causal association between sars-cov- infection and ischaemic stroke. table provides clinical and complementary data on the patients included (see also supplementary material for images and appendix for a description of the cases), as well as stroke aetiology and likelihood of causation due to hypercoagulability secondary to covid- . acute covid- comprises stages: early infection, pulmonary involvement, and severe hyperinflammation. [ ] [ ] [ ] in some patients, the inflammatory response is highly pronounced, triggering a "cytokine storm" and considerable t cell activation, with high levels of such laboratory markers as il- , ferritin, and c-reactive protein; these findings are associated with high mortality rates. the cytokine storm causes endothelial dysfunction, , [ ] [ ] [ ] which may also be favoured by direct viral invasion of endothelial cells through interaction between coronavirus s protein and ace receptors, expressed in the capillary endothelium. endothelial dysfunction increases thrombin synthesis and decreases fibrinolysis, contributing to a hypercoagulable state; this may explain the high rate of thrombotic complications observed in series of patients with covid- . , elevated d-dimer levels in these patients have therefore been proposed as a marker of hypercoagulability and poor prognosis. , hypercoagulable state has been suggested as an aetiopathogenic mechanism of stroke in patients with severe covid- , given that these patients present higher d-dimer levels. , this hypothesis was already considered during the - sars-cov epidemic, as ischaemic stroke was observed in middle-aged individuals with few vascular risk factors and severe infection. both sars-cov and sars-cov- present a high binding affinity for ace . a recent study reported cases of severe covid- and ischaemic stroke; these patients presented antiphospholipid antibodies and laboratory findings compatible with systemic inflammation and coagulopathy. antiphospholipid antibodies constitute the laboratory hallmark of primary antiphospholipid syndrome, but have also been detected in other systemic inflammatory diseases and viral infections, and are associated with higher risk of thromboembolic complications. in patients with severe covid- , other aetiopathogenic mechanisms of ischaemic stroke should be considered, including cardioembolism secondary to myocardial infarction or haemodynamic mechanisms secondary to cardiogenic or septic shock. microangiopathy associated with endothelial dysfunction has also been proposed as a pathogenic mechanism of ischaemia. in patients and of our series (table ) , the likelihood of a causal relationship between covid- and stroke is high, as these patients presented laboratory markers of systemic inflammation and hypercoagulability and the aetiological study found no evident cause for ischaemic stroke. patient presented cortical infarction in the absence of artery disease or emboligenic heart disease. patient presented stroke during hospitalisation, despite treatment with heparin at a prophylactic dose. as reported previously, these findings support the hypothesis of hypercoagulability as a possible cause of ischaemic stroke in patients with j o u r n a l p r e -p r o o f covid- and significant coagulopathy. , however, ischaemic stroke may be caused by multiple, complex pathogenic mechanisms, particularly in patients with respiratory involvement. in view of the current pandemic, aetiological studies often cannot be completed or are delayed. this underscores the need for consensus documents and adaptations to current stroke management plans, as in the recently published madrid stroke care plan recommendations. in patients and , the likelihood that covid- caused stroke was low, for several reasons. firstly, these patients were of advanced age and had multiple comorbidities; sars-cov- infection was an incidental finding, and stroke was most likely cardioembolic. furthermore, in both cases, stroke presented with neurological signs; no symptoms of sars-cov- infection were observed at stroke onset. these cases show that copresence of covid- and ischaemic stroke does not always imply a causal relationship; therefore, detection of sars-cov- infection should not interfere with the aetiological study of ischaemic stroke. , patients with covid- requiring hospitalisation should receive prophylactic anticoagulation with heparin; higher doses should be administered to critically ill patients and those at high risk of thrombosis. , a recent study reported lower mortality rates among patients treated with prophylactic doses of heparin who presented d-dimer levels times greater than the upper limit of normal (> mg/l) or a sepsis-induced coagulopathy score ≥ . this scoring system considers prothrombin time, platelet count, and sequential organ failure assessment (sofa) score, and has been proposed as a tool for early detection of sepsis-induced disseminated intravascular coagulation. however, in patients with ischaemic stroke and sars-cov- infection presenting coagulopathy and hyperinflammation, early treatment with intermediateor therapeutic-dose heparin is controversial due to the associated risk of haemorrhagic transformation. in fact, insufficient evidence is available to recommend early anticoagulation therapy , : the decision should be made on an individual basis based on the presence of a prothrombotic state and/or systemic inflammation, stroke size, and the risk-benefit balance. our study does present several limitations, mainly the small size of the patient series, our limited experience with managing patients with stroke and covid- , the difficulties of diagnosing and treating these patients during the pandemic, and the limited scientific evidence on ischaemic stroke in patients with covid- . the hypercoagulable state associated with the hyperinflammatory response triggered by covid- may be considered a potential cause of ischaemic stroke. however, stroke in these patients may involve numerous pathogenic mechanisms; studies with larger samples are needed to confirm this hypothesis and evaluate the role of endothelial damage secondary to viral invasion. patients with stroke and covid- should undergo a complete aetiological study, with the appropriate safety precautions always being observed. there is currently no evidence of the benefits of early anticoagulation therapy after ischaemic stroke in patients with covid- and hypercoagulability. future studies, ideally clinical trials, are needed to provide more robust evidence supporting the use of anticoagulants in these patients. meanwhile, the risk-benefit balance of this treatment should be assessed on an individual basis. the authors of this study have no conflicts of interest to declare. this study has received no specific funding from any public, private, or non-profit organisation. (table ) , presenting sudden-onset language alterations; he presented fever, cough, and dyspnoea days previously. the examination at the emergency department revealed fever and hypoxaemia associated with motor dysphasia and right supranuclear facial palsy. perfusion imaging detected hypoperfusion in the distal territory of the left mca (supplementary material, fig. ) and chest ct revealed signs of pneumonia due to covid- . the patient received intravenous fibrinolysis and was admitted to the intensive care unit for neurological and pulmonary monitoring. blood analysis results indicated systemic inflammation and elevated d-dimer levels ( table ) . although the results of subsequent rt-pcr tests were negative ( in nasopharyngeal exudate and one in bronchoalveolar lavage), serology tests yielded positive results for igm and igg antibodies against sars-cov- . progression was poor; the patient died days after onset of neurological symptoms due to severe nosocomial sepsis. year-old man with no relevant medical history, admitted due to respiratory insufficiency; rt-pcr results were positive for sars-cov- . he was admitted to the icu and required high-flow nasal oxygen therapy; respiratory symptoms improved and the patient was transferred to a general ward. twelve days after admission, he presented language alterations, dizziness, and vomiting; the neurological examination revealed horizontal-torsional nystagmus, dysarthria with intelligible speech, and left-sided dysmetria. an emergency multimodal ct scan revealed occlusion of the distal portion of the left superior cerebellar artery and the p segment of the left posterior cerebral artery (supplementary material fig. ). intravenous fibrinolysis was ruled out since the patient was outside the therapeutic window. a complete aetiological study yielded positive results for beta- glycoprotein igg antibodies ( u/ml; normal range, - u/ml), with negative results for anticardiolipin antibodies. the patient started pulmonary and neurological rehabilitation, progressing favourably. (table ) who was found in her home with left limb weakness. her relatives reported no symptoms of infection or neurological alterations in the preceding days. the examination performed at the emergency department revealed no fever or respiratory symptoms; the patient presented dysarthria, anosognosia, left homonymous hemianopsia, and mild left-sided hemiparesis. a head ct scan revealed subacute ischaemic stroke in the right hemisphere; chest ct findings were suggestive of covid- . rt-pcr testing of nasopharyngeal exudate yielded negative results. atrial fibrillation was detected days after admission; the patient worsened, developing fever and symptoms of pneumonia. clinical, laboratory, and radiological findings were compatible with covid- . the patient died due to treatment-resistant respiratory insufficiency. (table ) . she was transferred to our hospital due to symptoms compatible with right hemisphere stroke; multimodal ct revealed occlusion of the right mca. during her stay at the emergency department, she presented fever; rt-pcr testing of nasopharyngeal exudate yielded positive results for sars-cov- . the patient progressed favourably and was discharged with anticoagulation therapy. j o u r n a l p r e -p r o o f imagen -estudio de perfusión cerebral. se evidencia una hipoperfusión en territorios m -m de la arteria cerebral media izquierda, con aumento del tiempo de tránsito medio y sin datos de área de infarto (penumbra isquémica %). imagen -tc de cráneo de control horas tras el debut neurológico. a: corte bajo a nivel infratentorial; b: corte más alto a nivel supratentorial. se aprecia hipodensidad parenquimatosa en hemisferio cerebeloso izquierdo, giros occipitotemporales izquierdos y giro hipocampal izquierdo. ¿es esperable que haya cuadros neurológicos por la pandemia por sars-cov- ? neurología neurologic manifestations of hospitalized patients with coronavirus disease neurologic features in severe sars-cov- infection manual covid- para el neurólogo general coagulopathy and antiphospholipid antibodies in patients with covid- classification of subtype of acute ischemic stroke. definitions for use in a multicenter clinical trial. toast. trial of org in acute stroke treatment influencia de la infección sars-cov sobre enfermedades neurodegenerativas y neuropsiquiátricas: ¿una pandemia demorada? neurología covid- and the heart pathogenic human coronavirus infections: causes and consequences of cytokine storm and immunopathology immune responses in covid- and potential vaccines: lessons learned from sars and mers epidemic clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study. the lancet the role of cytokines including interleukin- in covid- induced pneumonia and macrophage activation syndrome-like disease anticoagulant treatment is associated with decreased mortality in severe coronavirus disease patients with coagulopathy tissue plasminogen activator (tpa) treatment for covid- associated acute respiratory distress syndrome (ards): a case series large artery ischaemic stroke in severe acute respiratory syndrome (sars) abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia risk of developing antiphospholipid antibodies following viral infection: a systematic review and meta-analysis. lupus elevated troponin in patients with coronavirus disease : possible mechanisms challenges and potential solutions of stroke care during the coronavirus disease (covid- ) outbreak. stroke atención al ictus agudo durante la pandemia por covid- . recomendaciones plan ictus madrid incidence of thrombotic complications in critically ill icu patients with covid- diagnosis and management of sepsis-induced coagulopathy and disseminated intravascular coagulation guidelines for the early management of patients with acute ischemic stroke: update to the guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the american heart association/american stroke association af: atrial fibrillation; aht: arterial hypertension; alt: alanine aminotransferase; aptt: activated partial thromboplastin time; ast: aspartate aminotransferase; ct: computed tomography; dm : diabetes mellitus type ; ecg: electrocardiography; icu: intensive care unit; mca: middle cerebral artery; nihss: national institutes of health stroke scale; np: not performed; pca: posterior cerebral artery; pt: prothrombin time; rt-pcr: real-time polymerase chain reaction; sc: subcutaneous; sca: superior cerebellar artery j o u r n a l p r e -p r o o f imagen -tc de tórax al ingreso. a: corte a nivel de lóbulos superiores. b: corte a nivel de lóbulos inferiores. se observan opacificaciones en vidrio deslustrado bilaterales de predominio derecho. presentan distribución central y sobre todo periférica. también existen consolidaciones parenquimatosas que afectan al lóbulo superior derecho, así como un derrame pleural derecho moderado.j o u r n a l p r e -p r o o f key: cord- -wqmynngg authors: sierra-hidalgo, fernando; muñoz-rivas, nuria; torres rubio, pedro; chao, kateri; villanova martínez, mercedes; arranz garcía, paz; martínez-acebes, eva title: large artery ischemic stroke in severe covid- date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: wqmynngg nan the coronavirus disease (covid- ) pandemic has spread rapidly all around the world. between march th and april th, , more than patients with a positive reverse transcriptase pcr for sars-cov- were admitted to our secondary hospital. eight of them had concurrent ischemic stroke during the viral disease. here, we describe the clinical and imaging features, and outcome, of these patients. stroke occurred, while in hospital in six patients and at home in the other two patients. all of them met the diagnostic criteria for severe covid- as previously defined [ ] . detailed description of cases is provided in the supplementary material (online resources , ). one was a woman and seven ( %) were men, with a median age of . years ( table ). none of them had had a previous stroke. hypertension was the most common vascular risk factor ( %). four patients were on antithrombotic therapy prior to admission: three patients were on antiplatelets (one as a secondary prevention after myocardial infarction, and two as a primary prevention due to a high vascular risk); and one on acenocoumarol due to atrial fibrillation. all the patients who suffered in-hospital strokes were on standard thromboprophylaxis with enoxaparine since admission except for the patient with atrial fibrillation, who was on subcutaneous enoxaparine mg bid. ischemic stroke occurred a median of . days after the onset of covid- symptoms (interquartile range, iqr . - . ). among hospitalized patients, stroke occurred a median of . days after admission (iqr . - . ). bilateral lung infiltrates on chest x-ray were present in all. at the time of stroke, turbidimetric d dimer was > , µg/l in % ( / ) of patients (median , µg/l; iqr - , ; normal value < µg/l). antiphospholipid antibodies were not obtained. overall, five strokes involved one cerebral arterial territory and three involved two or more arterial territories. all of them were large artery infarctions as diagnosed by clinical and cranial ct findings (four anterior circulation infarctions, three posterior circulation infarctions, and one with both anterior and posterior circulation infarctions). magnetic resonance imaging was not performed on any patient. only one patient met definite toast criteria for the diagnosis of large artery atherosclerotic infarction, and another one had a probably cardioembolic stroke due to preexisting atrial fibrillation (incomplete evaluation) [ ] . none of the other six patients met diagnostic criteria for atherosclerotic, cardioembolic, or small vessel ischemic stroke (three with cryptogenic strokes, and three with incomplete evaluation). intraarterial thrombi with absence of significant atherosclerotic plaques were observed in the intracranial or supra-aortic arteries in three out of four patients in which ct angiograms were obtained. four patients did not undergo ct angiography due to a worsening in their respiratory and neurological performance despite therapy. limitation of the therapeutic effort was applied in these cases, and patients died early after the stroke diagnosis without additional diagnostic workup. two patients had other thrombotic disorders electronic supplementary material the online version of this article (https ://doi.org/ . /s - - - ) contains supplementary material, which is available to authorized users. (one with a pulmonary embolism, patient no. in supplementary table; and another one with a floating aortic arch thrombus, patient no. ) . none of the patients met criteria for receiving reperfusion therapies of the occluded arteries. two of them were started on acetylsalicylic acid, and four received subcutaneous enoxaparine mg/kg bid. on evolution, four patients ( %) died, one remains in a minimally conscious state, one has a severe focal neurological deficit (left middle cerebral artery syndrome), and two have moderate focal neurological deficits, after a median follow-up of days for survivors. in this series of eight patients, although the evidence is limited by its observational nature and sample size, severe covid- was associated with non-atherosclerotic, large artery ischemic strokes. a high frequency of vertebrobasilar territory involvement was noted, and most patients did not meet diagnostic criteria for common causes of ischemic stroke [ ] . observed cumulative incidence of ischemic stroke during the period included in this series largely exceeds the expected incidence for our , admitted subjects during the days evaluated [ ] . at this point, in the growing knowledge about the mechanisms underlying the high morbidity and mortality associated to covid- , an atypical and enhanced form of acute coagulopathy secondary to endothelial disfunction and an inflammation-mediated prothrombotic state seem to be playing an important role. in the context of severe disease, vascular wall inflammation can initiate thrombus formation by activating endothelial cells, platelets, and leukocytes, which would trigger the coagulation pathway [ ] [ ] [ ] . this may induce a prothrombotic state that confers a high risk for ischemic stroke, either by a direct damage to a previously healthy endothelial wall or by enhancing a thrombotic effect in cases where a specific cause, such as atherosclerosis, is present [ , ] . if larger prospective studies confirm these observations, hypercoagulability associated with covid- might be a contributory cause for large vessel ischemic stroke. until robust evidence is available, the observation of intraarterial thrombi in the absence of significant atherosclerosis among these patients warrants consideration of individualized enhanced thromboprophylaxis for hospitalized patients with severe forms of sars-cov- infection. clinical characteristics of coronavirus disease in china classification of subtype of acute ischemic stroke. definitions for use in a multicenter clinical trial. toast. trial of org in acute stroke treatment sars -cov- and stroke in a new york healthcare system. stroke strokeaha stroke and transient ischemic attack incidence rate in spain: the iber-ictus study prominent changes in blood coagulation of patients with sars-cov- infection endothelial cell infection and endotheliitis in covid- characteristics of ischaemic stroke associated with covid- pathological inflammation in patients with covid- : a key role for monocytes and macrophages large-vessel stroke as a presenting feature of covid- in the young acknowledgments to the members of the "infanta leonor thrombosis research group"; to dr. pablo ryan; and to darryl solochek for editing the manuscript.funding none. conflicts of interest on behalf of all authors, the corresponding author states that there is no conflict of interest.ethical standard this study belongs to the covid- @vallecas cohort. the study has been approved by the hospital universitario infanta leonor ethics committee and has, therefore, been performed in accordance with the ethical standards laid down in the declaration of helsinki and its later amendments, and with the spanish data protection laws.consent to participate written informed consent was waived due to the retrospective nature of the study. collected data were anonymized, and each patient was identified by a unique alphanumeric identification code. key: cord- -d se v authors: aguiar de sousa, diana; van der worp, h bart; caso, valeria; cordonnier, charlotte; strbian, daniel; ntaios, george; schellinger, peter d; sandset, else charlotte title: maintaining stroke care in europe during the covid- pandemic: results from an international survey of stroke professionals and practice recommendations from the european stroke organisation date: - - journal: eur stroke j doi: . / sha: doc_id: cord_uid: d se v introduction: the coronavirus disease (covid- ) pandemic has been placing an overwhelming burden on health systems, thus threatening their ability to operate effectively for acute conditions in which treatments are highly time sensitive, such as cerebrovascular disorders and myocardial infarction. as part of an effort to reduce the consequences of this outbreak on health service delivery to stroke patients, the european stroke organisation has undertaken a survey aimed at collecting information on the provision of stroke care during the pandemic. methods: cross-sectional, web-based survey, conducted from march through april among stroke care providers, focused on reorganisation of health services, the delivery of acute and post-acute stroke care and the availability of personal protective equipment. results: a total of stroke care providers from countries completed the survey, most of whom worked in europe (n = , %) and were stroke physicians/neurologists (n = , %). among european respondents, ( %) reported that not all stroke patients were receiving the usual care in their centres and ( %) estimated that functional outcomes and recurrence rates of stroke patients would be negatively affected by the organisational changes caused by the pandemic. the areas considered as being most affected were acute care and rehabilitation. most professionals had to adapt their activities and schedules and more than half reported shortage of protective equipment. discussion: strategies to maintain availability of stroke care during the covid- outbreak are crucial to prevent indirect mortality and disability due to suboptimal care. conclusion: european stroke organisation proposes a set of targeted actions for decision makers facing this exceptional situation. stroke, health services, covid- , stroke care date received: april ; accepted: may the coronavirus disease (covid- ) outbreak has been spreading rapidly around the world and places an overwhelming burden on emergency systems, health-care facilities and health-care workers. also, governmental instructions together with the response pattern of the population, due to fear of infection in medical facilities, have led to a situation where several elective consultations and procedures have been postponed. resource restrictions for urgent health conditions, such as stroke and myocardial infarction, may have a significant impact on mortality and morbidity, potentially even larger than that of covid- disease itself. an increase in mortality associated with treatable conditions has been demonstrated during previous viral outbreaks such as the influenza a h n virus, in which a greater surge in hospital admissions was associated with significant increases in the mortality attributable to other diseases, including stroke and acute myocardial infarction. , currently, data are not available regarding the impact of the pandemic on access to and delivery of stroke care in europe. as part of the ongoing effort to reduce the consequences of covid- on health service delivery to stroke patients, the european stroke organisation (eso) has undertaken a survey aimed at collecting information on the current provision of stroke care. these results should provide relevant information to direct activities aimed at promoting the best possible care to all stroke patients during the pandemic and support stroke physicians and other professionals working in the field. a cross-sectional, web-based survey for stroke care providers was administered from march through april . as of march , , covid- cases and , covid- -related deaths had been reported in the european region, with , deaths reported from italy alone and a total number of infected people in spain already exceeding those reported in china. a -item draft survey instrument comprising closed-ended questions and two open-ended questions was developed by the first and senior authors and circulated and tested among the members of the executive committee of eso. refinements were made as required to facilitate better comprehension and to organise the questions. the provider used for survey application and server capacity was lamapoll (http://lamapoll. de). the final survey was made accessible through a link that was distributed by email to all eso members and advertised in the official social media channels of the society. eso is pan-european scientific non-profit organisation of stroke researchers and physicians, national and regional stroke societies and lay organisations that was founded in and had members at the time of this survey. before starting, participants were informed of the purpose of the study, target respondents and confidentiality. participants had to confirm they wished to submit their final responses at the end and a message acknowledging successful completion of the questionnaire was sent by the server. cookies and ip address analysis were used to identify potential duplicate entries from the same user, which were avoided by preventing users to access the survey twice. total completion time was recorded. the survey was anonymous and confidentiality of information was assured. participation in this survey was voluntary and was not compensated. the data that support the findings of this study are available from the corresponding author upon reasonable request. we focused on the reorganisation of health services and reallocation of professionals, delivery of acute and post-acute stroke care and availability of personal protective equipment. open-ended text fields for comments and suggestions were also included. a copy of the questionnaire is provided in full in the data supplement. demographic data were self-reported by the participants, including occupation, type of hospital and geographical location (country). the world health organisation definition of the european region was applied. responses from stroke care providers working outside of the european regions were excluded from the primary analysis but provided as supplementary material. because italy and spain were the most affected countries in europe at the time of the survey, sensitivity analyses excluding respondents from other countries were performed for items related with delivery of stroke care and availability of personal protective equipment. data are presented as numbers and percentages. data analysis was performed using microsoft excel for mac . the survey was completed by participants from countries on six continents. no responses were excluded. table shows the demographic and occupational characteristics of the european participants. the distribution per country is described in supplementary table . most of the respondents were stroke physicians/neurologists (n ¼ , %) from europe (n ¼ , %) and working at tertiary hospitals (n ¼ , %). the remaining participants were interventionalists ( %), rehabilitation physicians ( %), allied health-care professionals ( %) and other professionals working in the field (resident physicians, emergency physicians and intensivists; %). among european respondents, ( %) were stroke physicians/neurologists (table ) and ( %) reported having treated patients with stroke and covid- . a summary of the responses from the participants working outside europe is provided in the data supplement. among stroke care providers working in the europe, ( %) reported that not all stroke patients were receiving the usual care in their centres, with ( %) estimating that this was happening in more than one quarter of patients (table ) . of the respondents from italy and spain, ( %) reported being unable to provide the usual care to all stroke patients ( figure ). two hundred sixty-six european participants ( %) estimated that functional outcomes and recurrence rates of stroke patients would be affected by the changes in stroke care related to the covid- outbreak. the areas of stroke care considered as being the most affected by the current situation were rehabilitation (n ¼ , %) and acute stroke care (n ¼ , %). for topics related to medical management of stroke patients, only responses from stroke physicians or neurologists (n ¼ ) were included ( table ) ; ( %) european participants reported that stroke code pathways were affected at their centres. also, ( %) reported that their centre avoided admitting patients whenever possible and ( %) described lack of beds for stroke patients, while ( %) had been forced to direct stroke patients to other hospitals. about one in five physicians reported that several basic ancillary examinations were no longer available (n ¼ , %). closure of transient ischemic attack clinics was described by european respondents ( %). for questions related to endovascular treatment, we considered responses provided by stroke physicians/ neurologists and interventionalists. in europe, ( %) reported problems in endovascular treatment, particularly that this was not possible when there was a need for intensive care (n ¼ , %) or that they were no longer able to provide this treatment at their centre at all (n ¼ , %). the most common comment included in the openended text fields was the perception of a clear drop in hospital admissions for stroke and later arrival during this period. about two-thirds of european participants reported changes in their working situation, either related to new activities or modifications in the work schedules ( table ) . sixty-two ( %) described extended working hours due to a lack of personnel and ( %) reported the need to contribute to new tasks outside stroke care. almost one of every five professionals was doing most of the work from home. compared with those working in tertiary care centres, participants working in community hospitals were more likely to have similar schedules and activities as before the outbreak and less likely to work from home (supplementary figure ) . several specific strategies for team management were reported, including organisation of separate teams for different activities and rotation schemes that include periods of isolation. shortage of personal protective equipment was reported by more than half of the european respondents (n ¼ , %) and by % of the stroke care providers from italy and spain. this cross-sectional survey including stroke care providers from europe revealed profound changes in delivery of stroke care early during the early phase of the covid- pandemic. these answers reflect the participants' experiences and perspectives at a specific point in time during the outbreak in which the infection was rapidly spreading. only % of respondents considered that, in their centres, all stroke patients were still receiving the usual acute and post-acute care, and more than % estimated that functional outcomes and recurrence rates of stroke patients would be affected by the changes in stroke care related with the outbreak. european stroke care providers reported their most significant challenges centred on acute care and rehabilitation. although most professionals adapted their activities and schedules, substantial challenges were noted in maintaining the pathways for acute stroke patients and the quality of inpatient care, particularly in having sufficient resources to guarantee availability of beds for all patients and proper etiologic investigation. acute reperfusion strategies, secondary stroke prevention and rehabilitation, among several other interventions, have the potential to provide a significant and long-lasting benefit to patients with stroke, and the targets for the implementation of these treatments have been set before. [ ] [ ] [ ] [ ] even in a setting of increasingly limited resources, efforts to preserve essential services and to provide the maximum benefit for the population have to be made. importantly, rehabilitation should be also included in decisions regarding which health services are essential, as delayed access to these therapies can compromise health and functional outcomes. to overcome these demands, local and national health managers need to carefully plan the extent to which acute and post-acute stroke services should operate during the pandemic peaks and how their continuity can be maximised, mitigating the risk of a collapse of stroke care. also, multidisciplinary collaboration should be maintained to ensure a smooth workflow, as is the case with anaesthesia and intensive care for patients receiving endovascular treatment for ischaemic stroke. one in five respondents had treated patients with stroke and covid- . the current evidence suggests that covid- often triggers a strong inflammatory reaction that may predispose to ischaemia and thrombosis. as this combination of diseases is likely to become more frequent, it is important to ensure that effective reperfusion therapies and stroke unit care are also available for these patients, in parallel with a safe and efficient medical environment. also, proper evaluation should not be delayed, regardless of concerns about possible infection, and confirmed patients with covid- should be transferred to the designated medical institutions for further optimal medical treatment when indicated. shortage of personal protective equipment was a common concern, as it was reported by more than half of the respondents. stroke teams are in the frontline of the pandemic, meeting patients in the acute setting with unknown covid- status. establishing protected stroke code pathways , will contribute to adequate acute management of stroke patients with confirmed infection or unknown covid- status. furthermore, as highlighted by several respondents, it is crucial to communicate with the community so that people know they can continue to safely seek appropriate care when stroke symptoms ensue, and that this is critical. this report was not meant to be all inclusive of the undergoing changes and difficulties faced by health-care providers, hospitals and other health-care systems to maintain delivery of stroke care during this outbreak but to raise awareness among decision makers of the importance of preserving capacity to provide appropriate care to stroke patients during the covid- pandemic. after consideration of these key issues, eso reinforces the following recommendations: • stroke care is an essential health service and should be prioritised in the strategic planning to manage the demands related to the response to the covid- outbreak. • the general population should be informed that stroke is an emergency and treatment is still available, so they must continue calling emergency services immediately in case of suspected stroke. public education campaigns can be an effective way of raising awareness. • acute stroke teams are frontline workers. patients with unknown covid- status should be evaluated under 'protected stroke code' and therefore access to appropriate personal protective equipment is mandatory for all team members as well as clear protocols for individual protection. • stroke registers and researchers must deploy resources to evaluate the effects of the covid- pandemic on case volumes, time metrics and clinical outcomes. we suggest that the available data sources are used to assess changes in number hospital admissions, baseline characteristics, in-hospital workflow metrics, treatment rates and functional outcomes of stroke patients during this period. • as the outbreak progresses over time, countries should be able to increasingly resume post-acute care services for stroke patients, such as rehabilitation. as the current situation is likely to influence the organisation of health care for the next months or years, this may require the adaptation and expansion of rehabilitation facilities and staff to meet the communities' needs, both now and in the longer term. moreover, strategies to develop and implement telehealth services should be promoted and supported by health authorities. this study has several limitations. first, most participants were from tertiary centres and countries are not equally represented, limiting the scope of the conclusions and the generalisation of these findings. second, the survey was carried out during a short period and lacked longitudinal follow-up. because of the increasing dissemination of the infection, health-care strain may worsen and the long-term effects remain unknown. third, we were unable to distinguish whether the respondents worked in the same hospital or region or in different regions. finally, response bias may exist, and non-respondents may either be more likely to work in the most affected regions and not have the time to participate, or work in the least affected regions. strain of health services during the covid- pandemic has been causing major disruptions to stroke care in europe, with likely serious and long-term implications. shortage of personal protection equipment has been common among stroke care providers. efforts to maintain stroke teams and safe provision of stroke care, including reperfusion treatments, should be prioritised. the author(s) declared no potential conflicts of interest with respect to the research, authorship or publication of this article. the author(s) received no financial support for the research, authorship, and/or publication of this article. not required. the corresponding author (ecs) affirms that this is an honest, accurate and transparent account of the study being reported; that no important aspects of the study have been omitted; and that any discrepancies from the study as planned have been explained. all authors had access to the data in the study and can take responsibility for the integrity of the data and the accuracy of the data analysis. contributorship das and ecs initiated and coordinated the study. das, hbw, vc and ecs contributed to the development of the survey. das performed the principal analysis and drafted the manuscript. all authors interpreted the data and revised critically the manuscript for important intellectual content. a novel coronavirus from patients with pneumonia in china impact of the fall influenza a (h n ) pdm pandemic on us hospitals estimated global mortality associated with the first months of pandemic influenza a h n virus circulation: a modelling study coronavirus disease (covid- ) situation report - (data as reported by national authorities by stroke unit treatment. -year follow-up effect of treatment delay, age, and stroke severity on the effects of intravenous thrombolysis with alteplase for acute ischaemic stroke: a meta-analysis of individual patient data from randomised trials endovascular thrombectomy after large-vessel ischaemic stroke: a meta-analysis of individual patient data from five randomised trials action plan for stroke in europe covid- : operational guidance for maintaining essential health services during an outbreak: interim guidance world health organization what is the evidence for physical therapy poststroke? a systematic review and meta-analysis clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study protected code stroke: hyperacute stroke management during the coronavirus disease (covid- ) pandemic european society of minimally invasive neurological therapy (esmint) recommendations for optimal interventional neurovascular management in the covid- era the authors acknowledge the advice and useful comments of prof. martin dichgans in the development of this survey. the authors thank daniela niederfeld for her administrative support. supplemental material for this article is available online. key: cord- -j akzx authors: perry, richard; banaras, azra; werring, david j.; simister, robert title: what has caused the fall in stroke admissions during the covid- pandemic? date: - - journal: j neurol doi: . /s - - - sha: doc_id: cord_uid: j akzx nan during the current covid- pandemic there has been a decline in stroke admissions in centres all over the world [ , ] and no doubt this phenomenon has contributed to the sharp fall in the number of patients attending emergency departments in england during march [ ] . the explanation remains unclear. hypotheses fall into two main categories. either the incidence of stroke has declined during this period, or a higher proportion of patients who have strokes are never reaching stroke services [ ] . we reasoned that any change in the spectrum of stroke severity in patients presenting during the pandemic might yield important clues to distinguish between these two possibilities, as follows. if the main explanation is that a lower proportion of patients having a stroke are finding their way into stroke beds, then probably most of that decline will have been among those with the mildest strokes. these are the patients most likely to decide to manage their stroke at home, perhaps for fear of the risk of contracting covid- whilst in hospital. they are the most likely to have their neurological symptoms missed at a time of severe respiratory illness from the virus, or to be turned away from overstretched emergency services rather than being directed into the stroke pathway [ ] . finally, minor stroke symptoms are probably more likely to be overlooked in residents of care homes. on the other hand putative mechanisms for a decline in stroke incidence, such as reduced strain whilst people are not at work or lower levels of pollution [ ] , would not necessarily impact on strokes of any particular severity. we examined stroke severity in patients with a final diagnosis of acute stroke who were admitted to the hyperacute stroke unit at ucl hospitals, which provides the comprehensive stroke service for north central london in the united kingdom. figure shows the distribution of stroke severities (using the national institutes of health stroke scale) in admissions to our hyperacute stroke unit for two -day periods: before the decline in emergency admissions in england [ ] ( st february to th march, blue triangles) and after it ( st april to th may , red circles). the decline in the number of patients admitted with mild strokes (nihss ≤ ) was far more dramatic than was seen for moderate or severe strokes (nihss > ). it seems unlikely that a fall in the true incidence of stroke would have been so strongly biased towards mild strokes, and more plausible that the major factor driving this decline is that patients with mild strokes were no longer reaching our service during the second period. if patients with minor strokes are staying away from stroke inpatient services, as our data appear to suggest, then this is a worrying conclusion. without treatment about % of these patients will have a recurrent stroke within a week [ ] . on the other hand, the risk of catching the infection whilst in hospital is likely to be very low [ ] . the public health message is clear: individuals who think that they may be having a stroke, regardless of symptom severity, are much better off calling for an ambulance than staying at home. february (blue triangles, total patients) and for those presenting during the days from st april (red circles, total patients). the nihss is a score between and representing the degree of neurological impairment, higher scores representing more severe strokes. bin width = covid- and stroke-a global world stroke organization perspective the curious case of the missing strokes during the covid- pandemic emergency department syndromic surveillance system week public health england acute stroke care is at risk in the era of covid- population based study of early risk of stroke after transient ischaemic attack or minor stroke: implications for public education and organisation of services covid- : pcr screening of asymptomatic health-care workers at london hospital key: cord- -l re h j authors: sultana, shehnaz; venkata, kolla k; pranay, penagaluru k; usha, rani p; reddy, p.p. title: interferon gamma (ifnγ) + a/t gene polymorphism in south indian ischemic stroke patients date: - - journal: ann neurosci doi: . /ans. . . sha: doc_id: cord_uid: l re h j background: ischemic stroke is a complex vascular and metabolic process resulting in neuronal death and progression with time. cytokines play a role in immune response and also maintains the normal homeostatic environment of the central nervous system. ifn-γ is one of the key effector cytokines produced by nk and t cells that enhances microbicidal activity of macrophages and neutrophils. purpose: as the association of ifnγ + a/t gene polymorphism with stroke has not been investigated in indian population, we wanted to evaluate the association of this polymorphism with ischemic stroke in a south indian population. methods: we genotyped ischemic stroke patients and age-matched control subjects. results: statistical analysis showed a significant association of tt homozygote with ischemic stroke (or= . , % ci= . - . , p= . ), while aa (or= . , % ci= . – . , p= . ) and at(or= . , % ci= . - . , p= . ) genotypes were not significantly associated. a and t allele frequencies in stroke were . % and . % as against . % and . % in control group, respectively, thus, suggesting no statistically significant differences in the a (or= . , % ci= . – . , p= . ) and t (or= . , % ci= . – . , p= . ) allele frequencies between the two groups. conclusion: we conclude that the ifn-γ + tt genotype is associated with the increased risk of ischemic stroke. ischemic stroke is a complex vascular and metabolic process resulting in neuronal death and progresses with time. cytokines play a role in immune response and also maintain the normal homeostatic environment of the central nervous system. inflammatory cytokines play an important role in the etiology of cerebral infarction and they are under strong genetic control. as genetic traits contribute significantly to cerebral infarction variations in the genetic regulation of inflammatory system may increase the risk of the disease from individual to individual. ifn-γ has antiviral, immunoregulatory, and anti-tumor properties. atherosclerosis is an inflammatory disease, and plaque induced inflammation is considered a cause of intimal erosion and rupture and therefore leads to acute ischemia. , ifn-γ has important immunoregulatory roles and enhances both antigen specific and non-specific immune responses through actions on monocytes and macrophages. , complications related to infections such as chest and urinary tract infections, have been reported to occur in - % of all stroke patients within the first few days after stroke. , brain injury was identified as an independent risk factor for infectious complications in trauma patients due to a central nervous shutdown of the immune defense. , howard et al, reported association of immunosuppressive state with stroke. ifn-γ is one of the key effector cytokines produced by nk and t cells that enhances microbicidal activity of macrophages and neutrophils. several gene polymorphisms are associated with stroke in humans, association between the gene polymorphisms of inflammatory cytokines are meager. in the present study we have examined single nucleotide polymorphism in interferon gamma (ifnγ) at position + a/t in south indian ischemic stroke patients. fer containing triton-x was added to the whole blood sample, in-order to lyse the rbc and centrifuged to get the pellet. the pellet was lysed with wbc lysis buffer containing % sds, and then high molar concentration of nacl was added consecutively to separate out the protein fraction. finally, ice cold ethanol was added to get the dna which were separated and resuspended in te buffer and stored at - c until the pcr reaction was performed. the polymorphism in interferon gamma (ifnγ) at position + a/t was studied using amplification refractory mutation system polymerase chain reaction method (arms pcr). in brief, each reaction employed a generic antisense primer '-tcaacaaagctgatactcca- ' and one of the two allele-specific sense primers '-ttcttacaacacaaaatcaaat-ca- ' for 'a' allele and '-ttcttacaacacaaaatcaaatct- ' for 't' allele. for evaluation of the pcr amplification bp internal control was amplified using a pair of specific primers '-gccttccaaccattccctta- ' and '-tcacggatttctgtt-gtgtttc- '. the pcr incubation mixture in a total volume of µl consisted of mm tris-hcl, ph . ; mm kcl; mm dntps; . mm mgcl ; . units taq polymerase; . mm of each primer; . % gelatin and ng genomic dna. amplification was performed with an initial denaturation at °c for minutes, cycles were run with denaturation at °c for seconds, annealing at °c for seconds and extension at °c for seconds. the products were analysed on % agarose gel stained with ethidium bromide. the association between genotypes and stroke was examined by using odds ratio (or) with % confidence interval (ci) and chi square (χ ) analysis using epi info software (epi info cdc). all the statistical tests were two sided, and were considered significant at p value < . . genotypic frequencies were calculated according to the number of different genotypes observed and the total number of genotypes examined. yate's correction was applied wherever necessary. genotype frequencies were checked for deviation from hardy-weinberg equilibrium and were not significantly different from those predicted. the details on the demographic characteristics of the study population are shown in table . the mean age of the patients was . ± years as against the mean age of . ± years in the control group. the percentage of males among the stroke patients was . % (n= ), which was higher compared to controls . % (n= ), whereas the percentage of females was . % (n= ) in stroke patients and . % (n= ) in the control group. the percentage of hypertension was . % in stroke patients and . % in controls. the percentage of diabetes was . % among stroke patients and . % in control group. the percentage of smokers were more in patient group ( . %) compared to controls ( . %). the percentage of alcohol users in patients group ( . %) was more compared to controls ( . %). family history of hypertension in patients group ( . %) is more compared to controls ( . %). family history of diabetes in patients groups was . % as against . % in controls. family history of stroke was reported in . % of patients and . % of controls. in our case-control study, we genotyped ifn-γ + a/t polymorphism in ischemic stroke patients and in control subjects. the genotype frequencies of ifn-γ + a/t polymorphism among the patients and controls are shown in table . the distribution of genotypes was in hardy-weinberg equilibrium among controls. the frequencies of the "aa", "at", and "tt" genotypes of ifn-γ + a/t polymorphism in stroke patients were . %, . %, and . % as against . %, . %, and . % in controls, respectively. the genotypic frequency of "tt" homozygote showed a significant association with ischemic stroke (or= . , % ci= . - . , p= . ), while aa (or= . , % ci= . - . , p= . ) and at(or= . , % ci= . - . , p= . ) genotypes were nonsignificant. a and t allele frequencies in stroke were . % and . % as against . % and . % in control group, respectively, thus, suggesting no statistically significant differences in the a (or= . , % ci= . - . , p= . ) and t (or= . , % ci= . - . , p= . ) allele frequencies between the two groups. interferon gamma (ifn-) is an important cytokine in cellular immunity and the presence of thymidine at + correlates with microsatellite repeats associated with high cytokine production. in the present study we examined single nucleotide polymorphism in interferon gamma (ifnγ) at position + a/t and found a significant association of "tt" genotype with ischemic stroke. infectious complications in particular, bacterial pneumonia and their relevance for mortality are well known in acute stroke. the high incidence of infections in stroke patients is likely to be a result of an impaired immune function. a functional role of neutrophils in the development of strokeassociated injury remains controversial, and the contribution of specific lymphocyte subpopulations and their products to the pathogenesis of ischemic stroke are not clear. t-cell derived interferon-γ (ifn-γ) has been shown to contribute to the injury elicited by ischemia-reperfusion in other organs and ifn-γ mrna is increased in rat brain tissue after permanent focal cerebral ischemia. activation of the sns and the hpa by proinflammatory cytokines in systemic inflammation results in the release of glucocorticoids and catecholamines, which in- hibit further production of proinflammatory mediators. vagus nerve activation by inflammatory cytokines during endotoxemia was found to inhibit macrophage cytokine production through release of acetylcholine , and rapid activation of these pathways in inflammatory conditions protects the organism against any adverse effects of an overwhelming immune response. however, an excessive activation of inhibitory neuroendocrine pathways without systemic inflammation can inappropriately suppress the immune system and increase the risk of infections. intrathecal release of proinflammatory cytokines is associated with signs of systemic immunodepression and a high incidence of infections in neurosurgical patients. according to konstantin et al stress mediator blockade underlines the importance of functional defects in ifn-γ production in the control of infectious complications after stroke. γδ t cells are essential for pulmonary bacterial clearance and αβt cells are more critical in the peripheral blood in stroke induced infections. inflammation is an early and rate-determining step in the microvascular dysfunction and tissue injury associated with cerebral ischemia-reperfusion (i/r) is supported by several reports that describe a reduction in brain edema and infarct size in animal models of stroke treated with antibodies that block leukocyte adhesion. , the microvasculature of postischemic brain assumes an inflammatory phenotype that is manifested as endothelial activation and barrier dysfunction, enhanced generation of oxidants and inflammatory mediators, and the recruitment of adherent leukocytes and platelets. aspiration due to dysphagia is a known risk factor for pneumonia after severe strokes and other factors that might predispose stroke patients to pneumonia is an impaired immune responsiveness. , , . a study carried out in egyptian atopic patients showed a significant association of ifn-gamma gene polymorphism at position + a/t. study from china reported a significant association of ifn-gamma + a/t gene polymorphism and severe acute respiratory syndrome. a significant association was observed between interferon-gamma gene polymorphisms and systemic lupus erythematosus suggesting that elevated interferon gamma is associated with increased systemic erythematosus susceptibility. lai et al reported that genetic polymorphism of ifn-gamma gene is associated with individual susceptibility to cervical carcinogenesis. feher et al could not find any association between ifn-γ + a/t gene polymorphism and alzheimer disease. our study found a significant association of 'tt' genotype of ifn-γ + gene polymorphism and ischemic stroke in south indian population. the article complies with international committee of medical journal editor's uniform requirements for the manuscripts. genetics of inflammation and risk of coronary artery disease: the central role of interleukin- interferon-gamma: an overview of signals, mechanisms and functions atherosclerosis -an inflammatory disease recombinant interleukin suppresses the production of interferon gamma by human mononuclear cells il- inhibits the synthesis of ifn-gamma and induces the synthesis of ige in human mixed lymphocyte cultures complications after acute stroke medical complications after stroke: a multicenter study pneumonia: incidence, risk factors, and outcome in injured patients pneumonia following closed head injury acquired immunologic deficiencies after . trauma and surgical procedures stroke genetics update subtyping in ischemic stroke genetic research diagnosis and classification of diabetes mellitus; definition and . description of diabetes mellitus a non organic and non enzymatic extraction methods gives high yields of genomic dna from whole blood samples than do nine other methods tested interferongamma and interleukin- gene polymorphisms in pulmonary tuberculosis t-lymphocytes contribute to hepatic leukostasis and hypoxic stress induced by gut ischemia-reperfusion link h. il- and ifn-gamma mrna expression is increased in the brain and systemically after permanent middle cerebral artery occlusion in the rat pharmacological stimulation of the cholinergic antiinflammatory pathway the inflammatory reflex immunodepression following neurosurgical procedures stroke-induced immunodeficiency promotes spontaneous bacterial infections and is mediated by sympathetic activation reversal by poststroke t helper cell type -like immunostimulation inflammatory responses to ischemia and reperfusion in the cerebral microcirculation hu f g, an antibody recognizing the leukocyte cd /cd integrin, reduces injury in a rabbit model of transient focal cerebral ischemia platelet-leukocyte-endothelial cell interactions after middle cerebral artery occlusion and reperfusion screening for dysphagia and aspiration in acute stroke: . a systematic review aspiration pneumonia aspiration pneumonitis and aspiration pneumonia interferon gamma gene polymorphism as a biochemical marker in egyptian atopic patients the interferon gamma gene polymorphism + a/t is associated with severe acute respiratory syndrome interferon-gamma gene polymorphisms associated with susceptibility to systemic lupus erythematosus genetic polymorphism of the interferon-gamma gene in cervical carcinogenesis association study of interferon-?, cytosolic phospholipase a , and cyclooxygenase- gene polymorphisms in alzheimer disease key: cord- -hnbzidf authors: liu, liping; wang, david; brainin, michael; elkind, mitchell s v; leira, enrique; wang, yongjun title: approaches to global stroke care during the covid- pandemic date: - - journal: stroke vasc neurol doi: . /svn- - sha: doc_id: cord_uid: hnbzidf nan since the outbreak of coronavirus disease (covid- ), the healthcare system of the world has been overwhelmed by this pandemic. the most recent statistic showed that there are now over million people infected and over deaths in countries. this pandemic has presented a major challenge to the care of patients with other medical conditions such as stroke, which affects in people over the age of in their lifetime and kills about . million each year. there have been reports showing that stroke centres and hospitals are seeing a significant drop in stroke admissions since the pandemic. realising this challenge and urgency, the chinese stroke association convened a group of international stroke leaders and discussed the challenges facing stroke care worldwide and recommendations of stroke care during the covid- pandemic. the covid- pandemic is at different stages in different countries. while china is slowly opening up its cities after the lockdown, some countries may be at the plateau stage and others have not reached the peak yet. covid- is unlikely to be a short-term pandemic. both korea and china have seen pockets of resurgence of cases. there is concern that a second wave of the pandemic may come in the fall of . covid- will thus likely change our way of delivering stroke care for years to come. the world should be proactive in how to meet the challenges. the stroke care model may need to adapt, however, so that the care is not compromised and the risk of infection of healthcare providers is minimised. the work group identified five major issues challenging stroke care worldwide. first, there is an alarming drop of stroke cases presenting to stroke centres and hospitals. several surveys have reported a decrease of %- % in stroke cases of all types and a % decrease in interventional cases, such as acute thrombectomy. the latest survey data collected from the chinese stroke center alliance showed that among hospitals during the period of pandemic, the admission rate of patients who had a stroke decreased by as much as %- %. the reasons for this drop may include the fear of getting infected by patients who had a stroke and their families; reluctance to bother healthcare providers who are busy taking care of patients with covid- ; disruption of stroke systems of care due to increased demands for patients with covid- ; and reductions in stroke incidence due to changes in patterns of behaviour or other factors. second is the delay of care due to the need to screen for covid- . hospitals have seen prolonged door-to-treatment time due to the need to rule out covid- and take the precautions. in addition, the ability of a hospital to care for patients who had a stroke may diminish due to the need to minimise exposure and reallocate work force and resources. the third issue is the possible association of covid- and strokes. recent reports have suggested that young patients with covid- may be at increased risk of strokes, perhaps due to hypercoagulability related to the virus and particularly among patients with severe covid- . in addition, patients with transient ischaemic attack (tia) or minor stroke who do not seek immediate medical attention are at risk of developing worsening of stroke. fourth, healthcare providers, including emergency medical physicians, are being infected at a higher percentage in certain countries, which may decrease the work force providing stroke care. lastly, certain ethnic groups are especially vulnerable to covid- infection, possibly because of lower socioeconomic status and inability to fully practice social distancing, lack of access to healthcare, increased obesity and adverse health behaviours, and medical open access comorbidities, such as diabetes mellitus and hypertension. these groups are also at higher risk of having a stroke. realising such challenges, societies such as chinese stroke association, american heart association/american stroke association and american academy of neurology stroke section have published their guidance recently. - interventional (liu lp et al under review) and neurointensive care groups have also published their consensus statements. based on these statements and a need to call for uninterrupted stroke care during this pandemic, this work group has composed the following recommendations: recommendations we believe that during this uncertain time, safe delivery of timely and quality stroke care will require creativity, flexibility and attention to the evolving scientific evidence. as always, our focus should be to meet the needs of patients who had a stroke. there is a need to raise stroke awareness during this pandemic and to counteract the fear of the population, highlighting that stroke still is a time-dependent emergency. education should focus on recognition of the signs and symptoms of stroke and the need to go to the hospital since stroke can be lethal. with the report on covid- causing strokes in young, more research is needed to have a better understanding of its underlying mechanism. as for healthcare professionals, for those treating severe covid- patients who are intubated and sedated and difficult to perform reliable neurological examination, a routine ct of head without contrast to screen for possible strokes may be considered. ii. consider designating stroke centres as covid- ready stroke centres and allocate resources such as personal protective equipment (ppe) to support these centres. such designation can be arranged in a way that certified stroke centres can take turns in a city or area if they have many stroke centres in the vicinity. iii. all emergency rooms may consider designating an isolated private area for triage of suspected or confirmed patients with covid- who also have a stroke. this is where all patients who had a stroke presented within the time window for either intravenous thrombolysis or intraarterial thrombectomy should be triaged to. iv. all tia patients or patients with confirmed diagnosis of stroke should be tested for covid- if resources allow. v. all healthcare providers who are treating tia patients or patients who had a stroke without knowing patients' covid- testing results should don ppe as per local and institutional guidelines to minimise exposure. vi. at a stroke centre, consider designating one ct, one mri and one angiography suite to be used for suspected or confirmed covid- patients with stroke. coronavirus disease (covid- ) situation report - world stroke organization. learn about stroke stroke: a global response is needed available: www. world-stroke. org/ news-and-blog/ news/ the-global-impact-of-covid- -on-stroke-survey covid- : are acute stroke patients avoiding emergency care? why a mayo clinic expert has concerns about second wave of covid- covid- : plummeting stroke admissions and new protocols americans worry doctor visits raise covid- risk large-vessel stroke as a presenting feature of covid- in the young neurologic manifestations of hospitalized patients with coronavirus disease characteristics of health care personnel with covid- -united states need-extraprecautions/ racial-ethnic-minorities. html temporary emergency guidance to us stroke centers during the covid- pandemic on behalf of the aha/asa stroke council leadership consensus for prevention and management of coronavirus disease (covid- ) for neurologists preserving stroke care during the covid- pandemic: potential issues and solutions mechanical thrombectomy in the era of the covid- pandemic: emergency preparedness for neuroscience teams: a guidance statement from the society of vascular and interventional neurology key: cord- -sh ij f authors: wong, ka sing; chen, christopher; ng, ping wing; tsoi, tak hong; li, ho lun; fong, wing chi; yeung, jonas; wong, chi keung; yip, kin keung; gao, hong; wong, hwee bee title: low-molecular-weight heparin compared with aspirin for the treatment of acute ischaemic stroke in asian patients with large artery occlusive disease: a randomised study date: - - journal: lancet neurol doi: . /s - ( ) - sha: doc_id: cord_uid: sh ij f background: acute stroke patients with large artery occlusive disease (laod) have a distinct pathophysiology and may respond differently to anticoagulation treatments. we compared the efficacy of a low-molecular-weight heparin (lmwh), nadroparin calcium, with aspirin in asian acute stroke patients with laod. methods: acute ischaemic stroke patients with onset of symptoms less than h and laod (diagnosed by transcranial doppler imaging, carotid duplex scan, or magnetic resonance angiography) were recruited. patients were randomly assigned to receive either subcutaneous nadroparin calcium anti-factor xa iu/ · ml twice daily or oral aspirin mg daily for days, and then all received aspirin – mg once daily for months. this study is registered at www.strokecenter.org/trials (number ). findings: among patients recruited, ( lmwh, aspirin) had laod ( had intracranial laod only, had both intracranial and extracranial disease, and had extracranial disease only). the proportion of patients with good outcomes at months (barthel index ≥ ) was % in the lmwh group and % in the aspirin group (absolute risk reduction %; % ci − to ). analysis of prespecified secondary outcome measures showed a benefit in outcome for lmwh versus aspirin on the modified rankin scale dichotomised at – (odds ratio · , % ci · – · ). haemorrhagic transformation of infarct and severe adverse events were similar in both groups. post-hoc analyses of patients without laod, and all treated patients, showed similar proportions with a good outcome in aspirin and lmwh groups ( % vs % and % vs %, respectively). interpretation: overall, the results do not support a significant benefit of lmwh over aspirin in patients with laod. the benefits indicated in most outcome measures warrant further investigation into the use of anticoagulation for acute stroke in patients with large artery atherosclerosis, particularly in intracranial atherosclerosis. stroke is the third most common cause of death worldwide and the leading cause of disability in adults. the burden of stroke is particularly heavy in asia, where it accounts for more than half of worldwide mortality from stroke. acute intervention for ischaemic stroke is currently the subject of intensive clinical research. among medical treatments, aspirin , and tissue plasminogen activator [ ] [ ] [ ] have been shown to have a benefi cial eff ect on outcome. however, the treatment eff ect of aspirin is small, and use of tissue plasminogen activator is limited by its narrow therapeutic window. antithrombotic agents are used in acute ischaemic stroke to inhibit clot propagation, prevent reembolisation, and facilitate clot lysis. , however, randomised controlled trials have not found unfractionated heparin to be eff ective in improving functional outcome. several medium-sized randomised placebo-controlled trials using low-molecular-weight heparin (lmwh) or heparinoid for the treatment of acute ischaemic stroke have been reported since . [ ] [ ] [ ] [ ] only the fraxiparine in ischaemic stroke (fiss) study of nadroparin calcium in chinese patients was positive in its primary outcome, but this result was not reproduced in the larger fiss-bis study, the trial of org in acute stroke treatment (toast), nor the tinzaparin in acute ischemic stroke trial (taist) study. recent systematic reviews and meta-analyses of lmwh and heparinoids in acute ischaemic stroke have concluded that immediate fulldose anticoagulant therapy is not associated with net short-term or long-term benefi t, and the routine use of any type of anticoagulant is not supported. , however, debate has continued in asia on whether the results of the fiss study, the only positive trial of lmwh, were due to chance or related to ethnic diff erences in the underlying pathophysiological mechanism of ischaemic stroke. extracranial atherosclerotic stenosis is a well-known risk factor for stroke worldwide. by contrast, intracranial large artery occlusive disease (laod) is an important cause of stroke among asians, hispanics, and african americans. [ ] [ ] [ ] asian data have suggested that laod is the cause of ischaemic stroke in about a third to a half of patients. , the predominance of intracranial laod in asian stroke patients might explain why the benefi cial eff ect of lmwh in chinese patients was not reproduced in studies of white people. in concordance with this hypothesis, a post-hoc analysis of the toast study has shown that heparinoid treatment could increase the odds of a favourable outcome in patients with stroke secondary to laod. with this background of a positive trial and defi nite diff erences in stroke subtype, especially intracranial atherosclerosis in asians, uncertainty remains about the benefi t of lmwh for laod. the study objective was to test the hypothesis that subcutaneous nadroparin calcium is superior to aspirin in improving stroke outcome at months in patients with acute ischaemic stroke and laod. this study was an academically funded, investigatorinitiated, multicentre, randomised controlled trial with blinded outcome assessment, done at multiple trial sites in hong kong and singapore between april , , and sept , . the study protocol received ethics committee approval at all participating centres. all participants or their legally acceptable representatives provided written informed consent. patients who were diagnosed with acute ischaemic stroke were randomly assigned to receive either nadroparin calcium anti-factor xa iu/ · ml subcutaneously twice daily (lmwh group) or aspirin mg once daily (aspirin group) for days, and then all received aspirin - mg once daily for months. inclusion criteria were as follows: age - years; clinical diagnosis of acute ischaemic stroke; symptoms of stroke less than h before receiving the fi rst dose of trial medication (counted from time last known to be symptom free); presence of motor defi cit as a result of acute stroke, brain ct scan excluding intracerebral haemorrhage; women of nonchildbearing potential (ie, physiologically incapable of becoming pregnant, including any woman who was postmenopausal) or of childbearing potential but with a negative urine pregnancy test immediately before randomisation. if vascular imaging was done before randomisation, it had to show moderate or greater stenosis in the internal carotid, vertebrobasilar, middle cerebral, anterior cerebral, and posterior cerebral arteries as confi rmed by carotid duplex scan, transcranial doppler imaging, or magnetic resonance angiography, according to previously published criteria. , all randomised patients, except for two who were ineligible and two who withdrew their consent, received the allocated treatment and completed the study at months. if neuroimaging was not done before randomisation, results of the neuroimaging were interpreted without knowledge of the treatment allocation. only patients with laod confi rmed by neuroimaging were included in the primary analysis. exclusion criteria were as follows: prestroke modifi ed rankin scale (mrs) score greater than ; national institutes of health stroke scale (nihss) score greater than ; history of intracerebral haemorrhage; known contraindication for the use of lmwh or aspirin (including haemorrhagic diathesis); patient on anticoagulation therapy (excluding aspirin) before the onset of stroke or defi nite indication for anticoagulation; sustained hypertension (blood pressure > /> mm hg) immediately before randomisation; coexisting systemic diseases such as terminal carcinoma, renal failure (creatinine > μmol/l, if known), cirrhosis, severe dementia or psychosis, brain tumour or other signifi cant non-ischaemic brain lesion on brain ct scan, atrial fi brillation on ecg (past or present); chronic rheumatic heart disease or metallic heart valve; thrombocytopenia (platelet count < × /l, if known); or participation in another clinical trial. baseline data and measurements collected included demographics, medical history, and prestroke mrs and nihss scores. at day , or earlier if discharged, outcome was assessed by nihss, barthel index, mrs, and minimental state examination (mmse). at months after randomisation, nihss, barthel index, mrs, mmse, and international stroke trial (ist) questions were assessed by a clinician or nurse without knowledge of the treatment allocation. haemorrhage, thromboembolic events, adverse events, and overall mortality during treatment and follow-up were documented. the primary outcome was a combined endpoint at months, defi ned as survival with a barthel index of at least (good outcome), as used in the fiss-bis study. secondary outcomes included: nihss score at day and month ; change in nihss score between baseline and day , and between baseline and month ; mrs score at day and month (favourable outcomes were defi ned as survival with mrs score of - and also - ), mmse scores at day and month , ist questions at month (good outcome or independent defi ned as ist outcome "indiff erent or good", and bad outcome [dependent/dead] defi ned as ist outcome "dead or bad"); overall mortality at day and month ; and thromboembolic events during the study period (recurrent stroke, coronary syndrome, deep vein thrombosis, and pulmonary embolus). ct scans of the brain at randomisation and at day were read independently by radiologists who were unaware of the treatment allocation. the safety measures included haemorrhagic episodes occurring between days and , defi ned as the presence of any of the following: symptomatic haemorrhagic transformation of the cerebral infarct or symptomatic intracerebral haemorrhage not associated with cerebral infarction; asymptomatic haemorrhagic transformation of the cerebral infarct or asymptomatic intracerebral haemorrhage not associated with cerebral infarction; serious extracranial haemorrhages (eg, gastrointestinal bleeding, haematoma, haematuria); thromboembolic events during the study period (recurrent stroke, coronary syndrome, deep vein thrombosis, pulmonary embolus); death from any cause; and death related to haemorrhagic complications. all neurological events were assessed by an events evaluation committee. progressing stroke was defi ned as neurological deterioration from day to day after onset of symptoms, but excluding haemorrhagic transformation of infarct or infarct in another vascular territory. recurrent stroke was defi ned as neurological deterioration from day to month or infarct in another vascular territory. randomisation into the trial was done through the central randomisation offi ce at the clinical trials and epidemiology research unit in singapore by means of sealed envelopes or allocation via the internet. block randomisation was used (block sizes of and ), stratifi ed by regions (hong kong, kowloon, new territories, singapore), time from onset of stroke ( - h, - h), nihss score ( - , ≥ ), and whether neurovascular investigations were done before randomisation (vascular lesion present, vascular lesion status unknown), with a one-to-one treatment allocation. the treatment assignment was generated by computer. data management and statistical analysis were done at the clinical trials and epidemiology research unit in singapore independently of the investigators. in the toast study, % of the placebo group and % of the treatment group in the laod subgroup had a good outcome. for the purposes of sample size calculation, we assumed that the outcomes of our patients would be the same as in the toast study. with a two-sided test size of % and power of %, the required sample size planned for the trial was at least patients with laod. analyses were done on an intention-to-treat basis. when month effi cacy outcomes were not obtained, the last available outcome was used in its place (last observation carried forward method). the associations between treatment groups and the primary endpoints (combined outcomes) were determined using chi-squared tests. odds ratios (ors) with % cis were calculated. the two-sample t test was used to assess the quantitative secondary endpoints, and mean diff erences between treatment groups were presented with % ci. logistic regression and multiple regression analyses were done for binary and continuous outcomes, respectively, and adjusted for the stratifi cation variables: time from onset of stroke ( - h, - h), nihss score ( - , ≥ ), whether neurovascular investigations were done before randomisation (vascular lesion present, vascular lesion status unknown). in addition to the primary analysis of the laod subgroup, similar analyses were also done for all randomised and treated patients and the non-laod subgroup. the trial data were collected on printed forms, and subsequently entered on to computer by use of clintrial software (clinsoft corporation release . , lexington, ma, usa). statistical analyses were generated using sas version . (sas institute inc, cary, nc, usa). reporting of this study was done in accordance with the consort statement. for the purpose of this report, values of ors greater than · and positive values for risk reductions indicate an advantage of lmwh over aspirin. the funding sources had no role in the study design, data collection, data analysis, data interpretation, or writing of the report. the corresponding author had full access to all the data in the study and had fi nal responsibility for the decision to submit for publication. we enrolled patients in participating hospitals from april, , to september, . in hospitals where screening logs were available, we estimated that about · % of acute stroke patients were eligible as per the study protocol. common barriers for recruitment included late presentation, refusal, and the severe acute respiratory syndrome epidemic. four patients did not receive any trial medications and thus no data were recorded: two withdrew consent and two were ineligible due to presence of exclusion criteria (fi gure ). patients who were randomised ( lwmh, aspirin) were excluded from the primary analysis according to the protocol after vascular imaging investigations did not show any laod ( with vascular imaging done before randomisation, patients with vascular imaging done after randomisation) or because no vascular imaging could be done (n= ). our primary study population comprised the patients with confi rmed laod: patients with vascular imaging done before randomisation and patients with vascular imaging done after randomisation. the location of laod was solely intracranial in ( %) patients, solely extracranial in ( %), and both intracranial and extracranial in ( %). all patients underwent transcranial doppler examination, % underwent carotid duplex doppler examination, and less than % underwent magnetic resonance angiography. the baseline clinical and stroke characteristics of patients and baseline variables between the two groups were similar (table ), although there were slightly more patients with diabetes mellitus in the aspirin group. in the primary outcome analysis at months, the proportion of patients with good outcomes (barthel index all patients the or for the primary outcome remained unaltered after adjusting by the stratifi cation variables: time from onset of stroke, nihss score at baseline, and whether neurovascular investigation was done before randomisation (table ) . after adjustment, patients on lmwh still had a signifi cant advantage with a mrs score of - (adjusted or · , % ci · - · ). the mmse score of patients allocated lmwh became signifi cantly higher compared to those allocated aspirin (adjusted estimate of diff erence · , · - · ). however, an adjusted analysis that accounted for stratifi cation factors had little eff ect on the ors or estimates of the remaining secondary outcomes. there was no signifi cant diff erence in the occurrence of haemorrhagic transformation of infarct (symptomatic or asymptomatic), adverse events, or serious adverse events (haemorrhagic or non-haemorrhagic) between the two groups (table ) . in the post-hoc analysis of patients excluded because of the absence of laod, the proportion of patients with good outcomes at months with barthel index of at least was % ( of ) in the lmwh group and % ( of ) in the aspirin group (arr · %, % ci − to ). the effi cacy outcomes in terms of independence in these patients are shown in fi gure . secondary outcomes showed a signifi cant risk for lmwh versus aspirin in outcomes with mrs score - versus ≥ (lmwh % vs aspirin %; arr − %; or · , · - · ), but not for mrs - versus ≥ (lmwh % vs aspirin %; arr · %; or · , · - · ) and ist outcome (lmwh % vs aspirin %; arr − %; or · , · - · ). the mean mmse score was · (sd · ) for lmwh versus · (sd · ) for aspirin (p= · ). mean nihss scores were · (sd · ) for lmwh and · (sd · ) for aspirin (p= · ). the adjusted ors or estimates of the primary and secondary outcomes remained unchanged. no signifi cant diff erences in safety measures between the two groups were found (table ) . in the post-hoc analysis of all randomised and treated patients, the proportion of patients with good outcomes at months with a barthel index of at least was % ( of ) in the lmwh group and % ( of ) in the aspirin group (arr · %; % ci − to ). the effi cacy outcomes in terms of patients' independence are shown in fi gure . secondary outcomes showed no signifi cant benefi t for lmwh over aspirin in outcomes with mrs score - versus ≥ (lmwh % vs aspirin %; arr − · %; or · , · - · ) and for mrs score - versus ≥ (lmwh % vs aspirin %; arr · %; or · , · - · ), and ist outcome (lmwh % vs aspirin %; arr · %; or · , · - · ). the mean mmse scores were · (sd · ) for lmwh and · (sd · ) for aspirin (p= · ). the mean nihss scores were · (sd · ) for lmwh and · (sd · ) for this trial was designed to assess the eff ects of lmwh versus aspirin on acute stroke patients with laod (predominantly due to intracranial atherosclerosis). ischaemic stroke is a heterogeneous disease with three main stroke subtypes: cardioembolic, laod, and small vessel disease. because of the diversity of stroke mechanisms, the best acute treatment of individual stroke subtypes may be diff erent. previous acute trials of anticoagulation have not systematically targeted underlying arterial lesions. in patients with laod, atherothrombosis is a common mechanism and thus anticoagulation may be particularly useful in this stroke subtype. a previous post-hoc analysis suggested that anticoagulation may be benefi cial among patients with internal carotid occlusive disease. among acute stroke patients with intracranial atherosclerosis, microemboli were detected in % of patients by use of transcranial doppler monitoring, and % of patients had multiple acute infarcts on diff usion-weighted mri, suggesting artery-to-artery embolism was an important stroke mechanism in patients with middle cerebral artery stenosis. although our data did not show a defi nitive benefi t of lmwh over aspirin, the results were compatible with an earlier study on asian patients who were at high risk of intracranial atherosclerosis. moreover, the results also suggested that lmwh might be hazardous in patients without laod. future large studies of anticoagulation on acute stroke patients with laod should be done to clarify the role of anticoagulation in diff erent stroke subtypes. the choice of primary outcome measure is crucial in the case of acute stroke. the barthel index was used in this study and is the most commonly used disability measure in acute stroke trials. , however, the barthel index is a not sensitive measure among patients with relatively mild stroke. the stroke severity of our patients was relatively mild: the median barthel index score was and % of patients had a score of at least at months. several recent studies have used a dichotomised mrs score or combined several outcome measures in a global statistical test. the choice of primary outcome measure may determine whether a trial is positive or negative. future studies on patients with intracranial atherosclerosis may consider using a dichotomised mrs score as the primary outcome measure. we found that the lmwh group had slightly better cognitive function in terms of mmse scores. cognitive function plays a vital role for independent living. patients without physical impairment but who are cognitively impaired may need help for their daily functions. the diff erence in cognitive outcome might explain the diff erences in disability status, although there was no diff erence in the nihss scores (a measure of physical impairment). however, the diff erences could also indicate small diff erences in the baseline mmse in the groups. our data suggest that future acute stroke trials should measure cognitive function as an outcome indicator. this academically funded study was done without any substantial support from industry. moreover, the data analyses were done independently of the investigators. the use of (predominantly) ultrasound to delineate vascular lesion also strengthens the methodology of this study. however, use of open-label trial medication might have caused bias, even though the assessors at month were unaware of treatment allocation. the use of the last observation carried forward method could introduce substantial bias. in addition, the relatively small sample size could provide misleading conclusions on possible benefi t or hazard. however, the eff ect would be small in our analysis because there were only about % of missing data in our study. nevertheless, the results of this study should resurrect interest in large clinical trials on anticoagulation in acute ischaemic stroke patients with laod, especially intracranial disease. k s wong, c chen, p w ng, t h tsoi, h l li, w c fong, j yeung, c k wong, and k k yip participated in the design of the protocol, recruited patients, and wrote the draft of the manuscript. h gao and h b wong collected the case record forms, did the statistical analysis, and wrote the statistical results of the manuscript. all authors approved of the fi nal version of the manuscript. we have no confl icts of interest. professional services and medical development division, hospital authority head offi ce christopher chen (investigator) jonas yeung (investigator), bun-hey fung. northern district hospital ( patients): chi-keung wong (investigator), chi keung sung, siu-hung li. ruttonjee hospital tseung kwan o hospital ( patients): kin-lun tsang. references cast (chinese acute stroke trial) collaborative group. cast: randomised placebo-controlled trial of early aspirin use in patients with acute ischaemic stroke national institute of neurological disorders and stroke rt-pa stroke study group. tissue plasminogen activator for acute ischemic stroke low molecular weight heparin in acute stroke randomised double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ecass ii) thrombolytic stroke therapy: past, present, and future antithrombotic treatments in acute ischemic stroke acute ischemic stroke and heparin treatments low-molecular-weight heparin for the treatment of acute ischemic stroke fraxiparine in ischemic stroke study (fiss bis) publications committee for the trial of org in acute stroke treatment (toast) investigators. low molecular weight heparinoid, org (danaparoid), and outcome after acute ischemic stroke: a randomized controlled trial tinzaparin in acute ischaemic stroke (taist): a randomised aspirin-controlled trial anticoagulants for acute ischaemic stroke low-molecular-weight heparins and heparinoids in acute ischemic stroke: a meta-analysis of randomized controlled trials racial distribution of intracranial and extracranial atherosclerosis race-ethnicity and determinants of intracranial atherosclerotic cerebral infarction. the northern manhattan stroke study race, sex and occlusive cerebrovascular disease: a review use of transcranial doppler ultrasound to predict outcome in patients with intracranial large-artery occlusive disease intracranial stenosis in chinese patients with acute stroke antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery: a report of the trial of org in acute stroke treatment (toast) variability of magnetic resonance angiography and computed tomography angiography in grading middle cerebral artery stenosis the consort statement: revised recommendations for improving the quality of reports of parallel-group randomized trials resolved: heparin may be useful in selected patients with brain ischemia mechanisms of acute cerebral infarctions in patients with middle cerebral artery stenosis: a diff usion-weighted imaging and microemboli monitoring study glycine antagonist (gavestinel) in neuroprotection (gain international) in patients with acute stroke: a randomised controlled trial enhancing the development and approval of acute stroke therapies: stroke therapy academic industry roundtable health status of individuals with mild stroke design of future acute-stroke treatment trials this study was supported by the clinical eff ectiveness unit, hospital authority in hong kong, the national medical research council of singapore (nmrc/ / ), and the clinical trials and epidemiology research unit, singapore. we thank the drug manufacturer (sanofi aventis singapore, glaxosmithkline) for providing free samples of nadroparin for patients in singapore. we thank prof philip bath (university of nottingham, uk) for his comments on the draft manuscript. key: cord- - khsxhwv authors: aguiar de sousa, diana; van der worp, h. bart title: stroke care in europe during the covid‐ pandemic date: - - journal: eur j neurol doi: . /ene. sha: doc_id: cord_uid: khsxhwv in view of finite health care resources and the ethical principle of distributive justice, healthcare systems across europe have been adapted to provide care for patients with coronavirus disease (covid‐ ) while not neglecting other serious medical emergencies. policies to contain disease spreading and to preserve usual health care systems as much as possible differ considerably between countries. this article is protected by copyright. all rights reserved disease spreading and to preserve usual health care systems as much as possible differ considerably between countries. in this issue of the european journal of neurology, colleagues from italy, france and germany provide an overview of policy responses and changes in the provision of stroke care in their countries in the first few months of the covid- outbreak . although their report does not provide detailed data on case volumes, time metrics or clinical outcomes, this may provide guidance to those who are or will be faced with similar challenges by offering insight into reorganization strategies. several common experiences stand out from the report, albeit at somewhat different extent, such as a reduction in the numbers of stroke admissions, increases in the numbers of intensive care unit beds, reduction or suspension of elective interventions and outpatient visits, and institution of screening procedures and other protection measures to prevent the spread of covid- among patients and healthcare providers. however, it is also clear that the regions where the outbreak took place first, especially northern italy, have faced a much more dramatic situation due to the high volume of patients with covid- requiring hospital care. as a consequence, acute stroke pathways were redrawn, including transportation and triage protocols, and stroke physicians and nurses were redeployed. this change in practice was not restricted to italy: centralization of acute stroke care to a limited number of hospitals, with the remaining stroke units designated to covid- care, also occurred in france. importantly, the authors note that these major changes in organization of stroke care have likely reduced the use of reperfusion therapies and caused delays in some of those who received these treatments. this is in line with concerns raised in an earlier survey among stroke care providers in europe . provision of stroke care was less affected in germany, where no major reorganization of the stroke care system appeared necessary. this is may be explained in part by differences in health care systems, including the much higher number of intensive care beds in germany than in italy or france, and by the fact that the major outbreak occurred later in germany than in italy. in their report the authors offer an international perspective on the modifications in stroke care during the pandemic and provide insight into differences between countries in policy measures and in challenges faced by stroke care providers. some of the solutions emerge as potentially successful tools, such as the development of regional stroke care collaborations in highly affected this article is protected by copyright. all rights reserved regions, the implementation of public campaigns to encourage patients to continue seeking emergency care when experiencing acute stroke symptoms, and the use of telemedicine to perform routine follow-up visits. actual data on stroke incidence, hospitalisations, and outcomes are now needed to better understand the impact of the covid- outbreak on stroke and stroke care. research groups in several countries in europe and elsewhere are currently working on this, probably leading to valuable insights shortly. stroke care during the covid- pandemic: experience from three large european countries for the european stroke organisation. maintaining stroke care in europe during the covid- pandemic: results from an international survey of stroke professionals and practice recommendations from the european stroke organisation key: cord- - l b mqp authors: nguyen-huynh, mai n.; tang, xian nan; vinson, david r.; flint, alexander c.; alexander, janet g.; meighan, melissa; burnett, molly; sidney, stephen; klingman, jeffrey g. title: acute stroke presentation, care, and outcomes in community hospitals in northern california during the covid- pandemic date: - - journal: stroke doi: . /strokeaha. . sha: doc_id: cord_uid: l b mqp shelter-in-place (sip) orders implemented to mitigate severe acute respiratory syndrome coronavirus spread may inadvertently discourage patient care-seeking behavior for critical conditions like acute ischemic stroke. we aimed to compare temporal trends in volume of acute stroke alerts, patient characteristics, telestroke care, and short-term outcomes pre- and post-sip orders. methods: we conducted a cohort study in stroke centers of an integrated healthcare system serving . + million members across northern california. we included adult patients who presented with suspected acute stroke and were evaluated by telestroke between january , , and may , . sip orders announced the week of march , , created pre (january , , to march , ) and post (march , , to may , ) cohort for comparison. main outcomes were stroke alert volumes and inpatient mortality for stroke. results: stroke alert weekly volume post-sip (mean, [ % ci, – ]) decreased significantly compared with pre-sip (mean, [ % ci, – ]; p< . ). stroke discharges also dropped, in concordance with acute stroke alerts decrease. in total, patients were included: in pre- and in post-sip cohorts. there were no differences in patient demographics. compared with pre-sip, post-sip patients had higher national institutes of health stroke scale scores (p= . ), lower comorbidity score (p< . ), and arrived more often by ambulance (p< . ). post-sip, more patients had large vessel occlusions (p= . ), and there were fewer stroke mimics (p= . ). discharge outcomes were similar for post-sip and pre-sip cohorts. conclusions: in this cohort study, regional stroke alert and ischemic stroke discharge volumes decreased significantly in the early covid- pandemic. compared with pre-sip, the post-sip population showed no significant demographic differences but had lower comorbidity scores, more severe strokes, and more large vessel occlusions. the inpatient mortality was similar in both cohorts. further studies are needed to understand the causes and implications of care avoidance to patients and healthcare systems. shelter-in-place (sip) measures early in the pandemic. while these measures appear to have helped flatten the curve of covid- spread, there is concern that social isolation and fear of acquiring the infection in a healthcare setting may have led some patients with acute medical conditions like stroke and myocardial infarction to avoid calling emergency medical services or presenting to an emergency department (ed). [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] given that there are effective, time-sensitive treatments for acute stroke, including intravenous thrombolytic and endovascular stroke therapy, both of which improve long-term outcomes, avoidance of seeking health care for stroke symptoms may lead to increased disability and death. kaiser permanente northern california (kpnc) provides care for one-third of the population in northern california. we sought to determine whether a decrease in acute stroke presentations occurred during the early covid- pandemic in northern california and to assess differences in patient characteristics and hospital outcomes for those who presented for acute stroke evaluation during the pandemic compared with those who presented before the pandemic. this study was approved by the kpnc institutional review board, and informed consent was waived by the institutional review board. data from the study are available for sharing upon reasonable request to the corresponding author. kpnc provides care at medical centers serving a population of . million members, who are highly representative of the ethnic and socioeconomic diversity of the surrounding and statewide population. all kpnc hospitals are joint commission stroke certified- as primary stroke centers and as comprehensive stroke centers. there are ≈ . million ed visits and ischemic stroke discharges per year. in , we implemented the kpnc stroke expediting the process of evaluating and stopping stroke program. the program included immediate evaluation by a telestroke neurologist via video, expedited intravenous alteplase treatment, rapid computed tomography angiographic study, and expedited transfer and treatment for patients with large vessel occlusion (lvo). the study population included patients with suspected acute stroke who presented to kpnc facilities from january , to may , . all stroke alerts were evaluated by a telestroke neurologist, and data were recorded in standardized stroke assessment, treatment, and clinical notes. for patients deemed not to be candidates for acute stroke treatment, the stroke alert was canceled, and the teleneurologist recorded the initial evaluation and reasons for canceling. the telestroke neurologist proceeded with full acute stroke workup for all noncanceled stroke alerts. clinical and demographic data were available from electronic medical records. we evaluated trends in stroke alert volume, trends in ischemic stroke discharge volume, and acute stroke patient characteristics relative to regional and statewide sip orders for covid- . for stroke alert and discharge volumes, data were available from january , to may , . sip orders began on march , , for the counties in the san francisco bay area and on march , , for the state of california. for patient-specific data analysis, we selected the week beginning with march , , as a cut point. in addition, mobility data from the institute of health metrics and evaluation also supported this selection. stroke alert patients seen from january , to march , , were defined as pre-sip and those seen march , to may , , were in the post-sip cohort. on may , , governor newsom announced plans for stage gradual reopening for the state of california. stage began on may , . we selected may , (the last day of that week), as the end of the post-sip cohort because we were interested in comparing the patients who were presenting during the sip order (between march , , and may , ) to those seen pre-sip. we compared the mean weekly number of stroke alerts and inpatient stroke discharges during the pre-and the post-sip periods. to control for potential seasonal trend in stroke occurrence and potential temporal change due to annual health plan membership, we compared stroke alert volumes during the same months for versus . all stroke alerts identified through teleneurology notes were included. stroke discharges were defined as hospitalizations with a principal discharge diagnosis of ischemic stroke at kpnc facilities. patient characteristics including age, race/ethnicity, sex, and method of arrival were collected for all stroke alerts. we included history of atrial fibrillation, myocardial infarction, and stroke within the prior years. in addition, a longitudinal comorbidity score (comorbidity point score, version ), reflecting inpatient and outpatient diagnoses captured over the preceding months, was calculated for each patient. stroke mimics were defined as patients who had a principal discharge diagnosis other than cerebral infarction, nontraumatic intracerebral/subarachnoid hemorrhage, transient cerebral ischemic attack, hemiplegia, hemiparesis, or cerebral ischemia. for noncanceled stroke alerts, patients underwent a complete evaluation to confirm eligibility for acute interventions with either alteplase or endovascular stroke therapy. more detailed information was collected including last time known well (ltkw), initial national institutes of health stroke scale (nihss) score, treatment with alteplase, and presence of lvo. time to presentation shelter in place was defined as time from ltkw-to-ed-arrival time. door-to-needle time was the number of minutes from ed arrival until alteplase administration. door-to-needle time was calculated for patients in the study without application of accepted exclusions from the american heart association get with the guidelines. treatment time for inpatient stroke alerts was calculated from time of stroke alert to alteplase administration. patient outcomes included length of stay in days, discharge status, and inpatient mortality. to assess for differences between the categorical and continuous variables, pearson χ tests and kruskal wallis tests were used, respectively. t tests were used to assess differences in stroke volume for pre-and post-sip periods. we performed a multivariate logistic regression to assess whether patients from the post-sip period were more or less likely to be discharged home, adjusted for age, sex, race, comorbidity point score, version , nihss score, and treatment with alteplase, along with taking into account clustering by facility. all analyses were conducted using sas software, version . (sas institute, cary, nc). with a sample size of in the post-sip cohort and a -sided α-level of . , we had > % power to detect differences in proportions of at least . between cohorts. throughout the study period, adults received a stroke alert: in the pre-sip and in the post-sip period (table ) . from january to july , weekly stroke alert volumes ranged from to alerts per week ( figure a ). during january the weekly ischemic stroke discharge volumes also decreased post-sip ( figure b ) and have increased after may , , but not yet to the typical range. the percentage decrease in weekly stroke alert volumes varied across northern california ( figure ). patient demographics were similar in pre-and post-sip cohorts among all stroke alerts and also noncanceled stroke alerts (tables and ). there were statistically lower comorbidity scores in patients presenting with stroke symptoms post-sip (tables and ). in the post-sip cohort among all stroke alerts (table ) , more patients arrived at the ed by ambulance, and there were fewer stroke alert calls from walk-in or inpatient services (p< . ). noncanceled stroke alerts post-sip had similar ltkw-to-ed-arrival time as pre-sip ( hours post-sip and . hours pre-sip, p= . ). post-sip patients had higher nihss scores compared with the pre-sip cohort (p= . ). there were less stroke mimics seen as stroke alerts post-sip (p= . ). the percentage of patients receiving alteplase was not significantly different. median door-to-needle time among noncanceled stroke alerts was unchanged during the study ( minutes post-sip versus minutes pre-sip, p= . ). in addition, the median times from ltkw-to-needle time or alteplase treatment time were not significantly different between pre and post cohorts ( . hours, p= . ; table ). post-sip, among noncanceled stroke alerts, more patients had lvo and were referred for endovascular stroke therapy ( . % in post versus . % in pre, p= . ). furthermore, patients presenting to the ed after may , , were more similar to those in the pre-sip cohort (january , to march , ) with regard to having a lower nihss score, higher percentage of stroke mimics, and fewer lvos, but they were more similar to the post-sip cohort (march , to may , ) with regard to arriving more by emergency medical services and having a lower comorbidity point score, version , score (tables i and ii in the data supplement). removing stroke mimics, we examined hospital outcomes for those who were admitted after stroke alert ( table ) . length of stay in hospital was similar between pre-and post-sip cohorts ( table ). the discharge status was similar for the pre-and post-sip (p= . ). in an adjusted multivariate model, patients from the post-sip cohort were less likely to be discharged home (adjusted odds ratio, . ; p= . ). there was no difference in inpatient mortality between the cohorts (p= . ). in addition, none of the stroke alert patients had a positive severe acute respiratory syndrome coronavirus test within days of their index hospitalization. it has been reported by mass media , - and medical journals , - that since the outbreak of covid- , non-covid- -related visits in both the ambulatory and emergency settings have been dramatically decreased. our study revealed that stroke alert volumes and ischemic stroke discharges in northern california started to decrease in early march and dropped significantly after the announcements of sip orders. the stroke alert volumes have subsequently returned to the typical range since may , . post-sip, telestroke evaluation and treatment times were similar before and after the pandemic. for those who were admitted, there was no difference in the inpatient mortality rate between the pre-and post-sip cohorts or discharge disposition. declines in the number of outpatient visits were observed in all regions of the united states. visits declined ≈ % in mid-march and remained low through mid-april. while some have reported a delay in presentation from stroke onset to arrival, others have not found that. our data would suggest that potential stroke patients were not only missing the stroke alert window (up to hours after ltkw) but they were not coming in at all for admission and evaluation, as our stroke discharge volume has also decreased significantly. for those who were still presenting for evaluation, they did not delay much, as their ltkw-to-ed-arrival time and thrombolytic time did not change significantly. a national survey done by the american college of emergency physician reported that % of the surveyed adults said that they were concerned about contracting covid- from another patient or visitor if they went to the ed. twenty-nine percent had actively delayed or avoided seeking medical care due to concerns about contracting covid- . when considering a trip to ed, % were concerned about overstressing the healthcare system. our study findings revealed that patients who presented to our regional telestroke team for acute stroke evaluation appeared to be those with lower comorbidity scores and higher nihss scores. those with stroke symptoms and more comorbidities or with minor symptoms may have been more fearful to present to the ed. we also saw fewer stroke mimics presenting to the ed during the early pandemic. for those who did seek acute care, our study showed that it was possible to continue to treat acute strokes expeditiously during the pandemic. post-sip, door-to-needle time performance remained excellent as before the pandemic. with the announcement of stage gradual reopening for california, we observed a significant increase in the stroke alert volume. this later cohort had milder strokes and more stroke mimics, but these patients were still more likely to come in via emergency medical services and had a lower comorbidity score than those in the pre-sip cohort. examining stroke hospitalizations post-sip, we did not find any severe acute respiratory syndrome coronavirus -positive cases among these acute stroke patients. however, there was somewhat limited covid- testing during the study period due to more stringent criteria and less availability of testing kits. there was no change in inhospital mortality between the pre-and post-sip cohorts. it has been reported that covid- is strongly associated with neurological presentations, including stroke, hypercoagulable state, and lvo in the young. we observed a higher percentage of patients in the post-sip cohort with lvo and referral for endovascular stroke therapy. our study, however, cannot tease out whether the observed increased rate of lvo in the post-sip cohort reflected an actual increase in the incidence of lvo during covid- pandemic or just a relative decrease in non-lvo presentations. because of the retrospective nature of the study, we did not have direct data on stroke patients who were not presenting to the ed. however, given the consistent historical data from our telestroke program, we could gain some understanding of who may be staying home during the pandemic by examining the differences in patient characteristics between the cohorts. in addition, we did not have data regarding changes in how our emergency medical services partners may have triaged potential stroke patients during the pandemic and whether this might explain the observed changes in volume of stroke presentation during the post-sip period. stroke is the leading cause of long-term disability worldwide. delay in seeking evaluation and treatment for acute stroke symptoms may lead to more strokerelated complications. it was reported that us deaths soared in the early weeks of the covid- pandemic, far exceeding the number attributed to covid- . some metropolitan areas have reported seeing an increase in mortality rates at home. the outcome of patients who did not seek acute care for stroke symptoms deserves further investigation. we report a significant decrease in stroke alert volumes and ischemic stroke discharges in northern california after middle of march , with a return to normal volumes following the loosening of the initial sip orders. the spreading covid- pandemic, its related deaths, and public announcements of sip orders may have contributed to these decreases. in addition, patients with stroke mimics or less severe stroke presentations and more comorbidities may be avoiding seeking ed evaluation and care. there was no increase in inpatient mortality for stroke patients who were admitted and treated during the pandemic. to reduce future potential complications from untreated strokes, clearer and more targeted communications may be needed to advise patients with stroke symptoms to present for workup and management. further studies are needed to evaluate the potential unintended consequences to patient outcomes and to healthcare systems when patients with acute stroke avoid seeking emergent care. covid- ) -cases in the us covid- ) dashboard. world health organization collateral effect of covid- on stroke evaluation in the united states the untold toll -the pandemic's effects on patients without covid- neurologic manifestations of hospitalized patients with coronavirus disease in wuhan, china cost of identifying patients for carotid endarterectomy the covid- pandemic and the incidence of acute myocardial infarction where have all the heart attacks gone? the new york times covid- : stroke admissions, emergency department visits, and prevention clinic referrals the baffling case of ischemic stroke disappearance from the casualty department in the covid- era impact of the covid- outbreak on acute stroke pathways -insights from the alsace region in france delayed presentation of acute ischemic strokes during the covid- crisis falling stroke rates during covid- pandemic at a comprehensive stroke center delays in stroke onset to hospital arrival time during covid- impact of the covid- epidemic on stroke care and potential solutions the kaiser permanente northern california adult member health survey novel telestroke program improves thrombolysis for acute stroke across hospitals of an integrated healthcare system institute for health metrics and evaluation. https:// covid .healthdata.org/united-states-of-america/california risk-adjusting hospital mortality using a comprehensive electronic record in an integrated health care delivery system covid- : are acute stroke patients avoiding emergency care? medscape what impact has covid- had on outpatient visits? the commonwealth fund a shelter-in-place side effect: bay area people are afraid to go to the hospital impact of the covid- pandemic on interventional cardiology activity in spain covid- : a&e visits in england fall by % in week after lockdown reduction in st-segment elevation cardiac catheterization laboratory activations in the united states during covid- pandemic where are all the patients? addressing covid- fear to encourage sick patients to seek emergency care. nejm catalyst has covid- played an unexpected "stroke" on the chain of survival? it is money that matters: decision analysis and cost-effectiveness analysis covid- presenting as stroke covid- -related severe hypercoagulability in patients admitted to intensive care unit for acute respiratory failure large-vessel stroke as a presenting feature of covid- in the young deaths soared in early weeks of pandemic, far exceeding number attributed to covid- . the washington post there's been a spike in people dying at home in several cities. that suggests coronavirus deaths are higher than reported key: cord- -kjbhmsqr authors: morelli, nicola; rota, eugenia; terracciano, chiara; immovilli, paolo; spallazzi, marco; colombi, davide; zaino, domenica; taga, arens; michieletti, emanuele; guidetti, donata title: covid- -related stroke: barking up the wrong tree? date: - - journal: eur neurol doi: . / sha: doc_id: cord_uid: kjbhmsqr nan we are grateful to hooshmandi et al. [ ] (ene- - - ) for the interest shown in our article and for their comments. at the time of writing, piacenza was the second most heavily hit italian city by covid- pandemic ( . %) [ ], providing an exceptional perspective of the current situation in the neurological field. we previously emphasized how the main limit of our comments was the brief observation period, that is, month, that is when the outbreak of sars-cov- peaked. in the following period, only few small case series of covid- stroke patients have been reported [ ] [ ] [ ] [ ] [ ] [ ] . therefore, little information is available on stroke in this unknown pathological scenario. despite the lack of current scientific literature on the topic, which is limited to anecdotal reports, numerous hypotheses have been put forward as to the role of the thrombophilic state induced by -ncov and the likely increased risk of stroke in infected patients [ ] [ ] [ ] . from february to april , , covid- patients were admitted to our facility, of whom with concomitant ischemic stroke symptoms (mean age . ± . ). no young adult stroke patient was observed. there was no rare stroke etiology or unforeseen high incidence in stroke subtypes. severity of stroke evaluated by the nihss seems to correlate with extension of interstitial pneumonia documented with chest ct scan (personal data, in press). however, anecdotal evidence is collected in a casual or informal manner and relies entirely on personal testimony. therefore, it is generally considered to have a limited value, due to a number of potential weaknesses. for this reason, we agree with hooshmandi et al. that it is too early to consider a direct "cause-effect" relationship between -ncov infection and stroke occurrence so that further prospective and large-volume studies are warranted. the occurrence of different types of cerebrovascular diseases during the -ncov pandemic can be documented only by international multicenter studies. indeed, the prevalence of covid- is so high in pandemic hotspots that an incidental association between infection and neurological manifestations cannot be excluded. during a pandemic, when science and medicine are asked to provide answers, neurologists should strive to keep high scientific research standards and place trust in their clinical methods, starting with an accurate patient interview and then moving through standard neurological examination. the clinical path is then completed by the diagnostic confirmation through imaging, laboratory, electrophysiological, and pathological techniques. all of which leads to the question as to whether relating stroke to covid- may be tantamount to barking up the wrong tree. hopefully, time and research will be our mentors, as has often been the case. the case is much more baffling than we think large-vessel stroke as a presenting feature of covid- in the young neurologic manifestations of hospitalized patients with coronavirus disease in wuhan, china neurologic features in severe sars-cov- infection venous and arterial thromboembolic complications in covid- patients admitted to an academic hospital in acute ischemic stroke complicating common carotid artery thrombosis during a severe covid- infection could covid- represent a negative prognostic factor in patients with stroke? infect control hosp epidemiol cov-id- -related stroke rising evidence for neurological involvement in covid- pandemic the authors thank mrs. barbara wade for her linguistic advice. the authors have no conflicts of interest to declare. this research received no specific grant from any funding agency in the public, commercial, or not-for-profit sectors. no financial support was provided for the research, authorship and/or publication of this article. key: cord- - g kg tz authors: bres bullrich, maria; fridman, sebastian; mandzia, jennifer l.; mai, lauren m.; khaw, alexander; vargas gonzalez, juan camilo; bagur, rodrigo; sposato, luciano a. title: covid- : stroke admissions, emergency department visits, and prevention clinic referrals date: - - journal: the canadian journal of neurological sciences. le journal canadien des sciences neurologiques doi: . /cjn. . sha: doc_id: cord_uid: g kg tz we assessed the impact of the coronavirus disease (covid- ) pandemic on code stroke activations in the emergency department, stroke unit admissions, and referrals to the stroke prevention clinic at london’s regional stroke center, serving a population of . million in ontario, canada. we found a % drop in the number of code strokes in compared to , immediately after the first cases of covid- were officially confirmed. there were no changes in the number of stroke admissions and there was a % decrease in the number of clinic referrals, only after the provincial lockdown. our findings suggest that the decrease in code strokes was mainly driven by patient-related factors such as fear to be exposed to the sars-cov- , while the reduction in clinic referrals was largely explained by hospital policies and the government lockdown. there is a growing concern that patients with stroke symptoms are not seeking medical attention in the emergency department (ed) because of fear of being exposed to the severe acute respiratory syndrome coronavirus- (sars-cov- ). , however, to date, no study has formally evaluated the impact of the coronavirus disease (covid- ) pandemic on the number of stroke patients being assessed in the ed, stroke admissions, or referrals to stroke prevention clinics in canada. we, therefore, assessed the impact of the coronavirus disease (covid- ) pandemic on code stroke activations in the ed, stroke unit admissions, and referrals to the urgent stroke prevention clinic at london health sciences center university hospital's regional stroke center, serving a captive population of . million in ontario, canada. the primary outcome of this study was the number of code strokes. secondary outcomes were stroke unit admissions and urgent stroke prevention clinic referrals. the exposure was the covid- pandemic. we quantified the number of code strokes in world health organization (who) epidemiological weeks between february , , and april , , by interrogating the hospital's wireless paging system database. we chose february , , as the start date of the study period because it was the first monday after the covid- case was confirmed in london on friday january , . this was the third confirmed case in ontario. the study period started on a monday because this is the first day of who epidemiological weeks and it also allows for mitigating the bias of weekdays vs. weekend consults. we used the same who epidemiological weeks of as a comparator. we compared epidemiological weeks of vs. . these are matched weeks in both years, which are used for mitigating the bias of seasonal variations in stroke consults. code strokes included patients brought to the ed by the emergency medical services and walk-in strokes. additionally, we quantified hemorrhagic and ischemic stroke admissions to the stroke unit and referrals to the urgent stroke prevention clinic during the same period by reviewing the london ontario stroke registry, the inpatient census, and london health sciences centre's electronic booking system. the stroke registry is updated on a real-time basis. clinic referrals consist of patients with minor strokes or transient ischemic attacks (tias). on march , , the government of ontario implemented a provincial lockdown advising ontarians to avoid gatherings of over people, and the closure of recreational libraries, private schools (public schools were closed on march ), daycares, churches and other faith settings, and all bars and restaurants. on the same day, after a provincial order requesting all hospitals to implement pandemic plans by ramping down nonemergent clinical activities, the hospital implemented a service reduction policy. this resulted in the immediate transition of most outpatient clinics to telemedicine systems. on march , , the provincial government expanded the lockdown by ordering the mandatory closure of all nonessential workplaces and the enhancement of social distancing. to compare code strokes, stroke unit admissions, and clinic referrals in against , we plotted weekly numbers of consults in both years. we also plotted the number of confirmed covid- cases in london, ontario, and canada per , population as a reference of the local progression of the pandemic. the study data comprised a count of cases over a unit of time (epidemiological weeks), which follows a poisson distribution. for this reason, we decided to use a poisson model. due to the possibility of overdispersion of the data, we compared the results of negative binomial models and the poisson regressions for all outcomes by using the maximum likelihood method. in case of no differences between both types of models, we opted for the parsimonious poisson model. the number of code strokes, stroke unit admissions, and urgent stroke prevention clinic referrals were the outcome of interest in their respective models. we designed the models to test if there were effects attributable to the year ( vs. ) as a surrogate of the covid- pandemic or to the provincial lockdown on the weekly number of cases. the number of code strokes, stroke unit admissions, and stroke prevention clinic referrals were , , and in vs. , , and in (figure ). data followed a poisson distribution except for stroke prevention clinic referrals in . we therefore developed a negative binomial model. we found no differences between the poisson and negative binomial model, so we retained the former for all the prespecified outcomes. the model for code strokes revealed that there was a significant % reduction in the overall number of events in relative to ( %ci . %- . %). however, the march provincial lockdown was not significantly associated with any further decrease in the number of consults. accordingly, the figure shows that most of the reduction in code strokes occurred during the weeks of the pandemic preceding the provincial lockdown. in the stroke unit admission model, there were no significant differences between and , either before or after the provincial lockdown. the model for urgent stroke prevention clinic referrals showed no significant changes between and before the landmark date of march . however, there was a significant decrease of . % ( % ci . %- . %) in the number of referrals after the provincial lockdown. the figure illustrates steepest reduction in the number of clinic referrals was observed after the provincial lockdown and the consequent implementation of the hospital's service reduction policy. our findings offer insight into stroke systems of care utilization during the covid- pandemic in london, ontario, canada. code strokes dropped during the first weeks of february , corresponding to the period after the first confirmed covid- cases were officially reported in the province. there was no association between the provincial lockdown and the decrease in code strokes. as such, in line with worldwide concerns, we hypothesized that patients' fears to be exposed to the sars-cov- in the ed as soon as the first covid- cases were officially confirmed in london and the province may have influenced their decision to stay at home instead of seeking medical attention. interestingly, despite a reduction in the number of code strokes, we did not find significant differences in the number of admissions, which remain relatively stable during . this is conceivably explained by a pandemic-related selection of patients attending the ed, resulting in fewer stroke mimics and a larger proportion being admitted. it is also possible that patients with tias or very mild strokes (so that they do not qualify for either code strokes or for admission) decided to stay at home and not seek medical attention. these potential explanations remain on hypothetical grounds and warrant further investigation. the number of urgent stroke prevention clinic referrals did not change significantly during the first weeks of february . yet, we observed a steep drop after march , , meaning that the provincial lockdown may have impacted on physicians' willingness or ability to refer patients. the hospital's transition into a telemedicine system and a perceived uncertainty about whether the clinic was processing referrals may have also played a role. a recent report showed a drop in the numbers of patients in a commercial neuroimaging database from the usa associated with the rapid software platform (ischemaview). however, this study used a surrogate of the number of patients being assessed for acute ischemic stroke. another small study from the usa showed a drop in the number of stroke admissions, transfers from referral centers, telemedicine consultations, and ed visits. however, this study did not account for seasonal changes in stroke consults. in summary, these concerning results should encourage governments, scientific societies, and other relevant stakeholders to take urgent action aiming at improving stroke patients' awareness about the importance of seeking medical attention when experiencing stroke symptoms. health systems will also need to be prepared for future pandemics and for the backlash caused by fewer cerebrovascular events being prevented in patients with minor strokes or tias who will not receive the appropriate preventive treatments during the covid- pandemic because of not reporting their symptoms. hospital admissions for strokes appear to have plummeted, a doctor says, a possible sign people are afraid to seek critical help. washington podt stroke care and the covid pandemic. wso news & blog collateral effect of covid- on stroke evaluation in the united states falling stroke rates during covid- pandemic at a comprehensive stroke center a transient ischaemic attack clinic with round-the-clock access (sos-tia): feasibility and effects we specially thank naomi reintjes for collaborating with the stroke unit census. none of the authors have significant disclosures related to this work. mbb contributed to drafting the first manuscript and reviewed the final version of the manuscript for intellectual content.sf planned and performed the statistical analysis, and reviewed the final version of the manuscript for intellectual content.jlm reviewed the final version of the manuscript for intellectual content.lmm reviewed the final version of the manuscript for intellectual content.ak reviewed the final version of the manuscript for intellectual content.jcvg planned and performed the statistical analysis, and reviewed the final version of the manuscript for intellectual content.rb conceived the study, planned the statistical analysis, and reviewed the final version of the manuscript for intellectual content.las conceived and supervised the study, planned the statistical analysis, gathered the data, drafted the first manuscript, and reviewed the final version of the manuscript for intellectual content. key: cord- -cgec authors: al-jehani, hosam; john, seby; hussain, syed irteza; al hashmi, amal; alhamid, may adel; amr, dareen; ozdemir, atilla ozcan; shuaib, ashfaq; alhazzani, adel; ghorbani, mohammad; mansour, ossama; saqqur, maher title: mena-sino consensus statement on implementing care pathways for acute neurovascular emergencies during the covid- pandemic date: - - journal: front neurol doi: . /fneur. . sha: doc_id: cord_uid: cgec in the unprecedented current era of the covid- pandemic, challenges have arisen in the management and interventional care of patients with acute stroke and large vessel occlusion, aneurysmal subarachnoid hemorrhage, and ruptured vascular malformations. there are several challenges facing endovascular therapy for stroke, including shortages of medical staff who may be deployed for covid- coverage or who may have contracted the infection and are thus quarantined, patients avoiding early medical care, a lack of personal protective equipment, delays in door-to-puncture time, anesthesia challenges, and a lack of high-intensity intensive care unit and stroke ward beds. as a leading regional neurovascular organization, the middle east north africa stroke and interventional neurotherapies organization (mena-sino) has established a task force composed of medical staff and physicians from different disciplines to establish guiding recommendations for the implementation of acute care pathways for various neurovascular emergencies during the current covid- pandemic. this consensus recommendation was achieved through a series of meetings to finalize the recommendation. in the unprecedented current era of the covid- pandemic, challenges have arisen in the management and interventional care of patients with acute stroke and large vessel occlusion, aneurysmal subarachnoid hemorrhage, and ruptured vascular malformations. there are several challenges facing endovascular therapy for stroke, including shortages of medical staff who may be deployed for covid- coverage or who may have contracted the infection and are thus quarantined, patients avoiding early medical care, a lack of personal protective equipment, delays in door-to-puncture time, anesthesia challenges, and a lack of high-intensity intensive care unit and stroke ward beds. as a leading regional neurovascular organization, the middle east north africa stroke and interventional neurotherapies organization (mena-sino) has established a task force composed of medical staff and physicians from different disciplines to establish guiding recommendations for the implementation of acute care pathways for various neurovascular emergencies during the current covid- pandemic. this consensus recommendation was achieved through a series of meetings to finalize the recommendation. the novel coronavirus disease (covid- ) was first identified in the wuhan province of china in late december and spread rapidly around the globe. consequently, a pandemic characterized by a rapid spread through respiratory droplets with human-to-human contact was declared by the world health organization on march , ( - ) . covid- is the second coronavirus outbreak to affect the middle east, following the mers-cov reported in saudi arabia in . the united arab emirates (uae) was the first middle east country to report a coronavirus-positive case, following the wuhan coronavirus outbreak in china ( ). covid- is increasingly being recognized as a cause of thromboembolic phenomena, such as acute ischemic strokes and cerebral venous sinus thrombosis ( ) . published and anecdotal reports suggest that during the pandemic, there has been a drastic reduction in the number of stroke patients being evaluated in the emergency room (er) or being admitted to hospitals worldwide ( ) . it is highly unlikely that the incidence of stroke has suddenly changed or reduced. this could be explained by the inability to seek medical care due to the extreme restrictions established to limit virus transmission or fear of contracting the virus upon visiting the hospital. in addition tertiary care hospitals may be inundated with covid- patients, and as such, patients with stroke are being treated at secondary-care facilities or may not be transferred to comprehensive stroke centers at all. clearly, strokes remain an emergency, and patients should seek immediate care despite the current pandemic. healthcare personnel have a high risk of becoming infected during this novel pandemic, particularly before transmission dynamics are fully characterized. of the covid- cases reported to the centers for disease control from february to april , a proportion included data on whether the patient was a healthcare worker (hcw) in the usa, with up to % of cases identified as healthcare personnel ( ) . quarantines for hcws who have tested positive and for those with high-risk exposures could severely impact the smooth functioning of stroke units and may even jeopardize an entire department if it involves small numbers (e.g., a neurointerventional team). in addition, many hospitals are redeploying clinicians of all specialties to the care of covid- patients, thereby draining resources of care for other medical conditions. both of the above factors present a substantial challenge, even for well-established stroke centers, and stroke teams will likely experience staff shortages. it is likely that hospitals will be inundated with covid- patients. specifically, these patients will include individuals who are critically ill from a respiratory viewpoint; these patients will require intensive care unit (icu) hospitalization, and many will require ventilators. thus, disruptions in standard protocols such as post-thrombolysis and post-thrombectomy care should be expected, and variations in protocol or abbreviated protocols will be needed to efficiently utilize staffing and bed space while maintaining the best possible patient care. repatriation from a comprehensive stroke center to lower levels of care following a period of stability after critical procedures, such as mechanical thrombectomy, aneurysm occlusion, or hematoma evacuation, may be reasonable ( ) . the provision of adequate personal protective equipment (ppe) and clear guidelines on its application are imperative to protect healthcare personnel and to prevent viral spread among hcws. given that community transmission of covid- is wellestablished in most areas, all stroke alerts presenting to the er should ideally be treated as a potentially infected patient. while the use of ppe for maximum protection, as dictated by international and institutional bodies, is ideal, this practice may not be possible given the ppe shortages that are being encountered in many countries ( ) . thus, responses to code stroke may be delayed due to ppe unavailability. known or suspected covid- patients as well as carriers will likely require mechanical thrombectomy for large vessel occlusion. this situation poses challenges regarding anesthetic management, given the urgent nature of the procedure and an "unknown" covid- status. covid- has a high risk of spreading through droplets and aerosols ( , ) . bag-mask ventilation, intubation, extubation, and airway suctioning are aerosol-generating procedures, and any disconnection of the circuit risks further aerosolizing secretions. in theory, monitored anesthesia care (mac) may prevent intense aerosolization; however, stroke patients undergoing mac sedation may require supplemental oxygen via a nasal cannula mask or other methods, such as chin-lift or jaw thrust maneuvers, to improve oxygenation, which may increase the degree of airborne exposure to the anesthesia provider and other involved hcws. another consideration is the need to convert from mac to general anesthesia (ga) in a minority of patients. urgent intubation in a non-negative pressure room introduces an exposure risk to all team members within the room. in addition, workflows with regard to dedicated space for intubation pose additional challenges. while prehospital delays are expected, given travel, and transfer logistics amidst ongoing community lock-downs in many countries, several challenges remain once the patient arrives at the er. protocols for protected stroke alerts have been published. limited neurology personnel, ppe shortages, transfer times through designated corridors/elevators from the er to imaging with appropriate ppe, unavailability of computerized tomography (ct) scanners during disinfection periods, and time for donning/doffing ppe are all potential factors that may increase door-to-needle times when treating patients with intravenous thrombolysis as well as door-to-puncture for thrombectomy. to minimize exposure, staffing within the room should be kept to a minimum; however, some patients may be technically challenging, and an additional hand may be extremely helpful. challenges while operating with multiple layers of ppe are foreseeable. the physical and psychological burden of neurointerventional stroke calls, particularly during the current pandemic, is likely substantial, especially given the small size of these teams. as reported by a recent survey of neurointerventional nurses and radiology technologists from stroke centers in the usa, only centers ( %) had more than nurses or technologists in their call pools for stroke ( ) . many institutions with multiple angiography suites are reserving one dedicated suite for suspected covid- strokes or other emergencies. as a leading regional neurovascular organization, mena-sino has established a task force comprised of physicians, nurses, and medical staff from different disciplines (neurology, neurosurgery, interventional neuroradiology, and neurocritical care) to establish guiding recommendations for the implementation of acute care pathways for various neurovascular emergencies during the current covid- pandemic. these recommendations can be greatly enhanced by telemedicine options to minimize patient-physician interactions, as dictated by clinical needs. other international entities have also published different guidelines, all aiming at achieving "protected code stroke protocol" ( ) ( ) ( ) . we describe the following guiding recommendations to be implemented in the mena region to facilitate care for patients and to provide optimal protection for hcws. . patients must be properly triaged to guide the safety of their clinical encounter (figure ). be established across the different neurovascular pathologies ( table ) . this standardization will render treatments more efficient and will allow for optimal healthcare delivery, by establishing proper operational policies. . outpatient and office visits should be conducted virtually to avoid unnecessary contact between patients and physicians. . each patient should be transferred to another institution if required, as soon as he/she is sufficiently stable to receive the required intervention ( table ) . . covid and non-covid regions should be designated within the hospital to guide the safety and reciprocity of patient transfers between institutions. the following process is recommended for the referring hospital: for all stroke patients presenting directly to the er or being transferred, the following measures should be taken. emergency room . the er should be divided such that separate spaces and corridors are available for covid and non-covid patients. . to screen for symptoms of covid- in expedited manner to conform to the time-critical nature of stroke care (figure ) . . all patients should wear a surgical mask. . patients with a positive infection screen or those highly suspected, as reported by emergency medical services (ems) or er personnel should be roomed in a dedicated covid area or negative-pressure room if available. . telemedicine (telestroke) should be utilized when available to obtain history and to perform a neurological examination in order to limit direct contact between medical staff and patients. . a protective code stroke protocol should be established for patients with a positive covid screen. one member of the stroke team should perform the evaluation and provide therapy donning full ppes. . a scoring system should be established for risk stratification of hcw exposure and risk of coivd- infection ( table ) . acute imaging . standard hospital imaging protocols should be followed for acute stroke treatments. . if multiple ct rooms are available, a dedicated ct scan room for covid- patients should be established, provided that the addition of the chest ct does not incur a treatment delay of more than min. . if positive pulmonary symptoms are present, consider performing low-dose chest ct simultaneously with head ct the decision to treat a patient should take into account the seriousness of the covid- disease and prognosis, particularly with regard to endovascular thrombectomy. for patients with evidence of multi-organ dysfunction or critical illness, outcomes of endovascular intervention may be suboptimal, and the risks and benefits of such procedures must be weighed against the consumption of resources and potential exposure to caregivers. a multidisciplinary discussion among the treating physicians should be held to make the most appropriate treatment decision. . the anesthesia team should be notified as soon as possible regarding potential endovascular procedures. . conscious sedation should be considered as first-line treatment for patients with acute stroke interventions, if the patient is stable. however, a low threshold should be maintained for intubation in patients with respiratory distress, inability to protect the airway, posterior circulation stroke, vomiting, or agitation and for those who are uncooperative. . intubation should be performed in a negative-pressure room separate from the angiography suite or in a dedicated angiography suite with negative pressure capabilities. in the absence of negative pressure, an aerosol box can be a good substitute in special situations ( ) . . extubation should be avoided in the angiography suite and instead be performed in a negative-pressure room. . transfers should avoid breaking the initial ventilator circuit, bagging, or reconnection to a new ventilator. the following process is recommended for the referring hospital: . acute ischemic stroke a) all patients must be screened for covid- . the use of telecommunication is recommended if available. b) any patient with fever or respiratory symptoms should be disclosed upon the referral request to ensure proper precautions [as a covid- -positive individual or person under investigation [pui] ] and to ensure that trends of vital signs are properly recorded. c) the national institute of health stroke scale (nihss) must be documented, and the score must exceed for a transfer to be considered. d) perform brain non-contrast ct (ncct) to rule out hemorrhage or the presence of an established infarction (alberta stroke program early ct score (aspects) above ). e) perform cta to confirm the occurrence of large vessel occlusion and ct perfusion to identify a mismatch. a higher large vessel occlusion (lvo) score may be acceptable for transfer, depending on local logistic preparedness. f) patients with a high risk of covid- should wear a surgical mask. g) obtain chest ct at the time of the initial ct (groundglass appearance). h) if the patient presents with an unknown time of onset or a delayed onset, the option of obtaining a ct perfusion or a brain mri should be offered in the receiving hospital to assess any mismatch prior to a consideration of transfer. if this procedure is not feasible, the aspects should guide the transfer, with tissue imaging performed in the receiving stroke center. * * intravenous tissue plasminogen activator (iv-tpa) eligible patients should receive thrombolysis based on the protocol in the referring hospital (telestroke managed or guided by stroke neurology). . aneurysmal subarachnoid hemorrhage (asah) a) all patients must be screened for covid- , as described above. b) any patient with fever or respiratory symptoms should be disclosed upon the referral request to ensure proper precautions (as a covid- -positive individual or pui) and to ensure that the trends of vital signs are properly recorded. c) glasgow coma scale (gcs) and world federation of neurosurgical societies (wfns) grades must be documented (consideration for transfer: gcs > and wfns grade - ). d) perform brain ncct to document the sah and to exclude intraventricular hemorrhage or intracerebral hemorrhage (ivh-ich) and hydrocephalus requiring an external ventricular drain (evd). e) perform cta to confirm the presence of intracranial aneurysm and to rule out any other vascular pathology. f) obtain chest ct at the time of the initial ct (ground-glass appearance) for the above-mentioned reasons. g) if the cta is negative for aneurysm, the transfer should be aborted, and repeat vascular imaging (cta or digital subtraction angiography [dsa]) should obtained within days. * * in the case of a high-grade sah, improvement after the evd insertion should warrant a referral request. . after the need for an interventional procedure has been confirmed, the following steps should be taken: a) the patient should be intubated in the referring hospital, and a closed circuit should be ensured throughout the process of transferring from and to the referring hospital. b) the patient must be accompanied by a medical transfer team that follows strict ppe precautions. this team should be equipped to offer hemodynamic and ventilatory support during the transfer. c) the patient should be connected to a portable ventilator that will be used throughout the transfer process, including the angiographic procedure, to ensure that the closed ventilatory circuit is not interrupted. precautions during the endovascular procedure all patients should be treated as though there is a high suspicion of the patient being covid- -positive. accordingly, the following precautions should be implemented: . the angiogram set, pressure bags, and basic access catheters should be prepared for use before the patient enters the angiogram suite. ready-to-use verapamil and heparin syringes should be included in the angiogram set, and a vial of actylase (iv tpa) should be available in the cold zone. other antiplatelet agents can be added based on local protocols. . a high-efficiency particulate air (hepa) filter should be placed by the door of the angiogram suite. . all closets and cabinets should be closed during the angiography procedure. . the room should be labeled as covid- with no entry other than the angiography team. . intervention technicians should remain in the cold zone to limit exposure and to facilitate material handling. . the circulating nurse should remain in the cold zone, supervising the movement of personnel and the donning/doffing of ppe upon entry and exit of any angiography team member. . the angiography team in the hot zone should consist of • one scrub nurse • up to two interventionists • one anesthesia physician, with strict control on the airway to avoid suctioning and aerosol leaks . all interventional material should remain outside the angiography suite (in the cold zone) and should be handed to the scrub nurse upon request. . the arterial access sheath should be removed at the end of the angiographic procedure. manual compression or a closure device should be utilized for hemostasis. * * depending on the policy implemented, the patient can either remain in the treating hospital or be transferred back to their referring hospital. a recent study assessing the magnitude of mental health outcomes and associated factors among hcws treating patients exposed to covid- in china reported symptoms of depression ( ; . %), anxiety ( ; . %), insomnia ( ; . %), and distress ( ; . %) ( ) . healthcare providers may benefit from following the measures listed below. ◮ self-monitor and pace. ◮ regularly check in with colleagues, family, and friends (checkins may need to be virtual). ◮ take brief relaxation/stress management breaks. ◮ establish a covid-free discussion zone. ◮ seek reliable information and proper expert assessments to assist in making informed decisions if needed. ◮ focus efforts on what is within your power. ◮ check in with other colleagues to discuss work experiences. ◮ provide consultations and collegial support (remotely). ◮ allow for "hot debriefs, " e.g., following the stop- approach (summarize, things that went well, opportunities to improve, point to action and responsibility) adapted from the edinburgh emergency medicine model developed by ( ) . ◮ schedule time off from work for gradual reintegration into personal life. ◮ prepare for worldview changes in one's life that may not be mirrored by others. despite the current challenges encountered in the evt treatment of acute stroke and neurointervention, there remain opportunities to learn from the current pandemic experience, with applications for future disasters. in summary, our main recommendations are the following: -the risk of covid- (figure ) should be stratified in order to prioritize and optimize ( table ) the utilization of available resources during the covid- pandemic in the mena region, where resources are limited. -the role of telestroke in acute and clinical settings is critical for avoiding unnecessary contact between patients and physicians during the pandemic and to better utilize specialized stroke physicians with limited resources. -in an acute ischemic stroke, stringent prescreening criteria should be implemented to distinguish high-risk covid- patients from low-risk patients, with subsequent stroke protocols based on the covid- risk. -in asah patients, prescreening should be performed before admission and intervention, and a stringent high-risk protocol should be followed in the neuro-icu and during intervention based on prescreening results. in conclusion, the mena-sino statement provides guidance to interventionalists and hospitals for prioritizing medical care for neurovascular patients. while these guidelines consider patient safety and infection protective protocols, they do not replace sound clinical judgment, the consideration of patient-specific factors, or institutional policies and procedures. early transmission dynamics in wuhan, china, of novel coronavirus-infected pneumonia a new coronavirus associated with human respiratory disease in china a pneumonia outbreak associated with a new coronavirus of probable bat origin world health organization. coronavirus disease covid- data the baffling case of ischemic stroke disappearance from the casualty department in the covid- era clinical characteristics of covid- in new york city characteristics of health care personnel with covid- -united states early repatriation post-thrombectomy: a model of care which maximises the capacity of a stroke network to treat patients with large vessel ischaemic stroke conserving supply of personal protective equipment-a call for ideas a novel coronavirus from patients with pneumonia in china influence of thrombectomy volume on non-physician staff burnout and attrition in neurointerventional teams european society of minimally invasive neurological therapy (esmint) recommendations for optimal interventional neurovascular management in the covid- consensus statement of the saudi association of neurological surgery (sans) on triage of neurosurgery patients during covid- pandemic in saudi arabia protected code stroke: hyperacute stroke management during the coronavirus disease (covid- ) pandemic guidance on covid- and mr use guidelines for the early management of patients with acute ischemic stroke update to the guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the american heart association/american stroke association barrier enclosure during endotracheal intubation factors associated with mental health outcomes among health care workers exposed to coronavirus disease debriefing after resuscitation all authors contributed to the article and approved the submitted version. the authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.copyright © al-jehani, john, hussain, al hashmi, alhamid, amr, ozdemir, shuaib, alhazzani, ghorbani, mansour and saqqur. this is an open-access article distributed under the terms of the creative commons attribution license (cc by). the use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. no use, distribution or reproduction is permitted which does not comply with these terms. key: cord- -hsfh hw authors: ghoreishi, abdoreza; arsang-jang, shahram; sabaa-ayoun, ziad; yassi, nawaf; sylaja, p.n.; akbari, yama; divani, afshin a.; biller, jose; phan, thanh; steinwender, sandy; silver, brian; zand, ramin; basri, hamidon bin; iqbal, omer m.; ranta, annemarei; ruland, sean; macri, elizabeth; ma, henry; nguyen, thanh n.; abootalebi, shahram; gupta, animesh; alet, matias; lattazani, simona; desai, masoom; gagliardi, rubens j.; girotra, tarun; inoue, manabu; yoshimoto, takeshi; isaac, cristian flavo; mayer, stephan a.; morovatdar, negar; nilanont, yongchai; nobleza, christa o'hana s.; saber, hamidreza; kamenova, saltanat; kondybayeva, aida; krupinski, jerzy; siegler, james e.; stranges, saverio; torbey, michel t.; yorio, diana; zurrú, maría cristina; rubinos, clio aracelli; shahripour, reza bavarsad; borhani-haghighi, afshin; napoli, mario di; azarpazhooh, m. reza title: stroke care trends during covid- pandemic in zanjan province, iran. from the cascade initiative: statistical analysis plan and preliminary results date: - - journal: j stroke cerebrovasc dis doi: . /j.jstrokecerebrovasdis. . sha: doc_id: cord_uid: hsfh hw background: the emergence of the covid- pandemic has significantly impacted global healthcare systems and this may affect stroke care and outcomes. this study examines the changes in stroke epidemiology and care during the covid- pandemic in zanjan province, iran. methods: this study is part of the cascade international initiative. from february , , to july , , we followed ischemic and hemorrhagic stroke hospitalization rates and outcomes in valiasr hospital, zanjan, iran. we used a bayesian hierarchical model and an interrupted time series analysis (its) to identify changes in stroke hospitalization rate, baseline stroke severity [measured by the national institutes of health stroke scale (nihss)], disability [measured by the modified rankin scale (mrs)], presentation time (last seen normal to hospital presentation), thrombolytic therapy rate, median door-to-needle time, length of hospital stay, and in-hospital mortality. we compared in-hospital mortality between study periods using cox-regression model. results: during the study period, , stroke patients were hospitalized. stroke hospitalization rates per , population decreased from . before the pandemic to . during the pandemic, with a significant decline in both bayesian [beta: - . ; standard error (se): . , % cri: - . , - . ] and its analysis (estimate: - . , se= . , p < . ). furthermore, we observed lower admission rates for patients with mild (nihss< ) ischemic stroke (p< . ). although, the presentation time and door-to-needle time did not change during the pandemic, a lower proportion of patients received thrombolysis (- . %; p= . ). we did not see significant changes in admission rate to the stroke unit and in-hospital mortality rate; however, disability at discharge increased (p< . ). conclusion: in zanjan, iran, the covid- pandemic has significantly impacted stroke outcomes and altered the delivery of stroke care. observed lower admission rates for milder stroke may possibly be due to fear of exposure related to covid- . the decrease in patients treated with thrombolysis and the increased disability at discharge may indicate changes in the delivery of stroke care and increased pressure on existing stroke acute and subacute services. the results of this research will contribute to a similar analysis of the larger cascade dataset in order to confirm findings at a global scale and improve measures to ensure the best quality of care for stroke patients during the covid- pandemic. this study is part of the cascade international initiative. from february , , to july , , we followed ischemic and hemorrhagic stroke hospitalization rates and outcomes in valiasr hospital, zanjan, iran. we used a bayesian hierarchical model and an interrupted time series analysis (its) to identify changes in stroke hospitalization rate, baseline stroke severity [measured by the national institutes of health stroke scale (nihss)], disability [measured by the modified rankin scale (mrs)], presentation time (last seen normal to hospital presentation), thrombolytic therapy rate, median door-to-needle time, length of hospital stay, and in-hospital mortality. we compared in-hospital mortality between study periods using coxregression model. although, the presentation time and door-to-needle time did not change during the pandemic, a lower proportion of patients received thrombolysis (- . %; p= . ). we did not see significant changes in admission rate to the stroke unit and in-hospital mortality rate; however, disability at discharge increased (p< . ). in zanjan, iran, the covid- pandemic has significantly impacted stroke outcomes and altered the delivery of stroke care. observed lower admission rates for milder stroke may possibly be due to fear of exposure related to covid- . the decrease in patients treated with thrombolysis and the increased disability at discharge may indicate changes in the delivery of stroke care and increased pressure on existing stroke acute and subacute services. the results of this research will contribute to a similar analysis of the larger cascade dataset in order to confirm findings at a global scale and improve measures to ensure the best quality of care for stroke patients during the covid- pandemic. in december , a new and contagious strain of coronavirus, severe acute respiratory syndrome coronavirus (sars-cov- ), was identified among patients with pneumonia in wuhan, china. the disease caused by this virus is now named coronavirus disease (covid- ) ( ). the disease burden has extended beyond what would be expected from a contagious disease. covid- incidence and mortality are significantly correlated with noncommunicable diseases (ncds), including cerebro-and cardiovascular diseases ( ) and dementia ( ) . globally, ncds account for more than % of all deaths ( ) . therefore, any changes in incidence, prevalence, and mortality of these conditions may dramatically affect the burden of disease worldwide. during the pandemic, many countries have altered the delivery of healthcare in response to the need for additional capacity and resources through national hospital system restructuring ( ) . this reorganization has resulted in detrimental effects, including decreased patient capacity at stroke units and interruptions in the delivery of specialized stroke care services ( ) . such changes in the previously established delivery of care, particularly among older adults, may lead to increased mortality related to ncds. for example, between march and april , , england and wales reported an additional , deaths ( , related to covid- ) compared to their five-year average ( ) . in an attempt to understand the changes in stroke epidemiology and care related to covid- , we initiated a multicenter initiative known as the call to action: sars-cov- and stroke centers in countries. the present report provides information from one of the cascade centers and describes the statistical analysis plan used in the cascade cohort. this paper specifically examines changes in stroke hospitalization and care during the covid- pandemic in a cascade center in zanjan province, iran. furthermore, this manuscript will serve as a model for analysis in order to harmonize the results across all other cascade centers. the study was approved by the ethics committee of the zanjan university of medical sciences; ir.zums.rec. . . populations: this is the first report of the cascade initiative from one of the participating centers, valiasr hospital, zanjan, iran. valiasr hospital is a major stroke referral center with an annual catchment area of approximately , patients (census data ). we included all ischemic and hemorrhagic strokes, and excluded patients with transient ischemic attacks due to difficulties in their diagnosis and variable outcomes ( ) . stroke is defined according to the stroke council of the american heart association/american stroke association census definition and categorized based on neuroimaging findings, such as ischemic vs. hemorrhagic strokes ( ) . the first officially confirmed case and death of covid- in iran was reported on february ( ) . the first case and death in zanjan province were registered on february , . on march , , iran implemented a national lockdown, which ended on may , . we selected a study period from february , (the -year calendar month before the first confirmed covid- case in iran), and followed stroke trends until july , , as per cascade initiative protocols ( ) . variables of interest included hospitalization rate per week per , population (total ischemic and hemorrhagic strokes), male-to-female ratio, severity of stroke at admission [measured by the national institutes of health stroke scale (nihss)], functional status at admission and at discharge [defined by modified rankin scale (mrs) > ], presentation time (last known well to hospital admission), the proportion of patients who received intravenous tissue plasminogen activator (iv tpa) to total ischemic stroke incidence, door-to-needle time, door-to-ct time, hospital length-of-stay, and in-hospital mortality per admissions ratio (death before discharge). data are presented as mean± standard deviation (sd), absolute numbers with percentages (%), and median with interquartile range (iqr) according to the pattern of distribution. a chi-square test and independent-sample median test were used to compare the variables of interest within the study periods. due to the non-normally distributed pattern of our data, we used the spearman correlation coefficient to examine the association among variables of interest. to compare the variables of interest between the covid- period to the corresponding months in the previous year, we used two approaches: ) the bayesian hierarchical model (time series bayesian multilevel) and ) the interrupted time series analysis (its), to reduce the uncertainty that may occur when an outcome exhibits a time trend that might confound the intervention effect. in the bayesian hierarchical model, we classified the study period into three groups: a) the covid- period, defined from the first confirmed case to the last day of data analysis (i.e., to january , ). the bayesian hierarchical model allowed the control of the effects of independent variables (e.g., mrs and nihss at baseline and the in-hospital mortality), as well as random effects properties, and compared variables of interest in the three selected study periods. according to the pattern of data, we used bernoulli, poisson, gaussian, exgaussian, and asymmetric laplace family distribution. all results were shown with the % credible interval (cri), estimated based on the hamiltonian monte carlo method. in brief, cri in the bayesian models is an analog to the confidence interval (ci) in traditional frequentist analysis, including % of the probability distribution of the mean ( ) . we also used an interrupted time series analysis (its) with segmented regression analysis to examine the possible effects of the covid- pandemic on major stroke trends. the weekly rate of stroke data was included in the interrupted time series model. we used the autocorrelation function, partial autocorrelation function, ljung-box, durbin-watson, and dickey-fuller unit root tests to examine the assumptions of time series data. we used the auto-regressive integrated moving average (arima) model to account for autocorrelation. in addition, using the cox-regression model, we estimated the hazard ratio (hr) with % ci of in-hospital mortality. we used the multiple logistic regression model to compare the presentation time to hospital and door-to-needle time of cases with stroke stratified according to the severity of stroke before and during covid- . we assessed the model adequacy using rhat, gelman-rubin diagnostic plots, and loo. we used the stan, 'ggplot ', 'brms', consreg, and survival packages to perform statistical analysis in the r v. environment ( , ) . demographic data and clinical variables: during the study period, , stroke patients (mean age: . ± . years, male-to-female ratio: . ) were hospitalized. the median weekly admission rate was ± . patients. of these cases, had an ischemic stroke (mean age: . ± . years; male-to-female ratio: . ) and had a hemorrhagic stroke (mean age: . ± . years; male-to-female ratio: . ). table provides a comparison between stroke hospitalization trends and care before and during covid- . while a shift towards a younger age was seen at the onset of covid- in comparison to the two months immediately prior to the start of the pandemic (supplemental figure ) , there was no significant difference in the age of admitted cases. in addition, we did not observe any difference in male-to-female ratio and in-hospital mortality rates. in the spearman correlation analysis, while the hospitalization rate of ischemic stroke reduced during the pandemic (r=- . , p=< . ), we did not see a significant change in the hospitalization rate of hemorrhagic stroke (r= . , p= . ). we observed a significant reduction in the proportion of those with ischemic stroke receiving iv tpa (r=- . , p< . ). there was no change in the door-to-needle time during the pandemic (r=- . , p= . ). disability at discharge (measured by mrs) increased during the pandemic in both ischemic (r= . , p< . ) and hemorrhagic strokes (r= . , p< . ). we did not observe any changes in the presentation time, length of stay and inhospital mortality rate in both ischemic and hemorrhagic strokes. stroke hospitalization during covid- reduced from . per , population, in (tables & ) . there were no significant differences in the presentation time to hospital and door-to-needle time (adjusted for age and sex). using multiple logistic regression analysis, the number of those with nihss> who presented later than . hours during the pandemic were significantly higher than figure ]. finally, despite a decrease in the rate of pre-stroke disability at admission during the pandemic, we observed a significant increase of mrs scores at discharge for all strokes (adjusted for age and sex, mrs at admission, and length of stay), ischemic strokes (adjusted for age, sex, length of stay, nihss at admission, mrs at admission, and treatment with iv tpa) and hemorrhagic strokes (adjusted for age, sex, mrs at admission and length of stay; during the covid- pandemic in zanjan province, iran, we observed a significant reduction in the total number of stroke admissions, particularly among those with mild strokes. while some aspects of stroke care and outcomes (stroke unit admission, length of stay, door-to-needle time and in-hospital mortality) did not change, a significantly lower percentage of patients received thrombolytic therapy. disability at discharge increased significantly for all strokes during the covid- pandemic. the covid- pandemic has dramatically affected the entire health system, in part due to the significant association with ncds ( ). while social distancing, widespread testing, and contact tracing surveillance are crucial in reducing the burden of covid- , they are not sufficient to reduce the dual burden of communicable and ncds. in the current study, we observed a significant reduction in stroke hospitalization during the covid- pandemic. changes in vascular diseases have been reported during previous national crises and events such as the great east japan earthquake and tsunami disaster ( ) , as well as world and european football cup events ( , ) . however, a global crisis like covid- has not occurred since the influenza pandemic ( ) . in addition, the impact of covid- on the healthcare system will be sustained and longer-lasting, in contrast to the immediate impact of an earthquake or a major sporting event. therefore, it is important to closely monitor the changes in stroke rates during various phases of the pandemic. the cascade initiative will enable us to follow these trends across many centers worldwide. we observed a lower rate of admission among those with mild ischemic stroke (defined as nihss< ), which may be due to a delay in seeking treatment and fear of exposure to covid- in hospitals. this is an alarming finding for health care authorities, as even mild strokes may result in poor clinical outcomes, if not treated ( ) , ( ) . therefore, many of the patients who are not admitted are at higher risk of disability, recurrent stroke, and/or death. these findings may have particular implications during the pandemic and may suggest a more important role of telemedicine for preventive or therapeutic care in stroke. this can particularly benefit mild stroke patients who may be hesitant to visit a hospital but are more agreeable to contacting a healthcare provider remotely. the covid- pandemic has the potential to significantly impact patient outcomes following stroke and vascular disease. stroke care protocols in numerous countries have undergone changes in order to increase resources for covid- patients ( ) . despite the recent shift towards prioritization of covid- care, it is equally important to ensure that non-covid- patients, such as stroke patients, continue to receive timely access to care and adequate support. of note, in our center, there were no observed changes in stroke unit admission and in-hospital mortality rate, despite the decrease in available resources for stroke care. thus, it is still possible to provide sufficient care for patients, even in low-and middle-income countries, while working with limited resources. several factors have the potential to influence the reduction in the number of iv tpa cases. first, the limited experience of healthcare practitioners using iv tpa in settings of the sars-cov- infection could have influenced rates of administration. second, healthcare professionals may have faced difficulties in the evaluation and management of acute stroke patients who were at risk of acquiring covid- from suspected or confirmed covid- cases who were asymptomatic during the prodromal period. finally, healthcare professionals may have been concerned about possible ct scanner contamination before administering iv tpa. in the current study, we did not observe a significant change in door-to-needle time during the pandemic. therefore, a reduction in the proportion of cases receiving iv tpa cannot be explained by change in the chain of acute stroke care in our hospital. while presentation time to the hospital did not change during the covid- pandemic, we observed a significant increase in the proportion of those with severe stroke who presented later than . hours. this finding may be explained by a delay in the patient calling an ambulance, or due to changes in dispatch during the pandemic and can be a major reason for a lower rate of thrombolytic therapy during the pandemic. implementing comprehensive acute stroke management guidelines could aid in promoting the use of iv tpa in the pandemic. this approach should occur at a pre-hospital level to assure the safety of the public and encourage patients to present to hospital in cases of possible stroke, and at an in-hospital level to provide adequate sources for stroke care. we also found a significant increase in disability at discharge during the pandemic period. increased disability at discharge during the pandemic in our report was independent of the severity of stroke and mrs at admission, the rate of iv tpa injection, and length of stay. therefore, this increase in disability may be partially explained by delayed or limited access to early rehabilitation and early assisted discharge programs due to reorganization of these services ( ) . in addition, covid- has resulted in a number of healthcare professional shortages across the country. as a result, hospital systems have redeployed physicians, nurses, and other members of the healthcare team from different specialties to satisfy these shortages. consequently, specialists who are less experienced in neurological care were tasked to care for stroke patients. thus, it is possible that this redeployment is associated with a decrease in the level of care given to patients, as compared to before the pandemic. the increased disability rate upon discharge may be indicative of changes in stroke outcome, which may further amplify the overall burden of stroke. in addition, a lower rate of admission for mild stroke cases may lead to an increase in stroke recurrence, which may increase the potential for more severe strokes and death. these findings are particularly important in low-and middleincome countries ( ) , where stroke is frequently more prevalent than in many high-income countries ( ) , and with higher rates of recurrence ( ) , disability ( ) and death ( ) . furthermore, lifestyle changes, such as physical inactivity, unhealthy diet, and mental health and psychosocial problems related to covid- , may cause a rise in the occurrence of chronic health conditions and worsen the existing ones ( ) . our study has limitations. particularly, at this time, we report the results of stroke hospitalization from one center. these results need to be confirmed with other cascade centres to determine generalizability. the cascade initiative provides a unique opportunity to share these results promptly with several centers worldwide. we performed the analysis using r and will make the relevant scripts available to other centers to standardize the reporting of data. additionally, in the valiasr center, we do not perform endovascular therapy and therefore, are not able to comment regarding changes in large artery occlusion and its management during the covid- pandemic. we are also planning to perform subsequent studies comparing the rate of stroke hospitalization with changes in the trend of covid- confirmed cases and death among cascade centers. in addition, we will also compare trends of other acute emergency admissions, such as acute coronary diseases, with stroke in our centers. in summary, the cascade initiative provides an opportunity to assess the cumulative changes in stroke epidemiology worldwide in a timely manner. the current report provides valuable information regarding the evolving changes in stroke epidemiological data, including hospitalization, management and outcomes during the covid- pandemic, which can also be used as a prototype to enable the sharing of analytical models with other centers. we now have a name for the disease caused by the novel coronavirus covid- pandemic and burden of non-communicable diseases: an ecological study on data of countries correlations between covid- and burden of dementia: an ecological study and review of literature trends in premature avertable mortality from non-communicable diseases for countries and territories, - : a population-based study stroke care during the covid- pandemic: experience from three large european countries break in the stroke chain of survival due to covid- what is happening to non-covid deaths? call to action: sars-cov- and cerebrovascular disorders (cascade) rate and associated factors of transient ischemic attack misdiagnosis. eneurologicalsci an updated definition of stroke for the st century: a statement for healthcare professionals from the american heart association/american stroke association ministry of health and medical education in iran. covid- in iran adaptively setting path lengths in hamiltonian monte carlo a probabilistic programming language for bayesian inference and optimization the comprehensive r archive network occurrence of cardiovascular events after the great east japan earthquake and tsunami disaster cardiovascular events during world cup soccer the impact of world and european football cups on stroke in the population of dijon, france: a longitudinal study from to the influenza pandemic: lessons for and the future express transient ischemic attack study: speed the process! stroke a transient ischaemic attack clinic with round-the-clock access (sos-tia): feasibility and effects mechanical thrombectomy in the era of the covid- pandemic: emergency preparedness for neuroscience teams: a guidance statement from the society of vascular and interventional neurology socioeconomic status and stroke incidence, prevalence, mortality, and worldwide burden: an ecological analysis from the global burden of disease study excessive incidence of stroke in iran: evidence from the mashhad stroke incidence study (msis), a population-based study of stroke in the middle east five-year recurrence rate and the predictors following stroke in the mashhad stroke incidence study: a population-based cohort study of stroke in the middle east long-term disability after stroke in iran: evidence from the mashhad stroke incidence study five-year case fatality following first-ever stroke in the mashhad stroke incidence study: a population-based study of stroke in the middle east sedentary behavior: emerging evidence for a new health risk in-hospital survival (days presentation time (hours door-to-needle time (minutes total (%) or median (iqr) abbreviations: nihss: the national institutes of health stroke scale abbreviations: nihss: the national institutes of health stroke scale; mrs: modified rankin scale ** proportion to total stroke the authors have no conflict of interest related to this paper to declare. we would like to sincerely thank all centers participating in the cascade study during this extremely difficult period. the authors have not received any compensation for the current study.valiasr hospital is an active participating center in the safe implementation of treatments in stroke (sits) registry, and we would like to thank sits for its support. key: cord- -fb uzzua authors: venketasubramanian, narayanaswamy; hennerici, michael g. title: stroke in covid- and sars-cov- date: - - journal: cerebrovasc dis doi: . / sha: doc_id: cord_uid: fb uzzua nan there has been a recent report of large artery ischaemic stroke among young patients with coronavirus disease (covid- ) in the usa [ ] . the cause is felt to include coagulopathy and vascular endothelial dysfunction [ ] . there have been other reports of cerebrovascular events among covid patients in china [ ] and another coronavirus infection that led to severe acute respiratory syndrome in singapore [ ] . the case series are illustrated for comparison (table ) . it can be seen that the patients are older in china and singapore than in the usa, there is no consistent sex predilection, some may not have stroke risk factors, there is a variable range of time between illness and stroke onset (although in singapore times were reported only after hospital admission, all in intensive care), and most were severely ill/had a moderate or severe stroke, with high subsequent mortality and morbidity. cardioembolic mechanisms may have a causative role, but intravenous immunoglobulin given for severe acute respiratory syndrome has also been implicated [ ] . acute interventions included thrombolysis and thrombectomy [ ] . antiplatelets and anticoagulants were used for secondary prevention. more data are needed to better understand the mechanisms and treatment of stroke during coronavirus infections, even more so as those with prior stroke have worse outcome when they develop covid- [ , ]. the editors invite extra-expedited submissions of papers on an increasingly important topic stroke and the covid- infections. the authors have no conflicts of interest to declare. the authors did not receive any funding. large-vessel stroke as a presenting feature of covid- in the young clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study acute cerebrovascular disease following covid- : a single center, retrospective, observational study large artery ischaemic stroke in severe acute respiratory syndrome (sars) key: cord- -qgkwylmk authors: candeloro, elisa; carimati, federico; tabaee damavandi, payam; princiotta cariddi, lucia; banfi, paola; clemenzi, alessandro; gallazzi, marco; mauri, marco; rebecchi, valentina; baruzzi, fabio; giorgianni, andrea; tozzi, matteo; bianchi, massimo; ageno, walter; versino, maurizio title: an example of a stroke unit reshaping in the context of a regional hub and spoke system in the covid- era date: - - journal: front neurol doi: . /fneur. . sha: doc_id: cord_uid: qgkwylmk during the covid- outbreak, the neurology and stroke unit (su) of the hospital of varese had to serve as a cerebrovascular hub, meaning that the referral area for the unit doubled. the number of beds in the su was increased from to . we took advantage of the temporary suspension of the out-patient clinic and reshaped our activity to guarantee the / availability of recombinant tissue plasminogen activator (rtpa) intravenous therapy (ivt) in the su, and to ensure we were able to admit patients to the su as soon as they completed endovascular treatment (evt). in days, stroke patients were admitted to our hospital, and . % of them underwent ivt and/or evt, which means that we treated . patients per day; in the baseline period from to , these same figures had been . % and . , respectively. the mean values of the door-to-first ct/mri and the door-to-groin puncture, but not of the onset-to-door and the door-to-needle periods were slightly but significantly longer than those observed in the baseline period in patients. on an individual basis, only one patient exceeded the door-to-groin puncture time limit computed from the baseline period by about min. none of the patients had a major complication following the procedures. none of the patients was or became sars-cov positive. in conclusion, we were able to manage the new hub-and-spoke system safely and without significant delays. the reshaping of the su was made possible by the significant reduction of out-patient activity. the consequences of this reduction are still unknown but eventually, this emergency will suggest ways to reconsider the management and the allocation of health system resources. during the covid- outbreak, the neurology and stroke unit (su) of the hospital of varese had to serve as a cerebrovascular hub, meaning that the referral area for the unit doubled. the number of beds in the su was increased from to . we took advantage of the temporary suspension of the out-patient clinic and reshaped our activity to guarantee the / availability of recombinant tissue plasminogen activator (rtpa) intravenous therapy (ivt) in the su, and to ensure we were able to admit patients to the su as soon as they completed endovascular treatment (evt). in days, stroke patients were admitted to our hospital, and . % of them underwent ivt and/or evt, which means that we treated . patients per day; in the baseline period from to , these same figures had been . % and . , respectively. the mean values of the door-to-first ct/mri and the door-to-groin puncture, but not of the onset-to-door and the door-to-needle periods were slightly but significantly longer than those observed in the baseline period in patients. on an individual basis, only one patient exceeded the door-to-groin puncture time limit computed from the baseline period by about min. none of the patients had a major complication following the procedures. none of the patients was or became sars-cov positive. in conclusion, we were able to manage the new hub-and-spoke system safely and without significant delays. the reshaping of the su was made possible by the significant reduction of out-patient activity. the consequences of this reduction are still unknown but eventually, this emergency will suggest ways to reconsider the management and the allocation of health system resources. since the outbreak of covid- in lombardy, an italian region with a population of million people. during the pandemic, the ability to guarantee treatment for patients presenting with stroke within the time windows dictated by guidelines has become an issue. this is because most of the resources normally available in hospitals had to be devoted to the treatment of covid- patients. to face the problem of cerebrovascular and other time sensitive diseases, the governor of lombardy set up a hub-and-spoke organization with hub hospitals. it is noteworthy that this decision was taken in a few days, with little time for the hub hospitals to reorganize their activity. the hospital of varese had to serve as a cerebrovascular hub for the north-western areas of lombardy, meaning that its referral area was doubled and that the stroke patients could have been taken to varese either directly by the regional emergency transportation system (agenzia regionale dell'emergenza urgenza: areu) or from a spoke hospital located somewhere in lombardy. here we report how we have managed this situation and how our stroke unit (su) was able to maintain consistent performance levels whilst also becoming a hub. before the onset of the covid- pandemic, the neurology and stroke unit of the circolo hospital in varese consisted of beds. four beds were dedicated to the stroke unit since there were four mobile monitoring systems available. the monitors were placed next to the patient's bed and could not be remotely controlled. the medical staff consisted of full-time neurologists who belonged to the hospital and one half-time neurologist who belonged to the university of insubria. with different levels of involvement, all neurologists worked in the stroke unit but none of them was exclusively assigned to it. during the week, from a.m. to p.m. (daytime) at least one neurologist had to be present in the hospital, whereas from p.m. to a.m. (nighttime) one neurologist was available on call. on the weekends there was a neurologist in the hospital during daytime and one on-call during night-time. the nurse staff was shared with another units located on the same floor. in total, nurses dealt mainly with the neurology and stroke unit, of which were specifically trained for the stroke unit. intravenous therapy (ivt) with recombinant tissue plasminogen activator (rtpa) procedures were performed in the emergency department (ed) whilst endovascular therapy (evt) procedures were conducted in the angiographic room. after the procedures the patients were moved to the stroke unit, kept under observation in the ed, and if a major complication occurred or the patient was clinically unstable, they were moved to the intensive care unit (icu). immediately after the promulgation of the decree, the neurology and su were relocated in the nearby cardiac surgery ward, since most of the cardiac surgeons had to move to another hospital that served as a hub for cardiac surgery. thanks to this relocation, the su gained additional beds that were provided with a centrally and remotely controlled monitoring system. the number of neurologists was not increased but, given the substantial reduction of the outpatient clinic activity that was imposed by the lockdown, it was possible to reorganize the neurology department as follows: during the week, three neurologists were present in the su during day-time, two of which were present in the ward, and one in the ed. in addition, one neurology resident was available out of weekdays. during night-time, one neurologist was on call and another one was available as a possible back-up. on the weekends, during the daytime, there was one neurologist and one resident available both for the neurology and stroke unit and for the ed. during night-time, one neurologist was available on-call with an additional neurologist as a possible backup. as for the nurses, eight nurses were available during day-time and two at night-time. the regional indications dictated the rules for swab testing and for the personnel protection equipment that are described in a report on our hospital's neurosurgery hub ( ) . the swab test became mandatory for all the patients admitted to the hospital only after april . before that date, a swab test was performed on patients that were possibly considered to be sars-cov positive based on their clinical history, their body temperature, their respiratory symptoms and signs, and a chest x-ray (or ct). the ivt procedures were performed inside the stroke unit and not in the ed. all patients admitted to the ed were transferred to the su immediately after they underwent ivt or evt or when neither of these procedures was deemed possible or appropriate unless they had to be transferred to the icu. this was done to alleviate the burden on the ed. we collected the data on the patients that were referred to our hospital from march to april either for ischemic or hemorrhagic stroke or for intracerebral cerebral hemorrhage (ich), i.e., a timeframe of days following the promulgation of the decree of the lombardy governor for the institution of the hub-and-spoke system. since the data were collected from patients' clinical records, and since they were all treated according to guidelines on best clinical practice, our institution did not require ethical approval for this study. we performed a full diagnostic work-up on all patients and when indicated by italian guidelines [spread gl ( )], updated with the most recent aha/asa guidelines ( ), an ivt and/or an evt or a carotid endarterectomy (cea). for each patient we acknowledged how he/she had reached the hospital (without or with the regional emergency transportation system areu), the individual risk factors, the kind of stroke according to the trial of org in acute stroke treatment (toast) classification ( ), the location of the stroke according to oxfordshire classification (ocsp) ( ), the therapeutic procedures (ivt, evt, cea), and a justification in case no procedure was undertaken, the nih stroke scale (nihss) score before and after the procedure. we also acknowledged several time periods: onset-to-door (the time from the onset of the symptoms to the arrival at the ed), door-to-first ct/mri (the timeframe from the arrival of the patient at the hospital and the first neuroradiological procedure), door-to-needle (the timeframe from the arrival of the patient at the hospital and the beginning of ivt), and door-to-groin puncture (the timeframe from the arrival of the patient at the hospital and the beginning of evt). we defined as a baseline the data that has been collected from patients over a year period, from to , and for the different time periods we defined the th percentile value as the upper normal (i.e., not covid- ) limit. for the evaluation of the mean values computed for the covid- period, we calculated a z-value by considering the mean and the standard deviation values computed for the baseline period as the population values, and the number of observation in the covid- period as the numerosity value. for the comparison of observed frequencies computed for the covid- period, we computed chi-square values using the corresponding frequencies during the baseline to compute the expected frequencies. for the comparison of the variabilities, we computed an f value as the ratio between the baseline and the covid- variances. all the analyses were performed using microsoft excel ver. . , and for all of them the significance value was set at p = . . we did not turn down any case requests for the admission of a patient referred to our hospital. in the days following the promulgation of the decree, we observed patients: tias and strokes. in the same timeframe, ich patients were admitted to the hospital, mostly in the intensive care and in the neurosurgery units, while only in the neurology and stroke units. sixteen of these patients ( . %) underwent a revascularization procedure: patients ( . %) had ivt, ( %) had evt, and patients ( . %) had ivt followed by evt (bridging treatment). of the patients treated during the covid- period, . % were found to be significantly higher when compared to the baseline period, where only . % of patients were treated (chi-square = . ; p = . ). we thus treated . stroke patients per day, whereas the corresponding figure for the baseline period was . ; again, these two figures proved to be significantly different (chi-square = . ; p = . ). none of these patients had a major complication following the revascularization procedure, but patients had to be admitted to the icu for a few days before being transferred to the su. no patients were or became sars-cov positive. all of these patients reached the hospital by ambulance after the activation of the areu system. the main clinical features of the patients who underwent to recanalization procedures are reported in table . the following stroke risk factors were found in the patients treated: atrial fibrillation in ( %), ischemic heart disease in ( . %), diabetes in ( . %), a smoking habit in ( . %), hypertension in ( %), previous stroke in ( . %), timebased clinical history of a previous tia in ( . %). table shows the interventional time periods. the mean values of door-to-ct/mri and door-to-groin puncture were slightly, but significantly, longer than those measured in the large case series of patients collected from to , whereas the mean values of onset-to-door and door-to-needle were not. however, it is worth mentioning that if we considered the normal upper time limit computed from the data of the baseline period, only one patient exceeded the door-to-groin puncture time limit by about min. another interesting point is that some of the data presented a larger variability in the baseline period compared to the covid- period, as showed by the variances of the mean. this was true for the onset-to-door (f = . ; p < . ), the door-tofirst ct/mri (f = . ; p < . ), the door-to-groin puncture (f = . ; p = . ) but not for the door-to-needle (f = . ; p = . ) timeframes. four additional patients underwent cea. they were males and female and their median age was years with a range of - years. they all had a partial anterior circulation infarct and their median nihss score was at onset (range - ) and at discharge ( - ). their mean (and standard deviation) values for the onset-to-door and the door-to-first ct/mri were, respectively ( ) and ( ) min. we exceeded the normal time limit in one patient for the onset-to-door and in another patient for the door-to-ct/mri time period. the time between the admission and the surgical procedure ranged from to days. among the patients who did not undergo any revascularization procedure, eight ( %) could not be treated due to inappropriate timing [i.e., onset-to-door larger than h without dawn/defuse- trials criteria ( ) ( ) ( ) ]; in the baseline period, the corresponding figure was the same ( %). four of these patients did not activate the emergency system to get to the hospital. the outbreak of covid- has had a significant impact on health systems worldwide. the involvement of the nervous system in the sars-cov virus is now recognized ( , ) , and endothelial involvement is likely to play a key role ( ) ( ) ( ) ( ) ( ) . thus, the management of stroke in the covid- era has two aspects: one concerning covid- -related stroke ( , ) , and another about the need to meet the standards for the treatment of a time-dependent disease, despite having to allocate health system resources to the management of covid- . the latter had to be faced locally, and the reports about this topic were not available at the time of the pandemic onset ( ) ( ) ( ) . our data showed that despite the fact that the covid- pandemic imposed a reallocation of health system resources, largely toward the management of covid- patients, we were still able to guarantee a timely and safe approach for stroke patients. eventually, we had no covid- patients, but we still adopted an approach to safeguard them from potentially sars-cov positive patients. due to the hub-and-spoke system, the number of patients that underwent a recanalization procedure, and the percentage of patients eligible for treatment increased significantly. the onset-to-door and the door-to-needle mean time periods did not change as compared to the baseline period, whereas the door-to first ct/mri and the door-to-groin puncture were slightly but significantly increased. on an individual basis, only one patient exceeded the door-to-groin puncture limit by about min. the increase of the mean values was expected due to the additional safeguard measures that had to be adopted for potentially sars-cov positive patients. however, the variability of the duration of the different time periods was usually shorter in the covid- than in the baseline period, suggesting that the control of the sequence of the procedures was improved. this was made possible by the reshaping of the su in terms of both equipment and human resources. the hospital increased the number of monitored beds available in the su. the neurologists could focus on inpatient activity since the activity of the outpatient clinic was reduced and limited to those presenting for an acute or subacute problem. moreover, during the pandemic, patients were reluctant to be referred to the hospital because they were afraid of being infected, as suggested by the unexpected reduction of consultations for cardiovascular disorders. it is possible that when we go back to regular activity, we will find that many patients have underestimated their neurological symptoms. this could be the case of tia, which can last a short time and be overlooked. the number of patients admitted for a tia was quite low, in agreement with the report by diegoli et al. ( ) . however, in the months after the time period considered in this report, none of the patients that we admitted for a stroke had a clinical history positive for tia. if in the future we confirm this scenario, we should reconsider how medical resources are distributed. in italy we there is an issue of overuse of medical resources, and it is not unusual for a patient to have several medical consultations, laboratory, and instrumental examinations before concluding that "there is nothing wrong." often, this conclusion could have been reached with a thorough initial examination and less referrals. in conclusion, it is possible that this emergency period, which forced us to activate different procedures, will provide suggestions that will enable us to reconsider organization and lead to the implementation of more hub-and-spoke systems, to the reweighting of the out-and in-patient activities, and, therefore, to more careful examinations of the patient before asking for further clinical and instrumental examinations. the raw data supporting the conclusions of this article will be made available by the authors, without undue reservation. ethical review and approval was not required for the study on human participants in accordance with the local legislation and institutional requirements. written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements. coronavirus disease (covid- ) outbreak: single-center experience in neurosurgical and neuroradiologic emergency network tailoring spread -stroke prevention and educational awareness diffusion ictus cerebrale: linee guida italiane di prevenzione e trattamento guidelines for the early management of patients with acute ischemic stroke: a guideline for healthcare professionals from the american heart association/american stroke association classification of subtype of acute ischemic stroke. definitions for use in a multicenter clinical trial. toast. trial of org in acute stroke treatment change in stroke incidence, mortality, case-fatality, severity, and risk factors in oxfordshire, uk from thrombectomy for stroke at to hours with selection by perfusion imaging thrombectomy to hours after stroke with a mismatch between deficit and infarct guidelines for the early management of patients with acute ischemic stroke: update to the guidelines for the early management of acute ischemic stroke: a guideline for healthcare professionals from the neurological complications of coronavirus and covid- does sars-cov- invade the brain? translational lessons from animal models spectrum of neuropsychiatric manifestations in covid- large-vessel stroke as a presenting feature of covid- in the young reversible encephalopathy syndrome (pres) in a covid- patient hypertension, thrombosis, kidney failure, and diabetes: is covid- an endothelial disease? a comprehensive evaluation of clinical and basic evidence endothelial cell infection and endotheliitis in covid- covid- presenting as stroke covid- -related stroke acute stroke management pathway during coronavirus- pandemic stroke care during the covid- pandemic: experience from three large european countries decrease in hospital admissions for transient ischemic attack, mild, and moderate stroke during the covid- era all authors contributed to the management of the patients, conceived the study, contributed to the draft manuscript, and read and approved the final version. moreover, pt and fc collected the data in a suitable database for the following analyses. mv analyzed the data and wrote the manuscript. key: cord- -rzy mejb authors: duricki, denise a.; drndarski, svetlana; bernanos, michel; wood, tobias; bosch, karen; chen, qin; shine, h. david; simmons, camilla; williams, steven c.r.; mcmahon, stephen b.; begley, david j.; cash, diana; moon, lawrence d.f. title: corticospinal neuroplasticity and sensorimotor recovery in rats treated by infusion of neurotrophin- into disabled forelimb muscles started h after stroke date: - - journal: biorxiv doi: . / sha: doc_id: cord_uid: rzy mejb stroke often leads to arm disability and reduced responsiveness to stimuli on the other side of the body. neurotrophin- (nt ) is made by skeletal muscle during infancy but levels drop postnatally and into adulthood. it is essential for the survival and wiring-up of sensory afferents from muscle. we have previously shown that gene therapy delivery of human nt into the affected triceps brachii forelimb muscle improves sensorimotor recovery after ischemic stroke in adult and elderly rats. here, to move this therapy one step nearer to the clinic, we set out to test the hypothesis that intramuscular infusion of nt protein could improve sensorimotor recovery after ischemic cortical stroke in adult rats. to simulate a clinically-feasible time-to-treat, twenty-four hours later rats were randomized to receive nt or vehicle by infusion into triceps brachii for four weeks using implanted minipumps. nt increased the accuracy of forelimb placement during walking on a horizontal ladder and increased use of the affected arm for lateral support during rearing. nt also reversed sensory deficits on the affected forearm. there was no evidence of forepaw sensitivity to cold stimuli after stroke or nt treatment. mri confirmed that treatment did not induce neuroprotection. functional mri during low threshold electrical stimulation of the affected forearm showed an increase in peri-infarct bold signal with time in both stroke groups and indicated that neurotrophin- did not further increase peri-infarct bold signal. rather, nt induced spinal neuroplasticity including sprouting of the spared corticospinal and serotonergic pathways. neurophysiology showed that nt treatment increased functional connectivity between the corticospinal tracts and spinal circuits controlling muscles on the treated side. after intravenous injection, radiolabelled nt crossed from bloodstream into the brain and spinal cord in adult mice with or without strokes. our results show that delayed, peripheral infusion of neurotrophin- can improve sensorimotor function after ischemic stroke. phase i and ii clinical trials of nt (for constipation and neuropathy) have shown that peripheral, high doses are safe and well tolerated, which paves the way for nt as a therapy for stroke. ischemic stroke occurs in the brain when blood flow is restricted, causing brain cells to die rapidly. movements on the opposite side of the body are frequently affected . stroke victims also often exhibit lack of responsiveness to stimuli on their affected side. the w.h.o. estimates that, worldwide, there are million stroke survivors, with another million new strokes annually. the vast majority of stroke victims are not eligible for the few therapies that improve outcome because they arrive in hospital too late for reperfusion to be effective . treatment six hours or more after ischemic stroke is usually limited to rehabilitation: therapies that reverse sensory impairments and locomotor disability are urgently needed, and these must work when initiated many hours after stroke. neurotrophin- is a growth factor which plays a key role in the development, and function of locomotor circuits that express nt receptors, including descending serotonergic and corticospinal tract (cst) axons and afferents from muscle and skin that mediate proprioception and tactile sensation [ ] [ ] [ ] . however, peripheral levels of nt drop in the postnatal period . we and others had shown that delivery of nt into the cns promotes recovery in rodent models of spinal cord injury [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] but this involved invasive routes of delivery (e.g., intraspinal injection or intrathecal infusion) or gene therapy. we also recently showed that injection of an adeno-associated viral vector (aav) encoding full-length human nt (prepront , kda) into forelimb muscles hours after stroke in adult or elderly rats improved sensorimotor recovery . we had originally expected that aav would be trafficked from muscle to the spinal cord retrogradely in axons and that this would enhance secretion of nt by motor neurons, leading to sprouting of the spared cst , , and sensorimotor recovery. although nt protein was overexpressed in injected muscles, to our surprise we found little evidence for expression of the human nt transgene in the spinal cord or cervical drgs , using this dose and preparation of aav. this serendipitous result led us to reject our original assumption that sensorimotor recovery required expression of the human nt transgene in the spinal cord and to wonder whether peripheral infusion of nt protein would suffice. accordingly, here, we test the hypothesis that infusion of the mature form of the nt protein ( kda) into disabled forelimb muscles improves sensorimotor recovery. this is consistent with work by others including a study showing that a signal from muscle spindles can improve neuroplasticity of descending pathways and can enhance recovery after cns injury . notably, nt protein is synthesised by muscle spindles and can be transported from muscle to sensory ganglia and spinal motor neurons in nerves , , and from the bloodstream to the cns [ ] [ ] [ ] . this route of administration and time frame is clinically feasible so to take this potential therapy one step nearer the clinic, we next set out to determine whether intramuscular infusion of human nt protein (mature form, kda) would improve outcome after stroke (i.e., bypassing the use of gene therapy and spinal surgery). importantly, the mature form of the nt protein has excellent translational potential: phase i and ii clinical trials have shown that repeated, systemic, high doses of nt protein are well-tolerated, safe and effective in more than humans with sensory and motor neuropathy (charcot-marie-tooth type a) or constipation including in people with spinal cord injury [ ] [ ] [ ] [ ] [ ] . in contrast to other neurotrophins, nt does not cause any serious adverse effects such as pain probably because its principal high affinity receptor trkc is not expressed on adult nociceptors , . these studies pave the way for nt as a therapy for stroke in humans. we now show in a blinded, randomized preclinical trial that treatment of disabled upper arm muscles with human nt protein reverses sensory and motor disability in rats when treatment is initiated in a clinically-feasible timeframe ( hours after stroke). rats received unilateral focal cortical stroke or underwent sham surgery , (fig. a,b) . twentyfour hours after stroke, rats were allocated to treatment using nt or vehicle, infused into affected triceps brachii muscles for one month via implanted catheters and subcutaneous osmotic minipumps. experiments were performed in accordance with guidelines from the stroke therapy academic industry roundtable (stair) and others and our findings were reported in accordance with the arrive (animals in research: reporting in vivo experiments) guidelines. all surgical procedures, behavioural testing and analysis were performed using a randomised block design. all surgeries, behavioural testing and analysis were performed with investigators blinded to treatment groups. rats were randomised to surgery by drawing a rat identity number from an envelope and then a stroke/sham allocation from an envelope. allocation concealment was performed by having nt and vehicle stocks coded by an independent person prior to loading pumps. behavioural testing was conducted blind and codes were only broken after behavioural analyses were complete. lister hooded (~ months; - g) outbred female rats (charles river, uk) and adult c bl/ mice ( - weeks) were used. all procedures were in accordance with the uk home office guidelines and animals (scientific procedures) act of . rats were maintained (specific pathogen free) in groups of to in plexiglas housing with tunnels and bedding on a : hour light/dark cycle with food and water ad libitum. focal ischemic stroke was induced in the hemisphere representing the dominant forelimb ( supplementary fig. ), as determined by the cylinder behavioural test. stroke lesions (n = ) were performed as previously described . briefly, animals were transferred to a stereotaxic frame (david kopf instruments, usa) where a midline incision was made, the cortex was then exposed via craniotomy using the following co-ordinates [defined as anterioposterior (ap), mediolateral (ml)]: ap mm to − mm, ml mm to mm, relative to bregma. endothelin- (et- , pmol/µl in sterile saline; calbiochem) was applied using a glass micropipette attached to a hamilton syringe. µl of et- to was applied to the overlying dura to reduce bleeding, and immediately thereafter, the dura mater was incised and reflected. four μl volumes of et- were administered topically and four µl volumes were microinjected intracortically (at a depth of mm from the brain surface) at the following co-ordinates (from bregma and midline, respectively): ap + . mm, ml . mm ap + . mm, ml . mm ap + . mm, ml . mm ap - . mm, ml . mm temperature was maintained using a rectal probe connected to a homeothermic blanket (harvard apparatus, usa) placed under the animal which maintained rectal temperature at ± °c. prior to suturing, the animal was left undisturbed for minutes. modifying previous work , the skull fragment was then replaced and sealed using bone wax (covidien, uk). % ( / ) of rats survived this stroke surgery. sham-operated (n = ) rats received all procedures up to, but not including, craniotomy or endothelin- injection. animals were given buprenorphine ( . mg/kg, subcutaneously) for postoperative pain relief. our method of inducing stroke with et- is advantageous for evaluating regenerative stroke therapies for four reasons: ) our model produces ischemic lesions that model small focal human strokes rather than larger "malignant" strokes that tend to be fatal in humans ; ) our model targets sensorimotor cortex; ) our stroke model involves only low mortality rates and has reasonable reproducibility with a proven ability to detect therapies that induce neuroplasticity and functional recovery , ; ) our model causes sustained sensorimotor deficits (e.g., impaired use of limbs) which are common neurological symptoms of human stroke. structural images were obtained prior to stroke, hours after stroke and at one and eight weeks after stroke. mr imaging was conducted on a tesla (t) horizontal bore vmris scanner (varian, palo alto, ca, usa). animals were anaesthetised using . % isoflurane, in . l/min medical air and . l/min medical oxygen in an induction chamber. once anaesthetised they were secured in a stereotaxic head frame inside the quadrature birdcage mr coil ( mm internal diameter, id) and placed into the scanner. each animal's physiology was supervised throughout the procedure using a respiration monitor (biopac, usa) and a pulse oximetry sensor (nonin, usa) that interfaced with a pc running biopac. additionally, an mri compatible homeothermic blanket (harvard apparatus, usa) placed over the animal responded to any alterations in the body temperature identified by the rectal probe, and maintained temperature at ± °c. the t weighted mr images were acquired using a fast spin-echo sequence: effective echo time (te) ms, repetition time (tr) ms, field of view (fov) mm x mm and an acquisition matrix x , acquiring x mm thick slices in approximately minutes. at the end of the study (to avoid affecting blinding or randomization), lesion volumes at the hour time point were measured using a semi-automatic contour method in jim software under blinded conditions (xinapse systems ltd). functional magnetic resonance imaging (fmri) was performed in a subset of rats that did not receive intracortical injections of bda tracer (n = /group). images were acquired prior to stroke and at one and eight weeks after stroke during non-noxious somatosensory stimulation of the affected or less-affected wrist . this involves delivery of small electrical currents to a wrist whilst the subjects were kept anaesthetised using medium dose alpha-chloralose suitable for recovery and longitudinal (repeated) imaging . alpha chloralose anesthesia was prepared by mixing equal amounts of borax decahydrate (sigma) and alpha chloralose-pestanal (analytical standard, < % beta isoform, , sigma, uk) in physiological saline each at a concentration of mg/ml in a glass beaker at °c prior to filtering using a . µm filter. rats were first anaesthetised using % isoflurane, . l/min medical air and . l/min oxygen. a tail cannulation was performed and the animal was transferred to the mri machine. a bolus of mg/kg alpha chloralose-pestanal was injected intravenously and then the isoflurane was switched off after minutes. an infusion line for continuous application of alpha chloralose was then attached to the cannula at mg/kg/h over the experimental time. medical air ( . l/min) and oxygen ( . l/min) was continuously delivered throughout the scanning period . mr images were obtained using a tesla scanner (varian, agilent). initially, a t -weighted structural scan was acquired, using a fast spin echo (fse) sequence with repetition time (tr) = ms, echo time (te) = ms and field of view (fov) of x mm, yielding slices with voxel size of . x . x mm in approximately min. fmri scans were acquired using a multi-gradient-multi-echo sequence (tr = ms, tes = , , ms, voxel size . mm x . mm x mm, resolution x x , scan time s). volumes were acquired with a pseudo-random onoff stimulation of the forepaw at hz ( μs, ma pulse) using a platinum subdermal needle electrode (f-e , grass technologies, usa) and a tens (transcutaneous electrical nerve stimulation) pad. it has previously been shown that the use of a tens pad results in this intensity of stimulation being innocuous rather than noxious: whereas blood pressure is not altered at ma stimulation, it is increased with . ma stimulation (see references in ). the order of paw stimulation was also randomised. animals were closely monitored following the end of the scanning, given ml of saline (subcutaneous, room temperature) and were kept in a warmed incubator ( deg c) until fully conscious: this takes to hours due to slow pharmacokinetics of alpha chloralose. two animals died following alpha chloralose anaesthesia due to breathing difficulties in recovery. scans with obvious imaging artefacts were discarded, leaving final group numbers of n= , , and n= , , at weeks , and for nt and vehicle treated groups respectively. the resulting images were analyzed with spm- (statistical parametric mapping, fil, ucl). in order to make sure all lesions were in the same side of the brain, images with righthand side strokes were rotated about the sagittal mid-plane, so that the lesioned hemisphere always appeared on the left. functional scans were initially realigned to the first image in the timeseries in order to correct for movements of the head. the first volume of the functional scan was then spatially registered to the structural image, which was, in turn, linearly warped to a template brain. linear warping was used in this step in order to avoid deforming the lesion region. warping parameters obtained during registration of structural image to template were applied to the realigned functional time-series, resulting in structural and functional images that are all in a standard space. finally, functional images were smoothed using a gaussian kernel with full width half maximum of . x . x mm (twice the voxel size). because of the relatively long effective tr of the functional images, a pet basic model (one-sample t-test) was used for firstlevel analyses with covariates consisting of the pseudo-random stimulation pattern (paradigm), and the estimated movement parameters of each individual rat. volumes signal intensity was globally scaled and individual masks, generated from the fast spin echo (fse) structural scan for each rat brain at each time-point using a d pulse-coupled neural network (also registered to the template), were used as explicit masks for the first-level statistical analysis. contrast images from the first-level analysis were then carried onto a second-level (random effects) group analysis. effects of group (i.e. nt or vehicle treated) and stimulated paw (i.e. affected or lessaffected) were used to create statistical comparisons. a flexible factorial analysis was used to compare the difference between the nt and vehicle treated groups in the change from baseline to weeks . statistical parametric maps were generated using an uncorrected threshold of p < . ; images show group mean activations and t values are given. hours after stroke (immediately after mri), rats were allocated to treatment using a randomized block design. allocation concealment was performed by having nt and vehicle stocks coded by a third party. rats were anaesthetised as above and a small incision was made between elbow and axilla, and a small subcutaneous space was formed to the lower back. the osmotic pump with the catheter attached was positioned in this subcutaneous space and then an ultrafine, flexible catheter was implanted approximately millimetres into the proximal end of the long head of the triceps brachii muscle on the disabled side and this was sutured in place (prolene / , ethicon, uk). triceps brachii was selected as the site for infusion because this large muscle is involved in forelimb extension during walking and for postural support during rearing) rearing. note that in the triceps brachii, the end plates are located in the belly of the muscle . the catheter was made from stretchable and flexible silicone tubing (id = . inches, wall thickness = . inches, trelleberg, sf medical, uk, sfm - ) attached to the osmotic pump via larger gluedon tubing (id . mm, vwr international). a second section of this stiff tubing ( millimetres long) was inserted to guide the flexible catheter into the triceps; the guide was slid back after the silicone tube was implanted. catheters were connected to subcutaneous osmotic minipumps ( ml , alzet) containing either vehicle ( . % saline containing . % bovine serum albumin; sigma; a ; - - ) or vehicle containing recombinant human nt (kind gift of genentech inc., usa). pump flow moderators were mr-compatible (peek micro medical tubing, durect, # ). the original vials contained . mg/ml recombinant human ("rhu") nt in mm acetate, mm nacl, ph . . sds page and proteomic analysis indicates that this is the amino acid mature nt protein obtained after proteolytic cleavage of the amino acid proneurotrophin- (uniprot p ) ( supplementary figures and ). the nt dose ( µg/ hours) was selected based on previous experiments . pumps were replaced after two weeks and removed after four weeks. skin was sutured and analgesic administered as above. all rats survived this surgery. sham rats did not undergo this surgery. pilot experiments showed that the pump flow rate ( µl/hour) was sufficient to deliver substances ( . % saline containing % fast green, sigma) to the entire volume of the triceps muscles. rats (n = /group) were terminally anesthetised ( weeks following stroke, before pumps were removed) and triceps brachii and c spinal cord were rapidly dissected and snap frozen in liquid nitrogen prior to storage at - °c. tissue was homogenised in ice cold lysis buffer containing mm nacl, mm tris-hcl (ph . ), % np , % glycerol, mm phenylmethanesulfonylfluoride, μg/ml aprotinin, μg/ml leupeptin and . mm sodium vanadate, using approximately times the volume of buffer to the wet weight of tissue ( µl/mg tissue). protein content was measured and nt elisa was carried out according to manufacturer's instructions (emax, promega). n.b., promega nt elisa kits are no longer available. however, it was recently discovered that when performing elisa using other nt kits (r&d using "reagent diluent" and abcam using diluent a), measurements of nt from skeletal muscle lysates do not provide reliable quantitative data. this is due to so-called "matrix effects" as shown by poor recovery of spiked-in nt (< % or > %) and non-linear relationship between concentration of input material and estimated nt concentration based on a dilution series of muscle homogenate. to overcome the effect of interfering substances, samples should be diluted and appropriate diluents to prepare standards and diluted samples must be used. the abcam kit used with diluent b (not a), however, provided reliable quantitative results (dr. aline barroso spejo, unpublished results). we assessed sensory and motor deficits after stroke using the cylinder test (to assess postural support by forelimbs during rearing), adhesive patch test (to assess responsiveness to tactile stimuli), horizontal ladder (to assess forelimb and hindlimb skilled locomotion), a grip strength test and a test used to monitor unusual responses to cold stimuli (cold allodynia) , . all behavioural testing was carried out by an experimenter blinded to surgery and treatment groups. rats were handled and trained for three weeks on the horizontal ladder before the study began. preoperative baseline scores for the horizontal ladder, the vertical cylinder and the grip strength test were collected one week before surgery. the "adhesive patch" test was used to measure ) the time taken to contact stimuli on the wrists, ) the time taken to remove stimuli from the wrists, and ) the magnitude of lack of responsiveness to stimuli on the affected wrist , , , . for each trial, a round adhesive patch ( mm diameter, ryman) was applied to each wrist on the dorsal side and the animal was returned to its home cage. two times were recorded for both forepaws: ( ) contact and ( ) remove; where "contact" represents the time taken for the animal to contact an adhesive patch with its mouth, and "remove" represents the time taken for the animal to remove the first adhesive patch from its wrist. to determine whether the rats preferentially removed a sticker from their less-affected wrist before their more-affected wrist, the order and side of label removal was recorded. this was repeated four times per session until a > % preference had been found; if this was not the case a fifth trial was conducted. the magnitude of asymmetry was established using the seven levels of stimulus pairs on both wrists as previously described (figure a) . from trial to trial, the size of the stimulus was progressively increased on the affected wrist and decreased on the less affected wrist by an equal amount ( . mm ), until the rat removed the stimulus on the affected wrist first (reversal of original bias). the higher the score, the greater the degree of somatosensory impairment. walking: to assess impairments in forelimb and hindlimb function after stroke, rats were videotaped as they walked along a horizontal ladder. rats were videotaped crossing a horizontal ladder ( m) with irregularly spaced rungs ( to cm spacing changed weekly) weekly, times per session. any slight paw slips, deep paw slips and complete misses were scored as errors. the mean number of errors per step was calculated for each limb for each week (foot faults are routinely normalized "per step" after stroke although analysis of foot fault data with or without normalization led to the same conclusions being drawn). the cylinder test was used to assess asymmetries in forelimb use for postural support during rearing within a transparent cm diameter and cm high cylinder . an angled mirror was placed behind the cylinder to allow movements to be recorded when the animal turned away from the camera. during exploration, rats rear against the vertical surface of the cylinder. the first forelimb to touch the wall was scored as an independent placement for that forelimb. subsequent placement of the other forelimb against the wall to maintain balance was scored as "both." if both forelimbs were simultaneously placed against the wall during rearing this was scored as "both." a lateral movement along the wall using both forelimbs alternately was also scored as "both." scores were obtained from a total number of full rears to control for differences in rearing between animals. once scores had been acquired, forelimb asymmetry was calculated using the formula: × (ipsilateral forelimb use + / bilateral forelimb use)/total forelimb use observations (hsu and jones ). figure a ; mjs technology, uk). both the affected and less affected forelimb strength were each measured (simultaneously) at baseline, week , week and week following stroke. a pair of force transducers were used in parallel to measure the peak force achieved by a rat's forelimbs as its bilateral grip was broken by the experimenter gently pulling the rat by the base of the tail horizontally away from the transducer. the average of three strength readings was noted down per session and an average taken for both arms. the difference in grip strength was taken by subtracting the affected forepaw grip strength from the less affected grip strength. the presence or absence of cold allodynia was assessed using standard methods . rats were placed in a transparent cylinder ( cm diameter, cm height) atop a mesh wire floor. a drop ( µl) of acetone was placed against the centre of the forepaw. in the following s after acetone application the rat's response was monitored. if the rat did not withdraw, flick or lick its paw within this s period then no response was recorded for that trial ( , see below). however, if within this s period the animal responded to the cooling effect of the acetone, then the animal's response was assessed for an additional s, a total of s from initial application. the reasons for taking a longer period of time to assess the evoked behaviour were to measure only pain-related behaviour evoked by cooling and not startle responses that can occur following the initial application of acetone . moreover, the behaviour evoked by acetone is often an interrupted series of behaviours, thus it is important to give enough time to see all pain-related behaviours. responses to acetone were graded to the following -point scale: , no response; , quick withdrawal, flick or stamp of the paw; , prolonged withdrawal or repeated flicking of the paw; , repeated flicking of the paw with licking directed at the ventral side of the paw. acetone was applied alternately three times to each paw and the responses scored categorically. cumulative scores were then generated by adding the scores for each rat together, the minimum score being (no response to any of the six trials) and the maximum possible score being per forepaw. to visualize uninjured cst axons, six weeks after stroke, % biotinylated dextran amine (bda; , mw, invitrogen) in pbs (ph . ) was microinjected unilaterally into the uninjured sensorimotor cortex. animals were placed in a stereotaxic frame and six burr holes were made into the skull at the following coordinates (defined as anterioposterior (ap), mediolateral (ml): ) ap: + mm, ml: . mm; ) ap: + . mm, ml: . mm; ) ap: + . mm, ml: . mm; ) ap: + . mm, ml: . mm; ) ap: + . mm, ml: . mm; ) ap: - . mm, ml: . mm, relative to bregma. at each site, . μl injections of bda ( % in pbs) were delivered using a glass micropipette attached to a hamilton syringe inserted mm from the skull surface and delivered at a rate of . μl/min. animals were subsequently left for weeks before being perfused. tract tracing was not performed in rats that were to undergo functional mri or neurophysiology. as described below, we recorded from the ulnar nerve on the affected side and stimulated the ipsilateral median nerve or, in the pyramids, the corticospinal tract corresponding to the affected or less-affected hemisphere. at the end of the study, rats ( rats per group) were anaesthetised with an intraperitoneal injection of . g/kg urethane (sigma-aldrich). the rat was kept at °c with a homeothermic blanket system and rectal thermometer probe. tracheotomy was performed and a tracheal cannula inserted. the pyramids were then exposed ventrally by blunt dissection and removal of a small area of bone. the brachial plexus of the affected forelimb was exposed from a ventral approach by dissecting the pectoralis major. the ulnar and median nerves were dissected free from surrounding connective tissue and cut distally (to prevent twitches of target muscles). skin flaps from the incision formed a pool, which was filled with paraffin oil. the median and ulnar nerves supply flexor muscles in the forearm, wrist and hand. stimulation of afferents in the median nerve can generate responses in the ulnar nerve motor neurons. the proximal segment of each nerve was mounted on a pair of silver wire hook electrodes (with > cm separation). electrical stimuli of increasing amplitude from µa to µa, in μa steps, (single µs square wave pulse at . hz) were delivered from a constant current stimulator (nl a neurolog, digitimer) to the proximal segment of the cut median nerve. ulnar nerve responses to each stimulus were recorded from the pair of silver wire hook electrodes connected to a differential pre-amplifier and amplifier (digitimer) coupled via a powerlab (ad instruments) interface to a personal computer running labchart and scope software (ad instruments). an average of sweeps at µa was calculated online for each nerve and used to find the difference in amplitudes of monosynaptic reflexes evoked by median nerve stimulation. this was achieved using software to calculate the absolute integral of any response between . ms and ms, regardless of whether a response was observed qualitatively. cst stimulation experiment with ulnar recordings: ulnar nerve recordings were obtained during stimulation of each pyramid in turn. the concentric bipolar stimulation electrode (fhc cbbpc ) was located mm lateral to the midline and gently lowered through the pyramid up to a maximum depth of . mm while stimulating at μa ( pulses, pulse width µs; frequency hz). at the electrode location providing maximal ulnar nerve response, stimuli of increasing intensity were applied in the range of µa to µa, in µa increments. five sweeps were captured at each stimulus intensity. the number of spikes % greater than the noise, and falling between and ms, was calculated for each sweep. the average number of spikes for sweeps at each amplitude was calculated and the difference in the number of spikes elicited by stimulation of the pyramids from the lesioned or contralesional hemisphere. furthermore, the signal was rectified and the area under the curve was measured between and ms for each sweep and averaged for the sweeps at each intensity. each parameter was analysed using twoway repeated measures anova. graphs show mean and standard error of the mean for the area under the curve for stimuli given at µa. eight weeks after stroke surgery and two weeks after injection of bda, rats were terminally anesthetized with sodium pentobarbital ( mg/kg; i.p.) and perfused transcardially with pbs for minutes, followed by ml of % paraformaldehyde in pbs for minutes. the brain, c -c spinal cord, c and c drgs and both arms were carefully dissected and stored in % paraformaldehyde in pbs for hours and then transferred to % sucrose in pbs and stored at - °c. spinal cord segments c and c was embedded in oct and μm transverse slices were cut using a freezing stage microtome (kryomat; leitz, germany). ten series of sections were collected and stored in tbs/ . % azide ( mm tris, mm nacl, . mm nan , ph . ) at °c. cst axons were counted that crossed the midline, at two more lateral planes and at an oblique plane (figure a ) at c and c . for each rat, we estimated the number of cst axons per cord segment by calculating the average number of cst axons per section and then multiplying by a scaling factor (number of sections cut per segment). the total length of serotonergic processes was measured using a standard method designed specifically to measure serotonergic sprouting after neurotrophin treatment (see refs in ) and which is well suited for quantification of dense terminal arbors (e.g., in the dorsal horn of the spinal cord). processes were identified using the "adjust threshold" function in imagej and fiber lengths were measured in three areas: the dorsal horn, intermediate grey and ventral horn (fig. a ) in sections per rat. we calculated the ratio of the sides ipsilateral and contralateral to nt treatment for the three areas separately. immunofluorescence was visualized under a zeiss imager.z microscope or a confocal zeiss lsm laser scanning microscope. photographs were taken using the axio cam and axiovision le rel. . or the lsm image browser software for image analysis. nt protein was radiolabelled with µci ( . mbq) n-succinimidyl [ , - h]propionate ( h-nsp) and separated from unbound h-nsp using an Äktaprime purification system using a modification of a previous method the same treatment was repeated for mice h after stroke, with an incubation period of mins (n = ). in this set of experiments, . mbq of c sucrose (vascular marker) was injected towards the end of the incubation and the brain tissue samples also taken for capillary depletion analysis to distinguish nt or albumin in vascular endothelial cells from that in brain parenchyma. in brief, brain tissue was homogenized in physiological buffer ( µl per mg of tissue) and % dextran ( µl per mg of tissue) as described previously . the homogenate was subjected to density gradient centrifugation ( , × g for min at °c) to give an endothelial cell-enriched pellet and a supernatant containing the brain parenchyma and interstitial fluid (isf). the homogenate, pellet and supernatant samples were solubilized and counted as described above. distribution volume, vd, was calculated for all samples, including the endothelial pellet and brain parenchyma (isf). the values were corrected for c sucrose. data was analysed for capillary fraction, parenchyma and whole brain using one way anova and post hoc (bonferroni) t-tests. ug of protein was subjected to denaturing or non-denaturing sds page and visualised using colloidal coomassie brilliant blue staining. each band was excised separately, digested enzymatically (with trypsin) and subjected to lc/ms/ms analysis (dr. steve lynham, proteomics facility, kcl). in-gel reduction, alkylation and digestion with trypsin were performed prior to subsequent analysis by mass spectrometry. cysteine residues were reduced with dithiothreitol and derivatised by treatment with iodoacetamide to form stable carbamidomethyl derivatives. trypsin digestion was carried out overnight at room temperature after initial incubation at o c for hours. lc/ms/ms: peptides were extracted from the gel pieces by a series of acetonitrile and aqueous washes. the extract was pooled with the initial supernatant and lyophilised. each sample was then resuspended in l of mm ammonium bicarbonate and analysed by lc/ms/ms. chromatographic separations were performed using an ultimate lc system (dionex, uk). peptides were resolved by reversed phase chromatography on a m c pepmap column using a three step linear gradient of acetonitrile in . % formic acid. the gradient was delivered to elute the peptides at a flow rate of nl/min over min. the eluate was ionised by electrospray ionisation using a z-spray source fitted to a qtof-micro (waters corp.) operating under masslynx v . . the instrument was run in automated data-dependent switching mode, selecting precursor ions based on their intensity for sequencing by collision-induced fragmentation. the ms/ms analyses were conducted using collision energy profiles that were chosen based on the mass-to-charge ratio (m/z) and the charge state of the peptide. database searching: the mass spectral data was processed into peak lists using proteinlynx global server v . . with the following parameters: (ms survey -no background subtraction, sg smoothing iterations channels, peaks centroided (top %) no de-isotoping; ms/ms -no background subtraction, sg smoothing iterations channels, peak centroiding (top %) no de-isotoping). the peak list was searched against the uniprot database using mascot software v . using the following parameter specifications (precursor ion mass tolerance . da; fragment ion mass tolerance . da; tryptic digest with up to three missed cleavages; variable modifications: acetyl (protein n-term), carbamidomethylation (c), gln->pyro-glu (n-term q) and oxidation (m). lc/ms/ms analysis and interrogation of the data against the uniprot database identified nt from the excised and digested d gel bands. the results of the analysis and database searches are given in supplementary figure . database generated files were uploaded into scaffold (v . ) software (www.proteomesoftware.com) to create the .sfd file (pr lm d gel ). all samples were aligned in this software for easier interpretation and used to validate ms/ms based peptide assignments and protein identifications. peptide assignments were accepted if they contained at least two unique peptide assignments and were established at % identification probability by the protein prophet algorithm . the result table includes probability scores (mowse) for each peptide identified from the protein sequence. the threshold identity score corresponds to a % chance of incorrect assignment. peptides identified below these probabilities were accepted following manual inspection of the raw data to ensure that fragment ions correctly match the assigned sequence. the sequence coverage for each identified protein is represented in supplementary figure in yellow highlights. statistical analyses were conducted using spss (version . ). graphs show means ± sems (except where otherwise stated) and 'n' denotes number of rats. asterisks (*,**,***) indicate p≤ . , p≤ . and p≤ . , respectively. threshold for significance was . . histology and molecular biology data were assessed using kruskal-wallis and mann-whitney tests (due to small sample sizes). serotonergic fibre lengths was analysed by region using one way anova and post hoc (bonferroni) t-tests. pkcγ data was analysed using kruskal wallis and mann whitney tests. behavioural and mri data were analysed using linear models and restricted maximum likelihood estimation to accommodate data from rats with occasional missing values . akaike's information criterion showed that the model with best fit for the horizontal ladder data had a compound symmetric covariance matrix, whereas for the sensory test and mri data an unstructured covariance matrix was used. the model with best fit for the vertical cylinder had a compound symmetric covariance matrix, according to the - restricted log likelihood information criterion. baseline scores were used as covariates. degrees of freedom are reported to nearest integer. normality was assessed using histograms. t-tests were two-tailed unless otherwise specified. sample size calculations were presented previously . magnetic resonance imaging (mri) confirmed that infarcts included the forelimb and hindlimb areas in sensorimotor cortex (fig c) . there was no difference in the mean infarct volume between stroke groups at h, one or eight weeks after stroke (fig. d) . loss of cst axons was assessed at weeks in the upper cervical spinal cord using protein kinase c gamma (pkcγ) immunofluorescence , (fig. e) . stroke caused a % loss of cst axons in the dorsal columns relative to shams (fig. f) with no difference between vehicle and nt treated rats. together, the mri and pkcγ histology data indicate that there were no confounding pre-treatment differences in mean infarct volumes and that nt did not act as a neuroprotective agent, as expected, based on our previous results and given that treatment was initiated after the majority of cell death will have occurred. we used the "adhesive patch" test to assess forepaw somatosensory function. a sensory score was obtained by attaching pairs of adhesive patches to each rat's wrist on the dorsal side (fig. a) : a high score (e.g. ) denotes that a rat preferentially removed the smaller stimulus from their less-affected wrist (i.e., did not first remove the larger stimulus on their affected wrist). the two stroke groups exhibited a similar lack of responsiveness to stimuli on their affected wrists after one week (fig. b) . delayed treatment with nt caused recovery compared to vehicle: whereas vehicle-treated stroke rats showed a deficit relative to sham rats which persisted for eight weeks. importantly, there were no confounding differences in the time taken to contact or to remove a patch from either their less-affected or affected paw: after stroke, nt -treated rats and vehicletreated rats took longer to contact an adhesive patch relative to shams, but there was no difference between nt and vehicle treated rats (supplementary fig. a) . moreover, neither stroke nor nt treatment caused any deficit in the additional time taken after contact to remove the patch (supplementary figure b) . thus, delayed treatment of disabled forelimb muscles with nt improved responsiveness to tactile stimuli after ischemic stroke. walking was assessed using a horizontal ladder with irregularly spaced rungs (fig. c) . accurate paw placement during crossing requires proprioceptive feedback from muscle spindles . after one week, the two stroke groups made a similar number of errors with their affected forelimb when crossing a horizontal ladder (fig. d) . delayed nt treatment caused a progressive recovery after stroke whereas vehicle treated animals remained persistently impaired until the end of the study. this is consistent with previous work from our lab , . stroke also caused a modest unilateral hindlimb impairment on the ladder; infusion of nt into the forelimb triceps brachii did not improve this (supplementary figure ) . neurotrophin- also restored the use of the affected forelimb for lateral support while rats reared in a vertical cylinder (fig. e) . after stroke and vehicle treatment, rats used their affected forelimb less often than shams. nt -treated rats showed more frequent use of the affected forelimb relative to vehicle-treated rats (fig. f) . we used force transducers to measure grip strength of each forelimb (supplementary fig. ) . stroke caused transient weakness in both groups but infusion of nt into triceps brachii did not modify grip strength. we also found no evidence for pain (cold allodynia) on the affected or treated forelimbs, assessed by application of ice-cold acetone to the centre of the forepaw. cold allodynia was induced neither by stroke nor nt treatment (supplementary fig. ). in summary, infusion of nt protein into the triceps brachii induced recovery on both sensory and motor tasks that require control of muscles by pathways including corticospinal pathways, serotonergic raphespinal pathways and proprioceptive circuits. accordingly, we hypothesised that nt would induce neuroplasticity in multiple pathways. we examined anatomical neuroplasticity in the c cervical spinal cord because we knew from experiments using adult and elderly rats that the less-affected corticospinal tract sprouts at this level (as well as other levels) after injection of aav-nt into muscles including triceps brachii . indeed, anterograde tracing from the less-affected hemisphere (fig. b) revealed that infusion of nt protein increased sprouting of the cst in the c spinal cord (fig. a,b) across the midline and into the affected side at two more lateral planes, and also from the ventral cst. we assessed neural output in the ulnar nerve on the affected side, whose motor neurons are also found in c (range: c to c ) that supply muscles in the forearm including the hand , . to do this, we recorded responses during electrical stimulation of either the spared less-affected corticospinal tract (fig. c) or the partially-ablated corticospinal tract (fig. f) in the medullary pyramids. nt treatment led to enhanced responses in the ulnar nerve during stimulation of the less-affected (fig. d, e) and more-affected (fig. g, h) pathways. this result is consistent with the sprouting of traced cst axons (fig. a,b) and indicates that cst axons from both the stroke hemisphere and the contralesional hemisphere formed new synapses and/or strengthened preexisting connections in the cord on the treated side, most likely on pre-motor interneurons that lie between cst axons and motoneurons , . however, we did not find any evidence that nt strengthened the short-latency reflex from afferents in the median nerve to motor neurons in the ulnar nerve (fig. i-l) . we also found that nt treatment caused serotonergic axons to sprout in the ventral c spinal cord (fig. a-d) . anatomical and functional plasticity of corticospinal and raphespinal pathways is consistent with their expression of receptors for nt , , - . we conclude that nt caused neuroplasticity in multiple descending locomotor pathways including the raphespinal and the spared corticospinal tracts. these data are consistent with previous findings from our lab , that peripherally-administered nt can, directly or indirectly, enhance supraspinal plasticity after stroke. accordingly, next, we assessed the biodistribution of nt after peripheral administration. we measured the amount of total (rat and human) nt in the triceps brachii and c spinal cord. elisa was performed using a subset of five rats per group withdrawn at random from the study at the four-week time point: this revealed an increase in total nt protein levels in the triceps brachii on the treated side (fig. a ) and, surprisingly, on the untreated side (perhaps due to nt in endothelial cells; see below). we were not able to detect any increase in total nt in the c spinal cords (supplementary fig. ). however, elisa cannot distinguish exogenous human nt from endogenous rat nt because the amino acid sequences for mature human and rat nt are identical , . because elisa did not allow us to detect any small increases in exogenous human nt against the background of endogenous rat nt in the cns, we next used a more sensitive method for measuring trafficking of nt across the blood-cns barrier. recombinant nt protein was radiolabelled and purified. [ h]nt was injected intravenously into adult mice. radiolabelled albumin was used as a control because it does not enter the cns efficiently from the bloodstream. after , , , , , or minutes, brain, spinal cord and serum were taken for scintillation counting. nt progressively accumulated in the intact brain (fig. b) and cervical spinal cord (fig. c) . in plasma, the half-life of nt was short (fig. d) . our data is consistent with that from others who have shown that radiolabelled nt rapidly crosses the barriers between the blood and an intact cns [ ] [ ] [ ] and that a small amount of intact nt accumulates in the brain and cervical spinal cord (although the majority of nt is cleared rapidly from the bloodstream) [ ] [ ] [ ] . for example, after injection of nt into the brachial vein (which provides drainage from the triceps brachii), nt accumulates in the cortex, striatum, brainstem, cerebellum, sciatic nerve (and other regions of the nervous system involved with locomotion) . ischemia. minutes later, tissues were taken for scintillation counting. in contrast to [ h]albumin, [ h]nt accumulated in the brain (fig e) . to confirm entry of [ h]nt into brain parenchyma beyond endothelial cells, capillaries were depleted by gradient centrifugation to yield a supernatant containing brain parenchyma and an endothelial cell-enriched pellet . [ h]nt entered parenchyma (depleted of endothelial cells) at a level above that seen for [ h]albumin (fig. f ). transport of nt into the cns is apparently a receptor-mediated process as shown by ) the expression of nt receptors in rodent and human cns capillaries , and ) the ability of non-radiolabelled nt to compete for uptake of radiolabelled nt into the cns , , . in addition, we and others have shown that nt enters the pns after peripheral administration: after intramuscular overexpression of aav encoding nt , nt levels are elevated in the blood stream and nt accumulates in the ipsilateral drg , . we also found some evidence that nt is retrogradely transported from muscle to ipsilateral motor neurons . this is consistent with data showing that ) the blood-nerve barrier in drgs is permeable to proteins like nt , ) that after intravenous injection, radiolabelled nt accumulates in the sciatic nerve and ) that nt is retrogradely transported from muscle to the spinal cord or drg in nerves , , , . we conclude that neuroplasticity occurred in multiple locomotor pathways because peripherally-administered nt bound to receptors in the pns and cns. to explore the mechanism whereby nt improved responsiveness to stimuli attached to the affected wrist (fig. b) , we performed functional brain imaging (bold-fmri) during low threshold (non-noxious) intensity electrical stimulation of the affected wrist ( supplementary fig. ). as expected, prior to stroke, stimulation of the wrist resulted in a higher probability of activation of the opposite somatosensory cortex (supplementary fig. a ). fmri performed one week after stroke confirmed that somatosensory cortex was not active when the affected paw was stimulated in either vehicle or nt treated rats (p> . , supplementary fig. b ). this supports our claim above that there were no early differences between groups that could be explained by neuroprotection. fmri performed eight weeks after stroke revealed a trend towards perilesional re-activation of somatosensory cortex in both vehicle and nt treated groups (p< . , supplementary fig. c ). this is in line with human brain imaging studies showing that spontaneous sensory recovery is increased after stroke when more-normal activity patterns are observed on the affected side of the brain . however, these probabilities of re-activation were not big enough to survive correction for testing of multiple voxels (p-values> . ) although clearly they are in a location that might mediate recovery of somatosensation. a longitudinal analysis showed that at weeks (relative to pre-stroke baseline), there was some evidence that rats treated with neurotrophin- showed increased probability of activation of perilesional cortex (supplementary fig. d, p< . ) and showed decreased probability of activation of somatosensory cortex on the less-affected hemisphere (p< . ) relative to vehicletreated stroke rats. however, these apparent differences did not survive correction for testing of multiple voxels (p< . ). we conclude that both groups showed partial, spontaneous restoration of more-normal patterns of somatosensory cortex activation , but, conservatively, that nt did not further increase probability of activation of any supraspinal areas. these conclusions are consistent with previous fmri data from our laboratory ; we propose that the additional recovery of somatosensory function after nt treatment (fig. b) is due to changes in the spinal cord rather than in supraspinal areas. the batch of neurotrophin- protein that we used was produced more than a decade ago by genentech. we sought to determine whether any degradation had occurred and to confirm its amino acid sequence so that identical preparations of neurotrophin- could be made for future experiments. supplementary figure depicts results from a non-denaturing gel showing a higher molecular weight band ( kda) and a lower molecular weight band ( kda) consistent, respectively, with dimeric mature nt and monomeric mature nt . there was no evidence of degradation or aggregation. each band was excised separately, digested enzymatically (with trypsin) and subjected to lc/ms/ms analysis. proteomic analysis was consistent with both bands being mature nt with no evidence of residual prepro sequences (supplementary figure ) . we conclude that the higher molecular weight band is not prepront (~ kda) but rather corresponds to dimeric mature nt . this facilitated our ongoing experiments to evaluate nt as a therapy for stroke because most commercial preparations of nt consist of mature nt rather than prepront . treatment of disabled arm muscles with nt protein, initiated hours after stroke, caused changes in multiple locomotor circuits, and promoted a progressive recovery of sensory and motor function in rats. the fact that nt can reverse disability when treatment is initiated hours after stroke is exciting because the vast majority of stroke victims are diagnosed within this time frame . in contrast, the gold-standard drug for ischemic stroke, tpa, needs to be given within a few hours and is only administered to a minority. thus, nt could potentially be used to treat an enormous number of victims. nt has good clinical potential. firstly, phase ii clinical trials show that doses up to µg/kg/day are well tolerated and safe in healthy humans and in humans with other conditions , - . we used a threefold lower dose ( µg/kg/day) in this study: in future experiments we will optimize the dose and duration of treatment because it is possible that a higher dose of nt would promote additional recovery after stroke. secondly, there is good conservation from rodents to primates including humans in the expression of receptors for nt in the locomotor system , , [ ] [ ] [ ] . thirdly, in none of our rodent experiments has nt treatment caused any detectable pain, spasticity or muscle weakness (in line with the human trials); rather, after bilateral corticospinal tract injury in rats, intramuscular delivery of aav-nt reduced spasticity, slightly improved grip strength and showed a trend towards reducing mechanical hyperalgesia . in this study and in a previous study we used functional mri combined with electrical stimulation of the wrist in an effort to discover what neuroplasticity underlies recovery of somatosensory responsiveness to adhesive patches attached to the wrist. we confirmed work by others that recovery correlated well with more-normal patterns of increased bold signal surrounding the infarct (potentially in spared somatosensory cortex) , , , but we did not find strong evidence that nt further increased peri-lesional (or other) activation (either in this study or in our previous study ). instead, we now propose that nt increased somatosensory recovery by inducing neuroplasticity in spinal circuits involving cutaneous afferents. this is plausible because cutaneous afferents which mediate tactile sensitivity express trkc receptors . moreover, others have shown that dl spinal interneurons can gate cutaneous transmission . we have previously shown that nt normalises post-activation depression of output from spinal circuits evoked by stimulation of low threshold afferents from the treated wrist (which might include cutaneous afferents as well as proprioceptive afferents) although in those experiments we measured motor output rather than sensory transmission. in the future one might examine whether nt modulates gating of somatosensory inputs from the wrist to spinal interneurons . however, in the present work, the deficits in somatosensory responses were modest and might be difficult to dissect. with regard to corticospinal neuroplasticity, we have shown twice previously (in adult and elderly rats) that the less-affected corticospinal tract sprouts across the cervical midline after injection of aav-nt into affected forelimb muscles . others have shown that intrathecal infusion of nt induces sprouting of the corticospinal tracts and that injection of vectors encoding nt into muscles or nerve can induce corticospinal tract sprouting. here, our anatomical tracing confirmed that the less-affected corticospinal tract sprouted after infusion of nt protein into triceps and in future we will trace both tracts. this is because, in the present study, neurophysiology revealed that both corticospinal tracts underwent plasticity after unilateral infusion of nt protein. we propose that spared cst axons sprouted after nt entered the cns from the systemic circulation. this is consistent with data from us and others showing that radiolabelled nt entered the brain and spinal cord after intravenous injection [ ] [ ] [ ] . moreover, it has been shown that endogenous muscle spindle-derived cues induce sprouting of descending pathways after spinal cord injury in adult mice ; given that muscle spindles make nt endogenously , it is plausible that infusion of supplementary nt to muscle might enhance corticospinal sprouting after stroke. it is also notable that infusion of nt into a proximal forelimb extensor improved the accuracy of use of the affected forelimb when walking on a horizontal ladder but did not improve the accuracy of use of the affected hindlimb; this implies that circulating nt is not sufficient to improve hindlimb movements. moreover, we did not find any evidence that nt strengthened the short-latency reflex between afferents in the median nerve and motor neurons in the ulnar nerve; this may be because we infused nt into the triceps brachii whose afferents do not run in the median or ulnar nerve. this is consistent with previous work of ours showing that a reflex may be strengthened when its afferent comes from a muscle expressing higher levels of nt but not when its afferent comes from a muscle lacking transgenic expression of nt . finally, infusion of nt protein into triceps brachii did not improve forelimb grip strength: however, the grip strength task probably depends more on strength in hand and digit flexor muscles (into which nt was not infused) than on triceps brachii (elbow extensors). indeed, in previous work, injection of aav-nt into proximal and distal flexor muscles did modestly improve grip strength . taken together, these results indicate that it may be important to target nt to multiple muscles. however, it is not straightforward to reconcile all our findings with a single mechanistic explanation. it is possible that, additionally, nt was trafficked from triceps brachii in axons to motor neurons and/or by drg neurons where it induced expression of a molecule that was secreted and induced cst sprouting (e.g., bdnf or igf , ). nt is certainly trafficked to ipsilateral motor neurons and drg after intramuscular delivery , , , , and in this study we also showed, unexpectedly, a small increase in contralateral triceps (perhaps from nt in endothelial cells). diffusion of nt within neuropil is inefficient but spinal motor neuron dendritic arbors can be very large; some even extend across the midline and these might provide a widespread source of cues for supraspinal axonal plasticity (e.g., across the midline). to seek drg-secreted factors, we have performed rnaseq of cervical drg after injection of aav-nt into forelimb flexors , . in the future we will also seek motor neuron-derived cues. finally, it is interesting that the recovery continues even after infusion of nt is discontinued at four weeks. this is encouraging, from a translational perspective. we propose that the four-week long nt treatment induces changes in target neurons that persist (e.g., due to sustained modifications in gene expression). indeed, longer treatment with nt induces different intracellular signalling events in sensory axons than does brief treatment, thereby enhancing terminal branching . in the future, we will seek factors that are persistently increased in target neurons after nt treatment is discontinued. additionally, it may be that nt induces sprouting of cst axons that (after cessation of treatment) is followed by selection of synapses (e.g., strengthening or pruning) by a mechanism that is independent of nt . for example, it is known that corticomotoneuronal axon synapses are pruned by repulsive plexina -sema d interactions . to begin to dissect the mechanisms whereby nt promotes neuroplasticity and recovery after peripheral delivery, we are setting up a mouse model of stroke. in summary, treatment of disabled arm muscles with nt (initiated in a clinically-feasible timeframe) induces multilevel spinal and supraspinal neuroplasticity, improves walking and reverses a tactile sensory impairment. and hours later infusion of nt or vehicle into the disabled triceps brachii was initiated for one month. six weeks after stroke, anterograde tracer was injected into the contralesional hemisphere (blue). rats underwent weeks of behavioural testing. structural mri was conducted on all rats at hours, week and weeks after stroke and fmri was conducted in a subset of rats at baseline, week and week . electrophysiology was performed in the subset of rats which did not receive bda tracing. all surgeries, treatments and behavioural testing were performed using a randomized block design and the study was completed blinded to treatment allocation. c) t mri scans hours after stroke, immediately prior to treatment, showing infarct in coronal sections rostral (mm) to bregma. d) there were no differences between stroke groups in mean lesion volume at hours (mann whitney p values = . ). e) photomicrographs showing loss of figure : delayed nt treatment improved responsiveness to somatosensory stimulation, improved walking and partially restored use of the affected forelimb for lateral support during rearing. a-c) somatosensory deficits were assessed using pairs of adhesive patches attached to the rat's wrists. b) treatment with nt caused improvement compared to vehicle (linear model; f , = . , p< . ; post hoc p= . ): whereas vehicle-treated stroke rats showed a deficit relative to sham rats which persisted for eight weeks (linear model; f , = . , corticospinal axons were anterogradely traced from the less-affected cortex and were counted at the midline (m), at two more lateral planes (d and d ) and crossing into grey matter from the ipsilateral, ventral tract (ipsi). b) nt treatment caused an increase in the number of axons crossing at the midline (f , = . , p= . ; post hoc p value= . ), at two lateral planes denoted as d (f , = . , p< . , post hoc p value< . ) and d (f , = . ,p< . , post hoc p value< . ) and from the ventral cst on the treated side (f , = . , p= . , post hoc p value= . ). although stroke by itself caused sprouting at the midline at c (planned comparison p= . ), nt did not promote additional sprouting at c . n= /group were used for tract tracing. c-e) the cst from the less-affected hemisphere or f-h) lesioned hemisphere was stimulated in the medullary pyramids (before the decussation) and the motor output was recorded from the ulnar nerve on the treated side. d, g) the majority of spikes were detected between ms and ms, latencies consistent with polysynaptic transmission, in both vehicle-treated rats (grey) and nt treated rats (blue) when the less-affected or affected cst was stimulated. e, h) stimulus intensity was increased incrementally from µa to µa and the area under the curve were measured (between and ms) after stimulation of the affected or less-affected hemisphere. nt treatment caused increased output in the ulnar nerve during stimulation of either the affected cst (two-way rm anova intensity* group interaction f , = . , p= . , n= vehicle, nt ) or less affected cst (f , = . , p= . , n= vehicle, n= nt ). i, j) the heteronymous reflex from median afferents to ulnar motor neurons was recorded in the axilla. k) the monosynaptic component was measured. l) nt did not increase the strength of the monosynaptic component. the rats held bilaterally on to the pair of force transducers (top left) and the rat was pulled away horizontally and perpendicularly (towards the right) until the bilateral grip was broken. the force transducers provide a measure of strength (grams) for each upper limb. an average of three trials was taken per rat per week. grip strength (grams) are presented as group means ± sems. b) grip strength of the affected limb was subtracted from the unaffected limb strength, as an internal control (e.g., to control for differences in motivation, etc.). c) grip strength for the affected limb. d) grip strength for the less-affected limb. stroke caused a weak trend towards a transient decrease in strength on the limb affected by stroke (relative to shams; time f , = . , p= . ; p-values p= . and . , respectively) but multiple pairwise comparisons did not show significant differences at any timepoint (all p> . ). there was no difference between nt and vehicle treated rats overall (group f , = . restoring brain function after stroke -bridging the gap between animals and humans a comprehensive review of prehospital and in-hospital delay times in acute stroke care trkc-like immunoreactivity in the primate descending serotonergic system local and remote growth factor effects after primate spinal cord injury influences of neurotrophins on mammalian motoneurons in vivo expression and coexpression of trk receptors in subpopulations of adult primary sensory neurons projecting to identified peripheral targets the neurotrophins bdnf, nt- , and ngf display distinct patterns of retrograde axonal transport in peripheral and central neurons expression of neurotrophins in skeletal muscle: quantitative comparison and significance for motoneuron survival and maintenance of function nt- , but not bdnf, prevents atrophy and death of axotomized spinal cord projection neurons muscle injection of aav-nt promotes anatomical reorganization of cst axons and improves behavioral outcome following sci neurotrophin- expressed in situ induces axonal plasticity in the adult injured spinal cord adeno-associated viral vector-mediated neurotrophin gene transfer in the injured adult rat spinal cord improves hind-limb function differential effects of brain-derived neurotrophic factor and neurotrophin- on hindlimb function in paraplegic rats intramuscular aav delivery of nt- alters synaptic transmission to motoneurons in adult rats either brain-derived neurotrophic factor or neurotrophin- only neurotrophin-producing grafts promote locomotor recovery in untrained spinalized cats neurotrophin- enhances sprouting of corticospinal tract during development and after adult spinal cord lesions intramuscular neurotrophin- normalizes low threshold spinal reflexes, reduces spasms and improves mobility after bilateral corticospinal tract injury in rats spinal electromagnetic stimulation combined with transgene delivery of neurotrophin nt- and exercise: novel combination therapy for spinal contusion injury delayed intramuscular human neurotrophin- improves recovery in adult and elderly rats after stroke retrograde viral delivery of igf- prolongs survival in a mouse als model immune activation is required for nt- -induced axonal plasticity in chronic spinal cord injury expression of neurotrophin- promotes axonal plasticity in the acute but not chronic injured spinal cord activity-dependent increase in neurotrophic factors is associated with an enhanced modulation of spinal reflexes after spinal cord injury muscle spindle feedback directs locomotor recovery and circuit reorganization after spinal cord injury selective expression of neurotrophin- messenger rna in muscle spindles of the rat permeability of the blood-brain barrier to neurotrophins permeability at the blood-brain and blood-nerve barriers of the neurotrophic factors: ngf, cntf, nt- , bdnf penetration of neurotrophins and cytokines across the bloodbrain/blood-spinal cord barrier nt- promotes nerve regeneration and sensory improvement in cmt a mouse models and in patients neurotrophin- improves functional constipation tolerability of recombinant-methionyl human neurotrophin- (r-methunt ) in healthy subjects recombinant human neurotrophic factors accelerate colonic transit and relieve constipation in humans nerve growth factor-and neurotrophin- -induced changes in nociceptive threshold and the release of substance p from the rat isolated spinal cord unbiased classification of sensory neuron types by large-scale singlecell rna sequencing sustained sensorimotor impairments after endothelin- induced focal cerebral ischemia (stroke) in aged rats rodent models of focal stroke: size, mechanism, and purpose delayed treatment with chondroitinase abc promotes sensorimotor recovery and plasticity after stroke in aged rats on the use of alpha-chloralose for repeated bold fmri measurements in rats robust automatic rodent brain extraction using -d pulse-coupled neural networks (pcnn) contrast weights in flexible factorial design with multiple groups of subjects spatial characterization of the motor neuron columns supplying the rat forelimb ethosuximide reverses paclitaxel-and vincristine-induced painful peripheral neuropathy chondroitinase abc promotes plasticity of spinal reflexes following peripheral nerve injury the labelling of proteins to high specific radioactivities by conjugation to a i-containing acylating agent heat shock protein-based therapy as a potential candidate for treating the sphingolipidoses graphical evaluation of blood-tobrain transfer constants from multiple-time uptake data the distribution of the anti-hiv drug, ' '-dideoxycytidine (ddc), across the blood-brain and blood-cerebrospinal fluid barriers and the influence of organic anion transport inhibitors a statistical model for identifying proteins by tandem mass spectrometry analysis of longitudinal data from animals with missing values using spss chondroitinase abc promotes functional recovery after spinal cord injury cervical motoneuron topography reflects the proximodistal organization of muscles and movements of the rat forelimb: a retrograde carbocyanine dye analysis lack of monosynaptic corticomotoneuronal epsps in rats: disynaptic epsps mediated via reticulospinal neurons and polysynaptic epsps via segmental interneurons electrophysiological actions of the rubrospinal tract in the anaesthetised rat trka, trkb, and trkc messenger rna expression by bulbospinal cells of the rat motoneuron-derived neurotrophin- is a survival factor for pax -expressing spinal interneurons bdnf and nt- , but not ngf, prevent axotomy-induced death of rat corticospinal neurons in vivo human and rat brain-derived neurotrophic factor and neurotrophin- : gene structures, distributions, and chromosomal localizations neurotrophin- : a neurotrophic factor related to ngf and bdnf a revised role for p-glycoprotein in the brain distribution of dexamethasone, cortisol, and corticosterone in wild-type and abcb a/bdeficient mice the cell biology of the blood-brain barrier nerve growth factor-induced protection of brain capillary endothelial cells exposed to oxygen-glucose deprivation involves attenuation of erk phosphorylation expression of cannabinoid receptors and neurotrophins in human gliomas vascularization of the dorsal root ganglia and peripheral nerve of the mouse: implications for chemical-induced peripheral sensory neuropathies neurotrophin- administration attenuates deficits of pyridoxineinduced large-fiber sensory neuropathy neurotrophin- is a target-derived neurotrophic factor for penile erection-inducing neurons reemergence of activation with poststroke somatosensory recovery: a serial fmri case study correlation between brain reorganization, ischemic damage, and neurologic status after transient focal cerebral ischemia in rats: a functional magnetic resonance imaging study early prediction of functional recovery after experimental stroke: functional magnetic resonance imaging, electrophysiology, and behavioral testing in rats expression of mrnas for neurotrophic factors (ngf, bdnf, nt- , and gdnf) and their receptors (p ngfr, trka, trkb, and trkc) in the adult human peripheral nervous system and nonneural tissues trka and trkc expression is increased in human diabetic skin neurotrophin- -like immunoreactivity and trk c expression in human spinal motoneurones in amyotrophic lateral sclerosis changes in cortical activation patterns accompanying somatosensory recovery in a stroke patient: a functional magnetic resonance imaging study longitudinal changes in cerebral response to proprioceptive input in individual patients after stroke: an fmri study circuits for grasping: spinal di interneurons mediate cutaneous control of motor behavior intraspinal rewiring of the corticospinal tract requires target-derived brain-derived neurotrophic factor and compensates lost function after brain injury igf-i specifically enhances axon outgrowth of corticospinal motor neurons differential distribution of exogenous bdnf, ngf, and nt- in the brain corresponds to the relative abundance and distribution of high-affinity and low-affinity neurotrophin receptors distinct limb and trunk premotor circuits establish laterality in the spinal cord rnaseq dataset describing transcriptional changes in cervical sensory ganglia after bilateral pyramidotomy and forelimb intramuscular gene therapy with aav encoding human neurotrophin- . data in brief sad kinases sculpt axonal arbors of sensory neurons through long-and short-term responses to neurotrophin signals control of species-dependent cortico-motoneuronal connections underlying manual dexterity cst axons in the upper cervical dorsal columns weeks after stroke (right) relative to sham surgery (left), visualised using pkcγ immunofluorescence. f) stroke caused a significant loss of cst axons relative to shams in the dorsal columns there were no differences between nt and vehicle treated rats at one week (t-test p= . ). c) accuracy of paw placement by the affected forelimb during walking was assessed using a horizontal ladder with irregularly spaced runs. d) one week after stroke, nt and vehicle treated rats made a similar number of misplaced steps (t-test p= . ), expressed as a percentage of total steps. importantly, the nt group progressively recovered compared to the vehicle group (group f , = . , p< . ; post hoc p= . ) and differed from the vehicle group from weeks to (group x time f , = . , p< . ; post hoc p values< . ) and whereas the vehicle group remained impaired relative to shams from weeks to (p values< . ), from weeks to the nt group made no more errors than shams (post hoc p-values> . ). e) the vertical cylinder test assessed use of the affected forelimb for lateral support during rearing. f) stroke caused a reduction in the use of the affected forelimb during rearing in a vertical cylinder in both nt and vehicle treated rats relative to shams (group f , = . , p= . ; post hoc p values= . and . , respectively) with no differences between stroke groups at one week (p= . ). nt treatment caused a progressive recovery in the use of the affected forelimb grey circles) against time after iv injection (n= - mice/time) in adult mice. t-tests for nt vs albumin all significant for incubation times of , , , and (p values from < . to < . ***). the volume of distribution of [ h] nt or [ h] albumin in brain (vd =am/cp) is calculated as a ratio of counts per minute (cpm) in µg of brain and cpm in µl of serum for each time point and plotted against exposure time given by the term ∫ t cp(τ)dτ/cp. the rate of influx (ki) was calculated from the patlak plot of vd for  - μl/mg/s). c) [ h]nt entered the cervical spinal cord more abundantly than [ h]albumin. d) plasma half-life of nt for the normal adult mouse is ~ min (estimated from /normalised serum values). e) twenty-four hours after cortical ischemia, [ h]nt entered the brain more abundantly than [ h]albumin, measured minutes after iv injection. f) twenty-four hours after cortical ischemia there are no conflicts of interests of the authors. correspondence and requests for materials should be addressed to l.m (lawrence.moon@kcl.ac.uk) figure : focal cortical stroke caused impairment of the affected forelimb but modest or no impairment of the three other limbs. a) after stroke, nt treated rats recovered function of their affected forelimb on the ladder test relative to stroke vehicle controls and sham rats. nt treated rats recovered fully relative to shams (linear model and t-tests, p≤ . ). *** denotes group difference, p < . ; † denotes interaction of group with time, p< . . this subpanel is reproduced from figure to allow comparison with other subpanels). b) shows photograph of the horizontal ladder set up and insert shows a rat traversing the ladder. c) there was no difference in the number of foot faults made in any of the groups using the less affected supplementary figure : cold allodynia was caused neither by focal cortical stroke nor by treatment with neurotrophin- . the acetone test was used to see whether stroke and/or nt treatment caused any change in cold allodynia pain responses. the test involves applying a drop of acetone to the a) affected or b) less affected forelimb, and then allocating a score between and : higher numbers denote a heightened pain response. there is no evidence of painful behaviour based on this test in either forelimb. rm ancova with bonferroni post hoc tests. figure : elisa revealed that infusion of nt into triceps brachii did not cause detectable elevation of nt in homogenates of cervical spinal cord hemicords on the infused or non-infused side of the body (mann whitney p-values= . , . , respectively). figure : functional brain imaging during stimulation of the affected wrist revealed no enhanced probability of perilesional activation by neurotrophin- . the same rats were imaged prior to stroke and then one week and eight weeks after stroke and intramuscular treatment with either nt or vehicle. scans with obvious imaging artefacts were discarded, leaving final group numbers of n= , , and n= , , at weeks , and for nt and vehicle treated groups respectively. red voxels denote greater probability of activation during stimulation (versus stimulation off) whereas blue voxels denote lesser probability of activation during stimulation (versus stimulation off). a) prior to stroke, stimulation of the dominant paw led to a strong probability of activation in the opposite somatosensory cortex. b) one week after stroke, this activation was abolished by infarction. c) eight weeks after stroke, there was a slight trend towards a small perilesional area of reactivation in both groups. d) there was a slight trend towards greater perilesional reactivation in the nt group versus the vehicle group at weeks (relative to their baselines). however, all these heat maps of groups of rats show t-values obtained by statistical parametric map analysis without correction for multiple testing (p< . ) and there were no differences between the two groups for any voxels when the threshold for significance was corrected for multiple testing (p< . ; this data is not shown as the heat map was black). red voxels denote greater probability of activation during stimulation for the nt group than for the vehicle group whereas blue voxels denote lesser probability of activation for the nt group than for the vehicle group. when stimulating the less-affected wrist, there were no differences between the two groups for any voxels when the threshold for significance was corrected for multiple testing (p< . ; this data is not shown as the heat map was black). figure : different amounts of recombinant nt were run in four lanes of an sds page gel. two sizes of band of interest (lm _ and lm _ ) were detected following staining with colloidal coomassie brilliant blue. these protein bands were excised prior to separate enzymatic digestion and lc/ms/ms analysis. the apparent molecular weight of the upper band (~ kda) is consistent with either the pro-neurotrophin- precursor form or a dimer of the mature nt protein, whilst the lower band (~ kda) is consistent with the mature nt protein. sequencing revealed that both bands represent the mature nt protein. key: cord- -kui g w authors: balestrino, maurizio; coccia, alberto; boffa, alessandra silvia; furgani, andrea; bermano, francesco; finocchi, cinzia; bandettini di poggio, monica laura; malfatto, laura; farinini, daniele; schenone, angelo title: request of hospital care dropped for tia but remained stable for stroke during covid- pandemic at a large italian university hospital date: - - journal: intern emerg med doi: . /s - - -w sha: doc_id: cord_uid: kui g w reduced incidence of stroke during covid- pandemic was sometimes reported. while decrease in stroke incidence and fear of patients to go to the hospitals were sometimes invoked to explain this decrease, reduction in urban pollution was also hypothesized as a possible cause. we investigated statistically the incidence of ischemic and hemorrhagic stroke, and of transient ischemic attacks, at a large italian tertiary stroke center during the pandemic. we analyzed statistically the number of transient ischemic attacks (tia), ischemic strokes (is) and hemorrhagic strokes (hs) between march and may , , the peak of the covid- epidemic in italy, and compared them with the identical period of . we also analyzed the concentration of small particulate matter (pm( )) in and , to see if it could account for modified incidence of strokes or tia. we found a large, significant drop in tia (− %) during the pandemic compared to the same period of . by contrast, the number of hs was identical, and is showed a not significant − % decrease. pm( ) concentration, already low in , did not further decrease in . patients kept seeking hospital care when experiencing permanent neurological symptoms (stroke), but they tended not go to the hospital when their symptoms were transient (tia). the fact that we did not observe a significant decrease in strokes may be explained by the fact that in our city the concentration of small particulate matter did not change compared to . several papers reported decreased stroke incidence during the current covid- pandemic [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . actual stroke reduction due to biological effects of the covid- virus [ ] and fear of patients to go to the hospital [ ] have been invoked as possible causes of this decrease, but reduced air pollution has also been suggested as the possible cause of reduced stroke incidence during the pandemic [ ] . moreover, in the outbreak of middle east respiratory syndrome (mers), decrease of ischemic strokes was significant but limited ( . - . %), and hemorrhagic strokes were unchanged [ ] . we aimed at finding if and how the pandemic changed the incidence of ischemic and hemorrhagic strokes, and of transient ischemic attacks, at the policlinic san martino hospital in genoa, italy, a regional "hub" and tertiary stroke care center. we also wanted to investigate if changes in air pollution during the epidemics could explain possible differences in stroke incidence. we analyzed statistically the observed numbers of transient ischemic attacks (tia), ischemic strokes (is) and hemorrhagic strokes (hs) at the policlinic san martino hospital in genoa, italy, a regional "hub" and tertiary stroke care center. we considered as tia all cases where neurological symptoms completely disappeared within h. in addition to searching all cases that had been admitted to the neurology ward or to the stroke unit, we also searched all cases where a neurological consultation had been done. the latter lead enabled us to detect even cases that had not been admitted to the neurology ward nor to the stroke unit, as well as patients that had been discharged by the emergency room. we used the same definitions and search methods for and , so whatever isolated cases might hypothetically have been missed, they were equally distributed between the two years. genoa ranks sixth among italian provinces for number of covid- infections [ ] . we investigated the weeks (march -may ) between the legislative acts that initiated and loosened the prohibition to exit home ("lockdown") in italy. they include rise and fall of the contagion curve in italy, when the epidemics was most severe [ ] . we compared this period with the identical period (march -may ) of , and we analyzed statistically the differences using the program prism (graphpad, usa). to gauge possible effects of changes in air pollution on the results we observed, we studied the concentrations of small particulate matter (pm ) within the catchment area of our hospital that were reported during the study periods by the relevant municipal agency [ ] . during the study period, we observed tia (they had been in , − %); is ( in , − %); hs ( in , + %). since during the pandemic the " liguria" agency (providing emergency ambulance services in our region) were reorganized, ambulances brought to our hospital patients from outside its usual catchment area, too. therefore, we risked to underestimate a possible decrease in strokes. thus, we repeated the analysis considering only patients brought from the usual catchment area of our hospital. when doing so, the number of is in became (− % compared to ), and the number of hs became (same as in ). table summarizes the weekly incidence of the various conditions. figure depicts their occurrence in the single weeks. incidence of tia dropped significantly across almost all the study period; however, we did not observe a comparable, significant decrease of ischemic strokes. in some weeks, is were even increased compared to (fig. ) . we interpret these findings as demonstrating the reluctance of patients experiencing transient symptoms to go to the hospital (in agreement with what was hypothesized by other authors) [ , ] , that in our experience contrasts with their maintained tendency to seek hospital care despite the pandemic when their symptoms were permanent (stroke). this drop in hospital evaluation of tia is regrettable, because it likely impeded secondary stroke prevention, thus it is possible that a surge of is might have happened afterwards. while we do not currently have data neither proving nor disproving the hypothesis of this surge, we think that in future epidemics a communication effort should be made to encourage people with even transient neurological symptoms to keep seeking neurological care. other authors have also pointed out to the need to encourage hospital admission of non-covid patients in possible future epidemics [ ] . the number of hs did not change at all during the pandemic, a finding that was also reported in during the outbreak of mers, another coronavirus epidemics [ ] . the number of hs was small in both years, as it could have been expected since incidence of hs is usually only - % of all strokes [ ] [ ] [ ] . nevertheless, the fact that we observed a virtually identical number of hs in and in seems to us worth considering. we interpret it as meaning that hs patients kept seeking hospital care in the same way in the as they had done in . as for is, we found a not significant decrease in their occurrence during the epidemics. we cannot rule out that in a larger sample such a decrease might have resulted significant. however, we emphasize that is decrease was statistically not significant even in the face of a significant and table statistical analysis of the rate of observation of the various conditions during the study periods. entries are mean ± standard deviation. in the last column, the first or only p value compares with all observed patients, the second one compares with patients from the catchment area of our hospital only. fig. ). moreover, it was half the magnitude of tia decrease (− % for is vs. − % for tia). thus, even if the pandemic-related decrease in is incidence was actually real, in our city it was limited, and approximately of the same magnitude that was found during the outbreak of mers in [ ] . finally, we emphasize that severity of strokes in was comparable to what had been in , as shown by the national institute of health stroke scale and by the modified rankin scale at admission, that were both identical in the two periods. we are providing specific details of these scores in a further paper, now in preparation. finally, even if a true is reduction was demonstrated, it should be explained by a selective reduction in events triggering ischemic, not hemorrhagic, events. reduced air pollution has been suggested as a candidate for such an explanation [ ] . we analyzed the concentration of small particulate matter (pm ) in our city during the study periods in and . specifically, we consulted the official data reported by the "arpal" city agency [ ] , comparing the pm concentration in the measuring station of corso buenos aires, which is located within the catchment area of our hospital. we found that its daily concentration was (mean ± standard deviation) ± . μg/m in , ± . in , a not significant difference (paired t test). therefore, is may have decreased less than in other areas because pollution, quite low to begin with, was not improved further by the lockdown, thus did not contribute to lower is rate. further research should be done to better understand the relationship between stroke and air pollution. however, the fact that we did not observe decrease in air pollution during the epidemics lockdown period suggests that this may be the reason why we did not observe the decrease in strokes that other authors reported. summing up, patients experiencing transient symptoms refrained from going to the hospital, possibly for fear of contagion. by contrast, patients showing permanent symptoms kept seeking hospital care. among the latter ones, hemorrhagic strokes did not change at all compared to previous year, a finding that had already been observed in a previous similar epidemics [ ] . ischemic strokes showed a not significant decrease. such lack of significant decrease may be explained at least in part by lack of change in air pollution, a stroke triggering factor that has been hypothesized as a cause for is decrease during the pandemic [ ] . funding open access funding provided by università degli studi di genova within the crui-care agreement. we also acknowledge funding by the policlinic hospital san martino (genoa, italy). conflict of interest the authors declare that they have no conflict of interest. the study was performed in accordance with the ethical standards as laid down in the declaration of helsinki and its later amendments. informed consent all patients or their guardians granted on admission advance permission to use their anonimized data for scientific research purposes. open access this article is licensed under a creative commons attribution . international license, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the creative commons licence, and indicate if changes were made. the images or other third party material in this article are included in the article's creative commons licence, unless indicated otherwise in a credit line to the material. if material is not included in the article's creative commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. to view a copy of this licence, visit http://creat iveco mmons .org/licen ses/by/ . /. decline in stroke alerts and hospitalisations during the covid- pandemic where have our patients gone? the impact of covid- on stroke imaging and intervention at an australian stroke centre low stroke incidence in the tempistelestroke network during covid- pandemic-effect of lockdown on thrombolysis and thrombectomy acute stroke presentation, care, and outcomes in community hospitals in northern california during the covid- pandemic stroke code presentations, interventions, and outcomes before and during the covid- pandemic falling stroke rates during covid- pandemic at a comprehensive stroke center: cover title: falling stroke rates during covid- covid- : stroke admissions, emergency department visits, and prevention clinic referrals has covid- played an unexpected "stroke" on the chain of survival? the baffling case of ischemic stroke disappearance from the casualty department in the covid- era coronavirus disease and stroke impact of the middle east respiratory syndrome outbreak on emergency care utilization and mortality in south korea treat all covid -positive patients, but do not forget those negative with chronic diseases first-ever stroke and transient ischemic attack incidence and -day case-fatality rates in a population-based study in argentina incidence of first-ever ischemic and hemorrhagic stroke in a well-defined community of southern italy, - stroke incidence and outcomes in northeastern greece: the evros stroke registry key: cord- - c h la authors: yamakawa, mai; kuno, toshiki; mikami, takahisa; takagi, hisato; gronseth, gary title: clinical characteristics of stroke with covid- : a systematic review and meta-analysis date: - - journal: j stroke cerebrovasc dis doi: . /j.jstrokecerebrovasdis. . sha: doc_id: cord_uid: c h la background: the coronavirus disease (covid- ) potentially increases the risk of thromboembolism and stroke. numerous case reports and retrospective cohort studies have been published with mixed characteristics of covid- patients with stroke regarding age, comorbidities, treatment, and outcome. we aimed to depict the frequency and clinical characteristics of covid- patients with stroke. methods: pubmed and embase were searched on june , , to investigate covid- and stroke through retrospective cross-sectional studies, case series/reports according to prisma guidelines. study-specific estimates were combined using one-group meta-analysis in a random-effects model. results: retrospective cohort studies and case series/reports were identified including patients with covid- and stroke. the frequency of detected stroke in hospitalized covid- patients was . % ([ % confidential interval (ci)]: [ . - . ], i( )= . %). mean age was . ([ . - . ], i( )= . %), . % was male ( / patients). mean days from symptom onset of covid- to stroke was . ([ . - . ], p< . , i( )= . %). d-dimer was . μg/ml ([ . - . ], i( )= . %), and cryptogenic stroke was most common as etiology at . % ([ . - . ] i( )= . %, / patients). case fatality rate was . % ([ . - . ], i( )= . %, / patients). conclusions: this systematic review assessed the frequency and clinical characteristics of stroke in covid- patients. the frequency of detected stroke in hospitalized covid- patients was . % and associated with older age and stroke risk factors. frequent cryptogenic stroke and elevated d-dimer level support increased risk of thromboembolism in covid- associated with high mortality. further study is needed to elucidate the pathophysiology and prognosis of stroke in covid- to achieve most effective care for this population. the severe acute respiratory syndrome coronavirus (sars-cov- ) is a novel coronavirus that caused ongoing worldwide pandemic . clinical features of covid- range from asymptomatic to fever, cough, shortness of breath, and even death . associated neurological manifestation included mild disease such as dizziness, headache, impaired sense of smell and taste, and polyneuropathy, as well as impaired consciousness, stroke, seizure, and encephalitis [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . increasing evidence suggests that coagulopathy due to covid- leads to systemic arterial and venous thromboembolism including but not limited to acute ischemic stroke [ ] [ ] [ ] [ ] . initial case reports with stroke and covid- were alarming consisted of young patients without comorbidities , however, there were also reports of older patients with stroke risk factors and worse outcome . there were mixed laboratory data and case fatality rate in case series making it difficult to apprehend the overall characteristics of stroke with covid- . herein, this systematic review and meta-analysis were conducted to illustrate the reported frequency of stroke in hospitalized covid- patients, as well as the demographic and the clinical characterization of all reported patients with covid- and stroke. a review protocol does not exist for this analysis. included studies met the following criteria: the study design was an observational study or a case series or report, the study population was patients with covid- patients and stroke. articles that do not contain original data of the patients (e.g. guideline, editorial, review, and letter) were excluded from the secondary review. all observational studies, case series, and case reports which included patients with covid- and stroke (ischemic or hemorrhagic) were identified using a -level strategy. first, databases including pubmed and embase were searched through june th, . search terms included ((sars-cov ) or (covid- )) and ((stroke) or (cerebrovascular accident) or (cerebral infarction)). we did not apply language limitations. relevant studies were identified through a manual search of secondary sources including references of initially identified articles, reviews, and commentaries. all references were downloaded for consolidation, elimination of duplicates. two independent authors (m.y. and t.k.) reviewed the search results separately to select the studies based on present inclusion and exclusion criteria. disagreements were resolved by consensus. outcomes included age, sex, comorbidities, symptoms, days from covid- symptom onset to stroke, laboratory data such as d-dimer, c-reactive protein (crp), and cardiac troponin, etiology, treatment, and case fatality rate. among symptoms of stroke, any change in mental status such as lethargy, confusion, and coma were summated as altered mental status; this included patients who presented with new change in mental status, and those who continued to be comatose after weaning off of sedation for mechanical ventilation. fall or syncope was not included in this category. corresponding authors were contacted individually if there were any values suspicious for a misspelling. risk of bias in individual studies was reviewed using assessment of risk of bias in prevalence studies . to attempt to calculate frequency of stroke in hospitalized covid- patients, retrospective cohort studies focused on hospitalized covid- patients were utilized. for other estimates (age, days from symptom onset of covid- to stroke diagnosis, d-dimer, crp, troponin, and case fatality rate), retrospective cohort studies which targeted other population and case series as well as case reports were added to the studies above and combined using one-group meta-analysis in a random-effects model using dersimonian-laird method for continuous value and wald method for discrete value with openmetaanalyst version . . (available from http://www.cebm.brown.edu/openmeta/). the frequency of common comorbidities (hypertension, dyslipidemia, diabetes mellitus, acute coronary syndrome /coronary artery disease), atrial fibrillation, stroke/transient ischemic attack, and malignancy), etiology of stroke if specified in the articles, and treatment (tissue plasminogen activator (tpa), mechanical thrombectomy, and anticoagulation were calculated by summation of events divided by the number of total patients from all studies whose information is available for each value. any anticoagulation therapy except prophylaxis for deep venous thrombosis preceding the stroke diagnosis was included in the calculation, and whether it was intended for treatment of stroke, therapeutic anticoagulation for other thromboembolic complication, or part of treatment protocol for acute respiratory distress syndrome in covid- , was delineated in the result section when available. the prometa software was used to perform funnel plots (https://idostatistics.com/prometa /) for age. we did our systematic review and meta-analysis according to prisma guidelines. the database search identified articles that were reviewed based on the title and abstract. of those, articles were excluded based on article type (clinical guidelines, consensus documents, reviews, systematic reviews, and conference proceedings), conference abstracts, irrelevant topics, and articles without stroke with covid- . twenty-nine articles met the inclusion criteria and were assessed for the systematic review (figure e- ). nine articles were excluded for reasons including duplicate reports and article type. six articles were added after the second search on june , . there were retrospective cohort studies, case series, and case reports with patients of interest , , , , , . summary of risk of bias for prevalence studies for each retrospective cohort study was shown in table e- . extracted data as above is shown in table and for the retrospective cohort studies, and in table e this systematic review of studies identified covid- patients with stroke. the salient findings of the study can be summarized as the followings; ( ) the frequency of stroke in hospitalized covid- patients was . %, with mean days from covid- symptom onset to stroke at days, most commonly cryptogenic; ( ) even with early case series with younger patients without a pre-existing medical condition, the mean age was . , with slight male preponderance ( . %); ( ) stroke risk factors such as hypertension, dyslipidemia, and prior strokes were common as comorbidities; altered mental status was as frequent as . % as presenting symptom of stroke; ( ) elevation of d-dimer and crp were reproduced after synthesis of results; ( ) case fatality rate was as high as . % in patients with covid- and stroke. we revealed the frequency of stroke in hospitalized covid- patients was . %. stroke incidence in general population is estimated from . to . % were reported to be approximately seven times as likely to have an acute ischemic stroke as compared to patients with emergency department visits or hospitalizations with influenza. . previous study revealed that stroke risk increases after a systemic respiratory tract infection at most within days from symptom onset . on the contrary, the days from symptom onset to stroke with covid- in our study was days, longer than other systemic respiratory infection in pre-covid- era , potentially supporting late thromboembolism complications caused by immune-mediated coagulopathy of covid- . however, this duration between symptom onset of covid- and stroke was variable as represented by a high heterogeneity, and it is notable that some patients presented with stroke even without covid- symptoms . most common etiology of stroke was cryptogenic up to . % which is twice as high as that of general population at % . . % had multifocal stroke among patients whose detail of stroke was available. collectively, sars-cov- is potentially a higher precipitating factor for acute ischemic stroke compared to other classic respiratory infection such as influenza, possibly via immune mediated coagulopathy [ ] [ ] [ ] [ ] . early in the course of the pandemic, several cases of younger patients without comorbidities were reported , , ; however, our synthesized results re-demonstrated classic demographics of the population who are at risk for stroke even in covid- patients, including older age, male gender, and pre-existing medical condition such as hypertension, dyslipidemia, and diabetes. altered mental status was seen in . % as presenting symptom of stroke, which is more frequent than stroke in general ( - % in one study) . decreased level of consciousness is reported to be a risk factor for missed diagnosis of stroke in emergency room . along with delayed presentation and concurrent fever, this could potentially explain the relatively low rates of tpa administration; however, further investigation is needed to depict the safety and effectivity of tpa in patients with stroke and covid- . d-dimer and crp were elevated on average at . g/ml and . mg/l respectively in our study. previous report pointed out d-dimer greater than g/ml is a risk factor for severe covid- and mortality , . other report demonstrated d-dimer > . g/ml and crp > mg/l were related to critical illness of covid- , which may be associated with higher risk of hyper-inflammatory states and hypercoagulability and resultant pulmonary emboli and microscopic emboli . as a marker for acute inflammation and coagulopathy, elevated d-dimer was an adverse prognostic factor in h n influenza in , and also in acute ischemic stroke . since elevated d-dimer could be used as a risk assessment biomarker of recurrent stroke in general , and previous observational study showed that anticoagulation might be associated with improved outcomes among patients hospitalized with covid- , patients with stroke and covid- might benefit from anticoagulation therapy, especially with cryptogenic stroke . however, patients who are intubated under sedation with poor neurological exam warrant extra caution before initiating anticoagulation, since those patients could be at higher risk of ischemic stroke that could have hemorrhagic conversion undetected . neuroimaging should be considered in this population prior to anticoagulation to avoid iatrogenic hemorrhagic conversion of undiagnosed ischemic stroke. lastly, the case fatality rate in this population with stroke and covid- was conspicuously high at . %. it is higher than mortality from stroke in general population that differs significantly by age; according to a report of medicare beneficiaries over the time period to , the -day mortality rate was: % in patients to years of age, . % in those to years of age, and % in those older than years of age . mortality in hospitalized covid- patients reported in the early course of pandemic ranged from to % , - . this discrepancy in mortality of covid- patients with and without stroke could be secondary to withdrawal of medical care when the neurological prognosis is grave , , ; another possibility is that stroke is part of multi-organ failure and systemic coagulopathy whose mortality is higher than covid- patients in general. notably, prior stroke has been described as a risk factor for severe disease in covid- patients even without concurrent acute stroke, which could potentially support vulnerability of patients with cerebrovascular disease to covid- from undetermined cause . the cause of death in this population remains unclear with our study due to limited details about the cause of death from large cohort studies. further study is needed to elucidate pathophysiology and risk factors for stroke as well as outcome and best treatment measures in hope to lower mortality in covid- patients with stroke. this study has several limitations. first, this systematic review covered a brief period, and therefore the sample size may still be limited. second, only limited value was available ubiquitously in the reviewed studies. third, there was a substantial heterogeneity in patient population given high i and different inclusion criteria of the studies used in this analysis, such as hospitalization, requirement of intensive care, and large vessel occlusion that warranted mechanical thrombectomy. in addition, the case reports and case series that were included in this review could potentially have publication bias that more severe cases in a younger population without risk factors with large stroke burden tend to be published as this type of articles, compared to those who had stroke risk factors as comorbidities and suffered small lacunar strokes and covid- . furthermore, reported incidence of acute stroke could be lower than actual, since subtle signs of small stroke could have been missed by the providers especially when patients with covid- were sedated and intubated. this systematic review assessed the clinical characteristics of stroke in patients with covid- . the frequency of stroke in hospitalized covid- patients was . % and associated with older age and stroke risk factors. frequent cryptogenic stroke and elevated d-dimer level support increased risk of thromboembolism in covid- associated with high mortality. further studies such as prospective collaborative international registries are helpful to decipher the pathophysiology and prognosis of stroke in covid- to achieve the most effective care for this population to decrease mortality. a novel coronavirus from patients with pneumonia in china a pneumonia outbreak associated with a new coronavirus of probable bat origin neurologic manifestations of hospitalized patients with coronavirus disease guillain barre syndrome associated with covid- infection: a case report guillain-barre syndrome associated with sars-cov- infection: causality or coincidence? guillain-barre syndrome associated with sars-cov- covid- may induce 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associated with hospital admission and critical illness among people with coronavirus disease in new york city: prospective cohort study serum d-dimer changes and prognostic implication in novel influenza a(h n ) the association between serum biomarkers and disease outcome in influenza a(h n )pdm virus infection: results of two international observational cohort studies you lr, tang m. the association of high d-dimer level with high risk of ischemic stroke in nonvalvular atrial fibrillation patients: a retrospective study baseline d-dimer levels as a risk assessment epidemiological and clinical characteristics of cases of novel coronavirus pneumonia in wuhan, china: a descriptive study clinical characteristics of deceased patients with coronavirus disease : retrospective study clinical features of patients infected with novel coronavirus in wuhan, china clinical characteristics of hospitalized patients with novel coronavirus-infected pneumonia in wuhan, china figure legends figure . forest plots for characteristics of stroke patients with covid- (random-effects model); (a): the frequency of stroke days from covid- symptom onset to stroke; (c): d-dimer; (d): case fatality rate funding: none. there is no conflict of interest of this study. days from covid- symptom onset, d-dimer, c-reactive protein (crp), cardiac troponinshown as median [q , q ] or mean±sd unless specified otherwise. * specified as "range" in the original article. * -mean. * -only patients out of patients had available value in the article. acanticoagulation; nanon-applicable; tpatissue plasminogen activator. key: cord- -kgrfnkns authors: coote, skye; cadilhac, dominique a.; o’brien, elizabeth; middleton, sandy title: letter to the editor regarding: critical considerations for stroke management during covid- pandemic by inglis et al., heart lung circ. ; ( ): – . date: - - journal: heart lung circ doi: . /j.hlc. . . sha: doc_id: cord_uid: kgrfnkns nan to the editor, we thank inglis and colleagues for the recent csanz covid- cardiovascular nursing care consensus statement [ ] and for highlighting important issues in cardiovascular and cerebrovascular disease nursing management during the covid- pandemic. while many of the identified issues apply to patients with cardiac disease or stroke, several fundamental differences affecting patients with stroke require distinction. globally, stroke is a leading cause of disability and death. any delays in presentation or treatment contribute to long-term disability. transient ischaemic attacks (tia) can often precede a major stroke, and rapid identification of cause and initiation of targeted secondary prevention is a critical step in risk-reduction [ ] . stroke/tia presentations, particularly among those with milder symptoms, have fallen substantially across the world during the pandemic, potentially resulting in more severe stroke events or disability from delayed treatment [ ] [ ] [ ] . diagnosis of stroke and treatment involves multiple hospital departments and should be streamlined and guided by an interdisciplinary team. covid- has negatively impacted hospital workflows and has led to redeployment of staff resources, including nurses who work in stroke units [ ] . without the care of specialist multidisciplinary teams in a dedicated stroke unit, patients face higher rates of complications, disability and mortality [ , , ] . physically segregated emergency department workspaces impede workflows and can delay referrals to the stroke team, and lengthy brain scanner decontamination times can delay diagnosis and treatment decisions [ ] [ ] [ ] . with a causal relationship established between treatment delays and disability/mortality rates, these delays can have disastrous consequences [ ] . csanz covid- cardiovascular nursing care consensus statement: executive summary covid- and stroke -a global world stroke organization perspective delayed presentation of acute ischemic strokes during the covid- crisis impact of the covid- epidemic on stroke care and potential solutions ssa statement of stroke care during the covid- stroke society of australasia time to treatment with intravenous alteplase and outcome in stroke: an updated pooled analysis of ecass, atlantis, ninds, and epithet trials this de-valuing of hospital response times and services has resulted in the stroke society of australasia's plea to hospital executives to protect the integrity of stroke services [ ] .it remains essential that the face, arms, speech, time (fast) message detailing the signs of stroke is well publicised, and people with suspected stroke do not hesitate to call an ambulance. moreover, hospital workflows and processes, while needing to be flexible in these unprecedented times, should not be altered to such a degree that patients presenting with stroke are disadvantaged.j o u r n a l p r e -p r o o f key: cord- -wsnyq s authors: arora, rahul; singh, karan title: mid-air drawing of curves on d surfaces in ar/vr date: - - journal: nan doi: nan sha: doc_id: cord_uid: wsnyq s complex d curves can be created by directly drawing mid-air in immersive environments (ar/vr). drawing mid-air strokes precisely on the surface of a d virtual object however, is difficult; necessitating a projection of the mid-air stroke onto the user"intended"surface curve. we present the first detailed investigation of the fundamental problem of d stroke projection in ar/vr. an assessment of the design requirements of real-time drawing of curves on d objects in ar/vr is followed by the definition and classification of multiple techniques for d stroke projection. we analyze the advantages and shortcomings of these approaches both theoretically and via practical pilot testing. we then formally evaluate the two most promising techniques spraycan and mimicry with users in vr. the study shows a strong qualitative and quantitative user preference for our novel stroke mimicry projection algorithm. we further illustrate the effectiveness and utility of stroke mimicry, to draw complex d curves on surfaces for various artistic and functional design applications. . drawing curves mid-air that lie precisely on the surface of a virtual d object in ar/vr is di icult (a). projecting mid-air d strokes (black) onto d objects is an under-constrained problem with many seemingly reasonable solutions (b). we analyze this fundamental ar/vr problem of d stroke projection, define and characterize multiple novel projection techniques (c), and test the two most promising approaches-spraycan shown in blue and mimicry shown in red in (b)-(d)-using a quantitative study with users (d). the user-preferred mimicry technique a empts to mimic the d mid-air stroke as closely as possible when projecting onto the virtual object. we showcase the importance of drawing curves on d surfaces, and the utility of our novel mimicry approach, using multiple artistic and functional applications (e) such as interactive shape segmentation (top) and texture painting (bo om). horse model courtesy cyberware, inc. spiderman bust base model © david ruiz olivares (cc by . ). complex d curves can be created by directly drawing mid-air in immersive environments (ar/vr). drawing mid-air strokes precisely on the surface of a d virtual object however, is di cult; necessitating a projection of the mid-air stroke onto the user "intended" surface curve. we present the rst detailed investigation of the fundamental problem of d stroke projection in ar/vr. an assessment of the design requirements of real-time drawing of curves on d objects in ar/vr is followed by the de nition and classi cation of multiple techniques for d stroke projection. we analyze the advantages and shortcomings of these approaches both theoretically and via practical pilot testing. we then formally evaluate the two most promising techniques spraycan and mimicry with users in vr. e study shows a strong qualitative and quantitative user preference for our novel stroke mimicry projection algorithm. we further illustrate the e ectiveness and utility of stroke mimicry, to draw complex d curves on surfaces for various artistic and functional design applications. ccs concepts: •human-centered computing → virtual reality; •computing methodologies → graphics systems and interfaces; shape modeling; drawing is a fundamental tool of human visual expression and communication. digital sketching with pens, styli, mice, and even ngers in d is ubiquitous in visually creative computing applications. drawing or painting on d virtual objects for example, is critical to interactive d modeling, animation, and visualization, where its uses include: object selection, annotation, and segmentation [heckel et al. ; jung et al. ; meng et al. ] ; d curve and surface design [igarashi et al. ; nealen et al. ] ; strokes for d model texturing or painterly rendering [kalnins et al. ] ( figure e ). in d, digitally drawn on-screen strokes are wysiwyg mapped onto d virtual objects, by projecting d stroke points through the given view onto the virtual object(s) (figure a) . sketching in immersive environments (ar/vr) has the mystical aura of a magical wand, allowing users to draw directly mid-air in d. mid-air drawing thus has the potential to signi cantly disrupt interactive d graphics, as evidenced by the increasing popularity of ar/vr applications such as tilt brush [google ] and ill [oculus b] . a fundamental requirement for numerous interactive d applications in ar/vr however, remains the ability to directly draw, or project drawn d strokes, precisely on d virtual objects. while directly drawing on a physical d object is reasonably easy, it is near impossible without haptic constraints to draw directly on a virtual d object ( figure ) . furthermore, unlike d drawing, where the wysiwyg view-based projection of d strokes onto d objects is unambiguously clear, the user-intended mapping of a mid-air d stroke onto a d object is less obvious. we thus present the rst detailed investigation into plausible user-intended projections of mid-air strokes on to d virtual objects. ( c ) fig. . stroke projection using a d interface is typically wysiwyg: d points along a user stroke (a, inset) are ray-cast through the given view to create corresponding d curve points on the surface of d scene objects (a). even small errors or noise in d strokes can cause large discontinuities in d, especially near ridges and sharp features (b). complex curves spanning many viewpoints, or with large scale variations in detail, o en require the curve to be drawn in segments from multiple user-adjusted viewpoints (c). interfaces for d/ d curve creation in general, use perceptual insights or geometric assumptions like smoothness and planarity, to project, neaten, or otherwise process sketched strokes. some applications wait for user stroke completion before processing it in entirety, for example when ing splines [bae et al. ]. our goal is to establish an application agnostic, base-line projection approach for mid-air d strokes. we thus assume a stroke is processed while being drawn and inked in real-time, i.e., the output curve corresponding to a partially drawn stroke is xed/inked in real-time, based on partial stroke input [ iel et al. ] . one might further conjecture that all "reasonable" and mostly continuous projections would produce similar results, as long as users are given interactive visual feedback of the projection. is is indeed true for tasks requiring discrete point-on-surface selection, where users can freely re-position the drawing tool until its interactively visible projection corresponds to user-intent. realtime curve drawing, however, is very sensitive to the projection technique, where any mismatch between user intention and algorithmic projection, is continuously inked into the projected curve ( figure d ). d strokes projected onto d objects: e standard user-intended mapping of a d on-screen stroke is a raycast projection through the given monocular viewpoint, onto the visible surface of d objects. raycasting is wysiwyg (what you see is what you get) in that the d curve visually matches the d stroke from said viewpoint (see figure a ). ongoing research on mapping d strokes to d objects assumes this fundamental view-centric projection, focusing instead on speci c problems such as creating spatially coherent curves around ridge/valley features (where small d error can cause large d depth error upon projection, figure b ); or drawing complex curves with large scale variation (where multiple viewpoint changes are needed while drawing, figure c ). ese problems are mitigated by the direct d input and viewing exibility of ar/vr, assuming the mid-air stroke to d object projection matches user intent. d strokes projected onto d objects: physical analogies motivate existing approaches to de ning a user-intended projection from d points in a mid-air stroke to d points on a virtual object (figure ) . gra ti-style painting with a spraycan, is arguably the current standard, deployed in commercial immersive paint and sculpt soware such as oculus medium [ a] and gravity sketch [ ] . a closest-point projection approximates drawing with the tool on the fig. . mid-air drawing precisely on a d virtual object is di icult (faint regions of strokes are above or below the surface), regardless of drawing quick smooth strokes blue, or slow detailed strokes purple. deliberately slow drawing is further detrimental to stroke aesthetic (right). d object, without actual physical contact (used by the "guides" tool in tilt brush [ ] ). like view-centric d stroke projection, these approaches are context-free: processing each mid-air point independently. e ar/vr drawing environment comprising six-degree of freedom controller input and unconstrained binocular viewing, is however, signi cantly richer than d sketching. e user-intended projection of a mid-air stroke ( § ) as a result is complex, in uenced by the ever-changing d relationship between the view, drawing controller and virtual object. we therefore argue the need for historical context (i.e., the partially drawn stroke and its projection) in determining the projection of a given stroke point. we balance the use of this historical context, with the overarching goal of a general purpose projection that makes li le or no assumption on the nature of the user stroke or its projection. we thus explore anchored projection techniques, that minimally use the most recently projected stroke point, as context for projecting the current stroke point ( § ). we evaluate various anchored projections, both theoretically and practically by pilot testing. our most promising and novel approach anchored-smooth-closest-point (also called mimicry), captures the natural tendency of a user stroke to mimic the shape of the desired projected curve. a formal user study ( § ), shows mimicry to perform signi cantly be er than spraycan (the current baseline) in producing curves that match user intent ( § ). is paper thus contributes, to the best of our knowledge, the rst principled investigation of real-time inked techniques to project d mid-air strokes drawn in ar/vr onto d virtual objects, and a novel stroke projection benchmark for ar/vr: mimicry. overview. following a review of related work ( § ), we analyze the pros and cons of context-free projection ( § ), laying the foundation for our novel anchored projection, mimicry ( § ). we formally compare mimicry against the current baseline spraycan ( § ). e study results and discussion ( § ) are followed by applications showcasing the utility of mimicry ( § ). we conclude with limitations and directions for future work ( § ). our work is related to research on drawing and sculpting in immersive realities, interfaces for drawing curves on, near, and around surfaces, and sketch-based modelling tools. immersive creation has a long history in computer graphics. immersive d sketching was pioneered by the holosketch system [deering ] , which used a -dof wand as the input device for creating polyline sketches, d tubes, and primitives. in a similar vein, various subsequent systems have explored the creation of freeform d curves and swept surfaces [google ; keefe et al. ; schkolne et al. ] . while directly turning d input to creative output is acceptable for ideation, the inherent imprecision of d sketching is quickly apparent when more structured creation is desired. e perceptual and ergonomic challenges in precise control of d input is well-known [arora et al. ; keefe et al. ; machuca et al. machuca et al. , wiese et al. ] , resulting in various methods for correcting d input. input d curves have been algorithmically regularized to snap onto existing geometry, as with the free-drawer [ ] system, or constrained physically to d input with additional techniques for "li ing" these curves into d [arora et al. ; jackson and keefe ; kwan and fu ; paczkowski et al. ] . haptic rendering devices [kamuro et al. ; keefe et al. ] and tools utilizing passive physical feedback [grossman et al. ] are an alternate approach to tackling the imprecision of d inputs. we are motivated by similar considerations. arora et al. [ ] demonstrated the di culty of creating curves that lie exactly on virtual surfaces in vr, even when the virtual surface is a plane. is observation directly motivates our exploration of techniques for projecting d strokes onto surfaces, instead of coercing users to awkwardly draw exactly on a virtual surface. curve creation and editing on or near the surface of d virtual objects is fundamental for a variety of artistic and functional shape modeling tasks. functionally, curves on d surfaces are used to model or annotate structural features [gal et al. ; stanculescu et al. ] , de ne trims and holes [schmidt and singh ] , and to provide handles for shape deformation [kara and shimada ; nealen et al. ; singh and fiume ], registration [gehre et al. ] and remeshing [krishnamurthy and levoy ; takayama et al. ]. artistically, curves on surfaces are used in painterly rendering [gooch and gooch ] , decal creation [schmidt et al. ], texture painting [adobe ] , and even texture synthesis [fisher et al. ]. curve on surface creation in this body of research typically uses the established view-centric wysiwyg projection of on-screen sketched d strokes. while the sketch view-point in these interfaces is interactively set by the user, there has been some e ort in automatic camera control for drawing [ortega and vincent ] , auto-rotation of the sketching view for d planar curves , and user assistance in selecting the most sketchable viewpoints [bae et al. ]. immersive d drawing enables direct, view-point independent d curve sketching, and is thus an appealing alternative to these d interfaces. our work is also related to drawing curves around surfaces. such techniques are important for a variety of applications: modeling string and wire that wrap around objects [coleman and singh ] ; curves that loosely conform to virtual objects or de ne collision-free paths around objects [krs et al. ] ; curve pa erns for clothing design on a d mannequin model [turquin et al. ] ; curves for layered modeling of shells and armour [de paoli and singh ] ; and curves for the design and grooming of hair and fur [fu et al. ; schmid et al. ; xing et al. ] . some approaches such as secondskin [ ] and skippy [ ] use insights into spatial relationship between a d stroke and the d object, to infer a d curve that lies on and around the surface of the object. other techniques like cords [ ] or hair and clothing design [xing et al. ] are closer to our work, in that they drape d curve input on and around d objects using geometric collisions or physical simulation. in contrast, this paper is application agnostic, and remains focused on the general problem of projecting a drawn d stroke to a real-time inked curve on the surface of a virtual d object. while we do not address curve creation with speci c geometric relationships to the object surface (like distance-o set curve), our techniques can be extended to incorporate geometry-speci c terms ( § ). sketch-based d modeling is a rich ongoing area of research (see survey by olsen et al. [ ] ). typically, these systems interpret d sketch inputs for various shape modeling tasks. one could categorize these modeling approaches as single-view (akin to traditional pen on paper) [andre and saito ; chen et al. ; schmidt et al. ; xu et al. ] or multi-view (akin to d modeling with frequent view manipulation) [bae et al. ; fan et al. fan et al. , igarashi et al. ; nealen et al. ]. single-view techniques use perceptual insights and geometric properties of the d sketch to infer its depth in d, while multi-view techniques explicitly use view manipulation to specify d curve a ributes from di erent views. while our work utilizes mid-air d stroke input, the ambiguity of projection onto surfaces connects it to the interpretative algorithms designed for sketch-based d modeling. we aim to take advantage of the immersive interaction space by allowing view manipulation as and when desired, independent of geometry creation. we rst formally state the problem of projecting a mid-air d stroke onto a d virtual object. let m = (v , e, f ) be a d object, represented as a manifold triangle mesh embedded in r . a user draws a piece-wise linear mid-air stroke by moving a -dof controller or drawing tool in ar/vr. e d stroke p ⊂ r is a sequence of n points (p i ) n− i= , connected by line segments. corresponding to each point p i ∈ r , is a system state are the positions of the headset and the controller, respectively, and h i , c i ∈ sp( ) are their respective orientations, represented as unit quaternions. also, without loss of generality, assume c i = p i , i.e. the controller positions describe the stroke points p i . we want to de ne a projection π , which transforms the sequence of points (p i ) n− i= to a corresponding sequence of points (q i ) n− i= on the d virtual object, i.e. q i ∈ m. consecutive points in this sequence are connected by geodesics on m, they describe the projected curve q ⊂ m. e aim of a successful projection method of course, is to match the undisclosed user-intended curve. e projection is also designed for real-time inking of curves: points p i are processed upon input and projected in real-time (under ms) to q i using the current system state s j , and optionally, prior system states (s j ) i− j= , stroke points (p j ) i− j= and their projections (q j ) i− j= . stroke dynamics, captured from the controller's inertial sensors, or as nite di erences of stroke position, have been e ective in interactive sketch neatening [arora et al. ; iel et al. ]. we do not however, explicitly model stroke dynamics in our proposed projections, since early pilot testing did not suggest a relationship between stroke velocity/acceleration and intended stroke projection. context-free techniques project points independent of each other, simply based on the spatial relationships between the controller, hmd, and d object ( figure ). we can further categorize techniques as raycast or proximity based. . . raycast projections. view-centric projection in d interfaces project points from the screen along a ray from the eye through the screen point, to where the ray rst intersects the d object. in an immersive se ing, raycast approaches similarly use a ray emanating from the d stroke point to intersect d objects. is ray (o, d) with origin o and direction d can be de ned in a number of ways. similar to pointing behavior, occlude de nes this ray from the eye through the controller origin (also the stroke point, figure a ) if the ray intersects m, then the closest intersection to p i de nes q i . in case of no intersection, p i is ignored in de ning the projected curve, i.e., q i is marked unde ned and the projected curve connects q i− to q i+ (or the proximal index points on either side of i for which projections are de ned). e spraycan approach treats the controller like a spraycan, de ning the ray like a nozzle direction in the local space of the controller (figure b ). for example the ray could be de ned as (c i , f i ), where the nozzle f i = c i ·[ , , ] t is the controller's local z-axis (or forward direction). alternately, head-centric projection can de ne the ray using the hmd's view direction as (h i , h i · [ , , ] t ) (figure c ). pros and cons: e strengths of raycasting are: a predictable visual/proprioceptive sense of ray direction; a spatially continuous mapping between user input and projection rays; and ar/vr scenarios where it is di cult or undesirable to reach and draw close to the virtual object. e biggest limitation of raycast projection stems from the controller/hmd-based ray direction being completely agnostic of the shape or location of the d object. projected curves can consequently be very di erent in shape and size from drawn strokes, and ill-de ned for stroke points with no ray-object intersection. . . proximity-based projections. in d interfaces, the on-screen d strokes are typically distant to the viewed d scene, necessitating some form of raycast projection onto the visible surface of d objects. in ar/vr, however, users are able to reach out in d and directly draw the desired curve on the d object. while precise mid-air drawing on a virtual surface is very di cult in practice (figure ) , projection methods based on proximity between the mid-air stroke and the d object are certainly worth investigation. e simplest proximity-based projection technique snap, projects a stroke point p i to its closest-point in m (figure d ). where d(·, ·) is the euclidean distance between two points. unfortunately, for triangle meshes, closest-point projection tends to snap to the edges of the mesh (blue curve inset), resulting in unexpectedly jaggy projected curves, even for smooth d input strokes (black curve inset) ]. ese discontinuities are due to the discrete nature of the mesh representation, as well spatial singularities in closest point computation even for smooth d objects. we mitigate this problem by formulating an extension of panozzo et al. 's phong projection [ ] in § . , that simulates projection of points onto an imaginary smooth surface approximated by the triangle mesh. we denote this smooth-closest-point projection as π sc p (red curve inset). pros and cons: e biggest strength of proximity-based projection is it exploits the immersive concept of drawing directly on or near an object, using the spatial relationship between a d stroke point and the d object to determine projection. e main limitation is that since users rarely draw precisely on the surface, discontinuities and local extrema persist when projecting distantly drawn stoke points, even when using smooth-closest-point. in § . , we address this problem using stroke mimicry to anchor distant stroke points close to the object to be nally projected using smooth-closest-point. our goal with smooth-closest-point projection is to de ne a mapping from a d point to a point on m that approximates the closest point projection but tends to be functionally smooth, at least for points near the d object. we note that computing the closest point to a laplacian-smoothed mesh proxy, for example, will also provide a smoother mapping than π snap , but a potentially poor closest-point approximation to the original mesh. phong projection, introduced by , addresses these goals for points expressible as weighted-averages of points def. p p hon def. (a) computing weighted averages in on m, but we extend their technique to de ne a smooth-closestpoint projection for points in the neighbourhood of the mesh. for completeness, we rst present a brief overview of their technique. phong projection is a two-step approach to map a point y ∈ r to a manifold triangle mesh m embedded in r , emulating closestpoint projection on a smooth surface approximated by the triangle mesh. first, m is embedded in a higher dimensional euclidean space r d such that euclidean distance (between points on the mesh) in r d be er approximates geodesic distances in r . second, analogous to vertex normal interpolation in phong shading, a smooth surface is approximated by blending tangent planes across edges. barycentric coordinates at a point within a triangle are used to blend the tangent planes corresponding to the three edges incident to the triangle. we extend the rst step to a higher dimensional embedding of not just the triangle mesh m, but a tetrahedral representation of an o set volume around the mesh m ( figure ). e second step remains the same, and we refer the reader to for details. for clarity, we refer to m embedded in r as m , and the embedding in r d as m d . panozzo et al. compute m d by rst embedding a subset of the vertices in r d using metric multi-dimensional scaling (mds) [cox and cox ] , aiming to preserve the geodesic distance between the vertices. is subset consists of the high-curvature vertices of m. e embedding of the remaining vertices is then computed using ls-meshes [sorkine and cohen-or ] . for the problem of computing weighted averages on surfaces, one only needs to project d points of the form x d i is de ned as the point on m d with the same implicit coordinates (triangle and barycentric coordinates) as x i does on m . erefore, their approach only embeds m into r d (figure a,c) . in contrast, we want to project arbitrary points near m onto it using the phong projection. erefore, we compute the o set surfaces at signed-distance ±µ from m. we then compute a tetrahedral mesh t m of the space between these two surfaces in r . in the nal step, we embed the vertices of t m in r d using mds and ls-meshes as described above. note that all of the above steps are realized in a precomputation. now, given a d point y within a distance µ from m , we situate it within t m , use tetrahedral barycentric coordinates to infer its location in r d , and then compute its phong projection (figure b,c) . we fallback to closest-point projection for points outside t m , since phong projection converges to closest-point projection when far from m. furthermore, we set µ large enough to easily handle our smooth-closest-point queries in § . . we implemented the four di erent context-free projection approaches in figure , and had users informally test each, drawing a variety of curves on the various d models seen in this paper. alitatively, we made a number of observations: -head-centric and occlude projections become unpredictable if the user is inadvertently changing their viewpoint while drawing. ese projections are also only e ective when drawing frontally on an object, like with a d interface. neither as a result exploits the potential gains of mid-air drawing in ar/vr. -spraycan projection was clearly the most e ective context-free technique. commonly used for gra ti and airbrushing, usually on fairly at surfaces, we noted however, that consciously reorienting the controller while drawing on or around complex objects was both cognitively and physically tiring. -snap projection was quite sensitive to changes in the distance of the stroke from the object surface, and in general produced the most undulating projections due to closest-point singularities. -all projections converge to the mid-air user stroke when it precisely conforms to the surface of the d object. but as the distance between the object and points on the mid-air stroke increases, their behavior diverges quickly. -while users did draw in the vicinity and mostly above the object surface, they rarely drew precisely on the object. e average distance of stroke points from the target object was observed to be . cm in a subsequent user study ( § ). -e most valuable insight however, was that the user stroke in mid-air o en tended to mimic the expected projected curve. context-free approaches, by design, are unable to capture this mimicry, i.e., the notion that the change between projected point as we draw a stroke is commensurate with the change in the d points along the stroke. is inability due to a lack of curve history or context, materializes as problems in di erent forms. . . projection discontinuities. proximal projection (including smooth-closest-point) can be highly discontinuous with increasing distance from the d object, particularly in concave regions (figure a ). mid-air drawing along valleys without staying in precise contact with virtual object is thus extremely di cult. raycast projections can similarly su er large discontinuous jumps across occluded regions (in the ray direction) of the object (figure d ). while this problem theoretically exists in d interfaces as well, it is less observed in practice for two reasons: d drawing on a constraining physical surface is signi cantly more precise than midair drawing in ar/vr [arora et al. ] ; and artists minimize such discontinuities by carefully choosing appropriate views (raycast directions) before drawing each curve. automatic diretion control of view or controller, while e ective in d [ortega and vincent ] ), is detrimental to a sense of agency and presence in ar/vr. snapping. proximity-based methods also tend to get stuck on sharp (or high curvature) convex features of the object (figure b ). while this can be useful to trace along a ridge feature, it is particularly problematic for general curve-on-surface drawing. . . projection depth disparity. e relative orientation between the d object surface and raycast direction can cause large depth disparities between parts of user strokes and curves projected by raycasting ( figure c ). such irregular bunching or spreading of points on the projected curve also goes against our observation of stroke mimicry. users can arguably reduce this disparity by continually orienting the view/controller to keep the projection ray well aligned with object surface normal. such re-orientation however can be tiring, ergonomically awkward, and deviates from d experience, where pen/brush tilt only impacts curve aesthetic, and not shape. we noted that the occlude and spraycan techniques were complementary: drawing with occlude on parts of an object frontal to the view provided good comfort and control, which degraded when drawing closer to the object silhoue e, and observed the opposite when drawing with spraycan. we thus implemented a hybrid projection, where the ray direction was interpolated between occlude and spraycan based on alignment with the most recently projected smooth surface normal. unfortunately, the di erence between occlude and spraycan ray directions was o en large enough to make even smooth ray transitions abrupt and hard to control. all these problems point to the projection function ignoring the shape of the mid-air stroke p and the projected curve q, and can be addressed using projection functions that explicitly incorporate both. we call these functions anchored. e limitations of context-free projection can be addressed by equipping stroke point projection with the context/history of recently drawn points and their projections. in this paper we minimally use only the most recent stroke point p i− and its projection q i− , as context to anchor the current projection. any reasonable context-free projection can be used for the rst stroke point p . we use spraycan π spr a , our preferred context-free technique. for subsequent points (i > ), we compute: where ∆p i = (p i − p i− ). we then compute q i as a projection of the anchored stroke point r i onto m, that a empts to capture ∆p i ≈ ∆q i . anchored projection captures our observation that the mid-air user stroke tends to mimic the shape of their intended curve on surface. while users to do not adhere consciously to any precise geometric formulation of mimicry, we observe that users o en draw the intended projected curve as a corresponding stroke on an imagined o set or translated surface (figure ) . a good general projection for the anchored point r i to m thus needs to be continuous, predictable, and loosely capture this notion of mimicry. controller sampling rate in current ar/vr systems is hz or more, meaning that even during ballistic movements, the distance ∆p i for any stroke sample i is of the order of a few millimetres. consequently, the anchored stroke point r i is typically much closer to m, than the stroke point p i , making closest-point snap projection a compelling candidate for projecting r i . such an anchored closestpoint projection explicitly minimizes ∆p i − ∆q i , but precise minimization is less important than avoiding projection discontinuities and undesirably snapping, even for points close to the mesh. our formulation of a smooth-closest-point projection π sc p in § . addresses these goals precisely. also note that the maximum observed ∆p for the controller readily de nes the o set distance µ for our pre-computed tet mesh t m . we de ne mimicry projection as ( ) we further explore re nements to mimicry projection, that might improve curve projection in certain scenarios. planar curves are very common in design and visualization [mccrae et al. ] . we can locally encourage planarity in mimicry projection by constructing a plane n i with normal ∆p i × ∆p i− (i.e. the local plane of the mid-air stroke) and passing through the anchor point r i (figure b ). we then intersect n i with m. q i is de ned as the closest-point to r i on the intersection curve that contains q i− . note, we use π spr a (p i ) for i < , and we retain the most recently de ned normal direction (n i− or prior) when n i = ∆p i × ∆p i− is unde ned. we nd this method works well for near-planar curves, but the plane is sensitive to noise in the mid-air stroke (figure f) , and can feel sticky or less responsive for non-planar curves. o set and parallel surface drawing captures the observation that users tend to draw an intended curve as a corresponding midair stroke on an imaginary o set or parallel surface of the object m. while we do not expect users to draw precisely on such a surface, we note that is unlikely a user would intentionally draw orthogonal to such a surface along the gradient of the d object. in scenarios when a user is sub-consciously drawing on a o set surface of m (an isosurface of its signed-distance function d m (·)), we can remove the component of a user stroke segment that lies along the gradient ∇d m , when computing the desired anchor point r i in equation as ( figure c ): we can similarly locally constrain user strokes to a parallel surface of m in equation as: note that the di erence from eq. is the position where ∇d m is computed, as shown in figure d . a parallel surface be er matched user expectation than an o set surface in our pilot testing, but both techniques produced poor results when user drawing deviated from these imaginary surfaces (figure g -l). for completeness, we also investigated raycast alternatives to projection of the anchored stroke point r i . we used similar priors of local planarity and o set or parallel surface transport as with mimicry re nement, to de ne ray directions. figure shows two such options. in figure a , we cast a ray in the local plane of motion, orthogonal to the user stroke, given by ∆p i . we construct the local plane containing r i spanned by ∆p i and p i− − q i− , and then de ne the direction orthogonal to ∆p i in this plane. since r i may be inside m, we cast two rays bi-directionally (r if both rays successfully intersect m, we choose q i to be the point closer to r i , a heuristic that works well in practice. as with locally planar mimicry projection, this technique su ered from instability in the local plane. motivated by mimicry, in figure b , we also explored parallel transport of the projection ray direction along the user stroke. for i > , we parallel transport the previous projection direction q i− − p i− along the mid-air curve by rotating it with the rotation that aligns ∆p i− with ∆p i . once again bi-directional rays are cast from r i , and q i is set to the closer intersection with m. in general, we found that all raycast projections, even when anchored, su ered from unpredictability over long strokes and stroke discontinuities when there are no ray-object intersections (figure n ,o). in summary, extensive pilot testing of the anchored techniques revealed that they seemed generally be er than context-free approaches, specially when users drew further away from the d object. among the anchored techniques, stroke mimicry captured as an anchored-smooth-closest-point projection, proved to be theoretically elegant, and practically the most resilient to ambiguities of user intent and di erences of drawing style among users. anchored closest-point can be a reasonable proxy to anchored smooth-closestpoint when pre-processing the d virtual objects is undesirable. our techniques are implemented in c#, with interaction, rendering, and vr support provided by the unity engine. for the smooth closest-point operation, we modi ed panozzo et al.'s [ ] reference implementation, which includes pre-processing code wri en in matlab and c++, and real-time code in c++. e real-time projection implementation is exposed to our c# application via a compiled dynamic library. in their implementation, as well as ours, ( o ) fig. . mimicry vs. other anchored stroke projections: mid-air strokes are shown in black and mimicry curves in red. anchored closest-point (blue), is similar to mimicry on smooth, low-curvature meshes (a,b) but degrades with mesh detail/noise (c,d). locally planar projection (blue) is susceptible local plane instability (e,f). parallel (purple h,k) or o set (blue i,l) surface based projection fail in (h,l) when the user stroke deviates from said surface, while mimicry remains reasonable (g, j). compared to mimicry (m), anchored raycasting based on a local plane (purple n), or ray transport (blue o) can be discontinuous. d = ; that is, we embed m in r for computing the phong projection. we use µ = cm, and compute the o set surfaces using libigl ]. we then improve the surface quality using tetwild [hu et al. ], before computing the tetrahedral mesh t m between the two surfaces using tetgen [si ]. we support fast closest-point queries, using an aabb tree implemented in geometry sharp [schmidt ]. signed-distance is also computed using the aabb tree and fast winding number [barill et al. ] , and gradient ∇d m computed using central nite di erences. to ease replication of our various techniques and aid future work, we will open-source our implementation. we now formally compare our most promising projection mimicry, to the best state-of-the-art context-free projection spraycan. we designed a user study to compare the performance of the spraycan and mimicry methods for a variety of curve-drawing tasks. we selected six shapes for the experiment (figure ) , aiming to cover a diverse range of shape characteristics: sharp features (cube), large smooth regions (trebol, bunny), small details with ridges and valleys (bunny), thin features (hand), and topological holes (torus, fertility). we then sampled ten distinct curves on the surface of each of the six objects. a canonical task in our study involved the participant a empting to re-create a given target curve from this set. we designed two types of drawing tasks shown in figure : tracing curves, where a participant tried to trace over a visible target curve using a single smooth stroke. re-creating curves, where a participant a empted to re-create from memory, a visible target curve that was hidden as soon as the participant started to draw. an enumerated set of keypoints on the curve however, remained as a visual reference, to aid the participant in re-creating the hidden curve with a single smooth stroke. e rationale behind asking users to draw target curves is both to control the length, complexity, and nature of curves drawn by users, and to have an explicit representation of the user-intended curve. curve tracing and re-creating are fundamentally di erent ( c ) fig. . the two tasks used in our study-curve tracing with the target curve visible when drawing (a), and curve re-creation where the target curve is initially visible (b) but is hidden as soon as the participant starts to draw (c). drawing tasks, each with important applications [arora et al. ]. our curve re-creation task is designed to capture free-form drawing, with minimal visual suggestion of intended target curve. we wanted to design target curves that could be executed using a single smooth motion. since users typically draw sharp corners using multiple strokes [bae et al. ], we constrain our target curves to be smooth, created using cardinal cubic b-splines on the meshes, computed using . we also control the length and curvature complexity of the curves, as pilot testing showed that very simple and short curves can be reasonably executed by almost any projection technique. curve length and complexity is modeled by placing spline control points at mesh vertices, and specifying the desired geodesic distance and gauß map distance between consecutive control points on the curve. we represent a target curve using four parameters n, i , k g , k n , where n is the number of spline control points, i the vertex index of the rst control point, and k g , k n constants that control the geodesic and normal map distance between consecutive control points. we de ne the desired geodesic distance between consecutive control points as, d g = k g × bbox(m) , where bbox(m) is the length of the bounding box diagonal of m. e desired gauß map distance (angle between the unit vertex normals) between consecutive control points is simply k n . a target curve c , . . . , c n− starting at vertex v i of the mesh is generated incrementally for i > as: where d g and d n compute the geodesic and normal distance between two points on m, and v ⊂ v contains only those vertices of m whose geodesic distance from c , . . . , c i− is at least d g / . e restricted subset of vertices conveniently helps prevent (but doesn't fully avoid) self-intersecting or nearly self-intersecting curves. curves with complex self-intersections are less important practically, and can be particularly confusing for the curve re-creation task. all our target curve samples were generated using k g ∈ [ . , . ], k n ∈ [π / , π / ], n = , and a randomly chosen i . e curves were manually inspected for self-intersections, and infringing curves rejected. we then de ned keypoints on the target curves as follows: curve endpoints were chosen as keypoints; followed by greedily picking extrema of geodesic curvature, while ensuring that the arclength distance between any two consecutive keypoints was at least cm; and concluding the procedure when the maximum arclength distance between any consecutive keypoints was below cm. our target curves had between - keypoints (including endpoints). e main variable studied in the experiment was projection methodspraycan vs. mimicry-realized as a within-subjects variable. e order of methods was counterbalanced between participants. for each method, participants were exposed to all the six objects. object order was xed as torus, cube, trebol, bunny, hand, and fertility, based on our personal judgment of drawing di culty. e torus was used as a tutorial, where participants had access to additional instructions visible in the scene and their strokes were not utilized for analysis. for each object, the order of the target strokes was randomized. e rst ve were used for the tracing curves task, while the remaining ve were used for re-creating curves. e target curve for the rst tracing task was repeated a er the ve unique curves, to gauge user consistency and learning e ects. a similar repetition was used for curve re-creation. participants thus performed curve drawing tasks per object, leading to a total of × (objects) × (projections) = strokes per participant. owing to the covid- physical distancing guidelines, the study was conducted in the wild, on participants' personal vr equipment at their homes. a -minute instruction video introduced the study tasks and the two projection methods. participants then lled out a consent form and a questionnaire to collect demographic information. is was followed by them testing the rst projection method and lling out a questionnaire to express their subjective opinions of the method. ey then tested the second method, followed by a similar questionnaire, and questions involving subjective comparisons between the two methods. participants were required to take a break a er testing the rst method, and were also encouraged to take breaks a er drawing on the rst three shapes for each method. e study took approximately an hour, including the questionnaires. twenty participants ( female) aged - from ve countries participated in the study. all but one were right-handed. participants self-reported a diverse range of artistic abilities (min. , max. , median on a - scale), and had varying degrees of vr experience, ranging from below year to over years. irteen participants had a technical computer graphics or hci background, while ten had experience with creative tools in vr, with one reporting professional usage. participants were paid ≈ usd as a gi card. as the study was conducted on personal vr setups, a variety of commercial vr devices were utilized-oculus ri , ri s, and est using link cable, htc vive and vive pro, valve index, and samsung odyssey using windows mixed reality. all but one participant used a standing setup allowing them to freely move around. before each trial, participants could use the "grab" bu on on their controller (in the dominant hand) to grab the mesh to position and orient it as desired. e trial started as soon as the participant started to draw by pressing the "main trigger" on their dominant hand controller. is action disabled the grabbing interactionparticipants could not draw and move the object simultaneously. as noted earlier, for curve re-creation tasks, this had the additional e ect of hiding the target curve, but leaving keypoints visible. we recorded the head position h and orientation h, controller position c and orientation c, projected point q, and timestamp t, for each mid-air stroke point p = c. in general, we will refer to a task target curve by x, p s and p m as the mid-air strokes executed, and q s and q m , the corresponding curves created using spraycan and mimicry projection, respectively. we drop the superscript when the projection method used is not relevant, referring to a mid-air stroke as p and its projected curve as q. we formulated three criteria to lter out meaningless user strokes: short curves: we ignore projected curves q that are too short as compared to the length of the target curves x (conservatively curves less than half as long as the target curve). while it is possible that the user stopped drawing mid-way out of frustration, we found it was more likely that they prematurely released the controller trigger by accident. both curve lengths are computed in r for e ciency. stroke noise: we ignore strokes for which the mid-air stroke is too noisy. speci cally, mid-air strokes with distant consecutive points (∃ i s.t. p i − p i− > cm) are rejected. inverted strokes: while we labelled keypoints with numbers and marked start and end points in green and red (figure ), some users occasionally drew the target curve in reverse. e motion to draw a curve in reverse is not symmetric, and such curves are thus rejected. we detect inverted strokes by look at the indices i , i , . . . , i l of the points in q which are closest to the keypoints x k , x k , . . . , x k l of x. ideally, the sequence i , . . . , i l should have no inversions, i.e., ∀ ≤ j < k ≤ l, i j ≤ i k ; and maximum l(l + )/ inversions, if q is aligned in reverse with x. we consider curves q with more than l(l + )/ (half the maximum) inversions, to be inadvertently inverted and reject them. we compute distances to the keypoints in r for e ciency. despite conducting our experiment remotely without supervision, we found that . % of the strokes satis ed our criteria and could be utilized for analysis. for comparisons between π spr a and π mimicr , we reject curve pairs where either curve did not satisfy the quality criteria. out of curve pairs ( total strokes), ( . %) satis ed the quality criteria and were used for analysis, including pairs for the curve re-creation task and for the tracing task. we de ne di erent statistical measures (table ) to compare π spr a and π mimicr curves in terms of their accuracy, aesthetic, table . antitative results (mean ± std-dev.) of the comparisons between mimicry and spraycan projection. all measures are analyzed using wilcoxon signed-rank tests, lower values are be er, and significantly be er values (p < . ) are shown in boldface. accuracy, aesthetic, and physical e ort measures are shown with green, red, and blue backgrounds, respectively. and e ort in curve creation. we consistently use the non-parametric wilcoxon signed rank test for all quantitative measures instead of a parametric test such as the paired t-test, since the recorded data for none of our measures was normally distributed (normality hypothesis rejected via the kolmogorov-smirnov test, p < . ). . . curve accuracy. accuracy is computed using two measures of distance between points on the projected curve q and target curve x. both curves are densely re-sampled using m = sample points equi-spaced by arc-length. given q = q , . . . , q m− and x = x , . . . , x m− , we compute the average equi-parameter distance d ep as where d e computes the euclidean distance between two points in r . we also compute the average symmetric distance d s m as in other words, d ep computes the distance between corresponding points on the two curves and d s m computes the average minimum distance from each point on one curve to the other curve. mi mi c r y ( t r a c i n g ) s p r a y c a n ( t r a c i n g ) mi mi c r y ( r e -c r e a t i n g ) s p r a y c a n ( r e -c r e a t i n g ) (c) example strokes, orange points in (a, b) above. fig. . curvature measures (a,b) indicate that mimicry produces significantly smoother and fairer curves than spraycan for both tracing (le ) and re-creating tasks (right). pairwise comparison plots between mimicry (yaxis) and spraycan (x-axis), favour mimicry for the vast majority of points (points below the = x line). a linear regression fit (on the log plots) is shown as a dashed line. example curve pairs (orange points) for curve tracing (le ) and re-creating (right) are also shown with the target curve x shown in gray (c). for both tracing and re-creation tasks, d ep indicated that mimicry produced signi cantly be er results than spraycan (see table , figure c, ) . e d s m di erence was not statistically signi cant, evidenced by users correcting their strokes to stay close to the intended target curve (at the expense of curve aesthetic). . . curve aesthetic. for most design applications, jagged projected curves, even if geometrically quite accurate, are aesthetically undesirable [mccrae and . curvature-based measures are typically used to measure fairness of curves. we report three such measures of curve aesthetic for the projected curve q. we note that the smoothness quality of the user stroke p, was similar to q and signi cantly poorer than the target curve x. is is expected since drawing in mid-air smoothly and with precision is di cult, and such strokes are usually neatened post-hoc [arora et al. ] . we therefore avoid comparisons to the target curve and simply report three aesthetic measures for a projected curve q = q , . . . , q n− . we rst re ne q by computing the exact geodesic on m between consecutive points of q [surazhsky et al. ] , to create q with points q , . . . , q k− , k ≥ n. we choose to normalize our curvature measures using l x , the length of the corresponding target stroke x. e normalized euclidean curvature for q is de ned as where θ i is the angle between the two segments of q incident on q i . us, k e is the total discrete curvature of q, normalized by the target curve length. since q is embedded in m, we can also compute discrete geodesic curvature, computed as the deviation from the straightest geodesic for a curve on surface. using a signed θ i de ned at each point q i via polthier and schmies's de nition [ ] , we compute normalized geodesic curvature as finally, we de ne fairness [arora et al. ; mccrae and singh ] as a rst-order variation in geodesic curvature, thus de ning the normalized fairness de ciency as for all three measures, a lower value indicates a smoother, pleasing, curve. wilcoxon signed-rank tests on all three measures indicated that mimicry produced signi cantly smoother and be er curves than spraycan (table ) . antitatively, we use the amount of head (hmd) and hand (controller) movement, and stroke execution time τ , as proxies for physical e ort. for head and hand translation, we rst lter the position data with a gaussian-weighted moving average lter with σ = ms. we then de ne normalized head/controller translation t h and t c as the length of the poly-line de ned by the ltered head/controller positions normalized by the length of the target curve l x . an important ergonomic measure is the amount of head/hand rotation required to draw the mid-air stroke. we rst de-noise or lter the forward and up vectors of the head/controller frame, using the same lter as for positional data. we then re-orthogonalize the frames and compute the length of the curve de ned by the ltered orientations in so( ), using the angle between consecutive orientation data-points. we de ne normalized head/controller rotation r h and r c as its orientation curve length, normalized by l x . table summarizes the physical e ort measures. we observe lower controller translation (e ect size ≈ %) and execution time (e ect size ≈ %) in favour of spraycan; lower head translation and hi g h l y p r e f e r mi mi c r y s o me wh a t p r e f e r mi mi c r y ne u t r a l s o me wh a t p r e f e r s p r a y c a n hi g h l y p r e f e r s p r a y c a n s p r a y c a n mi mi c r y orientation (e ect sizes ≈ %, %) in favour of mimicry. noteworthy, is the signi cantly reduced controller rotation using mimicry, with spraycan unsurprisingly requiring % (tracing) and % (recreating) more hand rotation from the user. antifying users' tendency to mimic. e study also provided an opportunity to test if the users actually tended to mimic their intended curve x in the mid-air stroke p. to quantify the "mimcriness" of a stroke, we subsample p and x into m points as in § . . , use the correspondence as in eq. and look at the variation in the distance (distance between the closest pair of corresponding points subtracted from that of the farthest pair) as a percentage of the target length l x . we call this measure the mimicry violation of a stroke. intuitively, the lower the mimicry violation, the closer the stroke p is to being a perfect mimicry of x, going to zero if it is a precise translation of x. notably, users depicted very similar trends to mimic for both the techniques-with % (mimicry), % (spraycan) strokes exhibiting mimicry violation below % of l x , and %, % below % of l x -suggesting that mimicry is indeed a natural tendency. recall that users repeated of the strokes per shape for both the techniques. to analyze consistency across the repeated strokes, we compared the values of the stroke accuracy measure d eq and the aesthetic measure f between the original stroke and the corresponding repeated stroke. speci cally, we measured the relative change | f (i) − f (i )|/f (i), where (i, i ) is a pair of original and repeated strokes, and f (·) is either d eq or f . users were fairly consistent across both the techniques, with the average consistency for d eq being . % for mimicry and . % for spraycan, while for f , it was . % and . %, respectively. note that the averages were computed a er removing extreme outliers outside the σ threshold. alitative analysis e mid-and post-study questionnaires elicited qualitative responses from participants on their perceived di culty of drawing, curve accuracy and smoothness, mental and physical e ort, understanding of the projection methods, and overall method of preference. participants rated their perceived di culty in drawing on the study objects (figure ), validating our ordering of shapes in the experiment based on expected drawing di culty. accuracy, smoothness, physical/mental e ort responses were collected via -point likert scales. we consistently order the choices from (worst) to (best) in terms of user experience in figure , and reported median (m) scores here. mimicry was perceived to be a more accurate projection method (tracing, re-creating m = , . ) compared to spraycan (m = , ), with participants perceiving their traced curves to be either very accurate or somewhat accurate with mimicry (compared to for spraycan) (figure a ). user perception of stroke smoothness was also consistent with quantitative results, with mimicry (tracing, re-creating m = , ) clearly outperforming spraycan (tracing, re-creating m = , ) ( figure b ). lastly, with no need for controller rotation, mimicry (m = ) was perceived as less physically demanding than spraycan (m = ), as expected ( figure c ). e response to understanding and mental e ort was more complex. spraycan, with its physical analogy and mathematically precise de nition was clearly understood by all participants ( very well, somewhat) (figure a ). mimicry, conveyed as "drawing a mid-air stroke on or near the object as similar in shape as possible to the intended projection", was less clear to users ( very well, somewhat, not at all). despite not understanding the method, the participants were able to create curves that were both accurate and smooth. further, users perceived mimicry (m = . ) as less fig. . gallery of free-form curves in red, drawn using mimicry. from le to right, tracing geometric features on the bunny, smooth maze-like curves on the cube, maze-like curve with sharp corners and a spiral on the trebol, and artistic ta oo motifs on the hand. some mid-air strokes (black) are hidden for clarity. cognitively taxing than spraycan (m = ) (figure c ). we believe this may be because users were less prone to consciously controlling their stroke direction and rather focused on drawing. e tendency to mimic may have thus manifested sub-consciously, as we had observed in pilot testing. e most important qualitative question was user preference (figure b ). % of the participants preferred mimicry ( highly preferred, somewhat preferred). e remaining users were neutral ( / ) or somewhat preferred spraycan ( / ). we also asked participants to elaborate on their stated preferences and ratings. participants (p , , , ) noted discontinuous "jumps" caused by spraycan, and felt the continuity guarantee of mimicry: "seemed to deal with the types of ji er and inaccuracy vr setups are prone to be er" (p ) ; "could stabilize my drawing" (p ) . p , felt that mimicry projection was smoothing their strokes (no smoothing was employed): we believe this may be the e ect of noise and inadvertent controller rotation, which mimicry ignores, but can cause large variations with spraycan, perceived as curve smoothing. some participants (p , ) felt that rotating the hand smoothly while drawing was di cult, while others missed the spraycan ability to simply use hand rotation to sweep out long projected curves from a distance (p , ). participants commented on physical e ort: "mimicry method seemed to required [sic] much less head movement, hand rotation and mental planning" (p ) . participants appreciated the anchored control of mimicry in highcurvature regions (p , , , ) also noting that with spraycan, "the curvature of the surface could completely mess up my stroke" (p ) . some participants did feel that spraycan could be preferable when drawing on near-at regions of the mesh (p , , , ) . finally, participants who preferred spraycan felt that mimicry required more thinking: "with mimicry, there was extra mental e ort needed to predict where the line would go on each movement" (p ) , or because mimicry felt "unintuitive" (p ) due to their prior experience using a spraycan technique. some who preferred mimicry found it di cult to use initially, but felt it got easier over the course of the experiment (p , ). complex d curves on arbitrary surfaces can be drawn in ar/vr with a single stroke, using mimicry ( figure ). drawing such curves on d virtual objects is fundamental to many applications, including direct painting of textures [schmidt et al. ]; tangent vector eld design [fisher et al. ]; texture synthesis [lefebvre and hoppe ; turk ] ; interactive selection, annotation, and object segmentation [chen et al. ]; and seams for shape parametrization [lévy et al. ; rabinovich et al. ; sawhney and crane ] , registration [gehre et al. ] , and quad meshing [tong et al. ]. we showcase the utility and quality of mimicry curves within example applications (also see supplemental video). texture painting: figures e, show examples of textures painted in vr using mimicry. e long, smooth, wraparound curves on the torus, are especially hard to draw with d interfaces. our implementation uses discrete exponential maps (dem) [schmidt et al. ] to compute a dynamic local parametrization around each projected point q i , to create brush strokes or geometric stamps on the object. mesh segmentation: figures e and show mimicry used for interactive segmentation in vr. in our implementation users draw an almost-closed curve q = {q , . . . , q n− } on the object using mimcry. we snap points q i to their nearest mesh vertex, and use dijkstra's shortest path to connect consecutive vertices, and to close the cycle of vertices. a mesh region is selected or segmented using mesh faces partitioned by these cycles that are easy to draw in ar/vr, but o en require view changes and multiple strokes in d. vector field design: vector elds on meshes are commonly used for texture synthesis [turk ], guiding uid simulations [stam ], and non-photorealistic rendering [hertzmann and zorin ] . we use mimicry curves as so constraints to guide the vector eld generation of fisher et al. [ ] . figure shows example vector elds, visualized using line integral convolutions [cabral and leedom ] in the texture domain. we have presented a detailed investigation of the problem of realtime inked drawing on d virtual objects in immersive environments. we show the importance of stroke context when projecting mid-air d strokes, and explore the design space of anchored projections. a -participant remote study showed mimicry to be preferred over the established spraycan projection for projecting mid-air strokes on d objects in ar/vr. both mimicry projection and performing vr studies in the wild do have some limitations. further, while user stroke processing for d interfaces is a mature eld of research, mid-air stroke processing for ar/vr is relatively nascent, with many directions for future work. "in the wild" vr study limitations. ongoing pandemic restrictions presented both a challenge and an opportunity to remotely conduct a more natural study in the wild, with a variety of consumer vr hardware and setups. e enthusiasm of the vr community allowed us to readily recruit diligent users, albeit with a bias towards young, adult males. while the variation in vr headsets seemed to be of li le consequence, there was a notable di erence in shape and size of the d controllers. controller grip and weight can certainly impact mid-air drawing posture and stroke behavior. controller size is also signi cant: a larger vive controller for example, has a higher chance of occluding target objects and projected curve, as compared to a smaller oculus touch controller. we could have mitigated the impact of controller size by rendering a standard drawing tool in vr, but we preferred to remain application agnostic, rendering the familiar, default controller that matched the physical controller in participants' hands. further, no participants explicitly mentioned the controller ge ing in the way of their ability to draw. overall, our study contributes a high-quality vr data corpus comprising ≈ user strokes, projected curves, intended target curves, and corresponding vr system states. is data can serve as a benchmark for future work in mid-air stroke projection, and data-driven learning techniques for mid-air stroke processing. mimicry limitations. our lack of a concise mathematical denition of observed stroke mimicry, makes it harder to precisely communicate it to users. while a precise mathematical formulation may exist, conveying it to non-technical users can still be a challenging task. mimicry ignores controller orientation, producing smoother strokes with less e ort, but can give participants a reduced sense of sketch control (p , , ). we hypothesize that the reduced sense of control is in part due to the tendency for anchored smooth-closest-point to shorten the user stroke upon projection, sometimes creating a feeling of lag. spraycan like techniques in contrast, have a sense of ampli ed immediacy, and the explicit ability to make lagging curves catch-up by rotating a controller in place. future work. our goal was to develop a general real-time inked projection with minimal stroke context via anchoring. optimizing the method to account for the entire partially projected stroke may improve the projection quality. relaxing the restriction of real-time inking would allow techniques such as spline ing and global optimization that can account for the entire user stroke and geometric features of the target object. local parametrizations such as dem ( § ) can be used to incrementally grow or shrink the projected curve, so it does not lag the user stroke. hybrid projections leveraging both proximity and raycasting are also subject to future work. on the interactive side, we did experiment with feedback to encourage users to draw closer to a d object. for example, we tried varying the appearance of the line connecting the controller to the projected point based on line length; or providing aural/haptic feedback if the controller got further than a certain distance from the object. while these techniques can help users in speci c drawing or tracing tasks, we found them to be distracting and harmful to stroke quality for general stroke projection. bimanual interaction in vr, such as rotating the shape with one hand while drawing on it with the other (suggested by p , ), can also be explored. perhaps the most exciting area of future work is employing datadriven techniques to infer the user-intended projection, perhaps customized to the drawing style of individual users. our study code and data will be made publicly available to aid in such endeavours. in summary, this paper presents early research on processing and projection of mid-air strokes drawn on and around d objects, that we hope will inspire further work and applications in ar/vr. we are thankful to michelle lei for developing the initial implementation of the context-free techniques, and to jiannan li and debanjana kundu for helping pilot our methods. we also thank various d model creators and repositories for the models we utilized: stanford bunny model courtesy of the stanford d scanning repository, trebol model provided by shao et al.[ ] , fertility model courtesy the aim@shape repository, hand model provided by jeffo on turbosquid.com, and cup model (figure ) provided by daniel noree on thingiverse.com under a cc by . license. substance painter association for computing machinery experimental evaluation of sketching on surfaces in vr symbiosissketch: combining d & d sketching for designing detailed d objects in situ ilovesketch: as-naturalas-possible sketching system for creating d curve models fast winding numbers for soups and clouds imaging vector fields using line integral convolution -sweep: extracting editable objects from a single photo a benchmark 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polyhedral surfaces scalable locally injective mappings boundary first fla ening surface drawing: creating organic d shapes with the hand and tangible tools overcoat: an implicit canvas for d painting open-source (boost-license) c# library for geometric computing interactive decal compositing with discrete exponential maps analytic drawing of d sca olds meshmixer: an interface for rapid mesh composition crossshade: shading concept sketches using cross-section curves tetgen, a delaunay-based ality tetrahedral mesh generator wires: a geometric deformation technique gravity sketch. h ps://www.gravitysketch.com/ olga sorkine and daniel cohen-or flows on surfaces of arbitrary topology sculpting multi-dimensional nested structures fast exact and approximate geodesics on meshes sketch-based generation and editing of ad meshes elasticurves: exploiting stroke dynamics and inertia for the real-time neatening of sketched d curves designing adrangulations with discrete harmonic forms texture synthesis on surfaces a sketch-based interface for clothing virtual characters freedrawer: a free-form sketching system on the responsive workbench investigating the learnability of immersive free-hand sketching hairbrush for immersive data-driven hair modeling true form: d curve networks from d sketches via selective regularization key: cord- -a fzp bn authors: kamdar, hera a.; senay, blake; mainali, shraddha; lee, vivien; gulati, deepak kumar; greene-chandos, diana; hinduja, archana; strohm, tamara title: clinician's perception of practice changes for stroke during the covid- pandemic: perception of practice changes for stroke during covid- date: - - journal: j stroke cerebrovasc dis doi: . /j.jstrokecerebrovasdis. . sha: doc_id: cord_uid: a fzp bn background: approach to acute cerebrovascular disease management has evolved in the past few months to accommodate the rising needs of the novel coronavirus (covid- ) pandemic. in this study, we investigated the changes in practices and policies related to stroke care through an online survey. methods: a question, cross-sectional survey targeting practitioners involved in acute stroke care in the us was distributed electronically through national society surveys, social media and personal communication. results: respondants from states completed surveys with the majority ( . %) from comprehensive stroke centers. approximately half stated some change in transport practices with ( %) reporting significant reduction in transfers. common strategies to limit healthcare provider exposure included using personal protective equipment (ppe) for all patients ( ; . %) as well as limiting the number of practitioners in the room ( ; . %). most respondents ( %) noted an overall decrease in stroke volume. many ( %) felt that the outcome or care of acute stroke patients had been impacted by covid- . this was associated with a change in hospital transport guidelines (or . , p= . , % ci: . - . ), change in eligibility criteria for iv-tpa or mechanical thrombectomy (mt) (or . , p= . , % ci: . - . ), and modified admission practices for post iv-tpa or mt patients (or . , p= . , % ci: . - . ). conclusion: our study highlights a change in practices and polices related to acute stroke management in response to covid- which are variable among institutions. there is also a reported reduction in stroke volume across hospitals. amongst these changes, updates in hospital transport guidelines and practices related to iv-tpa and mt may affect the perceived care and outcome of acute stroke patients. a question, cross-sectional survey targeting practitioners involved in acute stroke care in the us was distributed electronically through national society surveys, social media and personal communication. our study highlights a change in practices and polices related to acute stroke management in response to covid- which are variable among institutions. there is also a reported reduction in stroke volume across hospitals. amongst these changes, updates in hospital transport guidelines and practices related to iv-tpa and mt may affect the perceived care and outcome of acute stroke patients. acute stroke care is time sensitive and requires a prompt multidisciplinary approach for effective management. the essential components involve rapid decision making for the need of thrombolytic therapy and/or endovascular intervention, and then transfer to a center with a higher level of care as described in the "hub and spoke" model . this model of practice allows for timely intervention for patients presenting at remote community hospitals and improves overall patient outcomes . as the novel coronavirus (covid- ) pandemic continues to evolve, hospitals across the nation have implemented new policies and protocols to ensure the safety of patients and practitioners, and to conserve or reallocate resources. we sought to survey the stroke community across the nation to understand the current changes in stroke systems of care. the primary objective of this survey is to understand the changes in practices and policies related to acute stroke care during the covid- pandemic. the secondary objective is to analyze the effect of these changes on the perceived impact of acute stroke care and patient outcome. this is an irb exempt, observational, population-based study led by researchers at the ohio state university. a cross-sectional survey of twelve questions (table ) the intended participants for this survey were practicing and training physicians and advanced practice providers (apps) on the front lines of stroke care. this included multiple specialties such as neurology, neurosurgery, internal medicine, and emergency medicine. to minimize recall bias we created a descriptive and detailed set of questions that were internally peer-reviewed prior to distribution. we also targeted health care professionals that would be the most informed about these practice changes. data were analyzed with spss for windows. descriptive statistics were used to report the characteristics of survey respondents. attitudes about hospital transport, specialty unit utilization, stroke volume and patient outcomes were compared to demographic characteristics with a chi-squared test. binomial logistic regression analysis was conducted using questions regarding change in stroke practice as independent variables to identify factors associated with perceived change in outcome or care. regression diagnostics were performed for each analysis. the statistical significance was set at p < . (two-sided). odds ratios (ors) and their % confidence intervals were used to quantify the associations between variables. we received a total of responses with a % completion rate. six surveys were excluded since the respondents were outside the target population ( rns, pharmacists, one neuroscience coordinator). the respondents included ( . %) attending/practicing physicians, ( . %) vascular neurologists, and ( %) neurocritical care specialists ( table perception of practice changes for stroke during covid- ). the majority ( . %) identified themselves as working in the setting of a comprehensive stroke center (table ) . survey respondents represented states. respondents reported the following: no change in hospital transport practices in ( . %), transferring most patients in ( . %), transferring only some patients in ( %), and significantly limiting the number of patients transferring in ( %). other responses included "we went on neuro-divert" and "yes, ems stopped bringing us patients altogether". most responded that mechanical thrombectomy (mt) ( . %), ruptured aneurysm ( . %), ich intervention ( %), and hemicraniectomy monitoring ( . %) warranted transport to a higher level of care. participants from many institutions reported implementation of new policies regarding acute stroke management to limit healthcare provider exposure, and these practices varied widely (table ) . common strategies to ensure patient and provider safety included using personal protective equipment (ppe) during evaluation of all patients ( . %) and limiting the number of practitioners in the room ( . %). despite increased precautions, most respondents ( . %) did not report change in eligibility criteria for interventional therapies such as iv-tpa or mt. other responses included elective intubation for mt patients to "reduce exposure in the angiography suite", and more conservative criteria for mt with regards to age and baseline modified rankin the covid- pandemic has multifactorial impact on the logistics of stroke care and has required rapid adaptation at stroke centers nationally. special considerations include: maximizing safety of healthcare workers and patients (appropriate ppe and adjustment in protocols to include enhanced screening of patients for covid- ), effect of mitigation policies on stroke volumes, and changes in protocols that would potentially add delays to time sensitive acute treatments. our study demonstrated the rapidly changing environment surrounding stroke patients in the era of covid- . stroke volumes were reported to be decreased. many respondents also felt that the outcome or care of stroke patients at his or her institution had been impacted by the covid- pandemic. based on our multicenter survey, it can be gleaned that across the country a majority of centers are seeing lower stroke volumes compared to pre-pandemic numbers. several centers noted that, despite the lower overall volumes, large vessel occlusion and major strokes have been on the rise. our findings are in alignment with several other reports - . one hypothesis for this phenomenon is patients' fearing or avoiding the emergency department due to the risk of covid- infection additionally, an argument can be made for proactive public education regarding the feasibility of safe delivery of acute stroke care despite the ongoing pandemic . although the covid- pandemic has redirected the healthcare focus and resources as a public health emergency, stroke continues to be a cause of neurologically devastating injury and remains an important cause of morbidity and mortality across the usa. hence continued efforts to ensure delivery of effective and evidenced based stroke care is critical. ultimately, nationwide procedural changes have been implemented to ensure the safety of patients, healthcare providers and hospital staff to allow for continued effective care throughout this pandemic. these necessary efforts can be streamlined in ways to decrease a delay in emergent care, as in the case of acute stroke patients. suggestions to consider include: expanding the availability and expediting the result processing of rapid rt-pcr sars-cov- testing both in the emergency department and from transferring hospitals to allow for efficient triaging; dedicating a single ct scanner and/or angiogram suite to limit cross contamination of patient's and streamline the turnover process; and/or intubating all patients requiring mt if covid- status is pending to ensure safety of providers without delaying door to groin puncture times. survey responses limit our data to subjective interpretations of stroke care at individual institutions. stroke quality metrics and objective outcomes were not incorporated into this study. while we did have survey respondents from almost every state in the usa, many have only - respondents, and several states appeared oversampled (california, michigan, ohio) which may limit external validity. sample size was also not prioritized because of the rapidly escalating disease burden within the united states and the need to report our results in a timely fashion. a majority of respondents were from comprehensive stroke centers, which may also limit application to primary stroke centers and community-based hospitals. the significance seen with change in stroke volumes dependent on area of speciality may potentially be confounded by the level of training and/or differing exposure rates to acute stroke care. similar significance seen in regards to region may reflect regional practices, though small perception of practice changes for stroke during covid- sample size limits utility of this finding. prior studies suggested differences in patterns of care and hospital characeristics based on location . it is evident from our questionnaire that change in practices for acute stroke care including hospital transport guidelines and policies regarding interventional therapies may impact perceived stroke outcome or care. as emphasized in the aha guidelines, hospital systems should make efforts to limit changes in established stroke practices. this is a pressing concern as current national and state wide restrictions may not lift for some time. what procedures are still considered essential requiring transport to a comprehensive stroke center during the covid- pandemic?* have stroke alert practices changed at your institution during the covid- pandemic?* is there any change in eligibility criteria for tpa or thrombectomy to limit staff exposure and save resources for pui or +covid- patients? have you changed admission practices for post-tpa or thrombectomy patients during the covid- pandemic?* has your stroke and/or neuro intensive care unit been affected by the covid- pandemic?* do you believe there has been a change in stroke volume at your institution in the setting of the covid- pandemic? do you believe the outcome or care of stroke patients at your institution has been impacted in the setting of the covid- pandemic? *select all that apply . *responses included "yes", "no" or "other" the hub-and-spoke organization design: an avenue for serving patients well telemedicine quality and outcomes in stroke: a scientific statement for healthcare professionals from the acute stroke management pathway during coronavirus- pandemic the baffling case of ischemic stroke disappearance from the casualty department in the covid- era mechanical thrombectomy for acute ischemic stroke amid the covid- outbreak: decreased activity, and increased care delays collateral effect of covid- on stroke evaluation in the united states outbreak on st-segment-elevation myocardial infarction care in hong kong, china invited commentary: an undermined regional acute stroke system amid covid- outbreak in south korea covid- , sars and mers: a neurological perspective preparing a neurology department for sars-cov- (covid- ): early experiences at columbia university irving medical center and the new york presbyterian hospital protected code stroke: hyperacute stroke management during the coronavirus disease society of neurointerventional surgery recommendations for the care of emergent neurointerventional patients in the setting of covid- endovascular therapy for patients with acute ischemic stroke during the covid- pandemic: a proposed algorithm mechanical thrombectomy in the era of the covid- pandemic: emergency preparedness for neuroscience teams: a guidance statement from the society of vascular and interventional neurology anesthetic management of endovascular treatment of acute ischemic stroke during covid- pandemic: consensus statement from society for neuroscience in anesthesiology & critical care (snacc)_endorsed by society of vascular & interventional neurology (svin), society of neurointerventional surgery (snis), neurocritical care society (ncs), and european society of minimally invasive neurological therapy (esmint) preserving stroke care during the covid- pandemic: potential issues and solutions regional variation in recommended treatments for ischemic stroke and tia: get with the guidelines--stroke key: cord- -v g eios authors: de silva, deidre anne; il fan, tan; d/o thilarajah, shamala title: a protocol for acute stroke unit care during the covid- pandemic: acute stroke unit care during covid- date: - - journal: j stroke cerebrovasc dis doi: . /j.jstrokecerebrovasdis. . sha: doc_id: cord_uid: v g eios background: acute stroke unit (asu) care is proven to reduce mortality and morbidity. during the covid- crisis, established physical units and care practices within existing physical units are likely to be disrupted. stroke patients with possible suspected covid- infection may be isolated in other wards outside the asu. methods: our hospital developed an adapted asu protocol which includes key elements for stroke unit care, can be utilized by staff not familiar with stroke care with minimal training and can be implemented in various settings. results: the adapted protocol has categories of acute monitoring (neurological observations, blood pressure and input-output monitoring, investigations and specific post-reperfusion issues), stroke complications (focusing on common complications) and unified team (describing daily check-ins, patient education, communication, discharge planning and post-discharge support). conclusions: details are presented in the article in a format that it can be adopted by other centers facing similar issues in order to ensure asu care is not compromised. limited resources, manpower shortages, tight infection control, physical distancing regulations and stay-at-home policies, we are all adapting our systems to care for stroke patients during this challenging time. there are different phases in the care of stroke patients and these may overlap; hyperacute care often involving reperfusion treatments, acute stroke unit (asu) management as an inpatient and subsequently rehabilitation focus in an inpatient or outpatient setting. there have been reports providing guidance and protocols for hyperacute reperfusion treatment provision such as the management of stroke activations, considerations for intravenous thrombolysis and endovascular clot retrieval.( - ) whilst some reports have commented on considerations along the spectrum of stroke care, ( , ) there has been little guidance beyond hyperacute stroke treatment. care in asu is proven to reduce mortality and disability with long lasting benefits up to years after stroke onset. ( ) during this pandemic, asu care is likely to be affected in many hospitals. many may have their physical stroke units displaced due to bed utilization needs for coronavirus disease (covid- ) infected and suspect cases. most hospitals have staff deployed outside their usual workplaces to cover emergency, isolation and screening services therefore disbanding the acute stroke unit team of multi-professional healthcare providers. in our hospital, we estimate that - % of our doctors, nurses and therapists from the stroke ward have been deployed to other areas. staff shortages are often compounded by quarantine of staff due to covid- patient exposure or acute respiratory illnesses. thus, patients may be scattered across various wards in the hospital, are being managed by healthcare providers who are unfamiliar with stroke care and are not trained to use established stroke pathways and protocols. furthermore, stroke patients who have concomitant acute respiratory symptoms or contact history will need to be isolated and therefore cared in areas other than the asu. at the singapore general hospital, our asu has remained physically intact but many asu staff have been deployed elsewhere asu due to the covid- crisis. the stroke team attending to patients at the emergency department don full personal protection equipment as patient's covid- risk status is unknown. once this has been determined, the patient may be admitted to isolation wards based on specific criteria. we have encountered stroke patients being managed in isolation wards due to suspected possible covid- infection, including some who had been treated with intravenous thrombolysis and endovascular clot retrieval. in order to orientate staff in these circumstances, our stroke team had to brief healthcare workers in these isolation wards on the care of these stroke patients, which was difficult as many had no neurology training and usually practice in other specialty areas. we realized that our asu pathway was developed to be used by healthcare workers trained to use it, familiar with its format and was too complex to be used by untrained staff. an interprofessional team with medical, nursing and allied health backgrounds at the singapore general hospital developed an adapted asu protocol that was easy to use and ensured that the key elements the acute stroke unit are maintained. this protocol focuses on the asu phase of stroke care with some rehabilitation aspects which occurs just before or after the asu phase. this tool may be useful to others facing similar issues in hospitals across the world. our adapted asu guide has components based on the asu acronym-acute monitoring, stroke complications and unified team approach. it has been outlined in a one-page document ( figure ) that can be provided to healthcare workers caring for stroke patients in isolation or non-asu wards so that the key elements of the proven stroke unit management are maintained and therefore stroke patients can benefit from its proven effects. it requires a short briefing and specifics for the individual patient should be handed over. we emphasize that the stroke team should continue care following inpatient admission to ensure that there is continuity of care for patients and their families. there are elements included in this section: neurological observations, blood pressure measurement, input-output charting, investigations and specific issues following hyperacute whilst this is not as comprehensive as the nihss, it is a reasonable alternative for untrained staff and covers key components. use of gcs is limited for assessing neurological deterioration in stroke. ( ) the frequency of observations should be specified and the nursing team should receive advice on when to activate the medical team of any differences in neurological status. blood pressure is particularly important in acute stroke patients and this is emphasized as a separate component. the frequency of measurements should be specified and targets above and below that require escalation should also be specified. daily input and output charting is important as patients may require intravenous fluids and their daily intake may be affected by the stroke. bowel movements should be noted to avoid constipation. investigations should be ordered mindfully to avoid unnecessary transfers and use of resources. if there is no urgent need nor significant impact on patient care, the managing team may choose to defer some investigations if there are pressures on hospital resources. for example, work-up to search for a possible patent foramen ovale may be deferred if the suspicion for this is low in a patient with cryptogenic stroke. there may be specific instructions for patients following thrombolysis and endovascular clot retrieval and these should be advised for individual needs accordingly. there are stroke complications emphasize in the adapted asu protocol which should be screened for, prevented, as well as detected and managed early should they occur. these are venous thromboembolism (vte), dysphagia complications including aspiration pneumonia, complications from tubes and lines, immobility complications and issues with nutrition. vte prophylaxis for stroke patients should be maintained for patients cared outside the asu. if the staff is not familiar with the indications, intermittent pneumatic compressions devices should be applied universally unless contraindicated. prevention of aspiration pneumonia is important may not be a particular issue outside the asu and thus is important to highlight. as the medical and nursing staff may not be trained to assess swallowing, all patients should have a speech therapy assessment for dysphagia screening if possible. prior to this, patients should be kept nil by mouth or fed through a nasogastric tube. other measures are to ensure that the appropriate diet consistency advised by the speech therapist is adhered to; elevate the patient's head of bed to minimum - degree if it not contraindicated during and at least minutes after feeding; stop feeds or diet if the patient is drowsy; and to not let the patient swallow food or drink if the patients is drooling, coughing, choking, has frequent throat clearing, is breathless after swallowing or has a wet or gurgling voice. unnecessary tubes should not be inserted and should be removed as soon as not needed including urinary catheters, intravenous cannula and nasogastric tubes. intravenous cannula insertion sites should be checked for signs of phlebitis every nursing shift. patients with stroke often have immobility and hence regular monitoring for pressure issues is needed. prevention of immobility complications is important and involves regular turning, protection of the hemiplegic shoulder with appropriate positioning, pressure area protection and out-of-bed mobilization. nutritional needs must be considered as swallowing may be affected. this is especially pertinent for patients on tube feeding. this section deals with components of asu care which are often inter-professional. we have included daily check-ins with the stroke team, patient education, communication with families, discharge planning and support after discharge. we have adopted daily telephone check-ins by the stroke team contacting the clinical team there is a system for patients to speak to and interact with families with facilitated teleconferencing. in addition, regular updates by the healthcare team to patient's loved ones are provided. discharge planning is different with the covid- crisis as many postdischarge services are not available due to lockdown or physical distancing restrictions. we attempt to attend to most issues as far as possible as an inpatient to avoid unnecessary outpatient visits. the stroke team physiotherapist checks in with patients by telephone weeks after discharge to assess coping at home and post stroke complications, and any particular issue is brought up to the appropriate stroke team professionals to address. a hospital contact number is provided so that stroke survivors can seek help if needed. appropriate rehabilitation needs are addressed for discharge. whilst usual rehabilitation services prior to the covid- pandemic may be curtailed due to lockdown, infection control and other reasons, other options such as tele-rehabilitation, home exercise program, guidance with videos may be considered. international stroke organizations have collated resources for use by stroke clinicians to facilitate the change of practice in treatment delivery.( - ) as care may be truncated due to the covid- situation, we advocate for outpatient follow-up for all patient at a multidisciplinary post-stroke clinic to ensure all loose ends are addressed. these clinics are currently face-to-face but we will soon be initiating a virtual post-stroke clinic for patients who will likely not require a physical examination such as those with no or minor residual deficits. stroke support organizations (sso) are not able to provide their usual host of services. we are encouraged by our local sso who has developed online befriending, support groups and other programs. patients should be referred to adapted care and support services for stroke survivors and their caregivers. the adapted asu pathway is a guide which has assisted care of stroke patients outside our usual asu physical ward and pathway, and by staff not familiar with stroke patient management. it was designed to be simple, require little training and cover key elements of asu care, and can be adopted by other hospitals and centers facing challenges of maintaining asu care during the covid- crisis. protected code stroke: hyperacute stroke management during the coronavirus disease (covid- ) pandemic. stroke acute stroke management pathway during coronavirus- pandemic temporary emergency guidance to us stroke centers during the covid- challenges and potential solutions of stroke care during the coronavirus disease (covid- ) outbreak acute stroke care in the coronavirus disease stroke unit trialists' collaboration. organised inpatient (stroke unit) care for stroke slim stroke scales for assessing patients with acute stroke: ease of use or loss of valuable assessment data? telerehabilitation services for stroke canadian partnership for stroke recovery. covid- resources informme -telehealth resources in response to covid- key: cord- -f if e q authors: yaghi, shadi; ishida, koto; torres, jose; mac grory, brian; raz, eytan; humbert, kelley; henninger, nils; trivedi, tushar; lillemoe, kaitlyn; alam, shazia; sanger, matthew; kim, sun; scher, erica; dehkharghani, seena; wachs, michael; tanweer, omar; volpicelli, frank; bosworth, brian; lord, aaron; frontera, jennifer title: sars -cov- and stroke in a new york healthcare system date: - - journal: stroke doi: . /strokeaha. . sha: doc_id: cord_uid: f if e q background and purpose: with the spread of coronavirus disease (covid- ) during the current worldwide pandemic, there is mounting evidence that patients affected by the illness may develop clinically significant coagulopathy with thromboembolic complications including ischemic stroke. however, there is limited data on the clinical characteristics, stroke mechanism, and outcomes of patients who have a stroke and covid- . methods: we conducted a retrospective cohort study of consecutive patients with ischemic stroke who were hospitalized between march , , and april , , within a major health system in new york, the current global epicenter of the pandemic. we compared the clinical characteristics of stroke patients with a concurrent diagnosis of covid- to stroke patients without covid- (contemporary controls). in addition, we compared patients to a historical cohort of patients with ischemic stroke discharged from our hospital system between march , , and april , (historical controls). results: during the study period in , out of hospitalized patients with diagnosis of covid- infection, patients ( . %) had imaging proven ischemic stroke. cryptogenic stroke was more common in patients with covid- ( . %) as compared to contemporary controls ( . %, p= . ) and historical controls ( . %, p< . ). when compared with contemporary controls, covid- positive patients had higher admission national institutes of health stroke scale score and higher peak d-dimer levels. when compared with historical controls, covid- positive patients were more likely to be younger men with elevated troponin, higher admission national institutes of health stroke scale score, and higher erythrocyte sedimentation rate. patients with covid- and stroke had significantly higher mortality than historical and contemporary controls. conclusions: we observed a low rate of imaging-confirmed ischemic stroke in hospitalized patients with covid- . most strokes were cryptogenic, possibly related to an acquired hypercoagulability, and mortality was increased. studies are needed to determine the utility of therapeutic anticoagulation for stroke and other thrombotic event prevention in patients with covid- . c oronavirus disease (covid- ), the illness caused by the severe acute respiratory syndrome cov- coronavirus, has an unclear impact on the cerebrovascular system. with over confirmed cases as of april , , new york state currently accounts for ≈ % of all confirmed cases worldwide. given early reports of an association between covid- and cerebrovascular disease, there is a critical, unmet need to define associations and outcomes of patients with cerebrovascular disease and covid- . understanding factors associated with stroke in patients with covid- will aid in the diagnosis, treatment, and prevention of covid- associated cerebrovascular disease as well as potentially identify underlying stroke. ; : - . doi: . /strokeaha. . mechanisms. in this study, we aim to characterize ischemic stroke in patients with covid- from a large healthcare system with a diverse patient population in the new york metropolitan area and compare these characteristics to those of contemporary and historical ischemic stroke controls without covid- . we obtained institutional review board approval from nyu langone health to perform the study, and informed consent was waived by the institutional review board. data from the study are available for sharing upon reasonable request to the corresponding author. this is a retrospective observational study including patients admitted to one of comprehensive stroke centers in the new york metropolitan area (nyu langone manhattan, nyu langone brooklyn in sunset park, brooklyn, and nyu langone winthrop in mineola, long island) with acute ischemic stroke hospitalized between march , , and april , . all consecutive patients with radiological confirmation of acute ischemic stroke during this time frame were included. in addition, we included consecutive patients from of our facilities (nyu langone brooklyn and nyu langone manhattan) with a discharge diagnosis of ischemic stroke between march , , and april , , as a historical comparator group (historical control). in general, patients underwent a standard diagnostic evaluation, including brain imaging, intracranial and extracranial vascular imaging, and cardiac evaluation, including ecg, in-house continuous cardiac telemetry for at least hours, and transthoracic echocardiography per institutional protocol. stroke subtype was classified based on the trial of org in acute stroke treatment classification. large artery atherosclerosis was defined as % or more narrowing in an artery supplying the ischemic infarct territory, small vessel disease was defined as a small (≤ . cm on head computed tomography or ≤ cm on diffusion-weighted imaging sequence) subcortical infarct in patients with risk factors for small vessel disease, cardioembolic was defined as the presence of a major cardioembolic source, such as atrial fibrillation, endocarditis, or ejection fraction ≤ %, and other was defined as an alternative mechanism such as dissection or known hypercoagulability, excluding de novo hypercoagulability in the setting of a covid- . cryptogenic was defined as cases not meeting criteria for any of the above stroke subtypes, including those with incomplete workup or with multiple competing high-risk mechanisms. in addition, we defined embolic stroke of undetermined source according to the criteria proposed by the cryptogenic stroke/ embolic stroke of undetermined source international working group. finally, we also classified strokes based on the ascod criteria (atheroclerosis, small-vessel disease, cardiac pathology, other cause, and dissection). the following variables were abstracted from the medical records of patients: . screening for covid- was performed at first provider contact and included evaluation for recent covid- exposure, history of fever or respiratory symptoms, or chest radiographic findings. in general, patients with a negative screen do not undergo covid- testing. a positive screen would trigger testing, and this is generally the case when screening could not be completed. assays for covid- were performed in accordance with standards established by the world health organization. a reverse-transcriptase polymerase chain reaction study was performed in each center's laboratory using a sample obtained via a nasopharyngeal swab. the primary variable of interest was covid- status (positive versus negative). no sample-size calculations were performed. all patients (cases and control groups) were divided into groups: group included patients with ischemic stroke and covid- (cases), group included contemporary patients with ischemic stroke without covid- (contemporary controls), and we then performed binary logistic regression analyses to determine baseline characteristics and laboratory values associated with stroke in the setting of covid- compared with historical and contemporary controls. in these models, we included variables with a -sided p< . on univariate models. in addition, we performed binary logistic regression analyses to determine the association between covid- related stroke and in-hospital mortality adjusting for age and admission nihss score. analysis was performed using spss version . (chicago, il), and a -sided p< . was considered significant. out of patients hospitalized with covid- infection during the study period, we identified a total of patients ( . %) who had radiologically proven ischemic stroke. among contemporary controls, % ( / ) underwent the covid- test and the rest screened negative and were not tested. of the patients (table ) figure shows brain and chest imaging of patients with covid- and cryptogenic stroke subtype. treatments before stroke symptoms/diagnosis included hydroxychloroquine ( . %, n= ), lopinavir-ritonavir ( . %, n= ), and tocilizumab ( . %, n= ). when compared with contemporary stroke controls, patients with covid- and stroke were younger the left shows chest imaging (ct or x-ray) and the right shows brain imaging of patients with cryptogenic stroke and covid- infection in our patient cohort. in binary logistic regression models (table ) , when compared with contemporary controls, patients with covid- had non-significantly higher admission nihss score (odds ratio [or] per point increase . [ % ci, . - . ], p= . ) and higher peak d-dimer in binary logistic regression models (table ) , when compared with historical controls, covid- positive patients were non-significantly more likely to be younger ( in this multi-ethnic study, we report key demographic and clinical characteristics of patients who develop ischemic stroke associated with acute severe acute respiratory syndrome cov- coronavirus infection. the observed rate of imaging-confirmed acute ischemic stroke in hospitalized patients with covid- of . % was lower compared with prior reports from chinese covid- studies. reasons for difference are unknown but could possibly be related to differences in the patient population studied in our patient population as compared to the other studies and other studies including hemorrhagic stroke and venous sinus thrombosis patients. in addition, the rate of ischemic stroke in our study may be an underestimate as the detection of ischemic stroke symptoms is challenging in those critically ill with covid- infection who are intubated and sedated. when classified according to the trial of org in acute stroke treatment criteria, a majority ( . %) of these patients were classified as cryptogenic stroke and . % met embolic stroke of undetermined source criteria. in contrast, . % of the contemporary covid negative control group and . % of the historical control group were classified as cryptogenic stroke, in keeping with other modern stroke cohorts. patients with covid- and stroke were very ill as a group; . % of patients required mechanical ventilation and . % had severe illness graded according to the american thoracic society/infectious diseases society of america criteria for pneumonia severity. our findings are congruent with other studies which reported an increased prevalence of neurological disorders in those with more severe infection. our study also shows that the number of covid- positive ischemic strokes has increased initially but seems to have peaked and then decreased. this finding may be related to the overall reduction in covid- admissions, likely due to social distancing and stay at home order ( figure ). in addition, a therapeutic anticoagulation protocol was instated in our institution the week of april sixth, , which suggests the use of therapeutic anticoagulation in patients with high d-dimer levels. this may have led to a lower rate to thrombotic complications including ischemic stroke in hospitalized covid- positive patients. furthermore, the number of patients with stroke hospitalized in the study period were less than historical controls. this witnessed low volume of acute emergencies during the covid- pandemic has been observed in other institutions as well. the reasons for this are unclear but possibly that patients with stroke and mild symptoms are staying at home and not presenting to the emergency department for stroke treatment. there are multiple, not mutually exclusive, possible mechanisms associating covid- with ischemic stroke. in patients with covid- requiring invasive respiratory support, the median duration of mechanical ventilation has been reported days, which renders them vulnerable to complications associated with critical illness and a prolonged intensive care unit stay including the risk for ( ) hypotension and inadequate cerebral perfusion; ( ) relative hypertension leading to posterior reversible encephalopathy syndrome; ( ) septic embolization in the case of superimposed bacterial infection; ( ) stress cardiomyopathy and an attendant reduction in left ventricular ejection fraction; and ( ) atrial fibrillation with or without a rapid ventricular response. additionally, severe covid- has been associated with a hyperinflammatory state (cytokine storm ) and hyperviscosity. progression to disseminated intravascular coagulation is more common in covid- than in other forms of critical illness; one case series reported an incidence of . % with associated % mortality. mortality is associated with higher fibrin-degradation product levels and prolonged prothrombin and activated partial thromboplastin times. d-dimer was elevated in % of patients with covid- in wuhan, which was associated with a higher risk of mortality, an association suggested to be driven at least partially by increased thrombotic complications. preliminary reports from china describe patients with covid- who developed multiple, bilateral ischemic cerebral infarcts, antiphospholipid antibodies, and hematologic indices suggestive of an acquired thrombophilia. during the first sars outbreak in the early s, postmortem studies demonstrated a florid vasculitis in multiple arterial beds, and it is not known whether this disease pattern occurs with severe acute respiratory syndrome cov- coronavirus infection. there are main implications for clinical care that arise from our data. first, many institutions are currently attempting to balance the benefits of rapid, structured neurological evaluations for patients with covid- exhibiting new neurological symptoms with the risks of exposing multiple team members to infection. as centers develop protocols for the prompt triage and assessment of patients with covid- , the co-occurrence of stroke and covid- should be considered when weighing these risks. second, stroke in the setting of covid- could be a manifestation of systemic hypercoagulability as shown in our patient population with higher d-dimer levels when compared with contemporary controls. further study is required whether therapeutic anticoagulation in this setting mitigates ischemic stroke risk. in fact, protect covid (a randomized trial of anticoagulation strategies in covid- ) is an ongoing randomized clinical trial testing the safety and efficacy of therapeutic versus prophylactic anticoagulation in patients with covid- infection and mild to moderate elevation in d-dimer level (url: https://www. clinicaltrials.gov. unique identifier: nct ). our study reports the clinical characteristics of a diverse patient population with ischemic stroke in the setting of covid- . we report subject level data, including key clinical variables, markers of disease severity, and diagnostic workup for ischemic stroke. our findings should be interpreted with caution in the context of a number of important limitations. first, our study was a relatively small, retrospective, observational study with potential for selection bias. second, we did not have outcome data on all patients as some are still admitted receiving active clinical care. third, we do not have complete laboratory investigations or diagnostic imaging for all study subjects, and therefore, some cryptogenic strokes may be related to another undiagnosed mechanism. this likely contributed to an increased prevalence of cryptogenic stroke subtype in patients with covid- infection. fourth, our study may not be fully representative of all patients with stroke in our healthcare system; patients who are critically ill may not be diagnosed with stroke due to impaired consciousness, confounding systemic illness, or withdrawal of lifesustaining therapies. fifth, since this report focused on ischemic stroke, we did not provide information on hemorrhagic stroke and venous sinus thrombosis occurring in patients with covid- . these complications in the setting of covid- need further study. finally, since not all patients were tested for covid- , it is possible that some asymptomatic patients with stroke may have been covid positive but were included in the control group. we observed a relatively low rate of imaging proven ischemic stroke in hospitalized patients with covid- infection. in patients with covid- and ischemic stroke, a majority of strokes were classified as cryptogenic, possibly related to an acquired hypercoagulability, and were associated with increased mortality. ongoing studies are testing the utility of therapeutic anticoagulation for stroke and other thrombotic event prevention, in select patients with covid- and laboratory evidence suggestive of hypercoagulability. affiliations from the department of neurology classification of subtype of acute ischemic stroke. definitions for use in a multicenter clinical trial. toast. trial of org in acute stroke treatment cryptogenic stroke/esus international working group. embolic strokes of undetermined source: the case for a new clinical construct overlap of diseases underlying ischemic stroke: the ascod phenotyping distribution and temporal trends from to of ischemic stroke subtypes: a systematic review and meta-analysis infectious diseases society of america/american thoracic society consensus guidelines on the management of community-acquired pneumonia in adults neurologic manifestations of hospitalized patients with coronavirus disease reduction in stsegment elevation cardiac catheterization laboratory activations in the united states during covid- pandemic covid- in critically ill patients in the seattle region -case series clinical and immunological features of severe and moderate coronavirus disease abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease procalcitonin in patients with severe coronavirus disease (covid- ): a meta-analysis clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study coagulopathy and antiphospholipid antibodies in patients with covid- the clinical pathology of severe acute respiratory syndrome (sars): a report from china acute neurology during the covid- pandemic: supporting the front line dr yaghi, b. mac grory, dr henninger, and dr frontera participated in study design and drafting the article. dr humbert, dr ishida, dr alam, dr lord, dr sanger, dr lillemoe, e. scher, dr kim, dr raz, and dr tanweer participated in data abstraction and article revision. dr trivedi performed the statistical analysis. this study is partially funded by the national institutes of health (nih), k ns from the national institute of neurological disorders and stroke of the national institutes of health. dr henninger is supported by k ns from the national institute of neurological disorders and stroke of the national institutes of health and congressionally directed medical research program/department of defense. dr henninger reports personal fees from astrocyte pharmaceuticals, inc and grants from national institute of child health and human development outside the submitted work. dr yaghi's previous institution received funding from medtronic for his effort in adjudicating outcomes for the stroke-af trial. dr dehkharghani received funding from ischemaview. the other authors report no conflicts. key: cord- -e idvknz authors: trifan, g.; goldenberg, f.d.; caprio, f.c.; biller, j.; schneck, m.; khaja, a.; terna, t.; brorson, j.; lazaridis, c.; bulwa, z.; alvarado-dyer, r.; saleh-velez, f.g.; prabhakaran, s.; liotta, e.m.; batra, a.; reish, n.j.; ruland, s.; teitcher, m.; taylor, w.; de la pena, p.; conners, j.c.; grewal, p.k.; pinna, p.; dafer, r.m.; osteraas, n.d.; dasilva, i.; hall, j.p.; john, s.; shafi, n.; miller, k.; moustafa, b.; vargas, a.; gorelick, p.b.; testai, f.d. title: characteristics of a diverse cohort of stroke patients with sars-cov- and outcome by sex date: - - journal: j stroke cerebrovasc dis doi: . /j.jstrokecerebrovasdis. . sha: doc_id: cord_uid: e idvknz background and purpose: severe acute respiratory syndrome coronavirus (sars-cov- ) infection is associated with stroke. the role of sex on stroke outcome has not been investigated. to objective of this paper is to describe the characteristics of a diverse cohort of acute stroke patients with covid- disease and determine the role of sex on outcome. methods: this is a retrospective study of patients with acute stroke and sars-cov- infection admitted between march to may , to one of the six participating comprehensive stroke centers. baseline characteristics, stroke subtype, workup, treatment and outcome are presented as total number and percentage or median and interquartile range. outcome at discharge was determined by the modified rankin scale score (mrs). variables and outcomes were compared for males and females using univariate and multivariate analysis. results: the study included patients, % of which were black, % hispanics/latinos, and % whites. median age was years. approximately % had at least one preexisting vascular risk factor (vrf). the most common complications were respiratory failure ( %) and septic shock ( %). compared with females, a higher proportion of males experienced severe sars-cov- symptoms requiring icu hospitalization ( % vs. %; p= . ). when divided by stroke subtype, there were % ischemic, % intracerebral hemorrhage and % subarachnoid hemorrhage. the most common ischemic stroke etiologies were cryptogenic ( %) and cardioembolic ( %). compared with females, males had higher mortality ( % vs. %; p= . ) and were less likely to be discharged home ( % vs. %; p= . ). after adjustment for age, race/ethnicity, and number of vrfs, mrs was higher in males than in females (or= . , % ci= . - . ). conclusion: in this cohort of sars-cov- stroke patients, most had clinical evidence of coronavirus infection on admission and preexisting vrfs. severe in-hospital complications and worse outcomes after ischemic strokes were higher in males, than females. background and purpose: severe acute respiratory syndrome coronavirus (sars- infection is associated with stroke. the role of sex on stroke outcome has not been investigated. to objective of this paper is to describe the characteristics of a diverse cohort of acute stroke patients with covid- disease and determine the role of sex on outcome. methods: this is a retrospective study of patients with acute stroke and sars-cov- infection admitted between march to may , to one of the six participating comprehensive stroke centers. baseline characteristics, stroke subtype, workup, treatment and outcome are presented as total number and percentage or median and interquartile range. outcome at discharge was determined by the modified rankin scale score (mrs). variables and outcomes were compared for males and females using univariate and multivariate analysis. the study included patients, % of which were black, % hispanics/latinos, and % whites. median age was years. approximately % had at least one preexisting vascular risk factor (vrf). the most common complications were respiratory failure ( %) and septic shock ( %). compared with females, a higher proportion of males experienced severe sars-cov- symptoms requiring icu hospitalization ( % vs. %; p= . ). when divided by stroke subtype, there were % ischemic, % intracerebral hemorrhage and % subarachnoid hemorrhage. the most common ischemic stroke etiologies were cryptogenic ( %) and cardioembolic ( %). compared with females, males had higher mortality ( % vs. %; p= . ) and were less likely to be discharged home ( % vs. %; p= . ). after adjustment for age, race/ethnicity, and number of vrfs, mrs was higher in males than in females (or= . , % ci= . - . ). in this cohort of sars-cov- stroke patients, most had clinical evidence of coronavirus infection on admission and preexisting vrfs. severe in-hospital complications and worse outcomes after ischemic strokes were higher in males, than females. coronavirus disease , caused by the severe acute respiratory syndrome coronavirus (sars-cov- ), usually presents as a respiratory illness. neurological manifestations can be seen in . % of patients. patients with vascular risk factors (vrfs), including history of stroke, tend to have worse prognosis. covid- triggers a robust inflammatory response which leads to hypercoagulability and thromboembolism. reports of stroke in patients with covid- are mostly limited to small case series or case reports of ischemic stroke (is), though intracerebral hemorrhage (ich) and subarachnoid hemorrhage (sah) have also been reported. , thus, our understanding of the relationship between sars-cov- and stroke is evolving. one key variable is sex. data from observational studies and registries show that males with covid- have a higher mortality rate than females. prepandemic epidemiological studies, in contrast, have shown that stroke mortality is higher among females, particularly at older age. the effect of sex on stroke patients with sars-cov- infection has not been investigated. the aim of this study was to describe the stroke characteristics of patients with sars-cov- and the presence of sex-specific variations in stroke presentation, complications, and outcome. baseline characteristics, laboratory and radiologic findings, in-hospital complications, treatments, and outcomes at hospital discharge were extracted from the electronic health records. laboratory data included blood and cerebrospinal fluid (csf) studies. for blood values, we analyzed first and maximum values for the comprehensive metabolic panel, complete blood count, coagulation studies, antiphospholipid antibodies and inflammatory markers (erythrocyte sedimentation rate, c-reactive protein, d-dimer, fibrinogen, ferritin, interleukin- , and lactate dehydrogenase levels). data from head computed tomography (ct), computed tomographic angiography, brain magnetic resonance imaging (mri), magnetic resonance angiography, conventional angiography, and transthoracic echocardiography or transesophageal echocardiography results were collected. sars-covv- was detected from nasopharyngeal or oropharyngeal swabs using polymerase chain reaction. patients were grouped based on clinical severity into ) asymptomatic, ) mild to moderate symptoms, and ) severe symptoms, defined as those requiring intensive care unit (icu) admission with or without mechanical ventilation. patients were subcategorized into is, ich or sah based on radiographic findings. is severity was assessed using the national institutes of health stroke scale score on admission. stroke mechanism was classified using the toast criteria into ) large-artery atherosclerosis, ) cardioembolism, ) small-vessel occlusion, ) stroke of other determined etiology, and ) cryptogenic stroke or stroke of undetermined etiology . ich severity was assessed using the ich score and the glasgow coma scale score on admission. sah grade was assessed with the fisher scale and hunt and hess scores at presentation. location was categorized into cortical, subcortical, infratentorial or mixed locations. disposition and outcome, determined by the modified rankin scale (mrs) score at discharge, were reported for each stroke subtype . results are presented as median and interquartile ranges (iqr) or total number (n) and percentage (%). baseline characteristics and stroke subtypes were compared for males and females using fisher's exact test or pearson's chi-square for categorical variables and mann-whitney u test for continuous variables. the association between sex (with female being the reference category) and mrs at hospital discharge, was investigated using multivariate logistic regression analysis adjusting for age, race/ethnicity, and number of vrfs. statistical analyses were done using spss version (spss inc, chicago, il). all tests of significance were tailed, with a threshold for significance of p< . . of the patients included in the study, % were males. median age for all patients was , and % where hispanic or black. table depicts cohort characteristics. the most common vrf at baseline was arterial hypertension ( %) followed by diabetes mellitus ( %). eighty nine percent had at least one vrf at baseline and % had three to four. stroke as the presenting diagnosis was observed in ( %) patients. approximately % of the patients had symptoms of covid- and % required icu admission. the most frequent stroke subtype was is ( %), followed by ich ( %) and sah ( %). respiratory failure was the most common complication ( %). the rate of venous thromboembolic events was %. echocardiographic information was available in % of cases. the most common cardiovascular abnormalities were reduced left ventricular ejection fraction ( %) followed by left atrial enlargement ( %), heart failure ( %), acute myocardial infarction ( %) and new onset atrial fibrillation/atrial flutter ( %). head imaging was obtained in all patients, with majority having a non-contrast computed tomography ( %). mri brain was available for % of patients and vascular imaging of the head or neck for %. initial median laboratory values on admission were elevated above normal ranges for ldh, ddimer, high-sensitive cardiac troponin, serum ferritin, crp, serum creatinine, blood urea nitrogen and il- (supplemental table i ). throughout the hospital stay, all these laboratory values increased (supplemental table ii) . anti-cardiolipin antibodies were obtained in patients (supplemental table iii) . csf studies were available in four patients, with a median protein level of mg/dl and median red blood cell count of number/µl. all csf studies were negative for sars-cov- . males and females had similar baseline characteristics. however, females had higher rates of mild to moderate covid- symptoms while males had higher rates of severe symptoms requiring icu admission. males also had higher rates of decreased ejection fraction ( % vs %, p= . ) and higher levels of ldh, albumin, total bilirubin and bun on admission compared with females. approximately % of the patients had neuroimaging evidence of acute is. strokes were noted on admission in approximately half of the cases, and % were clinically symptomatic with a median nihss of . infarcts were most often located cortically, and the most common etiology was stroke of undetermined etiology ( %) followed by cardioembolism ( %). a quarter of the patients had bilateral hemispheric infarction. the median time from last known well to hospital presentation was day. eight percent were treated with tissue plasminogen activator (tpa) and % with endovascular thrombectomy. the mortality was % and the median mrs at discharge was . withdrawal of care occurred in % of cases. no differences were observed in withdrawal of care among males ( %) and females ( %; p= . ). among those who survived, the median mrs was . males had higher case fatality, higher median mrs, and lower rates of good outcome than females ( table ) . females, in turn, were more likely to be discharged home than males. in univariate analysis, males had increased mrs at hospital discharge than females (or= . ; % ci= . - . ). this difference remained statistically significant after adjustment for age, race/ethnicity, and number of vrfs (or= . , % ci= . - . ) ( table ) . ich was diagnosed in % of patients with % of cases discovered during hospitalization. approximately % were clinically symptomatic with a median gcs score of and ich score of . the most common causes of ich were spontaneous ( %) and anticoagulation-related ( %). mortality rate was approximately % and the median mrs of those who survived was ( table ). in our cohort, there were three sah. all cases were clinically severe with an average gcs of , fisher scale score of and hunt and hess grade of , and two of them expired. in this multicenter study of patients with stroke and sars-cov- infection admitted to comprehensive stroke centers in the chicagoland area, males were more likely than females to have severe covid- manifestations and worse ischemic stroke outcome at hospital discharge. approximately % of the strokes were ischemic, % ich, and % sah, which is similar to the general distribution of stroke subtypes reported in non-pandemic nationwide registries and population studies. our current understanding of stroke in covid- is modeled after small observational studies and select populations. the study published by mao et al , for example, included patients with coronavirus disease who exhibited neurologic involvement. six were diagnosed with stroke, and five of these had severe covid- disease. in our cohort, we observed that the presentation of stroke patients with sars-cov- was more pleomorphic with almost % of our cases having mild to moderate symptoms of covid- or being asymptomatic at presentation. males were more likely to have severe sars-cov- manifestations requiring icu admission and mechanical ventilation, as well as higher levels of ldh at baseline and a trend for higher maximum levels of makers of inflammation. these observations are in agreement with cumulative data obtained from different countries that show that males with covid- have a . times higher case fatality rate than females. it has been proposed that sex-specific differences in innate and adaptive immune mechanisms, by regulating the development of autoimmunity and the response to the viral infection may explain, at least in part, this phenomenon. in a cohort of ischemic stroke patients with covid- admitted to a new york healthcare system, cryptogenic stroke accounted for approximately % of all the cases and large artery occlusion for . %. in another single center study that included acute ischemic cases, % of the patients had cryptogenic stroke, % cardioembolism, and % large artery atherosclerosis. there were no lacunar infarctions in either study. in comparison, we observed that the frequency of cryptogenic stroke in our study was %, large artery atherosclerosis % and lacunar infarction %. a direct comparison among the studies is confounded in that our cohort included more blacks and hispanics, who in combination, accounted for % of all ischemic stroke cases. in comparison, the other studies were largely enriched with whites. in addition, similar to a recent study that included ischemic stroke patients , our cohort had a higher prevalence of traditional vrfs which suggests a higher burden of atherosclerotic disease. incomplete stroke workup is likely to spuriously inflate the proportion of patients categorized as cryptogenic stroke. in addition, patients with severe covid- who were hemodynamically unstable may have been deemed unsafe for diagnostic stroke studies. in one of the studies referenced above, almost a quarter of the strokes had incomplete evaluation. thus, it is plausible that center-specific variations in the availability of ancillary diagnostic tests could affect the rate of cryptogenic stroke reported in different studies. several observational studies have shown that myocardial injury is association with coronavirus infection. in a cohort of patients with severe covid- , almost a third of them had newly diagnosed cardiomyopathy. in another study including patients with covid- , % had new or worsening heart failure. in our sample, the most frequently encountered echocardiographic abnormality was reduced left ventricular ejection fraction which, in univariate analysis, was more commonly seen in males than in females. other abnormalities included left atrial or right ventricular enlargement, newly diagnosed arrhythmias, heart failure, or myocardial infarction. it is not clear from our study if these abnormalities were the cause of the stroke or contributed to outcome. however, our findings highlight the importance of cardiac screening and monitoring in patients with sars-cov- and stroke. in relation to ischemic stroke, based on the hypercoagulable state associated with covid- and the results obtained in select cohorts, it was proposed that elevated apl titers leading to procoagulability and large artery thrombosis is a common mechanism of cerebral ischemia in sars-cov- . , in our study, one of patients had igm anti-cardiolipin antibodies and three had both igg and igm anti-cardiolipin antibodies. the titers in these four cases were modestly elevated. we did not identify cases with elevated titers of anti-β -glycoprotein- antibodies. though only a small number of patients had testing for apl, our results suggest that the development of apl in stroke patients with sars-cov- may not be as common as previously suggested. sars-cov- rna has been identified in the cerebrospinal fluid of a covid- admitted with meningitis suggesting the possibility of a direct viral invasion of the brain. in our cohort, csf analysis was done in only patients. in all of them, the evaluation for sars-cov- was negative. the rates of tpa in this study was almost half of our historical averages in our geographic area. in most cases, tpa was not offered due to late arrival to the hospital and unknown time of symptom onset. the mortality at hospital discharge, though elevated at %, was better than the % and % reported in other studies. , mortality and disability at hospital discharge were worse for males than females despite both groups having similar baseline characteristics. it is possible that the poor outcomes were influenced by more severe sars-cov- disease in males rather than stroke severity itself. there is a paucity of information about hemorrhagic stroke in sars-cov- patients. in this study, we included ich and sah patients. a previous study including patients with ich suggested anticoagulation therapy may increase the risk of ich. our results are in agreement with this observation as anticoagulation-associated ich was one of the leading causes of ich. there is virtually no information about sah in sars-cov- patients. our three cases had high-grade sah. in general, patients with ich and sah had a poor outcome with a mortality of approximately %. our study has several limitations. first, given the retrospective and observational nature of the study, the stroke workup was incomplete in some cases. second, outcomes were limited to hospital discharge and long-term data are still lacking. third, the sample size was small and thus limited our ability to perform subgroup analysis. fourth, in this study we included patients with radiologic evidence of acute cerebrovascular injury. though this approach enhances the accuracy of the diagnosis, we cannot exclude the possibility of missing stroke patients who were critically ill and unable to undergo brain imaging. nonetheless, our study is the largest cohort of sars-cov- patients with stroke yet reported. also, % of our cohort were blacks and hispanics which have been identified as populations disproportionally affected by furthermore, given the geographic location of the multiple institutions that participated in this initiative, our findings are representative of an urban and near suburban metropolitan area. in comparison, most papers that previously reported about stroke in covid- patients were limited to one center or one health system. in conclusion, we present the characteristics of stroke patients with proven sars-cov- infection. the large majority of our patients had pre-existing vrfs and manifested changes in laboratory markers of inflammation and coagulability. we identified males as more likely to onset to presentation, hours* ( ) ( ) ( . ) . university of illinois at chicago gtrifan@uic university of chicago hospital, fgoldenb@neurology loyola university health system jbiller@lumc loyola university health system mschneck@lumc alexian brothers hospital alexian brothers hospital university of chicago hospital, jbrorson@neurology university of chicago hospital northwestern university. nicholas.reish@northwestern loyola university health system. michael loyola university health system loyola university health system, paula.delapena@lumc university of illinois at chicago nshafi@uic.edu . miller kristin university of illinois at chicago, testai@uic.edu data collection was performed at each of the six participating centers analysis and manuscript preparation were performed at the university of illinois at chicago college of medicine, department of neurology and rehabilitation grant support: none disclosures: none neurologic manifestations of hospitalized patients with coronavirus disease clinical characteristics and outcomes of covid- patients with a history of stroke in wuhan coronavirus disease and stroke: clinical manifestations and pathophysiological insights large-vessel stroke as a presenting feature of covid- in the young considering how biological sex impacts immune responses and covid- outcomes classification of subtype of acute ischemic stroke. definitions for use in a multicenter clinical trial. toast. trial of org in acute stroke treatment stroke assessment scales. the internet stroke center. an independent web resource for information about stroke care and research sars-cov- and stroke in a new york healthcare system risk of ischemic stroke in patients with covid- ) vs patients with influenza acute cerebrovascular events in hospitalized covid- patients covid- and the cardiovascular system characteristics and outcomes of critically ill patients with covid- in washington state clinical course and risk factors for mortality of adult inpatients with covid- in wuhan, china: a retrospective cohort study update on the angiotensin converting enzyme -angiotensin ( - )-mas receptor axis: fetal programing, sex differences, and intracellular pathways characteristics of ischaemic stroke associated with covid- a first case of meningitis/encephalitis associated with sars-coronavirus- hemorrhagic stroke and anticoagulation in covid- covid- exacerbating inequalities in the us develop severe covid- syndrome and to have worse ischemic stroke outcomes at hospital discharge. further studies are necessary to elucidate the mechanisms that explain these associations. key: cord- - avavlu authors: anoop, kohli; charchit, gupta; shvet, dutta; chirag, madan title: “changes in stroke presentation in neo-covid patients: a case study” date: - - journal: interdiscip neurosurg doi: . /j.inat. . sha: doc_id: cord_uid: avavlu a year old male had a generalized seizure a week after symptoms of daily fever, rigors, and throat discomfort. he was hospitalized. magnetic resonance imaging brain showed multiple bilateral scattered infarcts. covid- swab test came positive. an elaborate panel of tests for young strokes, cardiac work-up was normal. at home, he complained of some visual blurring, slowing in thought processing, occasional loss of words. his face became significantly pigmented. a young male, covid- positive, showed multiple scattered infarcts. exaggerated pro-thrombotic activity of the nature of a cytokine storm, is the probable cause. was also normal. there were no lifestyle risk factors as smoking, alcohol intake, prior history of thrombosis in the lower limbs, diabetes, or hypertension or renal disease. the swab covid- rt pcr report came positive. he had salient neurological deficits at discharge two weeks after hospitalization, in a covid negative state. chiefly, he complained of blurring of vision, reported he had slowed down in his "mental processing", (being a school teacher of mathematics), dysnomia, and occasional transient "blank outs" and felt a certain heaviness in his head. mini mental state examination score was . he was oriented to time, place and person, intact memory but had delayed recall, less attentive, would speak less and was unable to follow complex commands. frontal assessment battery was done which revealed normal conceptualization and mental flexibility but impaired motor programming, sensitivity to interference, inhibitory control, and environmental autonomy. the chief physical finding was a significant pigmentation of his face (figure b ). he is presently on tab hcq mg, and a clopidrogel-aspirin ( mg, each) combination, lamotrigine mg, clobazam mg, prednisolone mg/day with folic acid supplements. anticoagulants were not considered appropriate in the absence of a thrombus besides they carried a small risk of hemorrhagic changes. three weeks after discharge, his complaints of blurring of vision, "slowing in his thinking process, and frequent "blank outs" showed significant amelioration. "blank outs" remained were possibly epileptogenic as came out in the electroencephalogram (figure ). the novel sars-cov- , perhaps the most appropriate terminology in terms of being the closest in series of covid viruses [ ] , and acute respiratory distress as the major presenting symptom. it is rather tragic that it has become pandemic beyond historical archives, and further spread its activity to other body systems. the mechanism at the core of this, is the propensity of the 's' protein in its tentacles, to merge with the cell wall angiotensin converting enzyme ii receptors. these allow ease of entry into cells, where an rna virus has the necessary environment to replicate a million times. so much for the acute inflammatory reactions in the lungs, resembling acute respiratory distress syndrome. [ ] the prothrombotic activity, is the next formidable weapon, where it can spread to cause acute venous thrombosis, to the extent of spreading as thrombo-embolic phenomenon to add to what was understood as purely inflammation of respiratory tissue. this has led to cautious use of anticoagulants, in critical cases. [ ] amongst the neurological complications strokes is perhaps on the forefront, due to requirement of deft handling, basic and even secondary care. this has led to various comprehensive editorials [ ] , american stroke association initiatives [ ] , counselling bodies, webinars, support groups. the thrust presently, and rather appropriately is on collecting data, and basic, even secondary management in neo-covid strokes. certainly, to jump at the theme even at the basic science level of research, of pathophysiology, beyond what may be speculative in the stroke event, may be premature and non-commensurate. amongst the noted studies [ ] are, describing four cases, that had strokes, but actual images, that may give a speculative clue to the cause, are not fully represented, probably due to lack of publication space. a noted study by avula et al [ ] , mentions four cases with occlusion of an ica, others with moderate tapering of mca, where infarcts occurred. this was a collection of cases from various centers. all were above seventy years, and had at least two major risk factors for strokes. the article is well illustrated, and at this stage of collecting all possible covid related stroke data, it records valuable information. neo-covid's ability to spread to different body tissues, including changes in antigenic behavior, one may expect, that stroke manifestations may differ too. stroke pathology is not a single entity, and it is usual even in routine therapy, to get clues as to the possible mechanism by neuroimaging. strokes can be embolic, thrombotic [ ] , immune related as antiphospholipid antibodies [ ] , major immunological vasculitis [ ] , artery to artery embolism [ ] , not to miss miller fisher's lacunar infarcts [ ] . the case under discussion, had fever with rigors, and started hcq once daily on his own, on the fifth day consulted his family physician for frequency of stools. inj. cefuroxime was given intravenously at home, during which he developed generalized tonic-clonic seizures. he was ventilated for a day, on account of the seizures. his respiratory system showed no abnormality. the covid test came positive. magnetic resonance imaging brain showed multiple bilateral hyperintense lesions on diffusion weighted images (figure a ) with corresponding apparent diffusion coefficient changes, confirming infarcts. intracranial mr angiogram was normal (figure b) , showing no thrombosis or stenosis, thereby making thrombo-embolic phenomenon, a strong possibility. visual evoked potentials, cervical mri were done to rule out a faint chance of demyelinating overlap. they were normal. such acute thrombotic events generally come under the umbrella term "cytokine storms" simply put, these are events, when a local thrombotic event, has a sudden unexpected widespread effect, affecting various tissues. the term was first used in , in a donor-host tissue reaction [ ] . it has been widely used, but of relevance the article, is its use in various bird-flu reactions. [ ] a noteworthy analysis is published in inflammation and influenza. [ ] another notable feature was the pigmentation of his face, the one at the time of discharge (figure b ), compared to a photograph of sept ' ( figure a ) and the last taken in follow-up this week (figure c ). hyperpigmentation is a known response to skin repair. binding to angiotensin converting enzyme ii, is essential in to this reaction. extending the speculation of widespread intracranial thrombotic emboli, embolization of extra-cranial vasculature cannot be ruled out. initial hypoxia could have set in motion the angiotensin converting enzyme ii reparative reaction, leading to facial hyperpigmentation, including reparative fibrosis, leading to dysmorphic facial feature changes [ , ] . steroids given as a part of brain edema therapy, by suppressing inflammation, somewhat substantiates the mentioned hypothesis in leading to de-pigmentation. besides the pigmentation, which is showing signs of reversal, there are morphological changes in his facial features, probably due to reparative fibrosis, is a skin complication not noted so far. he was discharged on hcq mg twice a week, aspirin, anti-epileptics, and prednisolone mg for ten days, now reduced to mg. the blurring is better, "blank-outs" have stopped, and he does not feel dull as before. pertaining to strokes in covid, though the final theme is appropriately set for future analysis, appropriate data, including convincing neuro-imaging may not be ignored, as it may be crucial in the final analysis. a case of multiple embolic strokes, involving bilateral cerebral hemispheres is presented. this case is perhaps the first one that shows clear multiple thromboembolic stroke phenomenon, facial pigmentation, adding a new variant to neo covid strokes. at the level of speculation, perhaps the "cytokine storm" flared up into a multiple thromboembolic phenomenon localized only to the brain. [ ] any association of a second order cephalosporin given intravenously in patient moderately symptomatic, is yet another aspect to note particularly in critical cases. [ ] manuscript details ) we confirm that manuscript complies with all instructions to authors. ) we confirm that authorship requirements have been met and the final manuscript was approved by all authors. ) we confirm that this manuscript has not been published elsewhere and is not under consideration by another journal )we confirm adherence to ethical guidelines and indicate ethical approvals from institutional committee and use of informed consent, as appropriate. antiphospholipid antibodies and recurrent thrombotic events: persistence and portfolio covid- presenting as stroke severe acute respiratory syndrome coronavirus (sarscov- ) and the central nervous system incidence of thrombotic complications in critically ill icu patients with covid- large-vessel stroke as a presenting feature of covid- in the young-correspondence. nejm improving stroke care in times of the covid- pandemic through simulation covid- -related stroke neurological complications of coronavirus and covid- marlag - cytokine storm of graft versushost disease: a critical effector role for interleukin- proinflammatory activity in bronchoalveolar lavage fluids from patients with ards-a prominent role for interleukin- insights into inflammation and influenza erythema multiforme-like eruption in patients with covid- infection: clinical and histological findings angiotensin ii stimulates melanogenesis via the protein kinase c pathway yuxiang zhi. cefuroxime-induced anaphylaxis key: cord- -fpxd ont authors: fifi, johanna t; mocco, j title: covid- related stroke in young individuals date: - - journal: lancet neurol doi: . /s - ( ) - sha: doc_id: cord_uid: fpxd ont nan evidence is mounting on the diverse neurological pre sen tations associated with covid . in a rapid review in the lancet neurology, mark ellul and col leagues nicely cover these findings, but we would like to emphasise the risk of associated stroke. as des cribed in this rapid review, severe acute respiratory syn drome coronavirus (sarscov ) might be more likely to cause throm botic vascular events, including stroke, than other coronavirus and seasonal infectious diseases. in fact, a · fold increase in the odds of stroke with covid compared with influenza was recently reported. the reported incidence of cerebrovascular dis ease in patients testing positive for sarscov ranges from % to %, poten tially equating to large numbers of individuals as the pandemic progresses in some countries. , the proposed mechanisms for these cerebrovascular events include a hypercoagulable state from sys temic inflam mation and cytokine storm; postinfectious immunemediated responses; and direct viralinduced endotheliitis or endotheliopathy, potentially leading to angio pathic thrombosis, with viral particles having been isolated from the endothelium of various tissue, including brain tissue. , multiple regions with high covid prevalence have reported stable or increased incidence of large vessel stroke and increased incidence of cryptogenic stroke (patients with no found typical cause of stroke), despite observing a decrease in mild see rapid review page stroke that is possibly secondary to quarantine and selfisolation. this quarantine effect is supported by a nationwide analysis in the usa of automated stroke imaging processing software showing decreased imag ing evaluation for stroke during the pandemic. our group observed that five patients younger than years who tested positive for sarscov , some with no vascular risk factors, were admitted with large vessel stroke to our hospitals during a week period (march to april , ) during the height of the pandemic in new york city (ny, usa). this was a fold increase in the rate of large vessel stroke in young people compared with the previous year, and the patients had laboratory findings that suggested a hypercoagulable state, leading to the postulation that stroke was probably related to the presence of sarscov in these young patients. since then, this observation of covid related stroke in young patients has been supported by additional data from other centres worldwide. the mean patient age in several thrombectomy case series of covid (mean age of · years in a series from new york city [ny, usa], mean age of · years in a series from paris [france], and mean age of · years in a combined series from new york city and philadelphia [pa, usa] ) is younger than the typical population having this procedure. furthermore, in patients presenting with large vessel stroke during the pandemic, data from the mount sinai health system in new york city confirm that patients who tested positive for sarscov were significantly younger, with a mean age of years (sd ), than patients who tested negative for sarscov , who had a mean age of years (sd ), mirroring the findings of the paris group. patients with covid who had imaging confirmed stroke and were admitted to another large new york city medical centre were again found to be younger, with a mean age of years (sd ), than a control group of patients with stroke who tested negative for sarscov and had a mean age of years (sd ). a casecontrol analysis of acute stroke protocol imaging from late march to early april, , across a large new york city health system showed that, after adjusting for age, sex, and vascular risk factors, sascov positi vity was independently associated with stroke. many reports have documented an increased thrombo sis risk early in covid and coagulation abnormalities in ddimer and fibrinogen can be found in patients with mild symptoms. there are many reports of early covid presenting with thrombotic events, which has led to the consensus to start anticoagulation therapy early in the covid disease course before any thrombotic event. there are reports in the literature specifically addressing macrothrombosis in the internal carotid artery in patients with mild respiratory symptoms of covid , and stroke as a presenting symptom of the disease. a multi centre series of patients with covid and either ischaemic or haemorrhagic events reported that % were younger than years. additionally, the report stated that two of patients with large vessel stroke were younger than years and without previous stroke risk factors. in this study, consistent with other case series, patients with covid fare worse in terms of clinical outcomes than patients with stroke who do not have covid . , this is probably related, in part, to the covid disease process. in conclusion, data supporting an association between covid and stroke in young populations with out typical vascular risk factors, at times with only mild respira tory symptoms, are increasing. future pros pec tive registries to study this association further, as well as studies of anticoagulation to prevent these poten tially life devastat ing events, are underway. we believe that, in otherwise healthy, young patients who present with stroke dur ing the pan demic, the diagnosis of covid should be thoroughly investigated. conversely, in patients with mild covid respiratory symptoms, a low threshold for investigation for stroke should be main tained if they present with new neurological symptoms. we declare no competing interests. see online for appendix the covid pandemic has led to unprecedented challenges. in particular, the impact of covid on neurological services and patients has been immense, as highlighted in a recent editorial. despite the heightened burden felt by neurologists, the dedication of our authors and reviewers is not waning. submissions to the lancet neurology between jan and june , , increased by around % compared with the same period last year. unabated expert advice from our clinical and statistical reviewers from around the world is ensuring the con tinued publication of the highest quality research and reviews for our readers. the journal continues to strive towards the goal of the lancet group of disseminating the best science for better lives. our achievement is reflected by the continued place ment of the lancet neurology as the leading clinical neurology journal, according to the journal citation report. the names of everyone who reviewed papers for the journal throughout are listed in the appendix; those who reviewed five papers, or more, are marked with an asterisk. we extend our warmest gratitude to all these reviewers. neurological associations of covid risk of ischemic stroke in patients with coronavirus disease (covid ) vs patients with influenza sarscov and stroke in a new york healthcare system endothelial cell infection and endotheliitis in covid central nervous system involvement by severe acute respiratory syndrome coronavirus (sarscov ) falling stroke rates during covid pandemic at a comprehensive stroke center: cover title: falling stroke rates during covid collateral effect of covid on stroke evaluation in the united states uk the neurological impact of covid largevessel stroke as a presenting feature of covid in the young covid is an independent risk factor for acute ischemic stroke stroke and mechanical thrombectomy in patients with covid : technical observations and patient characteristics treatment of acute ischemic stroke due to large vessel occlusion with covid : experience from paris cerebral ischemic and hemorrhagic complications of coronavirus disease emergent large vessel occlusion stroke during new york city's covid outbreak: clinical characteristics and paraclinical findings macrothrombosis and stroke in patients with mild covid infection intraluminal carotid artery thrombus in covid : another danger of cytokine storm? outcomes and spectrum of major neurovascular events among covid patients: a center experience key: cord- - oyvia d authors: farooque, umar; shabih, sohaib; karimi, sundas; lohano, ashok kumar; kataria, saurabh title: coronavirus disease -related acute ischemic stroke: a case report date: - - journal: cureus doi: . /cureus. sha: doc_id: cord_uid: oyvia d coronavirus disease (covid- ) is an active worldwide pandemic with diverse presentations and complications. most patients present with constitutional and respiratory symptoms. acute ischemic stroke remains a medical emergency even during the covid- pandemic. here we present a case of a patient with covid- who presented with acute ischemic stroke in the absence of common risk factors for cerebrovascular accidents. a -year-old male patient, with no prior comorbidities, presented to the emergency department (ed) with fever, cough, and shortness of breath for four days, and altered level of consciousness and right-sided weakness with the sensory loss for one day. on examination, the patient had a score of / on the glasgow coma scale (gcs). there was a right-sided sensory loss and weakness in both upper and lower limbs with a positive babinski's sign. the pulmonary examination was remarkable for bilateral crepitation. on blood workup, there was leukocytosis and raised c-reactive protein (crp). d-dimer, ferritin, thyroid-stimulating hormone (tsh), vitamin b , and hypercoagulability workup were normal. transthoracic echocardiography was also normal. covid- polymerase chain reaction (pcr) detected the virus. chest x-ray showed infiltrations in the left middle and both lower zones of the lungs in the peripheral distribution. computed tomography (ct) scan of the chest showed peripheral and mid to basal predominant multilobar ground-glass opacities. ct scan of the head showed a large hypodense area, with a loss of gray and white matter differentiation, in the left middle cerebral artery territory. magnetic resonance imaging (mri) of the head showed abnormal signal intensity area in the left parietal region. it appeared isointense on t image and hyperintense on t image. it also showed diffusion restriction on the diffusion-weighted (dw ) image with corresponding low signals on the apparent diffusion coefficient (adc) map. these findings were consistent with left middle cerebral artery territory infarct due to covid- . the patient was intubated in the ed. he was deemed unfit for thrombolysis and started on aspirin, anti-coagulation, and other supportive measures. patients with covid- should be evaluated early for neurological signs. timely workup and interventions should be performed in any patient suspected of having a stroke to reduce morbidity and mortality. the severe acute respiratory distress syndrome coronavirus- (sars-cov- ) appeared from wuhan, china, at the end of and became a pandemic involving the whole world [ ] . it can , be asymptomatic or present with fever, fatigue, body aches, dry cough, dyspnea, and complications like acute respiratory distress syndrome (ards), severe pneumonia, acute kidney injury, myocarditis, multiorgan failure, and death [ , ] . patients can also present with atypical gastrointestinal and neurological manifestations. here we report a case of a patient with covid- who presented with acute ischemic stroke without any predisposing conventional risk factors for cerebrovascular accident. a -year-old male presented to the emergency department (ed) with complaints of fever, cough, and shortness of breath for four days and altered level of consciousness, and right-sided weakness with sensory loss for one day. the patient was in his usual state of health when he developed fever and cough which was initially dry and later became productive with whitish sputum. the sputum was two teaspoons in quantity and difficult to expectorate. the patient also developed dyspnea during this time. the shortness of breath was sudden in onset, not associated with exertion, chest pain, sweating, palpitations, leg swelling, or any history of immobilization. the patient also denied any associated orthopnea or paroxysmal nocturnal dyspnea. three days later, he developed an altered level of consciousness which was sudden in onset and associated with right-sided paralysis and loss of sensations. there was no associated neck stiffness, headache, or seizure. the patient did not have any comorbidities, including hypertension or diabetes. there was no family history of hypertension, or diabetes as well. he did not smoke or drink alcohol. there was no recent travel history or any prior history of similar complaints. on physical examination, the patient was not oriented to time and place. his blood pressure was / mmhg, pulse was beats/minute, respiratory rate was breaths/minute, spo was % on % non-rebreather mask, and temperature was o f. on neurological examination, the patient had a score of / on the glasgow coma scale (gcs). power was / in both upper and lower extremities on the right side and / on the left side in both lower and upper extremities. babinski's sign was also positive on the right side. sensations were also absent in the right upper and lower limbs. there were no signs of neck rigidity. lung examination was notable for harsh vesicular breathing with bilateral crepitation. other systemic examinations were unremarkable. on laboratory investigations, complete blood count revealed a total leukocyte count of , cells/mcl (normal range: , to , cells/mcl), hemoglobin of . g/dl (normal range - . to . g/dl) with a mean corpuscular volume (mcv) of fl/cell (normal range - to fl/cell), and platelet count of , /mcl (normal range: , to , /mcl). serum electrolytes including serum sodium, potassium, chloride, urea, and creatinine were within the normal range. hemoglobin a c was . % (normal range: % to . %). d-dimer, ferritin, thyroid-stimulating hormone (tsh), vitamin b , and hypercoagulability workup were within normal limits. transthoracic echocardiography was unremarkable. real-time polymerase chain reaction (rt-pcr) testing for sars-cov- was performed using a nasopharyngeal swab which was positive. c-reactive protein (crp) was elevated to mg/l (normal value: less than mg/l). blood and urine culture did not yield any growth. a chest x-ray showed bilateral airspace opacifications in both lungs, more pronounced in the left middle and both lower zones, with relative sparing of the left upper zone and peripheral distribution ( figure ). this is a chest x-ray in the posteroanterior (pa) view showing bilateral infiltrates in both lower and left middle zones of lungs in the peripheral distribution ct scan of the chest showed multilobar ground-glass opacities with peripheral and mid to basal predominance. there was air space consolidation in the left lower lobe. there was no significant mediastinal lymphadenopathy. these findings were consistent with covid- ( figure ). the patient was intubated in the ed for hypoxemic respiratory failure. he was not deemed a suitable candidate for thrombolysis or neuro-intervention. so consequently, the patient was shifted to the intensive care unit (icu) and started on aspirin mg twice daily, subcutaneous low molecular weight heparin (lmwh) . ml twice daily, and intravenous dexamethasone cc twice daily. the family eventually decided to pursue comfort measures. covid- is a current worldwide pandemic with diverse complications. recent literature has shown multiple neurological manifestations including cerebrovascular accidents in patients with severe infection [ , ] . a single-center study of patients showed that cerebrovascular events were more common in patients with stroke risk factors such as hypertension, diabetes, and previous history of cerebrovascular accidents. the mean age of patients who developed stroke was also higher and the stroke group had a higher frequency of hepatic and renal dysfunction [ ] . sars-cov- infection has also been shown as an independent risk factor for ischemic stroke [ ] . here in our case also, the patient developed acute ischemic stroke in the absence of conventional vascular risk factors. the exact pathophysiology behind these cerebrovascular accidents is yet to be established. infectious/inflammatory syndromes are associated with an increased risk of stroke, probably due to different mechanisms involving prothrombotic state, alterations in lipid metabolism, platelet aggregation, and modifications in endothelial function [ ] . sars-cov- binds to the angiotensin-converting enzyme receptor. this binding results in a cytokine storm which leads to a hypercoagulable state in patients with covid- [ ] . critically ill patients with sars-cov- also show elevated d-dimer levels and platelet counts, which increases the propensity towards acute cerebrovascular episodes [ ] . the current covid- pandemic necessitates that extra measures be taken to provide care to stroke patients, along with measures aimed at minimizing the spread of infection. paramedics should develop an infectious screening policy in all patients before bringing them to the hospital [ ] . all suspected stroke patients should receive brain imaging within minutes of arrival in the ed. negative pressure carrier isolators can be used to isolate covid- patients during neurovascular imaging. the possibility as to whether anticoagulant or antiplatelet agents may be superior in stroke patients with covid- requires further consideration. similarly, no data exists to suggest a clear-cut benefit or risk with using intravenous recombinant thromboplastin plasminogen activator (rt-pa) therapy. a low threshold for initiating intubation, mechanical ventilation, and general anesthesia may be required in patients with covid- infection who are selected for mechanical thrombectomy to reduce exposure risk during the procedure [ ] . the mortality rate in covid- patients with stroke is very high [ ] . older age, high sequential organ failure assessment (sofa) score, cardiovascular diseases, secondary infections, ards, acute renal injury, lymphopenia, and elevated liver enzymes, crp, ferritin, fibrin, and d-dimers are some of the factors in covid- cases which can identify patients at risk of in-hospital mortality [ ] . patients of covid- can present with cerebrovascular accidents. stroke teams should be aware of this fact and screen the suspected patients for acute neurologic changes as soon as possible, so that management can be initiated in time, and morbidity and mortality can be reduced. in future, further analysis is needed on a larger scale to find out the true relationship between covid- and ischemic stroke and its pathogenesis. human subjects: consent was obtained by all participants in this study. in compliance with the icmje uniform disclosure form, all authors declare the following: payment/services info: all authors have declared that no financial support was received from any organization for the submitted work. financial relationships: all authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. other relationships: all covid- presenting as stroke evolutionary history, potential intermediate animal host, and cross-species analyses of sars-cov- neurological complications of covid- : a systematic review of literature. preprint (version ) available at research square neurologic manifestations of hospitalized patients with coronavirus disease acute cerebrovascular disease following covid- : a single center, retrospective, observational study covid- is an independent risk factor for acute ischemic stroke immunohematologic characteristics of infection-associated cerebral infarction covid- : consider cytokine storm syndromes and immunosuppression nervous system involvement after infection with covid- and other coronaviruses protected code stroke: hyperacute stroke management during the coronavirus disease (covid- ) management of acute ischemic stroke in patients with covid- infection: insights from an international panel trends in in-hospital mortality among patients with stroke in china clinical predictors of mortality due to covid- based on an analysis of data of patients from wuhan, china authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work. key: cord- -kck e ry authors: nan title: th annual meeting, neurocritical care society, october – , , vancouver, canada date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: kck e ry nan aging is associated with greater stroke risk and diminished stroke recovery. while the effect of aging on stroke recovery is well defined, the influence of aging on neuronal network activity and its correlation with stroke recovery is poorly understood. to study this, we performed serial whole-cortex imaging of spontaneous and evoked neuronal activity before and after stroke in young and aged mice and correlated those findings to behavioral outcomes. young ( - m, n= ) and aged ( m, n= ) thy -gcamp mice, underwent behavioral assessment and imaging before and , , , and weeks after infarct. infarcts were induced via exposure of somatosensory cortex to a laser ( mw, m) after injection of the photosensitive dye rose bengal. imaging followed placement of plexiglas windows and consisted of awake ( m) and anesthetized sessions ( m) with gcamp excitation via flashing of a nm led and acquisition via an emccd camera ( . hz framerate). somatosensory activation was via forepaw shock ( ma at hz for s x blocks). behavioral response was assessed by quantifying forepaw use during cylinder exploration ( m). aged and young mice exhibited similar baseline contralateral forepaw use (aged . ± . %; young: . ± . %) and evoked somatosensory cort . ± . x - ). whole-brain gcamp flourescence power in delta ( - hz) and infraslow ( . - . hz) ranges was significantly (p< . ) lower at baseline in aged mice. after stroke, aged mice developed greater long-term dependence on the unaffected limb (wk : aged . ± . %; young: . ± . %) - ). -stroke decrement in whole-brain gcamp fluorescence power was observed in aged animals. stroke in aged mice is associated with a greater decrement in local network activation, global mechanisms underlying age-related differences. hypernatremia and hyperchloremia is common after moderate-severe traumatic brain injury (mstbi) from saline resuscitation, osmotherapy administration, fever with insensible losses, limited free water administration, and diabetes insipidus. in isolation, hypernatremia and hyperchloremia are independent predictors of mortality in critically-ill patients; but this association has not been studied in mstbi, or in combination as physiologically occurring in patients. we examined whether hypernatremia and hyperchloremia in combination are independent predictors of in-hospital mortality in mstbi patients. we retrospectively analyzed prospectively collected data of consecutive mstbi patients enrolled in the optimism-study over a -year period. a semi-automated process provided all sodium and chloride values from the index hospitalization. time-weighted-average(twa)-sodium and chloride representing their "burden" over the entire hospitalization were calculated using a published formula. univariate and multivariable logistic regression were applied adjusting for impact-model-variables as validated predictors of mstbi mortality, osmotherapy, icu length-of-stay and ventilatory days. of patients analyzed, ( %) died. unadjusted mortality rates had a dose-response relationship with increasing sodium and chloride ( % for twa-sodium - mmol/l and % for twa-sodium > mmol/l; % for twa-chloride - mmol/l and % for twa-chloride > mmol/l; all p< . ). separately, twa-sodium (per mmol/l increase adjusted-or . ; %ci . - . ) and twachloride (per mmol/l increase adjusted-or . ; % ci . - . ) independently predicted mortality. in combination, however, twa-chloride remained an independent predictor of in-hospital mortality (per mmol/l increase or . , % ci . - . ), while twa-sodium did not (c-statistic . ; hosmer-lemeshow p< . ). to our knowledge, this is the first study to show that when concomitantly adjusting for hyperchloremia and hypernatremia burden, only hyperchloremia is independently associated with early mortality in mstbi. while not proving cause-and-effect, this suggests that hyperchloremia, and not hypernatremia as previously reported, deserves further attention in mstbi. if validated, this may have treatment implications for mstbi patients in the acute care phase. hyperosmolar therapy, with hypertonic sodium chloride (nacl) solution is often used in the treatment of cerebral edema and elevated intracranial pressure. recent reports have demonstrated that in patients with subarachnoid hemorrhage (sah) treated with hypertonic nacl, hyperchloremia is associated with the development of acute kidney injury (aki). we report a trial which compared two hypertonic solutions with different chloride content on the resultant serum chloride concentrations in sah patients. a low chloride hypertonic solution for brain edema (acetate), is a single center, double-blinded, double-dummy, pilot clinical trial comparing bolus dosing of . % nacl versus . % nacl/na-acetate for the treatment of cerebral edema in patients with sah. randomization occurred once patients who received hypertonic treatment for cerebral edema and/or elevated intracranial pressure (icp) developed hyperchloremia (serum cl- group, and to the hypertonic nacl/na-acetate one. the groups were well balanced in terms of severity of the sah, age, gender and risk factors. differerences between the serum chloride and sodium measurements, assessed from randomization to maximum during the icu course, were comparable between the nacl and nacl/acetate groups (cl: . ± . vs. . ± . , p= . ; na: . ± . vs. . ± . , p= . , respectively). nacl/acetate had a more prominent effect on immediate post dose sodium (increase of . ± . vs. . ± . ,p< . ). the rate of aki was lower in the na-acetate group ( . % in the nacl group vs. . % in the na-acetate group, p= . ). hyperchloremia preceded aki in . % of the cases; however, the time interval between hyperchloremia and aki was only a median of . days ). intention to treatment analysis demonstrated that treatment with hypertonic nacl/na-acetate hypertonic versus standard hypertonic nacl solution for patients with mild hyperchloremia, resulted in less events of a -center trials are needed to corroborate these results. up to . million people in the united states are living with physical, cognitive, and psychological sequelae after tbi. patients that sustain a moderate to severe tbi (mstbi) are heavily reliant on caregivers during their inpatient stay and for post-discharge care. there are limited data on how best to support caregivers in their role. the purpose of this study was to develop a checklist based on qualitative data that can be utilized by caregivers and clinicians to re-examine the particular needs of the caregiver at different periods in the acute, subacute, and chronic timeframe. patients with mstbi and their caregivers were recruited from two intensive care units (icus) in one institution to participate in semi-structured interviews at hours, one month, three months, and six months post-injury. transcripts of each interview were analyzed by two investigators who independently coded responses using a predetermined code list adapted from previously identified needs and concerns of other similar populations. based on the particular coded segments, a checklist and a list of strategies were derived to address the needs and concerns of caregivers. a total of patient-caregiver dyads were enrolled from x-y, with interviews completed; interviews with caregivers and with patients. caregiver interviews resulted in unique codes that corresponded to varying caregivers' needs and concerns which were developed into a checklist and list of strategies. the needs and concerns of mstbi caregivers should be assessed over time to provide the support necessary to assist in the care of mstbi survivors. implementation of a checklist, as well as a list of strategies, can allow for tailored interventions that improve the transitions of mstbi survivors from the icu to subacute/chronic care environments. malignant cerebral edema (mce) develops in a subset of those with hemispheric strokes, precipitating neurological deterioration and death if decompressive hemicraniectomy (dhc) is not performed in a timely manner. however, prediction of which patients will develop mce is imprecise based on baseline clinical and radiographic features imaging quantifies development of cerebral edema. we employ a recurrent neural network that learns from serial clinical and imaging data to enhance early prediction of mce. we identified patients with hemispheric stroke who had nihss and ct scans performed at baseline automated algorithm; midline shift (mls) was measured at the level of the septum pellucidum. we trained a recurrent neural network that incorporates sequential data and compared its performance to those of traditional models. we tried to maximize sensitivity for predicting mce (dhc or death) while optimizing prediction of those not requiring dhc (negative predictive value, npv). nine patients required dhc or died from mce. a linear classifier incorporating age, baseline nihss, and serum glucose had high npv ( %) but only % sensitivity for mce. a probabilistic gaussian mixed model (gmm) improved sensitivity to %. incorporating -hour nihss into gmm improved prediction (sensitivity %, npv %). the neural network was able to predict all cases of surgery and all of those not requiring surgery with % accuracy prediction. recurrent neural networks incorporating sequential clinical and imaging data from the first -hours after stroke may enhance our ability to predict which patients will need dhc. our promising pilot evaluation of this approach study requires validation in larger external stroke cohorts. aneurysmal subarachnoid hemorrhage(sah) survivors live with long term residual physical and cognitive disability. we studied whether neuromuscular electrical stimulation(nmes) and high protein supplementation(hpro) in the first two weeks after sah could preserve neuromotor and cognitive function as compared to standard of care(soc) for nutrition and mobilization. sah subjects with a hunt hess(hh) grade> , assigned to soc or nmes+hpro. nmes was delivered to bilateral quadriceps and gastrocnemius muscles daily during two minute sessions along with hpro(goal: . g/kg/day) between post bleed day(pbd) and . primary endpoint was atrophy in the quadriceps muscle as measured by the percentage difference in the cross sectional area from baseline to pbd on ct scan. all subjects underwent serial assessments of physical(short performance physical battery,sppb) cognitive(montreal cognitive assessment scale,moca) and global functional recovery(modified rankin scale,mrs) at pbd , , and . twenty-five subjects(soc= ,nmes+hpro= ) were enrolled between december and january with no between group differences in baseline characteristics( years old, % women, % hh> ). median duration of interventions was days(range - ) completing % of nmes sessions and % of goal protein intake. no difference in caloric intake between groups, but hpro+nmes group received more protein( . +/- . g/kg/d v . +/- . g/kg/d,p< . ). muscle atrophy at pbd was less in nmes+hpro group( . +/- . % vs . +/- . % ,p= . ). on univariate analysis, higher atrophy was correlated with lower daily protein intake (r=- . ,p= . ); and worse month moca (r=- . , p= . ),sppb(r=- . ,p= . ) and mrs(r= . ,p= . ). nmes+hpro subjects performed better on sppb(p= . ), were observed to have a lower mrs(p= . ) and obtained a higher moca(p= . ) than soc at pbd . nmes+hpro may reduce acute muscle wasting in lower extremities with a lasting benefit on recovery after sah. to better understand whether nmes and/or hpro are responsible for observed benefits, a larger, multicenter study is underway. increasing authorization rates for organ donation is the best way to grow the number of organs available for life-saving transplants. in order to improve our authorization rates and thereby provide more organs for life-saving transplants, our organ procurement organization (opo) partnered with donor hospitals to -led donation conversations and intensified the focus on a collaborative donation process. ned in the the opo during the authorization process by providing a timely notification of a potential donor and by work together on the timing of the donation discussion. the overall authorization rate has improved from % in to % currently. during this time frame, --led conversations has been compelling and a significant factor in improving authorization rates. equally impactful to improved authorization rates has been a % increase in cases involving a collaborative donation process (measured by timely referral and collaborative mention of donation). developing a strong partnership between an opo and a donor hospital is paramount to a successful donation process. critical factors such as timely referral notification and collaboration regarding the timing of the donation discussion can positively influence authorization outcomes. moreover, we -led donation conversations will lead to further increases in authorization which results in more lives saved through donation. quantitative eeg analysis is one part of multimodal monitoring in the intensive care unit due to high temporal resolution and ease of deployment. previously we have shown that dynamical properties of eeg signals can be used to differentiate focal vs. diffuse causes of coma (kafashan et al., ) , and that the intrinsic reactivity of eeg signals -a measure of responsiveness of the eeg to endogenously rare events -correlates with gcs score (inri, khanmohammadi et al., ) . here, we explore the possibility of localizing brain lesions using these dynamical features of eeg signals. we collected retrospective data from comatose patients (gcs< ) defined to have a focal injury. the patients underwent eeg recordings and imaging for routine purposes at barnes-jewish hospital nnicu. index (inri) , which consists of identifying intrinsic events, obtaining brain-state trajectories, and quantifying brain-state trajectories. we then used a neural network-based classifier to map the inri to lesion location using supervised learning paradigms with cross-validation. we used imaging to identify anatomical location of lesions and project them to a two-dimensional headmap. we trained a neural-network classifier to predict d lesion location from the inri dynamics of each eeg channel. we then assessed the correlation between predicted location and actual location using a cross-validation protocol. predicted locations significantly correlated with injury location (r> . ) when compared to correlations with randomly selected patients (r~ ). the results point to a systematic change in underlying neuronal-dynamics induced by brain lesions, that was captured through eeg dynamics and the concept of intrinsic reactivity. here we developed and evaluated a framework to localize brain injury through novel analysis of eeg dynamics. the results here, together with our previous work, suggest brain injuries can be detected and localized using eeg recordings. to examine whether changes in intracranial pressure (icp) waveform morphologies can be used as a biomarker for early detection of ventriculitis. of consecutive patients enrolled prospectively in a hemorrhage outcomes study from to , ( %) patients required external ventricular drainage (evd). only the culture-positive ventriculitis seen in ( % of all evds) patients were included in current analysis. based on our es per week, and additionally if infection was suspected. evds were left open for drainage, with icp monitored hourly by clamping. using wavelet analysis, we extracted uninterrupted segments of icp waveforms. we extracted dominant-pulses from continuous high-resolution data using morphological clustering analysis of icp pulse (mocaip). then we applied hierarchical k-means clustering using dynamic time warping distance to obtain morphologically similar groupings. we applied a top-down approach to split the clusters further, which stops when the mean distance of the waveforms to the centroid is less than a pre-clusters and further-split clusters (when equipoise existed) were categorized for broad comparison by clinician consensus. we extracted , dominant pulses from . hours of evd data. , pulses ( . %) occurred before positive culture, , pulses ( . %) were during culture positivity, and , pulses ( . %) occurred after clinical diagnosis was made. k-means identified clusters, which were further grouped into meta-clusters: tri/biphasic (green), single-peak (yellow) and artifactual (red) waveforms. . % of dominant pulses were tri/biphasic before ventriculitis, which reduced to . % during and . % after (p< . ). one day before the first positive cultures were collected, the distribution of meta-clusters changed to include more single-peak and artifactual icp waveforms (p< . ). the distribution of icp waveform morphology changes significantly prior to the clinical diagnosis of ventriculitis, and may be a potential biomarker. inducing normothermia with temperature modulating devices (tmds) is often associated with significant shivering. we tested the ability of a novel transnasal tmd to induce and maintain normothermia with minimal shivering in endotracheally intubated (et) cerebrovascular patients. single center study utilizing coolstat transnasal cooling device to achieve core temperature reduction by inducing an evaporative cooling energy exchange in the turbinates and upper airway thru a high flow of dehumidified air into the nasal cavity and out the mouth. primary goal was the ability to induce normothermia(t<= . c) within hours in et patients with fever(t>= . c) refractory to acetaminophen. continuous temperature measurements were obtained from tympanic and core(esophageal or bladder) temperature sensors. safety assessments included continuous monitoring for hypertension, tachycardia, and raised icp(when monitored). ent evaluations monitored for any device related nasal mucosal injury. shivering was assessed every minutes using the bedside shivering assessment scale(bsas). duration of device use was limited to hours, as regulated by the e care for temperature management. ten subjects(median age: years, bmi: . kg/m , %men) were enrolled with normothermia achieved in % of subjects. one subject did not achieve normothermia and was later refractory to other tmds. median baseline temperature was . +/- . c, with a reduction noted by hours( . +/- . v. . +/- . , p< . ) and sustained at hours( . +/- . v . +/- . , p= . ). time to normothermia was . +/- . hours. the median bsas was (range: - ) with only episodes necessitating meperidine across hours of study monitoring. no treatment was discontinued due to safety concerns. ent evaluations noted no device related adverse findings. inducing normothermia with a novel transnasal tmd appears to be safe, feasible and not associated with significant shivering. a multicenter trial testing the ability to maintain normothermia for hours is currently underway. traumatic coma is thought to be caused by disruption of the subcortical ascending arousal network (aan). this hypothesis has not yet been tested because tools to map aan connectivity in living humans have only recently become available. we implemented high angular resolution diffusion imaging (hardi) on an mri scanner in the intensive care unit to determine whether patients presenting with traumatic coma have disrupted aan connectivity. we performed high angular resolution diffusion imaging (hardi) in patients with acute severe traumatic brain injury who were comatose on admission and in matched controls. we used probabilistic tractography to measure the connectivity probability (cp) of aan axonal pathways linking the brainstem tegmentum to the hypothalamus, thalamus and basal forebrain. to assess the spatial specificity of cp differences between patients and controls, we also measured cp within four subcortical pathways outside the aan. compared to controls, patients showed a reduction in aan pathways connecting the brainstem tegmentum to a region of interest encompassing the hypothalamus, thalamus, and basal forebrain (patients: median . , iqr [ . , . ] controls: . [ . , . ], p = . ). examining each pathway individually, brainstem-hypothalamus and brainstem-thalamus cps (pc < . ), but not brainstemforebrain cp (pc = . ), were significantly reduced in patients. only one subcortical pathway outside the aan showed reduced cp in patients. we provide initial evidence for the reduced integrity of axonal pathways linking the brainstem tegmentum to the hypothalamus and thalamus in patients presenting with traumatic coma. our findings support current conceptual models of coma as being caused by subcortical aan injury. aan connectivity mapping provides an opportunity to advance the study of human coma and consciousness. limited knowledge about the physiology underlying coma recovery has decreased clinicians' ability to identify patients likely to benefit from continued intensive therapy. machine learning using quantitative eeg (qeeg) has shown potential to improve outcome prediction in cardiac arrest, but the relationship between qeeg trends and coma recovery had limited evaluation in large multicenter studies. seven hospitals contributed clinical and eeg data from comatose adult subjects with cardiac arrest who underwent continuous eeg and targeted temperature management. qeeg features evaluated included background frequency, burst-suppression ratio(> %), epileptiform discharges, and entropy. we utilized random forests to predict good (cpc - ) vs. poor (cpc - ) outcome at -months. model performance was evaluated using the auc at h intervals up to h. we analyzed , hours of eeg (+ tb) for , subjects ( good outcomes). unfavorable eeg features were common in subjects with good or poor outcomes (epileptiform discharges: %, % and burst-suppression: %, %, respectively). epileptiform discharge frequency peaked after rewarming in subjects with good outcome ( spikes/min at h), but continued increasing during cooling and rewarming for those with poor outcome ( - spikes/min from h- h). shannon entropy was always higher in subjects with good outcome. burst-suppression strongly predicted outcome for all centers but during different times, while epileptiform discharges predicted outcomes in five centers, entropy in three, and alpha-background in only one. outcome prediction was best with qeeg during cooling rather than after rewarming (auc . vs. . at h and h, p< . ). maximal auc at h for individual centers ranged from . - . . early qeeg trends carry useful information for coma recovery prediction, but marked heterogeneity in qeeg trends across centers can limit performance and reproducibility of machine learning prognostication algorithms. coexistence of favorable and unfavorable qeeg features in the same patient is common, suggesting that generalizable models for coma recovery prediction must leverage temporal trends. human consciousness depends on ascending projections from the brainstem. brainstem lesion mapping studies have identified a coma-specific sub-region of the dorsolateral pontine tegmentum. however, loss of consciousness (loc) can also occur following injury to cortical regions remote from the brainstem, a phenomenon that commonly occurs after penetrating head trauma but remains poorly understood. andexanet alfa has been shown to reduce anti-factor xa activity however outcome studies are lacking. we compare the efficacy of four-facto -pcc) vs andexanet in patients with factor xa inhibitor related bleeding. retrospective study was performed january to march , including patients with factor xa inhibitor related bleeding of whom wer -pcc vs treated with andexanet. outcome was analyzed using glasgow outcome scale (gos) at discharge, presented as good (score - ) and poor ( - ); length of stay (los) and invariables, and t-test for continuous variables. -pcc or andexanet were included in the study. bleeding source --pcc; vs andexanet cases, % of total -pcc n= , andexanet n= ) and trauma ( -pcc -pcc group was . d vs . d in the andexanet group; icu stay corresponded to . vs . days, respectively. outcomes evaluated through gos did not differ -pcc group vs % in andexanet group, -pcc group vs . % on andexanet group, p= ). unexpectedly, in-hospital mortality was higher on andexanet group -pcc group ( . %); with a similar trend observed in the cns subgroup. -pcc as a factor xa inhibitor related bleeding reversal agent was as effective as andexanet based on outcome scale, constituting an essential option for hemostatic control as cost differences can limit the use of andexanet. the mechanism by which early administration of tranexamic acid (txa) reduces mortality in traumatic brain injury (tbi) is poorly understood. in-vitro models suggest the glycocalyx is preserved with early txa administration, indicating that txa may inhibit glycocalyx breakdown. we hypothesized that early txa administration would result in vascular endothelial preservation as evidenced by lower levels of thrombomodulin, syndecan- , icam, and vcam. we analyzed a subset of subjects from the prehospital txa for tbi trial, which examined the efficacy and safety of prehospital administration of txa compared to placebo in patients with moderate or severe tbi who were not in shock. blood samples were collected upon admission and at hrs. glycocalyx breakdown markers were quantified using a luminex analyte platform. clinical variables were compared using wilcoxon rank-sum tests for non-parametric continuous data and chitests for categorical data. differences in median marker levels were evaluated using t-tests performed on log-transformed variables. significance was set at . . data from patients [placebo (n= ), txa (n= )] were analyzed. groups were well-matched for age, sex, injury mechanism, admission injury severity score, head abbreviated injury score, and presence of intracranial hemorrhage (ich) on admission ct. no differences were observed in any median marker levels on admission or at hours. however, admission levels of syndecan- in patients with ich (n= ) who received txa were lower than those in the placebo group ( . pg/ml [ . - . ] v. . pg/ml [ . - . ], p= . ). no differences in thrombomodulin, icam, or vcam levels were detected at either timepoint in the ich subgroup. administration of txa early after injury may attenuate endothelial release of syndecan- in patients with moderate or severe tbi and ich, potentially suggesting a selective role for txa in endothelial gl despite a rapid increase in the use of the oral factor xa inhibitors rivaroxaban and apixaban over recent years, there remains no standard management for associated life-threatening hemorrhage. andexanet -approved reversal agent available but its place in therapy remains controversial due to its high cost and a lack of head-to-head trials comparing it to four-factor prothrombin complex -pcc). we conducted a retrospective review of adult patients admitted with ich associated with rivaroxaban or apixaban and -pcc for anticoagulation reversal between may and april . the primary outcome was hemostatic efficacy using the annexa- study rating system (excellent, good, or poor) based on initial and repeat non-contrast ct head imaging within hours. secondary outcomes included the occurrence of thromboembolic events and -day all-cause mortality. we excluded patients whose hematoma was surgically evacuated before the -hour ct or who received multiple reversal products. ich patients met the inclusion criteria: andexanet patients ( spontaneous and traumatic) and -pcc patients ( spontaneous and traumatic). ( %) andexanet patients achieved excellent -pcc patients ( -pcc patients, ( %) achieved good (p= . ) and ( %) achieved poor (p= . ) hemostasis. thromboembolic events following -pcc patients (p= . ). thirty-day all-cause mortality occurred in ( %) andexanet patient and ( %) -pcc patient (p= . ). -pcc for reversing ich associated with rivaroxaban and apixaban. limitations include our small sample size and -pcc in this population now that andexanet alfa is widely available. a quality improvement project was undertaken to understand the risks of central venous catheter associated venous thromboembolism (vte) in the neuroicu setting. all patients who were admitted to the neuroicu and required a central venous catheter from / / to / / were included in the study. all catheters were placed under ultrasound guidance using the seldenger technique. the site of catheter insertion, duration of dwell time and subtype were recorded for each catheter that was placed. catheters were categorized as cooling catheters, large bore and dialysis catheters, or standard multi-lumen infusion catheters. clinical suspicion for vte such as extremity edema or unexplained hypoxemia triggered the standard of care use of ultrasound and/or lung ct angiography for diagnosis. vtes with an appropriate chronology and in the same vascular distribution as the suspected catheter were categorized as catheter associated. catheters in patients were included in the analysis representing catheter*days. a total of catheter related vtes were observed in our cohort. in a mixed neuroicu cohort the overall vte rate was . per patient days which is in line with prior published rates. multi-lumen infusion catheters had the highest rate of vte ( . ± . ) and cooling catheters had the lowest rate ( . ± . ). surprisingly, the highest rate of vtes was observed in catheters placed in the subclavian vein across catheter types ( . ± . ). we observed that multi-lumen infusion catheters had a higher rate of vte compared with cooling and large bore catheters. this finding may be related to longer dwell times for multi-lumen catheters ( . ± . vs [cooling] . ± . and [large bore] . ± . ). the subclavian vein was the site with the highest rate of vte which may be related to more lateral approach taken with ultrasound guided subclavian catheter placement. patients on direct acting oral anticoagulants (doacs) have high mortality after intracranial hemorrhage (ich). prothrombin complex concentrate (pcc) has been used off-label to treat ich while on doacs. pccs effect on laboratory markers of anticoagulation have varied. whether or not a change in laboratory markers of anticoagulation impact outcome is unknown. retrospective, single center design assessing patients on doacs that presented with ich and received pcc. the primary outcome is to describe changes in anti-thrombelastography (teg) parameters before and after receiving pccs. hemostatic efficacy (defined by international society on thrombosis and haemostasis criteria), and thrombosis rate are also reported. thirty five patients were included. patients were . +/- . years old and % were male. . % had traumatic brain injury related hemorrhage, % had primary intracerebral hemorrhage, . % had subdural hemorrhage, and . % had subarachnoid hemorrhage. median glasgow coma score at was . units/ml +/- . units/ml. on average teg r time decreased +/- seconds and teg act time decreased +/- seconds. hemostatic efficacy was excellent or good in % of patients and poor in %. thrombosis rate was . %. overall mortality was %. there was a modest response in laboratory parameters after giving pcc to patients with doac associated ich. the mortality in this cohort was high. whether a laboratory response in coagulation dosing, laboratory response, hemostatic efficacy and patient outcomes. in critically ill patients with tbi, agitated behaviors may often be threatening for patients safety and for clinical teams. antipsychotics are commonly used for the acute management of these agitated behaviors. however, animal tbi models suggest that repeated use of antipsychotic agents reduce cognitive and functional recovery. it remains unknown if the use of these agents negatively impact the functional recovery of tbi patients. our objective was to describe the use of antipsychotic agents and agitation/delirium monitoring practices in critically ill tbi patients. we conducted a retrospective observational study of adult icus in canada that manage tbi patients. consecutive adult patients with moderate/severe tbi admitted to icu between january and december were included. data were collected using standardized forms for up to a maximum of days in icu or until transfer out of icu. the primary outcome was incidence of antipsychotic use. we included patients ( patient-days) with a moderate ( %) or severe ( %) tbi. the majority tbi included falls ( %), mva ( %) and assaults ( %). antipsychotics were used in % of patients for a total % of patient-days. quetiapine, haloperidol, olanzapine, and risperidone were used in a %, %, %, % of patient-days, mostly for agitation, an unclear reason or delirium ( %, % and % of total patient-days, respectively). a delirium monitoring tool was used % of patient-days whereas the rass and sas were used in % and % of patients-days, respectively. despite uncertainties regarding their efficacy and safety, antipsychotics are frequently used in critically ill moderate/severe tbi patients in canada, mostly for the management of agitation. sedation/agitation tools are mostly used for the monitoring whereas delirium tools are more rarely used. traumatic venous sinus thrombosis (tvst) is increasingly detected on neuroimaging in acute head trauma, and may be an important contributor to elevated icp refractory to standard medical/surgical treatment, and in turn, higher morbidity/mortality and more complex icu course. we sought to identify clinical and neuroimaging features predictive of refractory icp issues in tvst patients treated in an urban level i trauma center. retrospective query of electronic radiology database from to using the phrase "venous sinus thrombosis". cases were reviewed and scored by a fellowship-trained neuroradiologist to define degree of occlusion (partial vs complete) and cause of sinus occlusion (extrinsic compression vs intrinsic thrombus vs both). additional patient characteristics included demographics, mechanism of trauma, cerebral venous sinus involvement, laterality, skull fracture, extra-axial hemorrhage and invasive neuromonitoring. refractory icp was defined as at least one spontaneous icp elevation >= minutes during icu stay despite use of first tier therapies for icp control. odds ratios were computed and adjusted by multivariate logistic regression for patient age, gender and initial gcs to determine association with refractory icp. among patients with radiologic diagnosis of tvst, developed refractory icp ( / = . %). statistically significant variables associated with refractory icp included involvement of internal jugular vein (aor= . , % ci . - . ), involvement of transverse sinus (aor= . , % ci . - . ) and presence of temporal bone fracture (aor= . , % ci . - . ) . potentially protective factors included sinus pathology secondary to extrinsic compression (aor= . , % ci . - . ) and coexisting epidural hemorrhage (aor= . , % ci . - . ). involvement of the internal jugular vein or transverse sinus and temporal bone fracture may represent sensitive features of tvst predisposing to refractory icp issues, while extrinsic compression of a sinus alone was found to be protective. monitoring cerebral autoregulation in traumatic brain injury (tbi) patients can indicate an individual cerebral perfusion pressure (cpp) target for which autoregulation is best preserved (cppopt): this offers a precision medicine approach with hypothetical advantage over the current 'one size fits all' strategy. large retrospective data suggest that managing cpp close to cppopt has a benefit in outcome. a prospective evaluation of cppopt guided therapy is needed, but before performing an outcome study it is necessary to assess the feasibility and safety of such a protocol. the primary objective of cogitate (cppopt guided therapy assessment of target effectiveness) is to demonstrate feasibility of individualising cpp at cppopt in tbi patients, expressed as the percentage of monitoring time for which cpp is within mmhg of regularly updated cppopt targets during the first days of intensive care unit (icu) admission. secondary objectives are to investigate the safety (increases of the treatment intensity level) and physiological effects of this strategy (changes in autoregulation indexes, organ function parameters). cogitate is a phase ii non-blinded, randomised controlled trial currently ongoing in the icu of cambridge, leuven, nijmegen and maastricht. severe tbi patients requiring intracranial pressure directed therapy, are enrolled in the first hours after icu admission and allocated into two groups. in the intervention group the cpp target (cppopt) is calculated using a (modified) algorithm previously described by liu x et al. and clinically reviewed -hourly. the control group uses a fixed cpp target ( - mmhg). patient re have been recruited so far. randomising between a fixed and variable cpp is feasible. after completion of recruitment and follow up in terms of assessment of safety and physiological parameters, we will consider progressing to a phase iii study. selective reduction of non-classical monocytes has been associated with reduced neutrophil activation in murine traumatic brain injury (tbi) models. similarly, cd -/cd -t cells or double negative t-cells (dnt) may exacerbate ischemic brain injury. this study sought to assess the expression of peripherally isolated t-cells and monocytes after acute tbi. all patients admitted with primary tbi to the neurotrauma icu between november and november were eligible for study. consent was obtained and blood samples were obtained within hours of injury. samples were compared to healthy age-and sex-matched controls. conventional flow cytometry techniques gating on all patients admitted with tbi to the neurotrauma icu between november and november were eligible for study. consent and blood samples were obtained within hours of injury. samples were compared to healthy age-and sex-matched controls. conventional flow cytometry techniques, gating on cd + and cd + were employed to identify t-cell and monocyte populations, respectively. data were analyzed using cytometric fingerprint binning and t-sne embedding, which captures the set of multivariate probability distribution functions and generates maps that facilitate quantitative comparisons. patients were compared to controls. after computational analysis, distinct t-cell phenotypes were identified, of which were statistically significantly different between patients and controls expressed as a fraction of cd + cells. three of these eleven subsets had a cd -/cd -(double negative) phenotype that were depressed among patients: cd -/cd -/cd + . % versus . %, p= . ; cd -/cd -/ + . % versus . %; p= . ; cd -/cd -/ +/ + . % versus . %; p= . . there was a three-fold decrease in the fraction of type , non-classical monocytes in patients than in controls [ . (iqr . - . ) versus . (iqr . - . ); p= . ]. similar patterns in monocyte expression were observed for the patients who had repeat analysis at hours. in this preliminary study, there were notable reductions in dnt populations and non-classical monocytes in patients with acute tbi, which may suggest recruitment to the cns. prior studies suggest that dnt play a critical role in the perpetuation of cerebral ischemia after acute stroke and that type monocytes modulate neutrophilwarranted. much of the secondary injury that occurs after traumatic brain injury (tbi) results from coagulation derangements related to disseminated intravascular coagulation (dic). extracellular vesicles (evs) are small ( . transduction. evs are released from all cell types, including platelets, endothelium, and granulocytes which are responsible for dic. we hypothesized that specialized flow cytometry techniques could identify a unique ev signature of dic in acute tbi. ev fluorescence panels were created assessing for endothelial cells (cd +, cd +), platelets (cd , cd a+, cd b+), erythrocyte markers (cd +) as well as brain specific biomarkers (s b). using a modified flow cytometry instrument for detection of small particles, side scatter signal is used to estimate ev size. samples were treated with triton, which disrupts vesicular membranes, abolishing evs. samples were prepared in trucount tubes with a known number of lyophilized beads, which enabled the determination of the plasma volume. all combinations of positive/negative expression were counted. there was no significant difference in the total number of evs in the panels between the patients and controls. of combinatorial analyses in the first ev panel, the following were significantly elevated after bonferroni correction: cd +/cd + . evs/ul plasma v controls (wilcoxon rank sum p= . ); cd +/cd + . evs/ul plasma v . controls (p= . ); cd +/cd a+ . evs/ul plasma v . controls (p= . ). brain biomarkers were also elevated: s b . evs/ul plasma v. . controls (p= . ). evaluate whether this expression correlates with secondary microvascular brain injury. s b evs (membrane bound, not free soluble protein) are significantly elevated in tbi patients; if reproducible, the significance of this remains to be elucidated. diabetes insipidus (di) following transsphenoidal craniotomy may lead to significant metabolic derangements. serum sodium imbalances are frequent and important; both hypo-and hypernatremia can be devastating neurologically. a project aimed at improving di management through predictive assessments and ddavp protocols could potentially improve patient outcomes. however, few predictors for the postoperative development of di have been reported. after institutional irb exemption, the records of patients undergoing endonasal transsphenoidal craniotomy between july and december were retrospectively reviewed. demographics, preoperative medical or radiologic diagnoses, medications, and laboratory values as well as intraoperative blood loss, urine output, and ddavp administration were assessed for correlation with the incidence of postoperative development of di using logistic regression. development of postoperative di was defined as postoperative ddavp administration and/or ddavp use upon or after discharge from hospital. of the patients developed postoperative di. patients . , and . , respectively). similarly, patients with increased intraoperative blood loss, increased intraoperative volume administration, nd intraoperative ddavp or vasopressin administration were also more likely to develop postoperative di (pwith logistic regression modeling adjusted for associations between outcome and potential risk factors, patients having a documented or clinical suspicion for a preoperative endocrinopathy had seven times higher odds of developing postoperative di compared to their peers (p-value . , % ci . - . ). in administration, and ddavp were independently associated with an increased risk of postoperative di; the odds of postoperative di were seven times higher in patients with a documented or clinical suspicion findings. the seminal mechanical thrombectomy (mt) trials had a median age of years. though some of these trials included nonagenarians, there is little data on their outcomes. we aimed to compare the procedural, discharge outcomes and complications, of mt for acute ischemic stroke (ais) in patients with ais admitted to two comprehensive stroke centers were enrolled prospectively in a mt, procedural outcomes, complications, and discharge disposition were compared in propensity scorematched groups (matched for nihss, pre-stroke mrs, ivdefined as a discharge to home/acute rehabilitation. of the ais patients, / ( %) nonagenarians underwent mt compared to / ( %) ) were propensity score-matched with a median admission nihss of and , and median aspects ( % vs %, p= . ), whereas ica ( % vs %, p= . ), and m ( % vs %, p= . ) occlusions were similar between the two groups. time to groin puncture ( ± vs ± ; p= . ), revascularization time ( ± vs ± ; p= . ), complication rates ( vs . %; p= . ) and inhospital deaths ( % vs %; p= . ) were similar among the two groups. % of nonagenarians had we present one of the largest series of mt among nonagenarians with % successful recanalization rates. in propensity score analysis almost half of nonagenarians ( %) were discharged to home/rehab, which is comparable to a younger cohort ( %). aggressive management is warranted in the oldest of the old. early neurologic deterioration (end) occurs in up to one third of stroke patients and is associated with poor outcome. no consistent definition of end exists regarding degree of nihss decline and timeframe. we evaluated the definition of end, predictive factors, and day outcomes in a cohort of critically ill stroke patients. this study is a retrospective review of consecutive ischemic stroke patients with nih stroke scale (nihss) intervention factors were obtained. end was defined as a delta nihss > at hours from admission. reperfusion was defined as a thrombolysis in cerebral infarction (tici) score of > b, cerebral edema treatment as any icp-lowering therapy, and poor outcome as mrs > at days. multivariable logistic regression analyses were performed to assess factors associated with end and poor outcome. patients (median age years, % women, median nihss ) met study criteria. % experienced end. admission nihss, administration of tpa, receipt of intraarterial therapy, and successful reperfusion were not associated with end. end was independently associated with older age (p= . ), sex (p= . ), and treatment of cerebral edema (p= . ) after adjusting for cerebral herniation and tracheostomy. poor outcome was associated with older age (p= . ), higher delta nihss (p< . ), not receiving tpa (p= . ), and placement of percutaneous endoscopic gastrostomy tube (p= . ). end patients had a higher median day mrs (p< . ). end as defined by a delta nihss > at hours predicts poorer outcome, but was not associated with tpa or intraarterial therapy, which contrasts with prior literature. this variance could be attributed to the end timeframe defined as hours rather than the typical samples sizes and comparison of end timeframes could clarify observed findings. annexa- was a single-arm, prospective, open-label study of andexanet in patients presenting with major bleeding within patients with spontaneous intracranial hemorrhage (ich). brain imaging was performed at baseline, and at and hours post andexanet treatment. subdural hemorrhage (sdh) thickness and ich volumetric analysis was performed using quantomo software. co-primary efficacy outcomes were change in anti- of patients enrolled in annexa- , nontraumatic ich was present in patients, including intracerebral +/-intraventricular in patients, subarachnoid in patients and subdural in patients. in this cohort, mean age was years (sd . ) administration was . hours (iqr . - . ); median time from symptoms to ct was . hours (iqr . - . ); and median time from ct to andexanet administration was . hours ). median intraparenchymal volume was . ml (iqr . - . ). among efficacy evaluable patients (baseline anti-treatment overall. in patients treated < hours after baseline imaging, hemostatic efficacy was . %; - hours after baseline imaging, . %; > hours, . %. within days, death occurred in patients ( . %). andexanet reduced anti--or apixaban-associated nontraumatic intracranial bleeding and with a high rate of hemostatic efficacy up to hours after treatment. spontaneous intracerebral hemorrhage (ich) is associated with high rates of mortality. multiple scoring systems exist however the original ich score remains most commonly used. we hypothesize that patients undergoing scuba, compared to medically managed patients, would have lower -day mortality than predicted. we performed a retrospective observational cohort study of consecutive nontraumatic spontaneous ich patients treated at a single, tertiary care, academic center from december to june . patients for each patient based on the admission ich score. a total of ich patients were included. the median age was (q = , q = ), gcs ( , ), and nihss ( , ) . sixty-three were deep hemorrhages and had intraventricular hemorrhage. median pre-operative volume was . ml ( . , . ). the expected -day mortality was . % while the observed mortality was %. on -day follow up, a mrs of - was seen in % of patients. patients undergoing scuba have an absolute risk reduction of . % in mortality than predicted by the ich score. good outcome to moderate disability, defined as mrs - , was achievable in almost half the introduction andexanet (coagulation factor xa [recombinant] inactivated-zhzo), a specific reversal agent for factor xa % of patients with major bleeding in the annexa- trial. however, little is known about the clinical factors associated with a hemostatic response in patients with intracranial hemorrhage (ich) receiving andexanet. annexa- was a prospective, single-arm, open-label study of andexanet in patients with acute major treatment was rated by an independent adjudication committee as excellent, good, or poor/none based on pre-specified criteria. all ich patients with evaluable he were included in the analysis. univariate and indication for anticoagulation, baseline antianti-platelet use, time from last dose to andexanet (and other time intervals), neurologic function, and hematoma characteristics were performed to identify factors predictive of he. of ich patients enrolled, ( . %) had evaluable he. in patients with ich, baseline antitime from symptoms to andexanet were all significantly associated with he. in multivariate analysis, time from last dose ( . h for excellent/good; . h for poor/none), time from symptoms to andexanet ( . h for excellent/good; . h for poor/none), and time from symptoms to scan ( . h for excellent/good; . h for poor/none) were independently associated with he. in ich patients treated with andexanet in the annexa- study, various time intervals were predictive of hemostatic efficacy. these findings suggest that shorter time intervals are associated with lower he and are consistent with the known relationship between time from symptoms and the risk of hematoma expansion. alterations in functional connectivity are associated with persistent cognitive deficits in survivors of aneurysmal subarachnoid hemorrhage (sah), but causation remains unknown. therefore, we sought to and behavior could be assessed. we used functional optical intrinsic signal imaging to measure spontaneous hemodynamic fluctuations -operated (n= ) and sah (n= ) mice. we tested behavior using the morris water maze, open field test, y-maze, and rotarod. timepoints were from days to months. we used the anterior prechiasmatic injection model of sah. . ), and visual cortex ( . vs. . ) at day following sham procedure or sah, as measured by the proportion of brain surface with a correlation coefficient > . (sham vs. sah, respectively, p< . ). -independent ng sah. a global connectivity index remained decreased until month following sah ( . vs. . , p< . ). an interhemispheric connectivity index was also he hidden platform test on the morris water maze (p= . ) and open field test ( vs. m, p= . ) at approximately weeks. there were persistent deficits on the y-maze for at least months ( % vs. % alternation, p= . with repeated measures at and months). there was no significant effect of sah on rotarod performance. we studied whether high-protein supplementation (hpro) and neuromuscular electrical stimulation (nmes) after subarachnoid hemorrhage (sah) could be a safe and feasible approach to reduce muscle wasting and improve long term recovery. assigned to standard of care (soc) or nmes + hpro. nmes was delivered to bilateral quadriceps and gastrocnemius muscles during two -minute sessions daily along with hpro (goal . g/kg/day) between post bleed day (pbd) and . tolerability was measured during each nmes session by assessing for agitation or discomfort. safety measurements included increased heart rate, blood pressure, or intracranial pressure (when monitored) during nmes. stimulation sites were assessed after each nmes for muscle injury or skin trauma. hpro tolerability was assessed by monitoring for gastric retention or emesis. safety measures included aspiration and evidence of acute kidney injury. nmes and hpro were discontinued if subjects refused. the goals were to administer at least % of nmes and hpro. muscle wasting was assessed with serial ct scans of the thighs. twenty-five subjects (soc= , nmes + hpro= ) participated with no differences in baseline characteristics ( years old, % women, % hh> ). median intervention days were (range: - ), with % of nmes sessions completed. two subjects had transient muscle soreness but no other adverse events. no adverse events were associated with hpro. the hpro group received % of the goal and more protein than soc (mean difference: . +/- . g/kg/d, p< . ). muscle atrophy at pbd was greater in soc group ( . +/- . % vs . +/- . %, p= . ). nmes and hpro are safe and feasible after sah. a larger pilot study is underway to understand whether nmes and/or hpro may beneficially impact neuromotor recovery after sah. lipocalin- (ngal) is released by activated neutrophils and astrocytes and mediates neuro-inflammation and iron regulation in hemorrhagic stroke models. blood ngal is an early biomarker in human ischemic l and neurofunctional outcome in sah patients. magnetic luminex assay, r&d systems) and assessed modified rankin scale (mrs) every months. patients with renal or severe liver dysfunction, active malignancy or intracranial infections were excluded. poor outcome is defined as mrs> . vasospasm was defined as > % reduction any vessel caliber on cerebral angiogram. continuous variables were compared with student's t or wilcoxon rank sum test depending on data distribution. one-way anova was used for multi-group comparison. sah cohort has mean age of . years, % women, % with poor -month outcome and % developed vasospasm. higher plasma ngal on post--sah days - (p= . ) and (p= . ) are associated with poor -month outcome. higher plasma ngal on postand ngal on post-sah days -- . ) early elevation of plasma ngal on post-sah day is associated with vasospasm and poor -month -sah - are associated with poor -month outcome. larger population studies are needed to validate plasma ngal as a potential sah biomarker. patients with aneurysmal subarachnoid hemorrhage (asah) are at risk of rebleeding prior to aneurysm obliteration. while placebo-controlled studies have shown that administration of either -aminocaproic acid (eaca) or tranexamic acid (txa) can decrease rebleeding, there has not been a comparison of the two in this patient population. because of a national shortage of eaca in , our hospital changed to txa. the purpose of this study is to describe the outcomes of asah patients treated with either eaca or txa. this is a retrospective chart review of patients who presented with an asah between / / and / / and were treated with either eaca or txa to prevent aneurysm rerupture. descriptive statistics were used. there were patients with asah who received eaca and who received txa. the groups were eaca group and . % in the txa group. the average time from admission to drug initiation was . ± . hours in the eaca group and . ± . hours in the txa group. no patient in either group experienced aneurysm rerupture after receiving the drug. similar numbers of patients in both groups had cerebral ischemia (eaca: % vs. txa: %) and extracranial thrombosis (eaca: % vs. txa: %). although txa is known to lower the seizure threshold, we found no increased incidence of seizures (eaca: % vs. txa %). there was a modest cost difference in favor of txa vs. eaca. there does not appear to be any major differences in outcomes in patients with asah treated with either eaca or txa for the prevention of aneurysm rerupture and a slight cost savings favoring txa. a larger prospective study is required to confirm these results. outcome prediction after aneurysmal subarachnoid hemorrhage (asah) is based on scores, which are determined once at admission. however, the occurrence of delayed ischemic neurological deficits (dind) depends on multiple concomitant and continuously changing factors. the goal of the study was to establish an automated analysis pipeline to predict dind from multimodal data. multimodal data (patients' history, imaging and laboratory values among others) from patients with asah were analyzed. dind was defined as new ischemia or perfusion deficits in native or contrastenhanced ct/mri and/or cerebral vasospasm in conventional, ct-/mr-angiography. a ranking of the features was performed by univariate regression analysis. only cases with < % of missing values were included in the model. among the tested features, the top , with a false discovery rate < . , were selected. missing values were imput random forest machine learning algorithm was applied. the performance of the prediction was estimated on the fly by predicting the observations that were not used for building the tree ("out-ofbag") across all trees. the final data matrix contained events described by features from patients. in the final model, the out-of-bag estimate of error rate was %, which reflected a % accuracy. the importance plot for different features revealed the importance of some parameters known in the context of inflammatory response, which is linked to the pathophysiological cascade leading to dind. these included counts of leucocytes, monocytes, neutrophils, and lymphocytes. however, other laboratory parameters, such as zinc and selenium, appeared to be of high importance in the model, which was somewhat unexpected. machine learning algorithms may be helpful to filter out predictive features from a large number. these features might be subsequently investigated regarding their predictive value on the occurrence of dind after asah. innate inflammation is a recognized mediator of dci after sah. we have shown that neutrophils and the neutrophil-derived enzyme, myeloperoxidase (mpo), mediate memory deficits in dci. how mpo affects memory is unclear. there is evidence that mpo, and its substrate h o , may act through astrocytes or directly on neurons. here we test mpos action on astrocytes and neurons. primary neuronal and astrocyte cultures were developed from wt and c bl/ thy -gcamp mice. to test if mpo or h o are toxic to neurons or astrocytes, cells were incubated with mpo ( . u/ml), h o ( . %), and mpo/ h o and evaluated with live/dead cell viability assay (thermofisher). to test if neuronal firing is affected by mpo, the same experimental conditions were examined in c bl/ thy -gcamp using video microscopy. neuron activation was stimulated with kcl (final concentration mm). addition of h o led to death in neurons and astrocytes. mpo did not affect cell death in either group. interestingly, mpo/ h o showed less cell death than h o alone suggesting a neuroprotective benefit of mpo. in neurons, kcl administered to untreated neurons led to continuous firing as evidenced by intense calcium signal. mpo addition did not change the firing rate when compared to baseline. after . hours of mpo pretreatment, activation with kcl showed a suppressed firing rate suggesting neuronal depression. the addition of mpo/ h o showed the same firing rate suppression as mpo alone. this study suggests that mpo acts directly on neurons to decrease function. in our model of neutrophilinduced development of dci, mpo is released in the meninges, diffuses to the brain parenchyma and acts directly on neurons to affect memory. this needs to be tested more thoroughly in an in vivo model of sah. how mpo specifically affects memory in neurons is an area of interest in our laboratory. delayed cerebral ischemia (dci) is a feared complication of subarachnoid hemorrhage (sah), leading to worse outcomes. electroencephalography (eeg) provides a useful, continuous monitoring tool for dci risk (claassen ; kim ; rosenthal ) and late-onset epileptiform discharges (ed) have high predictive value for dci (kim ; rosenthal ) . however, optimal parameters to assess ed contribution to longitudinal dci risk are unknown. we hypothesize that the evolution of ed frequency after sah can provide early identification of those at high dci risk. we analyzed continuous eegs from patients with moderate to severe aneurysmal sah. ed were identified using a commercial detection algorithm (scheuer ). we calculated ed frequency (per hour) after sah and compared mean ed frequencies between dci and control patients. we also evaluation, we performed group based trajectory analysis (gbtm) and calculated hourly receiver operating curves (roc). ed rates were higher in both dci and control groups during the clinical dci "risk period" of day - . overall mean ed frequency were significantly higher in dci patients (t-test, p= . ), including only pre-dci ed assessment (t-test, p< . ). hourly mean ed rates remain higher in dci patients from days - . using gbtm, we identified three distinct trajectories associated with dci ( %, %, %, p= . ), with group number selection optimized based on bayesian information criteria. hourly area under the roc (auc) calculations of ed frequency yielded a maximum performance of . . natural history of ed frequency in all sah patients coincides with the "high risk" time-period of dci. patients with dci have higher mean frequencies that remain elevated throughout this dci risk period. gbtm and auc calculations suggest longitudinal analysis of discharge frequency can differentiate dci risk, but integration of other waveform characteristics are needed to optimize prediction. aneurysmal subarachnoid hemorrhage (sah) has high morbidity and mortality. time to aneurysm repair, whether earlier or later in the course of the disease, may impact outcomes. however, optimal timing remains controversial. our goal was to describe the association between time to aneurysm repair and mortality and functional outcome. this study was conducted in two reference centers -one in rio de janeiro and one in porto alegre july to march , every adult patient admitted to the icu with aneurysmal sah was enrolled in the study. data were collected prospectively during the hospital stay. patients were divided into four groups according to the moment of aneurysm repair after bleeding: < days, to days, > days and not repaired. the primary outcome was in-hospital mortality. dichotomous variables were analyzed using twomortality as the reference group ( to days). a total of patients were included. median age was years, mostly female ( %). in the univariate analysis hydrocephalus, rebleeding, postoperative neurological deterioration (up to hours after procedure), delayed cerebral ischemia, as well as mortality and poor outcome, were associated with the different timing of aneurysm repair. in the multivariate model for mortality, poor grade sah, hydrocephalus, post-procedure neurological worsening and dci were independently associated with higher mortality. additionally, late repair was associated with lower mortality (or . ) as compared with occlusion between to days. our study shows higher mortality in patients submitted to aneurysm occlusion procedure between days and after ictus, when compared to late repair. more studies are needed to define the best timing of aneurism repair in patients that are not submitted to early occlusion. the biological mechanisms that influence abnormal cortical neurophysiology after aneurysmal subarachnoid hemorrhage (sah) are uncertain. we hypothesized that soluble st (sst ), a plasma marker of the innate immune response, is associated with events of electroencephalography (eeg) deterioration including new epileptiform abnormalities (eas) or new eeg background deterioration. -approved biospecimen repository, we evaluated patients with at least days of eeg monitoring and an early sst measurement (collected < days following sah). eas were defined as sporadic epileptiform discharges, lateralized rhythmic delta activity (lrda), lateralized periodic discharges (lpd), or generalized periodic discharges (gpd). background deterioration was defined as decreasing alpha delta ratio (adr), relative alpha variability (rav) or worsening focal slowing. the association between sst level and eeg-identified eas or new background deterioration was compared using the wilcoxon rank sum test. patients met inclusion criteria. early sst was collected at mean . ± . days after sah; patients had a subsequent sst measurement at ± . days. ( %) patients developed new eas during eeg monitoring, ( %) developed new background deterioration, and ( %) developed neither. median sst in patients developing new eas was higher ( . ng/ml ]) than in patients who did not develop new eas ( . ng/ml ], p= . ). this association between elevated sst and new eas was not present for sst samples collected at later time points. there was no difference in sst levels between patients who developed new background deterioration ( . ng/ml ) compared with those who did not ( . ng/ml ], p= . ). among patients admitted with aneurysmal sah, elevated sst in the first days is associated with the development of new eas on eeg monitoring. this association was not present at later time points, suggesting that the early inflammatory response may be linked to abnormal cortical neurophysiology. glial-mediated inflammation occurring early after status epilepticus (se) in rodent models has been implicated in the subsequent development of spontaneous recurrent seizures (srs). while this suggests anti-inflammatory strategies may be a target for therapeutic intervention, the appropriate timing for such an intervention is unclear. the aim of this work is to define the timing of early inflammatory changes using pro-inflammatory mir- and anti-inflammatory mir- a as biomarkers in a kainic acid mouse model of se. se was induced in - week old male c bl/ j mice (n= per timepoint) using intraperitoneal injections of mg/kg kainic acid. the onset of se was defined as the first class seizure using a modified racine scale. the intensity of the se episode was estimated by the total number of discrete class v seizures observed. after hours, the se was aborted with diazepam, and hippocampal tissue was harvested at hr, hr, hr, hr and hr. rna was isolated using trizole (life technologies) followed by qrt-pcr analysis to define the steady-state expression levels of mir- and mir- a and their targets, socs we observed a > fold increase in expression levels of mir- , reaching peak levels at hours. expression levels of mir- directly associated with the intensity of se. the level of socs mrna expression decreases after the peak expression of mir- . as the levels of mir- a were only conclusions mirna- expression shows an early increase within hours of se, reaching a peak at hours. mir- a shows a non-mir- initiated after se to determine if this can prevent the development of srs. nurses routinely screen for changes in neurologic status with serial clinical assessments. the objective of this study was to employ mixed methods to determine inter-rater reliability (irr), protocol adherence, and acceptability of a new tool we developed called serial neurologic assessment in pediatrics (snap) compared to the glasgow coma scale (gcs). snap assesses mental status, cranial nerves, communication, and four-extremity motor function/strength, with scales for children < -months, -months to -ye -years-old. snap was designed for use in a diverse population, including patients who are intubated, sedated, and/or have developmental disabilities. irr of independent snap assessments by pairs of trained nurses was assessed with multilevel cohen's kappa and linear weighted kappa, calculated through clustered bootstrap method to account for multiple assessments. we assessed protocol adherence with standardized observations. we conducted semi-structured interviews to assess acceptability and feas we thematically analyzed interviews in accordance with modified grounded theory framework. critical care nurses performed paired snap assessments on patients ( < -months; months to --years). there was substantial agreement between nurses (average kappa= . < -months; . -months to --years), and irr was unchanged for children who were intubated, sedated, and/or had developmental disabilities. irr was unchanged based on degree of experience using snap and for day vs. night-shift nurses. nurses had % protocol adherence. snap was easier to use and more precise at describing neurologic status of patients who were intubated, sedated, and/or had developmental disabilities than gcs. % of nurses preferred to use snap over gcs. when utilized by nurses, snap has substantial irr, excellent protocol adherence, and is acceptable and feasible to i neurologic decline. several studies demonstrate significant gender disparities in professional societies for critical care and neurology, but data for neurocritical care is lacking. we examined gender representation trends within the neurocritical care society (ncs), the largest international professional society for this subspecialty. we hypothesized that female representation has increased with achievement of gender equality in . a multidisciplinary writing group obtained approval from the ncs executive committee and endorsement by the women in neurocritical care (wincc) section. after review by the rush university irb, access was granted for the following rosters: general membership, board of directors, officers, committees, annual meeting speakers, grant, fellowship and other award recipients. we differentiated between female, male and unidentified gender. available membership rosters from listed members, with gender unknown for > %. in , of members . % were females, . % males, and . % unidentified. as of , / presidents ( . %) and - , female committee members increased from % to %; female committee chairs increased from % to %. to date, / ( . %) christine wijman young investigator awardees were female with no female recipients of the best scientific abstract award ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . % of presidential citation awardees - % from -e representation in guidelines writing groups ranged between %- % ( - ), and - % in consensus statements writing groups ( ) ( ) ( ) ( ) ( ) ( ) . - % ( awardees were women. within the ncs, a longitudinal increase in female representation has occurred over the last years but gender equality has not been achieved. we recommend focused efforts to facilitate inclusion and gender equity within ncs. with the push toward using large data sets in critically ill patients, the use and management of registries is becoming more relevant. clinical registries provide insight about associations and patterns in diagnosis, disease, and treatment. the integrity of the data is of utmost importance. this poster describes the quality control and data management methods for maintaining the integrity of a multicenter trial registry. we employed modifications to van den broeck's method of data organization to clean and manage the end-panic registry. the data management consisted of five phases: ) screening phase, ) data organization , ) diagnostic phase, ) treatment phase, and ) missing data phase. the screening phase consisted of distinguishing missing and extraneous data elements, outliers, inconsistent patterns/distributions and unexpected analysis results. the data organization phase consisted of treating blank cells and highlighting errors with data input. the diagnostic phase was used to clarify the true nature of the data points, and make sure the data presented was biologically possible. the treatment phase consisted of correcting variables. the missing data phase consisted of determining whether the missing data was informative or noninformative. currently the multi-center registry houses ~ . million discrete data points from , patients. there was a high correlation between the texas, ohio and california locations, and npi, dvl, cvl, mcvl, and pupil size. there was a low correlation between the texas, ohio and california locations, and pupil latency and presence/absence of cataracts. missing data was informative for age, race and ethnicity, and distribution of missing data caused an inquiry into methods for collecting data and implementation plans for change. this interdisciplinary method for cleaning and managing the end panic registry was able to identify and rectify errors. we would recommend others to use the methods to build, clean and manage clinical registries. objective was to describe current state of quality improvement (qi) processes implemented in neurocritical care units (nccu). a -question-survey was sent to members (physician, nurses, and pharmacists) of the neurocritical care society. we describe factors affecting the presence of nccu qi, barriers to qi, awareness of stroke (stk, cstk), stroke get with the guidelines (gwtg), trauma quality improvement program (tqip) and american academy of neurology (aan) performance measures, and examined factors affecting satisfaction with current practices. the response rate was . %; . % of respondents were from us teaching hospitals, . % practiced in dedicated neurocritical care units, and . % in a program with a neurocritical care fellowship. . % reported a dedicated nccu qi program. comprehensive stroke center (rr . , % ci . - . , p = . ), dedicated nccu (rr . , % ci . - . , p = . ), and ncc fellowship programs (rr . , % ci . - . , p = . ) were more likely to report dedicated ncc qi staff. external ventricular drain infection was the most commonly tracked ncc qi metric ( . %). respondents indicated the highest level of awareness for cstk ( . %), stk ( . %), and gwtg ( . %), but indicated a relative lack of awareness for tqip ( . %), and aan ( . %) perform satisfaction with existing ncc qi were: presence of a hospital qi program (rr . , % ci . - . ), p = . ), presence of a formal ncc qi program (rr . , % ci . - . ), p = . , and dedicated ncc qi staff (rr . , % ci . - . ), p < . ). insufficient hospital ( . %) and departmental support ( . %) were reported common barriers to the successful implementation of an nccu qi program. a dedicated staffed nccu qi program occurs in a minority of neurocritical care units, and the lack of such programs may lead to clinician dissatisfaction. institutional and departmental support may be critical elements of a successful and satisfactory implementation of nccu qi. the development and implementation of a nurse driven rounding model was instituted in the neuro icu of an academic medical center to increase effectiveness of team communication, practice autonomy and integration of nursing input into the interprofessional care plan. clinical nurses and neuro-intensivists developed a structured rounding tool to guide the nursing presentation of clinical information on rounds. the interprofessional team underwent education on expectations and processes. the rounding tool underwent a number of revisions over a -month period based on feedback from all team members and evolving patient care priorities. all team member roles in the rounding process were clearly defined with nursing leading patient assessment and goals. nursing satisfaction surveys assessed nursing attitudes regarding autonomy, decision making and rn-md communication via a point likert scale; mean values for each question domain were compared pre-and post-implementation. in total, nursing surveys were analyzed, pre-implementation and nurses postimplementation. mean response values evidenced significant improvement across all domains in the post-implementation group: autonomy ( . vs . , p< . ), rn decision making ( . vs . , p< . ), p< . ) . survey participation was good in both groups ( % pre-and % post-implementation). nursing satisfaction across multiple important domains improved following implementation of a nurse driven structured rounding model. application of a nurse-facilitated, structured model creates a standardized reliable process that can be observed by all team members in order to deliver data driven, high quality, efficient and effective care. multiple models for program development and care delivery in pediatric neurocritical care (pncc) have been proposed with varying degrees of success. here we present a unique model for building a dedicated pediatric neuro-intensive care unit (pnicu) through creation of a community of practice (cop). cop represents a mechanism for collective learning and production of repertoire of best practices through knowledge sharing, development of social capital, and support for organizational change. we utilized a bolman and deal -frame for organizational functioning (structural, human resources, political, symbolic) to describe the development of our pncc cop. we evaluated our pnicu with the standards outlined by the neurocritical care society (ncs) for a level neuro-intensive care unit. structural factors included forming pncc leaders across specialties (neurology, critical care, neurosurgery, radiology, nursing), opening (in ) a state-of-the-art, unique pnicu which includes wired rooms for continuous eeg monitoring and multimodal neuro-monitoring, meeting / ( %) of ncs standards. human resource factors included creating core groups of physicians and nurses with a primary role in pnicu, providing ongoing education through workshops, lecture series, and certification including enls and tncc, meeting / ( %) of ncs standards. politically, a pncc fellowship-trained, board-certified physician serves as medical director coordinating conception of collaborative partnerships across multidisciplinary experts. simultaneous creation of other specialty cohorts in pediatric critical care aided in departmental acceptance for the program, meeting / ( %) of ncs standards. symbolically, we set forth our shared purpose and strong commitment to foster cop that advances knowledge and best practices for pncc. using cop principles, we have accomplished many of the ncs standards over a relatively short period of time. we plan to further develop the program with particular focus on education, certification, and expansion to include allied health professionals. our roadmap may be applicable to any institution interested in developing a pncc cop/pnicu. intravenous (iv) anti-hypertensive infusions are often used acutely in patients with intracerebral hemorrhage (ich). there is a lack of standardization of titration and variation in goal blood pressure, and therefore their use is associated with increased icu length of stay (los) and cost. we examined the use of anti-hypertensive infusions in ich patients in our institution and developed a quality improvement intervention to reduce duration of infusion, icu los, and cost. patients were included if they were admitted to our icu from september -march with an icd- diagnosis of non-traumatic ich and received iv antihypertensive infusions. interventions introduced starting in november included interdisciplinary task force formation, provider education, updated rounding checklist, and emr order with clear blood pressure target. the primary outcome measure was duration of anti-hypertensive infusions determined by retrospective chart review, and secondary outcome measures of icu los and cost data were obtained from our finance department. over months, mean antihypertensive infusion duration reduced from . hours (n= ) to . hours (n= ). icu los reduced from . to . days. proportion of cases with discordant blood pressure goal documentation reduced from . % to . %, while discordance in documented goals to actual orders reduced from . % to . %. there were no significant increases in countermeasures (infusion restarts, icu readmission, and aki due to blood pressure lowering). extrapolating from finance data, and our baseline infusion duration and icu los data, iv antihypertensive infusions cost ~$ /hour. our improvement suggested $ in estimated cost savings in months. icu accommodation cost was approximated at $ /hour, for an estimated $ additional cost savings. a quality improvement based intervention targeting management of hypertension resulted in reduced duration of anti-hypertensive infusions, icu los, and cost. the intervention was feasible and ongoing data collection is warranted to assess sustainability. mortality and long-term-disabilities secondary to stroke are high. educating high-risk population with early stroke symptoms has been outstanding. however, education of post-stroke consequences (requiring resuscitation codes and goals-of-care awareness) is lagging. this study evaluates the understanding of such concepts by the admitted stroke patients (high risk population) and visitors (general population). were asked to answer a preliminary question about their original code status then read a self-explanatory sheet followed by revealing their revised code and goals-of-care choices. we used within-group logistic-regression-analyses to determine changes of codes among original coders and types of novel codes among post-survey coders. this included proposition of new short-term resuscitation (str-strp [partial]) codes. we used between-group chi-square-analyses to determine differences in education between groups. the odds of changes in no-coders were . , . in patients and visitors, (p-value= . , < . ) respectively. the odds of changes in dnr-coders= . , . , partial-coders= . , . , full-coders= . , . times those of the no-coders respectively (p-value< . ). the odds of novel-dnr-coders= . , and . , , . , . , . times those of novel-no-coders respectively (p-value< . ). str-coders originated from other-codes> no-coders. between-group analyses showed %, % of patients versus visitors changed their code status respectively (p-value= . ). goals-ofcare choices indicated tolerance towards temporary measures (tracheostomy and feeding-tube placement) and hemiplegic disabilities without poor mentation among the majority (~ - %) as a target for continuing care. pre-event (stroke) documentation of code status was approved among the majority of participants ( %). there is a misunderstanding of the resuscitation codes among both admitted stroke patients and general population. however, the difference between both indicates reception of some education among the stroke patients. str-strp are a good alternatives for many people. pre-event documentation -stroke outcome awareness are needed. early integration of palliative care improves communication, decision-making and social support in patients with acute stroke in the neurocritical care unit. the primary objective of this study was to analyze how early palliative involvement impacts communication between the healthcare team and patients/families. in this ongoing prospective study, patients with moderate to severe ischemic and hemorrhagic strokes were randomized into control and intervention arms. the control arm received routine icu care and the intervention arm received an early palliative care consultation. study assessments with the patient or surrogate decision maker were obtained at day - , and day - of icu care. comparisons were made for total scores on the questionnaire on communication (qoc), decisional conflict scale (dcs), and hospital anxiety and depression scale (hads). we performed an interim analysis utilizing the student's t-test and chi -square test on spss , with results below as mean + standard deviation. of patients enrolled ( intervention and control), % and % were female (p = . ). the average age was + and + years (p = . ). the majority ( % and %) were ischemic strokes (p = . ). admission nihss was + and + (p = . ). there was no difference in total qoc ( + , + , p = . ), hads ( + , + , p = . ), or dcs ( + , + , p = . ) scores. when comparing responses to individual questions, a trend toward improvement in qoc responses was observed "using words you can understand" (p = . ) and "answering all questions about illness" (p = . ). early integration of palliative care may improve communication between healthcare providers and patients/families, specifically with regards to using appropriate language that is understandable. routine daily chest radiographs (cxr) in mechanically ventilated patients (mvp) are often performed in the icu for "monitoring" purposes, despite lack of specific indications. routine daily tests are of questionable value and may increase costs without clinical benefit. the society for critical care medicine and choosing wisely campaign promote indication-based test ordering. studies involving medical-surgical icus demonstrate that indication-based versus routine daily cxrs in mvps results in cost-savings without jeopardizing outcomes. we implemented a quality improvement initiative targeting reduction of routine daily cxrs in mvps in the nsicu. we convened an interprofessional team of attending physicians, fellows, medical students and nurse practitioners. we conducted educational campaigns promoting evidence-based cxr utilization practices. standardized discussion of indication for cxr was incorporated into rounds. iterative process improvements were adopted beginning june . cxr utilization rates in mvps were measured the first weeks of , and and compared pre/post-intervention. hospital length of stay (hlos) was evaluated to monitor for complications resulting in prolonged hospitalization. implementation of indication-based ordering strategies decreased cxr utilization in mvps in the nsicu without increasing hlos. value-based care quality improvement initiatives can reduce costs without compromising clinical outcomes. patients transferred from nsicu to lower acuity units are vulnerable to readmissions and hospital acquired complications. standardized handoffs may help reduce this risk within academic institutions where physician trainees possess varying levels of clinical experience. we sought to implement a standardized handoff (i-pass) within inpatient neurology, focusing on high risk patient populations. residents and attendings were surveyed about inpatient handoff practices to inform implementation of i-pass. an electronic survey was administered in to residents and inpatient attendings in neurology at university of north carolina (unc). handoff practices among inpatient services (wards, consults, nsicu, and epilepsy) were evaluated. surveys assessed perceived quality of handoffs, as well as problems with handoffs leading to adverse events. surveys were sent to physicians ( residents, inpatient attendings); responses ( residents, inpatient attendings) were obtained (response rate, . %). -six percent of residents and % of attendings reported that problematic handoffs had been the primary or contributing factor to one or more adverse events. overall quality of handoffs involving nsicu patients transferred to lower acuity units was reported as a concern, with % of residents indicating the quality of these handoffs to be poor. in ranking inpatient services for prioritization of handoff interventions, % of residents identified nsicu handoffs as either their first or second highest priority. we also found residents exhibited a self-performance bias, with % reporting that they provided all pertinent information during handoffs most of the time, and only % reporting that they received all pertinent information during handoffs most of the time. inpatient handoffs are perceived as problematic by residents and attendings, with handoffs involving transfer of nsicu patients identified as high priority for targeted intervention. unc neurology has since implemented i-pass protocols to improve the safety of handoffs involving nsicu patients. targeted temperature management (ttm) to - c is the standard of care for post-cardiac arrest patients. recent literature has demonstrated a new trend of worsening morbidity and mortality postarrest due to under-utilization of ttm. management of post-arrest patients is a multidisciplinary health care effort, and knowledge of ttm rationale and protocol varies. normothermia ( - . c) also could have neuroprotective benefit in other clinical scenarios and is another indication for ttm. we hypothesized that a focused educational intervention would improve ttm protocol compliance. a multidisciplinary team developed a standard educational presentation and a question exam given as a pre-and post-test to residents, fellows, and critical care nurses. baseline data on ttm use was established followed by month prospective data collection post-intervention. data was extracted from arctic sun® machines on all ttm cases (post cardiac arrest and normothermia). the primary outcome was compliance with the ttm protocol measured by correct temperature target goals and appropriate duration, assessed by chi-square analysis. the secondary outcome measure was individual score improvement, evaluated by -variable students t test. there was a total of ttm cases pre-intervention, and ttm cases post intervention. there was a trend toward increased ttm protocol compliance ( % to %), however this was not statistically from pre-test (n= ) to post-test (n= ) after the education presentation (p< . , ci . to . ) among all health care participants. the resident, fellow, and nursing scores increased from % to %, % to %, and % to %, respectively. educational interventions for physicians and nurses caring for post-cardiac arrest and neurocritical care patients improved knowledge gaps and helped improve compliance with ttm protocol. additional education and process improvement activities are warranted to further improve protocol compliance, which may improve patient outcome. identifying the appropriate level of care needed for a patient presenting with acute intracerebral hemorrhage (ich) is often imprecise. the utility of prior work in triaging patients is limited by exclusion of non-primary ich patients, which is often difficult to determine prior to admission. this study aims to identify which admission factors are associated with icu level of care on presentation. this is a single-center retrospective review of patients admitted to our institution with ich in , regardless of etiology. all patients were admitted to the neurocritical care unit (nccu). icu level of care was defined as the need for mechanical ventilation, administration of vasoactive or insulin infusions, continuous renal replacement therapy, ventriculostomy, treatment of cerebral edema, temperature management, management of status epilepticus, or neurosurgical intervention. logistic regression was used to identify characteristics associated with icu level of care. patients (median age , % female, median admission gcs , median ich volume ml, % with ivh, % lobar, % infratentorial) were admitted with ich. ( . %) required intensive care. the most common interventions required were mechanical ventilation ( patients, . %), antihypertensi with need for intensive care included age ( vs. ), admission gcs ( vs. ), deep location of ich ( . % vs. . %), ich volume ( ml vs. ml), and presence of ivh ( . % vs. . %). on multivariate analysis, age (p = . ), admission gcs (p < . ), and deep location (p = . ) were independently associated with the need for intensive care. among all patients presenting with ich, age, admission gcs, and location of hemorrhage may help identify ich patients who need icu level of care. the impact of emergency neurological life support (enls) course on provider knowledge and selfreported comfort in management of neurocritically ill patients in a low-middle income country such as cambodia is unknown and explored in this study. in-person enls courses with english to khmer translated slides were conducted in hospitals in phnom penh, cambodia in may, . wilcoxon signed rank test and matched paired t-test were used to examine pre and post-course scores on translated knowledge-based multiple choice tests. a descriptive analysis was performed to evaluate provider comfort in management of neurocritically ill patients pre and post-course and amongst individual enls modules. overall, / healthcare providers participated; ( . %) physicians and ( . %) nurses. thirtythree ( . %) had acquired base specialty training in cambodia, ( . %) had completed subspecialty training in critical care medicine and ( . %) previously cared for neurocritically ill patients. pre-test sores were % [iqr ]; post-test scores were . % [iqr ]. though not statistically significant, posttest scores were higher for providers who had base specialty training in cambodia ( . % vs. . %, p = . ), subspecialty training in critical care medicine ( . % vs. . %, p = . ) and previous experience caring for neurocritically ill patients ( . % vs. %, p = . ). most ( %, n = ) reported that enls training had prepared them for management of neurocritically ill patients. enls courses may enhance the knowledge and comfort of healthcare providers in managing neurocritically ill patients in low-middle income countries, however this may depend on prior experience and minimizing language barriers. the impact of enls courses on outcomes in neurocritically ill patients in low-middle income countries warrants further study. neurocritical care has become increasingly subspecialized.yet, due to limited availability of dedicated neurocritical care units (nccus), often patients may need to be admitted to icus other than nccus. this survey based study was conducted to explore self-reported knowledge in recognizing and managing some common neurological emergencies such as stroke, status epilepticus, raised intracranial pressure etc among critical care nurses at a comprehensive stroke center. in january , we engaged nurses from icu units in this qi project-which included medical, surgical, neurocritical care, cardiac and cardiothoracic units as well as post-anesthesia care unit (pacu) and interventional radiology units. using institutional redcap anonymized surveys were sent to the nurses.information on demographic and critical care work experience was recorded. all participants answered questions with a likert type scale on their knowledge of several common neurological emergencies. nurses ( females, males) participated in the survey. ( %) had been working in an icu for years or longer. their self-reported level of knowledge in managing neurological emergencies revealed that more than half the participants did not feel comfortable managing patients with evds, ich, sah, raised intracranial pressure, tbi and traumatic spine injury patients. more than % of nurses were not satisfied with their current level of training to deal with neuroemergency and supported the need for dedicated training/ study time. icu nurses report gaps in fundamental knowledge in recognizing and managing common neuroemergencies. this highlights the need for providing ongoing training and education about neuroemergencies to critical care nurses to help maintain competencies. simulation training has been increasingly adopted in critical care specialties to promote active learning and create a reproducible platform for feedback. the role of advanced simulation as a core component of training in neurocritical care remains unclear, which may be due to uncertainty about the degree of fidelity needed. our objective was to determine if trainee knowledge and/or confidence differs when using standardized patients as compared to a multi-media simulation platform in a neurocritical care concepts training course. methods junior neurology residents engaged in simulated neurologic emergencies: a right mca stroke case, status epilepticus case, and a pontine hemorrhage/coma case. the mca stroke and status epilepticus cases were portrayed by trained standardized patients for half of the residents (group sp), while the other half interacted with the manikin supplemented with video clips of pertinent neurologic exam findings (group mv). both groups interacted with the manikin for the pontine hemorrhage/coma case. before and after the course, residents completed a -question multiple-choice test on management of neurologic emergencies and a survey about their confidence in managing neurologic emergencies. a detailed task checklist was used to assess decision making during the simulations. both resident groups had statistically significant higher knowledge and confidence scores after their training sessions (knowledge: pre: % vs post: %, p< . ; confidence: average pre: . to post: . , p< . ). however, there was no statistically significant difference between the two groups in either knowledge or confidence. the task checklist demonstrated significant variations in treatment practices and provided individualized areas for teaching. this pilot study suggests that trainees' knowledge and confidence in the management of neurocritical care concepts increases following simulated encounters, regardless of whether an actor-patient or multi-media simulation platforms is used. use of a task checklist uncovered important variations in protocol adherence among novice physicians. the accurate evaluation and determination of brain death has broad consequences on life-saving organ donation, closure for families, and length-of-hospital-stay. we have observed a concerning variability of brain death testing knowledge and comfort amongst neurology attendings and trainees at our institution. we aimed to create and apply a combined didactic and simulation training program to increase the knowledge and comfort in brain death evaluation, using our approved institutional brain death policy as reference. we hypothesized that participants who attended the training would show a measurable increase in their knowledge and comfort in the clinical evaluation of brain death. an experienced neurointensivist (> years of clinical practice) presented a -hour didactic session on brain death criteria, evaluation, and pitfalls to neurology residents and attendings. a high-fidelity simulation was implemented to allow practicing the brain death examination. knowledge and comfort levels were measured before and after learners had attended both sessions using electronic -exact-tests were applied to examine changes in knowledge and comfort in brain death testing pre-and post-exposure to the educational sessions. participants ( residents, attendings) completed pre-exposure, and ( residents, attendings) have completed post-exposure questionnaires thus far. knowledge significantly improved from pre-to post-exposure ( % correct, range - % improved to % correct, range - %; p= . ). comfort levels in performing the brain death examination pre-exposure also increased from pre-to postexposure (pre: "very comfortable- %","somewhat comfortable- %","neutral- %","somewhat or very uncomfortable- %" to post: "very comfortable- %", "somewhat comfortable- %","very uncomfortable- %" [p= . ]). exposure to a single combined didactic and simulation session improved the knowledge and comfort levels immediately post--exposure questionnaire response rates, as well as measurements of knowledge retention over a -and -month period and accurate application in practice. the safety and benefit of early mobilization in general intensive care units (icu) has been found to improve outcome and decrease length of stay. however, there is a lack of literature on early mobilization in the neuro icu (nicu) specifically, due to the complexity of the patients in the nicu and their disease processes. traditionally, patients were kept on bedrest after subarachnoid hemorrhage, intracerebral hemorrhage, ischemic stroke, and neurotrama, due to neurologic limitations such as fluctuation in mental status, requirement for sedation and paresis. additional challenges associated with mobility in this population include the potential for positional changes to impact intracranial pressure physician comfort level and concern for adverse neurological outcomes such as vasospasm or increased bleeding also decrease mobilization. while it is imperative to be cautious with nicu patients, prolonged bedrest and restricted mobility come with its own set of complications including muscle atrophy, decreased activity tolerance, delirium, pressure sores, nosocomial infections and deep vein thromboses. we sought to develop an early mobilization guideline that would help multidisciplinary staff identify which patients in the nicu should be mobilized early. a nicu physical therapist and the director of the nicu identified criteria for patients who were appropriate/inappropriate for early mobilization. all patients in the nicu should be mobilized early with the exception of the following exclusion criteria: unstable respiratory status, status epilepticus, contraindication to holding sedation, rass - , changing/worsening neuro exam, icp > mm hg, mean arterial pressure < or > mm hg, oxygen saturation < %, acute myocardial infarction, > vasopressors, clinical vasospasm, perfusional state, guidelines on early mobilization in the nicu can optimize patient mobility while minimizing complications associated with mobilization. introduction delivery, nurses must develop leadership skills and serve as full, collaborative partners with physicians and health professionals ( ). registered nurse (rn) inclusion into rounds has been shown to: improve interdisciplinary collaboration, incorporate learning in the workplace, increase leadership skills and improve team members' perception of unit flow and culture. attending physicians, rns, neurocritical care fellows, nurse practitioners, pharmacists and respiratory therapists were surveyed via surveymonkey to examine opinions regarding current rounding processes and potential opportunities in the neurocritical care unit (nccu). responses were aggregated to create scores for each topic, with the priority areas being the lowest relative scores based on a -point likert scale. survey responses were collected from nccu staff members ( % response rate). based on survey results, priority areas to enhance rounding satisfaction included: increasing collaborative decision making, creating entire team efficiency, completing rounds in a timely manner, increasing engagement and minimizing extraneous conversations and activities. other targeted areas for improvement included reserving time for prolonged family meetings for post-rounds, as well as focusing educational time and consistently utilizing the rounding checklist. based on areas of opportunity, a multidisciplinary committee was developed. one item created to enhance processes was the development and implementation of an rn facilitated presentation tool. to support this, a standardized presentation script and handoff tool were created and executed. six-month follow up survey results are pending at the time of submission. strategies to improve communication in multidisciplinary rounds are key to decreasing errors and improving care delivery. it is likely that a systematic data presentation by bedside rns will improve: staff perceptions of rounds, collaboration among all multidisciplinary staff members and rounding efficiency. the department of neurosurgery has a readmission rate goal of less than . for the fiscal year and less than . for the fiscal year of . over the past four fiscal quarters there has been an increase in the department's readmission rate, always exceeding the institutional goal. all readmissions in the institution's dashboard for q and q for and q and q of were reviewed by way of chart review. these were divided into spine vs cranial, planned vs unplanned readmission, reason for readmission and consistency vs inconsistency with the institution's dashboard. in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . in q the dashboard reported a readmission rate of . . the final calculated actual readmission rate was . . the most common reason for unplanned n reason for planned readmissions were shunt placements after lumbar drain trials. the dashboard was correct in predicting planned vs unplanned readmissions . % of the time. the coding on the backend of the institution's dashboard is missing many staged and planned readmissions and is only accurate in coding planned vs unplanned readmissions half of the time. this is resulting in falsely elevated readmission rates. despite the initial uptrend in readmissions, the actual readmission rates of the department are down trending and always below the institutional goal. this likely translates to other departments within the hospital. there needs to be a more efficient way to improve the coding and accuracy of the institution dashboards. the critically-ill neurological patients managed by specialized neurocritical care team is associated with improved outcome. in korea, limited data are available on improved outcomes after initiation of neurointensivist co-management in neurocritical care units (ncu). we evaluated the impact of a newly appointed neurointensivist on the mortality of patients admitted to the ncu. the study was conducted in intensive care unit (icu) beds of a large academic tertiary care hospital. neurointensivist co-management was initiated in march . the retrospective observational study compared the outcomes of patients before and after neurointensivist co-management. a total of patients were included, prior to and after the initiation of neurointensivist comanagement. patients admitted after neurointensivist co-management were older and had higher apache ii scores. icu mortality was significantly decreased in patients managed by neurointensivist ( . % vs . %, p= . ). the length of icu stay and duration of ventilator days were shorted in patients without co-management. neurocritically ill patients managed by specialized neurointensivist showed better clinical outcomes despite increased severity. social media has changed the way individuals communicate with each other and has altered the way society obtains information. in the past ten years, multiple articles have been published highlighting the ability to utilize social media for education of medical, nursing and pharmacy students. to our knowledge, cross discipline education utilizing these platforms has yet to be evaluated. with over . to implement a pharmacist led, social media based nursing education program and evaluate the perceived value of this education. a curriculum consisting of basic pharmacy related issues was developed and topics were posted to the ok users weekly. a pre-and post-education survey was sent out evaluating the program's effectiveness. email. of those nurses who received the pre-and post-education survey, a total of % and % completed the survey respectively. of those who completed the survey % received education via -education survey, there were no statistically significant differences in nursing performance on fact based questions after receiving education (p-value > . on all assessment questions). overall, % of the respondents reported a positive learning experience and wanted to continue this method of education delivery. the educational content. this project demonstrates the potential of utilizing social media as a means of cross discipline education; however, the solitary utilization of this platform should be used cautiously as this did not improve performance on assessment questions. consequently, targeted temperature management (ttm), either to maintain normothermia or induce hypothermia, is often advocated as a therapy to improve outcomes in brain injured patients. the physiological pathways that promote fever associated brain injury, and how these pathways might be modulated by ttm, remain unclear. this study examined the effect of fever and hypothermia on cerebrovascular pressure reactivity, a validated proxy of cerebral autoregulation. we included patients treated for brain injury from a single academic center. all patients had intracranial pressure (icp), invasive brain temperature, and arterial blood pressure (abp) recorded patient, mean prx over all periods of fever (> °c), normothermia ( - °c), and hypothermia (< °c) were calculated. differences in mean prx during normothermia, fever, and hypothermia epochs were then analyzed using paired student's t-test. the relationship between prx differences and total time spent normothermic was analyzed using linear regression. spent at a normal brain temperature (p = . , r = . ). in contrast, hypothermia was not associated with impaired cerebral autoregulation (p = . ). this study supports the hypothesis that impaired cerebral autoregulation may be one mechanism through which fever worsens outcome in brain-injured patients. the effect of fever on cerebral autoregulation appears to be more pronounced in patients that spend a longer amount of time in a normothermic state. interestingly, hypothermia was not associated with reduced prx, suggesting that the possible benefits of therapeutic hypothermia do not occur by improving the autoregulatory state. veno-arterial extra corporeal membrane oxygenation (va-ecmo) provides hemodynamic support in patients with refractory cardiogenic shock. these patients have a % incidence risk of cerebrovascular complications according to the extracorporeal life support organization database. reliable neuroassessments and neuroimaging are often limited by heavy sedation and risks of transporting these patients. transcranial doppler (tcd) can be a useful tool for cerebral hemodynamic assessment in these patients. we present four va-ecmo patients where tcd spectral waveforms provided key information on cerebral blood flow despite non-pulsatile flow. interpretable spectral waveforms were obtained in three of four patients. extensive embolization obscured flow patterns in one patient but clear cerebral perfusion with non-pulsatile waveforms was seen in the rest. two of the three remaining patients had high intensity transient signals (hits), suggesting cerebral microembolization. one patient showed pulsatility in cerebral waveforms despite no gross change in cardiac output on echo that helped guide decision to initiate ecmo wean. ecmo settings included flow at - l/min, map - mmhg, and paco between - mmhg. mca mean flow velocities were comparable to the systemic bp, and ranged from - cm/s in three patients and - cm/s in one patient. one patient suffered cerebral edema and two expired from withdrawal of care on sedation after multisystem organ failure without a chance neurological or neuroimaging assessment. the fourth patient retained consciousness and the ability to follow commands, but died from a massive gi bleed. tcd spectral waveforms can be useful bedside tools for patients on va-ecmo to assess for cerebral perfusion patterns. presence of hits reflecting microembolization can guide perfusionists to check for pulsatile flow, their relationship with systemic hemodynamics and va-ecmo settings is needed. cranial ultrasonography has a long history of use in neonates, but inadequate windows have limited its use in adults. a hemicraniectomy provides an obvious window for point-of-care intracranial imaging, providing similar views traditionally seen on ct and mri. we describe a standard approach and settings, presenting sample imaging demonstrating key anatomic landmarks. the hemicraniectomy ultrasonography preset was created and optimized using a phased array transducer with a - mhz frequency range. imaging parameters were tested and saved for d grayscale mode, with an emphasis on tissue harmonic imaging, adaptive image processing, and dynamic range. axial views are obtained from the ipsilateral temporal window, approximating the pterion, adjusting the probe to display a well-aligned view using the lateral ventricles as a landmark. by convention, the probe marker is placed anteriorly. the depth and focus are set to visualize the brain he probe craniocaudally permits visualization of the entire cranial vault. parasagittal and coronal views are obtained by placing the probe at the vertex, off midline, ipsilateral to the hemicraniectomy. several structures are clearly visualized and are available as landmarks for orientation. the ventricular system can be easily identified as hypoechoic spaces similar in appearance to ct or mr imaging. the brainstem and cerebellum, with its associated folia and peduncles are also easily seen. the thalami are identified as strongly hypoechoic paramedian structures. pathologic findings that can be easily seen include hydrocephalus, hemorrhage, and edema. aneurysm clips are hyperechoic with streak artifact, and ventriculostomy catheters can be seen as subtle hypoechoic areas within the cortex. hemicraniectomy pocus can be used to visualize the intracranial vault to facilitate evaluation of structural lesions and pathology at the bedside. the authors advocate adding hemicraniectomy pocus to the neurocritical care imaging arsenal in patients where this view is available. pain assessment is a challenge in critically ill patients with impaired consciousness, either because of sedation or concomitant severe brain injury. automated pupillometry has been used to assess the response to noxious stimulation in such patients. skin conductance, which has been used in the operative setting, has not been tested in this setting yet. the purpose of the study was to compare the pupillary response and skin conductance to pain stimulation in critically ill unconscious patients. prospective ongoing study including adult (> years) patients admitted to the intensive care unit of a university hospital and who were unconscious (glasgow coma scale < with a motor response < ) for several reasons. automated pupillometry (algiscan, idpupillary reflex dilation during tetanic stimulation. the tetanic stimulation ( hz) was applied to the skin area innervated by the ulnar nerve and was stepwise increased from to ma until pupil size had increased by % compared to baseline. the maximum intensity value allowed the determination of a pupillary pain index score ranging from (no nociception) to (high nociception): a pupillary pain peak per second ( concomitantly to tetanic stimulation. twelve patients (median age [ranges= - ] years; male gender / ) were included so far; eight patients had a primary brain injury ( / anoxic injury) and others were sedated because of shock with concomitant respiratory failure. all patients were under continuous intravenous sedation and analgesia; / were on vasopressors and / on continuous neuromuscular blockade. median gcs at the moment of pain assessment was [ - ] and median ppi was [ - ]; patients ( %) had adequate pain control. no changes of skin conductance variables were reported during pain stimulation. skin conductance was unable to detect insufficient nociception in critically ill unconscious patients. the cerebral arterial time constant (tau) reflects the time it takes to fill the cerebral arterial bed with blood during one cardiac cycle, and is derived from arterial blood pressure (abp) and middle cerebral artery flow-s with/without vasospasm (vsp) and delayed cerebral ischemia (dci) after aneurysmal subarachnoid hemorrhage (asah). ( ) ( ) . angiographic vsp and dci were adjudicated by neurointensivists. artifact-free cerebral arterial compliance and resistance. statistical comparisons were made using a two-tailed mann-whitney u-test. of asah patients, ( %) developed vsp and ( % of vsp) developed dci. patients had unilateral and bilateral vsp ( & % of vsp). one patient with unilateral vsp was available for monitoring prior to diagnosis. this patient had increased asymmetry in tau over time prior to diagnosis (slope: . s/day, r¬ : . ). tcd measures in patients were available prior to angiographic diagnosis of bilateral vsp, showing initial marginal asymmetry similar to the unilateral vsp case, then slightly decreasing asymmetry over time (mean slope: - cm/s higher in dci (p< . ). tau was . s greater for dci patients, however this did not reach significance (p= . ). explore the relationship of tau asymmetries with vsp and dci after asah. these may provide further insights into the pathomechanisms of vsp and dci while also having potential as a tool for earlier diagnosis of these important complications. pupillometry is more accurate and has higher inter-rater agreement than subjective pupil size and reactivity estimation. limitations include using a single high-intensity flash to evaluate the direct pupillary response only. we present preliminary data on using virtual reality-based pupillometry (vrp) with graded-intensity flashes and bilateral pupillary recording to monitor patients with large hemispheric infarction (lhi). we utilized a virtual reality headset-based system, i-pas (neurokinetics, pittsburgh, usa) to perform pupillometry. a total of homogeneous illumination flashes ( . to . cd/m², . sec on, . - . sec off) were presented to each eye while infrared cameras recorded pupillary area (mm ) continuously at samples/sec. this permits measurement of latency, magnitude and velocity of direct and consensual pupil constriction and dilation at each light intensity. : we performed pupillometry as described above in patients admitted with lhi from middle cerebral artery strokes. patients required decompressive craniectomy (dc) during the hospital course while the other patients did not require dc. bilateral graded-intensity pupillometry detected subtle changes in pupillary reactivity (peak constriction velocity in mm /s) prior to clinical deterioration, which were very pronounced when compared to normal control performance. singleneuropupillary index (npi) did not detect a change in pupillary reactivity in all but the most severe deterioration. virtual reality-based, graded intensity pupillometry is feasible in the intensive care unit and appears ed to set cutoff values that may aid in clinical decision making. limited access to conventional eeg results in significant delays to important diagnostic information, especially in patients with suspected non-convulsive seizures (ncs). recently, the rapid response eeg technology has proven to be clinically valuable. however, the economic aspect of this new technology has not been studied in detail. we retrospectively reviewed the use of the rapid response eeg device in our small community hospital over months since its launch in december . we performed limited chart review and collected information regarding eeg diagnosis, length of stay, and transfer to mothership hospital. we evaluated the clinical and economic impact of the device by considering the patients' clinical outcome and the estimated cost of hospitalization (~$ - /day) and transfer ($ - , ). metrics are not precise and are only estimates. the device was used in a total of patients. the treating physician or the nurse applied the device with and one with post-anoxic burst suppression. in patients with status epilepticus, seizures were aborted successfully, and median length of stay was . (national average of days). all patients were treated locally without requiring transfer to the main university hospital. considering the cost of rapid response eeg infrastructure and disposables (<$ , ) compared to conventional eeg systems (~$ , - , ) and eeg technologists (estimated to cost ~$ , - , ), and estimated range of $ , to $ , in annual savings because of shorter los and lesser transfers, this new technology seems economically advantageous. rapid response eeg system enabled significantly faster and easier access to eeg and helped detect a relatively high number of patients with gross eeg abnormalities. adopting the rapid response eeg improved emergent ncs detection and treatment in a cost-effective manner. patients requiring neurocritical care frequently have neurologic fluctuations of uncertain significance. we hypothesized that severe and prolonged events of neurologic deterioration (nd) have the greatest impact on discharge neurologic status and serve as intermediate indicators of poor outcome. we extracted nurse-documented gcs scores from electronic health record (ehr) data of consecutive patients admitted to a neurosciences intensive care unit (icu) or undergoing intracranial pressure monitoring (april - ) best initial -hour gcs (bestgcs- h), ) maximum magnitude of gcs decline (maxgcsdecline), ) duration of the episode of maximum gcs decline (dur-max), and ) the maximum duration of any gcs decline >= points (max pt-dur). we fit a -fold cross-validated logistic regression model predicting the final gcs - (vs. - ) and tested it in a % hold-out sample. we then evaluated the rates of poor outcome for combinations of these parameters. , consecutive admissions ( , unique patients) met inclusion criteria ( % with severe bestgcs- h ( - ), % with moderate bestgcs- h ( - ), and % with mild bestgcs- h ( - )). bestgcs- h, maxgcsdecline, dur-max, and max pt-dur, respectively, were independently associated with poor discharge gcs (or per standard deviation were . [ %ci . - . ], . [ . - . ], . [ . - . ], and . [ . -with a -point maxgcsdecline, the rate of poor outcome was % for patients with a severe bestgcs- h and >= -hour max-dur; % for patients with a severe bestgcs- h and < -hour max-dur; . % for patients with a mild bestgcs- h and >= -hour max-dur; and . % for patients with a mild bestgcs- h and < -hour max-dur. both the magnitude and duration of nd events are independently associated with neurological status at discharge. these empiric, informatics-derived thresholds may serve as useful intermediate outcomes facilitating the testing of biological associations and therapeutic interventions aimed at promoting neurologic recovery. unit. deteriorati worsening. we hypothesized that nonearlier than clinical deterioration. we prospectively collected data from patients with acute brain injury who are at a high risk of perfusion disturbance (sah, mmd, and severe anterior circulation ischemic stroke) between may and may . non--ry seconds neurological worsening were assessed using perfusion imaging and were categorized as hypoperfusion group and hyperperfusion group. baseline compared. non-monitoring should be highlighted in patients with high risk of deterioration. intracranial cerebral pressure (icp) monitoring is an integral part of acute brain injury management. while invasive icp monitor is the gold standard, there are several medical conditions that preclude its placement. non-invasive icp assessment tests (e.g. optic nerve sheath diameter, optic nerve disk elevation, pulsatility index, pupillary reactivity etc) have moderate accuracy when used individually. the aim of the present study is to validate a multimodal approach for intracranial hypertension detection. in this prospective study, patients with acute brain injury who had an evd placement for both icp measurement and treatment were included since march . we measured bilateral optic nerve sheath diameter (onsd) by ultrasound, bilateral optic nerve disk elevation (onde) by ultrasound, bilateral middle cerebral artery (mca) pulsatility index (pi) by using transcranial doppler and assessed pupillary reactivity with or without pupillometer as part of multimodal assessment for measuring intracranial pressure. we assessed the correlation and agreement of these values with icp measured by the evd. we included measurements in patients with acute brain injury. the presence of two or more values of mean onsd greater than mm, unilateral or bilateral presence of onde and mean mca pi greater than . has % sensitivity ( % ci . - . ) and . % specificity ( %ci . - . ) for predicting icp greater than mmhg. non-invasive multimodal assessment can be easily done by bedside, requires minimal training and seems to correlate well with increased icp. raised icp following acute brain injury is associated with poor outcome. monitoring with early detection is important in reducing sustained icp crisis. previous studies demonstrated rheoencephalography (reg) reflects cerebrovascular reactivity and may substitute invasive monitoring techniques. we hypothesized using a correlation coefficient between slow spontaneous changes in reg and systolic arterial pressure to calculate regx. reg measurements were obtained from ten patients with acute brain injury. analog waveforms of reg and arm bioimpedance pulse waves were recorded with a bioimpedance amplifier. we used the icm+ program (prx) calcu bioimpedance pulse waves (regx) instead of icp and invasive arterial pressure. visualized by previously established waveform changes on reg. a change in mean regx greater than the previous recording's mean regx value was clinically significant as opposed to absolute mean regx . one patient with a right ica infarction clinically deteriorated from moving all extremities to extensor posturing on the right and flaccid paralysis on the left with significant delta mean regx. another with bilateral aca distribution ischemic infarctions worsened from flexor to extensor posturing with significant delta mean regx. lastly, a patient with ventriculoperitoneal shunt malfunction repair improved from gcs to with multiple significant delta mean regx values between recordings. our series demonstrated clinical significance of patient specific delta mean regx suggesting importance of presenting mean regx for detection of changes in intracranial compliance. like presenting blood pressure and relative changes in blood pressure rather than absolute changes in blood pressure or specific values, regx was shown significant in a similar manner. regx is a realistic means of future noninvasive neuromonitoring. dialysis is characterized by markedly increased rates of stroke and cerebral micro-vascular disease, though the mechanisms by which dialysis modalities impact cerebral hemodynamics have not been well studied. this case series compares intra-dialytic cerebral hemodynamics measured by transcranial doppler (tcd) in patients receiving intermittent hemodialysis (ihd) versus peritoneal dialysis (pd). ten outpatient end-stage renal disease (esrd) without stroke were identified. tcd mean flow velocity averaged. six patients administered hemodialysis were followed over minutes, with mean arterial d every minutes. there was no statistically significant difference between dialyses group and no significant change over time. to quantify volatility in patient measurements over time, we calculated the coefficient of variation -sum test. to test if there was a difference in volatility between dialyses groups, we used a wilcoxon rankgroup (p < . ). in this small case series, though cerebral hemodynamics are not significantly different among stable measures are more stable over time for patients on the peritoneal dialyses group. end-stage renal disease (esrd) patients with acute neurologic injury are at risk of altered cerebral hemodynamics during dialysis. here, we present transcranial doppler (tcd) images revealing marked intra-dialytic increased distal vascular resistance and compromised flow velocity in an esrd patient with acute traumatic brain injury. the patient underwent continuous tcd monitoring during hemodialysis to monitor intra-dialytic cerebral hemodynamics. a year-old man with esrd on chronic presented with headaches after a fall. ct head revealed mm right convexity acute subdural hematoma with - mm leftward midline shift and right parietal parenchymal contusion. on arrival to the neuro-icu, the patient was afebrile, hemodynamically stable, and fully oriented with no focal deficits. repeat ct head six hours from initial was stable. the patient was started on his outpatient prescription of dialysis (dialysate na meq/l, blood flow rate ml/min), run without heparin. within first hours of hemodialysis patient developed progressive rightsided headache, which evolved to vomiting, decreased in level of consciousness, and left-sided weakness. he intermittently opened eyes to stimulation but required persistent painful stimulation to answer orientation questions. he had no changes in mean arterial pressure during hemodialysis. his serum bun had decreased from to mg/dl, and his serum sodium remained unchanged. emergent ct head was stable from prior. intra-dialytic tcd waveforms revealed progressively increased distal resistance to flow, measured by pulsatility index (pi) at his bilateral middle cerebral arteries (mca), and compromised mca velocities. this change was dramatic on the right, the same side as his subdural hemorrhage and cerebral contusion. esrd patients with critical neurologic injury are at risk for altered cerebral hemodynamics during dialysis. tcd ultrasonography may be a practical bedside tool to screen for patients at particular risk, and guide medical decision-making regarding dialysis prescription for esrd patients in the neuro-icu. point of care ultrasound (pocus) differs from diagnostic ultrasound in being often performed by clinicians and focused to acquire only relevant images to answer a specific clinical question. most ultrasound modalities have differentiated clinical indications where pocus is appropriate: the use of echocardiography to rule out tamponade in shock is considered pocus while the assessment of diastolic dysfunction in heart failure deserves a diagnostic exam. neuroultrasound has been used in various clinical indications like vasospasm, intracranial stenosis, collateralization, and emboli monitoring. these studies are mostly performed by sonographers as diagnostic studies. with emerging interest in assessing pocus indications, we performed a systematic literature review to identify all clinical indications of neuroultrasound and used a delphi based review by three experts to differentiate clinical indications where neuroultrasound could have point-of-care uses. two authors (lmh, gb) performed a systematic review to identify all reported modalities and clinical indications of neuroultrasound (tcd, duplex, b-mode, carotid, ocular and temporal) in medline, embase, cochrane, and scopus databases. three experts (jgd, ct, as) were surveyed using the delphi method to review each clinical indication and modality on whether it was focused on diagnosis or management and whether the clinical indication was a valid pocus. differences in opinion were settled with a final face-to-face discussion to reach a consensus. the systematic review determined total clinical indications of point of care use of neuroultrasound individualized by disease and modality. in indications it was considered a diagnostic adjunct, in instances it was considered an aide in management, and in instances it was determined to aid in both diagnosis and management decisions. there are many point of care indications of neuroultrasound in neurocritical care. this consensus opinion can guide clinicians to clinical indications where point of care use can aide in bedside diagnosis and management. in a systematic review, we reported current literatures on neuromonitoring methods in left ventricular assist device(lvad) population. we searched five databases (pubmed, embase, cochrane library, web of science, scopus, clinicaltrials.gov) related to lvad and neurological monitoring methods from inception through january . of unique citations, studies ( participants) met the inclusion criteria. the median age was . (interquartile range . - . , . % male). study designs were retrospective observational studies (n= ) and prospective observational studies (n= ). neuromonitoring methods studies included transcranial dopplers(tcd) for emboli monitoring(n= ) or cerebral autoregulation monitoring (n= ), traditional neuroimaging (ct/mri) (n= ), cerebral oximetry(n= ), carotid ultrasound (n= ) and plasma vad, articles studied pulsatile- current evidence on neuromonitoring in lvad is limited and there is no consensus on the indication and effectiveness on use of any neuromonitoring methods. the publications have significant heterogeneity adequate power are warranted to develop an optimal neurological monitoring protocol and prevention strategy. midbrain compression secondary to cerebral edema or hemorrhage results in high mortality and morbidity. quantitative pupillometry holds promise as a bedside indicator of worsening anatomic tissue shifts. because pupil reactivity relies on an intact neural network through the diencephalon and brainstem, compression can lead to changes in pupil size and reactivity. we studied markers of compression and pupillometry within hours of head ct in patients with anterior ischemic stroke (ais) or supratentorial intraparenchymal hemorrhage (iph) causing mass effect. we reviewed scans from patients with unilateral injury from ais (> / of mca territory) or iph (> ml). we assessed midline (mls) and pineal gland shift (pgs), as well as novel measurements of midbrain compression including interpeduncular shift (ips) and the ipsilateral and contralateral cerebral peduncle hemi-distances to the interpeduncular cistern (icphd, ccphd). multilevel modeling was used to analyze radiographic measurements with quantitative pupil metrics including pupil reactivity (dnpi) and size (dsize) differences between eyes. pupil reactivity and size differences were significantly associated with radiographic markers of midbrain noninvasive indicators of brainstem compression. evaluation of optic nerve sheath diameter (onsd) has been widely examined as both a correlate of intracranial pressure (icp), and a potential predictor of outcome after neurological injury. recent studies have evaluated sonographic measurement of onsd, yet clinical limitations to this approach persist. evaluation of onsd measurements via routine brain computed tomography (ct) imaging has been less studied, but offers potential for detection of increased icp in the absence of invasive monitoring. previous studies have employed a cross-sectional approach to onsd measurements via ct scan, primarily among patients with traumatic brain injury (tbi). however, no studies have evaluated serial correlations between ct onsd measurements and icp to evaluate strength of correlations during hospitalization, and across diagnosis types. the purpose of this study was to investigate correlations between onsd via serial ct imaging and icp among adult patients with neurological injury. retrospective cohort study of all adult patients admitted with acute neurological injury requiring icp monitoring and critical care admission. n= . diagnosis type included tbi ( %), aneurysmal subarachnoid hemorrhage ( %), intracranial hemorrhage ( %), cranial mass ( %), and other ( %). there was a strong, positive correlation between right/left onsd across all time points (r= . - , p< . ), suggesting a consistent bilateral response. correlations were strongest between initial inpatient ct scan onsd readings and icp (r= . , p< . ), but decreased over time. patients with increased icp across all diagnosis types experienced higher onsd values upon presentation to the emergency department (ed) and on serial ct scans throughout hospitalization (range . mm- . mm, p< . ). urements as a potential indicator of increased icp in the absence of invasive monitoring. serial ct brain imaging is often performed to evaluate for intracranial changes during hospitalization, and measurement of onsd during this imaging can contribute to decisions regarding more invasive monitoring. monitoring of burst-suppression-pattern (bsp) in electroencephalography (eeg) is relevant to control barbiturate-induced coma. currently, the assessment of bsp is based on continuous observation of the eeg with manual counting of bursts per minute (bpm) by experts, which is prone to inter-rater variability. we evaluated the reliability of a new algorithm for automatic bsp-detection compared to manual assessment in two thiopental-induced burst-suppressed patients. a bipolar -channel eeg-montage was recorded. the montage was bandpass filtered into typical eeg rhythms and segmented into secs -moonen metric, a distance matrix between all epochs in the first hour of data from patient us to cluster this matrix into clusters: burst, suppression and artifact. we labelled the rest of the (test) data from patient and patient by training support vector machine classifier from the labels produced by clustering. the eeg was scored by a neurologist to get ground truth bpm ranges (min, max for intervals of minutes to hour) for both patients. the algorithm provided estimated ranges of bpm for these intervals. the pilot data shows a high correlation of automatic burst counts compared to the manual counting. we found a significant pearson correlation (patient : . , p< . , patient : . , p< . ) and linear regression coefficient (patient : . , p< . , patient : . , p< . ) between estimated and ground truth bpm ranges. the automatic detection of the bursts provides an objective and fast assessment of bsp. the algorithm showed a slightly lower sensitivity due to the missing detection of very short or low bursts. we are ation. ventilated neurocritically ill patients is unknown and explored in this study. a retrospective cohort study was performed on patients admitted to the neurocritical care service between / / and / / , hospital-wide o shut down for maintenance and a switch to olerated with lowest being % owest spo of > % and spo < % amongst the patients in the pre and post-o shutdown groups. -tolerated. with the risk of hyperoxia and its potential negative effects on neuronal injury, a subset of neurocritically whole body hypothermia has been used as a treatment for patients with severe traumatic brain injury (tbi) since many years. invasive brain temperature monitoring is the most commonly practiced for target temperature management in these patients; however, complications are common due to the invasive nature of the procedure. the objective of the current investigation was to evaluate the association between brain temperatures obtained using a non-invasive sensor (accucor) and an intracranial pressure/temperature (icp) catheter during selective brain cooling in patients with tbi. aluated during a selective brain cooling over hours using both a parenchymal icp catheter (raumedic -pt) and the accucor sensor, with a catheter positioned in the nasopharynx. mean temperature values for each participant were obtained along the cooling intervention. outlier values derived from the accucor sensor were detected and removed prior to comparison. the variation in brain temperatures was calculated by mean temperature differences obtained using both measuring devices for each participant. mean brain temperature values were very similar between devices: . °c ( . °c- . °c) for the icp catheter and . °c ( . °c- . °c) for the accucor sensor (p-value: . , % ci: - . to . ). the median temperature difference between the devices was . ºc (minimum: - . °c, maximum: . °c, p-value: . ). our results suggest that there were no differences between brain temperature measurements conducted using the icp catheter and the non-invasive accucor sensor. this conclusion highlights the precision of non-invasive temperature monitoring, a safe alternative to the current invasive practice. monitoring procedures. sepsis-associated encephalopathy (sae) is a multifactorial syndrome, characterized as diffuse brain dysfunction that occurs secondary to infection in the body without overt central nervous system infection. the prognosis for sae is associated with the degree of cerebral damage. we investigated the relationship between the wavelet coherence of cerebral oxyhemoglobin (oxyhb) among different channels and outcomes in patients with sae. consecutive patients with sae were included. moreover, we included normal controls (n= ) for comparison. the cerebral oxyhb data were collected using functional near-infrared spectroscopy (nirsit, obelab inc.). the coherence between sections of prefrontal oxyhb oscillations in five frequency intervals (i, . - hz; ii, . - . hz; iii, . - . hz; iv, . - . hz; and v, . - . hz) were analyzed using wavelet coherence. in addition, we analyzed the coherence of electroencephalography (eeg) signal in three frequency intervals (delta, - hz; theta, - hz; and alpha, - hz). we evaluated the outcomes using glasgow coma scale (gcs) cores at discharge. the patients were categorized into three groups of normal control, good outcome (gcs - ), and poor outcome among the included sae patients (mean age, . years; and male, . %), patients ( . %) had a good outcome. in the poor outcome group, phase coherence was significantly lower compared to good outcome and the normal groups, especially for the myogenic frequency interval iii ( . ± . vs. . ± . vs. . ± . , p < . , respectively). however, the phase coherence of eeg signal was similar in two groups. our results demonstrated that the lower phase coherence of oxyhb in the myogenic signal, which originated from the vascular smooth muscle cells in the brain, was related to the poor outcome in sae patients. this suggests that evaluating cerebral dysfunction using wavelet coherence of oxyhb could be a useful outcome predictor following sae. external ventricular drain (evd) placement is a common procedure in the neurointensive care unit and intracranial hemorrhage (ich) is a recognized complication. in this study we sought to determine the factors associated with ich development after evd placement. retrospective study performed at a tertiary hospital. we identified all patients in whom an evd was placed over a month period. electronic chart review was done to obtain basic demographics, past medical history, use of antiplatelets/anticoagulants, type of catheter placed and presence of intracranial hypertension (ih). computed tomographies were reviewed to identify evd-associated ich. ichs were classified into symptomatic (gcs decline > points, intubation, outcome of death, or new focal continuous variables were analyzed with a proportion of the means test. the sample was comprised of subjects, had evd-associated ich. the median age was years. there was no significant difference in race or gender between patients with ich and those without ich. age, catheter type, history or inpatient use of anti-thrombotics, recent surgery, tpa use, heparin use, history of hypertension, hospital outcome, prior stroke, symptomatic hemorrhages, and icp spikes were analyzed, but only age ( . hemorrhage and . non-hemorrhage, p = . ), history of antithrombotic use ( / hemorrhage and / non-hemorrhage, p = . ) and icp spikes ( / hemorrhage and / non-hemorrhage, p = . ) were significantly associated with ich occurrence. three significant factors were associated with tract hemorrhages; age, history of anti-thrombotic use, and icp spikes. two of these factors have been previously supported by prior studies however, no prior study has correlated icp spikes to evd hemorrhages. additional studies may further validate the association between icp spikes and evd-related tract hemorrhages. targeted temperature management(ttm) aimed at helping to improve neurological outcomes associated with ischemic stroke have been studied continuously. however, it is not well known whether the parameters in ttm initiation, induction, maintenance will affect neurologic prognosis. we restrospectively reviewed medical records of the patients with large hemispheric infarction(lhi) who underwent ttm at snubh neurological intensive care unit from . . . to . . . onset to ttm initiation, induction period, ttm maintenance duration were investigated and dichotomized. neurologic prognosis was determined by the month death and modified rankin scale(mrs). a total of patients were included in the study. longer onset to ttm initiation(> hours) was associated with less month death. shorter ttm induction period(<= hours) was associated with less death rate, more fair outcome(mrs - ). ttm maintenance duration(within days or more) was not statistically correlated with neurologic prognosis. shorter ttm induction period may reduce death in lhi through maximizing icp control effect. the high mortality rate in patients with shorter onset to ttm initiation is likely to be related to the severity of initial symptom(mean nihss vs ). non-pulsatile continuous blood flow can cause endothelial dysfunction and small vasculature injury. the impact of non-physiologic blood flow on cerebral autoregulatory function and brain injury has not been extensively studied. we report a case of posterior reversible encephalopathy syndrome (pres) in a patient supported by a continuous flow pump, venoarterial extracorporeal membrane oxygenation (ecmo) for acute cardiogenic shock secondary to iatrogenic ventricular septal defect (vsd). a year-old male with hypertrophic cardiomyopathy was admitted for elective septal myectomy with an ascending aorta and hemi-arch replacement. the surgery was complicated by an iatrogenic vsd requiring urgent va-ecmo cannulation for cardiogenic shock. on day , ct brain achieved for poor neurological examination revealed extensive bilateral parietal, occipital and cerebellar hypodense lesions consistent with the typical imaging features of pres. a repeat ct brain on day depicted further extension of brain injury to the bilateral frontal lobes. due to worsening neurologic status, the decision was made to place an intracranial pressure monitor and lower the ecmo flow to return to a pulsatile flow state. the patient was closely monitored for improvement with paco levels, serial ct scans, and neurologic examinations. repeat ct scans on pod and depicted improvement in the bilateral cytotoxic edema with paco levels improving to - mmhg at a reduced ecmo flow rate of . - . l/min. his neurologic examination also improved with spontaneous movements noted in all four extremities. although neurologically cleared for heparin loading, he remained too hemodynamically unstable for open surgical repair and his surrogate decision makers decided to withdraw life-sustaining therapy. our case report illustrates the limited knowledge on the consequences of ecmo's impact on cerebral dynamic cerebrovascular autoregulatory changes in real-time that occur with patients with continuous flow pumps. hospital-onset unresponsiveness (hou) may occur in patients hospitalized for non-neurological conditions; while hou tends to be a transient systemic event, it may also indicate underlying neurological problems. quantitative pupillometry provides npi (neurological pupillary index), a quantitative measurement of pupillary light reflexes that have been traditionally assessed via subjective visual impression. we determined the clinical usefulness of npi in predicting the outcomes of patients who have experienced hou. hou was defined as a newly developed altered mental status and cases coded as "unresponsive" in the acdu (alert, confused, drowsy, and unresponsive) scale. we analyzed the demographics, radiological findings, etiology of hou, npi, in-hospital mortality, and -month modified rankin scale (mrs) scores. a total of cases in patients were analyzed, out of which cases ( %) had been assessed with quantitative pupillometry. cerebral herniation syndrome (chs) was found in ( %) cases; higher npi was associated with decreased risk for chs (odds ratio, . ; % confidence interval [ci], . - . ; p= . ), and no other factors were associated with the risk of chs. a total of ( %) cases showed in-hospital mortality. after controlling for clinical covariates and the presence of chs, lower npi was independently associated with increased risk for in-hospital mortality (odds ratio, . ; % ci, . - . ; p= . ). at a cutoff value of . , the specificity and sensitivity of npi for predicting in-hospital mortality were % and %, respectively. multivariate analysis showed an independent association between lower npi and unfavorable clinical outcomes (common odds ratio, . ; % ci, . - . ; p= . ). npi, a quantitative index of pupillary light reflex, was significantly associated with the risk of cerebral herniation and in-hospital mortality in non-neurological patients with hou. measuring pupillary light reflexes through quantitative pupillometry may be useful when responding to hou cases. target temperature management (ttm) improves survival and neurologic outcome and is recommended for cardiac arrest (ca) survivors by international guidelines. shivering is both an anticipated consequence and a major adverse effect of ttm. the bedside shivering assessment scale (bsas) is a simple, validated four-point scale that enables repeated quantification of shivering at the bedside. in this study, we examine the association between time to return of spontaneous circulation (ttrosc) and shivering (defined as bsas > ). data on post-cardiac arrest patients treated with ttm were collected from apache outcome database and medical records. baseline characteristics included age, apache iii scores, ttrosc (minutes), time to target temperature (ttt, minutes), and bsas > (percentage of hours bsas > /total number of hours bsas was done). outcome was survival to hospital discharge with good neurologic outcome. group and group included patients with ttrosc below or above the median respectively. all patients received continuous infusions of fentanyl and sedatives (propofol, midazolam, and/or dexmedetomidine) as per our institution's protocol. compared to group (n = ), group (n = ) had similar age ( ± vs ± , p = . ), similar apache iii scores ( ± vs ± , p = . ), longer ttrosc ( ± vs ± , p = . ), similar ttt ( ± vs ± , p = . ), more shivering ( . % vs . %, p = . ), and similar survival with good neurologic outcome ( % vs %, p = . ) respectively. ttrosc was strongly positively correlated with shivering (pearson correlation coefficient, r = . ). in comatose survivors of cardiac arrest who received ttm, longer ttrosc (indirect measure of brain injury) was associated with more shivering. these findings should be further investigated in prospective studies. pupillometry assessment of the pupillary light reflex (plr) is gradually replacing manual plr assessment. this new technology has led to a recent increase in clinical research and subsequent need to validate those results. mcnett et al. recently investigated the association between intracranial pressure (icp) and serial pupillometer values and found that pupillometry readings are different significantly in the setting of increased icp. this is a replication of the mcnett study in a larger multicenter cohort to explore these findings. data from the establishing normative data for pupillometer assessments in neuroscience intensive care (end-panic) registry include over , patients with a neurological condition. subjects with documented icp readings provided , observations (daily mean icp values) which were included in this analysis. statistical analysis (sas v . ) included descriptive statistics and to examine the differences . subject mean age was years, % were female and . % were caucasian. student t-test analysis was used to explore for differences. excepting latency and right eye npi, lower plr values were associated with higher icp (compared to low or normal icp) for all mean pupillometer/plr variables for both left and right eyes (t range [- . to . ]; p-value range [< . to . ]). the findings confirm and extend those of mcnett. patients with increased icp tend to have lower pupillometer readings. automated pupillometer is a non-invasive method that provides prediction of the icp trends which can help neurocritical care professionals in assessing patients with neurological conditions. encephalopathy is a common complication in cirrhotic patients. clinical manifestations are diverse, but few data are available on pupillary abnormalities in such patients. the aim of this study was to evaluate whether automated pupillometry could detect pupillary dysfunction in this patients' population. prospective ongoing study including the assessment of the pupillary changes to light stimulation using automated pupillometry (neurooptics, irvine, usa) in adult cirrhotic patients after icu admission. the degree of encephalopathy was scored by the glasgow coma score (gcs). severity of cirrhosis was assessed by the child-pugh and meld scores. severity of liver encephalopathy was assessed according to standard criteria. different biological variables, including ammonium (nh ), was measured to pupillary assessment. the median values of pupillometry-derived variables were collected for both eyes. -pugh and nh levels were found with any of the pupillometry-derived variables. no differences in pupillometry-derived variables were observed across different degree of liver encephalopathy. automated pupillometry did not show correlations between pupillary abnormalities and the severity of critically ill patients with liver cirrhosis. prognostication in comatose survivors of cardiac arrest (ca) remains challenging. the purpose of this study was to determine if early quantitative analysis of resting eeg can improve prediction of commandfollowing by post-ca day . we prospectively enrolled patients admitted after ca. clinical care was performed according to our institutional protocol, which includes continuous eeg monitoring. -minute resting eeg epochs were clipped daily; clips were excluded if seizures or other confounders were present. epochs from post-ca days - were preprocessed for artifact reduction, then analyzed for three quantitative metrics: power spectral density, permutation entropy, and coherence. we created a predictive model using partial least squares regression analysis to distinguish eeg data as from patients who would or would not recover command-following by post-ca day . cross-validation of results was accomplished with a -times random assignment of % of data as training set and % as testing set. eeg clips were analyzed from patients ( . % female, age . +/- . years, pre-morbid mrs . +/- . and cpc . +/- . ). cardiac arrests occurred out-of-hospital in %, witnessed in . %, and had bystander cpr in . %. mean time to rosc was +/- minutes, . % had a shockable initial ekg rhythm, and . % of patients received therapeutic hypothermia. prior to day , . % regained consciousness and . % had withdrawal of care. using eeg data alone, predictive ability (expressed as average area under the receiver operating characteristics curve) yielded auc . +/comparison, the same model was constructed using clinical features (absence of pupil and corneal reflexes by day ) or laboratory testing (peak nse level). the model combining clinical, laboratory, plus eeg data yielded auc . +/- . , an improvement vs clinical features (auc . +/- . , p< . ) or nse levels (auc . +/- . , p< . ) alone. quantitative eeg analysis may provide adjunctive prognostic information regarding short-term recovery of consciousness. international guideline recommended pupillary light reflex (plr) and/or cortical response (n ) to short-latency somatosensory evoked potentials (sseps) at hours after return to spontaneous circulation as the only strong predictors of unfavorable outcome in comatose patients after cardiac arrest. the aim of this study was to compare this algorithm with a multimodal approach including other prognostic tools. post hoc analysis of an international multicenter (n= ; n= patients) prognostic study on automated pupillometry in comatose post-ca patients. the primary study endpoint was the accuracy of npi in predicting -month unfavorable neurological outcome (uo), defined as cerebral performance category (cpc) of - (severe disability, unresponsive wakefulness or death). patients with findings on plr, sseps, npi and eeg were included; the highest nse was also recorded, whenever available. an npi < on day , a discontinuous eeg background or clinical myoclonus over the first days, bilaterally absence of n calculated as: false positive / favorable outcome. we included patients; ( %) of those had uo. using the approach of guidelines, unfavorable outcome at day was observed in / patients with absent plr and / with absent n ; / ( %) patients with uo were identified. using the multimodal approach, uo was identified in / patients with npi < , in / patients with discontinuous eeg, in / patients with myoclonus and this study suggests that a multimodal approach, including npi, eeg, sseps and nse, could identify a after physicians introduced the idea to declare death based on loss of brain functionality, many countries incorporated brain death into their legal criteria for death. we sought to learn about the global legal perspective on brain death declaration (bdd). we collected legal documents about declaration of death around the world by searching national legislative databases and google. we utilized google translate to convert all documents into english then searched for references to criteria for bdd. in cases where there was conflicting information, we consulted local experts. we located legal documents on death declaration for countries, of which included a reference to brain death. legally stipulated criteria for bdd were identified for / countries. with respect to prerequisites for bdd legal stipulations existed in: / countries on confounders to exclude, / countries on an observation period before bdd, / countries on the minimum temperature for bdd and / countries on the minimum blood pressure for bdd. an assessment for coma was legally required in / countries. the fact that spinal reflexes do not preclude bdd was included in the legal criteria for bdd in / countries. a broad reference to an assessment for brainstem areflexia was legally mandated in / countries. the legal criteria included specific reflexes to test in / countries (pupillary / , corneal / , oculocephalic / , oculovestibular / , gag / , cough / , and other / ). every country legally required an assessment for the inability to breathe spontaneously, but only / described apnea testing in detail. the number of clinical exams required for legal bdd ranged from - . ancillary testing was legally required in / countries. the legally stipulated criteria for bdd differ around the world. standardizing the global legal perspective on bdd would help prevent ) variability in practice and ) false bdds. up to % of patients monitored with pupillometry during therapeutic temperature management (ttm) after cardiac arrest will have sluggish (sl) or non-reactive (nr) pupils. the neuroimaging findings and injury patterns of these patients have not been reported. adult patients treated with ttm after cardiac arrest with available pupillometry data from the neuroptics npi- were studied. discharge outcome was classified as poor (po) if the cerebral performance category score was - , and as good if - . pupil size, percent constriction, and constriction velocity were determined throughout ttm using data from the worst eye at each assessment. the neurological pupil index (npi) was scored from (nr) to (brisk), with values < considered sl. computed tomography (ct) and magnetic resonance (mr) neuroimaging was reviewed by a neuroradiologist blinded to pupillometry and outcome data. poor outcomes occurred in / ( %) patients with nr pupils during ttm, / ( %) patients with sl pupils, and / ( %) with normal (nl) pupil reactivity. pupil size did not predict outcome, but pupillometry data during ttm predicted poor outcome with auc . - . . when nonreactive pupils were first detected, / ( %) were < mm. % of patients had ct imaging, and % had mr imaging a median of (iqr - ) hours after recovery of spontaneous circulation. cerebral edema or herniation were identified in / ( %) nr vs / ( %) sl and / nl patients (p< . ). midbrain injury identified by t sequences was identified in / ( %) nr/sl patients versus / ( %) nl patients (p= . ). midbrain abnormalities were identified more often in patients with nr/sl pupils than edema/herniation ( % vs %, p= . ). a minority of patients with sluggish or non-reactive pupils after cardiac arrest have evidence of cerebral edema or herniation. midbrain injury is a more common mechanism to explain this common neurologic deficit. cardiac arrest (ca) survivors are often comatose and their arousal recovery is dependent on the extent of hypoxic-ischemic injury (hii). long-term neurologic outcomes are variable, difficult to predict, and biased by withdrawal of life-sustaining therapy. somatosensory evoked potentials (ssep) remain the gold standard for predicting arousal potential, but is not broadly available. we hypothesized that early hi-resolution mri may help assess arousal recovery potential as predicted by electrophysiologic outcome. comatose survivors of cardiac arrest admitted to an icu between june and january who underwent ssep and mri were retrospectively identified. d-hii burden in predefined regions. semi-automated region-of-interest (roi) tools in mipav were used to draw borders on dwi around the upper brainstem including the ascending reticular activating system (aras) to assess voxel intensity and derive hii volumes. our outcome of interest was ssep findings classified in two prognostic categories: indeterminate (bilaterally present n s or unilateral presence of n s) and poor prognosis (bilaterally absent n s). we used paired t-tests to compare presence of signal abnormality and rois between patients with sseps predicting poor outcome or indeterminate prognosis. consecutive ca survivors (mean age of . , % female) were included. no significant differences were noted in baseline characteristics between groups though time to rosc was noted to be vs mins for indeterminate and poor outcomes (p = . extent did not predict ssep status. no significant difference was noted in the voxel intensities on adc in the midbrain or pontine tegmentum. quantitative mri measures of hii extent may be superior in predicting arousal potential in comatose survivors of ca compared with manual rating. a quantitative image analysis pipeline is being developed for measuring aras lesion burden and predicting electrophysiologic based outcomes in ca. despite promising preclinical results, the application of intra arrest therapeutic hypothermia (iath) during cardiopulmonary resuscitation have produced controversial results in clinical trials. the aim of this review was to analyze the effects of such therapy on relevant outcomes in patients suffering from out-of-hospital cardiac arrest (ca). the following databases have been searched up to th may for human trials: pubmed (from ), embase (from ), cinahl (from ), the cochrane library (from ) and ovid/medline (from ). the search strategy will use the following terms: "arrest" or "cardiac arrest" or "heart arrest" and "intra arrest" or "during cpr" or "intra cpr" and "hypothermia" or "therapeutic hypothermia" or "cooling". references from identified studies and relevant review articles have also been searched for additional eligible citations. the search has been limited to english publications and has been conducted in accordance with the international liaison committee on resuscitation (ilcor) process of evidence evaluation. a total of six human studies (n= ; treated with iath) including four randomized controlled trial (loe ), one retrospective and one prospective controlled study (loe ) were identified. two studies used trans-nasal evaporative cooling and others intravenous cold fluids. overall rate of return of spontaneous circulation was similar between iath patients and controls ( / ) when compared to control group. no differences were found in the subgroup of shockable vs non-shockable rhythms. different effects on outcomes were observed according to the method used to induce iath when compared to controls. iath was not associated with improved outcomes when compared to standard of care. however, the method used to induce iath may potentially influence the beneficial effects of such intervention. amantadine may improve functional recovery in the subacute state following brain injury. we aimed to characterize eeg signatures in patients with acute brain injury (abi) receiving amantadine that did and those that did not recover consciousness. we studied a consecutive series of patients with acute brain injury patients who were treated with amantadine as a neurostimulant between september and december . all patients were initially comatose and underwent eeg prior to and after the initiation of amantadine. the ability to follow commands was assessed daily based on prior published methodology (claassen et al, annneurol ). eeg features that were assessed included sleep stages, posterior dominant rhythm (pdr), and power spectral density plots. we applied a multivariate regression model using generalized estimating equations (gee) to identify eeg features correlated with recovery of command following. eegs were analyzed by a board certified neurophysiologists. -free eeg clips), patients ( %) recovered consciousness during hospitalization. ich was the most common etiology in ( %) patients, followed by sah in ( %) patients. on average amantadine was given for +/- days. patients ( %) had seizures, only patients ( %) after starting amantadine. in our gee model, age (p= . ), sleep structures (p= . ), pdr (p= . ), and cumulative dose of amantadine (p= . ) were all associated with recovery of command following. spectral features corresponding to higher levels of anterior forebrain corticothalamic integrity correlated with higher levels of consciousness in % of recorded patients after days of amantadine use. the best spectral pattern per patient was seen . days on average prior to recovery of consciousness. eeg may provide a biomarker that indicates subsequent recovery of consciousness in unconscious patients with an acute brain injury that are treated with amantadine. depletion of cerebral glucose (i.e., cerebral glucopenia) occurs commonly and is associated with poor outcome in traumatic brain injury and subarachnoid hemorrhage. however, the incidence of cerebral glucopenia after diffuse hypoxic-ischemic brain injury (hibi) is unknown. we characterized the burden of cerebral glucopenia after hibi and its association with markers of physiological distress and outcome. we retrospectively analyzed cerebral microdialysis data from a cohort of patients with hibi. patients survived sudden cardiac arrest and patient had severe hypoxia after polysubstance overdose. hourly values of cerebral glucose, lactate, pyruvate, and glycerol as well as continuous intracranial pressure (icp), arterial blood pressure (abp) and interstitial brain oxygen (pbto ) were recorded. associations between average glucose/patient-day versus average lactate:pyruvate ratio, glycerol, icp, pbto , and abp were analyzed using linear regression. burden of glucopenia (defined % time with glucose < . mmol/l) was analyzed by patient-day. the relationship between glucopenia burden and discharge outcome was analyzed using the wilcoxon rank sum test. lower cerebral glucose was associated with higher cerebral glycerol (p= . ), higher lpr (p= . ), higher icp (p< . ), and lower pbto (p= . ) levels. there was no association between abp and cerebral glucose (p = . ). glucopenia burden increased progressively over time and peaked by postinjury day . / patients had good outcome (defined as return of consciousness prior to discharge). there was no association between outcome and cerebral glucopenia burden (p = . ). cerebral glucopenia is common after hibi and associates with markers of cellular distress. the burden of cerebral glucopenia progressively increases over several days and appears to peak more than week after injury. although there was no association between outcome and glucopenia burden, the number of patients in this study with good outcome was low. the utility of cerebral glucose monitoring after hibi merits further study. international guideline recommends using bilaterally absence of pupillary light reflex (plr) and/or bilaterally absence of the cortical response (n ) to short-latency somatosensory evoked potentials (sseps) at hours after return to spontaneous circulation to predict unfavorable outcome in comatose patients after cardiac arrest. the aim of this study was to compare this algorithm with a multimodal approach including other prognostic tools. retrospective study of adult (> years) cardiac arrest patients admitted from january to march and who underwent multimodal monitoring. we collected demographic characteristics and cardiac arrest data, together with sseps, the presence of burst-suppression on early eeg, a neurological pupillary index on the automated pupillometry < at after arrest and a neuron-specific enolase (nse) -month unfavorable neurological outcome (uo) with cerebral we included patients; ( %) of those had uo. using the approach of guidelines, unfavorable outcome at day was observed in / patients with absent plr, in / with absent n and / with combined absent pupillary light reflex and n ; / ( %) patients with uo were identified. using the multimodal approach, uo was identified in / patients with npi < and / patients with bs on eeg. among the others, uo was associated with absent n in / patients and with high nse values in / patients. this approach identified / ( %) patients with unfavorable outcome. the area under curve to predict uo for the approach of guidelines was . , which increased to . with the multimodal approach. this study suggests the a multimodal approach, including npi and bs on eeg, sseps and nse, has a higher predictive value for uo than recommended predictive tools. there is a high prevalence of seizures following cardiac arrest (ca), but not well studied among survivors with good neurological recovery. we describe the prevalence of clinical and electrographic seizures, anti-epileptic use, and eeg characteristics of ca survivors with good neurological outcomes. adults with return of spontaneous circulation (rosc) after in-hospital or out-of-hospital ca between / - / were eligible. a consecutive sample of survivors with included. prevalence of seizures and antiepileptic drugs (aed) use within -months after discharge were collected using a questionnaire administered via in-person or phone. a board-certified clinical neurophysiologist reviewed the eeg. of patients surviving to discharge, ( %) with -months follow-up were analyzed. average age was ± years, ( %) were women, ( %) patients had witnessed arrest, ( %) received defibrillation, with an average rosc duration of ± minutes, and a median cpc of at discharge. there were no clinical seizures reported during hospitalization. of available ( %) patients with raw eeg (median duration of days), only ( %) patients had electrographic seizures, ( . %) had continuous background as their best eeg pattern, ( %) with discontinuous background, ( %) with epileptiform discharges, and ( %) patients had burst suppression pattern that recovered later to a normal eeg pattern. none of the patients had any malignant eeg patterns, ( %) exhibited reactivity to a verbal or tactile stimulation and ( %) had the presence of sleep structures and posterior dominant rhythms. surprisingly, ( %) patients were discharged on an aed. clinical seizures and aed use were reported in / ( %) at -months follow up. both short and long-term seizure burden are very low among the cardiac arrest survivors with good neurological recovery. underlying factors related to high utilization of aed before discharge warrants further investigation. objective: early neuro-prognostication in the intensive care unit pediatric patients is essential to enable effective care planning, triaging level of care, and family support. in coma, the reliability of biomarkers such as electroencephalogram (eeg), anatomical neuroimaging to determine potential for consciousness and future functional capacity are less established in children. herein we present two case studies highlighting resting state functional mri (rs-fmri) as a clinically new means defining real-time brain function in the pediatric critically ill population. rs-fmri measures spontaneous low-frequency fluctuations in the blood oxygen dependent (bold) signal to investigate the networks of the brain. a standardized acquisition of data on a tesla mri under light tool melodic. whole brain networks determined by independent component analysis with false discovery rate at p< . to detect major brain networks. cases describe two critically ill children. one, with severe brain injury related to acute necrotic encephalopathy, and the other with diabetic ketoacidosis induced cerebral edema and uncal herniation. both had slow eeg background with sleep features approximately a week after presentation and were comatose by exam on the day of rs-fmri. rs-fmri detected normal brain function in the long-range fronto-parietal network, intact language-area networks, and default mode network. atypical networks were detected in brainstem and deep grey in both children. by hospital discharge, both children were awake and communicative with spontaneous movements. case one remain with tracheostomy with intermittent ventilation, case two had residual left hemiparesis, vision and language intact, mild cognitive deficits. in the cases reviewed, rs-mri may offer an objective measure of functional brain capacity and potential for meaningful recovery with preservation of language and long range connectivity networks in critically ill pediatric patients. provision of positive end-expiratory pressure (peep) through a conventional ventilator during apnea testing for brain death determination removes the need for additional equipment such as a peep valve, allows for use of high peep during apnea in patients with severe hypoxic respiratory failure and facilitates detection of respiratory effort on flow scalars. the advent of ventilators that permit deactivation of the apnea backup setting has made such testing possible. our goal was to examine the feasibility of peep use with conventional mechanical ventilation during apnea testing, with a focus on premature termination and inadvertent external triggering. performed without disconnection from the ventilator (dräger evita® infinity® v ), with deactivation of the apnea backup. this was a convenience sample based on availability of appropriately trained -support and peep - cmh o. apnea was confirmed by absence of chest rise and respiratory effort on the flow scalar. adequacy of respiratory stimulus was established by a co > mmhg and -point co rise from baseline. endpoints included early termination of the apnea test prior to minutes because of patient instability, any oxygen desaturation below % and inadvertent external triggering. inadvertent external triggering required repeat of apnea testing. ten patients underwent apnea testing while connected to the ventilator. apnea testing for at least minutes was successful in all patients. apnea was confirmed in all cases. no patient suffered oxygen desaturation below % or other instability. there was one instance of inadvertent external triggering caused by jostling of tubing, necessitating repeat testing. apnea testing with provision of peep through a conventional ventilator to improve tolerance is feasible. inadvertent external triggering is uncommon but may occur. despite well-defined aan guidelines on brain death declaration, there is marked variability in its practice nationally. this highlights the need for targeted brain death education initiatives. communication with surrogates or families about a brain death diagnosis and its implications is integral to brain death declaration, yet this has not been studied in a simulation setting. we developed a brain death simulation curriculum at our institution addressing knowledge and surrogate communication skill development. as part of this curriculum, multi-disciplinary critical care fellows completed a pre-curriculum multiple choice (mc) knowledge test and survey (likert - scale) evaluating comfort and confidence. a mandatory one-hour neurocritical care attending-led didactic regarding guidelines and technical aspects of brain death examination was conducted. subsequently, each fellow performed an observed brain death examination (simman g mannequin) with feedback followed by a standardized family scenario with delivery of a brain death -simulation survey, mc questions, and provided feedback. statistical analyses used -tail wilcoxon signed rank test (p<. ). thirteen critical care fellows participated (neurology[ ], anesthesia[ ], trauma[ ], pulmonary[ ]). only one fellow had previous formal brain death training with the majority [ %, (n= )] only participating in - brain death declarations. there was significant improvement across all measures: self-rated knowledge ( . to . , pre-simulation to post-simulation, p= . ), knowledge relative to peers ( % to %, p= . ), confidence ( . to . , p= . ) and comfort ( . to , p= . ) with performing a brain death exam, and comfort with family discussion ( . to . , p= . ). test scores improved from % to % after simulation (p= . ). all fellows found the curriculum beneficial (with all aspects wellreceived). critical care fellows may lack experience with brain death declaration. didactics coupled with simulation-based education can improve objective knowledge and comfort with brain death declaration and surrogate communication. there is a growing disparity between availability and demand for neurologic expertise, particularly in smaller community hospitals. telemedicine has helped to bridge this disparity with respect to cerebrovascular disease and is used increasingly to deliver other types of neurologic expertise to patients. while the nihss is widely used in telestroke, other formalized neurologic exams have not been well studied. we seek to determine whether the components of a brain death exam can be reliably performed via telepresence. patients suspected of meeting brain death criteria were enrolled from july to may . standard bedside neurologic exam (bne) performed by the attending neurointensivist in accordance with our institutional protocol was compared with the telepresence neurologic exam (tne) performed by a study neurointensivist blinded to the findings of the bne and a trained bedside assistant. we analyzed the agreement between examiners regarding findings of coma, corneal reflex, pupillary light reflex, oculovestibular reflex, oculocephalic reflex, cough, gag, motor response, and apnea. we enrolled patients over months. proximate causes were intracerebral hemorrhage ( / ), anoxic brain injury, ( / ), and cerebral infarction ( / ). all examination components performed in the bne could be completed by tne. in cases, neither examiner could assess all exam components. in cases spinal cord injury precluded oculocephalic testing. in case refractory hypoxia precluded apnea testing. bne and tne agreed in % of testable components. in cases testing pupillary light reflex was reported as difficult in the tne but not the bne. all telepresence examiners reported high confidence that the exam findings were consistent with brain death. preliminary findings from our pilot study suggest that the use telepresence for brain death examination introduction traumatic brain injury (tbi) is often followed by the loss of con increases each day following the injury, but the contents of consciousness, also known as qualia, do not uniformly return. while there is some information about brain regions supporting arousal, less is known about circuits encoding contents of consciousness. some evidence supports a role for the thalamus in consciousness, but it is controversial whether it supports arousal, or has a more nuanced role in consciousness. to address this question, we combined intracranial recordings in patients recovering consciousness with neuroimaging of thalamocortical circuits. electrophysiology we recorded electrocorticography (ecog) from prefrontal cortex and anterior cingulate cortex, as well as scalp electroencephalography (eeg) from a standard - montage, during singleand parietal cortex based on coherence between the evoked responses in these regions when acc was stimulated. radiology. regions of structural damage were extracted from the post-tbi mri and diffusion tensor imaging (dti) radiographs. tractography using dsi studio™ was performed with seed regions placed in the bilateral mediodorsal nucleus of the thalamus. we found that in patients with injury isolated to the cortex and/or white matter, the cortico-cortical functional connectivity across frontoparietal networks was preserved, and these patients recovered consciousness. however, a patient with thalamic injury failed to recover consciousness, despite an increased level of arousal following injury. the functional connectivity across cortical regions was drastically lower following thalamic injury, even when the cortical damage was minimal. we propose that integration and communication of information across frontoparietal networks, which is required for contents of consciousness, is dependent on thalamic input. thus future efforts have to be focused on restoring this input. brain herniation is a deadly event that requires rapid administration of hyperosmotic agents (hoas) such as . % nacl. a recent retrospective study showed that intraosseous (io) cannulation provides a safe route for rapid administration of hoas compared to central venous catheters (cvc) and peripheral intravenous catheters (piv). prospective study to measure the time-to-treatment for . % nacl or mannitol via io, cvc, or piv. a data collection form ("brain code narrator") was created by nurses and providers to prospectively collect clinical data, hemodynamic measures, and time-to-treatment and administration route for hoas during brain codes. in addition, demographics, diagnosis, serum sodium (na+) and complete blood cell count, as well as immediate and delayed complications, and outcomes were collected. brain code narrator was used to collect data for patients: males with median (iqr) age ( - ) years. diagnosis included intracerebral hemorrhage (n= ), subarachnoid hemorrhage (n= ), and other (n= ). all patients were intubated. most patients were co-treated with induced hyperventilation. . %nacl ( cc) via cvc and io route and mannitol ( gm) via piv were administered during , , and events with median time-to-treatments of ( , ), ( , ) and ( , ) minutes, respectively (p value < . for all comparisons). no adverse events, such as hypotension or tissue injury were noted. preliminary data suggest that during brain herniation, administration of . % nacl via io or cvc is more rapid than iv mannitol. io cannulation for . % nacl may be an alternate route of administration of hoas during brian code. additional data will be provided regarding herniation reversal and long-term hematologic abnormalities. stress hyperglycemia is common in the critically ill and is associated with poor neurological outcomes in cardiac arrest patients. it is unknown whether glycemic dysregulation have different prevalence according to cardiac arrest etiology. we hypothesized that overdose-related cardiac arrest (odca) patients are more vulnerable to hypoglycemic events given the circumstances of arrest. we retrospectively studied cardiac arrest patients treated at two urban hospitals from the multimodal outcome characterization in comatose cardiac arrest (mocha) registry from - . we examined glucose dysregulation (hypoglycemia blood glucose [bg]< mg/dl, hyperglycemia bg> mg/dl) within first h from arrest in odca and non-odca cohorts. statistical analyses included paired/unpaired t-tests, chi-al dysfunction was defined by scores of gos- of the patients, ( . %) were odca. there were no differences in bmi, gender, ethnicity, or therapeutic hypothermia (th) treatment across cohorts, but odca patients were younger ( ± vs ± year-old; p< . ), had lower prevalence of diabetes ( . vs . %; p= . ) and lower hemoglobin a c ( . vs . %; p= . ). mean bg reduction from - h to - h in odca patients was significantly smaller ( . ± . vs . ± . mg/dl; p= . ) despite no difference in mean peak bg. bg nadirs were lower in odca patients ( . ± . vs . ± . mg/dl; p= . ). patients developed glycemic dysregulation: ( %) odca vs ( %) non-odca; odca patients were nearly two times more likely to develop hypoglycemia (rr . [ . - . ]; p= . ) but had no increased risk of hyperglycemia (rr . [ . - . ]). among patients with glycemic dysregulation, odca was associated with higher risk of in-hospital death or neurological dysfunction (or . [ . - . ]; p= . ). despite exhibiting blunted bg reductions to hyperglycemic treatment, odca patients were more susceptible to hypoglycemia in the first h postmanagement strategies should account for cardiac arrest etiology. sedation and neuromuscular blockade (nmb) in patients undergoing targeted temperature management (ttm) after cardiac arrest (ca) are recommended for patient discomfort and management of shivering. this study assessed the association between nmb use and neurological outcome in comatose survivors of ca who received ttm. data on post-cardiac arrest patients treated with ttm were collected from apache outcome database and medical records. ttm of °c or °c is chosen based on critical care physician's discretion. baseline characteristics included age, apache iii scores, time to return of spontaneous circulation (ttrosc, minutes), time to target temperature (ttt, minutes), and shockable rhythm (sr, %). outcome was survival with good neurologic outcome. compared to the no nmb group (n = ), the prn nmb group (n = ) and continuous nmb group (n = ) had similar age ( ± and ± vs ± , p = . , . ),similar apache iii scores ( ± and ± vs ± , p = . , . ), comparable ttrosc ( ± and ± vs ± , p = . , . ), longer ttt ( ± and ± vs ± , p = . , . ), comparable percentage of sr ( % and % vs %, p = . , . ), and similar proportion of patients with tt of vs ( % and vs %, p = . , . ) respectively. survival with good neurologic outcome was achieved in % in no nmb group vs % in prn nmb group (p = . ) and % in continuous nmb group (p = . ) in the present study, in comatose survivors of cardiac arrest who received ttm, use of nmb had no effect on neurologic outcome. the apnea test is an essential examination for the determination of brain death. however, hypotension, hypoxemia, and other complications during the apnea test can affect the stability of brain-dead patients, as well as organ function for recipients. therefore, it is necessary to establish standard guidelines for apnea testing. the modified apnea test (mat) comprises delivery of % oxygen through the endotracheal tube connected to manual resuscitator (ambu® bag) with the positive end-expiratory pressure (peep) valve after disconnection of -nine instances of the conventional apnea test (cat) were performed in brain-dead patients; instances of the mat were performed in brain-dead patients. the mean duration of the apnea test was . ± . minutes in the cat group and . ± . minutes in the mat group. there were no significant changes in paco , pao , or ph between the cat and mat groups (p = . , . , and . , respectively). in overweight patients (body mass index prevented dramatic reductions in pao and sao (p < . for both). in the patients who had hypoxic brain injury due to hanging, differences in pao and sao in the mat group were significantly smaller than in the cat group (p < . ). although mat, which was invented to maintain peep, was not efficient for all brain-dead patients, it could be helpful in selected patient groups, such as overweight patients or those who had hypoxic injury due to hanging. clinicians should consider this reliable short-term apnea test. coma is a serious complication that currently has no good biological markers. the hypothalamus plays an important function in consciousness circuity. orexin a/b, a neuropeptide produced in the hypothalamus has an excitatory effect on multiple target areas in the brain. previous orexin studies ry (tbi), stroke and comatose states. the goals of our study: ( ) the utility of orexin as a marker of coma recovery, ( ) the correlation between orexin and recovery at and days, ( ) correlation of orexin and glasgow coma score/score (gcs) over time, a prospective, irb approved study with a target n= with a diagnosis of coma due to stroke, including hemorrhagic, and tbi, treated in the neuro critical care unit at stony brook university ho collected from an external ventricular drain (evd) and corresponding blood serum samples on days , , and . there was no modification to the clinical treatment of individual patients. dictive of whether patients recovered consciousness vs deteriorated. logistic regression showed the relative risk of recovery vs. deterioration: , ( %ci - . ± . , . ± . , respective p-values= . e- , . epredictive of initial coma severity (gcs), with a correlation coefficient, r = . . correlation between - . , - . ). dictive of poor overall not appear as significant as the baseline level in predicting recovery. there has been limited research over the past decade on how race impacts survival from cardiac arrest. it has been suggested that black patients are more likely to have unsuccessful resuscitation and lower rates of survival to discharge, however, it is unclear if this difference is secondary to hospital factors or patient specific factors. more research is needed on racial disparities in post-arrest outcomes at urban medical centers. multimodal outcome characterization in comatose cardiac arrest (mocha) is an irb-approved multicenter observational study. this study sample consists of consecutive cardiac arrest patients treated at two urban hospitals from - . the sample includes both patients who experienced in-hospital and out-of-hospital cardiac arrest. the outcome of interest was in-hospital mortality. associations between race and mortality were evaluated by chi-square and relative risk (rr) with % confidence interval. we included white ( %) and black patients ( % were all found to be at no increased risk for in-hospital mortality relative to other gender and race combinations. there was no difference in location of cardiac arrest (i.e., inhospital vs. out-of- the lack of racial differences in mortality could possibly be explained by the similar rate of out-ofhospital arrests, similar initial non-perfusing rhythms, lower socioeconomic status of all patients, and strong focus of the participating hospitals on addressing racial disparities in the healthcare system. hyperglycemia is associated with poor clinical outcomes in critically ill patients, such as post-cardiac arrest (ca) patients. post-ca prognostication studies have studied clinical examinations, electrophysiology, biochemical changes, and/or neuroimaging, but studies regarding patient blood glucose levels are mostly limited to mortality outcomes. new analysis of glucose trends is needed to guide ca prognostication in order to determine favorable outcomes regarding neurologic functioning. this study was conducted using the irb-approved multimodal outcome characterization in comatose cardiac arrest (mocha) registry. the sample included ca patients admitted to a university-affiliated urban hospital from - . case selection was determined by availability of serial glucose measurements over the first hours post-ca and outcome scores at hospital discharge. poor functional outcome was defined as modified rankin scale (mrs) - or glasgow outcome scale extended (gose) - . statistical analysis included chi-square tests, and prognostic value was calculated by sensitivity. there was no significant difference in outcome regarding age, sex, race, or ethnicity. the study sample consisted of % diabetic patients, with no significant difference in outcome. patients with glucose levels > mg/dl at least once during the first hours post-ca were associated with poor functional outc there appears to be a correlation between glucose > mg/dl within the first hours and poor functional outcome. however, it is still difficult to reliably predict poor vs. good functional outcome due glucose management are needed to better understand this relationship. post-cardiac arrest organ injury is associated with high mortality rate after icu admission. despite improvement in the post-cardiac arrest care, temporal changes in patients' severity, intensity of care and neurological outcome remain poorly defined. the aim of this study is to describe how epidemiology of cardiac arrest characteristics, therapies and outcome have changes over years. retrospective study including adult (> years) cardiac arrest patients admitted from january to march after ca to a university hospital. we collected demographic characteristics and cardiac arrest data, together with main therapies and monitoring during icu and hospital mortality. a total of patients (median age [ - ] years; male gender %) were included over the study period. time to rosc was significantly longer in period i and iv when compared to others (p< . ). icu length of stay and lactate levels on admission were also significantly higher in the period iv than others. there was a progressive and significant increase of out-of-hospital ca, non-cardiac origin of arrest and non-shockable initial rhythm from period i to period iv. also, there was a significant increase in the number of patients developing acute kidney injury and hypoxic hepatitis over time, from period i to period iv. despite a more frequent use of coronary angiography and multimodal neurological monitoring, hospital mortality increased (from period i, % to period iv, % -p< decreased (period i, % to period iv, % -p= . ) over time. in this study, severity of anoxic injury and the incidence of post-cardiac arrest organ dysfunction increased over time. this was associated with a higher proportion of patients with poor outcome. pressure reactivity index (prx) based optimal cerebral perfusion pressure(cppopt) is associated with outcome after traumatic brain injury, but is not explored after cardiac arrest. we examined post-arrest patients who underwent invasive intracranial monitoring to explore characteristics of prx and cpp, and whether these were useful predictors of survival. we included all comatose cardiac arrest patients without primary neurological pathology that underwent invasive intracranial monitoring between - at our institution. cpp, mean arterial pressure(map), prx, cppopt, and deltacpp (cpp-cppopt) were calculated. systemic and brain physiologic measures were compared across the primary outcome of survival. in this pilot study we demonstrated the feasibility of acquiring cpp, prx, and cppopt for post-cardiac arrest patients. in this sample, none of the systemic and brain physiologic measures were associated with survival but the approach is limited by the bias towards poor outcomes in patients receiving monitors. interestingly, cppopt obtained from invasive intracranial monitoring generally ranged within physiologic norms. deltacpp for the single patient with good outcome was positive and small, consistent optimizing cerebral perfusion after cardiac arrest improves outcome are warranted. prognostication after cardiac arrest is challenge because of many confounding factors during hypothermia, severity of the brain injury is a key determinant of whether maximal resources, such as the use of extracorporeal membrane oxygenation (ecmo), mechanical circulatory support, or even coronary artery bypass grafting, are advisable or appropriate. therefore, early and accurate prognostication is essential for decision of therapeutic plan including maxima intensive modalities. in this study, we focused not only the prognosis estimation using mri but also initial ct-based prognosis estimation where features captured by modern deep learning (dl) technique were commonly used. we selected total cardiac arrest patients having initial ct at er, and brain mri after hours from cardiac arrest. diffusion weighted image (dwi, b = ), and apparent diffusion coefficient (adc) images calculated. cerebral performance category (cpc) scores were used as the main outcomes of survivors after cardiac arrest. both experienced neurologist and emergency medicine tried to predict the devised two cascaded deep convolutional neural networks (deep cnns). even fully experienced neurologist and emergency physician could not predict the cpc score exactly with the initial ct scan only and even additional diffusion mri (accuracy : %- % with initial ct only - % with additional diffusion mri). by using dl technique, among subjects of train set, subjects had the correct prognosis score ( . % accuracy) and among subjects of test set, subjects had the correct prognosis score ( . % accuracy) with initial ct scans only. with additional diffusion mri, . % accuracy and % accuracy. in visually equivocal initial ct scans, dl was more related to quantification than visual assessment. dl is superior and very useful for accurate prognostication especially with visually equivocal initial ct scan. cardiac arrest (ca) is associated with a high risk of dying and of neurologic impairment in survivors. target temperature management (ttm) improves survival and neurologic outcome and is recommended by international guidelines. this study assessed the association between the initial acute physiology and chronic health evaluation (apache) iii score and neurological outcome in comatose survivors of cardiac arrest who received targeted temperature management (ttm). data on post-cardiac arrest patients treated with ttm were collected from apache outcome database and medical records. ttm of °c or °c is chosen based on critical care physician's discretion. baseline characteristics included age, gender, apache iii scores, time to return of spontaneous circulation (ttrosc, minutes), time to target temperature (ttt, minutes), and shockable rhythm (sr, %). outcome included hospital mortality, and good neurologic outcome (defined as discharge to home or rehab). compared to the bad outcome group (n = ), the good outcome group (n = ) had similar age ( in comatose survivors of cardiac arrest who received targeted temperature management, the apache iii score calculated in the immediate post-cardiac arrest period was a poor predictor of neurological outcome. brain dead patients are victims of trauma, entering the health care system through emergency department (ed).in the ed, these patients are received with injuries and de-arranged physiological conditions that depends on time sensitive treatment and have the potential for improvement with proper management. our study tries to find out the predictors at admission that contributes to brain death (bd) so that their timely intervention can prevent bd a retrospective analysis of the data related to severity of injuries, physiological parameters and laboratory investigation including ct scan of the head at the time of ed admission of each patients were assessed once they were diagnosed brain death. logistic regression analysis was employed to determine the independent factor. p value of < . was considered significant. results brain dead patients records at the time of admission were analysed. on univariate analysis we found glasgow coma scale (gcs) < , blunt trauma chest (btc),skeletal injury, intraventricular hemorrhage (ivh),skull fracture,subarachnoid hemorrhage (sah),midline shift (mls),mean blood pressure (mbp)< mmhg,use of ionotropes, hemoglobin (hb)< mg/dl,international normalization ratio(inr)> . ,albumin< mg/dl,sodium level (na)> meq/dl,urea > mg/dl significantly related to bd.on further multivariate analysis ,we found gcs< (or- . ), btc (or- . ), ivh (or- . ), mls (or- . ), mbp < mmhg (or- . ), inr> . (or- . ), albumin < mg/dl (or- . ) and na level > meq/dl(or- . ) at the time of admission are strongly associated with bd. our study tried to find the predictors at the time of admission which may contribute to bd. addressing them may prevent patient from becoming brain dead. biomedical technology in critical care is advancing at a rapid rate, offering the potential to substantially improve performance through improved efficiency and productivity. recent evidence suggests that visual assessment of pupillary size and reactivity has limited interrater reliability and accuracy, hence, we examined the introduction and implementation of an automated pupillometer in an academic neurological icu. we evaluated clinicians' perceptions about the added utility of the pupillometer to the standard visual pupillary exam. -minute bedside education and demonstration of the pupillometer by a 'superuser', we conducted usability testing at the bedside. participants completed the end-user testing methodology, where they completed specified tasks designed to test the pupillometer's features and later completed a questionnaire regarding their ease of use and interpretation of results, comfort and confidence using the pupillometer, and their behavioral intention to use the pupillometer if adopted into the clinical environment to date, participants have completed questionnaires. participants were allowed repeat enrollment in the study. the participant's professional designations include registered nurses, residents and fellows and the majority have practised in the icu for to years. most of the participants are somewhat comfortable ( / ) performing the traditional visual pupillary exam and somewhat confident ( / ) with the results obtained from this exam. twenty-one, out of responses, were very comfortable in using the pupillometer, / were somewhat comfortable, and / were neutral. if this technology is introduced into icu, the majority ( / ) will use this device to conduct pupillary exams, and / would consider changing management based on the pupillometer results. this study outlines a strategy to evaluate usability and implementation of a newly adopted technology into the critical care environment. improved implementation methods and evaluation of implementation processes are necessary for successful adoption of new technology in acute care settings. propofol infusion syndrome (pris) is a rare complication of propofol infusion. it is characterized by metabolic acidosis, rhabdomyolysis, acute renal failure, hyperlipidemia, and rapid cardiac failure. risk factors for developing pris are: propofol infusion > hours, dosing > mg/kg/hr, critical illness, malnutrition, and use of vasopressors. we present a case of pris that developed after propofol infusion was turned off. a year old woman with medically intractable epilepsy and developmental delay, presented with generalized tonic clonic status epilepticus. she was refractory to benzodiazepines, so she was intubated and started on a propofol infusion. at mcg/kg/min of propofol, she was still having generalized clonic tonic seizures. she was transferred to our neurological icu for continuous eeg monitoring. propofol infusion was increased to mcg/kg/min ( mg/kg/hr) to control her seizures. she remained seizure free for hours. propofol was weaned over hours because she became hypotensive and required norepinephrine. when the propofol was turned off, cpk was , lactate was . , and creatinine was . . she received propofol for hours. twelve hours after propofol was stopped, she developed a metabolic acidosis, lactate increased to . , creatinine increased to . , urine output decreased, and cpk increased to > , . she then developed bradycardia with wide complex qrs, which progressed to asystole. she could not be resuscitated and died. our patient developed pris after propofol infusion was off for hours. she had many risk factors for developing pris, including high dose of propofol, critical illness, malnutrition, and use of vasopressors. pris can occur after propofol infusion has been stopped, and should be monitored for after the infusion has been discontinued in patients that are at increased risk. subdural hemorrhage (sdh) is a common cause of morbidity. we sought to study the impact of antithrombotic drugs on nontraumatic sdh. we retrospectively reviewed medical records of , patients admitted at massachusetts general hospital for sdh during to based on a research patient data registry. there were patients without history of head trauma included in the analysis. baseline demographic and clinical characteristic data were collected. the outcomes including gcs, modified rankin scale (mrs), sdh size, sdh expansion, surgical evacuation, mortality rates, length of stay (los), bleeding and thromboembolic complications were compared between two groups. multivariate logistic regression was performed to analyze association between poor outcome (mrs - ) and all potential predictors (age, diabetes, conditional variable regression method was used because of relatively small sample size to avoid overfitting the model. among patients included, ( . %) were on antithrombotic agents, either antiplatelets or anticoagulants, at presentation and ( . %) were not. anticoagulant and antiplatelet agents constitute . % and . % of nontraumatic sdh, respectively. all antithrombotic agents were discontinued on admission. nontraumatic sdh patients who were on antithrombotic agents had longer los ( . ± . , p= . ), higher rate of sdh expansion (or . ; %ci . - . ; p= . ), higher rate of disability at discharge (mrs - ) compared to no antithrombotic group (or . ; %ci . - . ; p< . ). on multivariate logistic regression analysis, antithombotic group had higher rate of poor outcome than no antithrombotic group (or . ; %ci . - . %; p= . ). use of antithrombotic agents prior to admission in nontraumatic sdh patients correlates with longer los, higher sdh expansion and increased disability at discharge. maintaining goal sodium levels in the neurocritical care population can be challenging. historically, at our institution, the supplementation of enteral sodium occurred by addition of table salt to tube feeding formulas by our dietary team. to make this therapy easier to standardize, monitor, and titrate, a new process was developed. continuous % hypertonic sodium chloride solutions are now administered enterally via feeding tubes. this also allows for the charting of the medication and immediate dose titrations. this pre-post analysis includes patients admitted six months prior to the implementation of the new enteral sodium process compared to patients admitted within one year after the new process change. demographic variables, as well as the indication for sodium goals, initial sodium levels, sodium level for -hours post-addition of enteral sodium supplementations, concomitant use of intravenous hypertonic saline, and achievability of goal sodium levels were collected. descriptive analytics were performed to compare groups. a total of patients were included in the analysis: in the pre-implementation group and in the post-implementation group. the most common indication for goal sodium levels in both groups was traumatic brain injury with head bleed; patients ( %) in the pre-implementation group and ( %) in the post-implementation group. ability to maintain serum sodium concentrations (defined as the ability to maintain goal sodium without the need for intravenous hypertonic saline for > h) within goal in the pre-implementation group was successful in % of patients (n= ) compared with % (n= ) in the post-implementation group. the use of continuous enteral % hypertonic sodium chloride solutions to target and maintain goal sodium levels provided similar efficacy compared to the addition of table salt to tube feeding formulas and is safer and easier to monitor and titrate. coagulation factor xa (recombinant), inactivated-xa inhibitor associated life--factor prothrombin complex concentrate (pcc) was utilized off- retrospective, single center, cohort study including adult intracranial hemorrhage patients who received discharge between efficacy (defined by international society on thrombosis and haemostasis criteria), thrombotic events, icu and hospital length of stay, and mortality. andexxa, coagulation factor xa (recombinant), inactivated-zhzo is indicated for patients treated with rivaroxaban and apixaban, when reversal of anticoagulation is needed due to life-threatening or indication. there is no available literature supporting the use of this drug in acute neurosurgical emergencies. we present our experience of patients treated with andexxa who required acute neurosurgical interventions as a life saving measure. patients were identified from may , to may , using an electronic database report identifying those who received andexxa and subsequent chart review at a single center quaternary care academic medical facility. factor xa inhibitor and time of dosing. patient and both had an external ventricular drain placed while in the emergency room. patient suffered from a cerebral hemorrhage with hydrocephalus while patient was found to have a primary ventricular hemorrhage with hydrocephalus. both were treated with four factor prothrombin complex concentrate (pcc) at an outside hospital. there were no bleeding complications during the procedures. two patients had a craniotomy performed. patient was diagnosed with an acute subdural hemorrhage with worsening midline shift despite receiving pcc at the outside hospital. patient four had an acute-chronic subdural hemorrhage with midline shift but did not receive pcc. in both craniotomy cases, there were no bleeding complications. andexxa was used in four patients taking apixaban or rivaroxaban undergoing lifesaving neurosurgical procedures despite no the utilization of acute extracranial and intracranial stents for the treatment of cerebrovascular pathology is increasing. the optimal antiplatelet agent and dose in this population and the utility of platelet function testing is unclear. all patients from january to april who were hospitalized and received ticagrelor to maintain intracranial or carotid stent patency in which platelet function testing (verifynow) was utilized to guide dosing were collected. relevant demographic, clinical, platelet reactivity unit (pru), and ticagrelor administration data was collected and qualitative assessment of pru results was performed. data was collected on patients and the maintenance doses utilized were , , (most frequent) or mg bid and loading doses of mg or mg. a total of patients' doses were titrated in order to achieve the goal pru range ( - ). among patients given a dose of mg % had a pru in the optimal range ( - ) as compared to % among patients given a dose of mg. twice as many patients given a dose of mg as compared to mg ( % vs %) had a pru between - . among the patients whose dose was titrated the average pru prior to dose escalation was , the average pru subsequent to dose escalation was , and the average pru prior to dose decrease was and the range in % of cases and was between - in % of cases. the utilization of platelet function testing to guide dose titration of ticagrelor to a desired pru range is feasible. a major limitation of this study is the lack of patient outcomes related to thrombosis or bleeding. rivaroxaban. the efficacy and safety of andexanet alfa have been evaluated in the annexa- study, which excluded patients receiving prothrombin complex concentrate (pcc) within the days preceding enrollment. however, there have been limited reports of patients receiving both pcc and andexanet alfa for oral factor xa inhibitor-associated major bleeding, without adverse effect. while thrombotic events were observed in % of annexa- patients, potential for additive risk when combining andexanet alfa and pcc is undefined. we describe a patient who received pcc followed by andexanet alfa for an apixaban-associated intracerebral hemorrhage, who subsequently suffered devastating embolic strokes. de-identified patient data were retrospectively collected from the electronic medical record a -year-old male presented with acute left-sided hemiplegia caused by a large right-sided temporal lobe intracerebral hemorrhage. the patient had a history of atrial fibrillation, for which he was anticoagulated on apixaban. the patient initially received intravenous (iv) pcc units/kg for prevention of hematoma expansion. the following day, minimally expanded hemorrhage was observed on repeat imaging concurrent with a measured apixaban level of ng/ml (reference range - ng/ml). as a result, high dose andexanet alfa was administered as an mg iv bolus, followed by an iv infusion of mg/minute for minutes. over the next several days, the patient's neurologic exam supratentorial strokes, likely embolic in origin. unfortunately, the patient did not survive hospitalization. the combination of pcc and andexanet alfa may carry with it substantial thrombotic risk, and cannot be routinely recommended. targeted temperature management (ttm) is used for neurological protection in patients with neurological injury but shivering during ttm can reduce therapeutic effect by increasing oxygen consumption and metabolic rate. cisatracurium used to prevent shivering has a shorter half-life than vecuronium and is not affected by liver and renal function. the objective of this study was to compare the efficacy and safety between two neuromuscular blockers in order to determine the benefit of cisatracurium. we reviewed medical records of adult neurological intensive care unit (ncu) patients who received st, to may st, . the efficacy between the two groups was confirmed by the presence of shivering and the recovery time of motor function. safety was determined by the incidence of bradycardia and hypotension, the duration of antibiotic use and the mortality rate after discontinuation of the neuromuscular blocker in ncu. recovery time of motor function was assessed using 'motor power' and 'glasgow coma scale (gcs)'. a total of patients were included in the study: patients in cisatracurium group and patients in vecuronium group. the incidence of shivering was . % and . % (p = . ) in vecuronium and cisatracurium, respectively. the median recovery time of motor function was . [ . - . ], . [ . - . ] hours (p < . ) based on the motor power score, . [ . - . ] hours and . [ . - . ] hours (p < . ) based on the motor response score of gcs, respectively. the safety was not significantly different between the two groups. recovery time of motor function was significantly shorter in the cisatracurium group than in the vecuronium group and there was no significant difference in the others. this study identified the benefits of cisatracurium in ncu under ttm. amantadine and modafinil are neurostimulants that may improve or accelerate cognitive and functional recovery after a stroke. this systematic review describes amantadine and modafinil administration patterns post-stroke, evaluates their impact on cognitive and functional outcomes, and identifies the incidence of adverse drug effects. an investigator-initiated medline search identified all full-text english-language publications describing the administration of amantadine or modafinil post-stroke from inception through october , . -stroke); intervention (amantadine or modafinil treatment); comparison (not required); outcomes (cognitive or functional recovery). amantadine and modafinil administration practices, cognitive and functional outcomes, and incidence of adverse drug effects were collected according to the preferred reporting items for systematic reviews and meta-analysis protocols (prisma-p) approach. quantitative analysis was not performed due to heterogeneity in the measures of clinical effectiveness. initially, , publications were identified. eight amantadine ( patients) and modafinil ( patients) publications were included. only ( %) amantadine patients and ( %) modafinil patients received treatment during an acute hospitalization. time from stroke to amantadine initiation was ( , . ) days and the initial dose was ( - ) mg/day. time from stroke to modafinil initiation was ( , ) days and the initial dose was ( - ) mg/day. under-responsiveness was the most common indication for neurostimulants (n= / publications; %). thirty-eight unique measures of clinical effectiveness were reported. a positive response in at least one measure of clinical effectiveness was reported in % and % of amantadine and modafinil publications, respectively. visual hallucinations (amantadine) and excitability/agitation (modafinil) were the most common adverse effects. amantadine and modafinil may improve or accelerate cognitive and functional recovery post-stroke, but higher quality data are needed to confirm this conclusion, especially in the acute care setting. levetiracetam is an antiseizure medication that is used in neurocritical care (ncc) patients to prevent or treat seizures. behavioral adverse events (ade) are reported to occur in approximately % of patients taking levetiracetam; however, the incidence of these ades in ncc patients are unknown and may be exacerbated due to their unique cns pathology. the purpose of this study is to identify the incidence of levetiracetam-associated behavioral (lab) ades in ncc patients. adult ncc patients receiving levetiracetam, admitted between november , and october , , and diagnosed with tbi, sah or ich, or cerebral infarction were included in this study. criteria for determination of lab ades included the following: ) diagnosis codes for delirium, agitation, irritability, hostility, violent behavior, insomnia, anxiety, or depression during this hospital admit; ) administration of an antipsychotic; ) positive cam-icu; and/or ) physical restraints. day of lab ade onset was determined by the start date of the antipsychotic or a positive cam-icu. there were patients included in this study; % males, median admit gcs was . the most common neurological injuries were ich ( %) and tbi ( %). lab ades were identified in ( %) patients. these were identified by diagnosis codes in % of patients, with delirium, depression, and agitation being most common; % received an antipsychotic, % had a positive cam-icu, % had restraints ordered, and % had more than one determining factor. lab ades were reported a median of (range - ) days after levetiracetam initiation. patients with tbi had the highest reported incidence of lab ades ( %). almost half ( %) of ncc patients that received levetiracetam experienced a behavioral ade, which was of levetiracetam use in ncc patients. the recommend the use of units/kg of four--pcc) or rting lower dosing strategies of apcc. in , a fixed, lowimplemented at our institution. the objective of this study was to evaluate the efficacy and safety of fixed, low-dose apcc this single-center, retrospective chart review included adult ich patients who received apcc for oral tcome was achievement of ich hemostasis. hemostasis was defined as no progression of hematoma on head ct within hours post-apcc. safety outcomes included in-hospital mortality and incidence of thromboembolic event (vte) within days post-apcc administration or up to the time of discharge, whichever came first. -four patients receiving apcc for reversal of factor xa inhibitor associated ich ( traumatic and spontaneous) were included for analysis. median age was years; % of patients had a past medical history of atrial fibrillation and % were anticoagulated with apixaban. median apcc dose was units ( - units), with a median weight-based dose of units/kg ( - units/kg). hemostasis was achieved in % of all patients with ich ( % in patients with traumatic ich, and % of patients with spontaneous ich). mortality rate was % and vte incidence was %. of hemostasis in the majority of patients and a low incidence of vte. ally ill patients, yet the optimal monitoring method is unknown. the purpose of this study was to describe the correlation between aptt and anti-xa levels in patients receiving prophylactic sq- a retrospective chart review of patients admitted years were included if they received sq--xa level drawn within hours of each other. aptt and anti-xa levels were then compared to determine correlation and descriptive analyses were performed. correlation was defined as normal aptt levels ( . - . seconds) paired with undetectable anti-xa levels (< . iu/ml), sub-therapeutic aptt ( . - . seconds) with sub-therapeutic anti-xa ( . - . seconds), therapeutic aptt ( - seconds) with therapeutic anti-xa ( . - . iu/ml), and supra-therapeutic aptt (> seconds) with supra-therapeutic anti-xa (> . iu/ml) levels. a total of patients and paired levels were analyzed. the median time between paired aptt and anti-xa levels drawn was . hours, and . % ( / ) of levels were drawn within hour of each other. anti-xa levels were drawn at a median of . hours after the sqpaired levels correlated, while . % ( / ) of levels drawn within hour of each other correlated. a spearman's correlation coefficient of . (p= . ) was found between aptt and anti-xa levels drawn within hour of each other. a sub-therapeutic aptt with undetectable anti-xa was demonstrated in . % of levels drawn within hour of each other. the sqanti-xa levels. there was no significant correlation between aptt and anti-xa levels in patients who received sq--sqh monitoring method in the neurocritically ill population. the utilization of acute extracranial and intracranial stents for the treatment of cerebrovascular pathology is increasing. the optimal intravenous antiplatelet agent for short-term bridging of patients who are unable to tolerate or do not respond adequately to oral antiplatelet agents is unclear. cangrelor offers potential advantages over glycoprotein iib/iiia inhibitors because response can be readily measured using platelet function testing (verifynow) and it has superior pharmacokinetics including a rapid on-set of effect and rapid clearance. patients with intracranial or carotid artery stents who were administered cangrelor for bridging purposes when oral antiplatelet agents were not feasible were assessed. relevant demographic, clinical and procedural data as well as cangrelor dosing and platelet function testing data were collected. patients had carotid artery stents. the indications for bridging were acute gi bleeding, inability to tolerate oral medications due to severe nausea/vomiting and two patients had an inadequate response to initial oral ticagrelor dosing based on platelet function testing. the dose of cangrelor utilized for all patients was . mcg/kg/min and all patients were on a cangrelor infusion for less than hours. platelet function testing (verifynow) was utilized to ensure adequate platelet inhibition and all patients demonstrated adequate inhibition on the prescribed dose. no stent thrombosis or bleeding was observed. cangrelor is a reasonable option when patients with intracranial or carotid stents necessitate an intravenous antiplatelet for bridging when oral antiplatelet medications are not feasible. current guidelines for the prevention and management of pain, agitation/sedation, delirium, immobility, and sleep disruption in adult intensive care unit (icu) patients recommend a multimodal analgesia-first strategy to minimize opioid and sedative requirements and encourage early mobilization. the purpose of this study was to evaluate the success of a stepwise multidisciplinary implementation of an analgesiafirst sedation pathway followed by introduction of an early mobility protocol in a neuroscience icu (nsicu). we retrospectively evaluated mechanically ventilated adult nsicu patients admitted to a single-center academic medical center. three-month time periods were evaluated at baseline (phase i), after implementation of the sedation pathway (phase ii), and after implementation of the early mobility protocol (phase iii). total of patients were evaluated: phase i (n= ), phase ii (n= ), and phase iii (n= ). we observed a progressive decrease in propofol use during each phase (i, ii and iii) (median . mg/day versus . mg/day versus . mg/day, respectively; p= . between phase i and iii) and increased dexmedetomidine utilization ( % versus % versus . % of patients, respectively; p< . ). opioidanalgesia requirements during mechanical ventilation were similar between groups. we observed a quicker time from admission to pt evaluation between phase ii and phase iii (median [iqr] of days [ ] [ ] [ ] [ ] [ ] [ ] versus days [ - ], respectively; p< . ). rehabilitation therapy was provided in . %, %, and . % of patients while admitted to the icu in phase i, ii, and iii, respectively (p= . ) and increased number of pt sessions provided per patient (median of [ - ], [ - ], and [ - ] sessions/patient during each phase, respectively). no adverse events related to early mobility were observed. interdisciplinary coordination and communication is necessary for effective unit-based practice changes as education alone is insufficient. a multidisciplinary approach to goal-directed therapy targeting pain management and light sedation increased opportunity for early mobility. the use of opioids in the neuroscience intensive care unit offset the balance of analgesia and reliability in performing neurological exam. in lieu of the current opioid crisis, we describe our center experience about the use of ketamine as an alternative medication with opioid sparing/lowering effect. retrospective chart review of patients admitted to nsicu with severe brain injury between november to april were performed. patients were separated into two groups of twenty by randomization and matching, each receiving either ketamine or propofol infusion. data collected includes age, gender, diagnosis, comorbidities, duration of ketamine, propofol and morphine equivalent (me) opioid dose. statistical descriptive analysis and independent samples t-test analytical analysis were performed to determine the difference of opioid use between two groups using spss software. the range of ketamine used over the mean period of . (range - ) days was - mcg/kg/min, while that of propofol over the mean period of . (range - ) days was - mcg/kg/min. / ( %) and / ( %) patients in the ketamine and propofol group required opioids respectively. the cumulative and mean morphine equivalent (me) dose for the ketamine group was . mg and . mg respectively, while on propofol, it was . mg and . mg. results of independent t-test analysis showed a significant p-value of . , indicating significant opioid dose reduction with ketamine. it is essential to recognize the effectiveness of ketamine as an opioid sparing/lowering agent with potential analgesic-sedative medication without significant side effects. introduction different indications. however, serious complications such as i -current pulmonary embolism in patients with a contraindication to unknown. this information would be needed to determine if opportunities for improvement exists. with approval from the local investigational review board (irb), during the period of - were identified from the interventional radiology department. only identified patient data was manually extracted via chart review to determine patient characteristics and a total of patients met inclusion criteria. . % were male. the most common neurocritical care diagnosis were intracranial hemorrhage( %), ischemic stroke ( %), central nervous system (cns) neoplasm ( %) and cns trauma ( %). . % of patients had at least venous thromboembolism (vte) was the most common indication ( %) followed by vte with contraindication for ac ( %), primary adjunctive treatment ( %) adjunctive prophylaxis ( %) and secondary adjunctive treatment ( %). in this single center study, to anticoagulation. andexanet alfa was approved in may for reversal of life-threatening hemorrhages for patients on anticoagulation with apixaban and rivaroxaban. since its approval the reversal of direct oral anticoagulant (doac) associated intracranial hemorrhages (ich) has been controversial. the objective of this study was to describe real world utilization of andexanet alfa at a large academic health system. we retrospectively reviewed patients who received andexanet alfa for an ich. patients were included if they received andexanet alfa from its time of approval to formulary through april , . baseline demographics, anticoagulation and reversal information was collected. a neurointensivist reviewed all imaging. intracerebral hematoma expansion was defined as > % increase in hematoma volume. subdural (sd) and subarachnoid hemorrhage (sah) expansion was defined as > % increase in maximal hematoma diameter. thirteen patients received andexanet alfa for ich. nine patients had an intracerebral hematoma, patient had an isolated intraventricular hemorrhage, patients had sd, and patient had a sah. the median age was (iqr - ) and % of patients were male. six patients were receiving a doac for stroke prevention, and a majority of patients ( %) were taking apixaban. the median glasgow coma scale was (iqr - ), and for patients with intracerebral hematomas the median ich score was (iqr - ). there was follow-up imaging available for patients, and patient had hematoma expansion. one patient died and another had interval surgery prior to repeat imaging. no patients had in hospital thromboembolic events up to days. of the patients, % of patients would have met exclusion criteria from the anexxa- trial. in this small sample of patients who received andexanet alfa for ich it appears hemostatic efficacy was achieved in a majority of patients with no thromboembolic events; however, larger trials are needed. lacosamide is a monotherapy or adjunctive therapy used for treatment of partial onset seizure that enhances slow inactivation of sodium channels. uncommonly reported adverse effects include pr interval prolongation, bradycardia, atrioventricular block, and ventricular tachyarrhythmias. an year-old male with history of atrial fibrillation, hypertension and aortic valve replacement on warfarin presented with an acute subdural hematoma after feeling lightheaded and falling. the patient reported having multiple recent syncopal episodes. he received prothrombin complex concentrate and vitamin k for warfarin reversal with an initial inr of . . he was started on levetiracetam and home medications of metoprolol and diltiazem were continued. the next evening, he had focal seizures, was given lorazepam and transferred back to the icu. he received lacosamide mg iv loading dose, and within minutes had a second episode of asystole. his blood pressure remained stable and he did not lose a pulse. he was given atropine x doses with no response therefore transcutaneous pacing was initiated. several minutes later, he became hypotensive and was started on isoproterenol and epinephrine infusions. ekg showed complete heart block. cardiology was consulted and placed a transvenous pacer. vasopressors were eventually weaned off however neuro exam remained poor. about a week later, family made the decision to transition to comfort measures and the patient passed away. lacosamide is an anticonvulsant primarily used for partial complex seizures. only a few cases of third degree atrioventricular block have been reported in the literature. this case of extreme atrioventricular bock with a lacosamide loading dose is not common, but a drug-drug interaction with metoprolol and diltiazem was suspected. prescribing lacosamide with beta-blockers or concomitant medications that prolong the pr interval should be done cautiously due to increased risk of atrioventricular block. tissue plasminogen activator (tpa) is currently the preferred agent for treatment of acute ischemic stroke. in about % of cases, patients will develop life threatening intracranial hemorrhage. currently the aha/asa guidelines and ncs guidelines recommend reversal of intravenous tpa with cryoprecipitate and platelet infusion. both society recommendations are based off low quality evidence and are given weak recommendations.theoretically, the mechanism of action of tranexamic acid (txa) makes it an appealing agent for reversal of tpa ; txa competitively inhibits activation of plasmin countering the mechanism of action of tpa. the purpose of this case report is to report and support usage of txa for reversal of thrombolysis with tpa. this is a patient case report in which an extensive review of the patient chart was conducted to provide an accurate history of events. extensive literature review was compiled to reflect current therapy guidelines and the off-label use of txa for reversal of tpa. year-old male presented to a tertiary care medical center with signs and symptoms of ischemic stroke symptomatic cerebellar hemorrhage. the delay in obtaining cryoprecipitate and platelet transfusion led the medical team to discuss alternative agents for the reversal of tpa. reversal with txa was discussed based on the medication's mechanism of action. txa mg/kg ( mg) was prepared at bedside and administered over minutes. repeat head ct showed no further progression of hemorrhage and there was an improvement in the patient's neurologic condition was noted hemorrhagic transformation following thrombolysis for ischemic stroke is a life threatening emergency. txa is an appealing option for reversal of tpa as it directly counters the mechanism of tpa and can be easily and quickly accessed. this case reports further strengthens and supports its usage. drug level monitoring is essential to optimize valproic acid (vpa) efficacy and minimize toxicity. total serum vpa levels of - mcg/ml are recommended, though free drug is more precisely responsible for vpa's pharmacologic effect. the interpretation of total vpa levels is complicated by the drug's complex protein binding characteristics. the use of free serum vpa levels has garnered interest, though the therapeutic range is not well defined. little is known about the relationship between free vpa levels and toxicity. we present a novel and unambiguous case of hepatotoxicity associated with elevated free vpa levels. de-identified patient data were retrospectively collected from the electronic medical record a -year-old male with a past medical history of refractory epilepsy was hospitalized for generalized tonic-clonic seizures. his prior home antiepileptic drugs (aeds) included carbamazepine and the vpa precursor divalproex. the patient's total and free vpa levels upon admission were . mcg/ml and . mcg/ml (laboratory reference range normal. the patient's home divalproex er dose was increased from mg twice daily to vpa suspension mg twice daily for his low total vpa level. on hospital day (hd) , the patient had a therapeutic total vpa level of . mcg/ml, but an elevated free vpa level of . mcg/ml in the setting concurrent with a free vpa level of . mcg/ml. the patient's vpa was then transitioned to alternative aeds due to hepatotoxicity concerns. the patient's clinical status later improved, and he was discharged probability scale implicated vpa as the probable cause of hepatotoxicity in this patient. measurement of free vpa levels helps guide dosing decisions and may reduce drug-related toxicity. limited case reports of osmotic demyelination syndrome (ods) treated with intravenous immunoglobulin (ivig) with or without plasma exchange (pe) are published, demonstrating variable neurologic recovery. the combination of ivig and pe led to complete neurologic recovery of our ods patient. electronic chart review to collect data for this case report. -year-old male presented with asymptomatic serum sodium of meq/l in the setting of intractable vomiting and decreased oral intake secondary to small bowel obstruction. his sodium was overcorrected by meq/l within first hours. he subsequently developed altered mental status with lethargy and became unresponsive on day with flaccid quadriparesis and minimal motor response to noxious stimuli. mri of brain revealed osmotic demyelination of central pons and bilateral basal ganglia. ivig was initiated on the day when ods was confirmed on mri. his serum sodium normalized. after day course of ivig g/kg, he could intermittently track with eyes but did not recover motor function. plasma exchange was initiated days after ivig. after sessions of pe, he started to move his right upper extremity antigravity and was attempting to verbalize. after sessions of pe, he moved all extremities antigravity, could talk although he had staccato speech and was able to ambulate with assistance. after sessions of pe, he was ambulating independently; his motor strength was +/ throughout. he was cognitively intact. at one month follow up in the clinic, he was neurologically completely intact, except for minimal upper extremity intention tremor. ivig with plasma exchange led to the remarkable neurologic recovery of a patient with ods. a randomized control trial comparing ivig monotherapy versus pe monotherapy versus the combination of ivig and pe is warranted to better clarify the appropriate treatment protocol in ods patients. digoxin is a commonly used drug in the treatment of heart failure patients but with no intrathecal indication. we describe a rare case of accidental intrathecal administration of digoxin during an elective caesarian section that lead to severe neurological deficits. a -year-old hispanic female underwent elective caesarian section with separate attempts at regional spinal anesthesia with bupivacaine due to failure of achieving adequate anesthesia with the first injection. risk management discovered that patient had erroneously received digoxin as the initial injection, confirmed by therapeutic serum levels of digoxin. two hours after delivering a healthy child, the patient's mental status deteriorated and she became unresponsive. she had three witnessed generalized tonic-clonic seizures and was emergently intubated for airway protection and received keppra. twenty-four hours in, patient remained comatose, continuous electroencephalogram revealed no seizures, magnetic resonance imaging (mri) brain showed diffuse, patchy hyperintensities involving bilateral frontotemporal lobes and basal ganglia. mri spine showed extensive cervical and thoracic cord edema. cerebrospinal fluid analysis showed white blood cells and protein count of . she received solumedrol milligram intravenous for doses followed by -day course of intravenous immunoglobulin (ivig). eleven days in, she was extubated. at discharge, she had intact upper extremity strength, intact speech, with no sensation or motor response below t level. mri showed mild thoracic cord edema. at day follow up, she had intact mental status and minimal improvement in motor strength and sensation below t . this is an extremely sad case of severe neurological deficits resulting from a grave medical error. there are only previously reported cases of intrathecal administration of digoxin in literature but the mri findings, duration of symptoms and neurological deficits were far more severe in our patient. neither cases reported use of high dose steroids or ivig either. neurological complications following organ transplantation can be a result of a myriad of infectious, toxic-metabolic, vascular and iatrogenic causes. given the wide range of possibilities, accurate diagnosis can be challenging. we present a case of acute hyperammonemia complicating renal transplantation. a -year-old female with a remote left mca stroke was evaluated for progressively worsening lethargy that started approximately a week after she had undergone deceased donor renal transplantation. her immunosuppression comprised induction with alemtuzumab plus methylprednisolone with long-term mycophenolate mofetil plus tacrolimus, and antibiotic coverage included valganciclovir, trimethoprimsulfamethoxazole and fluconazole. progressive deterioration in the level of consciousness progressing to coma with absent cough, gag reflex, sluggish pupils and no motor response resulted in the patient being intubated. neurological examination did not reveal any focal deficits besides her pre-existing right hemiparesis. pertinent investigations included an mri brain that showed no acute changes, eeg suggestive of triphasic waves and serial lumbar punctures showing elevated pressures in the - cm h o range. level of umol/l. in addition to appropriate pharmacotherapy and dietary protein restriction, the patient underwent continuous venoher mentation to baseline. additional investigations done to determine the etiology of the hyperammonemia showed the patient to be infected with ureaplasma urealyticum which was treated successfully with doxycycline and moxifloxacin. to our knowledge, this is the first report of ureaplasma urealyticum infection resulting in hyperammonemia fo management of hyperammonemia. in the absence of hepatic impairment, alternate etiologies of hyperammonemia should be sought. acute hyperammonemia requires prompt evaluation and treatment to reduce the mortality and morbidity associated with it. prevalence, characteristics, and outcomes related to ventilator associated events (vae) in neurocritically ill patients is unknown, and explored in this study. a retrospective study was conducted to examine prevalence, factors, and outcomes of patients with vae admitted to the neurocritical care service at harborview medical center between january , and december , . chi-square test, analysis of variance was used to compare patients by vae status. amongst neurocritically ill patients, vaes occurred in ( . %) patients. most common vae was ventilator associated condition, vac, ( . %), followed by infection related vac (ivac), ( . %), and possible ventilator associated pneumonia (pvap), ( . %). most common trigger for vae was an increase in positive end-expiratory pressure (peep). age (median [iqr ], male sex ( %), and bmi ( . %) were comparable across groups with and without vaes. patients with vae experienced higher intracranial pressures than those without vae( . mmhg vs. mmhg, p < . ). compared to patients without any vae, patients with any vae spent longer time on mechanical ventilation ( . vs. . days, p < . ), and in the intensive care unit ( . vs. days, p < . ). mortality ( . % vs. . %), median hospital length of stay ( . vs days) and discharge to home ( . % vs. . %) were similar across both groups. ventilator associated events are prevalent amongst the neurocritically ill. they are commonly triggered by changes in peep, and are associated with intracranial hypertension, increase length of mechanical ventilation and intensive care unit stay but may not affect mor associated with vae in subgroups of neurocritically ill patients and their impact on clinical outcomes warrants further examination. synthetic cannabinoids (sc) are a heterogeneous group of compounds initially developed to study the endogenous cannabinoid system. most sc interact with cb and cb receptors with much higher affinity -tetrahydrocannabinol. the popularity of sc is increasing in adolescents and young adults because of the ability to produce a marijuana-like high without being detected on routine drug screens. we hereby present a case of sc related status epilepticus, hypoxic respiratory failure, severe acute kidney injury (aki) and cerebral edema with fatal outcome. -year-old man with suspected sc adulteration of cbd oil presented with headache and status epilepticus. labs showed leukocytosis, triple acidosis, and tetrahydrocannabinol in urine. ct head showed diffuse cerebral edema with sulcal subarachnoid hemorrhage. intracranial pressure was elevated to - mmhg. hospital course was complicated by severe and refractory metabolic acidosis into hospitalization patient suffered cardiac arrest from pulseless ventricular tachycardia secondary to severe acidosis and metabolic derangements. after multiple attempts of resuscitation, care was withdrawn, and patient passed away. in this case, severe refractory metabolic acidosis proved to be fatal. this case highlights the many challenges in managing a critically ill patient with cerebral edema and renal failure with medically refractory metabolic acidosis. sc are undetectable on routine drug screens and exposure is difficult to establish. sc can lead to multi-organ failure and death that may result from cardiovascular events, respiratory depression, pulmonary complications, and aki. a high clinical suspicion is warranted in atrisk patients. exposure to sc may lead to cardiovascular, cerebral and renal complications that respond poorly to devise appropriate therapeutic strategies in managing such patients. benzodiazepines are the standard medication class for treating alcohol withdrawal symptoms (aws). in acute brain injury benzodiazepines may worsen delirium and its central nervous system (cns) depressant effects may decrease level of consciousness and make the neurological-exam unreliable. barbiturates have similar actions to benzodiazepines on gaba receptors and cause less cns depression. we present our center's experience with the use of phenobarbital in patients with aws and acute brain injury. retrospective chart review of twenty patients admitted in neuroscience intensive care unit(nsicu)with acute brain injury and aws was done. treatment protocol consisted of mg/kg ideal body weight(ibw) of phenobarbital loading dose divided into three intramuscular doses three hours apart, followed by a tapering daily oral maintenance dose for total of seven days. alcohol withdrawal symptoms were assessed using the ciwa score for severity. serum phenobarbital levels were drawn five hours after the third intramuscular dose. liver function tests were performed before loading dose and daily for -times the upper limit of normal triggered protocol discontinuation. none of the patients developed alcohol withdrawal seizures, one patient developed severe transaminitis. loading doses of phenobarbital did not cause hypotension. systemic toxicity was absent and phenobarbital serum levels drawn after the loading doses ranged between . - . mcg/ml (normal range - mcg/ml). patients decreased their ciwa score after the loading doses of phenobarbital suggesting improvement of withdrawal symptoms and there was decreased use of adjunctive medications (benzodiazepines) for management of aws. nine patients required adjunctive benzodiazepines and received mg or less of lorazepam. phenobarbital for management of aws was associated with minimal adverse effects and did not lead to systemic toxicity. phenobarbital can be used in patients with acute brain injury without exacerbating delirium and can decrease the need for adjunctive benzodiazepines. aneurysmal subarachnoid hemorrhage (asah) has a case fatality rate of up to % in patient that rebleed. cerebral arterial vasospasm (vsp) after asah is a leading reason for death and disability. nicardipine is used to treat hypertension and angina, and has been investigate for a potential use in the treatment of vsp after asah. intraventricular nicardine was used for treatment of severe asah after traditional methods failed (ie. ir, hypervolemia, permissive hypertension and intravenous inotropes). mg of nicardipine was mixed with preservative free saline by pharmacy to total ml in volume. ml of cerebral spinal flu drawn from the patient external ventricular device (evd). then the nicardipine solution was instilled and the evd was clamped for minutes. patient had transcranial dopplers (tcds) prior to injection and hours after injection and reopening of the evd. patient's vasospam temporized and neuro exam returned to pre spasm baseline. patient survived vasospam window and was transferred to long term care facility. in neuroscience icu (nsicu) maintaining balance between performing reliable neurological exam with adequate analgesia without causing significant sedation is challenging. ketamine has significant neuroprotective and anti-seizure properties. in spite of these unique neuro-friendly pharmacological profile, it's role in nsicu unit is not well defined. we describe our experience about the use of ketamine in neuro-critical care unit. retrospective chart review of patients admitted to nsicu in whom ketamine was used as first line agent for sedation and analgesia in intubated patients with varied brain injury from january to april was performed. safety parameters collected includes blood pressure changes, intracranial pressure changes, heart rate, arrhythmias, excess secretions and apneic spells. pco was monitored and hypercarbia was avoided. effectiveness was measured by requirement of additional sedation-analgesic medications while receiving ketamine. twenty patients with varied brain injury who were on ketamine infusion as first line agent were selected. mean age was . years (range - years) and patients were male. admitting diagnosis was hemorrhagic stroke ( %), ischemic stroke ( %), seizures ( %), carotid stenosis ( %) and tumor mass ( %). mean duration of ketamine infusion was . days (range - days) and dose range was - mcg/kg/min. no icp elevation was noted among the patients where the icp was monitored. none of the patients had uncontrollable elevated blood pressures nor major fluctuation in heart rate or respiratory rate requiring discontinuation of ketamine. ( %) patients had increased secretions without respiratory compromise. opioid use decreased significantly moreover additional sedation was not required while on ketamine infusion. ketamine is a safe and effective sedative-analgesic in neuro-critical care patients while at the same time allow for a reliable neurological examination to perform while on sedation. more research is warranted before it could be considered as the standard of care. oromandibular dystonia (omd) is a movement disorder characterized by involuntary, sustained muscle contractions of varying severity resulting in sustained spasms of craniopharyngeal muscles affecting the jaws, tongue, face, and pharynx that can lead to abnormal jaw opening or closing or tongue protrusion. these disorders are often treated with botulinum for improvement of symptoms. there is minimal literature related to omd treated for botulinum in the neurocritically ill patient population. we conducted a retrospective electronic medical record review from - of all brain-injured patients admitted to our neurocritical care unit who were diagnosed with omd and received botulinum toxin injections. etiology and location of brain injury along with clinical characteristics including resolution of symptoms were recorded. over a -year period, we injected patients with botulinum type a injection ( mouse units or m.u.) into bilateral masseter muscles for severe omd causing tongue biting/maceration and difficulty with oral care, and refractory to antispasmodics and muscle relaxant medications. among the patients, patients were sah, patient with ich/ivh, patient with bilateral brain injury after post pituitary neurosurgical procedure and patient with diffuse bilateral ischemic stroke related to sickle cell disease. all patients tolerated the procedure with no immediate complications. all patients had gradual improvement of omd albeit variable and only out of patients required a nd treatment. in this small series, injection of botulinum toxin for severe omd from brain injury causing tongue injury appears to be safe, tolerable, and efficacious in reducing enteral antispasmodics/muscle relaxants. no short-term or long-term adverse effects were noted and it helped nursing with oral care over time. larger randomized controlled trials should be performed to evaluate the effectiveness and safety of treatment with botulinum in the critically ill neurologic population. the neurosurgical intensive care unit (nsicu), a level trauma center in san antonio, cares for neuro critical patients. the use of central access catheters is essential for hypertonic fluid administration, vasoactive medications, and general critical care. in this unique population the risk of developing deep vein thrombosis (dvt) is higher compared to other patients due to reasons related to neurological injuries. the objective of this research was to determine the incidence and prevalence of dvt between the use of peripherally-inserted central catheters (picc) versus central venous catheters (cvc) in the nsicu. we prospectively evaluated consecutive patients with a cvc or picc in the nsicu from to . data was collected, by a team of apps on: surveillance vs non-surveillance ultrasounds, blood stream infections (clabsi), indwelling time, complications, and icu length of stay. a total of piccs were placed for catheter days, patients were diagnosed with a dvt related to the catheter, rate of . per catheter days. a total of cvcs were placed for catheter days, patients were diagnosed with a dvt related to the cvc, rate of . per catheter days. a total of dvts were diagnosed, one symptomatic patient and remaining dvts were identified during surveillance ultrasound. two complications were encountered during insertion of a cvc and picc which included development of hematoma on insertion of each catheter. the average length of stay for patients with a picc line was . days. the average length of stay for patients with cvc was days. the nsicu surveillance ultrasounds identified more dvts with the use of picc lines versus cvc warranted if surveillance ultrasounds should be routinely performed for nsicu patients. mortality with acute respiratory distress syndrome (ards) is as high as % in patients with subarachnoid hemorrhage (sah). many of the therapeutic modalities of ards carry potential deleterious effects on icp. we are presenting a challenging case of severe ards and sah. single case report. -year-old male who developed a sudden severe headache. emergent workup revealed a large cerebellar hemorrhage, sah with ivh and hydrocephalus secondary to a ruptured arteriovenous malformation (avm). emergent suboccipital decompressive craniectomy followed by external ventricular drain (evd) placement were performed and transferred to our facility for further aggressive care. hospital course was complicated by severe pseudomonas pneumonia with progression to severe ventilation strategies, sedation, paralysis and inhaled nitric oxide (ino) failed to correct hypoxia. on hospital day (hd) he continued to show refractory hypoxia and was placed on roto-prone® bed. continuous intracranial pressure (icp) monitoring was utilized with evd open at cmh o. prone positioning was attempted for hours daily. hypercarbia during prone positioning lead to elevated icp patient showed improvement of hypoxia, with termination of prone positioning and subsequent weaning of paralytics and sedation. he started following commands and was discharged to a long term care facility after avm embolization, placement of a tracheostomy, feeding tube and ventriculoperitoneal shunt. our patient made remarkable recovery from ards in the settings of obstructive hydrocephalus and sah. strict icp monitoring, ongoing ventilator adjustment and careful utilization of kinetic maneuvers for ards, including prone positioning, contributed. proning may be a consideration in patients with sah, obstructive hydrocephalus and ards with ongoing icp monitoring and ventilator adjustment, but larger scale studies are needed to explore its potential. paroxysmal sympathetic hyperactivity (psh) has been associated with worse outcomes following traumatic brain injury, possibly representing both a marker of injury severity and a source of secondary injury. prior studies suggest that psh is under-recognized and its treatment often delayed. the identification of admission risk factors for psh may facilitate earlier recognition, treatment, and targeted prevention. adults with severe tbi admitted to a neurotrauma icu for at least hours and hospitalized for at least days between january and december were retrospectively identified. consecutive psh-tbi patients (n= ) were identified via review of medication administration records as having been treated with propranolol and/or bromocriptine for at least hours. control-tbi patients (n= ) were matched to the psh-tbi cohort for age ( +/- years) and gcs (median ( , ) ). admission head cts were scored using marshall and rotterdam criteria. independent-samples t-tests, chi-squared, and multivariate analyses of variance were performed. age-matched cohorts did not differ by sex, race, bmi, trauma type, trauma mechanism, iss, or triss. icu admission vital signs differed between groups with psh-tbi demonstrating a higher hr (p= . ) and a trend towards higher sbp (p= . ), but no difference in core body temperature. neuroradiographic features associated with psh included significantly higher rotterdam ct score (p= . ), presence of ivh/sah (p= . ), basal cistern compression (p= . ), and trends toward higher marshall ct score (p= . ), presence of epidural hematoma (p= . ), and ct dai (p= . ). a multivariate analysis adjusting for admission gcs and sbp identified rotterdam score (p= . ), presence of ct dai (p= . ), and icu admission hr (p= . ) as independent predictors of psh. admission ct findings along with hr may help predict subsequent development of psh requiring treatment. early identification, treatment, and prevention of psh may mitigate its negative impact on tbi outcomes. hyperchloremia in patients receiving chloride-containing solutions can contribute to metabolic acidosis and acute kidney injury (aki), and has been associated with increased inpatient mortality, length of stay and aki in patients with spontaneous intracranial hemorrhage. whether hyperchloremia is a risk factor for mortality in patients with traumatic brain injury (tbi) is unknown. the purpose of this study is to determine if patients that develop moderate hyperchloremia while receiving continuous hypertonic saline (hts) have a higher risk of inpatient mortality. this was a retrospective chart review of patients admitted between january and september . included patients were over years old, admitted to the trauma service with a diagnosis of tbi, and received continuous % hts for at least hours for the management of cerebral edema. exclusion criteria were baseline end stage renal disease or hemodialysis, transition to comfort measures within hours or inconsistent documentation. the primary objective was inpatient mortality. secondary objectives were aki, hospital and intensive care unit (icu) length of stay. after tbi, mortality was higher in patients who experienced hyperchloremia, while aki and length of stay were similar. although randomized controlled trials (rcts) did not prove benefits of hypothermia for severe traumatic brain injury (tbi), brain ct images have not been evaluated in detail in these studies. we aimed to explore the prognostic value of brain ct findings in bhypo study. bhypo study was a multicenter rct to investigate the effect of therapeutic hypothermia in patients with severe tbi. the protocol included collection of brain ct data on admission and around day . using the ct database, we evaluated following findings: presence of intracranial lesion (acute subdural hematoma: asdh, acute epidural hematoma, cerebral contusion, subarachnoid hemorrhage: sah, or intraventricular hemorrhage: ivh), basal cistern compression, lesion laterality, marshall ct classification, and rotterdam ct score. hematoma thickness and midline shift were also measured. unfavorable outcomes were defined gos of to by glasgow outcome scale (gos) assessed at months. ct data were obtained from patients on admission and patients around day . there were no differences in ct findings between hypothermia group and fever control group. in the initial ct, univariate analysis showed that odds ratio (or) and % confidence interval (ci) for unfavorable outcomes were: shift > hematoma thickness ( . , . - . : p= . ), sah ( . , . - . , p= . ), sah or ivh ( . , . - . , p= . ), absent cistern ( . , . - . ; p= . ), and midline shift > mm ( . , . - . , p= . ). rotterdam score was significantly higher in patients with unfavorable outcome ( . vs. . , p< . ). regarding the day ct, bilateral lesion ( . , . - . , p< . ) and sah or ivh ( . , . - . , p= . ) were significant. no patients with absent cistern survived. patients were appropriately assigned in bhypo study in terms of ct findings. shift > thickness, sah, absent cistern, and rotterdam score were powerful prognosticator in severe tbi patients undergoing targeted temperature management. cerebral edema (ce) following traumatic brain injury (tbi) causes secondary injury and increased mortality. yet, conventional measurements of ce on head computed tomography (ct) inadequately accounts for ce. serial volumetrics may facilitate estimation of total brain volume. the objective of this study was to measure the reliability of this technique and identify a threshold for brain volume (bv) change which could be indicative of ce. a subset of patients (n = ) with intracranial hemorrhage on admission ct were identified from a prospectively enrolled cohort of subjects with trauma sufficient to warrant icu admission. using medical image processing, analysis, and visualization (mipav), two independent raters calculated bv on admission and follow-up head ct scans by measuring the volume of the intracranial vault and the absolute difference (ml^ ) and percent difference between the bv values of the two scans were calculated. intraclass correlation (icc) and pearson's correlations were calculated, and significance set at . . the overall reliability of bv measurements between raters was excellent (initial scan icc . volumetric analysis to estimate bv appears to be a reliable technique across serial head ct scans. bv changes of more than . % may represent a clinically significant threshold and should be further investigated. beneficial effects of therapeutic hypothermia in adults with traumatic brain injuries are controversial. we wanted to study the effect of therapeutic hypothermia (th) on outcomes after severe traumatic brain injury (tbi) in real practice using the nationwide inpatient sample in the united states. the nationwide inpatient sample was used to obtain data on all adults who had been discharged from to with a primary diagnosis of tbi who required mechanical ventilation, intracranial pressure monitoring, or craniotomy/craniectomy. the patients with th were assigned to the th group, and the rest were assigned to the control group. the primary outcome was in-hospital mortality, and the secondary outcomes included mean the length of stay, non-routine hospital discharge, mean hospital charges. only patients ( . %) out of a total of , underwent th. th group was younger ( . versus . years, p <. ),had a lower proportion of females ( . % versus . %, p= . ) and a higher rate of in-hopsital complication of deep venous thrombosis ( . % versus . % p = . ). when controlling for age, gender, comorbidities, in-hospital complications, hospital characteristics and disease severity, th was associated with an increased rate of in-hospital mortality (odds ratio, . ; % confidence interval, . - . ), longer mean length of stay ( . vs. . days; p< . ), and greater mean total hospital cost ($ , vs. $ , ; p< . ). there was no difference between the two groups in terms of non-routine discharge (odds ratio, . ; % confidence interval, . - . ), therapeutic hypothermia was associated with poorer outcomes in patients with severe tbi. our findings disfavor therapeutic hypothermia in severe tbi in routine clinical practice. it warrants further investigation in a prospective, randomized study. a rising incidence of subdural hematomas (sdh) has been attributed in part to increased use of anticoagulants and antiplatelets. anticoagulants also worsen the severity and prognosis of sdhs, but the impact of antiplatelets on prognosis is unclear. we hypothesized that antiplatelets would not affect sdh severity or outcome, while anticoagulants would be associated with more severe features and a worse functional outcome. we systematically identified and collected data on patients presenting with a new diagnosis of sdh in at a level i trauma center. we examined common markers of sdh severity in three cohorts of patients: those not on any antithrombotics, those on antiplatelets alone, and those on anticoagulants. categorical data was compared with chi-squared tests, and continuous data was compared with mann-whitney u tests. multivariable logistic regression was used to assess the impact of antiplatelet use on functional outcome at discharge, with a poor functional outcome defined as a score of - on the modified rankin scale. we identified patients with a new sdh during : ( . %) did not take antithrombotics, ( %) took antiplatelets, and ( . %) took anticoagulants. antiplatelets were not associated with increased sdh volume, thickness, or midline shift; anticoagulants were associated with increased volume (p< . ), thickness (p< . ), and a trend towards increased midline shift (p= . ). antiplatelets were associated with a better admission score on the glasgow coma scale (p< . ). when adjusted for age and gender, antiplatelets did not affect functional outcome (or . , p . , % ci . - . ), while anticoagulants were associated with poorer functional outcome (or . , p . , % ci . - . ). despite its known association with overall sdh incidence, premorbid antiplatelet use was not associated with sdh severity or a worse functional outcome at a level trauma center. the common data elements therapeutic intensity level (cde-til) score, quantifies the intensity of nursing and medical care aimed at preventing intracranial hypertension for patients with severe traumatic brain injury. we validated the cde til in our neurotrauma intensive care unit (nticu) and found the cde-til to be highly reflective of perceived and measured therapeutic burden but noted that the scale had a ceiling effect. specifically when icp was - mmhg and higher, the cde-til did not capture the escalating burden. in an attempt to eliminate that ceiling effect and to incorporate current h til (p-til). under a quality assurance approved protocol, retrospective chart review was performed on adult patients with severe tbi. the til score was derived using both the cde-til and the p-til for each hour nursing shift for the first full days of admission. the relationship between the cde-til and p-til and the icp were investigated. reliability testing of the p-til, including interrater reliability, and validation of the p-til are ongoing. the p-til and the cde-til are highly correlated (r= . ) and the relationship between the scores and the maximum icp are similar at icp less than mmhg. at higher icps however, the slope of p-til increases to . compared to the cde-til slope of . and illustrates a . times stronger correlation between the intensity of care level as measured by p-til and icp. the p-til has greater sensitivity for quantifying the intensity of therapy aimed at controlling icps, most significantly for patients with the highest icps, icps - mmhg and above, making it an ideal scoring system for communicating current nursing and medical needs of individual tbi patients as well as potentially predicting post-intensive care or post-discharge needs. patients are frequently brought into neurologic intensive care units in cervical spine immobilization after sustaining ground level falls or after being "found down." currently there is no consensus regarding cervical spine clearance in these patients as they are unable to participate in neurologic examination. after normal ct scans, mri scans are frequently employed to evaluate for ligamentous injury and radiographic signs of cervical instability. we conducted a retrospective chart review of patients who were admitted to the neurologic intensive care unit between and in cervical collars after ground level falls or after being found down (presumed ground level falls). patients were included in the study if they were obtunded on admission (gcs< ) with neurologic exams consistent with their cranial pathology. all patients underwent a high definition ct cervical spine or cta of the neck and were cleared if there was no radiographic evidence of fracture or instability. between - , eight patients were admitted to the neurologic intensive care unit that met inclusion criteria. average age at presentation was . years. cranial pathology on presentation included intraparenchymal hemorrhage, ischemic stroke, and subdural hemorrhage. all patients underwent a high definition ct cervical spine or cta neck which showed degenerative changes without fractures, subluxations or other evidence of instability such as increased atlantodental interval, or prevertebral soft tissue swelling. average follow up was . days range ( - ). there were no cases of cleared patients that suffered secondary neurologic injury or symptoms of cervical instability during the follow up period. our study illustrates that obtunded patients after ground level falls can safely be cleared of cervical spine precautions after a high definition ct cervical spine fails to demonstrate fractures, subluxations, or other evidence of cervical instability. this protocol limits the costs associated with mri scans and the risks associated with cervical immobilization. the elderly comprise the highest incidence of traumatic brain injury (tbi) hospitalizations and death, yet most tbi studies neglect the geriatric population. previous studies suggest women have better outcomes after tbi but are inconclusive. we examined differences in outcomes between sexes after tbi in the geriatric population. this is an observational study of patients and older admitted with tbi to a level trauma center. clinical variables including medical history, severity of injury (gcs> , gcs - , and gcs< ), mechanism of injury, and ct findings were collected. good clinical outcomes were defined as a gose > and measured at discharge and months. the chianalysis were used where appropriate. subjects were included in the analysis. ( %) women and ( %) men. average age was . (sd . ) with no significant differences between sexes. ( %) were mild, ( %) moderate, and ( %) severe. the most common etiologies were mechanical fall ( %), motor vehicle accident ( %), and syncopal fall ( . %). no differences in severity of injury or mechanism of injury were found. on admission ct, men had more contusions ( %v %;p= . ) and skull fractures( %v %;p, . ) compared to women. older age, and history of atrial fibrillation or congestive heart failure were associated with increased incidence of death. men were more likely to have in-hospital mortality ( %v %; p< . ). in multivariable logistic regression analysis controlling for other factors associated with mortality, men were significantly more likely to have in-hospital death (or- ;p= . ). at months, men were still found to have higher mortality (or- . ;p< . ). however, there were no significant differences in good outcomes between sexes at discharge ( %v %; p= . ) or months ( %v %;p= ). men have significantly higher mortality rates compared to women in the geriatric tbi population. differences are needed. partial brain tissue oxygen tension (pbto ) can be regulated by the fraction of inspired oxygen and the level of oxygen carrying capacity. we performed a systematic review of the literature using pbto directed treatment with red blood cell transfusion (rbct) to analyze clinical and physiological outcomes as well as adverse events following rbct. we performed a systematic review following the prisma guidelines and pre-registered with the prospero database. the following terms were used: [(brain tissue oxygen or brain tissue hypoxia or pbo ) and treatment] or [(brain tissue oxygen) or red blood cell transfusion) or pbo ) or traumatic brain injury) and red blood cell transfusion]. inclusion criteria were studies in which pbto was measured before and after rbct. the tool used for qualitative scoring was the grade score. risk of bias was assessed via rti and robins-i. a total of articles were screened of which four articles were included in the final analysis. the intervention performed was to administer to units of rbc depending on the hemoglobin level and the threshold set in each study. the clinical outcome was not described in any of the studies. there was an increase in pbto in all the studies, but it was primarily significant when pretransfusion pbto was less than mmhg. the grade certainty rating for the included articles was low to moderate. our review shows that a significant increase in pbto is primarily seen when pre-transfusion pbto is less than mmhg. clinical outcome and adverse events were not described in any of the included studies. in view of the known adverse effects of rbct in critically ill patients and the limited available literature we found, transfusion should only be reserved as a later tier measure for pbto correction, and possibly only when pbto is less than mmhg. withdrawal of life-sustaining therapy (wlst) is associated with % of deaths after severe traumatic brain injury (tbi). wlst frequently occurs within the first days of hospitalization, when prognosis is most uncertain. while patient factors play a role in the decision, institutional practice patterns and physician perception of prognosis also contribute, as demonstrated in canadian studies. we hypothesized that the rate and timing of wlst among patients with severe tbi vary across the united states. we conducted a retrospective cohort study of patients with severe tbi admitted in to us trauma centers included in the trauma quality improvement program. severe, isolated tbi was defined by diagnosis code and glasgow coma scale (gcs) score < . patients under , with severe non-head injuries, or with advanced directives were excluded. centers were grouped by us census region (northeast, midwest, west, south). multiple logistic regression for wlst was performed with region, patient demographics, gcs motor score, pupillary reactivity, and midline shift as covariates. regression -hospital mortality. variability may reflect inconsistent institutional practice patterns, regional cultural differences, and the difficulty of prognostication. more reliable and standardized prognostic assessments are needed in this population. introduction: pre-injury use of antiplatelet agents may increase hemorrhage size and hematoma expansion after traumatic brain injury (tbi). however, empiric platelet transfusions may result in significant morbidity and unnecessary expense and may not be justified. we sought to determine whether a thromboelastography (teg) platelet-mapping (pm) algorithm could safely reduce platelet transfusion without clinically relevant hematoma expansion. methods: a prospective standardized teg pm-based treatment algorithm was instituted to guide reversal of antiplatelet medications in tbi patients. the algorithm established reversal thresholds for arachadonic acid inhibition (aa-inhibition > %) and adenosine diphosphate inhibition (adp-inhibition > %). consecutive tbi patients were enrolled and compared to a historical cohort. hematoma volume was calculated by itk-snap. conclusions: a teg-guided antiplatelet reversal algorithm may significantly reduce platelet transfusions without clinically significant hemorrhage expansion. increasing partial oxygen arterial tension is one method to increase the partial brain tissue oxygen (pbto ). however the effects of hyperoxia on clinical outcomes and adverse effects remain elusive. to investigate the effects of normobaric and hyperbaric hyperoxia on pbto in patients with tbi, we performed a literature review following the prisma guidelines and pre-registered with the prospero database. the following search terms were applied: [(brain tissue oxygen or brain tissue hypoxia or pbo ) and treatment] or [(brain tissue oxygen) or brain tissue hypoxia) or pbo ) or traumatic brain injury) and hyperoxia]. prospective trials and observational cohort studies were included in this review. two reviewers assessed the risk of bias of each study using the rti item bank. a total of articles were screened, of which articles were included. only one study investigated the effects of combined hyperbaric/normobaric hyperoxia and another used hyperbaric as a separate intervention; the majority of studies were of normobaric hyperoxia. overall, an increase in pbto was observed with both normobaric and hyperbaric. clinical outcome was mostly missing; one study showed an absolute reduction in mortality and improvement in favorable outcome using glasgow outcome score at months. adverse events were also only scarcely reported; studies showed that hyperoxia did not induce cerebral toxicity by using markers of oxidative stress, and one study showed no evidence of pulmonary oxygen toxicity in either the hyperbaric or normobaric hyperoxia groups. normobaric and hyperbaric hyperoxia consistently induced an increase in pbto . improvement in clinical outcome was reported in some studies but did not reach statistical significance except in one. adverse events were not adequately investigated. larger prospective studies are required to investigate the clinical outcome effects of hyperoxia, its adverse consequences, and its role in the tiered approach towards brain tissue dysoxia. early prognostication, either from clinical and/or radiological information, is an important aspect in the settings of neurocritical care with limited resources. we sought to determine the values of two radiological scoring systems in predicting the outcome of traumatic brain injury (tbi) patients, which are marshall and rotterdam ct scores in indonesia. therefore, a physician can make a better priority to provide high-yield care to all tbi patients. a retrospective cohort was conducted in a national referral hospital from july to december . all tbi patients admitted to the emergency department (ed) and had an initial ct scan were included in this study. their classification of tbi and initial ct scan were reviewed and all patients were followed to see whether the patient died or alive until discharge from the hospital (in-hospital mortality). statistical analyses were conducted to find the predictive values (sensitivity, specificity, cut-off point, relative risk) of both scoring systems. of tbi patients admitted to ed, there were patients had an initial ct scan. most of them were categorized as mild tbi ( . %), then moderate ( . %) and severe tbi ( . %). in-hospital mortality was . %. with cut-off point in marshall and rotterdam ct scores, their sensitivity ( . % vs. . %, respectively) and specificity ( . % vs. . %, respectively) were similar. same things also found in their relative risks, which are . ( % ci . - . ) and . ( % ci . - . ). both marshall and rotterdam ct scores have significant values in predicting the outcome of tbi patients, thus it should be implemented in daily emergency practice to assist a physician in making further clinical decisions. midline shift (mls) in brain is a critical condition. if not diagnosed timely, it could lead to a devastating outcome. computed tomography (ct) scan is the gold standard technique to diagnose mls in neurosurgical patients. the aim of our study was to find out association between transcranial sonography [tcs] and ct scan in assessing midline shift in patients with tbi. in this prospective ongoing study, adult patients ages - years, of either gender, with tbi were included. demographic details were noted. all patients underwent ct scan, followed by tcs. mls on tcs was determined using standard technique. we noted the mls on ct scan and time window between ct scan and tcs was also measured. consciousness was assessed using glasgow coma scale (gcs) and gcs -pupil [gcs-p] scales. descriptive data are given as mean (sd) or number. spearman's correlation test was used to detect relationship between gcs and mls assessed by ct scan and tcs, and also gcs-p. the value of p< . was considered significant. a total of neurosurgical patients were studied. male to female ratio was : . the age was [ . ] years with weight of . [ . ] kg. ten patients had gcs< . the mean value of mls measured by tcs - . , p = . ). the correlation between tcs and ct scan with gcs was in significan respectively. however the value of gcs- in patients with tbi, mls can be successfully assessed using bedside, non-invasive and non-radioactive monitor tcs when compared to a ct scan. there is a good correlation between gcs and gcs -p. early post-tbi seizures are reported to occur within hours and between days - following tbi in . % and . % patients, respectively. early seizure prophylaxis with phenytoin in severe tbi patients is drugs with better safety profile have emerged as potential alternatives. the objective was to describe seizure prophylaxis practices in critically ill tbi patients. we conducted a retrospective observational study of adult trauma icus. we included consecutive adult icu patients with moderate and severe tbi admitted between jan and dec . data were collected using standardized forms. our primary outcome was the incidence of seizure prophylaxis use. we included patients with a moderate ( %) or severe ( %) tbi. the majority were men ( . %) with mean age of . (sd . ) an ( %) and mva ( %). a total of % required invasive icp monitoring. a total of patients ( %) received early seizure prophylaxis, % for moderate and % for severe tbi. phenytoin, levetiracetam or their combination were used in ( %), ( %) and ( %) of cases, respectively. twelve patients ( %) were previously treated for pre-existing epilepsy. a total of ( %) patients experienced a seizure ( at the trauma scene, in er, in icu and on the ward). among the severe tbi patients in icu for days or more, anticonvulsants were continued for the recommended days in % of cases. early seizure prophylaxis is inconsistently used in severe tbi patients in canada. phenytoin still remains the agent most used. despite the current recommendations, % with severe tbi did not receive prophylaxis and % for a shorter period than days. raised icp persistently in severe tbi patients may be detrimental. however, chest physical therapy (cpt) is equally necessary for preventing secondary factors influencing the risk in these patients. this study was intended to observe the impact of short-term rise in icp with manual cpt in severe tbi patients on outcome along with hemodynamics. this was a prospective, observational trial on adult patients, of either sex, aged - years, with severe tbi, on mechanical ventilatory support with continuous icp monitoring, and receiving cpt on regular basis, included in this study. the cpt was applied for minutes' duration and repeated after an interval of hours in between for a total sessions in a day. the measurement measured intracranial pressure, cerebral perfusion pressure, heart rate, mean arterial pressure (from start of the intervention until min after the intervention at min interval each), and gcs after each session of cpt along with final outcome/gos at the time of discharge and months. the rise in median intracranial pressure of . (- . , . ) and median cerebral perfusion pressure of . (- , . ) was significantly higher during intervention and after intervention phase. in contrast, a median heart rate rise of . ( . , . ) and mean arterial pressure rise of . ( . , . ) were comparable. however, in patients with high baseline icp (> mmhg), poor outcome was noted in terms of low gose ( , ), and higher mortality ( . %) at hospital discharge or months after injury. significant increase in icp in severe tbi patients post cpt for minutes at a time (total minutes each day) was not tolerable in this cohort. moreover, we observed significantly low gose in patients with sustained intracranial hypertension. the effect of manual technique of cpt on final (long-term) neurological outcomes remain inconclusive but with favorable respiratory outcome. survivors of moderate and severe traumatic brain injury (mstbi) require substantial care, much of which is provided by friends and family. we sought to describe the experience and unmet needs of survivors and their informal caregivers follow mstbi, particularly related to care transitions. this study was conducted in two intensive care units (icus) at a level trauma center. we conducted qualitative, semi-structured interviews with both patients and informal caregivers of mstbi survivors at hours, one month, three months, and six months post injury. informal caregivers were defined as friends or family who planned to provide care for the patient. patients were years or older with an mstbi, and not expected to imminently die of their injuries. eighteen patient-caregiver dyads were enrolled. one patient died within hours. at hours, caregivers were interviewed; at one-month caregivers were interviewed; at three months caregivers and one survivor were interviewed; and, at six months caregivers and seven survivors were interviewed. three themes were identified in the qualitative analysis of caregiver interviews: caregiver burden, caregiver health related quality of life, and caregiver need for information and support. experiences varied depending on time since injury, discharge disposition, functional neurologic outcome, caregiver access to resources, and likely multiple other additional factors. interviews with survivors were not insightful secondary to post-traumatic amnesia. this study provides new information about the experience of informal caregivers during the six months after their friend or family member survived an mstbi. caregivers reported that needs evolved over time. at three to months, few moderate to severe tbi patients were well enough to be interviewed, and information obtained by survivors was not insightful. interventions to promote caregiving may be a substantial opportunity to improve patient and caregiver-centered outcomes following tbi. vasospasm following traumatic brain injury (tbi) has a high incidence and a detrimental effect on the neurological prognosis. yet, it remains a neglected, poorly understood phenomenon and there are no guidelines for its management. herein we present a case of severe vasospasm following tbi that caused secondary delayed cerebral ischemia (dci). we further appraised the current literature aiming at identifying predictors of vasospasm in tbi. a y/o white woman presented to the hospital after a mechanical fall resulting in mild tbi with associated subarachnoid hemorrhage (sah). glasgow coma scale (gcs) at presentation was , with no neurological deficits. a non-contrast ct head revealed diffuse bilateral fronto, parietal and temporal sah without evidence of aneurysm or vascular malformations on ct angiogram (cta). toxicology screens were negative. at hours from tbi patient developed acute severe headache. a repeated cta showed right internal carotid artery (ica) and middle cerebral artery (mca) vasospasm with no ischemia identified on mri brain. patient was started on nimodipine. on day- patient developed acute left side hemiparesis and neglect with neuroimaging evidence of a complete right mca infarct. hemodynamic augmentation therapy was initiated with partial improvement of deficits. patient subsequently developed hemorrhagic conversion of the right mca infarct. on day- neuroimaging revealed resolution of vasospasm. patient had residual left side neglect and anosognosia. in line with prior literature our patient developed vasospasm in the large intracranial vessels, at hours from the tbi and earlier than in aneurysmal sah. however, differently from previous reports, gcs at presentation was > , age was > and despite vasospasm developing later than hours it was not associated with good outcome. eded to identify accurate predictors of vasospasm following tbi with secondary dci that could improve detection and management of this detrimental phenomenon. therapeutic hypothermia and/or cooling therapy has been hypothesized to have benefits in patients with traumatic brain injury (tbi). several systematic reviews (sr) are being performed to address this question, but their results are inconsistent. the objective of this study was to assess the methodological quality of sr that included randomized clinical trials (rcts) that assessed the effects of therapeutic hypothermia and/or cooling therapy in patients with tbi. a critical appraisal study was performed in order to assess any sr that fulfilled the inclusion criteria. an unrestricted search of the literature was carried out in march at four major electronic databases (medline, embase, lilacs and cochrane library). two independent reviewers selected the studies, extracted the data and appraised the methodological quality of the included sr using the amstar- (a measurement tool to assess systematic reviews) tool. an overall assessment of the confidence in the results was performed using the checklist available in amstar- website (https://amstar.ca/amstar_checklist.php). the confidence of the results may be graded as high, moderate, low or critically low. this grading is based on the adequacy of the sr to the domains of the amstar- . the search strategy retrieved references. after the selection process, sr were included. the sr were published between - and included to rcts. the overall confidence in the results from included sr was graded as critically low in . %, low in . %, moderate in %, high in . %. a high number of sr addressing similar clinical questions were published in a short period of time. the methodological quality was adequate in only few sr. clinical practice guidelines should considered this result when choosing the evidence synthesis to recommend for practice. neurogenic pulmonary edema (npe) is a clinical syndrome characterized by acute onset after central nervous system injury. the aim of this study was to investigate the clinical features of npe in patients with subarachnoid hemorrhage (sah). the authors retrospectively analyzed a total of patients with sah who were treated at our hospital from april to september . of these patients, were included in this study after the application of predefined exclusion criteria. patient demographics, aneurysm size and location, clinical characteristics, and patient outcomes were reviewed and compared between an npe and a non-npe group. sixteen patients ( . %) presented with npe at admission. among them, patients ( . %) recovered from npe immediately, and ventilatory support was withdrawn within days from onset. a univariate analysis showed that patients with npe were of younger age (p= . ), had a higher rate of vertebral (p= . ), and lower systolic blood pressure on admission (p= . revealed significant differences in the frequency of vertebral artery dissection (odds ratio (or) . , % ci . -- . , p= . ) between the groups with and without npe. no significant group differences were found in other factors, including heart rate, neurologic outcomes at discharge. vertebral art factors for npe. however, neurologic outcomes at discharge did not differ between groups, suggesting that poor outcome due to npe could be reduced by appropriate diagnosis and treatment. antibiotic-impregnated catheters (aic) are recommended for the prevention of ventriculostomy-related infections (vri). other antibiotic prophylaxis strategies following external ventricular drain (evd) placement vary widely by institution. the role of systemic antibiotics for this indication remains controversial. we retrospectively reviewed the charts of all patients having an evd placed between january , and december , . after excluding patients who died or were discharged within hours of evd placement or had an evd placed due to suspected meningitis, patients were categorized into the periprocedural (p) or no periprocedural (np) antibiotics group. patients were determined to have a vri if catheter and up to days after catheter removal. mann-whitney u test was used to analyze descriptive data and baseline demographics. chi-squared models were used to analyze the incidence of infection. included in the no periprocedural antibiotics group (age [ - ] years; % male) and were included in the periprocedural antibiotics group (age [ - ] years; % male). the most frequent indications for evd were subarachnoid hemorrhage (sah) [np: n= ( %), p: n= ( ), p< . ], intracranial hemorrhage (ich) [np: n= ( %), p: n= ( %), p= . ), and other, which included colloid cysts and tumors [np: n= ( . %), p: n= ( %), p< . ]. there were infections in the no periprocedural antibiotics group compared to in the periprocedural antibiotics group (p= . ). the most common pathogen was coagulase-negative staphylococci (n= , %). the use of periprocedural systemic antibiotic prophylaxis did not significantly reduce the incidence of vri. periprocedural systemic antibiotics may not be necessary in the setting of antibiotic impregnated catheters to reduce the incidence of infection. cerebral artery vasospasm is a rare complication of craniopharyngioma resection but can have life altering consequences including delayed cerebral ischemia if not quickly recognized and managed appropriately. we present a case of craniopharyngioma resection in a year old male complicated by refractory vasospasm and its management with intraventricular nicardipine. data regarding the operative management, time course, vasospasm and management was accessed retrospectively after patient discharge. a year old male with recurrence of a craniopharyngioma presented with left eye vision loss and was admitted to the neurosciences intensive care unit after transsphenoidal resection. intraoperatively, the tumor was noted to be adhered to the posterior communicating artery and the left anterior cerebral artery. dense invasion into the hypothalamus was noted. this portion was carefully resected to avoid progressive lethargy. computed tomography angiography revealed new mild narrowing of the left anterior and middle cerebral arteries and bilateral posterior cerebral arteries consistent with vasospasm. the patient was treated with a vasospasm bundle including nimodipine, euvolemia, and blood pressure augmentation. over the next twenty days, the patient continued to have a variable amount of vasospasm despite aggressive medical and intra-arterial management. on post-operative day . nicardipine was then infused into the evd once a day for days, resulting in rapid and sustained improvement in vasospasm. the mechanism of vasospasm following skull base tumor resection is unknown. presence of blood in the operative bed, direct surgical injury to the blood vessels, hypothalamic dysfunction and the release of inflammatory chemicals have all been proposed. treatment remains similar to treatment used in sah, utilizing nimodipine, euvolemia, blood pressure augmentation and intra-arterial verapamil. this case demonstrates the effectiveness of intraventricular infusion of nicardipine on refractory vasospasm. to present a rare case of bilateral internal carotid artery (ica) aneurysms presenting as trigeminal neuralgia (tn), with good outcome post surgical treatment. a -year-old woman presented with disabling tn for year, exclusively affecting the right maxillary and mandibular divisions. symptoms did not abate with trial of adequate doses of gabapentin, duloxetine, oxcarbazepine and indomethacin. thin-cut magnetic resonance imaging (mri) brain with and without contrast showed rare contact with wide-necked aneurysms of bilateral petrous-cavernous icas producing prominent mass effect on bilateral adjacent trigeminal nerves. carotid arteriogram redemonstrated ica aneurysms with left measuring . mm x . mm and right measuring . mm x hours post procedure, tn had completely resolved. patient was started on aspirin mg and clopidogrel mg daily and is being tentatively planned for intervention on left aneurysm. on her month follow-up appointment with neurology, she reports no recurrence of tn. in cases of aneurysmal causes of tn, presence of bilateral aneurysms causing mass effect on the trigeminal nerve at its root is a rare occurrence and needs high clinical suspicion. due to the high risk of rupture associated with giant and symptomatic aneurysms, treatment should be expedited and aggressive in order to not only address symptomatic tn but also to avoid the risk of aneurysm rupture in the future. surgical clipping and endovascular coiling with or without stenting has demonstrated remarkable symptom relief in reviewed literature for other types of intracranial aneurysm. moyamoya disease is a chronic cerebrovascular disease characterized by spontaneous and progressive stenosis or occlusion of the internal carotid artery and its branches. revascularization procedures have been shown to improve cerebral hemodynamics and decrease the risk of strokes, but several postoperative complications are known to occur. we present a case with a fairly rare complication with characteristic radiological findings after surgery. a -year-old girl with moyamoya disease underwent left superficial temporal artery (sta)-to-middle cerebral artery (mca) anastomosis with encephalo-duro-myo-synangiosis (edms), and did right sta-mca anastomosis and edms one year after the initial surgery. the procedures were uneventful and the occlusion time was minutes. she recovered from the anesthesia without neurological deficit, and mri on postoperative day (pod) demonstrated no ischemic lesions and patent bypass, although swelling of the temporal muscle attached to the brain surface was noted. on postoperative day , she experienced a transient neurological event (left hemiparesis). magnetic resonance imaging revealed large cortical and subcortical hyperintense lesions in the middle cerebral artery territory on diffusion-weighted imaging and apparent diffusion coefficient imaging. subsequently, the radiographic findings improved within several days with resolution of the symptoms. revascularization surgery for improving a patient's hemodynamics can prevent the development of strokes, but is known to be associated with perioperative cerebral infarction and cerebral hyperperfusion causing transient neurological deterioration, delayed intracerebral hemorrhage, and vasogenic edema.this case is a reminder that hemodynamic complications can develop subacutely in patients who have undergone successful revascularization for moyamoya disease. the radiological features and mechanisms of this rare condition associated with revascularization surgery for moyamoya disease are discussed. vasospasm with delayed cerebral ischemia is a rare but known complication of endoscopic transsphenoidal resection of pituitary adenoma. this complication has rarely been reported in cases of -arterial treatment have been favorable in some cases. electronic medical record review. the patient is a year old male who underwent subtotal resection of pituitary adenoma via an open right fronto-temporal approach. eight days post-resection he developed progressive headache and leftsided weakness which acutely worsened the following day. his nihss on presentation was , consistent with right mca syndrome. ct brain showed mass effect in the right frontal lobe with . mm midline shift. cta showed sluggish flow through right m branch suggestive of vasospasm. he was taken to cerebral angiogram post-op day and received right ica intra-arterial verapamil and right ica and mca angioplasty. he was started on nimodipine following the procedure. his exam improved significantly over the course of - days. he was discharged home on verapamil mg q hours. at three month follow-up his nihss was and his modified rankin scale was . in the case we present, the patient received intra-arterial treatment with verapamil and angioplasty - days after onset of symptoms. despite delayed presentation the patient ultimately achieved a favorable functional status. vasospasm and stroke post-pituitary tumor resection are complications of which patients should be adequately informed, especially when considering the possibility of good functional outcome with intraof this potentially debilitating and life-threatening complication and attention should be paid to utilizing techniques for early detection of vasospasm. neuromonitoring is an essential part of the management of neurocritical patients. many icus in developing countries manage their patients without monitoring icp. intensivists play a vital role in clinical judgments to manage their patients. raised icp are handled either by medical management or surgical procedures like decompressive craniotomy. the study aimed to see the outcome of patients with raised icp and compare medical vs surgical management in these patients without monitoring icp. a retrospective observational study was conducted among patients admitted from january to december in the icu of dhaka medical college hospital, bangladesh. patients who had etiologies of brain code, clinical presentations and or radiological findings consistent with raised icp were included. patents were grouped into neurosurgical and medical management groups. length of icu stays and mortality were observed. student's t-test and chi-square tests were used to see the statistical significance. total of patients was selected. mean age was . ± . years, and . % were male. traumatic brain injury was the most common cause of raised icp ( . %) among selected patients. . % of patients were managed medically, and neurosurgical procedures managed . % of patients. length of icu stay was higher in neurosurgical patients compared to medical management group ( . ± . vs . ± . ; p= . , non-significant). mortality was higher in neurosurgical patients compared to medical management group ( . % vs . %; p= . , non-significant). mortality was also higher in traumatic brain injury patients who underwent neurosurgery compared to medical management ( . % vs %; p= . , non-significant). neurosurgical management didn't show a better outcome in patients with raised icp when monitoring was unavailable in a resource-limited icu. chronic kidney disease (ckd) independently increases the risk of stroke and burden of ischemic small vessel disease (svd). effects of ckd on intracranial hemodynamics remain poorly defined. this study compared svd and a transcranial doppler (tcd)-based marker of intracranial vascular resistance (pulsatility index, pi) in post-stroke patients with and without ckd. within three months of a stroke. anterior and posterior circulation pi (aca, mca, and pca) significantly correlated with mri lesion volume in all patients. ckd strongly correlated with higher distal resistance (median ckd aca pi . in patients with recent stroke, mri svd volume is significantly associated with anterior and posterior circulation pi. significantly higher svd lesion burdens and anterior circulation pis were observed in patients with ckd. ckd is an independent determinant of increased intracranial vascular resistance in both anterior and posterior cerebral circulations. atrial fibrillation is associated with an increased risk of stroke and systemic embolism. we investigated the prevalence of coexisting subdiaphragmatic visceral infarction (sdvi) in patients with acute ischemic stroke due to atrial fibrillation and also evaluated independent factors of acute sdvi. we enrolled a consecutive series of acute ischemic stroke subjects with atrial fibrillation between mra or cta were excluded. all subjects were prospectively examined using abdominal mr imaging at . t and transthoracic echocardiography (tte) within days of onset. a multivariable logistic regression analysis with predefined variable (age and sex) and the potential confounders that were associated with sdvi i the mean age was . ± . years ( % males). onset-to-abdominal image time was . ± . days. among patients, acute coexisting sdvi ( renal and splenic infarctions and superior mesenteric artery occlusion) were found in patients with acute ischemic stroke and atrial fibrillation. twelve patients had a chronic sdvi; renal and splenic infarctions. no hepatic and bladder infarction was shown. severe significantly associated with the coexistence of acute sdvi and acute ischemic stroke attributed to atrial fibrillation in the logistic regression model. (adjusted or, . ; % ci, . - . ; p = . ). there was a significant relationship between the presence of acute sdvi and severe left atrial remodeling in acute ischemic stroke patients attributed to atrial fibrillation. based on these results, we suggest that abdominal mr imaging for evaluating coexisting acute sdvi should be considered in patients with acute ischemic stroke due to atrial fibrillation, especially with left atrial enlargement on tte. patients with large hemispheric infarction are likely to accumulate chloride due to commonly used hypertonic saline for lowering elevated intracranial pressure. however, the effect of chloride burden on clinical outcomes in these patients is not well studied. this study aims to investigate the impact of maximum serum chloride concentration during admission on in-hospital mortality in critically ill patients with large hemispheric infarction. we conducted a retrospective observational study of patients with large hemispheric infarction who were admitted to the neurocritical care unit, between march and june . patients were excluded if they had baseline creatinine clearance less than ml/min, required neurocritical care for less than hours. multivariable logistic regression models were used to evaluate the association of maximum serum chloride concentration during admission with in-hospital mortality. of eligible patients, ( . %) were died in hospital. compared to patients who survive to hospital discharge, those who died in hospital had higher maximum serum chloride level during admission ( . ± . vs . ± . , p< . ). each mmol/l increase in maximum serum chloride concentration was associated with increased risk of in-hospital mortality with an odds ratio of . ( % ci, . - . , p< . ). after adjusting for confounders including acute physiology, age, chronic health evaluation ii (apache ii) score, baseline serum glucose, base deficit, use of mannitol, hypertonic saline, therapeutic hypothermia, and incidence of acute kidney injury, maximum serum chloride level remained an independent risk factor associated with in-hospital mortality (adjusted odds ratio for every mmol/l increment, . ; % ci, . - . , p= . ). higher maximum serum chloride concentration was associated with higher in-hospital mortality in critically ill patients with large hemispheric infarction. these results suggest serum chloride level should be monitored as high chloride burden may cause poor outcomes on those populations. patients with acute ischemic stroke caused by large vessel occlusion may receive both ct-angiogram (cta) and digital subtraction angiogram in the process of evaluation and management of restoring perfusion. neither aha/asa stroke/imaging guidelines address indications for transcranial doppler (tcd) and/or carotid duplex ultrasonography (cus) in early stroke evaluation and most patients do not receive additional cerebrovascular imaging after reperfusion. we investigated the clinical utility of performing tcd/cus after reperfusion in guiding post-acute care stroke management. we reviewed inpatient ischemic strokes admitted to a comprehensive stroke center in . of these had tcd/cus done and had cta done prior to tcd. of these underwent either tissue plasminogen activator or thrombectomy for reperfusion. these cases were reviewed by two experts (kh, qv), who were blinded to each other, to determine if tcd/cus provided any added value after cta affecting patient management. a nominal group process was performed, using a third blinded expert (as) in case of disagreements to reach consensus. the reviewers reported cases where tcd/cus provided incremental value for management. value added by tcd/cus, as noted by experts, included detection of residual/recurrent mobile thrombus requiring anticoagulation, confirmation of reperfusion in a symptomatic patient, distinguishing between carotid stenosis and occlusion by showing string sign on carotid ultrasound, confirming hemodynamic significance of angiographic stenosis helping triage the need for stenting/endarterectomy, and new information on chronicity of carotid stenosis based on collateral flow patterns hence deferring further intervention. our experience shows a significant added value of performing tcd/cus in more than % of stroke cases in our review. the incremental information provided by ultrasound-guided further evaluation and management decisions in most of these patients. axons of the wallerian degeneration slow (wlds) mutant mice survive weeks after traumatic and ischemic nerve injuries. prior characterization of the mutant wlds protein showed that it is a fusion gene product between the non-functional, truncated n amino acids of ube b and full functional sequence of nuclear nmnat , a rate-limiting enzyme in nad+ synthesis. however, the molecular mechanisms by which the mutant wlds protein protects axons from stroke injuries remain unclear. we sought to understand how wlds is able to robustly protect axons from ischemic injuries, and in doing so possibly identify novel therapeutic targets to attenuate axonal loss in stroke. we first sought to understand the temporal and spatial requirements of wlds activity in protecting axons from ischemic injuries. to achieve this, we developed a novel tool to conditionally regulate the expression of wlds protein by modulating its post-translational protein stability. using this powerful technique, we asked how conditionally "turning on" or "turning off" wlds activity affects axonal survival following ischemic insults. moreover, as the only known function of wlds is in catalyzing nad+ synthesis, we designed a high-throughput pharmacological screen for nad+ analogs to evaluate whether the nad+ synthetic pathway mediates wlds axon protection. we found that conditional expression of wlds protein within - hrs after stroke injuries was necessary and sufficient to confer axonal survival, whereas turning off wlds activity post-injury abolished axon protection. this indicates that wlds activity is a local event in the axon, and exerts axonal protection within a critical time window even after the injury has occured. we further observed that exogenous addition of nad+, but not its precursors or immediate metabolites, was sufficient to confer axonal protection, while attenuating nad+ levels abolished wlds axon protection. this suggests that nad+ is a molecular mediator of wlds axon protection in stroke. we showed that wlds activity is a local axonal event, and uncovered a critical window of - hrs poststroke injury in which the course of axon degeneration can be halted or even reversed in mammalian neurons. moreover, we showed that this process is mediated by rising nad+ levels in axonal compartments through a novel nad+ dependent cell signaling cascade. these findings provide powerful insight into the molecular bases of wlds activity, and uncover new therapeutic targets to delay and potentially even reverse axon degeneration in stroke. unruptured intracranial aneurysm (uia) are incidentally found on the computed tomography (ct) or magnetic resonance angiography in about % of patients. because of the risk of intracranial hemorrhage (ich), the presence of uia is contraindication to intravenous thrombolysis for acute stroke. as noncontrast ct (ncct) is mostly used for thrombolytic therapy and uia is difficult to diagnose using a ncct, uia may be found after thrombolysis. among the patients with acute ischemic stroke treated with intravenous thrombolysis for consecutive years in one stroke center, patients diagnosed with uia by ct angiography immediately after thrombolysis, were enrolled. characteristics of uia and clinical outcomes such as ich and modified rankin scale (mrs) score at discharge were analyzed. among patients treated with intravenous thrombolysis, ( . %) patients were diagnosed with uia. ally relevant artery and patients an aneurysm less than mm in diameter. the median value of the initial national institutes of health stroke scale score was (range - ). the median mrs score at discharge was (range - ). there was no patient who had ich or aneurysm rupture during admission. intravenous thrombolysis could be safe and necessary to the patients with hyperacute ischemic stroke and incidental uia. recent studies suggest that variations in the constitution of the gut microbiome contribute to atherosclerotic burden and cardiovascular disease. while many gastrointestinal (gi) diseases are known to cause disruption of the normal gut microbiome in humans, the clinical impact of gi diseases on subsequent vascular disease remains unknown. we conducted an exploratory analysis evaluating the relationship between gi disease and ischemic stroke or acute myocardial infarction (mi). we performed a retrospective cohort study using claims between - from a nationally composite of ischemic stroke or acute mi. stroke and mi were assessed separately as secondary outcomes. in an exploratory manner, we evaluated the association of each gi disorder in the icd- -cm classification with our outcomes. we then categorized individual gi disorders by anatomic location, disease chronicity, and disease mechanism. we used cox proportional hazards models to examine associations with adjustment for demographics and established vascular risk factors. since this was an exploratory, hypothesis-generating study, we report only notable positive associations. among approximately , , beneficiaries, the following gi disorders were associated with an increased risk of subsequent ischemic stroke: gastric ulcer (hr, . , % ci, . - . ), duodenal ulcer ( . , . - . ), gastritis and duodenitis ( . ; . - . ), disorders of function of stomach ( . , . - . ), other disorders of stomach and duodenum ( . ; . - . ), gastrointestinal mucositis ( . ; . - . ), unspecified noninfectious gastroenteritis and colitis ( . ; . - . ) and gastrointestinal hemorrhage ( . ; . - . ). the following categories of gi disorders were associated with an increased risk of ischemic stroke: stomach disorders ( . ; . - . ), stomach and small intestine disorders ( . ; . - . ), ulcerative disorders ( . ; . - . ) and chronic gi disorders ( . ; . - . ). gi disorders were not associated with an increased risk of mi, and some demonstrated a reduced risk. several gi disorders were associated with an increased risk of ischemic stroke, but none were associated with an increased risk of mi to evaluate the relationship between serum neutrophil-to-lymphocyte ratio (nlr) levels and early neurological deterioration (end) in ischemic stroke patients with large-artery atherosclerosis (laa). we evaluated consecutive ischemic stroke patients due to laa between january and december within the first hours of admission. the nlr was calculated by dividing the absolute neutrophil counts by the absolute lymphocyte counts. among the included patients (n = ; male, . %; mean age, years), . % (n = ) had end events. in multivariate analysis, serum nlr level was independently associated with end (adjusted odds ratio, . ; % confidence interval [ . to . ], p = . ). visit time from symptoms onset, and insitu thrombosis and artery-to-artery embolization mechanisms were also found to be significant factors for end events. in the analyses regarding the relationship between serum nlr values and burden of vascular lesions, nlr levels were positively correlated with both the degree of stenotic lesions (p for trend = . ) and numbers of vessel stenosis (p for trend = . ) in a dose-response manner. we also compared the difference of serum nlr levels according to the stroke mechanisms from underlying vascular lesions. then, hypoperfusion and in-situ thrombosis mechanisms showed higher levels of nlr. however, only in-situ thrombosis mechanism had higher nlr values among the end groups compared to non-end groups (p = . ). serum nlr levels were associated with end events in ischemic stroke patients with laa mechanism. since nlr was also closely correlated with the relevant vascular lesions, our results indicated clues for underlying mechanisms of end events. transcranial doppler (tcd) can detect emboli in numerous cerebrovascular settings. although previous studies have suggested that microembolic signals (mes) may predict recurrent stroke, the practical significance of such findings remains unclear. this uncertainty has deterred the widespread use of embolic monitoring among clinicians. in a retrospective fashion, we investigated the real-world applicability of tcd by examining whether the presence of mes portends worsened clinical outcomes. we reviewed the charts of all ischemic stroke patients (n = ) who underwent mes monitoring from january to december . of the stroke subtypes reviewed, % were atheroembolic, % were cardioembolic, % were lacunar, % were dissection, % were hypercoagulable, % were cryptogenic, and % were due to other causes. +/- mes were detected in % of patients. mes were detected at an average of . +/- . db (with a detection threshold > . db). recurrent stroke was seen in % of patients (monitored over . +/- . days). patients with mes were more likely to have recurrent stroke ( % vs. %, p < . ), undergo a revascularization procedure ( % vs. %, p = . ), have a longer length of stay ( vs. days, p = . ), and have a discharge mrs - ( % vs. %, p < . ) compared to those without mes. multivariable logistic regression analysis showed that mes was an independent predictor of recurrent stroke (or . , % ci . - . ) and of poor discharge mrs - (or . , % ci . - . ) despite controlling for antithrombotic treatments and stroke subtypes. in the largest series of patients who underwent embolic monitoring with tcd, mes predicted ischemic stroke recurrence leading to worsened disability and prolonged hospital stays. given that mes can provide important prognostic information, tcd with embolic monitoring may be clinically useful in the workup of ischemic stroke. expanded patient eligibility for mechanical thrombectomy (mer) of acute ischemic stroke (ais) has resulted in a proportional increase of patients who require emergency angioplasty and/or stenting (eas) to achieve recanalization. post-stenting antiplatelet medication management continues to remain a challenge due to lack of immediate effect and rapid reversibility ideal for patients at high risk of stent thrombosis and hemorrhagic complications, especially after intravenous alteplase (tpa). cangrelor is an immediate-acting intravenous p y receptor inhibitor with rapid clearance and restoration of normal platelet within one hour of infusion termination. we describe our preliminary experience with administration of cangrelor in ais patients undergoing mer and requiring eas as rescue therapy. ten patients with ais who received cangrelor after mer were identified. median admission national tpa prior to mer. cangrelor drip was started immediately prior to eas. median duration of cangrelor drip was hours. dual antiplatelet was given a median time of hours before discontinuation of cangrelor. seven patients had repeat imaging at months confirming durable vessel patency and no restenosis. none of the patients experienced clinical deterioration, symptomatic intracranial hemorrhage, or recurrent strokes during the hospital stay. one patient underwent surgical decompression but did not develop any hemorrhagic complications. median mrs at discharge was , and median nihss at discharge was . in our case series, cangrelor was observed to be a safe alternative to oral antiplatelet drugs in the immediate perioperative period among ais patients who underwent mer and required eas, , including patients who received tpa and at high risk for malignant cerebral edema or hemorrhagic transformation who may require emergency surgical decompression. the response of the neonatal brain to hypoxic ischemic injury (hi) is developmentally specific therefore therapies for brain hi cannot be standardized across the ages. while arginases (arg; isoforms arg- /arg- ) are enzymes actively studied for their neuroprotective/neuroregenerative effects in various neurological conditions, in neonatal hi the arg effect remains unknown. to test the hypothesis that arg changes with neurodevelopment and after hi we exposed mice c bl/ (wild-type) to hypoxia-ischemia on postnatal day , as follows: permanent coagulation of left common carotid artery to induce ischemia, a h recovery period and exposure to % oxygen/balance nitrogen at °c for min to induce hypoxia. animals were perfused at h, h, h, h and day with % paraformaldehyde, brains were post-fixed, sectioned on a cryostat ( um) and examined histologically with cresyl violet stain to assess the degree of damage and arg spatiotemporal localization via immunohistochemistry. arg expression was measured by western blot and arg activity spectrophotometrically. arg expression and activity increase during development, however this increase is suppressed by hi. arg- expression increases on day after hi which corresponds to our findings of arg- accumulation at the penumbra site. cortical arg activity remains suppressed after hi, compared to that in the hippocampus, where it increases. spatiotemporally, arg- localizes into myeloid cells in cns. arg- expression increases in microglia as early as h after injury and remains elevated for a prolonged time. arg- is localized in pyramidal neurons of the indusium griseum, fasciola cinerea, neocortex and hippocampus (ca , ca ). arg- -expressing cells are damaged by hi, however they do not undergo spatial changes. microglial arg- strongly responds to hi and may play role in neuroinflammation and neuroprotection, while argand therapeutic potential of the arg-pathway in neonatal hi. sisco: helping stroke patients with thermasuit cooling trial is a phase study in ischemic stroke with rapid induction of hypothermia to within one hour. this patient had induction followed by early malignant edema requiring decompressive hemicraniectomy while c. this is the first report of hemicraniectomy in a therapeutically hypothermic patient. results y/o woman presenting with a left mca syndrome. initial imaging demonstrated left m occlusion. she received iv tissue plasminogen activator (tpa) followed by thrombectomy with tici recanalization within practice guidelines. she was enrolled in sisco trial. she was sedated with propofol, fentanyl, and versed for induction, reaching target temperature of degrees within minutes. she remained on sedation for shivering and temperature was maintained at degrees with the artic sun. imaging hours after stroke demonstrated completed infarct with edema, midline shift, and lateral ventricle effacement. hypertonic saline was initiated, and she underwent emergent decompressive hemicraniectomy. balancing the risk of worsening edema and coagulopathy caused by mild hypothermia, rewarming was initiated at . degrees c per hour. at the time of procedure patient was at . . a successful hemicraniectomy was performed without complications. six months demonstrated improvement with the patient returning home with modified rankin , and cranioplasty performed without complications. during sisco, an emergency decompressive hemicraniectomy for malignant mca syndrome was performed for a cooled patient without complication or increased bleeding. while therapeutic hypothermia has not shown an outcome benefit in previous clinical trials, these trials have had limitations rapidly reaching targeted temperature. this may have blunted the therapeutic effect. using thermasuit, patients are able to reach target temperature significantly faster. additional clinical trials are needed to determine if the therapeutic window for targeted temperature management in ischemic stroke patients improves outcome. iv rt-pa guidelines exclude therapeutically anticoagulated or thrombocytopenic patients. these exclusion criteria may limit thrombolytic therapy to patients who might benefit. the objective of this study is to determine if iv rt-pa is safe and whether it increases neurocritical care resource utilization in this patient population. retrospective analysis of iv rt-pa treated patients receiving oral anticoagulation (warfarin (inr > . )), novel oral anticoagulant (noac), therapeutic heparin, low-molecular weight heparin (lmwh), or with thrombocytopenia (platelets < k). patients were treated using smart criteria (consent obtained for off label rtafter treatment. increased neurocritical care resource utilization was defined as transfer from a primary to comprehensive stroke center solely for additional monitoring after off-label iv rt-pa use. patients were identified. patients received therapeutic warfarin and one had coagulopathy (unclear etiology); mean inr= . (range . - ). received therapeutic iv heparin, full dose ( mg/kg bid) lmwh, and therapeutic noacs. had thrombocytopenia (mean platelet count k). received intra-arterial (ia) rt-pa, and thrombectomy. there were sich ( . %); for all sichs there were mitigating factors that contributed (undiagnosed malignancy, adjunctive ia rt-pa, incorrect time of onset). two developed hematoma at the catheter site with no clinical effect. patient was transferred for the sole purpose of monitoring post off-label iv rt-pa. these data suggest that iv rt-pa can be safely administered in therapeutically anticoagulated and thrombocytopenic patients, and sich rates were similar to the ninds cohort. the use of iv rt-pa in these patients may increase eligibility for acute stroke therapy, particularly where ia therapy is unavailable. -pa in such patients does not appear to increase neurocritical care resource utilization though further study with a larger population is warranted. although proteinuria has been reported as a predictor of neurological deterioration, poor functional outcome and in-hospital mortality after ischemic stroke, scarce study investigated the relationship between proteinuria and the malignant middle cerebral artery infarction (mmcai). this study aimed to determine whether proteinuria is associated with the development of mmcai. patients with infarction in middle cerebral artery territory were reviewed. on admission, all patients underwent brain computed tomography (ct), the assessment of national institutes of health stroke scale (nihss) and alberta stroke program early ct score (aspects), and laboratory surveys, including urine analysis by using urine dipstick. patients with known intracranial lesions or possible urinary tract infection were excluded. patients with proteinuria were defined if urine dipstick demonstrates reading of + to +, while others were defined as patients without proteinuria. chronic kidney disease (ckd) was defined if either proteinuria or estimated glome identified. mmcai was determined if a progressive conscious disturbance or signs of uncal herniation were recorded with a midline shift > mm on a follow-up brain ct. we screened patients, and -five ( . %) patients developed mmcai, and ( . %) patients had proteinuria. patients with mmcai had a significant higher score of nihss, lower aspects, less likely being dyslipidemia, and more likely having ckd and proteinuria than patients without mmcai did. after adjustment for age, sex, dyslipidemia and aspects, patients with proteinuria (or= . , %ci= . - . , p= . ) and ckd (or = . , %ci = . - . , p= . ) had a signifi ml/min/ . m did not. in conclusion, proteinuria is associated with the development of mmcai. we suggest that proteinuria may be considered as a clinical predictor for the development of mmcai. although tpa has been shown to improve outcome in ischemic stroke across various etiologies, tpa is contraindicated in stroke secondary to septic emboli due to a significantly higher risk of bleeding. the goal of this study is to determine the safety and short-term outcomes of acute ischemic stroke patients who underwent mechanical thrombectomy due to septic emboli from infective endocarditis (ie). in this multi-center retrospective case series, we reached out to thrombectomy centers known to our principal investigator. we have so far collected data from hospitals across the us to look at outcomes after thrombectomy in patients who had an ischemic stroke from infective endocarditis. centers reviewed their database and did not have eligible cases. to date, we have collected a total of cases ( % male; average age ; % had a known history of ivdu). in % the valve implicated was bioprosthetic. % of the occlusions were m , with the remaining being the carotid terminus ( %) and m ( %). microbiology revealed that % were caused by streptococcus, % staphylococcus, % enterococcus, and % were polymicrobial. the average nihss on presentation was . . % had received tpa prior to the thrombectomy (of those, / were known to have ie). the average best nihss after thrombectomy was . (averaged across cases, the other case expired from new cardiomyopathy and multi-organ failure). % had hemorrhagic transformation (of those, / were tpa recipients). thrombectomy may be a safer and promising option in patients with ischemic stroke secondary to infective endocarditis. more data is required to compare the outcome of patients who received thrombectomy alone versus tpa followed by thrombectomy, and data collection is ongoing. therapeutic hypothermia may be an effective therapeutic measure for malignant cerebral infarction alternative to or in combination with decompressive craniectomy. the neuroimaging marker that suggests the favorable clinical course during therapeutic hypothermia is needed to predict the outcome and/or determine best and earliest timing to rewarm the patients. we included cases who received therapeutic hypothermia for malignant middle cerebral infarction in seoul national university bundang hospital between july and may . we measured hounsfield unit of ischemic core in serial computed tomography scans in each patient. the nadir of hounsfield unit of each patient was calculated. the difference of the nadir by the early clinical outcome (the survival at discharge) was analyzed. the mean age was . ± . and the male comprised . % (n= ). three patients underwent early decompressive craniectomy plus therapeutic hypothermia and patients received only therapeutic hypothermia. the mean target temperature was . ± . . a total of patients ( . %) survived at discharge. a total of computed tomography scans were analyzed (about scans per patient). the mean of the nadir hounsfield unit of each patient was . ± . in the deceased patients and . ± . in the survived patients, and the difference was statistically significant (p-value = . ) the nadir of hounsfield unit in the ischemic core was lower in the survived group than the deceased group in malignant ischemic stroke patients who received therapeutic hypothermia. the change in hounsfield unit in serial computed tomography scan may be used to estimate clinical course and optimal timing of rewarming or rescue craniectomy after therapeutic hypothermia. the volumetric analysis using semi-automated planimetry is currently being performed to elucidate this association further. mhz pulsed-wave transcranial doppler (tcd) increases the exposure of an intracranial thrombus to tenecteplase (tnk-tpa) and facilitates early reperfusion. the aim of the present study is to ascertain if tcd along with tnk-tpa could improve functional outcome in patients treated with tnk-tpa after acute ischemic stroke (ais). this is a single center, prospective, interventional study. patients with ais with national institutes of -tpa bolus) within hours of symptom onset, were randomly allocated ( : ) to either mhz pulsed-wave ultrasound for min. (sonothrombolysis)-intervention group or only tnk-tpa group. ultrasound was delivered using a mark head frame, immediately after the bolus of tnk-tpa. the primary outcome was improvement in the modified rankin scale score at days and . the secondary end points were the occurrence of symptomatic intracerebral haemorrhages and death. between january and march , patients were randomly allocated to the sonothrombolysis group and patients received only tnk-tpa. at the end of days, the sonothrombolysis group achieved mrs - in / ( . %) compared to / ( . %) in the tnk-tpa group. the p-value is . . the result is significant at p < . . the rate of sich and mortality were . % in each group. sonothrombolysis of patients treated with tnk-tpa for ais was feasible and safe, with some clinical benefits at days. the recanalization rates and outcome are better than studies done with alteplase. there was no increase in sich or mortality. tnk-tpa should be the preferred drug for thrombolysis in ais. the study should be carried out in multiple centers to see if the results of the present study can be validated. acute ischemic stroke is the second leading cause of death, especially if the patient did not receive the appropriate treatment geared towards a timely recanalization of the occluded vessels, including intravenous tissue plasminogen activator (iv t-pa) or endovascular thrombectomy. little emphasis is given to the augmentation of collateral flow to offset the deleterious effect of ischemia or lessen the progression of the penumbral tissue into infarction. we present our initial experience with such vasoaugmentation strategy in patients with acute ischemic strokes. we present o university. our series included patients with acute ischemic strokes. we excluded patients with a large vessel occlusion. all other patients were included regardless of whether they received iv-tpa or not. all patients had a ct angiogram including collateral imaging and ct perfusion study at baseline. after explaining to the patients or their next-of-kin, we started the patients on a standardized protocol of milrinone ( mcg/kg bolus followed by . mcg/kg/minute). outcome assessment was comparing the initial mrs and that of the mrs at discharge. chi square contingency analysis was used with a set level of significance of p < . . out of the patients, had good collaterals and had poor collaterals. one of those poor collaterals patient had good cross flow from pcom to the affected hemisphere, but still demonstrated poor collateral score. in our cohort, ( %) achieved good neurological outcome of mrs of or below with patients ( %) achieving a discharge mrs of . conclusions collaterals and small infarction core. the presence of cross flow wasn't helpful. the symptomatology of delayed cerebral ischemia (dci) after aneurysmal subarachnoid hemorrhage (asah) is variable and often challenging to detect, particularly in patients with poor-grade asah. we report severe symmetric quadriparesis as a previously unreported symptom of dci. a -yearwas significant for intact brainstem reflexes and withdrawal in extremities. initial treatments included aminocaproic acid and external ventricular drain insertion, followed by intra-aortic balloon pump placement for stress-induced cardiomyopathy. she subsequently underwent coiling of a ruptured left anterior choroidal artery aneurysm. on post-bleed day , she was noted to have new onset of decreased tone and minimal complex posturing to noxious stimulation in all extremities and severe inattention. transcranial doppler and digital subtraction angiography revealed moderate left greater than right middle cerebral artery and bilateral anterior cerebral artery vasospasm and she received balloon angioplasty and intra-arterial nicardipine twice. post intervention, her quadriparesis moderately improved but she continued to have decreased tone and delayed movement initiation. on post-bleed day , brain mri demonstrated infarcts in bilateral medial frontal lobes, bilateral basal ganglia & subinsular cortices. on day of discharge, she was able to spontaneously raise her left arm and legs, but only minimally moved her right arm to noxious stimulation. this case report adds severe symmetric quadriparesis to the myriad of possible clinical symptoms of dci after asah. awareness of this uncommon clinical presentation could lead to timely detection and management of delayed cerebral ischemia after asah and improved clinical outcomes. brain mri to determine infarct size is common in acute stroke management. many patients cannot undergo mri imaging due to instability, or imaging contraindications. a common ct head finding postthrombectomy is contrast extravasation, thought to be secondary to "leakage" of the blood brain barrier due to ischemia. we hypothesized that extravasation volume on post-thrombectomy ct scan correlates with final infarct size. using ct head as a proxy for final infarct size may help guide clinical decision making when mri scan is not possible. we retrospectively examined a prospectively collected, irb approved stroke code database from / / to / / . inclusion criteria included: anterior strokes that underwent thrombectomy, ct scan within hours of thrombectomy with contrast extravasation, a mri within days of the thrombectomy. demographics, diagnosis, imaging findings were extracted via chart review. we used the alberta stroke program early ct score (aspect) score, to approximate the area of contrast extravasation (ct) and area of dwi hyper intensity (mri). each region of extravasation on ct head was deducted from a score of , resulting in the "estimated infarct size (eis)". each region of mri dwi was was calculated. we demonstrated usefulness of aspect scoring for comparing infarct volume between ct extravasation and final dwi infarct size. post-thrombectomy contrast extravasation consistently underestimated final mri infarct volume by %. this relationship, if validated, may be useful to approximate mri stroke volume. dizziness is a vaguely-defined complaint involving the subjective experience of lightheadedness, disequilibrium, and room-spinning sensation. it is a frequently encountered problem in office visits and in the acute care setting, with approximately . million presentations to the emergency department annually. the differential diagnosis is broad, ranging from benign and of peripheral origin, to timesensitive and potentially fatal of central origin, including ischemic or hemorrhagic stroke and ms. it is estimated - % of patients with dizziness receive stroke diagnoses . despite the low percentage, diagnosis of posterior stroke is the one most feared to be missed by clinicians. we hope to establish a clinical scoring system for timely triage of presentation with dizziness. we retrospectively reviewed charts of patients admitted at hahnemann university hospital between and , following irb approved protocol. charts were chosen with primary inpatient admitting diagnosis: cerebral infarction due to thrombosis of basilar artery, dizziness and giddiness, and cerebral infarction due to embolism of post cerebral artery for a total of charts. patient charts were reviewed to identify predisposing factors, data points for each patient. of patients reviewed, were found to have infarctions involving the posterior circulation, . % diagnostic yield for stroke. we collected a total of data points to understand the disease process. predisposing factors identified were chronic kidney disease, diabetes, hypertension, and hyperlipidemia. surprisingly, previous stroke was not found to predispose to posterior fossa strokes. common exam findings on presentation were hemiparesis and hemisensory loss. statistical analysis is currently in process we discuss our results in the context of previous efforts aimed at developing clinical predictors for posterior fossa stroke in patients presenting with dizziness. high hir (hypoperfusion intensity ratio) is known to correlate with core size, infarct growth and worse clinical outcomes. traditionally larger infarcts have been associated with higher rates of malignant cerebral edema and need for decompressive hemicraniectomy. patients with high hir and malignant profile (tmax > s greater than % of penumbra) are associated with increased risk of malignant cerebral edema. as part of an ongoing study, we retrospectively identified all ais patients with lvo who underwent ctp imaging between january to june in our healthcare system within hours from symptom imaging studies (ct or mri) were analyzed. hir was dichotomized based on proportion of greater and less than . into malignant vs favorable profile and correlation for development of malignant cerebral edema and need for hemicraniectomy was analyzed using chi-square test of proportion for nominal variables and wilcoxon ranked sum tests for the (skewed) continuous and ordinal variables. a total of patients with lvo were identified with a median age of (iqr - ), nihss of . patients with high hir suggestive of a malignant profile (n= ), regardless of reperfusion, were associated with increased risk of malignant cerebral edema compared to those with a favorable profile (n= ) (p< . ). patients with malignant hir developed malignant cerebral edema compared to patients with favorable hir (rr= . , or= . ). patient with malignant hir underwent decompressive hemicraniectomy compared to none with favorable hir. higher hir and malignant profile, regardless of reperfusion, is associated with times increased relative risk of development of malignant cerebral edema. these patients benefit from close monitoring and aggressive care for malignant cerebral edema including osmolar therapy and potential surgical intervention. we present the case of a patient with basilar artery dissection with thrombus, who underwent successful mechanical thrombectomy with stenting and was ambulatory at discharge. patient is an -year-old female with past medical history of ehler's danlos disease who presented with left sided weakness after being found down by her family. nihss on arrival was (left sided weakness / ), bp / , glucose . her cta showed a basilar angiography was notable for a basilar dissection with reocclusion, which was treated with enterprise stent placement with tici reperfusion. mri post intervention revealed right pontine infarct, punctate infarcts in cerebellum. her exam at discharge was notable for improvement in her left sided strength, at / . she was subsequently discharged to inpatient rehabilitation. mechanical thrombectomy and stenting of the basilar artery remains a largely experimental procedure, with few guidelines and little data on outcomes. we present a case of a patient with a basilar dissection who at discharge was ambulatory and near baseline. blood viscosity (bv) is the intrinsic resistance of blood to flow and characterizes blood stickiness. several clinical and epidemiologic studies demonstrated an association between bv and the occurrence of major thromboembolic events. though bv appears significantly higher in cases of lacunar or cardioembolic strokes, relationships with demographic and laboratory findings during the acute stage of ischemic stroke are unknown. we investigated the relationship between baseline characteristics and bv within hours of symptom onset in patients with acute ischemic stroke. we enrolled patients aged years or older with documented histories of ischemic stroke or transient ischemic attack within hours of symptom onset. a scanning capillary-tube viscometer (sctv) (hemovister, pharmode inc., seoul, korea) was used to assess the whole blood viscosity (wbv). the mean age was . ± . years and . % were female. of patients, . % had a history of hypertension; %, diabetes; . %, hypercholesterolemia; . %, coronary artery disease; and %, stroke. additionally, . % were current smokers. sixty-one ( . %) patients were taking antithrombotics regularly. multiple linear regression analysis revealed that hematocrit was positively related with increased bv and prior antithrombotic use was related with decreased bv. hematocritadjusted partial correlation demonstrated that prior antithrombotic use was significantly associated with decreased bv. prior antithrombotic use is significantly associated with decreased blood viscosity within hours of symptom onset in patients with acute ischemic stroke. our findings indicate that antithrombotic medications prevent stroke by inhibiting platelet function and by changing the hemorheological profile. ischemic stroke accounts for % of stroke and is the second cause of death in brazil. the decision regarding thrombolytic treatment depends on clinical history, physical examination, and imaging. one challenge is the exclusion of situations called stroke mimics (sm). a total of patients admitted to the stroke unit were prospectively analyzed. they received a full clinical and laboratory evaluation for the diagnosis of stroke and aiming to rule out the sm possibility. the study looked up for stroke etiology, demographical and epidemiological data, stroke-specific scales, sis, the occurrence of seizures and blood pressure lower than mmhg at admission as variables of interest. the prevalence of sm and the use of thrombolytic therapy in this situation was concordant with medical literature. the risk associated with anticoagulation in acute ischemic stroke (ais) is uncertain. anticoagulation is generally not indicated for early secondary stroke prevention, but may be considered in certain conditions. we assessed the use of a weight-based institution-specific heparin nomogram in ais patients. -new haven hospital who received anticoagulation with a continuous heparin infusion in the setting of ais over a -month period. anticoagulation was initiated with an initial infusion rate of units/kg/hr without bolus, with subsequent increases in the infusion rate by unit/kg/hr, based on aptts obtained every six hours until two subsequent aptts were within goal range. we collected indication for anticoagulation, dose at therapeutic aptt, time to target aptt duration of anticoagulation, transition to oral anticoagulant therapy, cerebrovascular/cardiovascular events and major and minor bleeding complications. patients were included in analysis, % of which were male, with a mean age of ± years and an average weight of . ± . kg. indications for ac were: intracardiac thrombus ( %), (sub)occlusive intra-arterial thrombus ( %), arterial dissection ( %), thromboembolic events and hypercoagulability ( %). the median time between diagnosis of stroke and initiation of anticoagulation was hrs mins. the time to goal aptt was ± . hours with a mean infusion rate of units/kg/hr at time of goal aptt. % of patients were transitioned to an oral anticoagulant and % of patients experienced a cerebrovascular event while on heparin infusion. our institution-specific heparin nomogram provides a safe anticoagulation strategy in ais, but with a longer time to reach therapeutic goal aptt range compared to previously published data. a more aggressive titration strategy with consideration of a higher infusion start rate may facilitate reaching the target aptt within a shorter time frame. vertebral artery dissection (vad) is one of the most common identifiable causes of ischemic stroke in young age patients forming intramural hematoma. vad may occur spontaneously or secondarily to trauma, infection, or underlying arteriopathy. we report cases of spontaneous bilateral vad presenting with lateral medullary infarction a -year-old woman transferred to the emergency room with vertigo. days ago, she felt severe headache on the left temporal area. on neurologic examination, ptosis, facial hypesthesia, dysmetria on the left side were noted, and dysarthria, dysphagia, right beating nystagmus were noted also. she had no past medical history and no familial history of stroke or cephalo-cervical trauma. brain mri depicted acute infarction in left lateral medulla and dissecting aneurysm of right va and near occlusion of left va on carotid enhanced mra. disease was normal. she was treated with warfarin. a -year-old man visited to the emergency room with headache on the right occiput. on neurologic examination, ptosis, miosis, facial hypesthesia, dysmetria on the left side and hemibody hypesthesia on the right side were noted. he had no trauma history or risk factors for stroke except hypertension. brain mri depicted acute infarction in right lateral medulla and dissecting aneurysm in the bilateral vertebral arteries on carotid enhanced mra. laboratory tests showed no abnormal findings. all results were normal for young age stroke evaluation. he was treated with warfarin. although unilateral or bilateral vad due to trauma or underlying medical conditions has been reported, spontaneous bilateral vad is rare. it can present with lateral medullary syndrome or nonspecific symptoms such as headache only. physicians should include vad in the differential diagnosis for patients presenting with brainstem neurologic abnormality or headache, especially young patients. cerebrovascular complications (cvcs) occur in - % of patients with infective endocarditis (ie) and manifest as ischemic stroke, meningitis or cerebritis with % occurring during first weeks of treatment. ct or mri brain can diagnose cvcs but are insensitive early on, precluded in critically ill patients and only demonstrate the sequelae. transcranial doppler (tcd) can identify high-intensity transient signals (hits) associated with cerebral microembolization and may have a role in detecting emboli and preventing cvcs in ie. retrospective chart review and literature review. we found patients with strokes caused by ie at our institution from / to / . tcds were obtained on patients, abnormal for cerebrovascular abnormalities. only patients had minute emboli monitoring performed of which one revealed hits. though mri studies have shown microemboli in % of ie patients (duval ann intern med ), we only found studies using hits on tcds as indicators of stroke risk in ie. in a prospective study of patients with left-sided ie, cvcs occurred in % of patients with hits on tcds versus % of patients who did not (p= . ) ( lepur scand j infect dis ). two studies investigated and patients with cardiac sources of embolism and documented occurrence of hits in % and % of subjects, respectively, with highest prevalence of hits in patients with ie (sliwka stroke , georgiadis stroke . detection of hits using tcd emboli monitoring has a potential to be an important tool for identifying cases of ie at highest risk for cvcs, especially in the early stages of antimicrobial therapy. this can aid further research into preventative interventions beyond antibiotics like earlier valvular surgery or vacuum assisted vegetation extraction. therapeutic hypothermia is considered as an effective therapy to reduce cerebral edema and intracranial pressure for malignant middle cerebral artery infarction, which can be used as a life-saving treatment alternative to or combined with decompressive craniectomy. however, malignant hemispheric infarction involving whole anterior, middle and posterior cerebral artery territory has been regarded as untreatable by any measures. a -year-old man who had had right ventriculoperitoneal shunt for hydrocephalus since several years ago presented with global aphasia and right hemiplegia in may . the brain magnetic resonance imaging showed large acute infarction involving whole left hemisphere including anterior, middle and posterior cerebral arterial territory by occlusion of distal internal carotid artery. as his family refused decompressive hemicraniectomy, therapeutic hypothermia using surface-cooling method (arctic sun® ) was initiated with a target temperature of . . the maximal midline shift on brain ct was approximately mm, five days after stroke onset, which led to foramen of monro obstruction and hydrocephalus in the lateral ventricle of the opposite side. since the hydrocephalus was controlled by draining of the cerebrospinal fluid into the ventriculoperitoneal shunt, the right hemisphere was saved and brain edema combined with midline shift gradually improved. the patient finally survived and was discharged. this case may be the first that therapeutic hypothermia successfully treated large hemispheric infarction involving cerebral arteries without decompressive craniectomy. since the mass effect in our case was much larger than that of malignant middle cerebral infarction, we extended the duration of therapeutic hypothermia ( . ) to days, which prevented herniation syndrome. another interesting point is that we could manage contralateral hydrocephalus caused by extensive midline shift, heralding a fatal clinical course in malignant ischemic stroke, using the preexisting ventriculoperitoneal shunt. current aha / asa stroke guidelines list arteriovenous malformation (avm) as a contraindication for intravenous alteplase (iv tpa) in ischemic stroke. while the associated risk of spontaneous intracerebral hemorrhage varies across the differing types of intracranial vasculature malformations, very little data or case reports exist regarding the risk of hemorrhage with intravenous thrombolytics for ischemic stroke in patients with vascular malformations. a -year-old male with history of cirrhosis and known atrial fibrillation (not on anticoagulation) presented with acute onset left facial droop and left hemiplegia, nihss . onset of symptoms were within the . hour window for iv tpa. a ct head demonstrated an aspects score of . iv tpa was thus initiated. cta of the head and neck revealed a right middle cerebral artery occlusion. additionally, there was a subtle tortuosity of blood vessels within the dural surface of the right temporal lobe, suggestive of possible avm. given the stroke severity, tpa was continued and successful recanalization was completed by thrombectomy of the right m occlusion by aspiration, with confirmation of a dural based avm. the patient did well, with no complications from tpa or thrombectomy and was discharged home with an nihss . the decision to administer iv tpa in patients with symptoms of acute ischemic stroke is determined by last known well time and a non-contrasted ct. vessel imaging should not delay administration of iv tpa as incidental findings may arise which may cloud the use of iv tpa in patients who otherwise may benefit from therapy. this case provides further insight that iv tpa in those with intracranial vascular malformations may be given safely with minimally increased risk. the prevalence of stroke mimics (sm) can reach % of presumable stroke, according to some authors. its presentation can predict the diagnosis of sm with a sensitivity and specificity of % and %, respectively. this study aimed to comparatively evaluate these data in a population hospitalized in a stroke unit. the study prospectively analyzed a total of patients admitted according to the suspicion of sm, the definitive diagnosis, etiology, demographic and epidemiological data, specific scales for stroke including features and its sensitivity and specificity in a specific population. a cross-sectional analysis comprised ( . % female) patients, median age . years ( - ). the median nihss was ( -- in . % of patients. twenty-four patients ( . %) presented with initial suspicion of sm, which was confirmed in ( . %). after univariate analysis on were statistically significant (p = . and p = . , respectively). the multivariate logistic regression showed that the absence of facial paralysis (or= . , p= . , % ci= . - . ), seizure convulsion on admission (or= . , p= . , % ci= . - . ) and blood pressure at admission lower than mmhg (or= . , p= . , % ci= . specificity of . % and . % respectively, with an area under the curve of . (se= . , % ci= . -conclusions sensitivity and specificity, probably secondary to selection bias. these data are inferior to the literature but better adapted to this study population. information collected from chart review and direct patient care. a year-presented with pre-syncope, abdominal pain, and malaise. he was febrile and tachycardic, and subsequently admitted for sepsis. shortly thereafter, he experienced transient diaphoresis, expressive aphasia and right-sided weakness. mri brain showed punctate ischemic cerebellar infarcts. there was high suspicion for embolic phenomena from sepsis or he acutely decompensated to complete non-responsiveness during the echocardiogram. ct brain showed diffuse air emboli in cerebral vasculature and subarachnoid air. he was placed in the left lateral decubitus position and managed with high concentration oxygen. additionally, his antimicrobials were broadened to include fungal coverage. thoracic ct revealed free air in the mediastinum between the candidate for surgical repair of his left atrium due to hemodynamic instability. instead, he underwent urgent endoscopic esophageal stent placement. he then developed a stemi, also thought to be due to air embolus, and went into cardiac arrest with return of spontaneous circulation achieved. the following day, he developed renal failure and coded again. autopsy, in addition to massive cerebral edema and cardiac ischemia, demonstrated strep oralis bacteremia, bilateral adrenal infarcts and acute tubular necrosis. is crucial for the ability to coordinate aggressive care. open surgical repair of the left atrium and esophagus offers the best chance of survival, but its use may be limited by severe sepsis and hemodynamic instability. the efficacy of mechanical thrombectomy (mt) for acute ischemic stroke (ais) due to large vessel occlusion (lvo) is well established in the anterior circulation (ac). ais from lvo in the posterior circulation (pc) differs from the ac in myriad ways, including presentation and resistance to hypoxia. we aim to characterize the differences in risk factors and outcomes of mt for ac vs pc stroke. demographic data was collected for cases of ais undergoing mt from january to january with follow-up imaging and documented functional status at discharge. operative reports were reviewed for procedural data including stroke onset to groin puncture time, number of passes of the stent retriever, and onset to recanalization time. radiology reports of postprocedural non-contrast ct images of the head were assessed. during the study period there were eligible patients ( ac and pc). atrial fibrillation ( . % and . %, p= . ) and hyperlipidemia ( . % and . %, p= . ) were more common in ac strokes while family history of stroke was more common in pc strokes ( . % and . %, p= . ). mortality erence in procedural factors or hemorrhagic complications. ac stroke but not pc stroke. our data shows that pc stroke has a higher mortality rate than ac stroke after mt with no difference in procedural factors or hemorrhagic complications. the higher mortality rate in patients with pc stroke is likely inherent to severe disability from basilar artery occlusion rather than recanalization therapy. the data also support worse functional outcome in ac strokes with increasing age and number of passes. calcinosis is a dysregulation of vascular calcium deposition characterized by small vessel calcification and secondary fibrosis. the effect of systemic calcinosis on mineralization within the central nervous system is underreported and poorly understood. a -year old man presented to icu for possible hemorrhagic transformation of a recent left mca stroke. his medical history was notable for atrial fibrillation, end-stage renal disease, calciphylaxis on warfarin, and parathyroidectomy. his post-stroke hospital course was notable for mildly elevated serum phosphorus. the patient started apixaban two weeks post-stroke as anticoagulation for atrial fibrillation, and underwent a routine ct head one day later. the scan showed extensive high-density signal along the cortex of the recently infarcted left mca territory, initially misinterpreted as hemorrhagic transformation. the signal measured at - hounsfield units, higher than expected for acute blood. a dual-energy calcium overlap map post-processing revealed the high-density material was consistent with acute mineralization, possibly potentiated by the patient's previous calciphylaxis. this case illustrates accelerated mineralization as a mimic of acute hemorrhagic transformation. dual-energy ct is useful for differentiating hemorrhagic transformation from mineralization, and may play a special role in patients with renal disease or history of calciphylaxis. this case illustrates accelerated mineralization as a mimic of acute hemorrhagic transformation of stroke in a patient with esrd and history of calciphylaxis. dual-energy ct can differentiate between intraparenchymal hemorrhage and calcification with high accuracy using material decomposition. this imaging technique may have an especial benefit in patients with renal disease or disordered mineralization. accelerated mineralization post-stroke may worsen cerebral vessel compliance and risk of future stroke, and merits further investigation. systemic inflammatory response syndrome (sirs) without infection is a surrogate of a systemic immune response and has been related with poor outcome in several vascular diseases. we investigated associations of sirs with long-term functional outcome and contributing factors after intracerebral hemorrhage (ich). we analyzed consecutive spontaneous ich-patients from our prospective cohort-study ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . sirs was defined according to standard criteria: i.e. two or more of the following parameters during hospitalization: body-temperature < °c or > °c, respiratory-rate > per minute, heart-rate > per consisted of the modified rankin-scale(mrs) at three and twelve months investigated by adjusted ordinal shift-analyses. bias and confounding were addressed by propensity score matching and multivariable regression models. of patients with ich . % (n= ) developed sirs during hospitalization. sirs-patients showed more severe ich compared to without; i.e. larger ich-volumes ( . cm³, iqr( . - . ) versus . cm³, iqr( . - . );p< . ), increased intraventricular hemorrhage ( . %,n= / versus . %,n= / ;p< . ), and poorer neurological admission status (nihss , iqr( - ) versus , iqr( - );p< . ). ich severity-adjusted analyses revealed an independent association of sirs with poorer functional outcome after three (or . , % ci( . - . );p= . ) and twelve months (or . , %ci( . - . );p= . ). increased ich-volumes on follow-up-imaging (or . , %ci( . - . );p= . ) and prior liver dysfunction (or . , %ci( . - . );p= . ) were associated with sirs. in ich patients we identified sirs to be predictive of poorer long-term functional outcome over the entire range of mrs-estimates. clinically relevant associations with sirs were documented for prior liver dysfunction and hematoma enlargement. acute major bleeding secondary to trauma is a significant complication of anticoagulated patients. in -threatening in the absence of a specific reversal agent. annexa- was a prospective, single-arm, open-label study evaluating the efficacy and safety of -primary efficacy endpoints were percent change from baseline in antiefficacy over the first hours after treatment, as determined by an independent adjudication committee. safety outcomes (including thrombotic events and death) were evaluated over days. among patients enrolled in the study, ( . %) had a bleed associated with trauma ( intracranial [ich] , non-ich). mean age was . years. eighty-three patients took apixaban, rivaroxaban, enoxaparin, and edoxaban. of the ich patients, ( . %) had bleeding in multiple compartments. the mean hematoma volume in the trauma patients with single-compartment intraparenchymal bleeding was . cc. among efficacy-evaluable ich patients, of ( . %) had excellent or good hemostatic efficacy. the percent reduction in anti-ich patients taking apixaban and rivaroxaban, respectively. the -day rates of thrombotic events and mortality were of ( . %) and of ( . %), respectively. conclusions high rate of excellent or good hemostatic efficacy, with a relatively low occurrence of thrombotic events. these results are comparable to what was observed for annexa- patients with spontaneous bleeding events, and suggest that andexanet alfa could be a safe and effective treatment in the traumatic population. -factor prothrombin complex concentrates -related ich. adult patients ( years or older) admitted to yale--related ich who evaluated at approximately hours after the baseline ct scan. secondary outcomes included mortality and modified rankin score (mrs) at hospital discharge. chi-square test and multivariable logistic regression analysis were used for unadjusted and adjusted analyses, respectively. twenty--related ich were included in the s patients received aa). majority of the patients were anticoagulated for atrial fibrillation (n= , %). group (unadju patients ( %) in aa group (unadjusted p= . ). there was no difference in mrs at discharge, patients - compared to patients ( %) in aa group (unadjusted p= . ). multivariable analyses adjusted for age, sex, race, and baseline mrs confirmed the absence of these associations (all p> . ). in our limited sample size, there was no significant difference in the degree of hemostasis achieved, allvalidate these results are warranted. symptomatic intracranial hemorrhage (sich) following mechanical thrombectomy (mt) for acute ischemic stroke (ais) due to large vessel occlusion (lvo) is a rare but devastating complication. however, it is difficult to differentiate sich from contrast extravasation on early post-procedural computed tomography (ct). we aim to evaluate the rate of sich and whether the presence of hyperdensities (hd) on post-procedural ct predicts functional outcome after mt. demographic data was collected for cases of ais undergoing mt from january to january with available follow-up imaging and documented functional status at discharge. operative reports were reviewed for procedural data and radiology reports of ct head performed immediately, and - hours post-mt were assessed. of the patients studied, ( . %, / ) had hd on immediate postoperative ct and ( . %, / ) were contrast extravasation (ce) due to resolution of hd on ct at patients developed new hd on follow-up ct, resulting in a total of patients ( . %) having ich and ( . %) having sich. in subgroup analysis, cardiac comorbidities were more common in ce patients than ich patients ( . % and . %, p= . ) with no mortality or outcome differences. diabetes mellitus (dm) was more common in sich patients than those with ce and asymptomatic ich ( . % and . %, p= . ). the mortality rate of sich patients was higher ( % vs . %) and the survivors had worse discharge nihss than pat difference in procedural factors or preference for circulation between any groups. our data show that presence of hd on immediate postoperative head ct does not predict mortality and is not related to circulation or procedural factors. sich is more common in patients with dm and associated with higher mortality rate and poor functional outcome. consecutive patients admitted to the health system with tsd -pcc between may and april were analyzed. baseline demographics and outcomes were abstracted through -up ct. tsdh volume was calculated using the abc/ method. descriptive statistics were used to analyze the -pcc and its association with outcomes. -pcc for tsdh were analyzed. the median age was [ to ], -pcc was . units/kg. patients with he had a median dose of . units/kg ( . to . ) versus . units/kg ( . to . ) for patients without he. he was seen in % of patients (rivaroxaban in , apixaban in ). among patients with he, % of patients died or went to a skilled nursing facility vs % in those without he. discharge to home or acute rehab was lower in those with he ( %) versus those without he ( %) doac use was associated with higher rates of hematoma expansion and worse outcomes in patients -pcc. treatments for the reversal of doac related tsdh should be investigated intracerebral hemorrhage (ich) is associated with peripheral immune dysfunction and infection. we aim to evaluate peripheral immune responses to ich and associations with infection and ich outcome. consecutive spontaneous ich patients admitted to a tertiary center ( / - / ) were included. patients with secondary ich and transition to comfort measures within hours were excluded. ich score, discharge modified rankin score (mrs), antibiotics use, acute clinical infections including pneumonia, bacteremia, and urinary tract infection were systematically adjudicated using modified pantheris criteria. peripheral immune dysfunction was characterized by lymphopenia and lower lymphocyte to neutrophil ratio (lnr). continuous variables were compared using student's t or wilcoxon test; univariate associations assessed using pearson's or spearman's correlation depending on distribution. ordinal logistic regression used to evaluate independent effect of lnr on discharge mrs. (jmp pro . ). cohort had mean age years, % female, median ich score [iqr - ] and median discharge mrs of . thirty-nine patients had suspected clinical infection treated with antibiotics, where only met modified pantheris criteria for infection. lower %lymphocyte (p< . ) and lnr (p< . ) on post-ich days - were associated with worse discharge mrs and higher ich scores (p's < . ). lower mean lnr on post-ich days higher mean lnr on post-ich days - (p< . ). lnr on post-ich day is independently associated with mrs (p= . ) after adjusting for ich score and sex. acute post-ich lymphopenia and reduced lnr are associated with ich score, infection and worse discharge outcome. lnr emerged as independent predictor of ich outcomes in preliminary analysis. determine how acute lymphopenia mediates ich infection risk and outcome. prolonged length of stay (los) in the intensive care unit (icu) is associated with significant medical complications and higher costs in patients with spontaneous intracerebral hemorrhage (ich). aim of this study is to assess predictors of prolonged icu los in ich. we conducted a retrospective analysis of ich patients admitted to our institution over a seven-year period. demographics, clinical data, and laboratory studies at presentation were recorded. initial ct scans were reviewed to determine location, hematoma volume, and presence of intraventricular extension. surgical interventions, insertion of an external ventricular drain (evd), and medical complications, including infections and deep vein thrombosis/pulmonary embolism (dvt/pe) were reviewed. los was calculated based on the number of midnights spent in the icu. patients spending less than -hours in the icu were excluded. ichs were analyzed. the mean age was . ± . years and . % were females. prolonged los, defined by using the point of change and cumulative sum methodology analysis after normalization of the sample, was found to be > days. intubation at presentation (p< . ), presence of ivh (p< . ), insertion of evd (p< . ), surgical evacuation (p< . ), chest infections (p< . . ) and dvt/pe (p< . ) were associated with prolonged los, while location of the hemorrhage, hematoma volume, and ich score at presentation were found not to be significant. this is a preliminary analysis to identify predictors of prolonged icu-los in intracranial hemorrhage. chest infections and dvt/pe were associated with prolonged los. surgical intervention, intubation at presentation, and insertion of evd were also independent predictors. these findings suggest that early evd weaning or shunt placement, and potentially early tracheostomy could help in decreasing the icu-los in patients with ich. diffusion weighted imaging (dwi) lesions are found in nearly % of patients with acute spontaneous intracerebral hemorrhage (sich). however, the timing of dwi lesions after sich ictus remains unknown. the purpose of this study is to estimate the timing of new dwi lesions after acute primary sich. by establishing a time frame, potential pathophysiologic mechanisms for dwi lesions can be elucidated. between september , and january , , patients were enrolled in a prospective study examining dwi lesions in acute primary sich. enrolled subjects received a research brain mri after admission blinded to the clinical teams. during the same admission, select patients received a separate brain mri as part of clinical care. subjects with scans were identified from the study cohort, and their imaging evaluated for dwi lesions. when compared to the first mri scan, the presence of a new dwi lesion on the second mri scan was defined as a new dwi event. a kaplan-meier analysis was performed to estimate the time to a new dwi event from the first mri scan. among enrolled subjects, ( . %) had two brain mris. mean age was . years, % were male, and . % were african american. the median ich score was (iqr ). median time from sich onset to first mri was . days (iqr . ). median time from first mri to a new dwi event was . days ( % ci, . to . ). median time between the first and second mri was . days (iqr . ). our data suggest that new dwi lesions occur days after sich ictus. therefore, acute interventions during the first hours after sich admission may not be associated with dwi is needed to elucidate potential mechanisms associated with dwi lesions in sich. intracranial hemorrhage (ich) is a common complication in children on ventricular assist device (vad) support, though bleed severity is highly variable. this study examined factors associated with ich requiring neurosurgical intervention in this at-risk population. children aged month- years old admitted between - with a diagnosis of intraparenchymal hemorrhage (iph) or subdural hemorrhage (sdh) while on vad support were identified retrospectively from an institutional database using icd- and icd- codes, after obtaining irb approval. patients requiring neurosurgical intervention (ns+) were compared with those who did not (ns-) using manniables). in total, children met inclusion criteria. of those, / ( . %) required neurosurgical intervention bleeds occurred in patients ( / ns+, / ns-). ns+ patients were older at bleed (mean . ± . years vs . ± . years, p = . ). all ns+ patients were taking warfarin, versus / ns-patients (p= . ); none of the ns+ patients had supratherapeutic inr. number of antiplatelet agents did not differ between groups ( . ± . ns-vs . ± . ns+, p = . ). patients received a median of ct scans (iqr - ) with no significant difference between surgical and nonsurgical groups (p = . ). among our cohort, older children and those on warfarin were more likely to require neurosurgical neurosurgical treatment, though results should be interpreted cautiously given small numbers. patients received multiple ct scans, though only a minority ultimately required neurosurgical intervention. unnecessary ct scans in this population. elevated intracranial pressure (icp), usually monitored by invasive icp-measurements, is associated with mortality in intracerebral hemorrhage (ich). the non-invasive evaluation of pupillary function using automated pupillometry is increasingly used in critical-care settings. the association of various pupillary parameters assessed by automated pupillometry with icp is unestablished, specifically the sensitivity and specificity during icp-elevation and the performance of sympathetic versus parasympathetic parameters. we enrolled ich patients admitted to our neurocritical-care unit who received invasive icpmeasurement by an external-ventricular-drain (evd). we monitored parameters of pupillary reactivity [i.e. light-reflex latency (lat; s), constriction and re-dilation velocities (cv, dv; mm/s), and percentage change of apertures (per-change; %)] using a portable pupilometer (neuroptics®) as well as corresponding icp values up to every minutes for the duration of hospital stay. receiver operating characteristic (roc) analysis was performed to investigate associations between changes in pupillary reactivity and elevated icp. sensitivity and specificity of sympathetic and parasympathetic pupillary parameters were analyzed to evaluate associations between pupillary reactivity and icp-elevation in patients ( women, mean age . ± . years), without icp-elevation and no midline shift upon neuroimaging, assessments were compared to assessments in patients ( women, . ± . years) during icp-levels > mmhg and corresponding midline shift. roc-analyses revealed a significant negative association of all assessed pupillary parameters with icp-elevation. best discriminative thresholds for icp-elevation were: cv< . mm/s, per-change< %, lat< . s, and dv< . mm/s. the highest sensitivity and specificity (i.e. . % and . %; p< . ) for an association with concomitant icp-levels > mmhg were found for a combination of the parasympathetic parameters cv< . mm/s and per-change< %. our data suggest an association between non-invasively detected changes in pupillary reactivity and elevated icp. parameters of parasympathetic pupillary modulation seem most reliable to indicate icpelevation. spontaneous ich (sich) remains a deadly complication from the use of direct oral anticoagulants -pcc for the reversal of doac -pcc in the prevention of hematoma expansion (he) in doac associated sich across a large health system. consecutive patients who were admit -pcc between may and april were analyzed. baseline demographics and outcomes were abstracted through retrospective chart review. he was defined as volume> % or > . ml between baseline and follow-up ct. sich volume was calculated using the abc/ method and ivh score. descriptive statistics were used -pcc and its association with outcomes. -pcc for sich. the median age was ( - ), % were caucasian and --pcc dose of . units/kg ( . - . ) compared to . units/kg ( . to . ) with he. he was seen in % of patients (rivaroxaban in , apixaban in ). among patients with he, % of patients died or went to a skilled nursing facility vs % in those without he. discharge to home or acute rehab was similar in both groups while rates of mortality and discharge disposition were similar between those with and without he, -pcc. treatments for the reversal of doac related sich should be investigated further. elderly patients with mild traumatic brain injury (mtbi) are frequently admitted to an intensive care unit (icu), which is potentially both harmful and unnecessary. however, little exists to inform early decision making to determine appropriate utilization of icu care. here we sought to elucidate factors available upon admission to identify geriatric patients who could safely be monitored in a non-icu setting. adults + years admitted with isolated mtbi, defined as positive radiologic study and glasgow coma scale (gcs) - , between january -december were identified. primary outcomes were ernight stay, no surgery, no intubation, and discharged home) and glasgow outcome scale (gos). positive outcome was defined as gos - and a total of patients met criteria. of these, underwent emergent neurosurgical intervention., leaving for analysis. most presented with gcs ( . %) and were admitted to icu ( . %). nearly point decrease in gcs during hospital stay. upon discharge, . % were classified gos - . predictors . ), and no home use of anticoagulant/antiplatelet medication (p = . ). presence/type of a single intracranial hemorrhage (ich) was not significantly associated with outcome, but presence of bilateral or multiple lesions independently predicted poor outcome (p = . ). overtriage of patients to an icu is costly, resource intensive, and avoidable. here, we suggest a conservative framework to assist the determination of which patients can be safely observed in non-icu population who present with mtbi. perihematomal edema (phe) is a known predictor of outcome after intraparenchymal hemorrhage (iph), but factors contributing to edema formation are incompletely understood. tissue water uptake measured using hounsfield unit density on ct scan has emerged as a predictor of edema in ischemic stroke. the aim of this study was to examine this association in iph, where the theoretical driver for edema volume is not anoxic cellular injury, but rather exposure of tissue to blood. women's hospital were prospectively enrolled between september and march . phe and hematoma were identified on ct scans performed at admission and an average of . +/- . hours later. hematoma volume, hematoma surface area and phe volume were measured. net water uptake (nwu) was calculated as the percent change in phe hounsfield unit density compared to normal contralateral hemisphere. associations between variables were examined with pearson correlations and regression analyses. hematoma volume and surface area at admission were significantly associated with phe volume on the admission scan (r = . , p < . and r = . , p < . respectively) and at the follow-up time-point (r = . , p < . and r = . , p < . respectively). there was no association between nwu and phe volume at either time-point (r = . , p = . and r = - . , p = . respectively). in multivariable analysis, hematoma volume at admission remained an independent predictor of phe volume on the follow- these results suggest that, unlike in ischemic stroke, phe volume is not related to water content. rather, hematom may suggests new avenues to predict edema formation. the risk of hematoma expansion (he) in patients with recent intracranial hemorrhage (ich) receiving therapeutic anticoagulation (ac) is not known. we aim to characterize complication rates and factors associated with he in these patients. we performed a retrospective cohort study of adult patients at harborview medical center between - , who presented with ich and were therapeutically anticoagulated within weeks after the ich for a venous thromboembolic event (vte). we excluded patients with ich due to hemorrhagic conversion of ischemic stroke, venous sinus thrombosis, or an aneurysm consequently secured. we assessed the rate of he, defined as either radiographically proven expansion requiring cessation of ac, or death due to he. t-tests and chi-squared tests were used to analyze factors associated with he. - ), % were female. we identified % sdh, % iph, and % multicompartment ichs, % due to trauma, % hypertensive, and % other etiologies. anticoagulation was initiated an average of . +/- . days after ich. overall, % developed he, one third of whom died. most patients ( %) experienced no complications, % developed minor extracranial bleeding events with ac subsequently resumed. patients with he were older ( vs. ), had higher gcs ( vs. . ), lower hematoma volume ( % vs. % > cc), larger maximal sdh diameter ( . vs . mm), anticoagulated earlier ( vs. days), and lower maximal ptt ( vs. ), although trends were not statistically significant. there was a marginally significant association between he and the presence of hydrocephalus (p< . ). while ac in patients with acute ich can be safely tolerated, there is a substantial proportion demonstrating he. our analysis was limited by the sample size. larger studies are needed to identify clinical and radiographic features associated with complications. intracerebral hemorrhage (ich) is a disease that is associated with high morbidity and mortality. we examined our center's experience with surgery for ich and clinical outcomes. we prospectively enrolled patients with spontaneous ich from to . patients were divided into two groups based on whether they received surgical or conservative management. surgical interventions included hemicraniectomy and/or hematoma evacuation. multivariable regression analysis was conducted to compare the clinical outcomes after adjusting for potential confounders. adjusted odds ratio (aor) or adjusted mean difference (amd) were reported. we included patients, ( %) had surgery and ( %) did not. of the surgical group, ( %) had hematoma evacuation, ( %) had hemicraniectomy, and ( %) had both. clinical characteristics were comparable in both groups. in the surgical group, nihss and glucose were higher and creatinine was lower compared with the nonoperative group. through multivariable analysis, we identified independent predictors of surgery in ich patients including baseline hematoma volume (aor . , % ci . - . ; p= . ) and enlargement with (aor . , % ci . increase in hematoma volume, there was a % increase in the odds of having surgical intervention. was less likely to have a favorable discharge disposition to home or inpatient rehabilitation ( % vs. %; p= . ). surgery was independently associated with longer icu length of stay (amd . , % ci . ,- . ; p= . ) and hospital length of stay (amd . , % ci . - . ; p= . ) after controlling for potential confounders. in our patient population, baseline hematoma volume and expansion were independent predictors for surgery in ich patients. after controlling for other variables, surgery did not impact ich outcomes and was associated with prolonged icu and hospital length of stay. moyamoya disease (mmd), an intracranial vasculopathy characterized by internal carotid artery hypoplasia, often presents with intracerebral hemorrhage (ich) presumably due to rupture of fragile collateral vessels. although mmd-related ich is generally managed similarly to spontaneous ich, we present a case in which standard management strategies may have led to an unprecedented catastrophic outcome. case report. a previously healthy -year-old female presented to the emergency department with right-sided weakness, dysarthria, and headache. she was intubated for airway protection. a head computed tomography (ct) demonstrated a large left basal ganglia ich. ct angiogram revealed diffuse narrowing of the entire anterior circulation with robust posterior communicating arteries. brain magnetic resonance imaging (mri) revealed prominent collateral vessels and sulcal hyperintensities ("ivy sign") consistent with mmd. given these findings, systolic blood pressure was kept under mmhg for the first hours. the following day, the patient's mental status gradually worsened. workup including repeat head ct, infectious and metabolic panels, as well as electroencephalogram (eeg) were unrevealing except for a decreased end-tidal carbon dioxide (co ). two days after presentation, the patient acutely developed fixed and dilated pupils. eeg concomitantly revealed slowing and attenuation of the background. repeat ct head showed new diffuse cerebral edema with tonsillar herniation. despite hyperosmolar therapy, paralytics, pentobarbital, and cerebrospinal fluid diversion, no improvement was noted. unfortunately, brain mri revealed multifocal brainstem infarcts with superimposed duret hemorrhages. herein, we report diffuse cerebral edema as a complication of mmd-related ich. we hypothesize that disruptions of delicate cerebral autoregulatory mechanisms led to extensive hypoxic-ischemic injury. in the setting of ich, aggressive blood pressure management coupled with relative hypocapnia may have likely caused vasoconstriction of poorly compliant arteries leading to worsened cerebral blood flow and ischemia. therefore, because of its complex pathophysiology, traditional blood pressure and co targets should be revisited in mmd-related ich. it is unknown whether admission systolic blood pressure (sbp) differs among etiologies of intracerebral hemorrhage (ich). such differences may have implications for blood pressure -lowering strategies after ich. we compared admission sbp across ich etiologies among patients in the cornell acute stroke academic registry (caesar), which has enrolled all adults with non-traumatic ich at cornell from through . trained analysts prospectively collected demographics, comorbidities, and admission sbp, defined as the first recorded value in the emergency department or upon transfer from another hospital. ich etiology was adjudicated by a panel of board-certified neurologists using the smash-u criteria. we used anova to compare mean admission sbp among ich etiologies. after verification of model assumptions, multiple linear regression was used to adjust for age, sex, race, and glasgow coma scale (gcs) score. among ich patients in caesar, admission sbp varied significantly across ich etiologies, ranging from mm hg in those with structural vascular lesions to mm hg in those with hypertensive ich (p < . ). the overall difference in admission sbp across etiologies remained significant after adjustment for age, sex, race, and gcs score (p < . by the wald test). the mean admission sbp in hypertensive ich cases was mm hg ( % ci, - mm hg) higher than in ich cases of all other etiologies combined. among patients with a history of hypertension, the mean admission sbp was mm hg ( % ci, - mm hg) higher in hypertensive ich than in ich cases of all other etiologies combined. in a single-center ich registry, admission sbp varied significantly among different ich etiologies. our results suggest that admission sbp is associated with ich etiology rather than simply representing a physiological reaction to the ich itself. incidence of clinical seizures after intracerebral hemorrhage (ich) has been reported to range from . % to %, with the majority occurring at or near onset. in the present study, we investigate incidence of clinical seizures in ich subjects during hospitalization and evaluate whether clinical seizures are associated with poor clinical outcomes at discharge. a retrospective review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. demographics, admission gcs, admission nihss, admission mrs, incidence of clinical seizures and clinical outcome at discharge were recorded. associations between the presence or absence of seizures and clinical outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with ich were included. clinical seizures were identified in subjects ( . %), presenting in a median time of . days post-admission (iqr ). outcome was significantly worse for subjects who experienced a seizure compared to subjects who remained seizure-free, poor outcome (gos< ) was found on . % and . % respectively (or . , ]; p= . ). this increased risk was significant after controlling for gender, ethnicity, admission gcs, admission nihss, admission mrs higher in the seizure group compared to the seizure-free group, . % vs . % respectively (or . , % ci [ . - . ]; p= . ) after adjusting for mortality and severe vegetative state (gos , ) there was no statistical significant difference between both groups (p= . ). our study shows a significant association between clinical seizures and poor clinical outcome at hospital discharge after controlling for admission status and other type of complications; however, the presence of clinical seizures did not influence in-hospital rates of mortality. despite the well-established use of the national institutes of health stroke scale (nihss) score as a severity scale for ischemic stroke patients, it is still unclear which score is best for intracerebral hemorrhage (ich) patients. while some studies have looked at nihss and glasgow coma scale (gcs) as a predictor of mortality and -month mrs, there is a dearth in the literature looking at how they affect longer functional outcomes. in this study, we look at and compare how initial nihss and gcs predict month functional outcomes in ich patients. one-hundred patients who underwent minimally invasive ich evacuation, a standardized patient population, from december to october were retrospectively reviewed. we looked at nihss and gcs as a predictor of functional outcome at -months, defined as modified rankin scale (mrs) - . multivariate regression models were constructed using clinical and statistical inferences to predict mrs. these variables were also correlated with -month mrs in multivariate analyses. of patients, . % (n= ) were female and the average age was . (sd= . ). on admission, the median nihss was . (iqr . - . ) and the median gcs was . (iqr . - . ). multivariate logistical analyses showed that higher nihss predicts worse -month mrs, however gcs does not (p= . and . , respectively). correlation analysis with mrs at -months reveals that for every . point increase in nihss, mrs increased by . in this cohort, the admission nihss predicts -month mrs in ich patients while controlling for significant covariates, while gcs does not appear to. despite its simplicity and generalizability, the gcs lacks critical ich elements that the nihss includes. the usefulness of the nihss as a predictor of ich outcomes has been questioned, since ich patients often have depressed consciousness on presentation, however we demonstrate its utility as a predictor of -month functional outcomes. among patients with intracerebral hemorrhage (ich), it is unclear whether red blood cell (rbc) transfusions impact outcomes. we investigated the association between rbc transfusions and inhospital mortality in patients with ich. we performed a retrospective analysis using the national inpatient sample (nis) database. we used standard diagnosis codes to identify non-traumatic ich hospitalizations from through . our exposure was rbc transfusions during the ich hospitalization and the outcome was hospital mortality. we performed multivariable logistic regression to estimate the association between rbc transfusion and outcomes after adjusting for demographics, charlson comorbidity index (cci), and hospital characteristics. however, given the absence of ich severity and physiologic variable data within nis, we performed additional analyses in a separate, single-center ich cohort, adjusting for admission ich and apache-ii scores. of , non-traumatic ich hospitalizations in the nis, , ( %) patients received rbc transfusions. patients receiving rbc transfusions had more comorbidities than those not receiving rbc transfusions (cci > : % vs %). rbc transfusion was associated with increased odds of hospital mortality (adjusted or . ; % ci . - . ). in a separate cohort of primary ich patients, ( %) patients received rbc transfusions during their hospitalization. rbc transfusion was not associated with hospital mortality after adjusting for ich and apache-ii scores (adjusted or . ; % ci: . - . ). rbc transfusion was associated with increased odds of hospital mortality after ich. however, underlying medical comorbidities, acute physiologic derangements, and ich severity may account for some of these ns on outcomes after ich. deep venous thrombosis (dvt) is a common cause of morbidity and mortality in patients admitted to the neuro-intensive care unit (nicu). the aim of this work is to assess the incidence of dvt in patients diagnosed with intracerebral hemorrhage (ich) and study its demographic characteristics. a retrospective chart review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. subject demographics, admission status, incidence of dvt, hospital length of stay (hlos), intensive care unit length of stay (icu-los) and clinical outcome at discharge were recorded. data was analyzed to assess the prevalence dvt in this period. patients with ich were included. dvt was identified in subjects ( . %). median time to dvt from diagnosis was h (iqr ) after the initial symptoms of ich. the mean age of patients with dvt was . (sd . ) and subjects ( . %) were female. . % subjects were of caucasian ethnicity, . % african-american, . % hispanic, . %asian and . % were from other ethnicities. median hlos was days (iqr . ) and icu-los was days (iqr . ). moreover, . % of patients who presented a hospital-acquired dvt had a poor clinical outcome at discharge (gos< ). ich patients admitted to the nic large prospective trials are needed to understand the baseline characteristics of patients at risk of dvt as well as the utility of surveillance and different prophylaxis methods. studies have demonstrated an association between high average systolic blood pressure (sbp), and increased sbp variability with worse clinical outcomes in non-traumatic intracerebral hemorrhage (ich). nevertheless, the optimal blood pressure target remains elusive. we aim at introducing an alternative approach to assess blood pressure in the acute phase of ich, by using the metric of sbp dose, and showing that it provides a more robust association with clinical outcome. we retrospectively evaluated ichs admitted to our institution over a seven-year period. initial ct scans were analyzed to confirm the presence of intraparenchymal blood. blood pressure was recorded at presentation and hourly for the first -hours. mean sbp (msbp) in the first -hours was calculated; sbp dose (dsbp) was calculated via the trapezoidal method from area under the curve (auc), and divided in three groups: no dsbp (no time spent above mmhg), moderate dsbp (auc spent above mmhg), and high dsbp (auc above mmhg). discharge dispositions were used as surrogates of clinical outcome. poor outcome included death, hospice, and long term acute care hospital. -one patients ( . %) had poor outcome. of the patients in the no dsbp group none suffered poor outcome; % of the patients in the moderate dsbp group, and % of patients in the high dsbp group suffered poor mean sbp in predicting patient outcomes (p< . ). high dsbp in the first -hours was associated with worse clinical outcomes, and was a better predictor compared to msbp. blood pressure dose is a promising novel metric that deserves further study in the management of ich. despite lack of ich-specific therapies that improve outcome, current guidelines recommend treatment of ich at tertiary care centers. as such, ich comprises a large proportion of inter-hospital transfers (ihts) to comprehensive stroke centers (cscs) despite studies suggesting lack of mortality benefit and low csc resource utilization. the subset of patients who derive the most benefit from a csc is unclear. here, we create a triage model to identify ich patients who can safely avoid transfer to a csc. a retrospective cohort of patients with spontaneous ich transferred to our csc was used to develop our triage model. patients with early discharge from the neuro-icu without use of any csc resource during hospitalization were identified as low risk, non-utilizers (lr--nu were identified and used to develop a triage model which minimized the likelihood of release of patients requiring csc resource. this model was tested in a replication cohort for accuracy. the development and replication cohorts comprised and patients respectively of whom ( %) and ( %) were lr-nu. initial gcs and baseline ich volume were associated with lr-nu in multivariate analysis. presence of ivh and infra-tentorial location of ich were also included. initial gcs > , ich volume < ml, absence of ivh, and supratentorial location had an auc, specificity, sensitivity, ppv, and npv of . , . %, . %, . %, and . % respectively for identifying lr-nu. in the development cohort and patient in the replication cohort had a neurosurgical intervention. however mostly these were for non-emergent avm interventions. spontaneous ich patients with initial gcs > , ich volume < ml, no ivh, and supratentorial location might safely avoid iht to a csc. validation in a prospective, multicenter cohort is warranted. metastatic cardiac myxomas have many neurologic complications, including intracerebral hemorrhage. cardiac myxomas are rare intracardiac tumors. though most myxomas are benign, the risk of malignant spread to the central nervous system (cns) is well known. we describe a case of multiple recurrent intracerebral hemorrhages (ich) occurring in the setting of a recently treated cardiac myxoma. a -year old woman with a history of resected left atrial myxoma presented with a one-day history of left ear paresthesias. computed tomography (ct) of the head was performed and demonstrated ichs within the right frontal and parietal lobes and left cerebellar hemisphere. she had presented to an outside hospital several weeks earlier with similar symptoms with imaging demonstrating similar definitive evidence of malignancy or infection. conventional angiography was negative for vasculitis. brain biopsy showed no evidence of amyloidosis or glioma. at our institution, magnetic resonance imaging (mri) of the brain with double inversion recovery also revealed no evidence of vasculitis; however, the study was concerning for multiple cavernous malformations. underwent genetic testing. no mutations associated with familial cerebral cavernous malformations syndromes were identified. several months later, she returned to the hospital with recurrent symptoms. head ct and mri re-demonstrated multiple cavernous malformations with surrounding vasogenic edema, which were mildly increased compared with prior studies. given progression of her mri findings, concern for metastatic cardiac myxoma was raised. considering that - % of patients with cardiac myxoma will have some form of neurologic complication, all should receive a comprehensive neurologic evaluation. diagnosis is made with neuroimaging and brain biopsy. primary treatment of cardiac myxoma includes surgical resection. when cns lesions are present, chemotherapy or stereotactic radiosurgery should be considered. an association between spontaneous hyperventilation, severity of disease at presentation, and poor clinical outcomes has been reported in patients with subarachnoid hemorrhage (sah). we evaluated the relationship between early breathing changes and outcomes in patients with intracerebral hemorrhage (ich). consecutive patients with spontaneous ich were enrolled in an observational cohort study conducted between and at a comprehensive stroke center. patient characteristics and functional outcome at discharge were prospectively recorded. arterial blood gas (abg) measurements and mechanical ventilation settings in the first hours of admission were retrospectively collected, when available. hyperventilation was defined as pco < mmhg concurrent with ph > . in spontaneously breathing patients, excluding mechanically ventilated patients not overbreathing the set rate of a control mode. we assessed for an association between early breathing changes, hemorrhage severity and hospital outcomes by univariate and adjusted analyses. early abg data were available for of patients. patients with abg data had more severe hemorrhages than those without (median ich score versus , p< . ). hyperventilation occurred in ( %) of cases. there was no univariate association between hyperventilation and ich score, admission gcs score or initial hematoma volume. lower initial pco was associated with greater risk of in-hospital death (or . per mmhg, %ci [ . , . ], p= . ) after adjustment for ich score, pneumonia and mechanical ventilation requirements. spontaneous hyperventilation is less common after ich than sah ( % vs %, respectively) and not associated with initial disease severity. the association between lower pco and in-hospital mortality after ich, independent of neurologic severity and comorbid respiratory complications, is consistent with findings of greater delayed ischemia and worse outcomes in spontaneously hyperventilating sah patients. these associations may be mediated by a potentially modifiable underlying mechanism such as acute shifts in cerebral hemodynamics due to pco changes. ich or sah patients often undergo interhospital transfers to tertiary centers. acute clinical deterioration diversion is often implemented via external ventricular drains (evd's). the safety and efficacy of leaving the evds clamped or open during inter-hospital transfer is not known. we aimed to implement a pilot during inter-hospital transport for hemorrhagic stroke patient. under the neuroemergencies management and transfers (nemat) program, department of neurosurgery at mount sinai health system, we implemented this protocol in october, . patients with ich or sah requiring evd placement prior to inter-transfer to a specialized center for ich or sah within our health system were enrolled. recommendations for icp management, for post-evd drainage h and cm or lower for ich were included. evd was clamped for transportation and a dose g/kg of mannitol was given just prior to transportation. icp precautions were maintained throughout transportation. ( male, female_ patients who underwent inter-hospital transfers for ich (n= ) and sah (n= ) after placement of evds for raised icp at the transferring hospital were included. all patients required endotracheal intubation for transfer. / patients had an icp less than mmhg on arrival at the receiving hospital. conclusion: protocolized care for ich and sah patients with evds and icp management during interhospital transfers for patients is safe and feasible. such a protocol could an help facilitate potentially rapid and safe life saving inter-hospital transfers for hemorrhagic stroke patients with evds in large urban health system to to hospitals with specialized definitive neurosurgical and neurocritical care. intracerebral hemorrhage (ich) during pregnancy is abound with diagnostic and therapeutic dilemmas and contributes to pregnancy-related mortality. we present a pregnant patient with ich due to moyamoya disease to highlight these issues. case report. a -year-old -week pregnant asian woman presented after developing an acute onset headache followed by loss of consciousness. in the emergency department, she was comatose with bilateral pinpoint pupils and required intubation for airway protection. initial ct head showed predominantly intraventricular hemorrhage (ivh) that emanated from the left thalamus. ct angiogram revealed highgrade stenosis of the left m segment with moyamoya collateralizations. due to hydrocephalus, an external ventricular drain (evd) was placed. the patient required admission to the neurocritical care unit for further monitoring of exam and vitals. continuous fetal monitoring, and ultimately, successful csection on day of hospitalization was performed through collaboration with the obstetrics and gynecology (ob/gyn) team. cerebral angiogram confirmed the diagnosis of unilateral moyamoya disease as the cause of the patient's ivh. the patient was discharged initially to acute rehab and then home with minor cognitive deficits. the work-up and management of ich in pregnant patients can be challenging. moyamoya disease is a non-atherosclerotic cerebral vasculopathy that can be included in the differential diagnosis for ich in pregnant woman. the most common presentation of moyamoya disease in adults is ich, and it's mainly due to the rupture of dilated and fragile vessels in the basal ganglia, and rupture of saccular aneurysms within the moyamoya collaterals. pregnancy might increase the risk of ischemic or hemorrhagic stroke in women with moyamoya, but available data is controversial. cooperation between the neurocritical care and ob/gyn teams can assist in determining the risks and benefits of medications, imaging, and the need and timing for delivery, thus assuring optimal outcomes for the patient and infant. spontaneous intracerebral hemorrhage (ich) is severely disabling, and survivors often require extensive rehabilitation to maximize recovery. recovery for survivors discharged from index hospitalization is variable and incompletely explained by discharge functional capacity. we assessed whether discharge disposition was independently associated with long term recovery potential. patients with acute ich hospitalized at a tertiary care comprehensive stroke center between and were enrolled in a prospective, observational study that recorded demographics, standard severity s was measured by the modified rankin scale (mrs) at discharge and three months. discharge disposition were ordinalized by activity engagement level from highest to lowest as follows: home, ; acute inpatient rehabilitation (air), ; skilled nursing facili ; and long-term acute care hospital (ltach), . ordinal regression was used to assess the prognostic association between discharge disposition and three month functional status by mrs, adjusting for the ich score and mrs at discharge. among patients enrolled, survived and had complete in-hospital data for analysis, and three outcomes at three months (mrs - ; . % and . % respectively), with most either bedbound or dead ( . % and . % respectively). poor outcomes were less common among patients discharged to air ( . %) or home ( . %). the adjusted model found that a better discharge disposition was associated with more favorable three month mrs (odds ratio . , % ci [ . , . ], p= . ). discharge disposition captures prognostically important characteristics in patients with intracerebral hemorrhage beyond traditional case severity and functional status measures. outcomes are poor for a large majority of patients unable to return home or qualify for acute rehabilitation. whether the prognostic characteristics requiring nursing facility care are modifiable by increasing rehabilitation services in those care environments is not known. as a reversal agent for uncontrolled or life-threatening bleeding for patients taking apixaban and rivaroxaban. approval was based on the results of interim analysis of the ongoing annexa- multicenter, prospective, open-label clinical trial. our institution began using the drug in august . we report our clinical experience. we conducted a retrospective observational study of patients admitted to stanford medical center from -associated intracranial hemorrhage. -associated ich. the mean age was (+/- ). patients were male. the mean glasgow coma scale score was . hemorrhage types included intraparenchymal hemorrhage ( patients), subarachnoid hemorrhage ( patients), and subdural hemorrhage ( patients). hemorrhage was associated with head trauma in patients ( %). ten patients ( %) had "excellent" or "good" hemostasis defined by the annexa- criteria. three patients ( %) developed deep venous thrombosis. no patients developed pulmonary embolism or myocardial infarction. -day mortality was % ( patients). we describe a case series of patients who received andexanet alfa for intracerebral hemorrhage at a large medical center. the incidence of intracerebral hemorrhage (ich) is . per , person years. nontraumatic spontaneous ich is usually seen in setting of uncontrolled hypertension or cerebral amyloid angiopathy and commonly occurs in basal ganglia, cerebral cortex, brainstem or cerebellum. spontaneous ich in corpus callosum with intraventricular hemorrhage (ivh) is very rarely seen and reported. we present an unusual case of corpus callosum hemorrhage with ivh associated with a reversible cerebral vasoconstriction pattern (rcvs) on cerebral angiography. the demographic information and clinical reports were obtained from electronic medical records retrospectively. select neuroimaging was obtained from neuroradiology department. year old caucasian male with a past medical history of chronic obstructive pulmonary disease, essential hypertension, and prior ischemic stroke with residual right hemiparesis presented in unresponsive state when he was discovered on bathroom floor. neurological examination on admission showed no verbal response, eyes open, with reactive pupils, and withdrawal to pain in left arm and leg. blood pressure on admission was / mmhg. computer tomography (ct) of head showed large ich in rostrum, genu and trunk of corpus callosum with intraventricular extension and hydrocephalus. he was intubated for respiratory distress and external ventricular drain (evd) was placed. he was also treated with intraventricular alteplase mg injection for total of doses, hours apart. blood pressure was controlled with nicardipine infusion initially, a up ct head showed resolution of ivh over the next several days, however, no significant clinical improvement was seen. patient remained abulic and akinetic. cerebral angiography performed showed right pericallosal artery beading pattern consistent with rcvs. after transition to comfort care, the patient expired on the th day of hospitalization. spontaneous non-traumatic corpus callosum ichs are rare, and while other causes have been reported, this particular etiology is likely due to rcvs. intracerebral hemorrhage (ich) is a leading cause of disability and mortality. infections are a common complication observed in ich and might be associated with worse outcomes. we aim to evaluate the association between infections and clinical outcomes at hospital discharge. a retrospective chart review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. subject demographics, admission status, rates of infections including; pneumonia, urinary tract infection (uti), bacteremia and clinical outcome at discharge were recorded. associations between the presence or absence of infections and clinical outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with ich were included. infections occurred in subjects ( . %). uti was the most common infection ( . %) followed by pneumonia ( . %) and bacteremia ( . %). clinical outcome was significantly worse for subjects who experienced any type of infection during hospitalization, compared to non-infected subjects, poor outcome (gos < ) was found on . % and . % respectively (p= . ). this increased risk was significant after controlling for gender, ethnicity, ermore, an unfavorable discharge disposition -infected group, . % and . % respectively (p= . ). our study shows a significant association between infections and poor clinical outcomes at hospital intracerebral hemorrhage (ich) is a subtype of stroke associated with a high morbidity and mortality. low serum calcium levels have been previously associated with larger hematoma volumes, hematoma expansion and worse outcomes; however, the pathophysiological mechanisms are still not well understood. a confounding effect among serum calcium and magnesium levels has been previously considered. in the present study, we investigate whether hypocalcemia is associated with poor clinical outcomes controlling for serum magnesium levels. a retrospective chart review of consecutive patients with ich admitted to the baylor st. luke's medical center between january and december was conducted. serum calcium and magnesium levels were measured during hospitalization, hypocalcemia and hypomagnesemia were defined as serum levels below . mg/dl and . m/dl respectively. associations between serum calcium level and clinical outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with ich were included. hypocalcemia was identified in subjects ( . %). clinical outcome was significantly worse in the hypocalcemic group compared to the normocalcemic group, poor outcome (gos < ) was found in . % and . % respectively (p= . ). this increased risk was significant after controlling for gender, ethnicity, serum magnesium levels, admission gcs, admission death) was also higher in the hypocalcemic group compared to the normocalcemic group, . % and . % respectively (p= . ). our study shows a significant association between hypocalcemia and a poor clinical outcome after association. treatment of patients with intracerebral hemorrhage (ich) typically requires advanced care at a tertiary medical center. many patients present initially to regional or local emergency departments and require interfacility transportation to a referral center. mission hospital (mh) is a community-based nonacademic -bed tertiary care facility with comprehensive stroke center certification. we serve as the referral center for affiliated mission health hospitals and regional non-affiliated hospitals across counties. these hospitals are distributed throughout a mountainous and rural area with challenging terrain for transportation and limited resources for critical care transport. here, we aim to describe the current transfer paradigm and consistency of care provided during interfacility transport of ich patients prior to implementation of a dedicated ich regional interfacility transfer protocol. retrospective review of the electronic medical record was performed to identify all patients in calendar year admitted to mh with a principal diagnosis of nontraumatic ich who initially presented to another facility prior to transfer to mh. data, including demographics, transport service type, and transport sequential blood pressures, were collected. blood pressures during transport were analyzed to determine whether blood pressure exceeded our guidelines. patients with ich transferred to our referral center were identified. / ( . %) were transported via critical care transport, and / ( . %) were transported by local ems using general adult transport protocols. / ( . %) had uncontrolled hypertension as defined by or more bp readings above our guidelines. of these, / ( . %) were transported via critical care transport and / were transported via local ems. transport records were incomplete in / ( . %). elevated blood pressures during transport of ich patients are common. rural health systems are challenged by lack of critical care transport capabilities. we are currently implementing a dedicated protocol for interfacility transport care of ich patients. infratentorial intracerebral hemorrhage (ich) is associated with worse prognosis than supratentorial ich; however, infratentorial ich is often excluded or underrepresented in major studies of ich. we sought to evaluate the natural history of infratentorial ich stratified by brainstem or cerebellar location using a prospective observational study inclusive of all spontaneous ich presenting to our institution. using a prospective, single center cohort of patients with spontaneous ich between - , we conducted a descriptive analysis of baseline demographics, severity of injury scores, and long-term functional outcomes of infratentorial ich stratified by cerebellar or brainstem location. infratentorial ich occurred in ( %) of patients in our ich cohort. cerebellar ich occurred in ( %) and brainstem ich occurred in ( %). compared to cerebellar ich, brainstem ich had significantly worse severity of injury scores, including: admission glasgow coma scale (p < . ), ich score (p = . ), and national institute of health stroke scale (nihss) (p = . ). modified rankin scale (mrs) scores at months were significantly better in patients with cerebellar ich compared to brainstem ich (median [ . - . ] versus median [ . - . ], p = . ). patients with cerebellar ich were more likely to be discharged home or to acute rehabilitation (or . , % ci . - . ) but there was no difference in in-hospital mortality (or . , % ci . - . ) or cause of death (p = . ). patients with cerebellar ich who were alive at months had smaller hemorrhages and lower severity of injury on admission. patients with cerebellar ich have less severe symptoms at presentation and more favorable functional outcomes compared to patients with brainstem ich. it has been known that patients with intracerebral hemorrhage (ich) have a higher rate of acute renal tality. the factors such as medications for blood pressure control, blood pressure (bp) variations and use of contrast for imaging without history of previous kidney disease. we analyzed the records from hospitalized patients in the icu from to in a single academic center with primary diagnosis of ich and renal failure. a total of were analyzed, patients ( . %) were reported to ( . %) patients did not meet the criteria for renal risk, injury or failure and ( . %) did not have enough data for the study. antihypertensive therapy used within the first hours of admission was a combination of acei, arbs and b-blockers. patients showed a wide variability in blood pressure (max-min within a day) which could not be and use of iodinated contrast, since ct without contrast was the imaging study of choice in all patients. our observations did not show an association in between bp variability, type of antihypertensive therapy or use of iodinated contrast within the first hrs of admission to acute renal failure in ich patients either with or without history of renal disease. a larger study may be required to support this statement. milrinone, a phosphodiesterase inhibitor, has limited data as salvage therapy for cerebral vasospasm (cvs) secondary to aneurysmal subarachnoid hemorrhage (asah). to date, no study has compared patients treated with intravenous milrinone to a control group receiving standard treatment, primarily hemodynamic augmentation. we compared cvs duration in milrinone-treated patients to a control group, and evaluated additional safety and efficacy outcomes. this was a retrospective, single center, case control study. adult patients admitted to spectrum health or inclusion. the primary outcome was duration of cvs recorded on daily transcranial doppler exams. secondary outcomes assessed efficacy and safety. efficacy endpoints included, but were not limited to: incidence of ischemic stroke, interventions to treat cvs, icu/hospital length of stay (los), and in-hospital mortality. safety endpoints included vasopressor/inotrope requirements and incidence of arrhythmias. -treated and control patients. milrinone use was associated with a longer duration of cvs (p = . ), increased use of intraventricular medications for cvs (p= . ), greater vasopressor requirements (p = . ), and longer vasopressor duration (p= . ). there was no difference in arrhythmias or in-hospital mortality. icu los in milrinone versus control groups was . vs. . days (p= . ) and hospital los was . vs. days, respectively (p = . ). there were ischemic strokes in the milrinone group versus in the control group (p= . ). intravenous milrinone was associated with a longer duration of cvs in asah patients, greater vasopressor requirements, and trended towards a higher incidence of ischemic stroke, though not statistically significant. prospective, randomized, controlled trials are needed to further define the risks and benefits of milrinone therapy in asah patients. aneurysmal subarachnoid hemorrhage (asah) patients sustain several physiologic changes, including a rupture. mri is potentially useful for prognostication in asah but has not been well-studied in this patient population. we present our preliminary experience with multimodal mri in the acute period after asah. we hypothesized that changes in nodes of network critical to consciousness differ between patients with good and poor outcomes. thirty-four asah patients and healthy volunteers underwent multimodal mri at t. mri t images were segmented, and aslconsciousness (i.e., salience network, central executive network, default mode network). wilcoxon rankto test odds of modified rankin scale (mrs) - at months. asah patients had a mean age (±sd) of . ± . years, and controls were . ± . years (p< . ). prefrontal cortex - and - ). r age-matched studies with more subjects and additional mri sequences are needed to better determine mri's potential utility in asah prognostication. aneurysmal subarachnoid hemorrhage (sah) classically presents with the "worst headache of the patient's life" which can be very debilitating and persist for weeks. headache is often refractory to standard treatment, including opiates. pain is thought to be derived from meningeal irritation in the subarachnoid space. the sensory fibers in the anterior meninges are innervated by branches from the ophthalmic division of the trigeminal nerve, which is closely associated with the sphenopalatine ganglion (spg). spg blockade with local anesthetic, first described in , has used as a treatment for various types of headache disorder but has not been described in sah-associated headache. treatment approach is either transnasal or transcutaneous injection. this case series describes five patients who received spg blockade for intractable sah-associated headache. patients with acute aneurysmal sah in the neurocritical care unit were offered adjunct spg blockade for headache refractory to standard treatment. patients rated pain on a - numerical scale, both before and minutes after the procedure, which included either transnasal administration of ropivacaine using the tx device (tian medical) or transcutaneous administration of ropivacaine with decadron. ess score on admission (range - )); two ( %) received transnasal blockade and three ( %) received transcutaneous blockade. median pre-treatment pain score was (range their pain within minutes; the fifth reported % reduction of pain. transcutanous spg blockade resulted in complete pain relief in all patients. the effects were transient, and pain typically returned within hours. there were no complications associated with the procedure. repetitive spg blockade is a safe and effective adjunct treatment for sah-associated headache. a larger clinical trial is planned. tranexamic acid is recommended in the first hours after subarachnoid haemorrhage (sah) and before aneurysm treatment to reduce rebleeding. in brazil, patients are frequently submitted to delayed aneurysm occlusion after sah (> hours from ictus). the objective of this study was to evaluate the effects of tranexamic acid on hospital complications and outcome of patients with sah. all consecutive patients admitted with sah between and at a reference center were included. data were collected prospectively during the hospital stay. all sah patients within hours of ictus were considered eligible for tranexamic acid (ta) up to aneurysm occlusion. we analysed groups: no ta, low dose ta and high dose ta. the primary endpoint was mortality at hospital discharge. other outcomes included hospital complications such as rebleeding, delayed cerebral ischemia and adverse events such as deep venous thrombosis dvt) and pulmonary embolism (pe). one hundred forty five patients were included in the study. approximately half ( , %) received ta, with ( %) receiving low dose and ( %) high dose. at baseline, the high-dose ta group had more -dose group ( % vs %). patients in the low-dose group had lower rebleeding rates ( . %; p= . ) than the no-ta and high-dose ta groups. mortality was lower for the no-ta and low-dose ta groups as compared to the high-dose ta patients. moreover, patients that did not receive ta had longer icu and hospital lengths of stay. dvt/pe rates were very low in our cohort and not different between groups. our study showed that patients that received low dose of tranexamic acid had lower rates of rebleeding as compared to those that received no ta and high-dose ta. mortality was also lower in this group when compared to patients that received high-dose ta. aneurysmal subarachnoid hemorrhage (asah) carries high mortality and morbidity. symptomatic vasospasm is an important complication of asah. about thirty percent of patients with severe vasospasm do not respond to conventional management and will go on to develop delayed ischemic strokes. medical management in these patients are limited and require endovascular therapy with intraarterial vasodilators and angioplasty. milrinone has vasodilator properties and inotropic activity which has been used by intravenous and intraarterial routes for symptomatic vasospasm. in this study, we tested the safety and feasibility of intraventricular milrinone (ivm) in patients with severe vasospasm administered through the external ventricular drain (evd). a retrospective review of medical records of patients with subarachnoid hemorrhage who received ivm between - . ivm was given at a dose of . mg in ml sterile saline every hours through an evd that was subsequently clamped for h. patients received ivm for refractory vasospasm. among those, patients had ruptured asah and one patient had ruptured internal carotid artery pseudoaneurysm secondary to pituitary macroadenoma resection. the mean ivm doses were (range - doses). only one patient ( . %) developed ventriculitis days after ivm. there were no elevations of intracranial pressures with intraventricular administration of ivm. in patients with refractory vasospasm from aneurysmal subarachnoid hemorrhage, intraventricular milrinone administration seemed to be relatively safe. prospective trials are needed to further determine the safety and efficacy. rupture of cerebral aneurysm is the most common cause of subarachnoid hemorrhage (sah). hypertension is a particularly important risk factor for growing and rupture of cerebral aneurysm. in clinical practice, the non-adherence to anti-hypertensive medications is the most important cause of uncontrolled blood pressure. the aim of this study is to evaluate the effect of non-adherence to antihypertensive medications on the long-term prognosis of patients with hypertension and ruptured cerebral aneurysm based on the nationwide health claims database in korea. this study is retrospective cohort study using the national health insurance service-national sample cohort (nhis-nsc) in korea. we included non-traumatic sah patients (icd- ; i ) with hypertension who underwent endovascular coil embolization or surgical clipping for ruptured aneurysm. the primary outcome is defined as composites of recurrent stroke, myocardial infarction, all-cause death. adherence to anti-hypertensive medications is measured by calculating the proportion of days covered (pdc) based on the prescription records, which is treated as a time-dependent variable. we performed multivariate time-dependent cox regression analysis with adjustments for sex, age, diabetes mellitus, treatment morality (coil embolization or surgical clipping), and household income. -nsc, we found patients who received coil embolization or surgical clipping for aneurysmal sah. among them, patients with hypertension were included for analysis. during the . years of mean follow-up period, there were patients who had primary outcome. in the multivariate cox regression, poor adherence to antiindependently associated with increased risk of primary outcome (adjusted hr . , % ci . - . , p-value= . ). in this cohort study with real-world data, poor adherence to anti-hypertensive medications is a strong risk factor for worse prognosis in the hypertensive patients who underwent treatments for ruptured aneurysm. there is need for greater attention to adherence to anti-hypertensive medications in the high-risk patients. tcd is routinely used in aneurysmal subarachnoid hemorrhage (sah) for vasospasm surveillance. the value of tcd monitoring in non-aneurysmal sah (nasah) is unclear. in this study we sought to determine the clinical utility of performing tcd monitoring in a cohort of patients with nasah. retrospective case series study performed at a comprehensive stroke center in a university hospital. patients with sah in whom an aneurysm or other vascular lesion was not identified were extracted from a prospective database covering a year period. patients with nasah were categorized into perimesencephalic and diffuse sah based on the ct appearance. baseline demographics and clinical variables were obtained from the database. tcd results were obtained from a tcd database and conventional criteria were used to diagnose sonographic spasm. categorical variables were compared a total of nasah patients were identified; perimesencephalic and diffuse. spasm was identified in / ( %) perimesencephalic nasah patients and / ( %) diffuse nasah patients (p= . ). no differences were observed between groups in age (p= . ), discharge disposition (p= . ), median her score (p= . ) when comparing patients with spasm to those without spasm. similarly the median number of tcds (p= . ) did not differ among patients with and without spasm. the location of nasah did not influence the diagnosis of spasm (p= . ). sonographic spasm occurs in % of nasah patients but no specific clinical variable appears to influence its occurrence. the clinical significance of such finding needs further validation. complications following aneurysmal subarachnoid hemorrhage (asah) may be associated with early fluid status. this study aims to assess the relation of fluid balance and intravascular volume to outcomes including acute kidney injury (aki), delayed cerebral ischemia (dci), and vasospasm (vsp) in asah. consecutive asah patients were retrospectively collected including patient demographics and admission characteristics. intravascular volume on admission was measured by ivc ultrasound. daily fluid balance in the first days of admission were recorded along with changes in bun and cr. outcomes including dci and vsp were collected. spaghetti plots were used to illustrate trajectory patterns. a linear mixed effect model was used the test the trajectory of slopes. an interaction term between time and patient condition was used to test the slope difference between patient conditions. of patients underwent ivc ultrasound assessment of intravascular volume. patients were hypovolemic on admission with ivc collapsibility index > % or distensibility index > %. ivc slopes were found to be different by patient m balance decreased by - . ± ml/hr (p= . ) while it increased . ± . ml/hr (p= . ) in those - . ± . /hr (p= . ) while it increased . ± . /hr (p= . ) in those without dci (interaction p= . ). - . ± . /hr (p< . ) in those without vsp (interaction p< . ). patient hemodynamics on admission as determined by ivc ultrasound does not correlate with development of aki. however, fluid balance in the first days of admission may be associated with outcomes in asah. early prediction of delayed cerebral ischemia (dci) will improve management of subarachnoid hemorrhage (sah) patients. we used mass spectroscopy (ms) to undertake an unbiased interrogation of plasma proteins associated with dci. this is an observational prospective single-center study of patients admitted to a tertiary care center. serum samples from patients were obtained within hours post-admission. we performed analysis in cohorts separately at different times. the first cohort was a retrospective cohort of matched subjects ( no-dci vs dci). the second cohort consisted of matched subjects ( no-dci and dci). in both cohorts subjects were matched across dci status for age, sex and modified fisher scale. we performed t-tests across dci groups in both cohorts to identify proteins with a difference in concentrations between dci groups. we selected proteins with a p-value of < . for difference across dci in both cohorts as potential candidates. and proteins were identified in cohort- and cohort- respectively. we identified potential candidates in cohort- , and potential candidates in cohort- . six proteins were identified in both cohort- and cohort- (p-value cohort- and p-value cohort- ): complement factor h (p= . and p= . ); complement factor i (p= . and p= . ), antithrombin-iii (p= . and p= . ), histidinerich glycoprotein (hrg) (p= . and p= . ), fetuin-b (p= . and p= . ), and hemopexin (p= . and p= . ). all plasma protein levels were lower in the dci group. in our unbiased approach to identifying biomarkers of dci we identified potential candidates. the compliment cascade and antithrombin-iii has previously been identified as important in the pathophysiology of sah. of interest, we also identified hemopexin (part of the cd -heme-hemopexin scavenging system) and hrg which is associated with cerebral vessel contraction as potential -b has not been previously reported in sah. confirmatory testing needs to be performed to validate our findings. glycemic gap (gg), determined by the difference between glucose and the hba c-derived average glucose (adag), predicts poor outcomes in various clinical settings. our main objective was to evaluate various admission factors and outcomes in relation to gg. we retrospectively reviewed prospectively collected data on adult patients with aneurysmal subarachnoid hemorrhage. admission glycemic gap (agg) was defined as adag ( . ×hba c- . ) subtracted from admission glucose (ag). poor composite outcome was defined as death, tracheostomy, gastrostomy, and/or discharge to a nursing facility. spearman method was used for correlation. generalized linear model was used to test the difference in gg between patient categories. mixed effects model was used to test the difference in trajectory slopes in gg. area under the curve (auc) for roc curve was used to estimate prediction accuracy. sas . was used for all data analyses. the overall mean agg was . ± . mg/dl. agg was significantly correlated with ag (r= . , p< . ), gcs (r= - . , p< . ), lactic acid (r= . , p< . ), and procalcitonin (r= . , p< . ) on admission, but not with hba c (r= . , p= . ). there was a nonsignificant trend of higher agg in those with delayed cerebral ischemia ( . ± . vs. . ± . , p= . ). patients with poor composite outcome had both higher ag ( . ± . vs. . ± . , p= . ) and agg ( . ± . vs. . ± . , p< . ), but the difference in agg was more profound. trajectory slope in the first hours for gg did not differ in patients with poor vs. good composite outcome (- . ± . / hr vs. - . ± . / hr, p= . ), nor did it differ for pointof-care glucose testing (- . ± . / hr vs. - . ± . / hr, p= . ). agg had significantly better prediction accuracy than ag in predicting poor composite outcome (auc: . ± . vs. . ± . , p= . ). admission glycemic gap served as a better predictor of poor outcome than admission glucose. additionally, agg was correlated with ag, lactic acid, and procalcitonin, and inversely correlated with gcs. the use of standardized management protocols (smps) has been shown to improve patient outcomes for multiple neurocritical diseases. however, whether smps improve outcomes after subarachnoid hemorrhage (sah) is currently unknown. we aimed to study the effect of smps on -month mortality and neurologic outcomes following sah. a systematic review of randomized control trials (rcts) and observational studies was performed by searching multiple indexing databases from their inception through january . studies were limited -traumatic sah reporting mortality, neurologic outcomes, and delayed cerebral ischemia (dci). data on patient and smp characteristics, outcomes, and methodologic quality was extracted into a data collection form. methodologic quality of observational studies was assessed using the newcastle ottawa scale (nos). a total of , studies were identified; were assessed in full and met the criteria for inclusion. two studies were rcts and were observational. smps were divided into four broad domains: management of acute sah, early brain injury, dci, and general neurocritical care. the most common smp design was control of dci, with studies targeting this domain. overall, studies were of low quality; most described single-centre case series with small patient sizes. observational studies scored between and on the -point nos. dci and neurologic outcomes were defined inconsistently in the literature, leading to significant challenges in their interpretation. given the substantial hetereogeneity in reporting practices between studies, a meta-analysis could not be performed. the effect of smps on sah remains unknown due to major limitations in study design and quality. notable deficiencies relate to heterogeneous definitions of dci and inconsistent application of standardized neurologic assessment scales. our study highlights the need for rigorous rcts to determine whether the use of a protocol impacts outcomes in critically ill patients with sah. elevated serum chloride has been associated with increased inflammatory markers, worsened systemic hypotension, and renal injury. little is known regarding the effects of hyperchloremia on neurological outcomes after subarachnoid hemorrhage (sah). we reviewed prospectively collected data on adult patients who were admitted for spontaneous sah from to . chloride values were examined on days - . hyperchloremia was defined as serum chloride of meq/l or greater. the primary outcome was delayed cerebral ischemia (dci). secondary outcomes included hospital mortality and month modified rankin scores (mrs). chi-square test and two sample t-test were employed to assess dci and month mr analyze hospital mortality. sah patients were included in the analysis, ( %) developed dci and ( %) did not. patients with dci had higher rates of hyperchloremia on day ( % vs. %, p= . ), day ( % vs. %, p= . ), and day ( % vs. %, p< . ) than patients without dci. after controlling for age, hunt and . , p= . ) and day (or . , p= . ) were associated with higher likelihood of experiencing dci. good functional outcome (mrs - ) was seen in of patients ( %) at months. rates of hyperchloremia were significantly lower in the good outcome group at all time points. after multivariate analysis, hyperchloremia on day (or . , p= . ), day (or . , p< . ), day (or . , p= . , and day (or . , p< . ) were independently associated with decreased odds of good functional outcome at months. early hyperchloremia was associated with dci and worse functional outcomes from sah. the impact of chloride load and fluid management strategy on sah outcomes warrants further investigation. headache is the most common complaint of patients presenting with aneurysmal subarachnoid an efficacious adjuvant therapy in the management of sah-induced headache. we performed a retrospective chart review of patients treated for sah in the neurocritical care unit at a eceived steroids. dexamethasone ( mg every hours) is typically administered for - days in patients with headache refractory to acetaminophen and oxycodone. nursing documented numeric ( - ) pain scores were collected every two hours. we used paired t-tests to compare mean, maximum, and minimum daily pain scores on the day before and during steroid administration. we used multivariate analysis to assess for factors associated with steroid responsiveness, defined as an improvement of or more points in mean daily pain score. there were steroid treatment periods among patients ( % female, mean age ± . , median hunt--two ( %) were classified as steroid responsive. mean daily pain scores decreased by . points (p = . ) during steroid administration. responders reported higher pre-treatment pain scores ( . vs . , p = . ) and demonstrated greater decrease in mean pain scores ( . vs -. points, p < . ). there was no decrease in mean pain scores during the two days following therapy. in multivariate analysis, there was a weak signal that patients who underwent surgical clipping were more likely to have steroid responsive headaches (or . , . no other demographic or clinical characteristics were associated with steroid responsiveness. a subset of patients with sah induced headache may have a favorable, transient response to steroids. tterns and influence on opioid requirements. cerebral vessel vasospasm (cvv) is a feared complication following aneurysmal subarachnoid hemorrhage (asah). there has been an association between cvv and delayed cerebral ischemia which accounts for a great deal of morbidity and mortality following asah. though the majority of patients with cvv respond to blood pressure augmentation, many patients go on to develop delayed ischemic neurologic deficits despite aggressive therapy. there is some suggestion in the literature that intraventricular milrinone (ivm) may be useful in the treatment of cvv. retrospective case series of patients with asah that were treated with one or more doses of . mg index (pi) and frequency of intraventricular milrinone dosing was collected. all patients were treated at cleveland clinic in the neurologic intensive care unit between and . paired t-test analysis was patients in our cohort were dosed with ivm between and times. there were no significant differences territory. there was also no effect of ivm on cvv over time. there were no direct complications secondary to ivm in these patients. based on our results, ivm was non-therapeutic for the treatment of cvv in patients with asah. our data be conducted to evaluate the safety and efficacy of this treatment. our retrospective analysis suggests that the use of intraventricular milrinone may be non-therapeutic for the treatment of cvv. clinical and research tool for riskelement by the national institute of neurological disorders and stroke sah working group. there are few data assessing the we distributed a survey to a convenience sample of attending physicians that care for patients with questions regarding the definitions of the scale components (thin vs. thick, intraventricular blood vs no to determine the overall inter-ing. thirty-three respondents ( % neurocritical care fellowship trained, % ucns certified in neurocritical care, . % neurologists, median years (iqr - ) in practice, treating median of patients (iqr - ) with sah annually from institutions) completed the survey. twenty-three ( . %) reported r measurement of thin vs. thick blood, and . % correctly identified that blood in any ventricle is scored - . ) for the ct scans, which is considered poor agreement. agr regarding the definitions of the score components. the national institute of neurological disorders and stroke sah common data elements may require further clarification in order to standardize research in cerebral vasospasm leading to delayed cerebral ischemia (dci) is one of the most significant factors impacting functional outcome following subarachnoid hemorrhage (sah). although vasospasm is prevalent in this population, treatment options are limited. in recent years, several published case series have reported a positive effect of intrathecal (it) nicardipine for the treatment of vasospasm. we now report a single center one year retrospective cohort experience with intrathecal (it) nicardipine for the treatment of cerebral vasospasm following sah. all patients discharged in with a diagnosis of non-traumatic sah, either aneurysmal or idiopathic, were included in the analysis. demographics, risk factors, clinical course, radiological dci and functional outcome were analyzed. during , patients were admitted with aneurysmal (n= ) or idiopathic (n= ) sah. the mean age was . ± . and . % were women. low grade hemorrhage (h&h - ) was found in . %, medium (h&h ) in . % and high grade (h&h - ) in . %. cerebral vasospasm was diagnosed in . % of the patients, and it nicardipine was used in % of these patients (n= ). only . % of the patients required angiography to treat vasospasm. tcd data was available for patients who received it nicardipine. treatment reduced mean velocities in all arteries within one day (reduction of . - . %, p< . ). this effect remained through the treatment, until the vasospasm resolved. one patient suffered from bacterial ventriculitis. the overall rate of radiological dci, as found in a blinded post treatment assessment of patients' imaging, was . %. in this cohort, . % had a favorable functional it nicardipine is a safe and potentially effective treatment for cerebral vasospasm and prevention of the subsequent ischemic changes. we are currently expanding the analysis to prior years, however, future prospective controlled trials are still needed to evaluate the safety and efficacy of this treatment. patients remain at high-risk for vasospasm, delayed cerebral ischemia (dci), and hydrocephalus after diversion is often necessary in ma additional benefit over standard management by facilitating intracranial blood clearance and decreasing rate of vasospasm and dci, albeit with a possible increased risk of shunt dependency in historical studies. in this study, we assessed safety outcomes among patients who underwent this procedure. retrospective review of outcomes in pa cisternal drain placement at a single institution. between drain placement. the median hunt-hess score was , but the study population skewed towards large drain dwell duration was . days. radiographic vasospasm occurred in all but one patient ( . %) and developed meningitis/ventriculitis, none fatal. the mean length of stay in the icu was . days. sixteen patients ( . %) were discharged home, twenty-one to acute rehab ( . %), one to subacute rehab ( . %), and two died ( %). among survivors, shunt-dependency occurred in / ( . %), compared to the . %- . % range reported in prior literature. in the study population, cisternal drains appear to be safe as measured against historical cohorts, with comparable or lower shunt-dependency rates. this suggests the viability of further prospective studies to determine the appropriate population for and role of cisternal drainage in the management of asah. estimates of seizure onset after aneurysmal subarachnoid hemorrhage (asah) vary widely, reported rates range from % to %. moreover, seizures increase mortality and disability in patients with asah regardless of common asah complications such as: rebleeding, delayed cerebral injury and vasospasm. we sought to establish the frequency of seizures in asah patients, along with their impact over prognosis, during hospitalization and upon discharge. a retrospective review of consecutive patients with asah admitted to the baylor st. luke's medical center between january and december was conducted. subject demographics, admission gcs, admission mrs, incidence of clinical seizures and clinical outcome at discharge were recorded. associations between the presence or absence of clinical seizures and outcome, measured by the glasgow outcome scale (gos), were investigated using a multivariate logistic regression model. patients with asah were included. clinical seizures were identified in subjects ( . %). outcome was significantly worse for subjects who experienced a clinical seizure compared to subjects who remained seizure-free during hospitalization, poor outcome (gos< ) was found on . % and % respectively (or . , ]; p= . ) this increased risk was significant after controlling hospice, death) was more common for the seizure group compared to the seizure-free group, . % vs . % respectively, however this difference did not reach significance (or . , ]; p= . ) our results showed a low frequency of clinical seizures ( . %) after asah, when compared to other series that have identified an increased incidence of seizures through multimodal approaches. as indexed by gos, along with a non-significant trend towards an unfavorable discharge disposition, among patients with seizures. vasospasm and delayed cerebral ischemia (dci) account for % of the morbidity and mortality after aneurysmal subarachnoid hemorrhage (asah). perfusion ct has been shown to be useful in identifying vasospasm, but this technique is less sensitive to microvascular perfusion changes. mr perfusion (mrp) has been increasingly used in the acute ischemic stroke population and avoids ionizing radiation. we hypothesized mrp may predict the presence of vasospasm by providing measures of impaired cerebral perfusion. we performed a retrospective cohort study with consecutive asah patients between december and august . patients who underwent mrp for concern of dci followed by digital subtraction angiography (dsa) within hours were included. quantitative volumetric analysis was performed at several thresholds of cerebral for the presence of a tmax> lesion. exact wilcoxon rank sums test was used to compare perfusion volumes between patients treated endovascularly versus not treated for vasospasm. we identified patients with a total of mri studies meeting inclusion criteria ( patients treated, patients not treated). no tmax> s hypoperfusion lesion was identified in the untreated group, while / ( %) of the treated patients had at least some delay of tmax> s (p= . ). performance of mrp to detect vasospasm was sensitivity . ( %ci . - . ), specificity . ( %ci . - . ), ppv . ( . - . ), npv . ( %ci . requiring treatment for vasospasm. significant perfusion delay by tmax > s is present in patients requiring endovascular vasospasm treatment after asah. these results suggest that mrp may be a useful tool for patient triage for vasospasm therapy, and further studies are indicated for comparison to other screening methods for vasospasm. recent studies have suggested inflammation and immune dysregulation are important pathophysiology in aneurysmal subarachnoid hemorrhage (asah), and neutrophil to lymphocyte ratio (nlr) was considered as significant clinical predictor of unfavorable outcome including delayed cerebral ischemia (dci). we analyzed nlr of asah patients during ttm, and proposed that the changes in nlr may reflect therapeutic effect of ttm in asah. this retrospective single-center study included asah patients from november , to may , , among which patients underwent ttm after surgical procedures, and other patients didn't undergo ttm. target temperatures were . °c to °c and the durations of ttm were to days. we reviewed the changes of nrl of each patient during ttm and identified whether they had dci, and analyzed in-hospital outcome and -month outcome as measured by the modified rankin scale (mrs). there was no statistically significant difference of overall outcome between ttm group and non-ttm group, but ttm group showed slightly lower rate of dci and better functional outcomes. among the patients, patient who developed dci had higher nlr, and the decreasing rate of nlr was higher in ttm group than non-ttm group. higher decreasing rate of nlr in asah patients while undergo ttm may show the therapeutic effect of ttm. monitoring the trend of nlr value may be helpful in predicting the prognosis of asah patient and estimate the efficacy of ttm for individual patient. eventually, nlr may play important role in deciding practice strategy while treating ttm in asah patients. hydrocephalus is generally regarded as a progressive or static process, but there are few reported cases of transient obstruction of the ventricular system. here, the authors present a rare case of spontaneous symptomatic obstructive hydrocephalus that self-resolved. additionally, a brief review of the literature is performed. records of the patient presented were reviewed in a retrospective manner for all relevant information. pubmed was then searched for all relevant articles. here, we discuss the case of a gentleman in his late 's who presented with worsening confusion and lethargy in the setting of spontaneous subarachnoid and intraventricular hemorrhage. pre-hospital medication includes a daily fish oil supplement; he takes no anticoagulation or antiplatelet agents. approximately one year prior to admission, he experienced an episode of spontaneous left temporal intracerebral hemorrhage. this was attributed to amyloid angiopathy, as evidenced by multiple microbleeds observed on susceptibility weighted imaging at that time. the patient's neurocognitive status steadily declined admission, and he eventually became obtunded. in the process of transferring the patient to the intensive care unit for intubation and external ventricular drain placement, he suddenly became more awake and interactive. the patient's clinical symptoms completely resolved within - hours. no surgical intervention was undertaken. repeat head ct demonstrated that blood products seen in the third ventricle on previous imaging had now migrated into the fourth ventricle. lateral ventricular size had decreased from the prior scan. the following morning, his family members commented that the patient was back to his baseline. transient episodes of obstructive hydrocephalus have rarely been reported in the literature, and are generally associated with an inciting event such as trauma or hemorrhagic stroke. it is possible that there is a higher incidence of transient hydrocephalus, but medical/surgical interventions are performed before the condition is permitted to resolve on its own. raised intracranial pressure (icp) can be a dire consequence of extensive neurologic injury. medical management of elevated icp using intermittent doses of . % hypertonic saline (hts) and/or mannitol is relatively safe and effective for treating refractory intracranial hypertension. at our institution, prior to escalating to sedation and paralysis, hts and mannitol are scheduled. in this study, we aim to describe our experience with scheduled . % hts. methods doses of . % hts during acute admission were included in our retrospective evaluation. only patients who received scheduled . % for anticipated or acute elevated icp in the setting of high-grade subarachnoid hemorrhage (sah) were included. the primary outcome was to characterize efficacy of sustained icp control, by measuring frequency of icp > mmhg and need for escalation of icp management. safety outcomes included incidence of hypernatremia (sodium > meq) and metabolic acidosis. seven out of ( %) patients who received intermittent scheduled doses of . % hts were in the setting of highwere greater than mmhg and no patients required escalation of icp management for the duration of therapy. the median number of doses and duration of . % hts therapy were doses and days (iqr . than meq and patients ( %) developed metabolic acidosis in the setting of hyperchloremia. administration of scheduled intermittent . % hts in the setting of high-grade sah is relatively safe and achieves sustained icp control without need for escalation of icp management. comparative studies of scheduled intermittent . % hts vs alternative medical therapies for icp management are warranted. use of contrast-enhanced computed tomography (ct) studies to evaluate neurological disorders have increased due to its non-invasiveness, fast image acquisition, easy accessibility, and minimal complications. one such procedure is ct myelogram that delineates the extent of spinal stenosis and helps in neurosurgical planning. however, it can result in intracranial migration of contrast medium leading to contrast-induced-encephalopathy (cie). we report cases mimicking as subarachnoid hemorrhage after ct myelogram who subsequently developed cie. case : a -year-old man with chronic low back pain (clbp) was evaluated for confusion, headache due to "intracranial bleed". ct showed diffuse cerebral edema and hyperdensity in the subarachnoid space. external ventricular drain (evd) was placed for suspected post-sah hydrocephalus. however, ct and ct angiogram did not show any cerebrovascular malformation. the patient developed severe encephalopathy and left hemiparesis. repeat ct head showed worsening cerebral edema and hours prior to presentation. severe cerebral edema and left hemiparesis necessitated the use of dexamethasone with improvement in clinical symptoms and examination returning to near baseline. case : a -year-old man with clbp was admitted for "sah" and associated cerebral edema with hydrocephalus. the initial presentation was confusion, double vision, and headache. ct showed diffuse cerebral edema with sulcal effacement, loss of basal cisterns and dilated lateral ventricles. ct and ct angiogram did not show a days prior to presentation. evd placed for hydrocephalus was quickly weaned off the improvement of ventriculomegaly. the patient was discharged with complete resolution of symptoms. cie should be suspected in patients with encephalopathy after ct myelogram. non-contrast ct head is to be interpreted in conjunction with clinical history to avoid unnecessary procedures that might further worsen cie. seizures and ictal-interictal continuum (iic) activity may impact recovery from acute brain injury (abi). empiric antiepileptic drug (aed) intensification for electrophysiologic activity of uncertain significance is challenging to evaluate given structural neurologic deficits, variable pharmacodynamics, and potential sedative effects. we analyzed the eeg and electronic medical records to identify electrographic biomarkers predicting clinical response to aed therapy. we ascertained patients undergoing continuous electroencephalography (ceeg) during admission for abi from a prospective big data repository of clinical data including regularly sampled glasgow coma scale (gcs) scores and med -specific spectral power (alpha - hz, theta - hz, and delta . - hz) and graph theoretical metrics of eeg functional connectivity were compared at time intervals before and after aed therapy. patients met inclusion criteria. , aed doses were administered (mean . +/- . unique aeds per patient). initiating the first aed was followed by a . -point average improvement in gcs (p= . x - ); initiating a second or third aed yielded no significant change, and adding a fourth, fifth, or sixth aed was followed by a . -point worsening in gcs (p= . ). improvement in gcs hours after aed administration was heralded by decline in eeg delta power and rise in network density in the hour following treatment. decline in gcs was heralded by an early rise in delta power and decline in network density. patients with the highest tertile of eeg improvement (greatest combination of rising eeg density and declining delta power) had a consistently improving gcs trajectory in the hours following medication administration, whereas those in the lowest tertile had a consistently worsening gcs trajectory. empirically intensifying aed treatment for disorders of consciousness after abi has diminishing benefit after the initial agent. quantitative eeg biomarkers of early treatment response appears to robustly predict clinical response following aed treatment. new-onset refractory status epilepticus (norse) describes patients with no seizure history who develop refractory status epilepticus (se). the majority progress to super refractory status epilepticus (se). we present a single-center case series of super refractory norse patients to highlight unique features of this group. retrospective chart review was performed to identify adults (age> ) admitted to the columbia university neurological icu from / - / who required continuous midazolam infusions for treatment of super refractory norse. outcome was defined as modified rankin score (mrs) at hospital discharge. descriptive statistics were performed using microsoft excel. of the cases, %(n= ) had a prodrome prior to seizures (infectious, psychiatric or both). patient age was bimodally distributed with %(n= ) less than years old and %(n= ) over . the most common comorbidity was an underlying autoimmune/rheumatologic condition ( %,n= ), though most patients had no pre-existing conditions ( %,n= ). the average stess score was (standard deviation . ). the majority ( %,n= ) remained cryptogenic despite extensive testing. etiologies were identified in %(n= ) - with nmda encephalitis and two with cns infections. immunomodulatory treatment included steroids in %(n= , started on average days from seizure onset, range - ), intravenous immunoglobulin in %(n= , day , range - ) and plasmapheresis in %(n= , day , range - ). the average icu and hospital stays were (range - ) and (range - ) days, respectively. on discharge, %(n= ) had a good outcome (mrs - ), %(n= ) had fair outcome (mrs - ), %(n= ) had poor outcome (mrs - ) and %(n= ) died. compared to prior studies of all norse patients, our cohort with super refractory se were younger, had more frequent prodrome, longer icu and hospital stays and fewer identified autoimmune/paraneoplastic antibodies. the mortality rate was similar to prior studies, but among survivors, super refractory patients were less likely to have a good or fair outcome. we aimed to assess the management of refractory status epilepticus (rse) in developing (ding) and developed (dev) economies, as the management of this condition is resource intense and poorly standardized. investigators from continents collected a large cohort study of rse patients treated between / - / . case-report-forms were finalized at the annual ncs meeting. rse was defined as se that failed to respond to a benzodiazepine and at least one non-anesthetic antiepileptic agent, and was managed with midazolam (mdz) or propofol(pro). the united nations world-economic-situation-prospect was used to identify sites as being from dev or ding economies. four from dev ( patients) economies were included. patients from dev economies were slightly sicker (stess score . ± . vs. . ± . , p< . ). management of patients from dev economies more frequently involved prolonged eeg monitoring (continuous % vs. %, p< . ) but mdz ( . ± . vs. . ± . mg/kg/h) and pro ( ± vs. ± mcg/kg/min, p< . ) doses were higher in ding economies. breakthrough seizures were more common in ding ( % vs. %, or . , p= . ), but no difference in vasopressor use ( % vs. %; n.s.) or withdrawal seizures ( % vs. % n.s.) was seen. hospital ( ± vs. ± days, p< . ) and icu stays ( ± vs. ± days, p< . ) were longer for patients in ding economies. modified rankin scale at discharge was associated with higher stess scores (p= . ) but did not differ between ding and dev economies. direct comparisons between rse patients managed in ding and dev economies are challenging as the baseline level of illness differed but this dataset provides unique insights into differences in utilization of technology (i.e., eeg monitoring), medications (duration and dosage of anesthetics), and length of stay in different health care systems. larger follow-up studies need to explore matched cohorts and explore differences between private-public hospital settings. unlike most anesthetics ketamine acts as an nmda antagonist. we examine the efficacy of intravenous ketamine in the treatment of rse in a large series. retrospective case series of status epilepticus patients admitted between and who underwent treatment with ketamine, patients underwent multimodality monitoring (mmm). we compared patients with complete seizure cessation after ketamine with those without using chi-square and sample t-test. mean age was +/- years old, % of patients were female. seizure burden was decreased by % within hours of starting ketamine in patients ( %), with complete cessation in ( %). average rate of ketamine infusion was . +/- . mg/kg/h, with duration of . +/- . days. average dose of midazolam was +/- . mg/kg/h. ketamine was started on average +/- day after midazolam. patients without complete seizure control after initiation of ketamine ( / patients) were more commonly cardiac arrest patients % vs % (p=. ), and had lower stess score +/- vs +/- (p=. ). all other characteristics were not statistically significant between the two groups including; age, gender, ketamine infusion dosages and duration, apache score, and midazolam infusion dosages. patients ( %) were weaned off pressors after initiating ketamine infusion. when compared the mmm values h before and after ketamine initiation, intracranial pressure values ( +/- vs +/- ), cerebral perfusion pressures ( +/- vs +/- ), cerebral blood flow ( +/- vs +/- ), and lactate/pyruvate ratio ( +/- vs +/- ) were relatively stable. pbo values increased from +/- . to +/- . in our cohort ketamine infusion had a meaningful decreased in seizure burden in rse. our preliminary data also suggests that ketamine infusion didn't affect the intracranial pressure. continuous eeg (ceeg) is widely used to detect seizures (sz) in patients with acute brain injury. however, studies examining sz and epileptiform abnormalities (ea) using ceeg in acute ischemic stroke (ais) are limited. therefore, we aimed to describe the prevalence of electrographic patterns (sz and ea) in ais and its association with outcomes at discharge. retrospective chart review identified patients with ais who underwent ceeg between / and / . demographics, comorbidities and other relevant clinical factors including nih stroke scale (nihss) and treatment interventions were abstracted. ceeg closest to admission (median days) was reviewed for background, sz and ea (lateralized and periodic discharges (lpds and gpds) lateralized rhythmic delta activity (lrda) and sporadic epileptiform discharges (seds). computed tomography or magnetic resonance imaging of brain closest to the time of ceeg was analyzed for midline shift, hemorrhagic transformation (ht) and cortical involvement. outcomes measures were mortality and functional outcome in modified rankin scale (mrs) ( - good and > poor outcome) at discharge. of the patients, had sz and had ea ( . % lpd, . % lrda, . % gpds and . % seds). those with cortical involvement had higher rate of ea and sz compared to those with subcortical stroke ( . % vs . %, p= . ). no difference was found in sz and ea prevalence with regards to age, sex, nihss, midline shift or ht. overall mortality was . %. absence of posterior dominant rhythm (pdr) was associated with increased mortality ( . % when pdr absent vs . % when present, p= . ). sz and ea did not affect mortality or mrs at discharge. despite high frequency of ea ( %), the risk of sz in ais was low at . % and their presence did not impact functional outcome or mortality. however, eeg background with absence of pdr was associated with increased mortality. nonconvulsive seizures (ncs) are a common complication in patients admitted to neuroscience intensive care units and are associated with worse outcomes. ncs can only be diagnosed with continuous eeg (ceeg) monitoring. intermittent conventional ceeg review by neurophysiologists typically occurs - times a day, therefore patients may be seizing for extended periods of time before the seizure is detected. our study aims to evaluate the accuracy of a quantitative eeg (qeeg) trend, the automated seizure detector (asd) in detecting patients' first seizure, which could aid in rapid detection of ncs. this retrospective study includes review of ceeg and qeeg data from adult patients admitted to a single institution neuro icu who developed ncs on ceeg monitoring. independent conventional ceeg review without qeeg by two board-certified neurophysiologists determined the first seizure occurrence for each patient (gold standard). this was compared to the seizure detection sensitivity of the p asd (persyst, inc., prescott az), an algorithm with no user-adjustable settings. recordings from ncs patients were used. mean age was . years and % was female. seizures had variable durations and spatial extents. the sensitivity of p asd was . % ( % ci . - . ) and specificity was . % ( % ci . - . ). mean false alarm rate was . /hour (sd . ) in the time elapsed from the start of ceeg recording until first seizure occurrence. overall, p asd accurately detected the first seizure in % of patients, disregarding false positives. overall, median time to clinical seizure detection was . hours (iqr . hours). this analysis shows that the persyst p asd may have clinically useful sensitivity and specificity in critically ill patients admitted to a neuroscience icu. in conjunction with a low false alarm rate, incorporation of qeeg asd may lead to a reduction in time for seizure recognition. the incidence of early seizures (es) in traumatic brain injury (tbi) ranges between - %. however, the incidence of es after a non-severe tbi (nstbi) with traumatic hemorrhage (th) is unknown. moreover, the data about seizure prophylaxis (sp) in this population remains inconclusive. we aim to determine the incidence of es in nstbi and the efficacy of sp. we respectively reviewed all adult patients with nstbi with evidene of a th on presentation from to . patients with history of epilepsy or receiving antiepileptic drugs (aed) were excluded. we collected demographic data, the type, severity and mechanism of injury; the need for neurosurgical intervention (nsi); es; and sp use. a total of patients met our inclusion criteria, . % had mild tbi; mean age of . years (sd . ); . % males; and . % had subdural hematoma (sdh). same level fall was the most common ( . %) patients had an es in the sp group ( clinical) vs of ( . %) in the non-prophylaxis group (all clinical) (p = . ). levitiracetam as sp was used in . %. patients with combined sdh and traumatic subarachnoid hemorrhage or with multicompartment hemorrhage were more likely to have es than sdh alone (p = . and . , respectively). nsi was not a predictor for es in our cohort. the incidence of es in nstbi patients in our cohort falls within the previously reported ragne. however, it appears to be higher compared to reported rates for mild tbi. es were more likely in the sp group, which might indicate a clinical selection bias. prospective studies are required to further determine the predictors of es and the effect of sp on outcomes in nstbi patients. patients with psychogenic non-epileptic attacks (pnea) sometimes receive aggressive treatment leading to intubation. this study aimed to identify patient characteristics that can help differentiate pnea from true status epilepticus (se). we retrospectively identified patients with pnea and se who were intubated and underwent continuous had acute brain injury or progressive brain disease as a cause of status epilepticus were excluded. we compared clinical features, treatments and outcome between patients who were intubated for pnea and those who were intubated for se. of , patients who underwent ceeg monitoring, we identified and patients intubated for pnea and se, respectively. compared with patients intubated for se, intubated pnea patients were more likely to ( ) be < years of age ( % vs %, p< . ), ( ) be female ( % vs %, p< . ), ( ) be white ( % vs %, p< . ), ( ) have a history of a psychiatric disorder ( % vs %, p< . ), ( ) have no history of an intracranial abnormality ( % vs %, p< . ), and ( ) have a maximum systolic blood pressure < mm hg ( % vs %, p< . ). patients with - of these risk factors had a % ( / ) likelihood of having pnea, those with - had a % ( / ) chance of having pnea, and those with - had an % ( / ) chance of having pnea. sensitivity for pnea among those with - risk factors was % and specificity was %. pnea in patients presenting with emergent convulsive symptoms can be predicted with a high degree of certainty based on the presence of specific demographic, past medical, and physiologic risk factors. care should be taken to avoid over-sedation and unnecessary intubation in this at-risk patient population. a recent systematic review indicates that the mortality of status epilepticus (se) is about . % with a non significant downward trend in recent years. mortality has not changed much despite aggressive management. this study investigates trends and predictors of in-hospital mortality due to status epilepticus at national level in united states. we performed a cross-sectional analysis using the nationwide inpatient sample (nis), - , of us adult hospitalizations with status epilepticus. annual rate of in-hospital mortality was calculated using nis weighting. we identified our status epilepticus patient subset from using codes (dx = . ) from the international classification of diseases, th edition. potential factors associated with in-hospital mortality were assessed using logistic regression. of , hospitalized patients with status epilepticus, , ( . %) died during the index hospitalization. across - , . % of se patients died; with a downward but not statistically significant trend in-hospital mortality from . % ( ) to . % ( ) (p = . ). se patients with inhospital mortality were more likely to be women, older, and with a higher proportion of medical comorbidities, in-hospital complications and extreme loss of function as per all patients refined diagnosis al failure, apr drg severity, mechanical ventilation, tracheostomy, sepsis, pulmonary embolism, acute kidney injury and respiratory insufficiency. mortality due to se was lower than previously reported. mortality has had a non-significant downward trend in the years studied. age, female gender, medical complications and poor baseline functional status are important predictors. availability of aggressive treatment has not modified significantly mortality which requires further study. pregabalin (pgb) is an approved adjunctive treatment for focal epilepsy in adults. pgb lacks drug-drug interactions, has a favorable safety profile and can be rapidly titrated-attractive characteristics for its use in the neurocritically ill. however, data remain limited regarding its use in the icu setting. we are sharing our experience with pgb in neurocritically ill patients with refractory seizures. charts of eight adult patients admitted received pgb were reviewed retrospectively. demographics, antiseizure drug (asd) regimen, and h of eeg data pre-and post-pgb were analyzed descriptively. the cohort comprised eight patients ( females) with mean age of . years. mean icu stay was . days. three patients underwent a neurosurgical procedure related to their primary admission diagnosis, an asd prior to first seizure captured on eeg. prior to pgb, patients had failed on average ( - ) other asds trials. pgb was dosed - mg/day in - divided doses, following a load of - mg. pgb lead to a significant reduction on hourly median seizure burden: . to seizure/h and . to . min/h. pgb led to complete seizure cessation in patients within h and in out of within h of administration. pgb allowed for de-escalation of asd regimen in out of patients. pgb was well tolerated with the exception of mild sedation in patients, which did not warrant further intervention/neurodiagnostics. in this critically ill cohort with refractory seizures, pgb successfully aborted seizures in % of patients. include prospective pregabalin treatment protocols. to describe the first known reported case of utilization of electroconvulsive therapy (ect) to treat super refractory status epilepticus (srse) in pregnancy. we present the case of a year old caucasian female at weeks gestation with pmh focal and generalized seizures who was treated for srse successfully with ect after failed pharmacological treatment. the most likely etiology of srse was sudden cessation of medications upon pregnancy. eeg showed types of seizure activity: rhythmic theta waves over right temporal region with evolution and independent generalized seizures. treatment included use of approximately antiepileptics including , propofol, pentobarbital, magnesium, ketamine, topiramate and valproic acid over the course of days in addition to modifying epilepticus remained super refractory with appearance of mixture of sharp waves on weaning off sedation. she underwent ect with right unilateral electrode placement on day with remarkable improvement in eeg pattern and resolution of srse with single session. patient was back to baseline level of awareness at the time of discharge. on follow up in clinic, she had significant improvement in seizure control with normal fetal development and delivery. treatment of status epilepticus in pregnancy is challenging given the unknown effect of prolonged sedation or hypothermia on fetal development. alternative treatments like ect, vns, dbs, ketogenic diet and hypothermia are sporadically used. use of ect is not considered first or even second line treatment in srse, despite its safe profile, especially in pregnancy. this case adds to the available literature on the success of ect for treatment of srse and puts emphasis on the need for a clinical trial regarding use of ect in srse. the importance of neurocritical care (ncc) has been recognized. but no dedicated educational system for it exists in japan. we have established version of an educational ncc hands-on seminar. this study investigated its effects. this study was a prospective, before-after study using questionnaires and examinations. it was a full-day version . the learning concept was to identify the various methods for maintaining cerebral oxygen balance to prevent secondary brain injury. participants attended five skill sessions: intracranial pressure monitoring, trans-cranial color flow image, targeted temperature management, neuro examination, and eeg, and four scenario sessions: post-cardiac arrest syndrome, subarachnoid hemorrhage, traumatic brain injury, and non-traumatic acute weakness. they had examinations before and after the seminar. the primary outcome was the improvement on examination scores after the seminar. secondary outcomes were the degrees of satisfaction with it and confidence of participants in ncc. we evaluated the improvement of the outcome using wilcoxon signed rank test. a p-value of . or less was considered as significant. thirty-nine physicians and one nurse participated in the seminar. we excluded ( . %) participants because their answers were incomplete. we had ( . %) physicians who are in emergency or intensive care medicine, and ( . %) other professionals. their median age group was in their s (iqr: - ) with median intensive care medicine experience of years (iqr: . - . ). the percentage of correct answers, scores in the examination, improved significantly from (iqr: . - . ) to (iqr: . - . ) after the seminar (p< . ). eighteen ( . %) participants were satisfied with it, and the number of professionals who could not feel ncc-confident decreased from ( %) before the seminar to after its completion (p< . ). our seminar successfully improved the physicians' knowledge of ncc, and gave them more confidence in ncc. glutamic acid decarboxylase (gad) is the rate-limiting enzyme to convert glutamate to gammaaminobutyric acid (gaba). autoantibodies targeted against gad have been implicated in a number of syndromes with neurologic manifestations including stiff-person syndrome, cerebellar ataxia, limbic encephalitis, and epilepsy. we highlight an atypical presentation of this rare disorder with several unique features to the neurological intensive care unit. -year-old woman with pmh of dm, remote left insular ischemic stroke, and recent right leg dystonia presented after being found down with rightward eye gaze deviation, gtc shaking, and urinary incontinence. she required midazolam, lorazepam, loading doses of levetiracetam and fosphenytoin, and propofol infusion to achieve clinical seizure control. despite these interventions, eeg showed ncse with left temporal seizures and anterior midline epileptiform discharges. propofol was titrated to burst suppression. she had several other active medical problems including kidney injury, transaminitis, and myoclonus. seizures and myoclonus were greatly improved after the addition of clonazepam; however, she remained encephalopathic. pertinent diagnostic results included ferritin , ng/ml, ldh , units/l, il- r u/ml, b -micr and serum gad ab titer nmol/l. mri brain showed prominent superior frontal lobe cortical edema. bone marrow biopsy demonstrated good cellularity without malignancy. skin biopsies on three random samples were positive for perivascular dermatitis with telangiectasia. she was started on high dose steroids with subsequent progressive mental status improvement. anti-gad ab associated vasculitis is an exceedingly rare occurrence whose diagnosis previously involved brain biopsy. this case is unique given her acute presentation with refractory status epilepticus, systemic involvement, and diagnosis on skin biopsy. while management has involved immunotherapy, specific treatment guidelines do not exist. given her marked response to clonazepam and corticosteroids, we advocate for early initiation of gabaergic medications such as benzodiazepines and use of immunotherapy. epileptic seizures are a serious complication in patients with subdural hemorrhage (sdh), resulting in increased mortality rates. the incidence of new onset seizures in these patients is unclear. we examined the incidence for new onset seizures and status epilepticus (se) in sdh patients. we examined patients diagnosed with sdh and epilepsy between september to december . we included patients with new onset seizures and extracted those who had seizures after sdh evacuation. clinical and radiographic characteristics, and outcomes of those patients were described. we screened patients diagnosed with sdh, traumatic or non-traumatic. underwent a surgical intervention and ( %) patients had a seizure during their hospital stay. among those who had a seizure, patients had prior history of epilepsy, and had a new onset seizure. although sdh patients with history of epilepsy showed higher incidences of seizures than those with no history (p= . ), sdh patients with history of epilepsy mostly did not evolve into se and those who had no history of epilepsy usually did. there was no significant difference in patients developing se when compared to those without se between the sdh thickness, midline shift, temporal lobe involvement or age of blood (acute or chronic). seizure occurrence in patients with sdh is commonly new onset; however, they are infrequent. in addition, sdh patients with no history of epilepsy have a higher tendency to develop se as opposed to patients with history of epilepsy. larger multicenter cohort studies need to be done for evaluation of these findings. sequoia hospital in redwood city, ca implemented the ceribell rapid response eeg system in to expand its access to eeg for in-patient usage. previously, the hospital had no access to after-hours eeg and the majority of their eegs happened in the icu. this quality improvement project was initiated to understand how access to rapid eeg impacted clinical care and financial metrics across at sequoia hospital. data was analyzed for all patients who received either conventional or ceribell eeg from january , including the department where eeg was conducted, time of day of eeg was ordered, time when eeg began, and clinical diagnosis based on the eeg. data was also captured on patient transfer due to lack of eeg. % of eegs were ordered after hours after the introduction of ceribell, compared to nearly no eegs done after hours before ceribell. % of patients with ceribell eegs were diagnosed with seizures. in , of ceribell eegs, eegs occurred in the in-patient unit or ed. in % of patients with a high suspicion of seizure, seizures were ruled out as a result of reading the ceribell eeg. the introduction of ceribell eegs has greatly expanded access to eegs at sequoia hospital. before ceribell was introduced, eegs mostly occurred in the icu and nearly all happened during regular hours. after ceribell was introduced, eeg was also heavily utilized in the ed and the in-patient unit and gave sequoia eeg access during after hours. as a result of this expanded access and earlier application of eegs, patients have been treated more appropriately. tranexamic acid (txa) is an intravenous antifibrinolytic agent that is used routinely for elective surgery. we report a case of inadvertent intrathecal injection of txa resulting in refractory status epilepticus. case report. a -year-old healthy female admitted for bilateral total knee replacement was inadvertently administered mg of txa intrathecally instead of bupivacaine. soon after administration, she intubated, administered levetiracetam, started on a propofol infusion, and transferred to the neurointensive care unit (nicu). she developed persistent spontaneous and stimulus induced generalized myoclonus refractory to propofol. midazolam infusion was added. nchct and cta demonstrated pneumocephalus, but no acute arterial or venous thrombosis or stroke. veeg revealed generalized nonconvulsive seizures occurring once per minute, not correlating with spinal myoclonus . propofol and midazolam infusions were increased to mcg/kg/min and . mg/kg/hr, respectively, to achieve burst suppression, and valproic acid was added. over the following week, the drips were adjusted to suppress seizure activity. by hospital day , she was weaned off all infusions without recurrence of seizures. by hospital day , she was on levetiracetam monotherapy. she was discharged to rehab after a -day hospital course, and was discharged home days after initial presentation. residual deficits at the time of discharge included mild cognitive impairment and gait instability. she remains seizure-free since hospital day on levetiracetam mg bid. we report a case of refractory status epilepticus and spinal myoclonus after accidental intrathecal txa administration. with aggressive management, the patient survived with mild residual deficits. the mechanism by which txa causes status epilepticus and spinal myoclonus is hypothesized to be related to its inhibitory effects on gaba and glycine receptors, respectively. ictal bradycardia (ib) is a serious complication of temporal lobe epilepsy. if left untreated, ib can cause serious injuries related to syncope, complete heart block and death. management of this phenomenon is controversial: should you treat the seizures or the arrhythmia? we describe the management of a patient who presented with multiple syncopal episodes and found to have symptomatic bradycardia in the setting of temporal lobe seizures. a -year-old male with a recently resected brainstem cavernoma presented with episodes of 'spacing out', face tingling and transient periods of amnesia. he was started on topamax and lamictal. several months later, he began having multiple syncopal events (upwards of a day) that eventually brought him the hospital for evaluation. he was found to be bradycardic with a heartrate in the thirties and had sinus pauses lasting up to ten seconds requiring atropine, an isoproterenol infusion and transcutaneous (tc) pacing. he was also found to have another cavernoma in the right temporal lobe. eeg revealed epileptic activity within the right anterior temporal lobe with correlation to his tc pacing and ib events. lamictal was replaced with keppra and the seizure activity was controlled. he had a pacemaker implanted, after which he did not have any further episodes of syncope and no further seizure activity. the cavernoma was resected a few months later, and he did well postoperatively. ib is an uncommon, but serious, complication of temporal lobe epilepsy. the temporal insula plays a role in the parasympathetic activity of the heart which can cause ib. it may be beneficial for patients who present with symptoms characteristic of temporal lobe seizures or repeated falls/drop attacks to have a full cardiac work up to rule out ib in order to determine if a pacemaker is warranted. the ceeg has had rapid growth within neurological monitoring within the icu, however its still disparate resource in the icus of latin america. is important to know the real situation in colombia about the accessibility to ceeg monitoring. an anonimus survey of questions was conducted from october to april . it was answered by intensivists from latin america, europe, asia and usa. (n= ) considering the accessibility to the ceeg, the ceeg clinical indications and the ceeg monitoring extends (hours) in the icu, we can conclude that colombia is aligned with other countries in the world. in the icus of colombia less than half of the intensivists make decisions in ¨real time¨ with the ceeg and have access to the qeeg modality. the most common cause for non-presciption of ceeg was scarce resources (equipment and human resorces support from a neurology service). cefepime is a fourth-generation cephalosporin with broad-spectrum coverage used to treat infections in critically ill patients. neurotoxic effects have been associated with cefepime, including myoclonus, reduced consciousness, and seizures. we report a case of a patient receiving cefepime who developed non-fluent aphasia and non-convulsive status epilepticus (ncse). two seizure drug trials (levetiracetam and fosphenytoin) failed before marked clinical and electrographic improvement with clobazam. other than cessation of the offending agent, there is little known about the management of cephalosporin associated non-convulsive status epilepticus. data was collected from our institution's health record. a -year-old female with a history of diabetes, chronic kidney disease, recent coronary artery bypass grafting, and mitral valve repair presented with pseudomonas aeruginosa cellulitis of the sternotomy site. on day six of cefepime therapy she developed non-fluent aphasia. mri brain and toxic-metabolic work-up was unrevealing. eeg was consistent with non-convulsive status epilepticus. she failed to respond to standard levetiracetam or fosphenytoin therapy. lorazepam was given with marked improvement in her eeg. clobazam was subsequently started resulting in marked improvement in the patient's language and sustained resolution of ictal pattern on eeg. epileptogenic effects of ß lactam antibiotics are thought to be due to competitive antagonism of the gabaa receptor. beside the recommendation of withholding offending agents when safe to do so, there is no guidance in the literature regarding the appropriate antiepileptic drug choices for the treatment of cephalosporin associated ncse. in this case, clobazam, a benzodiazepine, was an effective treatment. given the theorized mechanism gaba antagonism of cefepime, it is possible that benzodiazepines may ch is needed regarding the optimal seizure control for various etiologies of ncse. when treating seizures and ncse, consideration should be given to the possible mechanism of action of the suspected offending agent. hashimoto encephalopathy is a rare disease. clinical manifestations include abnormal behavior or psychosis, seizures, encephalopathy. pathophysiology is not completely known but it has been associated with autoimmune thyroiditis. we report a case of hashimoto encephalopathy with status epilepticus which responded well to steroids and relapsed following steroid taper. -year-old previously healthy woman was admitted with encephalopathy, new-onset seizures, and delusional behavior for past - weeks. mri brain was unremarkable. eeg showed status epilepticus with right fronto-central origin. she was treated with multiple antiepileptic medications including evaluation for infections, autoimmune and paraneoplastic etiologies revealed elevated thyroid peroxidase, antithyroglubulin and mildly elevated gad antibodies. whole body ct showed no malignancy. she was diagnosed with hashimoto encephopathy. she was treated with iv steroids and ivig. her clinical improvement correlated with decrease in thyroglobulin antibody levels from . to . and thyroid peroxidase antibody levels from . to . . she was discharged on oral steroids and admitted again in few weeks with a relapse of behavioral issues and seizures following steroid taper. she was treated with high dose iv steroids, this time followed by rituximab with significant improvement. she was discharged again on oral steroids with very slow taper and close follow up. our patient had hashimoto encephalopathy and had relapse following taper of steroids. hashimoto encephalopathy is rare condition and is often under-diagnosed. anti-thyroglobulin and thyroid peroxidase antibodies should be checked in patients where no other etiology of new onset status epilepticus is identified. along with seizure management, they should be treated with immunomodulators. closer follow up is needed while tapering the steroids as relapse can occur with behavioral issues and seizures and they may benefit from steroid sparing long term immunomodulatory treatment. non-convulsive seizures (ncszs) and non-convulsive status epilepticus (ncse) are common in critically ill patients. both are associated with neurophysiological disturbances, and even mortality if untreated in a timely manner. [ ]continuous electroencephalogram (ceeg) monitoring has been proven to be effective in diagnosing ncszs and ncses, and assessing the efficacy of treatment thus it is a vital investigation. [ ] we conducted a national survey on the availability of ceeg monitoring within neuro critical care units (nccu) in the uk. to ensure accuracy the consultant in charge or st - covering the nccu was contacted by telephone and asked a serious of questions regarding their use of ceeg and reporting. hospitals were identified as having either stand alone or mixed nccu. responses were obtained from of the units contacted. only % of nccus were able to perform ceeg monitoring from am- pm this dropped to % at night. in % of nccus the itu consultant did not feel confident to analayse the ceeg and make treatment decisions based upon in. the inability of % of nccu to perform ceeg is very concerning, as a single eeg may miss episodes of status, and also makes treatment to achieve burst suppression very difficult. in addition, there appears to be a training gap in ability of icu doctors ability to interpret ceeg. commissioning standards may need to be modified to encourage take of this vital monitoring technique. in addition systems such as possibly setting up a central remote analysis site for all ceeg data for england might improve time to diagnosis and treatment whilst still remaining economically. traumatic brain injury (tbi) is the leading cause of disability in children. neuroimaging is essential for the acute evaluation of moderate-severe tbi, although its prognostic utility is unclear. magnetic resonance imaging (mri) allows for detailed characterization of diffuse axonal injury (dai), the hallmark pathology described in non-penetrating tbi. higher dai grade in adults correlates with worse outcome, but this association has not been rigorously tested in children. we hypothesize that acute rotterdam score and dai grade predict short-term functional outcome in children with acute tbi. patients admitted to stanford children's hospital for acute tbi were identified via retrospective chart review based on icd and icd codes for tbi. inclusion criteria were age > mo and < yrs with blunt, closed head trauma and mri brain obtained during hospitalization. exclusion criteria included history of epilepsy, prior tbi, developmental delay, and penetrating or non-accidental trauma. the first head ct and brain mri obtained during hospitalization were used for analysis of rotterdam score and dai grade, respectively. discharge destination (home versus facility) was used as a marker of short-term functional outcome. multiple logistic regression analysis on cohort of children revealed that lower gcs and ventriculostomy were independent predictors for discharge to acute rehabilitation (or . and , respectively) versus discharge home. neuroimaging analysis revealed that more severe dai significantly correlated with discharge to a rehabilitation facility (p= . ), while rotterdam ct score did not correlate with discharge destination (p= . ). our study demonstrates that higher dai grade is associated with worse short-term outcome in pediatric patients understand the short-and long-term prognostic value of acute neuroimaging in pediatric tbi. , niteroi, brazil zika virus has been associated with several neurological complications. we aim to present three cases of zika associated subacute encephalitis, all requiring intensive care. all patients derived from the rio-zikv-gbs study cohort. all were diagnosed with mac-elisa and pcr for case : -year-old man admitted with lower extremities weakness and urinary retention, preceded by -capsular area, extending to the corona radiata and cerebellar peduncles. he was treated with a -day cycle of intravenous immunoglobulin (ivig). he was discharged one year later due to protracted weaning from mechanical ventilation. case : -year-old man admitted with lower extremities weakness, dysphagia, and dysphonia. days before he presented with and middle cerebellar peduncles, extending to pyramidal tracts. he was treated with ivig. he was discharged after acute treatment and, one year later, presented only with ataxic gait. case : year-old woman admitted with disorientation and behavioral impairment. a week before she presented with % mononuclear) with mild protein elevation. mri revealed hyperintense -t levels. she was also treated with ivig. a year later her neurological exam returned to baseline. all patients had similar clinical presentation, starting with atypical measles syndrome, later evolving to a subacute encephalitis. all showed similar radiological findings, resembling the ones observed with japanese encephalitis, another flavivirus. this new entity is likely a result of zikv-mediated autoimmune activation and it is a challenge for neurocritical care units worldwide. there are two described forms of necrotizing encephalopathy: multifocal necrotizing leukoencephalopathy (mnl) and acute necrotizing encephalopathy (ane). mnl is characterized by multiple microscopic foci of white matter necrosis and is sporadic with predilection for the pons in patients with sepsis or immunosuppression. ane is characterized by multiple foci of grey and white matter disease and is either sporadic or familial; it is typically triggered by febrile viral illness in children without evidence of cerebral infection. a case report with review of the clinical, laboratory, radiographic, and pathologic data. a -year-old woman with post-traumatic epilepsy was admitted with acute encephalopathy and respiratory failure secondary to h n and strepotococcal pneumonia. she developed refractory hypoxemia requiring proning and eventually veno-veno extra corporeal membrane oxygenation. her neurological exam declined with no response to painful stimuli and absent corneal reflexes. continuous restricted diffusion lesions of the cerebral white matter, splenium of the corpus callosum, brainstem, cerebellar peduncles, and deep cerebellum. she died after transition to comfort care and autopsy was pursued by family. neuropathologic evaluation revealed microscopic acute and subacute necrotizing lesions throughout the white matter of the cerebrum, pons, and cervical spinal cord. there were similar lesions throughout the thalamus with sparing of other gray matter structures. there was no significant lymphocytic inflammation or meningoencephalitis. this presentation is consistent with mnl, yet the thalamic involvement is more characteristic of ane. however, ane is rare in adults and typically affects both the grey and white matter. our case affected mostly white matter with microscopic lesions in the grey matter of the thalamus. this case is unique in that it has features of both known necrotizing leukoencephalopathies without clear classification. pharmacotherapy after traumatic brain injury (tbi) aims to prevent secondary insults by optimizing brain homeostasis. to better understand the relationships between medication infusions and cerebral dynamics, we investigated their associations with cerebral compliance (cc), autoregulation (ca) and heart-rate variability (hrv). a retrospective analysis of severe tbi patients admitted to the pediatric icu who underwent brain multimodal monitoring was performed. ca, cc and hrv were estimated by using different parameters: ca by using the pressure reactivity index -a pearson correlation coefficient; cc by using the rap indexa correlation between icp and pulse amplitude; hrv by heart-rate root mean square of successive differences. analysis of variance was used to investigate cerebral dynamics differences during narcotic/sedation (dexmedetomidine, fentanyl, propofol), barbiturate (pentobarbital), vasoactive (epinephrine, milrinone, nicardipine, norepinephrine, phenylephrine) and paralytic (vecuronium, rocuronium) medication infusions. children were identified ( female; ages - years). ca values were significantly higher (i.e. larger positive values) in patients who received vasoactive infusions than those who did not (epinephrine ( . ± . ), norephinephrine ( . ± . )). cc values were much larger (closer to ) in patients who received barbiturate and paralytic infusions compared to those who received narcotic/sedation infusions (pentobarbital ( . ± . ), vecuronium/rocuronium ( . ± . ), fentanyl ( . ± . ), dexmedetomidine ( . ± . ), propofol ( . ± . )). hrv displayed significantly larger values in patients who received narcotic/sedation infusions compared to those who received barbiturate infusions (propofol ( . ± . ), dexmedetomidine ( . ± . ), pentobarbital ( . ± . )). these results suggest vasoactive infusions (epinephrine and norepinephrine) are associated with impaired ca, narcotic/sedation infusions (dexmedetomidine and propofol) are associated with improved cc and greater hrv, and barbiturate infusions (pentobarbital) are associated with impaired cc and less hrv after severe tbi. prospective analysis is needed to validate these associations and investigate whether these medications may be contributors or epiphenomena of altered cerebral dynamics. sleep wake disturbances (swd) after pediatric traumatic brain injury (tbi) requiring critical care admission are poorly quantified, but may have important implications for patient recovery. we conducted a systematic review to quantify swd after pediatric tbi requiring critical care, identify interventions for swd, and determine the association between swd and other post-intensive care syndrome (pics) morbidities after tbi. injury requiring neurocritical care published after and reporting a sleep or fatigue outcome. studies focused on concussion or mild tbi without differentiation of intracranial injury requiring critical care hospitalization were excluded. risk of bias was assessed for included studies. a meta-analysis was not performed due to heterogeneity of included studies. search results yielded articles. abstract review yielded articles, and studies were included in the final analysis ( observational, case reports). we found children with tbi had significantly more swd when compared to controls. studies reported over one third of tbi patients have swd, some persisting for years after injury, but often failed to delineate phenotypes of sleep problems. most studies used subjective measures with questionnaires or interview. seven studies used a validated sleep questionnaire. three studies with total patients presented objective data on swd using actigraphy (n= ), polysomnography (n= ), and electroencephalography (n= ). outside of one case report, no studies evaluated interventions for swd following pediatric tbi. swd in children surviving tbi were associated with pics morbidities including reduced quality of life, behavioral problems, and neurocognitive impairment. heterogeneity and risk of bias among studies was high. research is needed to quantify swd, including identifying phenotypes and utilizing objective measures of sleep. evaluation of pharmacological, psychological, and behavioral interventions for swd is warranted given associations between swd and pics. current guidelines for pediatric severe traumatic brain injury (tbi) recommend maintenance of mean intracranial pressure (icp) under mmhg. increasing evidence has suggested that icp waveform characteristics may be important in understanding the impact of pressure on cerebral physiology. our study objective is to investigate strength of association of brain tissue oxygenation with icp waveform characteristics. retrospective analysis was performed on pediatric patients with tbi who underwent multimodality monitoring including measurements of pbto and icp between january , and january , . data were limited to relatively normal values of pbto between and mmhg and icp values between and mmhg. univariate linear regression was performed to assess strength of association between pbto and icp waveform characteristics including, mean icp values, icp pulse amplitude (amp), and minimum and maximum values of the icp waveforms. patients were identified ( female, ages - years [mean . ; interquartile range . - . ]). pbto was negatively associated with all icp characteristics following analysis. the correlation coefficient (r) was stronger with respect to the relationship of pbto to amp (r = - . ) as compared to mean icp (r = - . ), maximal icp (r = - . ) and minimal icp (r = - . ). p-values were < . for all measurements. these data provide preliminary evidence that icp pulse amplitude is associated with pbto . these findings suggest that icp waveform amplitude should receive greater scrutiny in understanding the impact that icp has on pbto after pediatric severe tbi though further research is necessary to confirm this finding. sarcoidosis is a systemic disease characterized by formation of noncaseating granulomas. in - % of cases, sarcoid infiltrates the central nervous system causing a myriad of clinical symptoms and imaging findings. although rare, neurosarcoidosis commonly involves the brainstem, hypothalamic-pituitary axis, leptomeninges, and spinal cord, causing symptoms such as cranial neuropathies, hypopituitarism, aseptic meningitis, and seizures. based on the review of literature, neurogenic shock as a complication of neurosarcoidosis has not been previously reported. a retrospective chart review was performed on the patient's medical records to obtain laboratory results, imaging studies, and treatment modalities. we demonstrate a case of neurosarcoidosis that initially presented with neurogenic shock, seizure-like activities, and anterograde amnesia. a -year-old african american man with neurogenic shock and seizure-like activities was transferred to our neurointensive care unit. initial workup revealed panhypopituitarism, including hypothyroidism and central diabetes insipidus. mri of neuro-axis was significant for diffuse parenchymal and leptomeningeal enhancing lesions of unclear etiology, including the hypothalamic-pituitary axis, bilateral mesial temporal lobes, and cervical spinal cord. he was intubated for airway protection and treated with dopamine infusion for hypotension and bradycardia thought to be a manifestation of neurogenic shock from his extensive cervical spinal cord lesion. despite significant cervical cord involvement, he remained with good strength throughout. he was extubated after a short course of high dose steroids and stabilization of electrolytes and endocrine function however was found to have anterograde amnesia -pet revealed hypermetabolic lymphadenopathy throughout the neck, chest, abdomen, and pelvis without cardiac involvement. he subsequently underwent lymph node biopsy which revealed noncaseating granulomas. neurosarcoidosis is an infiltrative disease process with varied clinical and imaging presentations. although neurogenic shock is classically seen as a complication from spinal cord injuries above the t segment, neurosarcoidosis affecting the cervical spinal cord can also present with neurogenic shock. the primary goal of traumatic brain injury (tbi) management is the prevention of secondary injury achieved by invasive intracranial pressure (icp) monitoring. near infrared spectroscopy (nirs) is a continuous, noninvasive surrogate measure of cerebral blood flow and oxygenation making it a potentially useful adjunct in the management of tbi. we aimed to determine the association between regional oximetry (rso ) and icp in pediatric tbi. the association between rso and icp was estimated retrospectively in pediatric patients with severe tbi. digital record using univariate dynamic structural equations modeling with a % credible interval ( % ci) for the standardized regression coefficients (src). of study patients had documented events. the association between rso and icp varied between patients and event type. no events triggered by changes in rso occurred. a significant positive (src= . , % ci= . - . ; src= . , % ci= . - . respectively). a negative r this was not significant (src=- . , % ci=- . - . ). during times without intracranial hypertension, changes in icp were positively associated with changes in rso , which may be related to changes in cerebral blood flow. our results also suggest that cerebral desaturation may be seen during periods of intracranial hypertension. our data supports the utility of nirs as an adjunct to understanding changes in icp, however further research is needed to determine if these findings are clinically relevant. rapidly progressive (< hours) primary angiitis of the central nervous system (pacns) has rarely been reported in the literature. most cases have resulted in death. here, we describe the neurocritical care course of a patient with rapidly progressive pacns who survives with a good outcome. data was collected prospectively through direct patient care and chart review. a -year-old previously healthy male presented to an emergency room in acute coma. initial head ct showed diffuse cerebral edema and a left thalamic intracerebral hemorrhage. non-contrast brain mri c perivascular enhancement suggestive of cerebral vasculitis. an external ventricular drain was placed for intracranial pressure monitoring and cerebrospinal fluid sampling, which showed a neutrophilic pleocytosis (wbc= , % pmn). brain biopsy on hospital day (hd) # was consistent with a diagnosis of necrotizing pacns. rheumatologic evaluation was negative for systemic inflammatory disease. therapy included methylprednisolone, plasma exchange, and cyclophosphamide. his hospital course was complicated by ventilator-associated pneumonia, thrombocytopenia, cerebral salt-wasting, and malignant intracranial hypertension which was treated with hypertonic therapy, barbiturate coma, and hyperintensities and resolution of perivascular enhancement. he required tracheostomy and percutaneous gastrostomy and was discharged to a ventilator facility on hd # . on discharge, he was awake and texting on his cell phone. at -month follow-up, his modified rankin score was . our case demonstrates that rapid diagnosis, early immunosuppressant therapy, and aggressive neurocritical support in collected on the optimal therapy of the patients with rapidly progressive pacns. , detroit, mi, united states cerebral amyloid angiopathy (caa)-related inflammation, or cerebral amyloid angiitis is an uncommon disease that presents with acute symptoms secondary to a solitary area of vasogenic edema. this series examines patients presenting with acute neurological symptoms and imaging out of proportion to their exam, suggesting this is a common trend in this diagnosis. cases were collected through epic review, using slicer/dicer to select patients with both snomed diagnoses of caa and cns vasculitis, and snomed diagnosis of caa concurrently treated with prednisone - . cases: ( ) year old female with prior diagnosis of caa presents with transient worsening of right arm dexterity and word-finding difficulty. ( ) year old female presented with loss of vision in the right eye lasting for hours ( ) year old female presents with two days of word-finding difficulty and confusion, using her car remote for her television ( ) year old male presenting after being unable to find words and acting out for two days ( ) year old male with prior diagnosis of caa presents with one day of confusion and nonsensical speech.( ) year old male with history of bilateral occipital hemorrhages of cryptogenic etiology presents with two days of new onset dizziness and left hemianopsia. in each case, patient was identified to have a focal area of vasogenic edema on mri that was significant and alarming in comparison to the patient's presenting symptoms. swi mri showed numerous microbleeds elsewhere to the vasogenic edema consistent with caa. considered differentials included herpes encephalitis, melas, cadasil, and cns vasculitis due to lupus, however all patients exhibited a neurological exam less severe than expected of differentials mentioned prior. all patients were administered an oral steroid regimen with taper for an average of weeks and their symptoms resolved on follow up. use of cranial ultrasound (cus) in pediatrics has been limited to neonates or infants and transcranial doppler (tcd) for stroke risk in children with sickle cell disease. we describe a clinical case showing the utility of performing cus/tcds to assess for new intracranial process in a pediatric patient where head ct was difficult to obtain due to high frequ assessment of waveforms on tcd can be a useful bedside tool in assessing progression of cerebral edema in pediatric patients unable to get a head ct. -month child with acute respiratory distress syndrome required veno-venous ecmo and therapeutic anticoagulation complicated by intracranial hemorrhage with intraventricular extension, mm leftwards midline shift, and hydrocephalus. heparin was reversed and evd was placed. since heparin sedation/paralysis. osmotic therapy was guided by elevated icp. days later, the ability to monitor icps became unreliable due to intermittent evd dra repositioning was deferred because of bleeding risk and lack of clarity whether device malfunction or unsafe because of waveforms with robust arterial diastolic flow and venous flow signifying that icp was lower than plaining unreliability of and repeat head ct showed no gross change. cus and tcd can be a useful tool to screen for high icp using midline shift and spectral waveform analysis in pediatric patients where ct may be contraindicated or challenging to obtain. the structure of intensive care has evolved as the field of medicine has created needs for specialized care. large pediatric hospitals frequently have separated cardiac icu from general pediatric icus, however further subdivision is rare, which differs from adult institutions that often have surgical and neuro icus. this subdivision capitalizes on concentration of expertise and collaboration across providers to improve patient outcomes. texas children's hospital recently opened a new pediatric icu tower and subdivided the picu into six specialty units: surgical, neurology/neurosurgery, pulmonary, hematology/oncology, medical and transitional (for patients with complex needs). we sought to retrospectively review similar patients fitting predefined neuro icu criteria both pre and post move to determine if patient outcome measures were different after cohorting patients. we conducted a retrospective review of neuro icu patients before and after our specialty icu model by comparing june-august to june-august . patients were identified using local data from virtual pediatric systems (vps, llc) and outcomes collected from the electronic medical record utilizing automated data query. primary analysis included patient demographics and outcomes including icu length of stay (los), mortality, prism- and pim- risk of mortality scores. early subgroup analysis included patients with icp monitoring devices in both cohort groups. and patients were in the pre and post cohort group respectively, of which had icp monitors in each group. median time to icp measurement was (iqr - ) and minutes (iqr - ) respectively in pre and post groups (p = . ). icu los, mortality, prism- and pim- were not statistically different. we have developed an algorithm to capture the neuro icu population for future study. preliminary investigations will hopefully confirm patients benefit from this model after programmatic maturity is achieved. west nile virus (wnv) is a mosquito transmitted arbovirus that is endemic in the united states. only % with acute infection develop fevers, and only less than % develop neuroinvasive disease. although the presentation of acute flaccid paralysis is not uncommon, it is extremely rare to visualize the destruction radiographically. here we highlight a case of aggressive neuroinvasive disease with radiographic changes. results y/o caucasian male with arthritis on methotrexate and tofacitinib presented with encephalopathy and generalized weakness. initial evaluation included mri and lumbar puncture. initial mri did not demonstrate etiology of symptoms. lumbar puncture was consistent with viral meningitis (wbc , rbc , glucose and protein ). patient was started on broad spectrum coverage. there was no growth on bacterial or fungal cultures. pcr biofire was negative for acute viruses. weakness progressed, and required intubation for neuromuscular respiratory failure. diagnostic evaluation was repeated days later. repeat mri demonstrated changes on dwi and t weighted imaging, following the motor addition to continued acyclovir, plasma exchange was initiated for an attempt at treatment. the patient's mental status improved, and he refused further treatments including tracheostomy. he was extubated and comfort care was provided given his continued neuromuscular respiratory failure. this case demonstrates severe neuroinvasive west nile encephalitis and flaccid paralysis with radiographic findings. being immunocompromised and age increase his risk for rare presentation of aggressive disease. evidence regarding adequate caloric requirements of critically ill patients with acute brain injuries is suggesting potential risk of caloric debt in neurocritically ill patients. the primary objective of this study was to determine whether guideline recommended weight-based dosing provides adequate caloric requirements compared to indirect calorimetry (ic) measurements in this population. this was a single center, retrospective, observational case-crossover study that included adults admitted within days from admission. we compared resting energy expenditure (ree) determined via ic to the lower (bmi< kg/m : kcal/kg and bmi - kg/m : kcal/kg) and higher (bmi< kg/m : kcal/kg and bmi - kg/m : kcal/kg) actual body weight-based dosing guideline recommendations. we hypothesized that guideline recommended lower-weight based nutrition will not match the caloric demand of patients with acute brain injuries. a total of metabolic studies were performed in patients ( % ich, % non-traumatic sah, % ischemic stroke, % tbi, % status epilepticus, % other etiologies). the mean age was + years, mean weighed + kg with a bmi of + kg/m , and had mean baseline gcs of + . on average ic was obtained on day of admission. lower weight-based recommended nutrition did not provide adequate caloric needs as measured by ic adjusted for obesity ( ± vs ± kcal/day, p< . ). however, higher weight-based recommendation matched the caloric demand as measured by ic ( ± vs ± , p= . ) . in this preliminary analysis, higher weight-based dosing for nutrition matched the caloric demand of critically ill patients with acute brain injury. our results need to be confirmed in future larger prospective studies. central venous catheter (cvc) insertion is common in neurocritically ill patents. standard practice is to obtain a chest radiograph (cxr) to evaluate for the presence of complications, such as pneumothorax (ptx) and catheter misplacement. point-of-care ultrasound (us) has been suggested as an alternative methodology to assess for these complications by using a flush test. patients admitted to our neuro icu between / / - / / who required cvc placement were the subject of this quality improvement analysis. cvc's were placed in the internal jugular (ij) or subclavian (sc) vein followed immediately by lung us to assess for ptx. then, apical or subcostal four-chamber view of agitated saline injected through the distal port of the cvc (ie. flush test) was performed to assess for proper placement. we observed the time delay between start of agitated saline instillation and visualization of contrast in the right atrium and ventricle. this was then interpreted as appropriate (contrast present in </= cardiac cycles) or not. twelve patients were included in this analysis. no patients had a ptx on us or cxr. one patient had a misplaced catheter detected by an abnormal flush test after subclavian cvc insertion using the landmark technique. this was further confirmed by us visualization of the cvc terminating in the ipsilateral ij vein. after immediate removal and reinsertion, followed by an appropriate flush test, cxr then confirmed accurate placement. ultrasound evaluation of cvc complications took < minutes in all cases while it took an average of minutes for the cxr to be avai a potential savings of $ . for each cvc inserted by avoiding the cost of a cxr. in conclusion, we demonstrated us post cvc placement to be an accurate, fast, and potentially less expensive method of confirming cvc placement compared to cxr. major professional critical care societies recommend shared decision-making using decision aids (das) to reduce surrogate decisions incongruent with patient values and preferences and decisional conflict. no das currently exist for any decisions in the neurologic intensive care unit (neuroicu), including goalsof-care decisions. using multilevel input from stakeholders, we recently developed a goals-of-care da for critically-ill traumatic brain injury (tbi) patients that meets international da standards. we aimed to adapt this da to intracerebral hemorrhage (ich) and hemispheric acute ischemic stroke (ais) to widen its applicability and fulfill the shared decision-making needs of surrogate decision-makers of stroke patients. we adapted the existing goals-of-care da by replacing the tbi prognostication model with diseasespecific outcome models as recommended by da quality-standards. we selected the validated month ich-model and -month hemicraniectomy trial outcome data for ais because they include validated long-term outcome assessments. next, we performed acceptability and usability testing of both das using validated scales in family members recruited from two academic neuroicu waiting rooms. we successfully modified the das and created new icon-arrays to optimize the display of predicted outcome probabilities and uncertainties, as has been shown in risk communication studies. twenty family members from two centers participated in acceptability and usability testing. median usage time was ± minutes. usability was very good (mean system-usability-scale-score = / ). % of amount, balance and comprehensibility. we developed three goals-of-care das for surrogates of critically ill tbi, ich and ais patients that include disease specific icon-arrays to communicate outcome probabilities meeting international da standards. das is ongoing, in preparation for a future multicenter comparativeeffectiveness trial. our rigorous development process following international da standards may serve as a template for other neuroicu das. neurocritical care patients receiving rate-based enteral nutrition (rben) consistently received less than their full prescription of enteral nutrition (en) volume due to interruptions in feeding. rate-based en does not allow the nurse to increase the rate after interruptions leaving patients at risk for underfeeding (kim et al. , yeh & peev, . low caloric intake over time is associated with a) immunosuppression, b) impaired wound healing, c) muscle wasting, d) increased hospital and intensive care unit (icu) lengths of stay, e) increased costs, and f) increased mortality (barker et al. , elke et increase the likelihood of adult neurocritical care patients receiving the predetermined goal of % or more of the prescribed volume of enteral nutrition over the course of the nccu length of stay through the use of a volume-based en (vben) protocol which allows the rn to increase the tube feeding rate after interruptions occur. a retrospective pre and postimplementation chart review was conducted on patients aged or greater and less than years with a neurological-related injury or disease process who received en for three or more days during their nccu stay. despite no significant differences in characteristics or gastrointestinal complications between the groups, there was a significant increase in the percentage of prescribed en volume delivered over the course of nccu stay of . percentage points in the vben group (m = . , sd = . ) as compared to the rben group (m = . , sd = . ), t( , n = ) = . , p << . , two tailed, unequal variances. vben can be safely implemented in the neurocritical care population and is associated with significant improvement in en volume delivery. pain, agitation, delirium, and machine support in the icu. a--intensive care syndrome (pics), manifest as psychological and physical debilitation that persists beyond discharge. a-neurocritically ill patients is not known. practices aligned with individual elements of the apopulation were deemed beneficial for patients within this cohort. we asked the question, does the implementation of the a- systematic training on a--professional teams was implemented. baseline data, total bundle compliance, and individual element compliance were measured and analyzed using an approach adopted from the published sccm icu liberation campaign. mortality, ventilator hours, delirium, length of stay (los), and cost were compared to baseline against the third month post education to evaluate the impact of a- preliminary analysis suggests that increased compliance with a-whether wholly or in part, resulted in improved value of care, as evidenced by a decrease in mortality from % to %, as well as a reduction in total icu los adjusted by acuity from . days to . days. this translated into a reduction in cost. as additional experience (and data) become available, further analysis is planned to evaluate the impact of a- early results from a systematic implementation of aand pertinent to improving patient outcomes and value of care. many neurologic diseases are incurable, and patients are faced with prognostic uncertainty, progressive decline and early mortality. as a result, acgme requires training in serious illness communication for all neurology residents; however, only % of programs offer formal education. to address this gap at our institution, we created a training program for neurology residents to improve their skills, attitudes, and behaviors regarding serious illness conversations we designed and implemented a -hour training program utilizing the serious illness conversation guide (ariandnelabs.org). the training program is comprised of a didactic session, a simulated patient experience and debriefing. residents were asked to have a goals of care (goc) conversation with family members (actors) of a patient with catastrophic stroke. a faculty facilitator observed each interaction, allowing residents to self-assess, obtain feedback from the actors and peers and then practice specific components of the conversation. residents filled out a survey both prior to and following the simulation and the faculty filled out an evaluation for each of the residents. led out a pre-survey. the majority ( / ) felt that the residency did not adequately prepare them to have goc discussions though more than % of residents reported feeling comfortable and confident performing these discussions. despite this confidence, the observing faculty found / residents require direct supervision and are not ready to have these conversations independently. the residents struggled with conveying prognosis, maintaining silence, and dealing with strong emotions. all residents reported the training was a helpful, rewarding experience and improved their overall abilities to discuss goc, address prognosis, and explore end-oflife issues. this small pilot study demonstrates an innovative model to improve residents' communication skills surrounding effective goc discussions even when they report increased confidence and independence in these difficult conversations. studies of patient outcomes in mechanically ventilated icu patients have discovered associations among sedative drugs, patient characteristics (demographics and illness), burst suppression (brain inactivation), and mortality. however, association does not imply causation. it remains unclear ( ) whether unintentional burst suppression has a causal effect on mortality, ( ) the degree to which drugs directly impact mortality, and ( ) whether drugs impact mortality indirectly by causing burst suppression. patient characteristics are a possible source of confounding. we estimated causal effects of unintentional burst suppression, critical illness severity and the anesthetic sedation on in-hospital mortality in mechanically ventilated icu adult patients. this was a longitudinal study with an observational cohort of adult icu patients. eeg recordings were obtained for each patient and reviewed by clinical neurophysiologists per institutional protocol to determine the presence of burst suppression in each epoch ( - hour segment). the causal effects were estimated using causal statistical inference (pearl's do-calculus). to assess the robustness of our results towards unmeasured confounding, we performed sensitivity analysis using the e-value. % confidence intervals were created using bootstrapping. on average, increased drug exposure causes a % increase in mortality ( % bootstrapped confidence interval -. , . ) and a % increase in burst suppression incidence (. , . ). burst suppression mediates % of the impact of drug exposure on mortality and is associated with a % increase in mortality (. , . ). increased severity of illness causes a % increase in mortality (. , . ), and a % increase in burst suppression burden, measured by the percent of epochs during which patients experienced burst suppression (-. , . ). unintentional burst suppression contributes substantially to in-hospital mortality. however, unintentional burst suppression appears to be affected more by patient characteristics such as severe critical illness than by high exposure to sedative drugs. infectious endocarditis (ie) is a growing health concern, with increasing incidence in the context of the opioid epidemic. we described a large case series of patients with ie at an urban, academic safety-net hospital. clinical data on patients with diagnosis of ie were entered into an endocarditis work group single-center registry. the mission of the multidisciplinary group is to optimize clinical care, especially as it pertains to cardiac surgical management. we reviewed demographic information, history of prior cardiac valve replacement, intravenous drug use (ivdu), blood culture results, and diagnostic studies (ie echocardiogram, brain ct/mr imaging, and conventional angiography). between november and may , consecutive patients (mean . years; aged - years; % male) with ie were admitted to our center. patients had a history of ivdu in % of cases. unique microbes were isolated, most commonly staphylococcus species ( mssa, mrsa, other). polymicrobial infection occurred in patients. on echocardiogram, vegetations were seen on tricuspid ( ), mitral ( ), aortic ( ), and pulmonic ( ) valves. patients had multi-valve involvement. patients underwent brain ct or mri demonstrating-cerebral infarctions ( ), subarachnoid hemorrhage (sah) ( ), intracerebral hemorrhage (ich) ( ), brain abscesses ( ), and mycotic intracranial aneurysms ( ). neurologic complications occurred most frequently in the setting of mitral valve disease ( infarcts, sah, ich) and in those with staphylococcus ( ) and polymicrobial infection ( ). tricuspid valve vegetations were associated with cerebral infarcts and ich. despite frequent association with ivdu, left-sided cardiac valve vegetations were common. mitral valve involvement, staphylococcus species and polymicrobial infections were associated with increased risk for neurologic complications. neurologic complications also occurred in patients with right-sided valvular disease, suggesting a need for increased surveillance in this population. acute neurological conditions such as traumatic brain injury (tbi), cerebrovascular accident (cva), and hypoxic-anoxic injury (hai) can significantly impact a patient's functional status, and life expectancy. older adults may have poorer outcomes, especially those with premorbid conditions. studies have shown a preference for less aggressive care if patients and/or families anticipate a shorter life expectancy, or poor outcome. as such, early delivery of prognostic information and discussion of goals of care (goc) can be crucial for patients prior to transfer to a tertiary care facility. this is a retrospective cohort study of patients aged and older with cva, hai, or tbi who died within hours of charts were reviewed to assess documentation of pre-transfer goc discussions, code status change after transfer, prevalence of palliative care consultation, and other utilization markers. patients met inclusion criteria with . % being male and . % female with median age . . the majority of patients were transferred from an emergency department ( . %). only . % of patients had documented goc discussions prior to transfer. only . % patients of patients underwent surgical intervention. after transfer, . % of patients downgraded their scope of treatment to comfort measures prior to death, with this being even higher in those and older ( . %). palliative care consultation took place in only . % of patients after transfer. while transfer to a tertiary medical center is sometimes necessary, only . % of patients had documented goc discussions and the majority ( . %) downgraded their scope of treatment to comfort measures after transfer suggesting a potential opportunity for earlier goc discussion and possible avoidable hospital transfers. these findings can inform the design of future interventions to improve communication and decision-making regarding goals of care in patients with high mortality neurological conditions. a neurological emergency response team (nert) was implemented at a dedicated neuroscience hospital in an academic medical center in anticipation of higher patient volumes with the extended treatment window for acute ischemic stroke. goals of the nert are to ensure safe and effective care transition into the acute care setting and a standardize approach to neurological emergency. a dedicated clinical team examined the current structure for safe & effective patient triage, monitoring and transition from the interventional neuroradiology (inr) suite to the neurocritical care unit. clinical nurses with over three years' experience in neurocritical care were vetted, trained & scheduled to provide / continuous coverage. after patients were triaged via telemedicine technology, the nert nurse was alerted via automatic text message system and prepared to receive the patient via ambulance to the inr suite. during the assembly of the inr team, the nert nurse assessed and monitored the patient and initiated diagnostic testing. upon completion of intervention, the nert initiated transfer of care to the neurocritical care unit. stroke volume and door to treatment times were evaluated pre-and post-intervention. in , ischemic stroke patients were admitted through the inr suite, with being treated with endovascular intervention. in , ischemic stroke patients were admitted, with patients being treated with endovascular intervention. since the implementation of the nert, average median arrival time to skin puncture for intervention decreased by seven minutes with a % increase patient volume. a dedicated neurological emergency response team is an effective model to support the increase in patient volume for evaluation of acute ischemic stroke intervention. this approach demonstrates the potential for efficient, safe and timely triage, intervention and care transition to the neuro icu for stroke patients. arctic ground squirrels (ags) endure harsh winter environments through hibernation. curiously, ags are resistant to stroke and other ischemic injuries independent of season or metabolic state. the details of physiologic and cell autonomous genetic adaptations underlying this metabolic resilience is largely unknown. the resilient metabolic and mitochondrial phenotype of ags neural cells was examined in vitro after exposing cells to hypoxia, hypothermia, or mitochondrial toxins and assaying for cell survival, mitochondrial morphology, and oxygen consumption rate. a cdna library prepared from ags cells and nucleofected into mouse neural cells exposed to metabolic stressors was used to perform a functional genetic screen. a bio-informatics pipeline identified screened candidates with key amino acid substitutions that may have evolved to optimize stress response function. newly described dcas base editors capable of substituting c->t (and g->a) were used to systematically mutate and explore the role of identified proteins in mediating the ags optimized adaptive stress response. we found that ags neural cells exhibit marked resistance to all metabolic stressors. this is associated with enhanced mitochondrial function and improved morphology. the functional genetic screen identified a network of evolutionarily-conserved ags transcripts imparting cytoprotection. use of dcas base editors on candidates suggested by the bio-informatics pipeline, confirmed the coordinated role of specific components of the oxidative phosphorylation (oxphos) and endoplasmic reticulum (er) stress response systems in imparting mitochondrial and neuroprotection in our in vitro model. we gained key functional insights into how specific amino acid substitutions in the machinery of the oxphos and er stress responses systems alter mitochondrial function to impart cytoprotection to metabolic insults. this detailed dissection of the ags optimized adaptive stress response pathway will serve as an template for the development of new neuroprotective treatments. acute ascending weakness with respiratory failure is a frequent syndrome encountered in the neurocritical care unit (nccu), often related to demyelinating or infectious etiology. however, here we describe a case of acute ascending weakness with encephalopathy, respiratory failure and autonomic instability that was related to confirmed endocrinological etiology. prospectively collected data was retrospectively extracted from the electronic health record in a patient known to our nccu team. a -year-old male with medical history of childhood meningitis was transferred to the nccu after initially presenting to an outside emergency department (ed) with a chief complaint of bilateral lower extremity weakness progressing to paraplegia over hours. six hours into his course in the ed, he developed bilateral upper extremity paresis and respiratory distress. physical exam in this ed was additionally notable for areflexia and a sensory level at t . he was intubated, initiated on ivig and methylprednisolone, and airlifted to our institution. upon arrival, telemetry showed frequent supraventricular tachycardias refractory to standard treatment. labs (including cerebrospinal fluid) were notable only for serum potassium < . meq/l, thyroid stimulating hormone < . uiu/ml, t . uiu/ml ( . -- . ). he was diagnosed with thyrotoxic periodic paralysis. at endocrinology's urging, the patient was given propranolol mg iv every minutes for doses, propylthiouracil and hydrocortisone. in the hours following propranolol, his potassium improved, his paralysis and encephalopathy resolved, and he was ultimately extubated without difficulty < hours after admission. review of symptoms performed after improvement revealed recent symptoms consistent with hyperthyroidism. intensivists should remain aware of the differential diagnoses that can manifest with motor weakness and respiratory failure. in this patient, severely elevated thyroid hormone led to thyrotoxicosis and subsequent profound hypokalemia. acquiring a thorough history and reviewing laboratory abnormalities remain paramount for timely diagnosis. the objective of the study is to determine the prevalence of disability among icu survivors one year after admission, and factors influencing functional outcome. we conducted a population based cohort study in the icus of the mayo clinic, rochester, mn. we enrolled consecutive patients from the mayo clinic study of aging (mcsa) and then admitted to medical or surgical adult icus at mayo clinic, rochester between january , , and december , . patients admitted to the neuroscience icu were excluded. we collected their demographic and clinical variables, length of icu stay, functional and cognitive status (before and after icu admission), comorbidities (components of charlson score), and apache were retrieved from the electronic medical records using multidisciplinary epidemiology and translational research in intensive care (metric) data mart. one-year functional outcome was categorized using the modified ranking scale (mrs) with scores to representing good functional outcome. cases were included and ( . %) patients were alive one year after icu admission. of them, patients had one-year follow-up functional assessment and ( . %) of them had good functional outcome. on multivariable analysis, poor one-year functional outcome (death or disability) was more common among women, older patients, baseline cognitive impairment (mild cognitive impairment or dementia), higher charlson scores, and longer icu stay (all p< . ). after excluding deceased patients, these associations remained unchanged. in addition, ( . %) of patients who had post-icu cognitive evaluation, experienced cognitive decline after the icu admission. approximately two-thirds of survivors maintained or regained good functional status one year after icu hospitalization. older age, female sex, greater comorbidities, abnormal baseline cognition, and longer icu stay were associated with poor functional recovery. shared decision-making using decision aids (da) is recommended by major professional critical care societies for surrogate decision-making in the icu to reduce decisions incongruent with patient values and preferences and decisional conflict. we converted a paper-based goals-of-care da in critically-ill tbi patients to a digital da. we applied eye-tracking-technology in a single-masked randomized study to understand the effects of and optimize the da navigation design to facilitate information processing. we created two digital das: ( )unmodified conversion of the paper-da with horizontal, top-justified static navigation (control) vs. ( )vertical, left-justified navigation with page subsections and page completion checkmarks (experimental), which encourages users to view pages in order. sixteen healthy participants were randomly assigned to the two groups (n= /group, masked to da assignment) and navigated through the das. using t-tests, we compared user disorientation and usability using validated scales, and eye movements (fixation and saccades) recorded with eye-tracking-technology. impact of navigation on usability was assessed with linear regression, adjusting for disorientation(system-usability-score= b + b *disorientation). disorientation was significantly less in the experimental da (mean . vs. . ;p= . ;smaller values indicating increased disorientation) with no difference in usability (mean system-usability-scale scores vs. ;p= . ;scores> indicating good usability[range - ]). regression analysis revealed a significant association between disorientation and usability (p= . ), with disorientation explaining % of the variation in system-usability-scale scores (adjusted r = . ). eye-tracking measurements revealed longer average fixation per page in the experimental da (mean . s vs. . s;p= . ) and a higher ratio of information processing to search per page (fixation-duration over total duration of both fixations and saccades on a page; mean . vs. . ;p= . ). eye-tracking-technology suggested that the experimental navigation design significantly improved the navigation experience resulting in less disorientation and participants spending less time searching and more time processing the information. while there was no difference in subjective usability, we found a significant association between improved navigability and higher usability. high-fidelity simulation has become an important mode of learning in medical education. currently, there is little data regarding the impact of simulation-based learning in neurocritical care training. in may , we presented a poster at the american academy of neurology annual meeting introducing a comprehensive simulation-based curriculum for neurocritical care training at uc san diego (ucsd). in this poster, we aim to present additional preliminary findings regarding trainee comfort levels, interest, and areas of improvement. this is a single-group pre-post study involving current residents of the ucsd department of neurology. simulation sessions consist of interactive, faculty-led, and checklist-based clinical scenarios (ischemic stroke, intracranial hemorrhage, status epilepticus, spinal cord emergencies) followed by debriefing sessions. collected data assesses for self-perceived comfort/confidence levels, future interest, and checklist item completion. between january and july , pgy - neurology residents participated in various simulation sessions on ischemic stroke, intracranial hemorrhage, and status epilepticus. prior to the session, . % of all trainees reported no more than somewhat comfortable in treating neurological emergencies despite having received some type of neurological emergency training through didactic lectures. rtable in treating the specific simulation case in observation of each simulation session pinpointed specific areas of improvement amongst trainees on an individual basis (i.e. time to intubation after benzodiazepine administration in refractory status). preliminary results suggest that simulation-based learning is valuable and applicable in the neurocritical care training process, allowing trainees to feel more comfortable in managing acute neurological deterioration and faculty to directly observe trainee skill in a controlled setting. through this project, we hope to highlight the need for simulation-based education in neurocritical care training by providing evaluative information and generalizable curricular examples. chimeric antigen receptor (car) t cell therapy for refractory/relapsed hematologic malignancy often causes severe neurologic side effects ranging from encephalopathy and aphasia to fulminant cerebral edema and death. the cause of neurotoxicity is poorly understood. we sought to develop a score based on clinical and laboratory parameters to predict which patients would develop cart-associated neurotoxicity. all patients undergoing cart therapy at brigham and women's hospital for relapsed/refractory hematologic malignancy were prospectively studied. patients were assessed daily during their admission for cytokine release syndrome (crs) and neurotoxicity. vital signs, laboratory data, and medication administration records were extracted from the medical record. logistic regression was used to determine which clinical and laboratory features were significant predictors of developing neurotoxicity. patients were included. experienced crs and experienced neurotoxicity. early (within days after cart infusion) fever and elevated serum c-reactive protein (crp), timing of crs onset, crs grade, and treatment with tocilizumab were all significant predictors of neurotoxicity. using roc curves, optimal discriminators were defined and used to derive a score to predict neurotoxicity. one point was assigned for fever, serum crp > . mg/dl, and each dose of tocilizumab administrated, zero to four points for crs grade, and zero to three points for day of crs onset. this score ranged from to for our cohort and had an auc of %; a score >= predicted neurotoxicity with a sensitivity of % and a specificity of %. bootstrap analysis was used to demonstrate robustness. we used regression analysis to develop a score that can prospectively predict which patients are most likely to suffer from neurotoxicity related to cart therapy. this score can be used for triaging and resource allocation during the care of the patients after treatment with cart therapy. when brain herniation is impending, every minute matters; so the efficient and expedient procurement of all components required for external ventricular device (evd) placement is vital to neurological preservation. the neurosurgical residents at the university of rochester medical center often struggled to assemble the appropriate supplies for an evd placement in a timely manner when patients were not yet admitted to the neuro intensive care unit (neuro icu). additionally it was difficult to track equipment use and supply costs. in response, the neuro icu's quality improvement (qi) team designed an evd "go bag" in an effort to improve delays in care, patient experience, and avoidable costs. the multidisciplinary neuro icu qi team collaborated to design a portable bag that contained all equipment necessary for evd placement. two neurosurgery residents performed time trails, in real emergency situations, by measuring the time from decision to place an evd in emergency department (ed) critical care bay, to collecting the equipment from the neuro icu and return to the bedside in the ed. times were compared with and without using the evd "go bag". the evd "go bag" decreased the time to placement of an evd by up to minutes when compared to the traditional method of retrieving all evd equipment from the neuro icu stockroom. time reduction was due to the speed of gathering supplied and the ability for the neuro icu staff to bring the evd "go bag" to the patient's bedside. the evd "go bag" allowed for better tracking of monetary costs and equipment, allowing for appropriate billing and stocking of supplies. a system was developed where the bag was checked and restocked daily by the critical care equipment technicians and the neuro icu charge nurse despite a growing number of prognostication models in neurologic emergencies, prognostic uncertainty remains inevitable and plays a central role during goals-of-care decision-making for incapacitated critically ill patients. we aimed to examine surrogate decision-makers' communication needs and physicians' strategies for communication of prognostic uncertainty during family meetings for critically ill traumatic brain injury (citbi) patients. we qualitatively analyzed semi-structured interviews of surrogates of citbi patients from two level- u.s. trauma-centers and tbi expert physicians from u.s. trauma-centers. open-ended questions about prognostic uncertainty were asked. interview transcripts were analyzed with the investigatortriangulated-inductive-framework-approach in nvivo-software. prognostic uncertainty was identified as the most difficult aspect of decision-making for surrogates by physicians and surrogates alike, although most surrogates had some pre-existing expectation or understanding of it. % of physicians observed that uncertainty is distressing for families, with % employing specific measures to limit uncertainty. over half of physicians described explaining the concept of uncertainty so surrogates understand that physicians can estimate the odds but not predict the future. physicians typically conveyed prognosis using a range of outcomes, and conveying certainty only for prognostic extremes. surrogates found uncertainty around prognosis was lessened when physicians explained all possible treatment options, with support from clinical data. roughly half noted that too much certainty in providing a prognosis, without a range of possible outcomes, led to distrust in the information provided by the physician, increasing decisional conflict. the vast majority of physicians admitted statistical uncertainty in deriving prognosis, particularly for patients with tbi, and cited mistrust of prognostic models when deriving long-term prognosis. most physicians felt that uncertainty around prognosis led to increased incidence of tracheostomy and feeding tube placement. these results provide foundational knowledge for physician-family communication, by identifying important gaps between surrogates' communication needs and physicians' practices about prognostic uncertainty. the rapid rise in social media utilization among both patients and healthcare providers has moved a considerable portion of conversation around health and disease to the digital space. today, roughly nine-in-ten american adults use the internet, with % of internet users participating in social media. the power and reach of social media platforms makes it imperative for clinicians to be aware of the trends in the public narrative around common disease processes. in this study, we analyzed the last . years of postings ("tweets") from a popular social media platform, twitter, to characterize themes and trends in the digital conversation around stroke, the leading cause of long term disability in the us. tweets under the hashtag #stroke, published from january st to april th , were extracted through symplur signals, llc. a total of , #stroke tweets were qualitatively coded and sentiment analysis was performed after selection for relevance among all homographs. accounts owned by stroke-related advocacy groups were found to be the most prolific contributors of #stroke postings, with content mostly around primary stroke prevention (risks and signs). among the most popular associated hashtags, over half of the tweets focused on comorbidities and the challenges of the stroke recovery process (top trending words included #aphasia, #lockedin, #survivor, #depression). our preliminary analysis describes trends in themes and stakeholder participation in the current #stroke online conversation. it also exposes important gaps in the public discourse beyond the setting of academic and research online communities, namely around existence of therapeutic treatments, availability of resources for patients and families navigating the recovery process, and possibility of successful recovery and long term outcomes. such knowledge around the digital stroke narrative may provide valuable context to intensivists and stroke clinicians interacting with patients and families affected by stroke. the field of autoimmune neurology, specifically the autoimmune encephalitides, has expanded since the early 's. increasingly newer antibodies to various parts of the nervous system are being identified in discovered in patients with meningoencephalomyelitis, or some spectrum of these three singular entities. data was reviewed from electronic medical records for this case report. a previously healthy year-old male initially developed a case of aseptic meningitis, progressing to encephalitis and then extensive longitudinal myelitis leading to profound paresis and respiratory failure. an extensive workup was performed, including evaluation for rare infectious and ominant leukocytosis ( /μl and /μl) and elevated protein (> mg/dl). he was treated empirically with antibiotics which were discontinued after negative results and cultures. after therapy with high dose iv steroids he had minimal improvement and pl had improvement in his symptoms. he was started high dose prednisone with plans to slowly taper after return with positive anti- in review of the literature our patient had several characteristics consistent with others who were also antipsychiatric symptoms. many reports state steroids lead to remission and improvement, however in this case our patient did not have substantial recovery until after the initiation of plex. at this time it is hether these antibodies instead represent a marker of other underlying disease from cytotoxic t cell damage to astrocytes. the united council for neurologic subspecialties (ucns) accredits neurocritical care (ncc) subspecialty fellowships and certifies neurointensivists. in , the american board of medical specialties (abms) approved the application for ncc subspecialty certification by american board of psychiatry and neurology (abpn) and the accreditation council for graduate medical education (agme) approved ncc fellowship training in . previous studies have shown significant heterogeneity in ncc fellowship training and procedural competencies and that many programs do not have the necessary resources for a transition to acgme accreditation. in , an online survey of abpn neurology diplomates was utilized to estimate the number of neurologists practicing ncc, their ncc fellowship training experiences, whether their institutions required certification in ncc, their scope of practice, and their interest in pursuing abpn certification in ncc. survey respondents indicated that they practiced ncc. based upon ucns and other data, this is estimated to be at least % of all neurologists practicing ncc. % of ucns-certified ncc respondents identified the primary scope of their practice as academic involving a fellowship program, and % of non-ucns-certified ncc responders identified themselves as private practitioners. nearly % of fellowship trained ncc respondents obtained ucns certification. % of ucns-certified ncc respondents reported that their institutions required ucns certification, whereas % of non-ucnscertified ncc respondents reported no institutional requirements for certification. over % of respondents thought ncc training was relevant to their current clinical practice. most respondents indicated that they planned to take the abpn ncc examination, and > % of respondents reported that abpn certification would most benefit them by improving their colleagues' perceptions about the quality of certification. ncc training and certification is valued by most neurologists practicing ncc, and most believe that abpn ncc certification will advance the recognition of the field of ncc. cerebral edema is a severe complication of acetaminophen-induced acute liver failure (apapprimary objective was to describe the characteristics of patients with cerebral edema in the setting of apap- this analysis is part of a large, retrospective observational study inclusive of apap-year period from a regional transplant center. we used standardized data collection tools and trained defined cerebral edema based on the interpretation of this ct by a blinded radiologist. we performed univariate analysis based on the presence of cerebral edema. of a total of patients, had data on ct brain imaging. the mean age was . ± . years, and patients ( . %) were female. of patients with neuroimaging, ( . %) had evidence of cerebral edema. patients with cerebral edema had higher average ammonia levels on day of hospital admission ( , % ci - vs. , % ci - mcg/dl). patients with cerebral edema also had significantly higher meld scores by -hours ( . , % ci . - . vs. . , % ci . - . ). this significant difference persisted for subsequent hospital days. thirteen patients ( . %) with cerebral edema received intracranial pressure monitoring. mortality within -days was . % (n= ) if cerebral edema was present vs. . % if absent (n= ). the odds of death within -days, if cerebral edema was present, was . ( % ci . - . ). one patient with cerebral edema died awaiting transplant, and received liver transplant. in this study, cerebral edema was present in % of patients hospitalized for apapwith higher mortality. elevated intracranial pressure and cerebral edema are leading predictors of poor outcomes and mortality in patients with head trauma, intracranial hemorrhages, or acute ischemic strokes. while hypertonic saline (hts) is the mainstay of treatment, recent trials in critically ill populations have demonstrated a reduction in kidney related adverse events with the use of balanced crystalloid groups when compared to . % sodium chloride (nacl). the purpose of this study is to assess adverse kidney outcomes and risk of in-hospital mortality associated with hts in a neurocritical care population. a retrospective cohort study was conducted at a large academic medical center on adult patients in the neurosciences icu who received % nacl and/or . % nacl from july , to july , . the primary endpoint was major adverse kidney events (make- ), defined as at least one component of the composite: in-hospital mortality, receipt of new renal-replacement therapy, or persistent renal ays. baseline characteristics, indication for hts, pertinent lab values including changes in serum electrolyte concentrations, total hts volume and associated sodium and chloride milliequivalents, and patient outcomes were collected. statistical analysis was performed using spss software. in the chloride increase > mmol/l group, patients ( . %) experienced the primary outcome of make- , patients ( . %) experienced in-hospital mortality and patients ( . %) experienced aki primary outcome of make- , and patients ( . %) experienced in-hospital mortality (p= . ). the primary outcome occurred more often in the chloride increase > mmol/l group and in-hospital mortality accounted for the majority of the outcome in both groups. this was not statistically significant due to the sample size and unbalanced comparator groups. social media has been shown to be a valuable tool to improve knowledge, attitudes, and skills. it has been theorized that the success of medical education through social media can be contributed to increased learner engagement, real-time feedback, and enhanced collaboration. we hypothesize that social media is underutilized in critical care medicine in comparison to other specialty fields of medicine and surgery. a list of medical specialties as hashtags were run through "hashtagify" software. this software crossreferences up to , data points on instagram and twitter and assigns a "popularity score" for certain topics. the phrase "critical care" was cross-referenced through a database of medical news run by doximity over a month in comparison to other topic tags. in total, articles concerning the topic "critical care" were posted on doximity news over days. in comparison, there were articles posted under "cardiology," under "internal medicine," and under "emergency medicine." with respect to hashtag utilization on social media, critical care was under-represented, with a popularity score of . this was in comparison to other specialties such as neurology ( ), dermatology ( ), emergency medicine ( ), and ophthalmology ( ). within the critical care hashtag, the major influencers were those representing critical care nursing. despite the large amount of news pertaining to critical care on professionally-curated forums such as doximity, there is significant under-representation in social media. within the hashtag, "critical care," the major influencers represented critical care nursing suggesting that critical care physicians are even further underrepresented. this is in line with previous research suggesting the underrepresentation of medical doctors in social media. given that social media has been shown to be a valuable tool in enhancing medical education, we believe that a greater effort should be made to engage critical care physicians on social media outlets. there is a call for increased diversity in national and international annual meeting participation in terms of attendance, committee participation, leadership, awards and speakers. the neurocritical care society annual meeting(ncs-am) speaker qualifications are not specified in the bylaws. the speakership patterns of the ncs-am have not been examined. we described the speakership patterns in ncs across a -year time span ( ) ( ) ( ) and delineated the trends of united states-neurocritical-care-fellowship- longitudinal cohort study. the ncs-am conference program, a readily available online document, for the years - , were reviewed by the study authors. speakers were identified from the conference program. our primary outcome was the trend of speaker characteristics across the -year time span. our secondary outcome was to determine speakership trends among united states-neurocritical-care-fellowshipinstitution of employment at the time of the meeting. a total of speakers were included in this study, of which % were male. majority of the speakers were us-based( %), mid-to late-career ( %) and were physicians ( %). the speakers were ± years from fellowship. in -years, there was an increased trend towards international, non-physician and early-career speakers' trained from johns hopkins university (jhu) ( , %), massachusetts general hospital (mgh) ( , %) and cornell/columbia university ( , %); while the most common sites of employment at the time of the meeting were jhu ( , %), mgh ( , %) and university of pittsburgh medical center ( , %). this is the first study to evaluate speakership trends across a -year period of the ncs-am. diversity has ble institutional bias are unclear and deserves to be studied further to better define speaker selection in the ncs annual meeting. these data may also be utilized to explore opportunities for collaboration and diversity in future ncs-ams. urinary tract infections (utis) are the fourth most common type of healthcare-associated infection, primarily caused by instrumentation of the urinary tract. there is a %- % increased risk of patients acquiring a catheter-associated urinary tract infection (cauti) for each day an indwelling urinary catheter (iuc) remains in place. in critically ill patients, iuc placement is often required for precise urine output measurement. subarachnoid hemorrhage (sah) patients often require iuc's during the cerebral vasospasm period (i.e. post-bleed day, pbd - ) to maintain euvolemia. this places sah patients at increased risk for developing a cauti. in our local neurosciences intensive care unit (nsicu), an infection control team observed higher cauti rates as compared to the hospital and national average necessitating changing our urinary catheter utilization policy. we report change in practice pattern with implementation of new unit policy the intermittent catheterization (ic) algorithm includes clinician review of the patient's total intake and output and current clinical status. retrospective chart review of cauti incidence (rate per catheter days) and device utilization ratio (no. urinary catheter days/ no. patient days) months before and after implementation of the new policy. time periods were compared using appropriate statistical tests pre-and post-intervention the ic algorithm was implemented to reduce iuc utilization rate with aim to reduce cauti rates. the time periods studied were may to april (pre-intervention period) and may to april (post-intervention period). cauti rates decreased from . ± . during the former time-period to . ± . during the latter time period (p= . ). similarly, device utilization ratio decreased from . ± . to . ± . (p< . ). in addition, use of female and male external catheter devices were encouraged leading to increased utilization systemic team based implementation of policies can result in adoption of positive practices and reduce hospital acquired infectious complications. managing neurological emergencies, particularly overnight, is very challenging for neurology trainees at the beginning of their residency. preparation is key to ensure residents have the skills, confidence, and knowledge to manage acute scenarios. we developed a one-week immersive bootcamp to educate new neurology residents about neurological emergencies prior to the start of the academic year. the bootcamp includes the fourteen emergency neurological life support (enls) modules designed by the neurocritical care society, thirteen faculty-created didactics, nine case-based discussions, and four resident-created simulations. the bootcamp teaches residents about the management of acute ischemic stroke, acute non-traumatic weakness, anoxic brain injury, coma and brain death, intracranial hemorrhage, intracranial hypertension, meningitis, neuromuscular emergencies, status epilepticus, spinal cord emergencies, subarachnoid hemorrhage and traumatic brain injury. residents are also taught about communication with families during and after neurologic emergencies in a didactic session on breaking bad news. it is important for all neurology residents to be adept at managing neurological emergencies. however, having these skills is particularly important for residents in a military program, as residents in the military may ultimately be deployed overseas or stationed at facilities with minimal support, responsible for handling all neurological emergencies, regardless of their sub-specialty. enls training and didactics teach residents about the fundamentals of neurological emergencies. case-based discussions provide residents to act out the way they would utilize this knowledge in a risk-free environment that is translatable to acute clinical situations. the combination of enls training, didactics, case-based discussions and simulations into a one-week immersive bootcamp early in residency should, therefore, provide a solid knowledge base about management of neurological emergencies for incoming neurology residents and allow them to consolidate that knowledge leading to safe and effective management of neurological emergencies. trends and predictors of in-hospital mortality for status epilepticus: national inpatient sample study head or heart: ictal bradycardia and temporal lobe epilepsy julia bevilacqua higher dai grade correlates with worse short term outcome in pediatric traumatic brain injury anna janas; scott hamilton; zachary threlkeld; max wintermark post-intensive care syndrome amongst families of icu patients, including post-traumatic stress disorder (ptsd), is highly prevalent after patient discharge but understudied. the psychological model of "attachment theory" describes how people respond when being separated from loved ones; various "attachment styles" have been associated with the development of ptsd in other settings. adults can be "secure" (comfortable depending on others and being alone) or "insecure." the hypothesis of this exploratory study was that insecure family members of neuro icu patients would be more likely to report ptsd six months after patient hospitalization compared to secure family members. eligible participants were family members of neuro icu patients at a single center who already had attachment styles (secure vs. insecure) defined via a standard survey, the relationship questionnaire, during an earlier study in . over - , these subjects were asked by mail to complete the impact of events scale-revised (ies-r) six months following discharge or patient death. participants were considered to have ptsd if ies- / returned a completed ies-r ( . %). ( . %) of these subjects reported a secure attachment style vs. out of ( . %) insecure respondents (p= . ). this small study did not show a significant difference in rates of post-discharge ptsd amongst neuro icu family members with secure vs. insecure attachment styles, however was only powered to discover a large difference between groups and the rate of ptsd in our population was markedly lower than sible association in larger cohorts with an overall higher prevalence of post-discharge ptsd would be insightful. key: cord- -f w fw q authors: nan title: abstracts presented at the neurocritical care society (ncs) th annual meeting date: - - journal: neurocrit care doi: . /s - - - sha: doc_id: cord_uid: f w fw q nan external ventricular drain (evd) management after subarachnoid hemorrhage (sah) is thought to influence patient outcomes and complications. evidence from single center randomized controlled trials suggest that an early clamp trial is safe and associated with shorter icu stay and fewer evd complications. however, a recent survey revealed that most neuro icu's across the us still adopt a gradual wean and continuously draining evd strategy. therefore, we sought to determine the optimal approach at our institution. we reviewed consecutive patients admitted to our institution from to with nontraumatic sah requiring an evd. in , our neurocritical care unit revised our internal evd management guideline from a gradual wean to an early clamp trial approach. we performed a retrospective multivariate analysis to compare outcomes before and after our guideline change. patients that were gradually weaned after institution of the new guideline were also included in the early clamp trial group. we observed a significant reduction in ventriculoperitoneal shunt (vps) rates after changing to an early clamp trial approach ( % early clamp vs % gradual wean, p= . , or= . on multivariateanalysis). there was no increase in delayed vps placement at months ( . % vs . %, p= . ). an early clamp trial approach was also associated with a shorter mean evd duration ( . vs . days, p< . ), shorter icu length of stay ( . vs . days, p= . ), shorter hospital length of stay ( . vs . days, p< . ), lower rates of non-functioning evd ( % vs %, p= . ), and fewer ventriculostomyassociated infections ( . % vs . %, p= . ). we found no difference in symptomatic vasospasm rates between the groups ( . % vs . %, p= . ). an early clamp trial approach is associated with fewer complications and shorter length of stay compared to a gradual evd wean. prospective multicenter studies are needed to provide further insight into the best strategy. autoimmune encephalitis refers to rare sometimes paraneoplastic conditions in which the immune system attacks the brain, leading to altered function. delayed diagnosis and treatment potentially leads to permanent neurological injury or death. the primary objective of this study was to analyze the admission and discharge modified rankin scale (mrs) assessments among patients diagnosed with autoimmune encephalitis, and to identify any effectiveness of immunosuppressive therapy on a subset of these patients. through retrospective chart review we identified patients that met currently accepted clinical and serological criterion for autoimmune encephalitis. clinical data was obtained on these cases and a modified rankin score mrs was assessed on both hospital admission and discharge or subsequent 'best clinical' visit. assessment of "improvement" from initial therapy was based on any decrease in mrs score and clinical neurological functional improvement in accordance with physician and patient affirmation by the time of discharge. seventy-seven patients met criterion for clinical or serological autoimmune encephalitis. of these patients, had cancer and did not have known cancer. fifty-seven ( %) patients underwent immunosuppressive therapy with corticosteroids, ivig, and/or plasma exchange and patients experienced a decrease in mrs score. improvement from initial treatment was %, %, %, and % for admitting mrs scores or through respectively. the p-values for improvement from initial immune therapy based on an mrs of , , or compared to an mrs of were . , . , and . respectively. immunosuppressive therapies for patients with an initial mrs score of , or may have a higher yield than for those with an mrs of . these therapies are generally reserved for those with an mrs of or greater. further study is needed to assess functional improvement in those with autoimmune mediated encephalitis treated with immunosuppressive therapies. many patient, family and hospital factors have been associated with obtaining consent for organ donation after brain death (bd). we evaluated potential factors that played a role in the consent rate in a large tertiary hospital over a period of . years. we evaluated all declarations in our hospital's bd registry between january and june regarding consent for donation. we cross-matched the hospital electronic medical records with the records of the local organ procurement organization to identify this population. patients were included in the registry ( . % african american) and were approached for donation. there was a . % consent rate for organ donation. there was no significant relationship between sex, admission diagnosis, icu (neuro vs. medical vs. surgical), physician specialty (neurology vs. other), time from event to bd declaration or religion and decision to donate. families were more likely to consent to donation if the patient was non-aa ( % vs % for aa, p< . ), was younger ( . vs . , p= . ), had a lower creatinine at the time of death ( . ± . vs . ± . mg/dl, p= . ), and had an apnea test completed ( % vs %, p= . ). in a logistic regression model, only aa race and pao independently predicted refusal of donation (odds, %ci, . , p< . and . , p= . , respectively) . although the majority of bd patients in this large series were aa, their families were times less likely to consent for organ donation than non-aa families. there is an urgent need to explore the reasons for low donation rates in this population. post-anoxic myoclonus is seen in up to % of patients who remain comatose, and historically was felt to be a poor prognostic sign. little distinction has been made in the literature between epileptic (cortical) vs subcortical myoclonus. from consecutive cardiac arrest patients that did not return to baseline (may -may ) we identified % (n= ) patients with clinical myoclonus. basic demographics and characteristics of their arrest were collected and eeg reports were reviewed. raw eeg including video was reviewed by two epilepsy-trained neurologists, whenever available. myoclonus was subcategorized into subcortical and cortical based on the presence of a preceding eeg correlate. jerk-locked eeg back-averaging was performed on two representative patients. the average age of patients with myoclonus was +/- years, and % (n= ) survived to discharge. cortical myoclonus was twice as likely as subcortical myoclonus ( % vs %, respectively). compared with patients without myoclonus, patients with myoclonus were more likely to have longer, more severe arrests. patients with subcortical myoclonus were at risk for electrographic seizures, although at a lower rate than those with cortical myoclonus ( % vs %, respectively). mortality rates did not differ between patients with cortical and subcortical myoclonus ( % vs %). patients with cortical myoclonus were more likely to be discharged in a vegetative state compared to those with subcortical myoclonus ( % vs %, respectively (or . ; %ci . - . ). amongst survivors, good functional outcome at discharge did not differ between cortical vs subcortical myoclonus ( vs %, respectively). jerk-locked eeg back-averaging was useful in distinguishing subcortical from cortical myoclonus. myoclonus is seen in every sixth patient with cardiac arrest. cortical and subcortical myoclonus cannot be distinguished using clinical criteria. both may have good outcomes when managed with targeted temperature management and an aggressive antiepileptic regimen. intoxication by central nervous system (cns) depressant drugs can lead to anoxic brain injury by cardiac or respiratory arrest. we tested the hypothesis whether intoxication by these drugs contributes to mortality in acute anoxic brain injury we utilized healthcare cost and utilization project databases (nationwide inpatient sample and kids' inpatient database) to obtain patients admitted with diagnosis of anoxic brain injury. patients with drug intoxication (opioid, alcohol, sedative/hypnotic drugs) were identified. regression analysis was used to assess relationship between drug intoxication status to in-hospital mortality. the regression model was adjusted for age, gender, chronic medical comorbidities, presence of cardiac arrest and hospital characteristics. we analyzed a total of , patients with anoxic brain injury out of which ( . %) had drug intoxication and % were reported to have cardiac arrest. median age was years and % patients were males. in-hospital mortality was %. among the survivors, % underwent feeding tube placement and % had tracheostomy. drug intoxication was a significant positive predictor of inhospital mortality with adjusted odds ratio . ( . - . ), p= . . cns depressant drug intoxication is associated with higher in-hospital mortality in patients with acute anoxic brain injury. cardiac arrest affects approximately , individuals every year and is the third most common cause of mortality in the us. currently, there is no way of reliably risk stratifying survivors of cardiac arrest. identifying early predictors of outcome is vital for triaging and clinical trial enrollment. we proposed to identify key clinical and laboratory parameters that can reliably predict long-term outcomes among comatose survivors of cardiac arrest. this was a retrospective chart review of comatose survivors of cardiac arrest. we gathered data regarding several clinical (age, pre-arrest mrs, gcs on admission, and hours, presence/absence of shock and respiratory failure) and laboratory parameters (troponins, lactate, creatinine, and alt at admission, and peak values within the first and hours) as well as characteristics of the cardiac arrest (duration, arrest rhythm, location, and bystander cpr). we used a dichotomized gos ( - vs - ) at months as the primary outcome. we performed univariate and multivariable analysis to identify predictors of poor outcome. a total of patients were enrolled. on univariate analysis, higher age, higher pre-arrest mrs, lower gcs at hours, non vf/vt arrest rhythm, in-hospital arrest location, absence of bystander cpr, and shock were statistically significant (p < . ) for poor outcome. in multivariable analysis, only higher prearrest mrs and lower gcs at hours were independent predictors of poor outcome; no bystander cpr demonstrated a trend for being an independent predictor. none of the early laboratory data achieved statistical significance for predicting poor outcome. we identified several clinical predictors of poor outcome in our small cohort of comatose survivors of cardiac arrest. the above variables need to be analyzed among a larger cohort that includes all survivors of cardiac arrest in order to develop an injury severity score that can help risk stratify cardiac arrest survivors. after cardiac arrest, somatosensory evoked potentials (sseps), eeg characteristics, and mri are routinely used to evaluate comatose patients. the relationship between structural hypoxic injury, absent cortical potentials and the generation of background reactivity or epileptogenic potentials is unclear. here we evaluate a consecutive series of patients with cardiac arrest that were studied with sseps and evaluate clinical, eeg, and mri measures to study the dissociation between hypoxia-induced thalamic disconnection and spontaneous cortical activity. in this retrospective cohort study, all comatose patients post-cardiac arrest who received sseps were identified and reports were reviewed. patients were found; one patient with a high cervical cord injury was excluded. we recorded presence of cortical (n ) and subcortical evoked responses (p ), whenever available. based on the closest available eeg (maximum days from ssep recording) we determined reactivity, background characteristics (diffuse suppression or burst-suppression versus all other backgrounds), and presence of generalized periodic discharges (gpds) or seizures. diffusion weighted or t flair abnormalities in the thalamus were evaluated based on available mris. chi-square and fisher's exact test were applied as applicable. of patients with ssep, ( %) had absent n s, and % of those (n= ) had absent p . eeg reactivity was possible, albeit less common, in patients with absent n s ( % vs %, p< . ), but none of the patients with absent p s had a reactive eeg. those with absent n s were more likely to have diffusely suppressed or burst-suppressed background ( % vs %, p= . ) and to have abnormal thalamic signal on mri ( % vs %, p= . ). gpds, stimulus-induced gpds, and seizures were equally common in those with and without n s. the integrity of the somatosensory thalamo-cortical pathway does not appear to be necessary for presence of reactivity or generation of periodic epileptiform discharges. all families of patients who have become brain dead (bd) should be offered the choice of donation. this does not always happen and the factors that lead to approaching them or not are not known. our objective was to evaluate which factors influence the donation coordinators (dc) working for an organ procurement organization approach families after brain death we evaluated all declarations in our hospital's bd registry between january and june regarding consent for donation and cross-matched the hospital electronic medical records with the records of the local organ procurement organization. in order to refine neurologic prognosis in cardiac arrest patients we sought to incorporate heart rate variability into a multimodal prediction model. heart rate variability has been shown in animal studies to be preserved in survivors of cardiac arrest. in our preliminary study, we retrospectively analyzed patients admitted to the university of virginia who had undergone a cooling protocol following cardiac arrest. analysis of heart rate variability for each patient was done in the frequency domain using the fast fourier spectral transform with spectral bands at . - . hz for high frequency (hf) and low frequency (lf) power within the frequency band . - . hz. the unit-less lf/hf ratio was considered a measure of balance between sympathetic and parasympathetic tone. over a -year period, a total of patients were cooled. patients ( %) had ceeg, ( %) had routine eegs and ( %) had sseps performed. numerous patients ( , % of all arrests or % of all eegs performed) had malignant patterns, defined as burst suppression, severe suppression, or generalized periodic discharges. of the sseps, had an absent n (none survived to discharge) and had an n that was present ( survived to discharge). patients with absent n s and malignant eegs had lower lf/hf ratios when compared to survivors with present n s ( . vs. . ). the trend towards parasympathetic dominance following a severe neurologic injury and loss of normal sympathetic tone in those patients with absent n s and malignant eegs and may serve as an additional marker of poor prognosis following cardiac arrest. physicians often struggle with the intricacies of brain death determination and communication about end-of-life care. in an effort to remedy this situation, we introduced an educational initiative at our medical school to improve student comprehension and comfort dealing with brain death. beginning in july , students at our medical school were required to attend a -minute brain death didactic and simulation session during their neurology clerkship. students completed a test immediately before and after participating in the initiative. of the students who participated in this educational initiative between july and june , ( %) consented to have their data used for research purposes. students correctly answered a median of % of questions (iqr - %) on the pretest and % of questions (iqr - %) on the posttest (p< . ). comfort with both performing a brain death evaluation and talking to a family about brain death improved significantly after this initiative ( % of students were comfortable performing a brain death evaluation before the initiative and % were comfortable doing so after the initiative, p< . ; % were comfortable talking to a family about brain death before the initiative and % were comfortable doing so after the initiative, p< . ). incorporation of simulation in undergraduate medical education is high-yield. at our medical school, knowledge about brain death and comfort performing a brain death exam or talking to a family about brain death was poor prior to development of this initiative, but awareness and comfort dealing with brain death improved significantly after this initiative. this initiative was clearly a success and can serve as a model for brain death education at other medical schools. early withdrawal of life support (ewls) is a major factor in deaths following hypoxic ischemic injury after cardiac arrest (ca) in patients receiving targeted temperature management (ttm). appropriate timing of prognostication, and subsequent withdrawal of life support is recommended in recent guidelines, but is not always followed in clinical practice. we describe the impact of ewls in a multicenter registry database. using data from the international cardiac arrest registry (intcar), we defined ewls as withdrawal in the first three days of hospitalization. among all patients treated with targeted temperature management, we developed a logistic regression model to predict ewls. we then performed a propensity score and evaluated the incidence of good outcome between deciles of risk for ewls. patients entered into intcar from - from different hospitals were included. mean age was (± ) years, mean cpr duration was (± ) minutes, ( %) had a shockable rhythm, and ( %) received bystander cpr. support was withdrawn in , with ( %) events classified as ewls. ( % of total cohort). among patients with support withdrawal, older age (p= . ), nonshockable rhythm (p= . ), increased ischemic time (p= . ), and shock on admission (p< . ) were associated with ewls. among propensity matched patients grouped into deciles of probability for ewls, survival with good functional outcome occurred in % ( th decile), % ( th), % ( th), % ( th), and % ( th decile). early withdrawal of life support after cardiac arrest occurs frequently, and is associated with age, duration of cpr, a non-shockable rhythm, and shock at the time of admission. a cohort of patients propensity-matched to those with ewls had - % survival with favorable neurologic outcomes. these data support that in most patients receiving ttm, conservative and delayed prognostication after cardiac arrest is appropriate. brain herniation (bh) is a deadly event that requires immediate central venous access for infusion of hyperosmotic agents, especially . % nacl. traditional venous catheters, whether peripheral or central, takes several minutes to place, and requires skill for successful placement, thus delaying critical treatment. intraosseous (io) cannulation has been shown, at least during cardiac arrest, to be a secure and rapid means of central vascular access that requires limited training. however, limited data exists on the use of io in bh for administering . %. the aim of study of this study is to measure changes in serum sodium and bh reversal after administering . % via io. retrospective chart review of patients with acute neurologic injury requiring . % and io placement due to a lack of central access. demographics, diagnosis, gcs, sodium (na+), and pupillary reactivity, and immediate and delayed complications were collected. results patients included: males, age range - yo. diagnosis include intracerebral hemorrhage ( n= ), extra-axial hematoma (n= ) and sah (n= ). gcs ranged to . all patients were intubated. most patients were co-treated with hyperventilation, nabicarb, mannitol, and propofol. io was placed in tibia ( ) or humerus ( ); all placed correctly on first attempt. comparing hr post- . % nacl treatment to pretreatment: na+ level increased in of ; gcs improvement in of ; and returned pupillary reactivity in of . no adverse events reported, such as shock, cardiac arrest, tissue or limb injury. preliminary data suggest that during bh, io cannulation results in safe and timely . % administration in patients with no central access. additional safety data is needed, particularly with regards to the potential for myonecrosis. however, if safe, io cannulation should replace central line placement as the initial route of central venous access during bh. the pupillary light reflex is associated with outcome after cardiac arrest as a dichotomous variable (present/absent) at various time points following resuscitation (rosc). infrared pupillometry provides quantitative measures including pupil diameter (pd), and neurological pupil index (npi) which ranges from (nonreactive) to (brisk) and reflects velocity and degree of pupil constriction in response to a standardized light stimulus. these measures may provide early prognostic information to guide therapy. comatose adult survivors of cardiac arrest treated with targeted temperature management were monitored with the neuroptics npi- pupillometer. outcomes were defined as good (go) if discharge cerebral performance category score was - , and poor (po) if - . data are presented as median (iqr). groups were compared using non-parametric statistical tests. fifty-one patients were enrolled; the median age was ( . - . ), and ( %) were male. initial rhythm was vt/vf in %, asystole in %, and pea in %. outcome was good in ( %) patients. the initial pd did not differ between outcome groups [ . ( - . ) po vs . ( - . ) go]. the initial npi was lower in poor outcome patients [ . ( . - ) vs . ( . - . ) go, p= . ] measured . ( . - . ) hours after rosc. npi dropped below in more poor outcome patients [ ( %) vs ( . %) go, p= . ], and to zero in ( %) poor vs ( %) good outcome patients (p= . ). receiver operator characteristic curves confirmed that initial npi predicted poor outcome better than pupil diameter (auc . vs . , p= . ). a low neurological pupil index predicted poor outcome - hours after resuscitation from cardiac arrest, and dropped to abnormal levels (< ) and to zero (reflecting a non-reactive pupil) more often in patients with poor outcomes. additional research is needed to define potential confounders, optimal timing, and thresholds for different levels of neurological risk with pupillometry. prediction of death in a timely manner after withdrawal of life support (wls) is essential during organ donation after cardiac death (dcd). we aimed to develop a modified version of the recently develop dcd-n score to improve the specificity of prediction and test it in a specific group of patients with catastrophic brain injuries referred for dcd. we analyzed prospectively collected data by our local organ procurement agency on all consecutive adults with severe neurological injury evaluated for dcd across centers in the usa from march to may . we analyzed three variables used in the dcd-n score (corneal reflex, cough reflex and oxygenation index) and substituted the fourth variable for vasopressor support. a total of patients, mean age (sd± ) years were included in the final analysis. anoxic brain injury was the most common cause of death ( %) followed by stroke ( %). in multivariate logistic regression analysis adjusted for age and cause of death, absent corneal reflex (or . , % ci . to . , p = . , points), absent cough reflex (or . , % ci . to . , p = . , point), vasopressor support at high doses (or . , % ci . to . , p < . , points) and o ind ci . to . , p = . , points) were associated with the likelihood of death within minutes of specificity % and auc . . the modified dcd-n score has a greater specificity in predicting death within minutes of wls and is developed specifically from a cohort of patients evaluated for dcd. future prospective studies are needed for further validation of this scoring system. significant number of the patients with anoxic brain injury have poor neurological recovery. this created a significant anxiety in families who often request early prognostication. this study was conducted to evaluate possible ultra-early prediction of good neurological recovery in patients undergoing hypothermic protocol for anoxic brain injury retrospective chart review of the patients with anoxic brain injury was conducted. all patient underwent standard evaluation and management in the early stages of icu care, including initiating of hypothermic protocol with intravenous cooling device. all patients underwent evaluations with eeg and ssep within first day after admission during hypothermia phase and mri brain after re-warming. total of charts were reviewed. patient had normal ssep and normal mri. all patients had good neurological recovery, except for one patient who died secondary to severe cardiac failure eeg did not have any predictive value for the good neurological outcome when it was done during hypothermic protocol. normal ssep may a reliable predictor for good neurological recovery. apnea test is the essential component to confirm brain death by stimulation of respiratory center in brainstem. guidelines recommend that apnea testing should meet the criteria of disconnection from mechanical ventilator, and oxygen supplying by catheter. however, during the apnea test under this technique, disconnection from ventilator may induce hypoxia due to abrupt decruitment of alveoli and pulmonary barotrauma such as pneumothorax. there are some studies that suggest continuous positive airway pressure can be effective for patients with hemodynamically instability and respiratory impairment. we suggest a novel method of apnea test by using ambu bag with positive end-expiratory pressure (peep) valve to avoid abrupt change of peep during the apnea test. apnea testing was performed by using ambu bag with peep valve to adult brain death patients. ambu bag was not bagging during the testing and just connected to endotracheal tube with l/min of % oxygen. peep valve was applied the same peep of previous mechanical ventilator. on the apnea testing, vital signs and ekg were monitored. arterial blood gas analysis were measured and minutes after disconnection from mechanical ventilator. there were no significant differences in mean pao between before and after apnea test ( ± and ± , p= . ). mean arterial blood pressure were ± mmhg and ± mmhg before and after the test, respectively. during the intervention and following observation, arrhythmia or pulmonary complications had not occurred. we suggest a novel method of apnea testing which is a simple and easy technique by using ambu bag with peep valve to minimize decruitment of alveoli. this method shows vital signs and respiratory oxygenation of the patients remained stable during the test. declaration of brain death based on clinical exam has been plagued with challenges. as a result, ancillary testing such as nuclear scintigraphy cerebral blood flow (cbf) studies have been recommended. we present a case in which the apnea test could not be completed due to hemodynamic instability and where the nuclear scintigraphy cbf study resulted in a false declaration of brain death. a y/o male was admitted with bilateral hearing loss and confusion. on day two, the patient developed blurred vision, and an mri confirmed bilateral cerebellar and pontine infarctions. by day four, he had developed diffuse cerebral edema in the cerebellum, brainstem, and bilateral occipital lobes, and we proceeded with the clinical exam for brain death. all cranial reflexes were absent; however the apnea exam could not be completed due to blood pressure instability. a nuclear scintigraphy cbf study revealed the complete absence of radiotracer activity, and the patient was pronounced dead. two hours later, the patient regained a gag reflex. on the following day, the clinical exam, with the exception of apnea testing, was again consistent with brain death. a cerebral angiogram was performed and demonstrated normal blood flow to the anterior circulation. the patient was ultimately pronounced dead on day eight after two separate complete clinical brain death exams, including apnea testing, were performed. cerebral angiography showed essentially normal blood flow where nuclear scintigraphy showed no blood flow. nuclear scintigraphy cbf studies are commonly recommended when apnea testing cannot be completed. given the dramatic differences in the results observed between these modalities, a reevaluation of this practice should be considered. patients' perceptions of recovery moderate outcomes, however studies exploring the specific cognitive, functional, and psychological domains associated with subjective perceptions of recovery at hospital discharge after cardiac arrest (ca) are lacking. this is a prospective, observational cohort of patients admitted to columbia university medical center after ca, and survived to hospital discharge between / - / . patients with sufficient mental status to perform a neuropsychological exam and a questionnaire at discharge were included. subjective perceptions of recovery were assessed via responses to the forced-choice dichotomized question, "do you feel that you have made a complete recovery from the arrest?"objective outcome measures of recovery included: repeatable battery for neuropsychological status (rbans), modified lawton physical self-maintenance scale (l-adl), barthel index (bi), cerebral performance category scale (cpc), center for epidemiological studies-depression scale (ces-d), and post traumatic stress disorder-checklist (ptsd-c). chi-square, wilcoxon-rank sum, and logistic regression were used to compare the respondents, and determine factors associated with subjective perceptions of recovery. patients were included with mean age of ± years; % were men and % were white. % responded not having made a complete recovery. no significant differences were found between respondents in terms of demographics, charlson comorbidity index, arrest-related variables, rbans, l-adl, bi, pre-or post-arrest cpc scores. those responding that they had not made a full recovery had higher rates of ptsd-c ( % vs %, p< . ), and depression ( % vs %, p= . ). moreover, everyone that screened for ptsd (n= ) reported not having made a complete recovery. patients with higher ptsd scores were more likely to report not having made a complete recovery (or . ; p< . ) after adjusting for age, gender and depression scores. presence of post traumatic stress disorder symptomatology at discharge, and not neurocognitive or functional status, is highly associated with post-cardiac arrest patients' subjective perceptions of recovery. early eeg background reactivity is a strong predictor of neurological recovery after hypoxic-ischemic brain injury despite hypothermia and sedation. unfortunately, expert interrater-agreement on visual scoring of eeg background reactivity ranges from - %. recent studies indicate that machine-learning approaches using quantitative eeg (qeeg) might yield equivalent or superior performance to current eeg reactivity assessment practices, however its ability to predict outcomes has not been tested. we hypothesized that a qeeg reactivity method can predict long-term functional outcome in hypoxic ischemic brain injury. we retrospectively reviewed clinical and eeg data of cardiac arrest patients managed with hypothermia at two university hospitals. eeg reactivity was tested daily using a structured exam consisting of auditory, tactile, and visual stimulation. our quantitative eeg method evaluated changes in eeg spectra, entropy, and frequency features during seconds before and after each stimulation-step ( qeeg features used). only the first eeg reactivity assessment for each subject was used in the final analysis. good outcome was defined as cerebral performance category of - at six months. a penalized multinomial logistic regression was utilized for feature selection and a random-forest classifier was employed in the training and validation sets. model performance evaluation metric was the area under roc curve (auc). outcome and eeg data was available for a total subjects, and cases were excluded due to presence of burst-suppression, periodic epileptiform discharges, or eeg artifact. forty-seven subjects were included in the final analysis. mean age was . (standard deviation . ) years and . % had good outcome. the combination of four features provided best outcome prediction performance with an auc of . (kolmogorov-smirnov test, skewness, two-group test, and renyi entropy). early qeeg reactivity is predictive of good outcome at six months. a quantitative approach to eeg reactivity analysis might facilitate accurate and individualized prognostication in hypoxic-ischemic brain injury. hypoxic-ischemic brain injury is the leading cause of morbidity and mortality following cardiac arrest, and the ability to predict neurologic recovery in comatose cardiac arrest survivors is limited. functional mri measures brain network connectivity and resting-state network connectivity can be measured in comatose patients. the default mode network (dmn) is one resting state network that has been correlated with consciousness. we hypothesized the degree of connectivity in the dmn and other resting-state networks would correlate with consciousness recovery in post-cardiac arrest coma. consecutive patients with hypoxic-ischemic coma were enrolled. functional mri was obtained on all patients on post-arrest day - on an inpatient tesla mri. the connectivity in multiple resting-state networks was analyzed using pearson's correlations between component maps for each subject and previously defined standard network maps. connectivity in the default mode network and in additional resting-state networks was correlated with outcome. good outcome was defined as consciousness recovery at any point in the acute hospitalization. patients were included in this study. the mean age was ± years ( - ) and were male. patients survived with good outcome. the primary arrest rhythm and the duration of cardiac arrest did not differ between groups (primary rhythm as vt/vf: % vs %, good vs poor, p= . ; cardiac arrest duration: . ± . minutes vs . ± . minutes, good vs poor, p= . ). patients with good outcome had significantly higher mean network connectivity ( . ± . vs . ± . , good vs poor, p= . ). dmn connectivity showed a trend towards significance ( . ± . vs . ± . , good vs poor, p= . ). in comatose patients following cardiac arrest higher fmri measured resting state connectivity correlated with consciousness recovery. functional connectivity may be developed as a prognostic biomarker. sedative and analgesic infusions and neuromuscular blockade agents (nmba) are commonly used for comfort, suppression of shivering, and reduction of metabolic activity during targeted temperature management (ttm) after cardiac arrest. the optimal sedation and analgesia regimens are unknown. we sought to describe variability in sedation and shivering management practices at us and european cardiac arrest receiving centers. international cardiac arrest registry (intcar) centers were surveyed regarding sedation protocols for ttm after cardiac arrest. the survey was administered via redcap with a response rate of %. ten united states and european centers completed the survey. shivering is measured at ( %) of centers and recorded at ( %) centers. ten centers use nmb to control shivering prophylactically, centers use nmb only if shivering occurs, and centers increase opioids or sedatives when shivering occurs, but do not use nmb. the most common sedative was propofol ( / centers), followed by midazolam ( / ) and the most common analgesic was fentanyl ( / ) followed by remifentanyl ( / ). , , and centers report having a sedation target of light, moderate, or deep respectively. a sedation scale is used at ( %) centers, targeted to patient comfort at ( %) centers. daily sedation lightening is protocolized when rewarming starts at ( %) centers, when normothermia is reached at ( %) and not specified in the remainder of groups. of patients who awaken, centers report that they expect this to occur at ( centers), ( centers) and ( centers) hours respectively. among cardiac arrest receiving centers internationally, there is significant variability in ttm sedation and shivering management strategy. our hospital policy allows an optional sbd (with an apnea and a cerebral blood flow test) or a dbd (with an apnea test). we have evaluated the adoption of and reason for performing a single brain death exam (sbd) vs two (dual) brain death exams (dbd) and their impact on organ function and consent for organ donation. we evaluated our hospital's bd registry between january and june regarding sbd or dbd. we also cross-matched our electronic medical records with the records of the local organ procurement organization. of bd declarations, ( %) were sbd and ( %) dbd. during the st five years, % of all bd exams were sbd and during the second %. patients with sbd were older ( . ± . for sbd vs . ± . years for dbd, p= . ), had a primary neurologic diagnosis ( % vs %, p< . ) and were admitted to the neuro-icu ( % vs %, p< . ). during the nd exam, . % patients were on equal or higher dose of pressors. sbd patients had lower k+, bun, creatinine and heart rate, but higher peak na+ and apnea pao (for all p< . ), although apnea ph and paco were similar. the time between injury to bd pronouncement was shorter in sbd by . hours. there was no difference in consent rate between sbd and dbd ( % vs %, p= . ). at our institution, bd declaration was more often done by dbd exams, although the primary diagnosis and the unit of admission influenced the decision. an increased adoption of sbd exams was noted after the aan bd guidelines, supporting sbd exam, were published. although the number of exams did not affect rate of consent for donation, surrogate markers indicated better function of organs after sbd, while dbd patients stayed in the icus over a day longer. there are no data supporting better numbers or function of organs in donors after brain death (bd), if there is a shorter waiting period (as expected with single brain death exam [sbd] ) from the time that bd is declared to the time the patient arrives at the operating room (or). our goal was to find if the number of brain death exams, either sbd or dual (dbd), had any impact on the number of organs recovered and transplanted we evaluated our hospital's bd registry between january and june regarding sbd or dbd and cross-matched our electronic medical records with the records of the local organ procurement organization out of bd declarations, led to consent, of which ( . %) after sbd and ( . %) after dbd. there was a trend for longer consent to or time for dbd ( . ± . hours vs . ± . for sbd, p= . ). there was no difference in the number of organs recovered or transplanted based on the number of exams ( . ± . vs . ± . organs/patient recovered and . ± . vs . ± . transplanted for sbd vs dbd, respectively, p> . ). there was a trend for more lungs to be transplanted after sbd exam ( % vs %, p= . ), but this was not found with kidneys, heart, liver, pancreas or intestines. in multiple logistic regression models, adjusting for variables pertinent to each individual organ function (for example, bun or creatinine level for kidneys, blood gases for lungs etc), the number of exams was not an independent predictor for successful transplantation conclusions sbd exam led to similar numbers of organs transplanted compared to dbd exam in this single center registry analysis. more rapid brain death declaration, as with sbd, is not a factor that influences organ transplantation the glasgow coma scale (gcs) is a standardized and commonly used way of assessing important aspects of neurological condition for critically ill patients. while it is a validated tool for prognostication, it is unclear whether serial measurements add value to this prognosis. we used a large set of serially collected gcs measurements to assess the impact of gcs score on the trajectory of neurological recovery as well as factors affecting score variance. gcs total and subscores ( , time points from , patients) recorded hourly by registered nurses in the neurosurgical intensive care unit (nsicu) between january, and may, were analyzed retrospectively. k-means clustering provided groups with similar progression characteristics during nsicu stay. k-means clustering provided groups with similar progression characteristics during nsicu stay. descriptive features for each cluster were binned into histograms and evaluated for similarity using and kruskal-wallis tests. linear correlations of the sub-scores were very high (eye-verbal: . , eye-motor: . , verbal-motor: . ), while compositional variance was low for aggregate scores. hour-to-hour variance in gcs correlates to significant nsicu activities such as nursing shift changes. among patients with similar minimum gcs scores during their stay, those that recovered were significantly less likely to have deteriorated in the hospital ( , p<< . ). for patients with a minimum gcs<= , those that arrived at their minimum score (i.e., did not deteriorate in nsicu) were . % more likely to recover than those who deteriorated in-hospital (kw, p<< . ) . patients that experienced recovery show significantly greater improvement as early as hours after their minimum score (kw, p<< . ). the gcs is unnecessarily complex for most nsicu patients and can be represented by fewer variables. serial gcs measurements do provide value for prognosis and may be able to distinguish patients with potential to recover early in their hospital course. stroke is a major cause of death and disability, and common admission to neurological intensive care units. preferences for cardiopulmonary resuscitation (cpr) are often discussed, but there is limited understanding of cpr outcomes among stroke patients. systematic review and meta-analysis of published literature from to among stroke patients undergoing in-hospital cpr. preferred reporting items for systematic reviews and meta-analysis, metaanalysis of observational studies in epidemiology, and utstein guidelines were used to construct standardized reporting templates. detailed searches of pubmed and cochrane libraries were supplemented with hand-searched bibliographies. primary data from studies meeting inclusion criteria at two levels were extracted, i) survival to hospital discharge after cpr, and stroke as a primary admitting diagnosis, and the less restrictive, ii) survival to hospital discharge after cpr with stroke listed as a comorbidity, were meta-analyzed to generate weighted, pooled estimates of survival to hospital discharge. of articles screened, there were articles ( %) that underwent full review. three articles met primary inclusion criteria, specifically identifying patients with stroke as a primary admitting diagnosis. twenty additional articles met secondary inclusion criteria, listing stroke as a comorbidity. there was an % ( % confidence interval (ci) . , . ) rate of survival to hospital discharge rate from a combined sample of patients that received in-hospital cpr. among the more heterogenous population of inpatients with stroke listed as a comorbidity, there was % ( % ci . , . ) rate of survival to hospital discharge. adherence to utstein reporting guidelines was poor, and neurological outcomes were measured in ( %) of studies. survival to hospital discharge among stroke patients is lower relative to general hospital populations. these preliminary findings highlight the need for improving the quality of evidence to inform patient and provider discussions of cpr among stroke patients. there is often a tendency to treat patients with traumatic brain injury (tbi) and a glasgow coma scale (gcs) score of on presentation less aggressively because of low expectations for a good outcome. based on the crash trial database, a prognosis calculator has been developed for the prediction of outcome in tbi patients. our aim was to investigate whether the crash calculator can be used for prognostication in patients with tbi and gcs of on presentation. we performed a retrospective review of patients with tbi and a gcs score of from / to / . the crash calculator has been validated to estimate mortality at days and death and severe disability at six months (glasgow outcome scale-gos - ). the calculator uses country of origin (usa in our dataset), age, gcs, pupils reactivity to light, presence of major extracranial injury, and findings on ct scan of brain (petechial hemorrhages, obliteration of the third ventricle or basal cisterns, subarachnoid bleeding, midline shift, and non-evacuated hematoma). the individual prognosis for mortality at days and unfavourable outcome at months was calculated and compared with the actual outcomes. a total of patients were included. a tend toward underestimation of the risk of mortality at days was found (estimated mortality was % compared to actual mortality of %; difference of %, p = . ). however, the estimation of outcome at months was accurate (estimated gos - was . % compared to actual of . %, p = . ). the crash prognosis calculator underestimated the risk of mortality, but accurately predicted unfavourable month outcome in patients with tbi and gcs of on presentation. pending larger studies to validate our findings, we believe that crash calculator can only support -not replace -clinical judgment. there are no nationally enforced standards regarding brain death. few data exist on how brain death is determined across the u.s. we used claims data from - from a nationally representative % sample of medicare defined as icd- -cm code . . the primary outcomes were evaluation by a neurologist or neurosurgeon, defined as a physician evaluation-and-management claim associated with the medicare provider specialty codes for neurology or neurosurgery, during the dates of the hospitalization. cpt codes were used to ascertain ancillary testing: brain radionuclide imaging, transcranial doppler ultrasound, or electroencephalography for brain death determination. exact binomial confidence intervals (cis) were used to report proportions. we identified patients with a brain death diagnosis. common associated neurological diagnoses were stroke ( patients; . %), cardiac arrest ( ; . %), and traumatic brain injury (tbi) ( ; . %). head ct or brain mri was performed in . %; this was true of . % of cases of stroke or tbi versus . % of cardiac arrests. neurologists were involved in the care of patients ( . %; % ci, . - . %). they were more commonly involved in the care of stroke ( . %) or cardiac arrest ( . %) than tbi ( . %) or other conditions ( . %). neurosurgeons were involved in cases ( . %; % ci, . - . %), mostly after tbi or stroke. two hundred patients ( . %; % ci, . - . %) were seen by a neurologist or neurosurgeon. twenty-nine patients ( . %; % ci, . - . %) underwent any ancillary testing. two hundred and nine patients ( . %; % ci, . - . %) were seen by a neurologist or neurosurgeon or underwent ancillary testing. in a nationally representative cohort of elderly patients, one-third of patients with a brain death diagnosis were not evaluated by a neurologist or neurosurgeon or by using ancillary tests. traumatic brain injury (tbi) is a major cause of death and disability in the us. recent advances in d illustration ( di) can precisely quantify intracranial pathology on computed tomography (ct). the current standard of measurement, abc/ , demonstrates variability in precision with bleed phenotype. the aim of this project is to assess accuracy automated di and compare it to standard abc/ measurements. baseline ct scans collected during the protectiii multicenter clinical trial (n= ) were retrospectively reviewed by a central neuroradiologist. subdural and epidural hematomas were identified (n ). the radiologist calculated abc/ score using osirix (mac) and radiant (pc) workstations. in a blinded fashion, research assistants concurrently generated di using the following methods: dicom data were resampled to . mm thickness slices and symmetrized using image analysis software (aquarius terarecon inc, ) . lesions were then compiled into single volumetric regions of interest ( d slicer v . , ) . hemorrhages were divided into two groups for analysis: group . volume of hemorrhage bland-altman analysis. this study was irb approved. there is a significant difference between the results of the di and abc/ methods. in group . the estimated relative bias between the two measurements (after transformation) is . (sd . ; pvalue . ; % ci . , . ). in group , the relative bias is - . , sd . , pvalue < . , % ci (- . , - . ). the di method calculates detailed surface area measurements in large and small volume hemorrhages, while abc/ averages cross-sectional area. the abc/ estimates vary by bleed phenotype and offer less topographical precision than di. this is particularly true in extra-axial hemorrhages, which are numerous studies have shown a significant association between hypotension and poor outcome in patients with head injuries. prior investigations have demonstrated that generation of negative intrathoracic pressure (itp) in ventilated patients with brain injury improves mean arterial pressure (map) and lowers intracranial pressure (icp). we hypothesized that augmentation of negative itp by breathing through an impedance threshold device (itd) with cmh o of inspiratory resistance would improve mean arterial pressure in a porcine model of intracranial hypertension. six spontaneously breathing female pigs ( . ± . kg), anesthetized with propofol, were subjected to focal brain injury through inflation of an french foley catheter placed in the epidural space. once a stable injury was obtained, baseline data were collected for minutes followed by minutes of itd use. results are reported as mean ± sd. the itp without the itd during inspiration was - . ± . mmhg, compared to - . ± . mmhg with the itd, p< . . following brain injury, map (mmhg) was significantly higher during itd use ( ± vs. ± ; p< . ). cerebral perfusion pressure (mmhg) was also significantly higher during itd use ( ± vs. ± ; p< . ). icp (mmhg) was not significantly different between groups ( . ± . vs. . ± . ; p= . ) although end tidal carbon dioxide levels (mmhg) were significantly higher during itd use ( ± vs. ± ; p< . ) presumably due to lower respiratory rates during itd use ( ± vs. ± ; p= . ). contralateral cerebral blood flow (ml/ gm/min) was similar between groups ( ± vs. ± ). in this porcine model of intracranial hypertension, spontaneous respirations through an itd significantly improved map and cpp. this approach could be utilized to prevent hypotensive episodes in the setting of brain injury. the impact of applying nanotechnology and biomedical engineering to improve the management of patients with spinal cord injuries (sci) is still not accurately described, nor understood. a systematic review of the literature was conducted, according to prisma criteria, to identify publications revolving around "sci+nanotechnology" and "sci+biomedical engineering" indexed on pubmed in the period - . furthermore, the database of clinicaltrials.gov was searched to highlight the stage of translation of this research into clinical practice through randomized clinical trials (rct). finally the uspto database was interrogated to identify the number of pertinent patents filed in northamerica in the same timeframe. the literature on bioengineering and nanotechnology contributions to sci is exponentially growing, with almost % of articles published between and . its quality and the interest of the scientific community are high, as confirmed by the average impact factor ( . ) and the average number of citations ( ) of articles published in the last two years. this field still represents a niche of sci research: the articles reviewed represent only . % of all articles on sci published in the same decade. this trend is confirmed on clinicaltrials.gov: out of rct on sci only few focus on the application of those technologies, furthermore out of articles spurring from the rct identified were published after , and % after . interestingly, with patents registered by the uspto, the interest in the commercial application of this research seems vivid. currently, the most promising areas of research are: nanofabrication/nanoscaffolding for structural repair, nanodrugs for regeneration, and design of neural interfaces for functional therapies. this review showed that both universities and independent research institutions (mostly from usa, china and european union) are driving this research race; the figures provided above suggest its potential to become a successful example of translational medicine. there are no neuroprotective and neuroregenerative treatments available for traumatic brain injury (tbi). clinical trials investigating potential treatments such as therapeutic hypothermia and progesterone have failed. pre-clinical studies indicate there may be a role of stem-cells in promoting neuroprotection/neuroregeneration in-vivo in animal models of tbi. we aim to provide a pre-clinical literature review into stem-cells as a potential therapeutic option in tbi-animal models. a literature search was conducted on pubmed and google scholar using the terms "traumatic brain injury", "stem-cell", "preclinical", and "animal studies". studies were included if there was an in-vivo animal model of tbi with either intravenous or intra-cortical stem-cell transplantation, along-with a control group, and investigated either motor or behavioral outcomes, or a combination. twenty-seven studies (n= animals) satisfied the criteria. / ( . %) animals were investigated for outcomes. studies harvested stem-cells from human-source, whereas harvested stem-cells from animal-source. bone-marrow stromal-cells (bmsc) were used in studies, neural stemcells (nsc) in , and miscellaneous in . / ( . %) animals received any stem-cell transplantation, whereas were controls. of animals receiving stem-cell transplantation ( ), ( . %) showed significantly better outcomes relative to control animals in each individual study, with exception of one study. amongst transplanted animals, functional outcomes did not differ significantly when grouped by stem-cell type (p= . ), transplantation route (p= . ), and source (p= . ). animals were followedup until week (n= studies), weeks (n= ), weeks (n= ), or > -weeks (n= ). this pre-clinical data demonstrates that stem-cell transplantation may have treatment potential in tbi as shown by improvement in functional outcome in as many as three-quarters of all animals that were treated with stem-cells. this data provides a foundation for the design of clinical translational studies. age of trauma patients including those with asdh is increasing as stated by national trauma registers. we were especially interested if age > years significantly influences outcome compared to younger patients and if other factors like initial gcs have an influence too. methods midline shift, if asdh was surgically removed, additional contusions, comorbidities and intake of anticoagulants. outcome was analyzed using the glasgow outcome scale (gos) at hospital discharge (gos ) and if possible months after discharge (gos ). uni-and multivariate analysis (cox regression model) was performed using the sigma stat softwar . . adverse outcome p= . . in addition, all patients > years with an initial gcs died whereas only % of younger patients with initial gcs died (p< . ). this was the only significant result in the multivariate analysis the monovariate analysis of our data showed a significantly higher risk for adverse outcome after asdh whe it should be considered if it is reasonable to transfer them from local hospitals to a specialized neurosurgical clinic, especially in times of limited resources. reported incidence of pulmonary edema in isolated head injury varies from - %. lung sonography is a potentially useful non invasive technique to detect extravascular lung water(evlw). this study aimed to identify the presence of evlw using lung ultrasound (b lines > per lung field) in chead injured patients admitted to icu . secondary objectives were to compare diagnostic accuracy and time to identification of evlw using chest x ray versus lung ultrasound. association of evlw with duration of mechanical ventilation (mv)and icu stay were observed after ethical clearance (iec no. int/iec/ / ), patients with head injury requiring mv and critical care were enrolled in the study. daily routine chest x ray and bedside lung ultrasound were done from the day of icu admission until the patient was on mechanical ventilator support. four inter costal spaces (ics) were scanned in semi recumbent position; third and sixth ics on either side of sternum till mid clavicular line. evlw was reprted as > b lines per lung field scan sonographically. details of mv and icu management were noted . evidence of evlw at the time of admission using sonography and cxr was recorded in and patients respectively. during icu stay . % patients showed evlw using lung usg (vs patients on cxr). mean delay in detection of evlw on cxr after detection on ultrasound was . ± . days. patients with low gcs, s. albumin, pao /fio ratio and greater apache ii and saps ii had significantly higher incidence of evlw. duration of weaning, mechanical ventilation and icu stay was significantly longer in patients with presence of evlw (p < . ) conclusions: lung ultrasound appears promising in detecting evlw earlier than chest x ray and may aid to minimize the duration of mechanical ventilation, weaning and icu stay . antiepileptic drugs (aeds) are recommended by guidelines for prophylaxis of early post-traumatic seizures (pts) associated with traumatic brain injury (tbi). there has been an increased use of both phenytoin and levetiracetam for this indication. the purpose of this study is to determine the incremental cost-effectiveness of phenytoin compared with levetiracetam for early pts prophylaxis in tbi patients. a cost-effectiveness study was conducted comparing phenytoin and levetiracetam for early pts prophylaxis during the days post-tbi. patients were included if they were years or older, received a study drug, and had a diagnosis of tbi. patients were excluded if they had a history of epilepsy, did not sustain a recent tbi, were initiated on both study drugs concurrently, or were switched to pentobarbital for elevated intracranial pressure. data was collected via retrospective chart review using electronic medical records and publically reported costs. effectiveness was measured as having a successful seizure prophylaxis regimen (sspr), which was defined as ) no clinical or electrographic seizure, ) no discontinuation of study aed, ) no cross-over of study aed to different aed, or ) no addition of aed during the days of therapy. the costs included costs of the study drugs, phenytoin level, and eeg. the data was used to calculate the primary endpoint, the incremental cost for the incremental change in sspr or the incremental cost effectiveness ratio (icer). the phenytoin regimen (n= ) cost $ . and had an sspr of . %. the levetiracetam regimen (n= ) cost $ . and had an sspr of . %. the icer was $ for each % increase in sspr with levetiracetam. the sspr of phenytoin and levetiracetam were similar. because patients who received phenytoin may differ from those who received levetiracetam, further analysis is needed prior to drawing any conclusions about the cost-effectiveness of levetiracetam relative to phenytoin. augmented renal clearance (arc) has been reported in up % of critically ill tbi patients and may impact therapeutic drug concentrations. improved predictors of arc are needed. serum cysc, a validated marker of glomerular filtration, has not been examined as a marker for arc in critically ill tbi patients. this pilot study tested the hypothesis that serum cysc concentrations are lower than reference values following tbi. adult tbi patients enrolled in the ukccts-unctracs prospective study of arc effects on drug clearance, were eligible. cysc serum concentrations (elisa -r & d cysc) were measured daily for up to days and compared to reference values. descriptive statistics and student t-test for continuous measures (patient vs. reference lower range cysc) were calculated. the first ten patients [ m/ f, mean age= . years ( - y/o), median gcs= (iqr - )] provided a total of serum cysc for analysis. each patient provided at least samples (range - ) for up to seven days. measured serum cysc concentrations were below the reference range in of samples. the overall mean cysc concentration was . + . mg/l vs expected mean of . + . . (ns) measured values fell below the lower reference range in patients ( m/ f) for the first study days (mean = . + . vs . + . p< . ). the mean difference between measured concentration and reference value was . + . mg/l. after days, four patients ( m/ f) remained below reference values with a mean difference of . + . mg/dl. preliminary results show cysc was not consistently below reference ranges in all tbi subjects. a subset of subjects showed significantly lower cysc within seven days of injury. the relationship between cysc and arc needs to be further examined as analysis continues. functional connectivity of the default mode network (dmn) is believed to be necessary for recovery of consciousness after coma. however, dmn connectivity has not been comprehensively studied in patients with acute severe tbi. we hypothesized that dmn connectivity in patients with acute severe tbi is associated with level of consciousness. we prospectively enrolled patients admitted to the intensive care unit for acute severe tbi and performed resting-state functional mri (rs-fmri) as soon as safely possible. dmn functional connectivity was assessed by rs-fmri analysis of the blood-oxygen level dependent (bold) signal using a seed-based approach. pearson's correlation coefficients were calculated between the mean bold time series within dmn nodes and all other regions in the brain. level of consciousness was assessed at the time of the scan using the coma recovery scale-revised (crs-r). two-sample t-tests were performed to identify brain regions with connectivity differences between conscious and unconscious subjects. we then tested for associations between level of consciousness and dmn connectivity within these regions. we enrolled patients ( male, mean+/-sd age +/- years) and matched controls ( male, age +/- years). rs-fmri was performed . +/- . days post-injury. at the time of rs-fmri, patients' levels of consciousness were coma (n= ), vegetative state (vs; n= ), minimally conscious state (mcs; n= ), and post-traumatic confusional state (ptcs; n= ). connectivity within the medial prefrontal cortex and posterior cingulate was selectively reduced in unconscious patients (coma and vs) compared to conscious patients (mcs and ptcs; false discovery rate-corrected p < . ). when these regions were further interrogated, connectivity correlated with crs-conclusions dmn functional connectivity correlates with level of consciousness after acute severe tbi. traumatic brain injury (tbi) is a substantial source of death, disability, and healthcare utilization. many older tbi patients present to community hospitals and are transferred to trauma centers for further care; however, little is known about the provision of care and patient outcomes at the final receiving hospital. we described trauma center care among geriatric transfer patients with tbi. we conducted a secondary analysis on a sub-cohort from a prospective multi-center study focusing on ambulance and emergency department (ed) care of injured older adults transported via ambulance. the current analysis focused on tbi patients transferred to the region's level i trauma center from another hospital. transfer paperwork from the originating hospital was reviewed and we conducted a detailed medical record abstraction, including computed tomography (ct) findings, procedures, length of stay (los), and ed disposition. data were collected on transfer patients. thirty had confirmed abnormalities on head ct ( . %). the mean age was years (range: - ), % female, and the most frequent mechanism of injury was falls ( %). average los was . days (range: - , median los . ), with patients staying one day or less. ct findings included subdural hematoma ( %), subarachnoid hemorrhage ( %), and intraparenchymal hemorrhage ( . %). five patients required neurosurgical intervention ( %), eight required icu admission ( %), two were discharged from the ed ( %), and two transitioned to inpatient hospice ( %). tbi is a frequent cause of transfers to trauma centers. in our sample, admission occurred in the majority of patients, but neurosurgical intervention was less common. however, for appropriately selected patients, strategies such as telemedicine may reduce transfers thus saving resources and improving continuity of care for patients and their families. this is an area in which future research is warranted. the prospects and timing of decannulation may affect surrogate decision making regarding tracheostomy for traumatic brain injury (tbi) patients, yet predictors of decannulation are unknown. methods tracheostomy admitted to an affiliated acute rehabilitation hospital between january and december . patients who had life-sustaining measures withdrawn were excluded. admission data, including injury characteristics and presence of lung injury on initial chest x-ray, and inpatient complications were compared. patients were followed throughout rehab and to the point of decannulation. patients lost to follow up were eliminated from analysis. time of decannulation was verified by inpatient physician notes. a cox proportional hazards model was created to determine factors associated with the time to decannulation and reported as hazard ratios (hr). there were tbi patients admitted to the icu during study period and ( % men, mean yearsold, median gcs ) underwent tracheostomy after ± days of intubation, of which were followed throughout rehabilitation. overall cannulation time was ( - ) days. ( %) patients had their trach removed prior to discharge from rehab after ( - ) days of cannulation. in a cox proportional model adjusting for sex, reintubation, aspiration pneumonitis, and presence of lung injury on admission chest x-ray; a higher hospital discharge gcs was associated with a shorter time to decannulation (hr, . ; % ci, . - . ; p =. ) while patients who required inpatient dialysis had a longer time to decannulation (hr: . ; % ci, . - . ; p = . ). the majority of tbi patients that require tracheostomy will be decannulated prior to discharge from rehab. longer durations of tracheostomy cannulatio hospital discharge and those that receive inpatient dialysis. goal directed therapy (gdt) is thought to be associated with outcome after traumatic brain injury (tbi). our team applied gdt to standardize care in patients with moderate to severe tbi, who were enrolled in a large multicenter clinical trial. physiologic goals were defined a priori in order to standardize care across sites participating in the protect iii trial. data were collected hourly for all randomized subjects (n= ). hours where gdt were not achieved were classified as "transgressions". these included: map . ; platelets mg/dl; and sbp mmhg. the proportion of hours spent in transgression was calculated for each parameter and grouped by quartile. poor outcome was defined via stratified dichotomy of the gos-e. data were adjudicated electronically and via expert review. for each parameter, the association between outcome and either ( ) occurrence of transgression or ( ) cumulative duration of transgression was estimated via logistic regression model, and backward selection was used to identify the physiologic parameters associated with outcome. subgroup analyses were performed in subjects with intracranial monitoring (ticp, n= ) . parameters significant at alpha . are reported. prolonged duration of transgression was associated with poor outcome when: glucose> mg/dl (p= . ); hgb mg/dl (p= . ) and inversely associated with map mg/dl (p= . ) or and was inversely associated with map< mmhg (p= . ). the protect iii clinical trial rigorously monitored compliance with gdt after tbi. multiple significant associations between physiologic transgressions and patient outcome were found. the data suggest that reducing physiologic transgressions is important to minimizing patient morbidity after tbi. the measurement and management of intracranial pressure (icp) is a key component in the care of severe head injury. extracranial ventricular drains (evd) have remained the standard due to the ability to lower icp with the drainage of cerebrospinal fluid (csf). placement of an evd is a more invasive procedure than intraparenchymal icp monitors (ipm) and it is unclear if the use of an evd improves outcomes. we hypothesized that early placement of an evd, in adult patients with severe head injury, would not affect outcomes. utilizing data from the citicoline brain injury treatment (cobrit) trial, a prospective multicenter study, we identified patients who met the inclusion criteria; ) placement of an icp monitoring device, ) glasgow coma score (gcs) less than , ) evd placement prior to arrival or within hours of arrival at the study institution. primary outcome was glasgow outcome score-extended (gose) at days post injury. secondary outcomes included neuropsychological evaluations at days post injury, mortality, and length of icu stay. logistic regression with forward-stepwise predictor adjustment and propensity score adjustment was performed to assess the independent association between evd placement and outcomes. patients who received an evd prior to or within hours of arrival at the study institution had worse gose at days ( . ± . vs . ± . , p= . ), higher in hospital mortality ( % vs %, p = . ), and did worse on out of neuropsychological measures at days. there was no difference in icu length of stay ( . ± . vs . ± . , p= . ). early placement of evds in severe adult head injury is independently associated with worse outcomes and higher in hospital mortality. goal directed therapy (gdt) is thought to be associated with outcome after traumatic brain injury (tbi). our team applied gdt to standardize care in patients with moderate to severe tbi, who were enrolled in a large multicenter clinical trial. physiologic goals were defined a priori in order to standardize care across sites participating in the protect iii trial. data were collected hourly for all randomized subjects (n= ). hours where gdt were not achieved were classified as "transgressions". these included: map . ; platelets mg/dl; and sbp mmhg. the proportion of hours spent in transgression was calculated for each parameter and grouped by quartile. data were adjudicated electronically and via expert review. for each parameter, the association between outcome and either ( ) occurrence of transgression or ( ) cumulative duration of transgression was estimated via logistic regression model, and backward selection was used to identify the physiologic parameters associated with mortality. subgroup analyses were performed in subjects with intracranial monitoring (ticp, n= ). parameters significant at alpha . are reported. mortality was . % and . % in the full and ticp cohorts. prolonged duration of transgression was associated with increased mortality for: hgb . (p mg/dl (p mg/dl (p= . ), and sbp . (p . (p= . ). covariates inversely related to mortality included single occurrence of map mmhg (p< . ). the protect iii clinical trial rigorously monitored compliance with gdt after tbi. multiple associations between physiologic transgressions and mortality were observed. the data suggest that maintaining physiologic measures within gdt guidelines may be important in preventing deaths. current outcome models in moderate-severe traumatic brain injury (mstbi) include only admission characteristics. yet, mstbi patients commonly have prolonged intensive-care-unit(icu)-stays with high risks to develop icu complications, lending to the hypothesis that these may be additionally associated with outcomes. the objective of this study was to examine the incidence rates of pre-specified medical and neurological icu complications, and their impact on post-traumatic in-hospital mortality and month functional outcomes. we analyzed mstbi patients consecutively enrolled in the prospective observational optimismstudy at a level- trauma center between / - / . poor outcome was defined as glasgow outcome scale - . multivariable logistic regression was employed to adjust for admission characteristics and icu-length-of-stay. the mean age was ± years, % were men, and median motor glasgow-coma-scale and injury-severity-scores were (iqr ; ) and (iqr ; ), respectively. the three most common medical and neurological icu complications were: hyperglycemia ( %), systemic inflammatory response syndrome ( %) and fever ( %); intracranial pressure crisis (icp; [ % of n= with icp-monitor]), brain edema requiring osmotherapy ( %), herniation ( %). multivariable models were adjusted for age, marshall-ct-classification, motor glasgow-coma-scale, pre-admission hypotension, icu-length-of-stay and injury-severity-score. after adjustment, in-hospital mortality was significantly associated with in-icu-cardiacarrest (or ; %ci . - . recent studies suggest benefits for early tracheostomy in patients with traumatic brain injury (tbi), yet data regarding who will require tracheostomy is lacking. ad lifesustaining measures withdrawn were excluded. admission and inpatient variables were compared. multivariable logistic regression analyses were used to assess admission and inpatient factors associated with receiving a tracheostomy and to develop models predictive of tracheostomy. there were patients ( % men, mean years-old, median gcs ) meeting study criteria with tracheostomy performed in ( %). admission predictors of tracheostomy included gcs, marshall score, injury mechanism, pao /fio ratio, and number of quadrants on chest x-ray with consolidation. inpatient factors associated with tracheostomy included the requirement for an external ventricular drain (evd), number of operations, pneumothorax, inpatient dialysis, aspiration, reintubation, and the presence of hospital acquired infections. multiple logistic regression analysis demonstrated that the development of hospital acquired infection (adjusted odds ratio [aor], . ; % confidence interval [ci], . - . ; p < . ), number of operations (aor, . ; % ci, . - . ; p < . ), pneumothorax (aor, . ; % ci, . - . ; p = . ), reintubation (aor, . ; % ci, . - . ; < . ), penetrating tbi (aor, . ; % ci, . - . ; p= . ) and placement of evd (aor, . ; % ci, . - . ; < . ) were independently associated with patients undergoing tracheostomy. a model of inpatient variables only was more strongly associated with tracheostomy than one with admission variables only (roc auc . vs. . , p< . ) and did not benefit from addition of admission variables (roc auc . vs . , p= . ). potentially modifiable inpatient factors have a stronger association with tracheostomy than do admission characteristics. existing traumatic brain injury (tbi) guidelines are designed primarily for the evaluation and management of tbi in tertiary care centers with advanced neuroscience capabilities. military special operations medical providers, however, are often required to treat and sustain patients in austere environments with limited resources for up to hours. tbi management guidelines directed specifically toward the care of these patients are needed. a review of recent operational experiences involving tbi and a survey of military special operations medics prompted a multidisciplinary expert panel to develop draft clinical practice guidelines/recommendations for prolonged field management of tbi. the panel conducted an in-depth review of literature on tbi and related topics and adapted existing and emerging therapies to address the unique challenges encountered in prolonged field care. tbi management while optimal management of pbto is not fully established. the objective of this -coeur arterial blood gas was drawn (icp, cpp, hemoglobin, temperature, pco and pao ). probes were localized in normal appearing white matter. we used a was calculated. a total of data sets were collected from patients (mean age . ± . , median gcs , mortality range from to ). mean pao for the group as a whole was mmhg (± ) and mean cpp was mmhg (± ). mean duration of pbto monitoring was . days (± . ). taking into account all determinants of pbto and using a protocolized approach to correct pbto , the mmhg for a few days. high pao values are possibly required due to the fact that oxygen delivery to the brain is rate-limited by diffusion and impaired by oedema or microvascular ischemia. it should be noted that pulse oximetry is not sensitive to detect pao below this level. traumatic brain injury (tbi) and stroke are extremely common causes of acute brain injury (abi), which cause long term disability and permanent neurological impairment. coma and stupor are common manifestations of abi, due to interruptions of the ascending reticular activating system (aras). neuro stimulants can improve functioning of the aras. despite decades of research there is a paucity of prospective high-level evidence utilizing neuro stimulants to help with earlier awakening from coma and stupor in abi. we reviewed the literature using the grade level of evidence (loe) methodology. we performed a preliminary literature search of the national library of medicine (nlm) using search terms abi and stimulants. within the literature we searched for timing of stimulant use among abi studies and included all forms of abi such as tbi, stroke, and anoxic injury. we retrieved total results, of which we excluded since they did not meet grade high loe criteria or were "n of " studies or aggregates. only high loe randomized studies or meta-analyses were found. among these various stimulants were investigated including methamphetamines such as methylphenidate and lisdexamfetamine, caffeine, armodafinil, galantamine, and amantadine. methylphenidate had randomized trials and a meta-analysis in subacute tbi but reported only attention as a main outcome. we were unable to draw broad-level recommendations about optimal timing, best stimulant, and patient centered outcomes from this data. there is insufficient data to recommend optimal stimulant, timing, and dosing among heterogeneous abi disease models. we propose conducting future homogenous abi neuro stimulant trials in for safety, tolerability, dose-finding, optimal timing, and outcomes based efficacy. neuro stimulants could play a role in earlier awakening and extubation in abi which could improve outcomes similar to sedation/vacation bundles in icu's currently if studied adequately. tbi remains the leading cause of death and disability in young adults in the us and europe. thus far, pharmacological and non-pharmacological intervention studies did not confirm benefits on functional outcomes. the inducible enzyme nitric oxide synthase (inos) is upregulated in response to brain injury, causing excessive production of no, a key driver of secondary injury after tbi. the antipterin vas is a structural analogue of the endogenous nos cofactor and a potent in-vivo selective inhibitor of inos. a randomized, placebo-controlled phase study examined dose levels of vas in patients with acute moderate or severe tbi. cerebral microdialysis showed pharmacologically relevant drug concentrations close to the injury and a tendency for vas to increase the arginine/citrulline ratio, an indirect marker of nos inhibition (stover et al., j neurotrauma ). vas conferred a significant benefit on the extended glasgow outcome scale interview (egos-i) at and months after injury. no changes in systemic blood pressure or partial brain oxygen pressure were noted. a recent pharmacokinetics and pharmacodynamics study further corroborated the selective inos inhibition by vas . the confirmatory nostra phase trial (eudract no. - - ; clinicaltrials.gov identifier nct ) was initiated in . adult patients with a nonrequiring intracranial pressure monitoring, are randomized : to vas or placebo, administered in addition to standard of care, as intravenous continuous infusion for hours, starting between and hours post tbi. the primary efficacy endpoint is egos-i at months post injury. additional endpoints include the daily therapy intensity level and tbi-specific quality of life measures. continuous safety monitoring is performed by an independent committee. nostra iii, the only ongoing registration study in acute moderate and severe tbi, is sponsored by vasopharm gmbh, and plans to recruit patients by q . a glasgow coma scale (gcs) score of on presentation in patients with traumatic brain injury (tbi) portends a poor prognosis. consequently, there is often a tendency to treat these patients less aggressively because of low expectations for a good outcome. we performed a retrospective review of patients with tbi and a gcs score of . demographics, apache iv scores , pupillary reactivity to light, intracranial pressure (icp), icp burden (the number of days with an icp spike > mm hg as a percentage of the total number of days monitored), and outcome (mortality and glasgow outcome scale-gos at months, with good outcome defined as gos of - ). patients were divided into groups: group (gos = - ) and group (gos = - ). a total of patients were included. the overall mortality rate was . %. at -month, patients ( . %) achieved a gos - . compared to group (n = ), group (n = ) had higher average apache iv score ( ± vs ± , p = . ), more patients with bilateral fixed pupils ( % vs %, p = . ), and higher icp burden ( ± vs ± , p = . ). gos score - was achieved in % of patients presenting with bilateral reactive pupils versus . % of patients presenting with bilateral fixed pupils (p = . ). . % of patients with tbi and a gcs of at presentation achieved a good outcome at months. apache iv scores, icp burden, and pupillary reactivity were significant predictors of outcome. we believe that patients with severe tbi who present with a gcs of should still be treated aggressively initially since a good outcome can be obtained in a significant proportion of patients. elevated circulating catecholamine levels are independently associated with functional outcome and mortality after isolated traumatic brain injury (tbi). we assessed the ability of peripheral catecholamine levels to improve the prognostic performance of the crash and impact-tbi models. prospective, observational, multicenter cohort study, conducted at three level trauma centers in canada and usa. epinephrine (epi) and norepinephrine (ne) concentrations were measured in the peripheral blood at admission (baseline), , and h after trauma. outcome was assessed at months and dichotomized into favorable [extended glasgow outcome scale (go -tbi models, which identified core prognostic markers of severe tbi. the baseline model (m ) included age, gcs and pupillary size/reactivity. the model (m ) included m + hypoxia, hypotension and marshall ct classification. model and included m + epi levels, and m + ne levels, respectively. the risk models performance was assessed by comparing receiver operating characteristic (roc) curves, and by the use of integrated discrimination improvement (idi) index. m had significantly higher roc and idi than the baseline model (m ), to predict mortality. m had a roc = . ( . - . , p = . ) and idi = . (p = . ). the prediction of mortality was not improved by including ne [m = roc = . ( . - . , p = . ) and idi = . (p= . )]. the integrated discrimination improvement index indicated the prediction of unfavourable outcome by the baseline model was improved by including epi (idi = . , p= . ), and ne (idi = . , p= . ) in the models. catecholamine levels improved risk models performance to predict mortality and unfavorable outcome after traumatic brain injury. following traumatic brain injury (tbi), depression is common and may influence recovery. small trials demonstrated that various drugs are beneficial in managing depression following tbi, but no large, definitive study has been conducted. we performed a meta-analysis to estimate the potential benefit of anti-depressant medications following tbi. multiple databases were searched using the terms "anti-depressant tbi," and "depression treatment tbi" to find prospective pharmacologic treatment studies of depression following tbi. studies were excluded if they did not measure depression as an outcome. effect sizes for anti-depressant medications in post-tbi patients were calculated for within-subjects designs that examined change from baseline after receiving medical treatment and treatment-placebo designs that examined the differences between anti-depressants and placebo groups. a random effects model was used for both analyses. of titles screened, studies were included, with total patients. medications evaluated included selective serotonin reuptake inhibitors, monoamine oxidase inhibitors, and tricyclic antidepressants. pooled estimates showed significant reduction in depression scores for individuals after pharmacotherapy (mean change [mc] - . , % confidence interval [ci]: - . to - . ) and significant difference in reduction of depression scores between medications and placebo in the pooled estimate (standardized mean difference of four trials [smd] - . , % ci: - . to - . ); however only one of the four treatment-placebo studies found medications significantly reduce depression scores more than placebo. this meta-analysis found a significant benefit of pharmacotherapy for treatment of depression in patients with tbi. however, there was a high degree of bias and heterogeneity regarding tbi severity, time since injury, depression severity, and demographics. larger prospective studies on the impact of anti-depressants on post-tbi depression are warranted to better understand treatment effects and the relationship of post-tbi depression and outcome more broadly. pleural effusion (pe) has been reported in % of medical icu. there is little published data on the prevalence and clinical significance of pe in mechanically ventilated patients with traumatic brain injury. head injury patients admitted to icu for mechanical ventilation (mv) within - hours and gcs > were assessed for eligibility. presence of pe was assessed by serial cxr on daily basis and volume of effusion was estimated and recorded. in case there was no evidence of pe on cxr, a bedside sonography in semi recumbent position was done within h of icu admission. pleural fluid volume was estimated based on -point classifications on sonography. details of mechanical ventilation and icu management were recorded. successful weaning was defined as ability to breath spontaneously for h. primary aim was to observe prevalence of pe in mv head injured patients. as secondary measure; impact of pe on duration of mv, weaning and length of icu stay were compared. study enrolled patients. three baseline cxr showed pe. total of ( %) patients developed pe in icu. patients had evidence of pe on both cxr and usg. patients had only sonographic evidence of pe, which were not detected on cxr. significantly more minimal effusions were detected on sonography ( / , p= . ). duration of mechanical ventilation and duration of icu stay were significantly more in patients with pe. (p= . , mann whitney rank sum test) there was no significance difference in duration of weaning in patients with and without effusion ( . ± . , . ± . , p= . ). chest ultrasonography increased the detection rate of pleural fluid. patients with pe had longer duration of mechanical ventilation. early detection may be associated with shorter period of mechanical ventilation and icu stay spine surgery can trigger a systemic inflammatory response syndrome and lead to hypotension requiring vasopressors. as sepsis is a major differential diagnosis in the post-operative period, the objective of this study is to understand the prevalence of a true systemic infection in this setting. retrospective review of all consecutive adults with post-operative shock requiring vasopressors following spine surgery in an academic tertiary medical center. a total of patients, median age years (iqr - ), were included in the final analysis. comorbidities included a median bmi of (iqr - ), coronary artery disease ( %) and diabetes mellitus ( %). median estimated blood loss was cc (iqr to cc). circulatory volume was adequately replaced in a total of % patients within hours post-op. all patients received crystalloids, and an additional % received multiple (> ) units of prbcs transfusion. adequate urine output was confirmed in ( %) of the patients. the maximum median rate and duration of each vasopressor infusion was as follows: phenylephrine mcg/min (iqr - , n = ), hours (iqr - ), norepinephrine mcg/min (iqr - , n = ), hours (iqr - ), epinephrine mcg/min (iqr - , n = ), hours (iqr - ) and vasopressin . units/min, hours ( - , n = ). of the patients, ( %) met at least sirs criteria. infection was confirmed in a total of patients; positive respiratory or blood cultures in ( %) patients and positive urinalysis or urine culture in ( %). two patients ( %) were diagnosed with myocardial infarction. no patients had pulmonary embolism. our study suggests that the risk of infection and sepsis in patients with persistent shock following spine surgery is small but not negligible. larger multicenter studies are needed to confirm our findings and to identify the predictive factors. ischemic and hyperemic injuries may occur unnoticed after severe traumatic brain injury (tbi) and contribute to additional brain damage. maintaining an adequate cerebral perfusion is considered crucial in preventing such injuries, as deviations from autoregulation-guided optimal cerebral perfusion pressure (cppopt) are associated with greater mortality and disability. this makes reliable estimation of cppopt an interesting diagnostic and treatment tool for monitoring. cppopt is defined as the cerebral perfusion pressure (cpp) at which the pressure reactivity index (prx) is minimal. the leading method for estimating cppopt automatically, by aries et al. ( ) , fits a parabola to pairs of prx and cpp data. the method uses preset heuristics to reject the fit as unreliable, namely when the parabola is too "shallow" or does not cover a certain cpp range. as a result, the cppopt estimates could be generated only about - % of the time. moreover, the manually set heuristics potentially restrict the generality of the model. here, we propose an alternative method based on bayesian inference. treating prx at each time as a function of cpp corrupted by noise serves as a "forward model" that can be inverted to yield, for a given data set, a temporally evolving posterior probability distribution over cppopt. the mean of this distribution is a bayesian estimate of cppopt; we find that these estimates are generally consistent with those obtained from the classic method. importantly, the width of the distribution at a given time serves as a metric of uncertainty about cppopt estimation. we find that this uncertainty tends to be large at time points where the classic method with preset heuristics rejects the fitted parabola. our method makes manually setting rejection criteria unnecessary. bayesian estimation of cppopt holds promise as a tool for providing additional decision support in the care of individual tbi patients. quantitative parameters derived from continuous eeg (ceeg) have been useful to understand evolution of traumatic brain injury (tbi) and the impact on regional networks. these parameters are often interrogated at a global level rather than region-specific. the regional evaluation of quantitative eeg parameters may provide an objective assessment of regional network function, and be of predictive value for prognostication continuous eeg was performed in patients with tbi, and mri imaging was obtained during acute and chronic time points post injury (within days and months, respectively). the extended glasgow outcome scale (gose) assessed clinical recovery at months, with good recovery defined as gose score - and poor as gose score - . volumetric measurements of selected brain regions, both cortical and subcortical, were obtained at acute and chronic time points. quantitative parameters derived from ceeg, such as percent alpha variability (pav) and hemispheric symmetry, were calculated continuously and anatomically (frontal, temporal, occipital) through the acute hospitalization course. we hypothesized that persistent regional variation in alpha power post injury would lead to brain regionspecific atrophy and may predict outcome at months acute pav within the first hours post injury was poor in patients with poor outcome. in addition, patients with poor outcome had significantly more atrophy in the thalamus, hippocampus, and temporal and occipital lobes. asymmetry of the hemisphere pav values correlated with both brain atrophy and clinical outcome regional asymmetry of pav within the first hours post injury correlates with chronic brain atrophy and clinical outcome after tbi after moderate and severe traumatic brain injuries (tbis), individuals are often admitted to an intensive care unit (icu), and later require intensive rehabilitation. many neuro-icus engage therapists and physiatrists for rehabilitation and therapy during a patient's icu admission. however, the optimal timing, intensity, and components of rehabilitation needed while in the icu are not known and practice patterns are highly variable. the goal of this study is to describe the rehabilitation practices to identify whether there is consensus on best practices. an electronic survey asking participants to describe tbi rehabilitation practices in their icu was distributed via redcap through the neurocritical care society (ncs) and american congress of rehabilitation medicine (acrm) websites. potential respondents were first asked if they cared for patients with tbi in the icu, and if they answered "yes," they were invited to complete the survey. two email reminders were sent to each group for completion. after weeks, the data were extracted and analysis completed. there were respondents who reported that they cared for patients with tbi in the icu ( attending physicians, advanced care practitioners, therapists, nurses, fellows, and other). of these, % recommended early rehabilitative care. the most common reasons to wait for the initiation of physical therapy and occupational therapy were normalization of intracranial pressure (icp) ( % and % respectively) and hemodynamic stability ( % and % respectively). speech therapy was typically recommended after extubation ( %) and normalization of icp ( %). the majority of clinicians caring for patients with tbi in the icu support early rehabilitation efforts, typically after a patient is extubated, intracranial pressure has normalized and the patient is hemodynamically stable. prospective studies evaluating the merits of these self-reported rehabilitation initiation criteria are warranted. high-dose methylprednisolone (hdmp) has been studied as a potential therapeutic option for acute sci, with mixed results regarding efficacy and consistent suggestion of complications. we conducted a retrospective cohort study of acute sci patients extracted from the medical information mart for intensive care iii (mimic-iii) database to evaluate the hypothesis that steroid-related adverse drug events (ades) occur less often than in published clinical trials using hdmp. three groups of patients coded for acute sci were identified from mimic-iii from june to october : hdmp recipients per nascis ii/iii protocols (hdmp, n = ), patients who received some steroids but not per nascis ii/iii protocols (non-hdmp, n = ), and patients who did not receive steroids (no steroids, n = ) . demographics and data on complications of steroid therapy were extracted. one-way anova or student's t test were used to evaluate continuous variables; chi-squared or fisher's exact test were used for nominal or categorical variables. there were no differences in steroid-related ades between the three groups. there were higher average blood glucose readings in recipients of any steroids compared with the no steroids group, and more variation in blood glucose readings in hdmp recipients compared with the other two groups. there was a higher icu los and ventilator time in the hdmp group compared with the other two groups. compared with three other trials examining similar use of hdmp in acute sci, there were higher rates of pneumonias overall, though lower rates of urinary tract infections, skin & soft tissue infections, pressure ulcers, and superficial thromboemboli/thrombophlebitis. the results of this study are consistent with previous works related to the potential for harm regarding the use of hdmp or any steroids in acute sci. changes in selected adverse event profiles may be due to standardization of icu supportive care over time. cervical spinal immobilization and clearance protocols are important steps in the minimization of secondary spinal cord injury. patients with primary neurologic diseases are frequently found down and placed in rigid cervical collars despite sustaining minimal-to-no cervical injury. in these patients, neurologic dysfunction can complicate and delay cervical clearance. decreasing time spent in cervical spinal immobilization could improve patient care by allowing greater access to / range-of-motion of the neck, increasing patient comfort, and decreasing skin breakdown. through retrospective chart review over a -month period, we collected the following: the rationale behind each mri, any mri evidence of cervical instability, the result of any ct imaging, and the basic mechanism of any trauma. for patients that were simply found down, any evidence of trauma either by history or physical exam was recorded. during the study period, there were instances where an mri of the cervical spine was performed. of those mris, ( %), were performed for cervical spinal clearance. sixty-one ( %) of mris were ordered without any ct imaging first. of the patients with a normal ct, six ( . %) were found to have mri evidence of cervical instability. notably, of the patients who were found down, there was only one instance where the mri demonstrated instability. that patient had extensive facial injuries suggestive of an unwitnessed fall. in the patients that were found down with no history or evidence on physical exam of trauma, there was no mri instability. for patients that are found down without any history or evidence on physical exam of trauma, a ct of the cervical spine is likely sufficient for cervical spinal clearance. acute subdural hematoma (asdh) represents a major clinical entity in severe traumatic brain (stbi), approximately % are accompanied by various extents of asdh. stbi has been reported to cause cerebral circulatory disturbances at an acute stage and had the worst circulatory disturbance among stbi. in this study, we focused on the cerebral circulation of asdh, evaluated the absolute left-right difference between cerebral hemispheres and compared the cerebral circulation between the favorable outcome group and the unfavorable group. we retrospectively reviewed patients with asdh. they were admitted to our hospital from to . in these patients, we simultaneously performed xenon-computed tomography (xe-ct) and perfusion ct to evaluate the cerebral circulation on post-injury days - . we measured cbf using xe-ct and mean transit time using perfusion ct and calculated the cerebral blood volume (cbv). a significant absolute difference in cerebral circulation between the hemispheres among different types of tbi was observed in mtt. there was no significant difference in these parameters between left-right hemispheres with asdh among the favorable outcome group and unfavorable group. although there was no significant difference in age, gcs at the onset of treatment, cbf and cbv, there was significant difference only in mtt between the favorable outcome group and unfavorable group. the circulatory disturbance in patients with asdh occurs diffusely despite the focal injury. additionally, in unfavorable patients, the circulatory disturbance is worse than in favorable patients. because asdh suffered ischemia more than other types of stbi, we had to perform not only removal of the occupying lesions, but also neurointensive care, including whole-body management and hypothermia therapy for the ischemic brain after surgery. we have to adopt a treatment strategy appropriate to the pathophysiology of the different tbi types. kcentra is -factor prothrombin complex concentrate that is fda approved for reversal of warfarin. there is limited research describing the use of kcentra for coagulopathy in the setting of traumatic intracranial hemorrhage. here, we show the largest ever retrospective review for the use of kcentra in the setting of traumatic intracranial hemorrhage. retrospective chart review was performed from - for patients with intracranial hemorrhage who presented to the r adams cowley shock trauma center. patients who received kcentra were identified. basic clinical information was obtained including cardiac/stroke history, blood pressure, glasgow coma score, medication history, and categorization of hemorrhage. pre and post inr level was assessed. hemorrhagic expansion was assessed with ct scan up to up to hours. disposition and thromboembolic events were recorded. forty-four patients were identified as receiving kcentra in the setting of traumatic intracranial hemorrhage. pre and post kcentra dosing inr was found to be significantly different (p< . ) across the two groups assessed (warfarin and tbi/noac coagulopathy). seventeen patients ( . %) had hemorrhagic expansion as determined on ct scan. disposition (home vs rehab vs death) was found to have three significant variables: history of stroke, hemorrhagic expansion, and admission glasgow coma score. eight patients ( . %) were found to have thromboembolic events. here, we show the largest retrospective review describing the clinical use of kcentra for coagulopathy reversal in the setting of intracranial hemorrhage. overall, kcentra is shown to be a safe and effective drug for the reversal inr. importantly, our reported hemorrhagic rate of . % is lower than established rates reported in the literature for warfarin/coagulopathic patients with intracerebral hemorrhage ( - %). the prognostic importance of hemorrhagic expansion was highlighted in the disposition analysis which showed that zero patients were discharge home if there was recorded expansion. despite the impact of post-traumatic amnesia (pta) duration on long-term functional outcome after traumatic brain injury (tbi), radiologic predictors of pta duration are lacking. we hypothesized that the number of traumatic microbleeds (tmbs) detected by gradient recalled echo (gre) magnetic resonance imaging (mri) in neuroanatomic regions that mediate memory correlates more strongly with pta duration than does the number of global tmbs. using a prospective outcome database of patients treated for mild-to-severe tbi at an inpatient rehabilitation hospital, we retrospectively identified patients who underwent acute mri with gre. pta duration was determined by the galveston orientation and amnesia test, orientation log or chart review. a rater blinded to pta duration identified tmbs on the gre datasets globally and in neuroanatomic regions that mediate memory, including the hippocampus, fornix, corpus callosum, thalamus, and the temporal lobe. associations between global and regional tmbs (in the mentioned locations) and pta duration were tested using spearman rank correlation coefficients. the cohort was comprised of % ( hippocampus and corpus callosum tmbs are associated with pta duration, and thus may have greater utility for predicting functional outcomes than global tmb number. validation of these findings in larger prospective studies is indicated. using a large two-center cohort of penetrating traumatic brain injury (ptbi) patients, we previously developed the survival after acute civilian penetrating brain injuries (spin) score, a logistic regressionbased parsimonious risk stratification scale for estimating survival after civilian ptbi. the objective of the present study was to externally validate the spin-score. our multicenter validation cohort comprised ptbi patients retrospectively identified from three u.s. level- trauma center registries. the spin score variables (motor gcs [mgcs], sex, pupillary reactivity, self-inflicted ptbi, transfer status, injury severity score [iss] and inr) were collected from the trauma registries supplemented by chart review. using the spin-score multivariable logistic regression model from the original study, receiver-operating-characteristic area-under-the-curve (roc-auc) analysis and hosmer-lemeshow goodness-of-fit testing was performed. the mean age was ± years, and patients were predominantly male ( %), with % white and % black. in-hospital mortality was %, and -month mortality of discharge survivors was . in this multicenter external validation study, the full spin-model predicts in-hospital survival after ptbi with excellent discrimination and calibration. after removing inr from the model, discrimination remained excellent, but model calibration diminished. the full spin-score may provide important information to guide families and physicians after civilian ptbi. limited data has described alterations in vancomycin pharmacokinetic (pk) parameters in traumatic brain injury (tbi) patients that have resulted in sub-therapeutic concentrations. the primary objective of this study is to evaluate the pk parameters of vancomycin in tbi patients to determine if using the common clinical practice of capping creatinine clearance (crcl) to ml/min in determining dosing impacts achievement of therapeutic concentrations. this was a single-center, retrospective study of patients at least years of age with tbi who received vancomycin and one reported steady-state vancomycin serum level from april to december . predicted pk parameters based on population data using actual and capped creatinine clearance (crcl) at ml/min were compared with calculated pk parameters based on serum trough concentrations at steady state. the difference was assessed using a two-sample wilcoxon rank-sum test where p < . was considered statistically significant. when using actual crcl [median ml/min patients with tbi experienced crcl that were greater than predicted. based on the results of this study, actual crcl is more accurate at predicting vancomycin pk than the common practice of capping crcl at ml/min. therefore, actual crcl should be used when determining vancomycin dosing regimens in patients with tbi to achieve desired therapeutic concentrations. neurocritical care is traditionally provided within institutions in urban centers while access in rural communities has been limited. transport to urban centers is not always favorable for a variety of reasons including critical patient condition, family wishes, weather, and geography. our hypothesis is that tele-neurocritical (tele-ncc) can extend access to this service with meaningful impact on icu outcomes. a tele-ncc pilot study was initiated within intermountain healthcare. starting / / , the study included all ischemic stroke patients admitted to the icu of one primary stroke center in utah. tele-ncc consultations were provided by ncc physicians at our flagship hospital located three hundred miles from the spoke site. tele-ncc consultations occurred via an existing telehealth platform developed inhouse. primary outcomes for this pilot study were icu and hospital lengths of stay (los). secondary outcomes include stroke complication rates and results on a provider satisfaction questionnaire. to date, tele-ncc consultations have been performed with median hospital los = days (iqr . - . ) and icu los = . days (iqr - ). in the months prior to the pilot, there were admissions to the icu for ischemic stroke with median los = days (iqr . - . ) and icu los = . (iqr - . ). for this small sample size, the p-values for comparison of hospital and icu lengths of stay before and after tele-ncc are . and . respectively. tele-ncc care can have significant impact on icu outcomes by expanding access to critical support from neurocritical care specialists. tele-ncc expands access to not only consultation on critical neurological emergencies, but also on when to de-escalate from the icu or in end of life discussions with which general icu teams may not be comfortable. these impacts could be measured as important decreases in hospital and icu los. hospital readmissions increase health care costs, increase patient exposure to nosocomial disease, and imply patients were not stable for discharge. because readmissions are a target for hospitals and payers, several centers have developed predictive readmission scores in order to identify high-risk patients. we contend that these general readmission scores are not suitable for neurocritically ill patients and that specific predictive score must be developed to identify high-risk patients. we conducted a retrospective chart review of consecutive patients admitted to our neuroscience critical care unit. we recorded the readmission scores, reason for admission, length of stay,and if they were readmitted. we then compared the median readmission scores between the two groups. after removing patients without readmission scores or died at the end of the original admission,we analyzed the records of patients. patients were more likely to be readmitted if they were initially emergently hospitalized or had malignancy. readmitted patients had a longer original hospital length of stay. we found no difference median readmission score between those who were readmitted, and those who were not. most readmitted patients ( . %) had an original "low-risk" readmission score. we found that our center's score was poor in predicting readmission for neurocritical care patients and that several components of the score do not apply to our patient population. we propose that to accurately predict readmission,centers should create their own unique readmission scores for more homogeneous admission populations. clinical evaluation of the level of consciousness in non-communicative patients can be very challenging. in this study, we aimed to evaluate the nurses and nursing assistants' (nas) perception of the consciousness on patients suffering from disorder of consciousness (doc). through their activities, nurses and nas have an extended observation time of patient's behavior, and make repeated implicit assessments of patients' clinical state of consciousness. we hypothesized that even in the absence of a structured and explicit evaluation of consciousness (in contrast for instance with the coma recovery scale revised -crs-r), nursing expertise could be a valuable measure to improve assessment of state of consciousness in doc patients. this was a prospective observational single-center study. our primary objective was to correlate the nurses and na's assessment of doc-patients' consciousness quantified through an analogic visual scale (the "doc-feeling score") with the results of the standard methods (including crs-r, fmri, electrophysiology). the secondary objective was to identify elements which correlate with this assessment and/or with the expert's diagnosis (such as visual pursuit, patient's participation to nursing, motor responses to verbal command or adapted reactions to painful care). . linear regression reveals a good correlation between the "doc-feeling score" and the crs-r gold standard (r = . , p-value < . , figure ). global assessment of the level of consciousness by all the caregivers interacting with the patient using the "doc-feeling score" is reliable and can improve assessment of state of consciousness in doc patients. investigating causes of deterioration in neurological patients is important to anticipate these complications and improve outcomes. this is a prospective observational study performed at an academic tertiary care trauma, stroke and neurorehabilitation center. data was collected over a year from rapid response system activations (rrsa). in one year, our center had admissions. rrsa were performed on patients. most common admission diagnosis was ischemic stroke ( %). most common rrsa organ system involvement was respiratory system (n= , . %). the only predictors of death or new limitation of care in those patients who had rrsa were age ( years vs years, p < . ) and history of cancer ( %) vs ( %) p= . . . % (n= ) of rrsa happened during day shift and . % (n= ) during night shift. . % (n= ) of rrsa happened around shift change and were more likely to result in an unplanned icu admission. . % (n= ) of rrsa happened within hours of admission and were more likely to result in unplanned icu admissions. the most common reasons for in hospital decompensation in neurological inpatients are nonneurological. most common organ system involvement responsible for rrsa is respiratory system. the only predictors of death or new limitation of care were history of cancer and age and older. rrsa activations were more frequent during day shift. however, there was no different in the outcomes we evaluated between day and night shifts. rrsa happening around shift change wew more likely to result in unplanned icu admission. rrsa within hours of admission showed an increased risk of unplanned icu admission when compared to rrsa happening after hours of admission. neurocritical care is a growing field with an increasing number of dedicated neuroscience intensive care units. in this dynamic context, it is unclear which types of physicians provide neurocritical care across the united states. we performed a retrospective cohort study using claims data from a nationally representative % within analyzed critical care procedures . the primary outcome was physician specialty, defined by medicare provider specialty codes. in a sensitivity analysis, we excluded claims for services on the day of admission and claims associated with a diagnosis of cardiac arrest, since these activities may often occur outside of neuroscience intensive care units. we identified between and , neurologists were responsible for approximately one-quarter of neurocritical care services among a nationally representative cohort of elderly patients. critically-ill patients on mechanical ventilation (mv) cannot verbally communicate. research suggests several phenomena occur in patients during mv because of impaired communication including anxiety, loss of control, loneliness, and compromised interaction (schou and egerod, ) . for neurocritical care patients, this can be especially profound when coupled with cognitive and motor/sensory deficits. currently, the blom® speaking valve (sv) is the only approved product available that allows phonation in ventilator-dependent patients with tracheostomy. sv trials are known to facilitate vent-weaning. the current standard of care (passy-muir speaking valve, minute trials), is contra-indicated in patients who cannot tolerate cuff deflation. as such, the blom® sv was evaluated for clinical and quality efficacy. we retrospectively evaluated clinical outcomes associated with blom® sv on mv during a trial in a neuroicu of a large tertiary center between / / and / / . baseline demographics, diagnoses, physiologic, sedation, delirium, mobility and swallowing parameters, length of stay, ventilator modes and settings, ventilator days, work of breathing and presence of pneumonia were abstracted along with patient, family and interdisciplinary staff satisfaction survey results. patients were recommended for blom® tracheostomy. patients received sv trials. of the trials were performed, % ( ) were optimal/completed ( + minutes); % ( ) were suboptimal/completed trials ( - minutes); % ( ) unable to complete. satisfaction results from patients/families were positive compared to the interdisciplinary team survey results. remaining parameters currently in analysis with results pending, to be completed by end of august, . impaired communication during mv is suboptimal for neurocritical care patients. our clinical experiences with blom® sv showed positive and negative outcomes. positive benefits were enhanced patient/family engagement and family satisfaction. unanticipated obstacles included significant increase in patient fatigue during sv trials, often delaying ventilator weaning. further study is needed to determine efficacy in this population. patients with clinical signs of cerebral herniation require immediate intervention known as a "brain code". in our neurosciences critical care unit (nccu), a rapid response program is in place to ensure the safety of . % hypertonic saline's use (high risk medication) and to expedite its delivery to the bedside given the emergent need for this medication when ordered. our institution, however, is lacking a more holistic and structured approach to cerebral herniation syndrome that include components of tiers zero to three emergency neurological life support elevated icp or herniation protocol. the neurocritical care communication council consists of bedside staff nurses, nursing leadership, advanced practice providers (nurse practitioners and clinical nurse specialist), pharmacists, respiratory therapists and physicians. the council identified processes during neurological brain codes that could be improved as a result of using a bedside debriefing tool. the unit leadership council of the nccu reviewed literature on hospital debriefing tools and referenced this organizations current resuscitation debriefing tool. from these sources, a brain code debriefing form was constructed. a clinical tool was developed with the expectation of standardizing the brain code process in this nccu. the brain code debriefing form will be piloted to determine unit and system wide value. pre-and postimplementation data will be collected to discover areas of improvement for optimized patient care. through the development of this debriefing tool, it was ascertained that a clinical practice guideline for impending cerebral herniation would be beneficial to further guide and direct evidence-based care. thus, a preliminary algorithm for identification and emergency treatment is in process. the americas medical center is a -bed tertiary hospital complex, located in the city of rio de janeiro. the center was elected by the international and the brazilian olympic committees as the referral hospital for the olympic family (of), comprised of athletes and their crews, support and technical personnel, credentialed media and credentialed governmental representatives from the participating countries. the neurology and neurocritical care teams were selected to head a comprehensive program of acute emergency neurology, including a -bed neurocritical care unit (nicu), and - emergency neurology service. we hereby describe our experience during the olympic games in rio de janeiro, brazil results neurological assessments were conducted in patients from the of, of these involving athletes from countries. the most common reason among athletes were traumatic brain injuries (tbi), with politraumas (all involving cycling), mild tbi ( of boxing, of field hockey, of rowing and of cycling) and moderate tbi (cycling and water polo). three patients were admitted to the nicu: ischemic strokes and politraumas with tbi. motor vehicle accidents with associated tbi involving the of were surprisingly frequent, with assessments, none requiring admissions. finally, ct scans of head, ct scans of the cervical spine and mri scans ( brain and spine mri) were performed to assess the patients. of note, cases of seizures, functional deficits, multiple sclerosis flare and psychiatric complaints were observed affecting the of. not only that multiple sports-related injuries were observed, cases of diverse acute neurological issues were reported involving members of the of. olympic games are complex events mobilizing thousands of people, and a comprehensive and detailed plan for neurological emergencies is of extreme importance the term "handoff" has been defined as the "transfer and acceptance of responsibility for patient care that is achieved through effective communication, passing patient-specific information from one caregiver or team of caregivers to another to ensure the continuity and safety of the patient's care" (patterson and wears, ) . the joint commission reported that two-thirds of sentinel events occur at the time of patient handoff, which led to a national patient safety goal, requiring standardized process for handoffs (the joint commission on accreditation of healthcare organizations, ) . to support this npsg, a nccu specific handoff tool and timeout process were created to support the transition from or to nccu. nccu postoperative handoffs were identified as an area to enhance staff satisfaction and patient safety. baseline data to evaluate the frequency of neurosurgery report was performed in may . using a qualtrics survey in june , staff satisfaction with current ns or report was obtained from nccu rns, nps, and fellows evaluating whether they felt they received: accurate medical history, accurate information about performed procedure, sufficient handoff for patient care, specific patient goals, recent pharmacological intervention, anticipated concerns regarding diagnosis/procedure, estimated blood loss, blood/fluid intake, airway concerns, complications and overall satisfaction with handoff. a taskforce of rns, nps, neurointensivists, and neurosurgeons was established, ending with the creation of a handoff tool and timeout process. the new tool and process were initiated and two months later, a repeat survey was sent to evaluate staff satisfaction and perceived effectiveness of the new process and handoff tool. currently being tabulated at time of submission. using standardized, open communication techniques including handoff tools and a timeout throughout the perioperative period is crucial to positive outcomes and can improve perioperative care in the nccu patient and increase satisfaction and collaboration of all team member during or handoff. in the age of the healthcare reform and rising costs, it is important for strategic service lines to explore cost saving and care efficiency strategies. beginning in september , physician and administrative leadership within the duke neurosciences intensive care unit (neuroicu) began investigating per patient cost to explore opportunities to decrease direct cost to the neuroicu, cost to the patient, and reduce redundancy of care. with assistance from health system finance, the team assessed the following data points within each cost group and compared these values to that of our peers within the us news and world report top honor roll: · number of units · direct cost per unit · total direct cost our performance according to our peers in the following cost areas was: .pharmacy-ranked th out of .laboratories-ranked th out of .radiology-ranked th out of .cardiovascular-ranked th out of . based on these performance metrics, neuroscience administrative and medical leadership developed a project grid of prospective initiatives and identified the following for each cost area: ·stakeholder-led teams inclusive of providers, nursing, and administration ·duration or impact of each initiative: short, medium, or long ·activity phases based on duration the stakeholder-led groups would propose and validate projects based on scope and duration. at each group's meeting, members reviewed charge level financial data by activity code for the group's respective cost area to develop applicable initiatives. multiple initiatives are currently underway including those within the cost areas of pharmacy, laboratories, and radiology. included among these initiatives is a change in routine resistant organism screening and cervical spine clearance. other initiatives will be target intravenous anti-hypertensive treatment and laboratory frequency. the total cost savings from these initiatives can only be estimated at this point but will likely be in excess of $ , for the calendar year. it is uncertain whether dedicated neurocritical care units are associated with improved outcomes for critically ill neurologically injured patients in the era of collaborative protocol-driven care. we examined the association between dedicated neurocritical care units and mortality, and the effects of standardized management protocols for severe traumatic brain injury. we surveyed trauma medical directors from centers participating in the american college of surgeons trauma quality improvement program (tqip) to obtain information about icu structure and processes of care. survey data were then linked to the tqip registry, and random-intercept hierarchical multivariable modeling was used to evaluate the association between dedicated neurocritical care (ncc) units, the presence of standardized management protocols and mortality. we performed three sensitivity analyses reclassifying ncc units by restricting to closed units, under ucns director leadership, and exclusion of neurotrauma units. data was analyzed from , adult patients with isolated severe traumatic brain injury admitted to tqip centers between to . fifty icus were dedicated neurocritical care units, whereas were general icus. rates of standardized management protocols were similar comparing dedicated neurocritical care units and general icus. care in a dedicated neurocritical care unit was not associated with improved risk-adjusted in-hospital survival (or . ; ( % ci . - . ; p= . ). the results from the model were robust in our sensitivity analyses. the presence of a standardized management protocol for these patients was associated with lower risk-adjusted in-hospital mortality (or . ; % ci . - . ; p= . ). compared to dedicated ncc models, standardized management protocols for severe traumatic brain injured patients are low-cost process-targeted intervention strategies that may improve clinical outcomes. understanding the differences in processes of care within the context of icu structure is necessary to better understand mortality differences observed between centers, and may help in the design of future trials for severe tbi patients. complex multidisciplinary care of patients in the neurocritical care unit requires reliable and effective communication to minimize medical errors. we implemented a structured rounding process that incorporates ahrq-endorsed team strategies and tools to enhance performance and patient safety (team stepps) to improve interprofessional collaboration between team members. we convened a project team of physicians, advanced practice providers (apps), nurses, respiratory therapists, and pharmacists in a -bed nicu. we defined structured rounding processes and implemented team stepps strategies to promote closed-loop communication between team members during daily rounds. the assessment of interprofessional team collaboration scale (aitcs-ii) was administered to team members at baseline and months post-intervention. impact on overall team collaboration and subscale domains of team partnership, cooperation and coordination was assessed. the possible range of the overall collaboration score is to ; higher scores indicate better collaboration. the survey was completed by ( %) staff at baseline, and ( %) staff post-intervention. overall team collaboration scores improved significantly pre and post-intervention ( . ± vs . ± , p < . ), as did subdomain scores of team partnership ( . ± . vs . ± . , p < . ), collaboration ( . ± . vs . ± . ), and coordination ( . ± . vs . ± . ., p < . ). perceived shared understanding of patient daily goals between nurses and providers (physicians/apps) increased from % to % (chi-square . ; p < . ). % of staff reported that the intervention shortened or did not affect the duration of rounds. of those who reported longer duration of rounds, % responded that the intervention was worthwhile. interprofessional team collaboration can be enhanced by structured rounding and communication workflows. by promoting closed-loop communication during daily rounds, shared understanding of patient daily goals between team members is increased, and may optimize quality and safety of patient care. advanced practice providers (apps) are increasingly utilized to provide clinical care within neurocritical care units (nsicu) . despite the complex issues in this patient population, the specific educational and orientation needs of these providers have not been established. to meet the demands for rapidly and effectively training apps to provide advanced neurocritical care (ncc), a structured educational curriculum was developed and integrated within the standard orientation and on-boarding process for newly-hired app within our nsicu. this curriculum was designed with measurable learning goals, objective assessments of goal achievement, and opportunities for additional education and remediation at multiple steps within the program. the curriculum has three phases with distinct goals and assessments. phase i covers basic triage and resuscitation issues for the acutely-decompensating patient. phase ii covers general critical care principles in significantly greater depth. phase iii provides detailed experience and exposure to specific ncc issues. each phase incorporates relevant reading assignments with a tailored study guide, as well as a multiple-choice question post-test to demonstrate knowledge acquisition. phases ii and iii also include an oral exam incorporating hypothetical patient scenarios to allow the app to demonstrate comprehension and application of the goals for each phase. each phase lasts approximately to weeks with the expectation that the entire orientation curriculum will be completed within six months of employment. in addition to the educational curriculum, phases i and ii include working alongside a more senior app preceptor and providing bedside care for a progressively increasing number of patients. apps not meeting minimum established standards on any aspect of the curriculum are provided additional remediation and instruction by the preceptor and ncc faculty based on an individualized learning plan. a standardized educational curriculum provides a structured learning environment for new apps in the field of neurocritical care. reimbursement changes from the centers for medicare and medicaid services and value based purchasing systems have made quality improvement linked to clinical outcomes more crucial than ever. in one neuroscience icu, providers and nurses collaborate to address key infection parameters that impact patient outcomes. quality metric data in one neuroscience icu was collected over a period of fiscal years. outcome measures, consisting of glycemic and temperature control, and ventilator weaning strategies, were obtained after certain parameters were enforced over two years and then compared to the initial year. the urinary catheter utilization has decreased by over %, with catheter associated urinary tract infections decreased by % in years (p-value < . ). central line utilization decreased by %, with a % decrease in central line associated blood stream infections in years (p-value . ). new ventilator weaning strategies were put into place utilizing adaptive support ventilation mode, which decreased total ventilator days by days/year . successful weaning and extubations resulted in no recorded ventilator-associated pneumonia in the last years. this neuroscience icu maintains glucose below mg/dl more than % of the time. regarding temperature control data, a normothermia protocol was implemented that utilizes aggressive temperature control coupled with bromocriptine administration. as a result, % of patients had a temperature less than °c. all of the quality initiatives that have been implemented have improved the observed/expected mortality ratio by . %. this study shows that by optimizing infection control, temperature management, glycemic control and ventilation strategies, there is an overall positive impact on the patient's morbidity and mortality. as evidenced by these results, this institution is now a top performer when compared in a national clinical database. this presentation will share the pragmatic strategies to create a culture of quality improvement in any neurocritical care unit or patient care organization. health care records are not accessible universally at point of care delivery. in developing countries like thailand a large proportion of health care records are still paper based. patients may not able to convey relevant information about their own medical problems and medications during patient-physician encounters or in the event of emergency. our purpose was to create a simple platform for recording relevant basic healthcare information through a system that can be securely accessed even in countries like thailand. our vision is to improve healthcare communications and leverage social media in thailand and other developing countries, particularly for patients with lower levels of education or socioeconomic status. we created a cloud-based personal healthcare information platform 'meid' that uses a qr code scanned from wristbands and other products like stickers to access patient information. conventional methods require a treating team to request medical records from a patients' prior hospital visits including visits at different medical facilities. time lost during this process can potentially cause delay in treatment decisions. we also aim to improve health literacy in thailand. application name 'meidth' is available in both apple store and google play. we launched meid in thailand in april of . we have more than , active users and have sold more than wristbands. the meid thailand facebook page has received , likes. there are at least two patients that have already benefited from this product: one of these patients received intravenous tissue plasminogen and had a good outcome. timely access to his past medical history and medications via meid was a key in this case. our cloud based personal healthcare information platform using qr codes from wristbands and stickers can help increase health literacy, decrease times to appropriate treatment, improve patient safety and decrease healthcare costs. clinical pharmacists have become an integral part of multidisciplinary medical teams. expanding the role of pharmacists in the neurocritical care units has the potential to positively impact the quality of patient care and provide costs savings. this study examines these potential benefits at one neurocritical care unit. we reviewed patient medication profiles and had formal rounds with a pharmacist four times per week. for the purposes of this study, the focus was on minimization of a select number of high expense drugs. nine months of baseline data was compared to three months of post intervention data. interventions were performed at the time of rounding, which involved timely conversion to enteral formulas, changes to alternative medications or discontinuation of medications. we then performed a cost-benefit analysis to assess the net amount of money saved by reducing inappropriate pharmacy drug use following the interventions. average cost of nicardipine was $ , pre-intervention, compared to $ , post-intervention (pvalue . ). the cost of iv levetiracetam usage on average was $ , pre-intervention and $ , post-intervention (p-value . ), while the cost of iv dexmedetomidine was $ pre-intervention compared to $ post-intervention (p-value . ). average expense per month was reduced by approximately $ , per month compared to the average expense per month from the previous months (p-value . ). appropriate use of stress ulcer prophylaxis was also positively impacted; patient days/month on famotidine was reduced by approximately % from baseline, patient days (pre-intervention) vs days post-intervention. pharmacist interventions within a neurocritical care unit are known to be beneficial clinically for patients, however this study also shows that their interventions offer substantial cost benefits and should justify creating collaborations between pharmacists and neurointensivists. multi-disciplinary rounds have been shown to improve patient outcomes. the objective of this study is to observe the effect on patient care, team dynamic, and nursing satisfaction before and after the implementation of a nursing-led rounding model in the neurological icu. prior to the implementation of the nursing-led rounds quality initiative, nurses in the neurointensive care unit (nicu) were asked to answer a brief survey on basic demographics and perceptions of team dynamics and satisfaction in the nicu. a multidisciplinary systems-based rounding sheet inclusive of the abcdef bundle and previous nicu checklist was created and revised with extensive bedside and senior nursing educator input. while rounding, nurses presented and clinicians were to in real-time come up with an assessment and plan and relay these to the nurse and other team members. any questions, educational pearls or concerns by the clinician team or the bedside nurse were encouraged during these rounds. nurses completed a month post-implementation survey. of the full-time nicu nurses ( %) responded to both the pre-implementation and postimplementation surveys. a bimodal distribution of nursing experience was noted with % new nurses (< year) and % experienced nurses ( years+). more than half of the nurses ( %) reported doing both night and day shifts as opposed to being exclusive to only day or night. there was an increase in the nursing perceptions of participation during rounds as well as education during rounds. nurses felt significantly more involved with patient decision making and felt that they were able to give input into the patients care. the implementation of a nursing-led rounding structure may be beneficial to communication, education and overall patient care. as the project continues, we hope to further examine common icu objective measures as well as other subjective measures such as patient satisfaction scores and communication perceptions. with increased elective and non-elective volume, directing the flow of admissions has become essential to the efficient operation of inpatient strategic service lines. this is especially true in the neurosciences where widespread acute ischemic stroke intervention has placed an especially high demand on comprehensive stroke centers. as a result, an important collaboration was formed at duke between the health system, transfer center and neurosciences to create an algorithm-driven multi-hospital triage and pre-hospital care system called phast (pre-hospital acute services team). in this abstract, we present the formation and current state of this service. this effort was formally begun in the spring of with an initial focus on centralizing the admission process into the duke neurosciences intensive care unit (neuroicu) by an icu physician. after some initial success, it was clear that the service line would benefit from a more formalized process. as a result, a successful multidisciplinary collaboration with a core group of physicians and administrators was formed to develop algorithms and to overcome multiple administrative and legal hurdles. over a period of months, multiple algorithms were developed to systematize neuroscience admissions including acute ischemic stroke and vascular and non-vascular neuroscience emergencies. in an effort to decrease door-to-intervention times as well as effectively mitigate the impact of limited bed-space availability, this system now serves hospitals including with acute neurointerventional services and the rd with a burgeoning neurohospitalist program and incorporated rehabilitation services. in addition to systematizing the transfer and admission process, quality assurance, improvement, and educational processes are in a place. the current state of phast is that of a young but maturing and now essential service for duke neurosciences. extubation involves removal of an endotracheal tube (ett) and is a common intensive care unit (icu) procedure. extubation failure occurs in - % of icu patients and can be difficult to predict accurately. we hypothesized that a multivariate re-intubation scale calculation (risc) model could predict extubation failure better than a single variable like rapid shallow breathing index (rsbi). after irb approval, we conducted a retrospective review of data on mechanically ventilated icu patients above years of age who were not receiving mechanical ventilation through a tracheostomy tube from january , , through december , at mayo clinic rochester. various data points were gathered on these patients via electronic medical records search, and reintubations within hours of extubation were identified. univariate and multivariate logistic regression models were used to predict reintubation after extubation and construct a risc estimate. we included a total of patients which were randomly divided into a derivation set (n= ) and validation set (n= ). in the derivation set, patients had a mean age of ± years, and % were men. three hundred and ninety three extubation failures occurred within hours. predictors of extubation failure included underweight status, gcs score>= , mean airway pressure at minute= ml and total mechanical ventilation days>= in the final multivariable model. risc score was calculated using the validation set and ranged from to . logistic model result shows that, as risc increased by , the odds of having extubation failure was . fold higher (c-index= . ). roc analysis shows that the best cut off for risc was >= vs. < , which demonstrated a sensitivity of . , specificity of . and auc= . . the current risc model warrants further exploration in a prospective study to help critical care providers to decide when extubation can be done more safely. this report presents results of the nd nationwide survey concerning neurocritical care units (ncus) in china. this is an observational cross-sectional survey and close-ended self-reported questions were used. the questionnaire was sent to different provinces (autonomous regions and municipalities) across china from october st, to january st, . basic information, equipment and device information, and staffing and organization information were investigated. in total, questionnaires from ncus at hospitals in regions were received. most of the hospitals with ncus were large-scale (average hospital beds: ), teaching ( . %), and tertiary hospitals ( . %). the average number of ncu beds was , occupying . % of the total number of beds in their department. most of the equipment and devices ( / ) were available in over % of the ncus. however, some devices were centralized by hospital and operated with assistance from other departments. a total of full-time doctors and full-time nurses were employed at the ncus. a few of the ncus achieved a doctor-to-bed ratio of . : ( . %) and a nurse-to-bed ratio of : ( . %). and respiratory therapists, clinical dieticians, clinical pharmacists, and physiotherapists were present in . %, . %, . % and . % of the ncus. the number of ncus increased, the availability of ncu equipment became more sufficient, and the staffing of ncus improved. however, we should pay attention to the management of specialized ncu equipment, the shortage of ncu staff, and the need of ncu training. automated devices collecting quantitative measurements of pupil size and reactivity are increasingly used for critically ill patients with neurologic disease. however, there is limited data on the effect of ambient light conditions on pupil metrics. to address this issue, we we tested the range of pupil reactivity in healthy volunteers in both light and dark conditions. we measured quantitative pupil size and reactivity in seven healthy volunteers with the neuroptics- pupillometer in both bright and dark ambient lighting conditions. bright conditions were created by overhead led lighting in a room with ample natural light. dark conditions consisted of a windowless room with no overhead light source. the primary outcome was the neurologic pupil index (npi), a composite metric ranging from - in which > is considered normal. secondary outcomes included resting and constricted pupil size, change in pupil size, constriction velocity, dilation velocity and latency. results were analyzed with multi-level linear regression to account for both inter and intra-subject variability. seven subjects underwent ten pupil-readings in bright and dark conditions, yielding total measurements. mean resting pupil sizes were . v. [ . - . ], p< . ). all additional secondary outcomes except latency were also significantly different between conditions. we found that ambient light levels impact pupil parameters in healthy subjects. however, changes in npi are small and more consistent in varying lighting conditions than other metrics. further testing of patients with poor pupil reactivity is necessary to determine if ambient light conditions could influence clinical assessment in the critically ill. practitioners should standardize lighting conditions to maximize the reliability of their measurements. neural stem cells (nscs) are known to have anti-inflammatory effect in strokes in previous studies. however, the mechanism of anti-inflammatory effect in direct co-culture with nscs in hemorrhagic stroke remains unclear. the aim of this study was to investigate whether direct co-culture with nscs modulates hemolysate-induced inflammation in raw . cells. we stimulated raw . cells with hemolysate to induce hemorrhagic inflammation in vitro. hemolysate-activated raw . cells were co-cultured with hb .f directly for hours. following direct co-culture, the production of cycloxygenase- (cox- ), interleukin-signal regulated kinase (erk) were assessed by western blotting, and tumor necrosis factor (tnfevaluated by enzyme-linked immunosorbent assay (elisa). hemolysate generates an activation of inflammatory response in raw . cells. direct co-culture with hb .f significantly suppressed the phosphorylation of erk / in hemolysate-activated raw . cells. the expression of inflammatory mediators such as cox- , il-by direct co-culture with hb . f cell. in addition, the expression of cox- , il-attenuated by erk inhibitor (u ). our results demonstrated that direct co-culture with hb .f cells reduced the inflammatory responses in hemolysate-activated inflammation via suppressing erk / pathway. this suggests that nscs treatment can suppress the inflammatory response in hemorrhagic stroke. no pharmacological intervention improves outcomes after primary intracerebral hemorrhage (ich). we developed a novel therapeutic approach based on known biological function of endogenous apolipoprotein e (apoe). apoe is a key mediator of neuroinflammatory responses and modifies recovery from a variety of acute and chronic brain injuries. unfortunately, intact apoe holoprotein does not cross the blood brain barrier (bbb) and cannot be administered as a neurotherapeutic. we created apoemimetic peptides that cross the bbb and down-regulate neuroinflammatory responses in vitro and in vivo. cn- , our lead candidate, is a -amino acid apoe-mimetic peptide derived from apoe's receptorregion. cn- retains anti-inflammatory and neuroprotective effects of intact apoe, was well-tolerated in preclinical studies, readily crosses the bbb, and demonstrates excellent pharmacokinetic, safety, and tolerability profiles in phase studies. this is a multicenter, open-label phase a trial of cn- in patients with acute primary supratentorial ich. a total of participants between the ages and years across study centers, with a confirmed radiographic diagnosis of spontaneous, primary supratentorial ich. patients will be evaluated for eligibility within hours of symptom onset. eligible participants will receive cn- intravenously over --minute infusion every hours up to day maximum. participants will be monitored daily throughout the treatment phase and receive standard-of-care treatment for the duration of the study. primary: to assess safety of cn- administration in primary ich. secondary: to evaluate effects of cn- administration on --day mortality and functional outcomes. exploratory: to investigate feasibility of radiographic surrogates of clinical outcomes using perihematomal edema measurements on serial brain ct and mri, and investigate feasibility of serial biochemical markers of neuroinflammation as surrogate measure of perihematomal edema and clinical outcome. cn- represents a first-in-class agent now entering phase clinical trials in patients with acute ich. novel oral anticoagulant (noac) associated intracranial hemorrhage is a life-threatening condition for which activated prothrombin complex concentrate factor eight inhibitor bypassing activity (feiba) may be used for reversal. few studies report its use in spontaneous or traumatic intracranial hemorrhage. our institutional protocol is reversal with feiba units/kg and escalating doses as needed. the safety and efficacy of this protocol was assessed. we performed a retrospective review of adult patients presenting to a level trauma center between - with spontaneous or traumatic intracranial hemorrhage while on a noac . we evaluated the medication they presented on, indication for anticoagulation, location and size of the hemorrhage, presentation gcs, dosage of feiba recieved, change in size of hemorrhage on serial imaging as well as time between serial images, complications from reversal, and need for blood product transfusion. we identified patients with an acute intracranial hemorrhage while on noacs. patients underwent a baseline head ct documenting acute intracranial blood, were reversed with feiba ( u/kg), and underwent repeat imaging hours later per protocol. ten ( %, / ) patients had no increase in hematoma volume on repeat imaging. two underwent neurosurgical procedures (aneurysm coiling, sub-occipital craniectomy) without intra-operative bleeding complications. five ( % / ) patients had clinically insignificant increase in size of hemorrhage. of those, one underwent a subsequent neurosurgical procedure, which was already anticipated. two ( %, / ) patients had clinically significant hematoma enlargement. of those, one underwent urgent craniectomy (indicated based on initial presentation) and one required a ventriculostomy for hydrocephalus. two patients had no repeat imaging. adjusted dose feiba ( units/kg) may be an effective alternative to standard dose ( unit/kg) for reversal of noacs in acute intracranial hemorrhage. our experience showed clinically significant hematoma expansion in % of patients and no increase in unplanned neurosurgical procedures after reversal with feiba. here we sought to determine if there is an association between recanalization success and rate of hemorrhagic transformation amongst patients who have undergone intra-arterial thrombectomy for ischemic stroke secondary to anterior circulation large vessel occlusion (lvo), many treated at extended time from last seen well (lsw) after mri assessment. stroke patients with anterior circulation lvo treated with thrombectomy between april, to june, were studied. group-wise comparisons were made between patients with post thrombectomy hemorrhage (as confirmed by a single, blinded neuro-radiologist reviewer) and patients without hemorrhage. failed or incomplete recanalization was defined as mtici < b. symptomatic intracranial hemorrhage (sich) was defined as validated hemorrhagic conversion or parenchymal hematoma plus point decrease in nihsss. pertinent baseline characteristics were recorded and analyzed. sich was more prevalent amongst patients with tici< b recanalization (or . [ ci . - . ]). interestingly there was a low rate of sich amongst patients with tici= recanalization ( / [ . %]). although many patients were treated at advanced time lsw no excess rate of sich was observed. baseline characteristics including age, presentation nihss, and presentation aspects were similar among the two groups. rates of sich are low after successful mri seleted thrombectomy regardless ot time lsw. patients with poor recanalization show increased rates of sich in keeping with past literature. our data suggest that thrombectomy after mri selection may be safe and effective for patients at extended time lsw of tor patients with unknown lsw. cta spot sign is associated with hematoma growth, a common complication of intracerebral hemorrhage (ich) that portends worse outcomes. magnesium and calcium are cofactors in the clotting cascade and for platelet aggregation. we tested the hypothesis that magnesium and calcium levels are associated with the presence of the cta spot sign. patients with spontaneous ich presenting to northwestern memorial hospital were identified from a prospective observational registry. inclusion criteria included cta obtained within hours of symptoms onset and admission magnesium and calcium levels. cta spot sign (active contrast extravasation on ct angiography) was identified by a board-certified neurointensivist or neuroradiologist. variables suggesting association with spot sign at p< . were assessed for inclusion in a logistic regression model, and a parsimonious predictive model for ct spot sign was developed using backward stepwise variable selection. patients (age ± . years, % male, median ich score [iqr - ]) were included. seventeen ( . %) patients with cta spot sign were identified. admission magnesium was . +/- . and calcium was . +/- . . lower magnesium (or . , % ci . - . , p . ), lower calcium (or . , % ci . - . , p . ), and higher ich score (or . , % ci . - . , p . ) were independently associated with ct spot sign. magnesium and calcium level on admission are associated with the presence of a cta spot sign in patients with ich. magnesium and calcium supplementation may be attractive therapeutic targets for preventing harm from hematoma growth. cerebellar intraparenchymal hemorrhage (iph) is a rare and likely underreported complication of subdural hematoma (sdh) evacuation. we present two cases of post-operative iph and review the literature. case . an -year-old man underwent craniotomy for evacuation of a chronic right frontoparietal sdh. post-op ct showed pneumocephalus. the patient was extubated and clinically improved. three days post-operatively, he became lethargic and a ct brain revealed a cc right cerebellar iph. he was unable to safely swallow, declined a feeding tube and died under hospice care nine days later. case . a year-old man underwent craniotomy for evacuation for a left convexity sdh. routine post-op ct revealed an incidental left cerebellar iph. he returned to baseline one month later. only four such cases have been reported in the literature ( - ). two cases led to death within one week and two recovered, one with significant deficits. five more occurred following burr hole drainage of sdh and two others following drainage of subdural hygromas ( , - ). the incidence of cerebellar iph following supratentorial craniotomy has been reported in up to . % of cases with significant morbidity or mortality ( ). it occurs irrespective of age, pre-existing coagulopathy or arteriovenous malformations. size of insult and amount of csf loss do not correlate to iph, despite the fact that cerebral blood flow imaging shows over-drainage of cerebrospinal fluid (csf), causes intracranial hypotension and subsequent damage to dural veins ( , ). iph also occurs independently of operating room position, even though having the head turned is thought to compress venous drainage in the neck and cause congestion ( ). cerebellar vasculature may be more sensitive to changes in intracranial pressure, though why this does not lead to complications more routinely is not clear. cerebellar iph should be considered in cases of neurological decline after sdh evacuation. intracerebral hemorrhage (ich) location predicts outcome, but most studies have examined differences between deep, lobar, and infratentorial locations. this study aims to characterize specific deep ich locations in a diverse cohort. the ethnic/racial variations of intracerebral hemorrhage (erich) study is a multi-center, prospective, u.s.-based study. subjects with supratentorial deep ich, known ich volume, and three-month follow-up data were included. logistic regression was used to evaluate the association between location and poor outcome (mrs > ). receiver operating curve (roc) analysis was performed to identify ich volumes specific for poor outcome by location. thalamic, putaminal, and caudate ichs were included. median ich volume was largest in putamen ( ml), followed by thalamus ( ml) and caudate ( ml, p<. ). intraventricular hemorrhage (ivh) was most prevalent in caudate ( %), followed by thalamus ( %) and putamen ( %, p < . ). subjects with thalamic ich were older ( vs vs years, p < . ) and more likely hypertensive ( % vs % vs %, p= . ) than those with putaminal and caudate ich, respectively. compared to thalamic, putaminal ich had more ich expansion ( % vs %, p < . ) and surgery ( % vs % p = . ) but fewer external ventricular drains ( % vs %, p < . ). thalamic location predicted poor outcome (or . , % ci . - . ) at days after adjustment for age, sex, premorbid disability, ich volume, ich expansion, ivh, and admission gcs. roc analysis identified ml for thalamic and ml for putaminal ich without ivh as having % specificity for poor outcome. there are significant differences in characteristics and outcomes within deep ich. specificity estimates for the identified ich volume thresholds require external validation. these findings may have implications for prognostication and clinical trial design. racial differences in outcome after intracerebral hemorrhage (ich) among asians, native hawaiians and other pacific islanders (nhopi) have been inadequately studied since these racial groups have been historically aggregated into a single racial category. a multiracial prospective cohort study of ich patients was conducted from to at a tertiary center in honolulu, hi to assess racial disparities in come after ich. favorable outcome was defined as month modified rankin scale (mrs) score £ . patients with no available -month functional outcome, race other than asians and nhopi, and baseline mrs > were excluded. multivariable analyses using logistic regression were performed to assess the impact of race on favorable outcome after adjusting for the ich score, early do-not-resuscitate (dnr) order and dementia/cognitive impairment. a total of patients ( asians, nhopi) were studied. overall, ( . %) achieved favorable outcome at months. nhopi were younger than asians ( . ± . vs. . ± . years respectively, p< . ), and had higher prevalence of diabetes ( . % vs. . % respectively, p= . ), obesity ( . % vs. . respectively, p< . ), and lower prevalence of early dnr order ( . % vs. . % respectively, p= . ) and advance directive presence ( . % vs. . % respectively, p= . ). nhopi race was a predictor of favorable outcome in the unadjusted model (or . , % ci: . , . ) and after adjusting for the ich score (or . , % ci: . , . ) but not in the final model (or . , % ci: . , . ) . in the final model, the ich score remained as the only independent negative predictor of outcome (or . , % ci: . , . per point). nhopi are more likely to achieve favorable functional outcome after ich compared to asians even after controlling for ich severity. however, this association was attenuated after adjusting for dnr status and baseline cognitive factors. intracerebral hemorrhage (ich) patients often require continuous antihypertensive infusions. we sought to identify clinical and care process predictors of anti-hypertensive infusion duration, and tested whether infusion duration independently predicts intensive care unit length of stay (icu los) after adjusting for validated measures of ich illness severity. we identified spontaneous ich patients admitted / - / to a tertiary center, excluding those transitioned to comfort care within hours. we abstracted demographic and clinical variables from the medical record. we calculated the total duration each patient received continuous infusion of an antihypertensive medication. we categorized glasgow coma scale score as - ; - ; or < . two reviewers independently classified ich location and etiology. we determined univariate associations of clinical variables to anti-hypertensive infusion and performed regression analysis to determine the effect of continuous infusion on icu los. we identified spontaneous ich patients and excluded for early comfort care. in the remaining , mean age was [ - ] years, % were female, median ich score was [ - ], and % had lobar hemorrhages. continuous infusion included nicardipine, clevidipine, labetalol and diltiazem. a total of ( %) patients received anti-hypertensive infusions, mean hours. mean time to enteral antihypertensive administration medication was . hours, and mean icu length of stay was . days [ . - . ]. predictors of longer antihypertensive infusion duration were male gender (p= . ), non-lobar ich (p= . ), non-caucasian race (p< . ), younger age (p< . ), higher initial systolic (p= . ) and diastolic bp (p= . ), worse gcs category (p< . ), and longer time to first enteral medication (p< . ). anti-hypertensive infusion duration independently predicted icu los (p< . ) after adjusting for age, race, gcs category, time to enteral antihypertensives, and ich score. worse gcs category, younger age, non-lobar ich location, and race are significant independent predictors continuous iv antihypertensive infusion duration, which is significantly associated with longer icu stay. patients with sich have a high risk of vte. pharmacological prophylaxis such as unfractionated heparin(ufh) has been demonstrated to reduce vte. however, published datasets exclude patients with recent ich out of concern for hematoma enlargement. aha/asa guidelines recommend ufh - days after hematoma stabilization while the eso has no recommendations on timing of ufh. there are few data for patients who received ufh before hours. our institutional practice is to begin ufh following sich after hours of clinical and radiographic stability. we examine the impact of this practice on risk of hematoma expansion. we performed a retrospective cohort analysis of sich patients admitted in - to a single us university hospital. demographic and clinical characteristics were abstracted. ich was measured via d volumetrics for an admission ct, a hour follow-up, and a follow-up prior to discharge. percent hematoma growth between -hour ct and discharge ct was calculated. risk factors for expansion > %, including early heparin use, were analyzed via oneway t-test and chi-squared tests. results sich patients analyzed had a median ich score of (iqr - ) and median admission gcs of (iqr - ). %( / ) patients received early ufh. %( / ) suffered hematoma expansion > %. overall mean hematoma growth was higher with early ufh (ufh hr - %,p= . ). in multivariate analysis, ich score, gcs and initial hematoma size did not predict > % hematoma expansion. early vte prophylaxis at hours from sich had a statistically significant increase in hematoma size, but this increase is clinically insignificant. in this cohort, early ufh did not increase risk of significant hematoma expansion. further prospective trials are warranted, given the high risk of vte in this population. antiplatelet therapy at the time of spontaneous intracerebral hemorrhage (sich) may increase the risk of hemorrhage expansion and mortality. current guidelines recommend consideration of a single dose of desmopressin in sich associated with cyclooxygenase- inhibitors or adenosine diphosphate receptor inhibitors. this study sought to compare outcomes in patients that received desmopressin for antiplatelet reversal in the setting of sich to similar patients that did not receive desmopressin. this retrospective chart review of the electronic medical record included adult patients admitted for sich that were on antiplatelet agents at the time of diagnosis. patients that received desmopressin were compared to similar patients that did not receive desmopressin. exclusion criteria included traumatic brain injury, active coagulopathy and thrombocytopenia. the primary outcome was the incidence of hematoma expansion. additional outcomes included average increase in hematoma volume, in-hospital mortality and functional outcome at hospital discharge. overall, patients ( received desmopressin, did not receive desmopressin) were included for analysis. incidence of hematoma expansion was not different between groups ( % with desmopressin vs % without desmopressin, p= . ). average largest increase in hematoma volume on follow-up imaging from baseline was not different ( . ± . ml with desmopressin vs . ± . ml without desmopressin, p= . . in-hospital mortality was significantly higher in the desmopressin group ( % vs % without desmopressin, p= . ) as well as the incidence of a modified rankin score of - at discharge ( % vs % without desmopressin, p= . ). administration of desmopressin for antiplatelet reversal in sich does not appear to reduce the incidence of hematoma expansion. further studies assessing temporal relation of desmopressin administration and hematoma expansion are needed to confirm the results of this single-center retrospective study. clinical outcome after intracerebral hemorrhage (ich) remains poor. definitive phase- trials in ich have failed to demonstrate improved outcomes with intensive systolic blood pressure (bp) lowering.we sought to determine whether other bp parameters-diastolic bp, pulse pressure (pp), and mean arterial pressure (map)-showed an association with clinical outcome in ich. we retrospectively analyzed a prospective cohort of patients with spontaneous ich and documented demographic characteristics, stroke severity, and neuroimaging parameters. consecutive hourlybp recordings allowed for computation of systolic bp, diastolic bp, pp, and map. threshold bp values that transitioned patients from survival to death were determined from roc curves. using inhospital mortality as outcome, bp parameters were evaluated with multivariable logistic regression analysis. patients who died during hospitalization had higher mean pp compared to survivors ( . ± . mmhg vs. . ± . mmhg; p= . ). the following admission variables were associated with significantly higher in-hospital mortality (p < . ): poorer admission clinical condition, intraventricular hemorrhage, and increased admission normalized hematoma volume. roc analysis showed that mean pp dichotomized at . mmhg, provided a transition point that maximized sensitivity and specific for mortality. the association of this increased dichotomized pp with higher in-hospital mortality was maintained in multivariable logistic regression analysis (or . ; %ci . - . ; p < . ) adjusting for potential confounders. widened pp may be an independent predictor for higher mortality in ich. this association requires further study. a national confidential enquiry into patient outcome and death (ncepod) report concerning management of aneurysmal subarachnoid haemorrhages in the uk suggested up to half of patients received suboptimal consideration for organ donation. as demand for organs continues to increase, so does the need to pursue all potential sources of donor organs. subarachnoid haemorrhages have an estimated mortality of % and can potentially provide younger donor organs with less chronic pathology. this is a comprehensive picture of donation rates within a tertiary centre. retrospective data regarding all deceased patients on the neuro-intensive care unit during with aneurysmal subarachnoid haemorrhage as the cause of death was obtained from the nhs blood and transfusion team. the local audit committee provided ethical approval. data regarding organ donation was extracted and compared to national data, then analysed using fisher's exact test. referral rates were %. this is greater than the national average of . % (p= . ), yet only . % of referred patients proceeded to organ donation. consent was withheld in . % of potential donors. nationally . % of donors are lost due to non-consent (p= . ). . % of consented patients were unable to donate organs, similar to national figures (p= . ). referral rates within this centre are excellent; consent remains the main obstacle. consent rates can be improved using a long contact model where specialist nurses in organ donation establish relationships with relatives prior to any discussion of donation. the ideal discussion is a pre-planned collaboration involving a senior doctor and a specialist nurse. early brain stem testing may facilitate earlier acceptance of death by relatives whilst reducing the duration of the multi-systemic effects of the associated hyperresponsive cascade on donor organs. neurosurgeons should be encouraged to suggest organ donation when declining referrals. further work is needed to assess the barriers to instituting these measures and inspiring change. spontaneous brainstem hemorrhage has been historically associated with high mortality. however, updated data on the frequency and outcome of spontaneous brainstem hemorrhage is scarce vis-a-vis advances in neuro-critical care. the purpose of this study was to investigate the frequency and outcome of spontaneous brainstem hemorrhage. records of consecutive intracerebral hemorrhage (ich) patients presenting to an urban academic medical center from january though december were reviewed. cases with brainstem hematomas were isolated for analysis. data on demographics and outcomes were collected and analyzed. sub-group analysis was also done to look at outcomes based on location of hemorrhage in the brainstem. of consecutive spontaneous ich patients, ( . %) presented with brainstem hemorrhage; ( . %) were pontine, ( . %) mesencephalic, and ( . %) were located in both the pons and the midbrain. the average age was . years and ( . %) were men. median glasgow coma scale on presentation was . . thirty-day mortality rate was . %, with in-hospital deaths and deaths post discharge. two and patients were discharged home or a rehabilitation facility, respectively. in subgroup analysis, thirty-day mortality for midbrain, pons and combined pons/midbrain hemorrhage was %, % and %, respectively. spontaneous brainstem hemorrhage remains an uncommon but highly fatal clinical entity. more than one-half die within days. only a minority are discharged to rehabilitation or home. in sub-group analysis, location of brainstem hemorrhage was shown to influence outcome, with % mortality in case of combined pons/midbrain hemorrhage, and more than % mortality with pontine hemorrhage. midbrain hemorrhage was associated with good outcome with % survival. patients with intracerebral hemorrhage (ich) frequently present with hypertension. it is unclear whether this is due to preexisting hypertension (prhtn) causing the bleed, an effect of the bleed, or both. we retrospectively analyzed a single-institution cohort of ich patients presenting between and . data included home antihypertensive use; asbp; tte, and ekg and imaging results; and nicardipine administration. the primary objective was to assess the relationship between prhtn and asbp, while the secondary objectives were to assess the relationship between prhtn, imaging and acute antihypertensive requirements. ich patients met inclusion criteria. in our assessment for prhtn, we found that % of patients were on antihypertensives, % had lvh on ekg, and % had lvh on tte. there was a significant relationship between lvh on tte and lvh on ekg (p< . ), but not between home antihypertensive use and presence of lvh using either modality. asbp was higher for all patients with markers of phtn, but this was only significant for patients with lvh on tte ( mmhg, iqr - vs. mmhg, iqr - , p < . ) and patients with lvh on ekg ( mm hg, iqr - vs. mm hg, iqr - , p< . ). all patients with markers of prhtn were more likely to require nicardipine, but this was only significant for patients with lvh on tte ( % vs. %, p= . ) and patients with lvh on ekg ( % vs. %, p= . ). all patients with markers of prhtn were more likely to have deep bleeds (p= . for patients with lvh on ekg vs. those without lvh on ekg). there was no relationship between any markers of prhtn and the presence of a spot sign. in patients with ich, prhtn is related to higher asbp, deep bleed location, and increased acute antihypertensive requirements. all spontaneous intracerebral hemorrhage (sich) patients, including those with low severity are uniformly admitted to the intensive care unit (icu) at our institution. many may not benefit from this high-intensity observation and leave the icu within hours without experiencing any complications. identifying low-risk characteristics could aid in triaging such patients to stroke units instead. retrospective data collection of all sich patients admitted to our institution from june , -june , included ich score, need for surgical interventions, medical complications, and icu/hospital los. we analyzed variables predicting short (< hour) icu los among low severity (ls-ich) patients (defined as those with ich score - ). ( %) of sich patients had ich scores of - , of which just under half ( ) had icu los hr. they also spent significantly fewer days in hospital ( vs . , p< . ). we could not identify a clear ich score cutoff that was sensitive enough to predict short icu los. however, requirement for antihypertensive infusion and early clinical deterioration correlated strongly with longer icu los p< . . there appears to be a subset of mild ich patients (ich score - ) who do not require icu observation. a risk assessment score incorporating gcs and ich volume may be able to delineate this low-risk population who could instead be admitted to a stroke unit, with the potential for significant cost saving and hospital efficiency. obesity has been linked with relative longevity in several disease conditions. this relationship has been termed the "obesity paradox." in this study we sought to evaluate the impact of obesity on short-term outcomes in patients with intracerebral hemorrhage (ich). patients admitted with a diagnosis of ich were selected from the - nationwide inpatient sample (nis) database, using icd- codes. patients with ich were dichotomized based on the presence of obesity as a coexisting diagnosis based on icd- codes and diagnosis related groups. the primary outcome measure was in-hospital mortality. length of stay and total charges were also examined as resource utilization measures. of obesity is a major health care burden as evidenced by higher resources utilization. counterintuitively, obesity appears to be associated with lower in-hospital mortality in ich patients. one possible physiological basis for this could be that the higher ldl levels on presentation result in a lower likelihood of hematoma expansion. recent short-term outcome analysis indicates association of spontaneous intraventricular hemorrhage (ivh) related hydrocephalus with incontinence and gait dysfunction. we explore the association of hydrocephalus scores, intraventricular alteplase and clinical variables with these outcomes at long term follow up in survivors from the clear iii trial. clear iii, a randomized, multi-center, double-blinded, placebo-controlled trial was conducted to determine if pragmatically employed external ventricular drainage (evd) plus intraventricular alteplase improved outcome, in comparison to evd plus saline in patients with ivh causing obstructive hydrocephalus. we assessed hydrocephalus scores on survivors at diagnosis, days and . incontinence and dysmobility were defined using -month barthel index subscores (< for bladder and < for mobility, respectively). outcome measures were predictors of incontinence and gait dysmobility at year after ich. this prospective observational study analyzed consecutive ich-patients (n= ) treated at the neurological and neurosurgical departments of the university-hospital erlangen, germany over a month inclusion period ( / - / ). we analyzed the influence of patient characteristics, inhospital measures and functional status on treatment recommendations and on oac initiation during -month follow-up. clear treatment recommendations by attending stroke physicians seem necessary to ensure oac initiation after ich. oac showed beneficial associations; however data here suggests the presence of an indication bias introduced by treatment recommendations and outpatient care during follow-up. therefore, observed association with age and functional status might affect unadjusted analyses. although recently, non-vitamin k antagonist oral anticoagulants (noacs) therapy in patients with non valvular atrial fibrillation have half the incidence of intracerebral hemorrhage (ich) compared to warfarin. however, it would be still controversial subject that outcome of noac-associated ich (nich) might be worse or better than warfarin-associated ich (wich). in this study, we investigated clinical outcome and radiological finding of ich between two different anticoagulation treatments. retrospective review of medical records was performed for , patients who admitted with ich from to in seoul national university bundang hospital. clinical characteristics, functional outcome, location and volume of ich, and all-cause mortality within days were analyzed. among those patients, patients with wich and patients with nich were included. lesion location was common in supratentorial deep area ( . %, . %), lobar area ( . %, . %) and brainstem and cerebellum ( . %, . %) in the nich and wich group, respectively. no significant difference found in initial nihss ( . vs ), discharge nihss ( . vs ), mrs ( to ) at discharge ( . % vs . %), mrs ( to ) at discharge ( . % vs . ), mrs ( to ) at days ( . % vs . ) and mrs ( to ) at days ( . % vs . ) in nich and wich group. we did not find any difference between nich and wich for allcause mortality at discharge ( % vs %), days ( . % vs %), and year ( % vs %). median baseline ich volume was not significant difference in two groups ( . vs . ). in our study, functional outcome, mortality, and baseline ich volume were similar following nich and wich. because of low statistical power due to small sample size in our study, further studies with prospective larger patient cohorts will need to be conducted. novel oral anticoagulants (noac) are increasingly used as an alternative to vitamin-k antagonists (vka) such as warfarin for anticoagulation and have shown lower rates of intracranial hemorrhage in several randomized clinical trials. it has been suggested that noac-iphs might be particularly dangerous, yet the literature regarding hematoma characteristics and outcomes between noac-iphs and vka-iphs is inconclusive. given the lack of standardized reversal strategies and lack of information on outcomes following noac-associated iph, the aim of this meta-analysis was to compare ) mortality; ) hematoma volume, and ) risk of hematoma expansion in patients who developed an iph on noacs versus vka. a meta-analysis of the literature through december was conducted using pubmed, embase and cochrane databases in accordance with prisma guidelines. pooled risk ratios (rr) were calculated for mortality and hematoma expansion and pooled mean difference (md) was calculated for hematoma volume (ml) using random-effect (re) and fixed-effect (fe) models. noac-iph was not associated with increased mortality (re and fe: rr: . ; %-ci: . ; . , i = . %, p-heterogeneity= . ; studies) and hematoma expansion (re and fe: rr: . ; %-ci: . ; . , i = . %, p-heterogeneity= . ; studies) compared to vka-iph. the hematoma volume of noac-iph was smaller than vka-iph (re: md: - . ml; %-ci: - . ; - . , fe: md: - . ml; %-ci: - . ; - . ; studies), but with considerable heterogeneity that could not be alleviated (i = . %, p-heterogeneity . ). noac-iph was not associated with increased mortality or hematoma expansion compared to vka-iph and may be associated with a smaller hematoma volume. controversy exists regarding blood pressure (bp) reduction and perihematomal ischemia (phi). we investigated the association of acute bp reduction and presence of qualitative and quantitative phi in a large prospective cohort of intracerebral hemorrhage (ich). consecutive patients from the prospective nih funded dash study (> years, primary spontaneous ich) were included. phe volume was outlined on t /flair and ich volume on gre; these and adc were co-registered. tissue characteristics was defined as: ce = adc x - mm /sec. the association of clinical, radiographic factors and bp at baseline and hours with qualitative perihematomal and/or remote ischemia (i.e. dwi bright adc dark) and quantitative ce on adc were determined. patients ( % female) with mean age ± , and nihss (iqr , ) were included. mri time was . hours (iqr , ). % had lobar ich. ich volume was cc (iqr , ). % had perihematomal ( %) or remote ischemia ( %). % of patients had areas of perihematomal adc cc) was associated with higher absolute ( ± mm hg, p= . ) and relative ( % ± % vs % ± %, p= . ) map reduction, younger age (p= . ), h/o tia/stroke (p= . ) and larger ich volumes ( vs cc) (p< . ). in multivariate analysis, map reduction was not significantly associated with ce whereas ich volume was (p= . ). perihematomal and remote ischemia is frequently seen after ich, but the severity of phi is small and of unclear significance. bp reduction may be associated with phi but this was not an independent predictor. introduction: patients with left ventricular assist devices (lvads) receive anticoagulation and antiplatelet therapy to prevent pump thrombosis. consequently, neurological events including intracranial hemorrhage (ich) are one of the most feared causes of morbidity and mortality in these patients. there is little evidence to guide initiation of anticoagulation after such ich events. methods: this is a retrospective, single academic center analysis of lvad patients from - . the electronic medical record was reviewed after irb approval for the physiologic, laboratory, and radiographic data of these patients as well as survival or cause of death by days or by discharge. results: during the analysis, patients were reviewed, of which ( . %) had intracranial hemorrhage. one patient was excluded from analysis after care was transitioned to hospice, thus follow-up scans were not obtained. the remaining patients were receiving both aspirin ( - mg daily) and warfarin ( - mg daily) with an inr of . - . (mean= . ) at the time of ich. aspirin ( - mg daily) was resumed within - (mean= . ) days post ich. warfarin was resumed - (mean= . ) days post ich at - mg (mean= mg) with goal inr ( . - )-( - ) depending on device. there was death due to withdrawal of life support in setting of multiple comorbidities, though follow-up scan days post warfarin resumption revealed no evidence of rebleed. the remaining patients showed no evidence of rebleed on ct scans at months post warfarin resumption and were subsequently discharged to rehab facilities or home with modified rankin scores - (mean= . ). conclusion: in this review of lvad patients, about % suffered ich, and of those survivors aspirin was safely resumed within days and warfarin was safely resumed as early as days post-event. further studies are needed in order to establish safe practice guidelines and risk factors to prevent ich. intracerebral hemorrhage (ich) remains a devastating form of stroke, and perihematomal edema worsen outcomes after ich. recent studies have demonstrated the safety of minimally invasive surgery (mis) for hematoma removal, but the efficacy of mis in the treatment of ich is controversial. this study aimed to evaluate the effect of mis compared with medical treatment for basal ganglia ich. we retrospectively analyzed the clinical outcomes of prospectively collected data from two stroke centers. the treatment strategies of the two stroke centers for basal ganglia ich are different; one stroke center underwent mis and the other stroke center medically treated according to the current guidelines. we hypothesized that mis could reduce perihematomal edema and improve functional outcomes compared to medical treatment. primary outcome of this study was a modified rankin scale (mrs) at months after ich occurrence. a total of patients with basal ganglia ich were treated with different treatment strategies; patients underwent mis and patients received medical treatment. no statistically significant differences were found in age, sex, hematoma volume, and glasgow coma scale scores between the groups. a better functional recovery (mrs < ) at months was found in the medical treatment group than the mis group ( . % vs . %, p < . ). no significant differences were observed between groups in terms of mortality. our findings suggest that the best medical treatment improves functional recovery after basal ganglia ich compared to mis. these results are contrary to other studies of ich, and further randomized trials are required. perihematomal edema (phe) after intracerebral hemorrhage (ich) is thought to be predominantly vasogenic. the presence and extent of cytotoxic edema (ce) is controversial. we investigated phe diffusivity (phed) and factors associated with ce. consecutive patients from the prospective nih funded dash study (> years, primary spontaneous ich) were included. phe volume was outlined on t /flair and ich volume on gre; these and adc were co-registered. tissue characteristics was defined as: ce = adc x - mm /sec. clinical and radiographic factors associated with ce were determined. cytotoxic edema is detected in the perihematomal area, early after ich and is associated with younger age, larger ich and prior h/o tia/stroke. its clinical significance needs to be studied further. hemorrhagic stroke carries a high mortality rate and determining prognostic factors during initial presentation can aid redirecting intensive care unit (icu) management. we described the physiological profile and clinical outcomes of hemorrhagic stroke patients in a colombian icu. we retrospectively reviewed all hemorrhagic stroke patients admitted to our icu from - . clinical characteristics, outcomes, available laboratory values and hourly vital signs from the first hours in the icu were retrieved and analyzed. our primary stroke center admitted patients, ( %) were hemorrhagic. out of these, required icu management, representing % of the total icu admissions during this time frame. intracerebral hemorrhage (ich) was present in patients while subarachnoid hemorrhage (sah) was seen in . the latter had a median fisher score of . for all patients, the most common risk factors were hypertension ( . %), dyslipidemia ( . %) and smoking ( . %). icu mortality was . % ( . % with ich and . % with sah). mean sequential organ failure assessment (sofa) score was significantly greater in patients who died ( . vs. . , p< . ) and mean glasgow coma scale was significantly lower ( . vs. . , p< . ). vasopressors were required in patients ( . %), mechanical ventilation in ( . %), and half of the patients requiring either support therapy died. only patients ( . %) had fever in the first hours and all died. mean coefficient of variation for systolic, diastolic and mean blood pressure was significantly lower in patients who survived. mortality cases were more likely to have hypokalemia and hypomagnesemia than surviving patients ( . % vs. . % and . % vs. %, respectively). icu-admitted hemorrhagic stroke patients have a poor prognosis. sofa and gcs are accurate predictors of mortality. certain electrolyte disturbances, fever and a higher variation of blood pressure during the first hours were associated with a worse outcome. the association between worsening cerebral edema and unfavorable outcome in ich patients has been described in rcts. the objective of this analysis was to compare hospitalized spontaneous ich patients with and without perihematomal edema (phe) expansion and to evaluate relationships between hypertonic saline (hts) use, peak serum na, phe expansion, and short-term outcomes. we conducted a cross-sectional study of consecutive spontaneous ich patients admitted to a single center from / - / . head cts during the first week of admission, use of hts, and phe (using abc/ method) were evaluated. phe expansion of % or more was considered worsening edema. outcomes of interest included time to peak na, poor disposition (not home or inpatient rehabilitation), discharge mrs - , and in-hospital death. of ich patients, % experienced worsening phe. there was no difference in age, race, sex, arrival bp arrival, or vascular risk factors in patients with or without worsening phe. however, for each mm of midline shift (mls) present on initial head ct, odds of phe expansion was decreased by % (or . , %ci . - . , p= . ). mls on initial head ct was the best discriminator of phe expansion (auc . ( %ci . - . ). although hampered by small sample size, our data indicates that finding that ich patients with degree of mls on initial head ct is the best radiographic predictor of had lower odds of phe expansion. those without mls at presentation may be at risk of phe expansion, and counterintuitively may be those most in need of aggressive medical management. may suggest a role for intensive osmotherapy in patients with favorable imaging at presentation. intracerebral hemorrhage (ich) is a devastating stroke with high mortality rates. previous studies have shown a potential role of immune cells as a prognostication method. a high neutrophil to lymphocyte ratio was associated with poor outcomes after ich. we sought to determine whether absolute lymphocyte count(alc) at admission was predictive of outcomes in patients with ich. we performed a retrospective chart review of all patients admitted to our hospital with a diagnosis of ich from january to december .we collected baseline demographic characteristics, medical history, ich scores, differential leucocyte, platelet and total leucocyte(tlc) counts at admission. the functional outcomes after ich were measured using modified rankin scale (mrs) at discharge. mrs of and were considered poor outcomes. statistical analysis was done after grouping lab values into higher and lower groups with respect to the normal reference ranges a total of patients with ich were admitted to our center during the study period. patients were included in the study and the rest were excluded due to lack of differential leucocyte counts at admission. % ( of ) had poor outcomes. univariate analysis using fisher's exact test showed significant association between low alc levels ( . ) were also found to be significantly associated with worse outcomes (p = . , . , . , respectively). however, after multivariate analysis, only low absolute lymphocyte counts retained significant association (p = . ). intracerebral hemorrhage patients with low absolute lymphocyte counts at admission have a higher probability of poor outcomes at discharge. further studies are required to confirm our results. intraventricular hemorrhage (ivh) is a significant predictor of poor outcome after intracerebral hemorrhage (ich), and may differentially predict hydrocephalus and mortality among blacks vs. nonblacks. we aimed to confirm these findings in a separate cohort of spontaneous ich patients with severe ivh. the cleariii-ivh trial was a randomized, multi-center placebo controlled trial examining the effect of intraventricular alteplase versus saline, on outcomes in patients with spontaneous ivh. we retrospectively analyzed data on all patients, including self-reported race/ethnicity, medical comorbidities, presentation characteristics and functional outcomes. represented race/ethnic groups with > subjects per group were ( . %) white/non-hispanic (wnh), ( . %) white/hispanic (wh), ( . %) black/african american/non-hispanic (bnh), and ( . %) asian. bnh were significantly younger than rest of the cohort with median age [interquartile range] [ , ] years, had more hypertension( %, p= . ), and significantly higher rates of antihypertensive medication non-compliance ( . %, p= . ). wnh had more frequent coronary artery disease ( . %, p< . ), use of vitamin k antagonists ( . %, p= . ) and elevated inr on presentation ( . %, p= . ). bnh had significantly more frequent hydrocephalus on presentation ( . %, p= . ), and a higher rate of ventriculoperitoneal shunt placement ( %, p= . ). neither ich nor ivh volume at enrollment, nor ivh remaining at end of treatment differed significantly between race/ethnic groups. however, bnh patients were more likely to have greater than % ivh reduction, a recognized endpoint for better functional outcomes in cleariii ( . % vs. %-wh; . %-wnh; . %-asian; p= . ), and this difference persisted in those who received intraventricular alteplase (p= . ) and after adjustment for diagnostic ivh volume (p= . ). race/ethnicity was not an independent predictor of mortality or poor outcome at or days on multivariable logistic regression. although functional outcomes did not differ significantly among race/ethnic groups, differences in risk factors, hydrocephalus/shunting post ivh and response to thrombolytic therapy warrant further exploration. investigators from the randomized trial of unruptured brain arteriovenous malformations (avm) trial (aruba) reported in that interventions to obliterate unruptured avms resulted in greater morbidity and mortality compared to medical management. we investigated whether patterns of avm treatment changed after aruba's publication. we used inpatient and outpatient claims data from - from a nationally representative % sample of medicare beneficiaries. unruptured brain avms were identified using icd- -cm code . . the date of first avm diagnosis was coded as occurring before or on november , (online publication of aruba) versus after. outcomes were referral to a neurologist or neurosurgeon, and interventional treatment. interventional treatments were identified using cpt codes - , - , , , or - . the likelihood of outcomes after versus before aruba was compared using survival analysis with log-rank tests and cox proportional hazards models adjusted for age, sex, race, and the charlson comorbidity index. we censored patients at diagnosis of intracranial hemorrhage. we identified , patients with a mean . (± . ) years of follow-up after diagnosis of unruptured brain avm. diagnosis was most often by neurologists ( . %), neurosurgeons ( . %), and internal medicine specialists ( . %). after aruba publication, there were no changes in -year cumulative rates of referral to a neurosurgeon ( . % after, . % before; p = . ) or neurologist ( . % after, . % before; p = . ), but there was an increase in avm treatment ( . % after, . % before; p = . ). after adjustment for demographics and comorbidities, there was an increased likelihood of interventional management (hr . ; % ci, . - . ) after aruba's publication. in a nationally representative cohort of elderly patients, we found an increase in interventional avm management after publication of aruba. this is notable given that our data pertain to older patients who are generally seen as less suitable surgical candidates. elderly patients with severe intracerebral hemorrhage (ich) are often projected to have future functional dependence but unclear degree of cognitive recovery. surrogates for such patients frequently weigh multiple concerns when facing the difficult decision of whether to prolong life with tracheostomy and gastrostomy tube insertion versus pursue comfort care. we aimed to characterize distinct groups of surrogates in these situations, based solely on how they prioritize their concerns. subjects recruited from a probability-based us population sample completed an online best-worst survey that presented the above scenario and asked the respondent to prioritize concerns as the patient's surrogate. clusters were identified with latent class analysis after weighting data to match the us census demographic distribution. class solutions were replicated times from random starting seeds, with the solution chosen after factoring in akaike's information criterion. we identified distinct decisional groups among respondents (response rate = . %). all groups reported multiple concerns as important, but group ( . %) was more concerned than any other that the patient was too old to live with disability. group ( . %) focused on ensuring agreement among other family members. group ( . %) was concerned that the patient might suffer if tube feeding and iv fluids were stopped and that the prognosis could be incorrect. group ( . %) had numerous considerations that were comparably important but prioritized paying for long-term care. groups varied in whether they would actually request prolonging care for the patient (group = . %, g = . %, g = . %, g = . %, p< . ). in a multivariate model, religious affiliation and frequency of attending religious services were the only variables independently predicting group membership. we identified distinct profiles of decisional patterns for surrogates of severe ich patients with uncertain prognosis. these data will inform development of strategically tailored decision aids. cerebral venous sinus thrombosis (cvst) represents an important cause of both ischemic and hemorrhagic strokes in young people. while recent guidelines recommend management in a stroke unit, the impact of neurocritical care in this condition has not been studied. we aimed to assess whether the introduction of a neurocritical care program influenced clinical outcomes in cvst patients. we retrospectively reviewed electronic medical records of adult patients admitted to yale new haven hospital's neuroscience icu (nicu) between and with a diagnosis of cvst. demographics, vascular risk factors, comorbidities, length of stay and discharge modified rankin scale (mrs) were collected. patients were excluded for age hours of presentation. we compared two time periods, before (epoch , - ) and after (epoch , - ) the introduction of continuous staffing of cvst cases by neurointensivists in the nicu. univariable and multivariable logistic regression were utilized to model the odds of poor outcome (dichotomized mrs - vs - ). fifty-three patients with cvst met the inclusion criteria during the study period (mean age (+/- ) years, % female). patients were identified for epoch and patients for epoch . overall, patients ( %) had a good (mrs - ) outcome. for epochs and , good outcomes were observed in ( %) and ( %) patients, respectively (p= . ). in both univariable and multivariable regression analysis (adjusted for age and sex), admission during epoch was associated with a significantly reduced odds of a poor outcome (or . , ci . - . ; p = . ) and (or . , ci . - ; p= . ), respectively. in this small, single-center cohort of patients with cvst, most patients experienced a good outcome. the institution of continuous neurointensivist coverage was independently associated with better outcomes. further validation in prospective, multicenter cohort studies is needed. thrombelastography (teg) provides a dynamic assessment of clot formation, strength, and stability. we examined relationships between teg parameters and outcomes from intracerebral hemorrhage (ich). we prospectively enrolled patients with spontaneous ich between to . teg was performed at the time of admission. we divided patients into two groups based on the presence or absence of hematoma expansion (he). clinical characteristics, baseline teg values, and outcomes were compared between the two groups. multivariable regression analysis was conducted to compare the differences of teg components between the two groups after adjusting for potential confounding effects. we included patients, ( %) with he and ( %) without he. patients with he were more often male and had higher rates of aspirin use, lower incidence of intraventricular hemorrhage, and larger baseline hematoma volumes. after controlling for potential confounders, mean r time was independently associated with he ( . ± . vs. . ± . mi significantly higher risk of he with or . ( % ci: . , . ), p=< . . patients with hematoma expansion were more likely to have poor neurological outcome (mrs - ) at discharge ( % vs. %, p= . ) and had higher mortality rates ( % vs. %, p= . ). overall, patients ( %) died in the hospital. following multivariable analysis, patients who died had significantly lower mean delta ( . ± . vs. . ± . mins.; p= . ) and smaller angle ( . ± . vs. . ± . degrees; p= . ) than those who lived. hematoma expansion and mortality from ich are independently associated with slower clot formation on teg. baseline teg identifies significant coagulation disturbances which may predict poor outcome and represent potential targets for therapeutic intervention. intracerebral hemorrhage (ich) patients often present with acute hypertension requiring intravenous and enteral antihypertensive medications. we performed a cohort study to determine clinical predictors of time to enteral antihypertensive medication and its effect on icu length of stay (icu los). we identified consecutive spontaneous ich patients admitted from / to / to a tertiary center, and excluded those transitioned to comfort care (cmo) within hours of admission. we calculated time from hospital admission to first enteral (oral or feeding tube) antihypertensive. we abstracted demographic and clinical variables. two reviewers examined medical records and classified ich location and etiology. we determined univariate and adjusted associations of clinical variables to time to enteral antihypertensive medication and performed regression analysis to determine effect on icu los. we identified patients and excluded for early transition to cmo. endotracheal intubation (p= . ), higher ich score (p< . ), no outpatient antihypertensive use (p= . ), and non-lobar ich location (p= . ) predicted longer time to starting enteral antihypertensive in adjusted analysis. presenting systolic or diastolic bp, time of icu admission (day vs. night), sex, and race were not significant predictors of time to enteral antihypertensive. time to enteral anti-hypertensive is the strongest predictor of icu los (p< . ) after adjustment for age, gcs, ich score, sex, race, and duration of iv antihypertensive infusion. patients with higher ich scores, intubation, no prior antihypertensive use, and non-lobar ich are at risk for increased time to enteral antihypertensive administration. timely enteral antihypertensive administration is an important and potentially modifiable predictor of icu los in acute ich. overall mortality from intracerebral hemorrhage (ich) represents a combination mortality from a potentially fatal disease as well as practice variation around treatment withdrawal of care. early do-not-resuscitate (dnr) rates are independently associated with in-hospital mortality and may serve as a proxy for withholding aggressive care. the american heart association (aha) guidelines recommended that dnr orders should not be applied before hours out of a concern that less aggressive care would lead to a self-fulfilling prophecy and excess mortality. we performed a retrospective analysis of temporal trends among primary ich patients presenting to all nonfederal emergency departments in california from to using data from the office of statewide health planning and development (oshpd). demographic information, clinical covariates (such as mechanical ventilation, craniotomy), and early dnr status within hours were collected and analyzed using segmented regression to evaluate for differences in linear trends from - compared with - . over a use of early dnr orders for ich patients has steadily decreased over the last years, even after adjusting for age and disease severity. the pace of this downward trend did not significantly change around the time when recommendations on early dnr use for ich in aha guidelines were revised in . spontaneous intracerebral hemorrhage (ich) is a common form of stroke that often results in severe morbidity or death. for most ich, there are no proven therapies for acute management. evidence suggests minimally invasive surgical evacuation of ich may result in improved patient outcomes. the enrich clinical trial is designed to determine the efficacy and economic impact of early ich evacuation using minimally invasive, transulcal, parafascicular surgery (mips) compared to standard guideline-based management. in this abstract we present the trial design and rationale at the foundation of the enrich clinical trial. enrich is an adaptive, prospective, multi-center clinical trial designed to enroll up to patients with acute ich. patients are block-randomized based on hemorrhage location (lobar vs basal ganglia) : to mips or standard management. included patients are - years, gcs - , baseline mrs , presenting within hours from last known well and found to have a spontaneous, cta-negative, supratentorial ich ( - ml). primary efficacy will be determined by demonstrating significant improvement in the mean utility-weighted mrs at days after enrollment. economic effect of mips will be determined by quantifying the cost per quality-adjusted life-years gained at pre-determined time points. the rationale for early intervention is to interrupt the time-dependent ich related pathophysiology caused by mechanical pressures and the pro-inflammatory secondary cascade that leads to worsened cellular injury and edema formation. the planned enrichment strategy acknowledges that hemorrhages in varied locations may have a differential response to mips. study adaptation, in the form of enrichment, may occur if pre-determined futility rules are met for the primary outcome in either of the two locations. enrich is designed to establish the clinical and economic value of early mips in the treatment of ich. enrollment was initiated in december . early seizures (< days) after intracerebral hemorrhage (ich) may be associated with the presence and degree of perihematomal cytotoxic injury. we explored the association between perihematomal diffusivity (phd) and early seizures after ich. consecutive patients from the prospective nih funded dash study (> years, spontaneous ich) were included. all patients had multimodal mri within weeks. perihematomal edema (phe) volume was outlined on t /flair and ich volume on gre; these and adc were coregistered to analyze phd. eeg monitoring was performed for clinical suspicion of seizure. mean adc values of phe and the percentage of phe volume were compared between the seizure and no-seizure groups, with adc values as vasogenic edema. results ( %) of a total of patients had early seizures at a median of day post ich. mean adc in the phe region was higher in the seizure group (mean: +/- vs +/- , p= . ). ich, absolute, and relative phe volumes were not different between groups. the phe of the seizure group had a lower percentage of cytotoxic edema ( % vs %, p= . ) and a higher percentage of vasogenic edema ( % vs %, p was the most predictive of seizure with auc = . , though adc thresholds between - had largely similar auc's. phe volume of > % (of adc > ) identified patients with seizure with sensitivity of . , specificity of . , and remained significant in multivariable analysis. patients with early post-ich seizures have higher mean perihematomal adc and a larger percentage of vasogenic edema in the perihematomal region. vasogenic edema due to bbb breakdown and perihematomal inflammation rather than cytotoxic injury is associated with early post ich seizures. novel neuroprotective treatments hold the promise to improve patient outcomes by broadening time windows of intervention and reducing hypoperfusion and reperfusion injury in the era of mechanical thrombectomy for acute ischemic stroke. hibernating species, such as arctic ground squirrels (ags), demonstrate remarkable resilience to ischemic and reperfusion injuries. bioinformatic analyses of genomes of hibernating species reveals signatures of convergent evolution in genes regulating stability and formation of mitochondrial respirasomes. hypoxia pre-conditioning (hpc) also leads to improved survival upon subsequent exposure to hypoxia, and is associated with increased stabilization of respirasomes. the respirasome is a macromolecule consisting of oligomers of complex i, iii, and iv. cox a l is a key mediator of respirasome stability via interactions with complex i and iii. in this study, we explored the role of cox a l in mediating respirasome stabilization in ags neural stem and progenitor cells (nsc/npcs) as well as mouse nsc/npcs exposed to hpc. respirasome stability was assessed using blue native gel electrophoresis and mitochondrial metabolism assessed by measuring oxygen consumption in vitro (seahorse metabolic analyzer). exposure to mild hypoxia and induction of hif leads to stabilization of respirasomes, upregulation of hif, and modulation of mitochondrial metabolism. interestingly, overexpression of the ags isoform of cox a l, which has amino acid substitutions in residues mediating respirasome stability, recapitulates the effects of hypoxia on respirasome stability and mitochondrial metabolism without altering hif expression. targeting respirasome stability by modulating cox a l is a potentially novel neuroprotective target for treatment of ischemic injuries. testing of these hypotheses in pre-clinical models of stroke is on-going. acute stroke symptoms need timely diagnostics in order to ensure best outcomes. as a non-academic, community-based center located in rural western nc, where we are the regions only comprehensive stroke center, we developed a process to intake stroke patients quickly directly from ct to interventional radiology when applicable. a smooth transition reduces the quantity of time from imaging to interventional suite, ultimately reducing the time it takes to prepare to actively treat a patient. interventional radiology value stream mapping started in june . multidisciplinary team worked in multiple work groups to design and create "code ir stroke now". flow chart created to show multiple moving parts simultaneously, to streamline transition from er (sometimes this includes triage from the region also) to ir. an ir "ready" criteria was made, er and ir checklists, followed by post procedure debrief and treatment plans/order set to standardize care and documentation. first mock code ir was done / / , this was critiqued/perfected. "go live" date: / / . we continue process improvement today. in first three months, patients have gone through this process. average compliance for goal door to puncture < min went from . % to %. door to groin times reduced from minutes to minutes. our performance is minutes quicker than other comprehensive stroke centers ( m avg gwtg database). saved an average of million neurons per patient. total of million neurons saved on average since / / ! door to groin times can be reduced with streamline approach to care. multidisciplinary team approach, including house supervisors, anesthesia, switch-board in addition to the bedside staff and providers can make a smooth transition from the time a large vessel occlusion is identified to getting the patient to the interventional suite. activation of "code ir stroke now" page activates this team / . it is unknown whether antithrombotics for secondary stroke prevention in patients with acute ischemic stroke (ais) due to infective endocarditis (ie) reduce the rate of secondary ais or increase major bleeding. we conducted a multi-center, retrospective cohort study from - of patients with ais secondary to left-sided ie, separated into two groups (antithrombotic vs no antithrombotic). antithrombotics included antiplatelets and/or therapeutic anticoagulation. the primary outcome was a composite of recurrent ais and major bleeding. secondary outcomes included ais and major bleeding individually. a binary logistic regression model adjusted for age and native vs prosthetic valve involvement was used for outcome evaluation. the final analysis included patients ( antithrombotic vs no antithrombotic). median age was years and ( %) patients had prosthetic valve infections. infecting organisms were mostly methicillin sensitive s. aureus ( %) or streptococcus spp. ( %). valve repair/replacement occurred in ( %) patients. aspirin with or without another antithrombotic ( %) was the most common antithrombotic treatment. the primary outcome occurred in . % vs . % of patients with antithrombotics vs no antithrombotics, respectively (or . ; % ci . to . ). ais ( . % vs . %; or . ; % ci . to ) and major bleeding ( . % vs . %; or . ; % ci . to . ) were similar between groups. a subgroup analysis of aspirin monotherapy vs no antithrombotic yielded similar results for the primary outcome ( . % vs . %; or . ; % ci . to . ) and ais ( . % vs . %; or . ; % ci . to . ). major bleeding was increased, however ( . % vs . %; or . ; % ci . to . ; p= . ). antithrombotics after ais secondary to ie were not associated with a decrease in recurrent ais or an increase in major bleeding. aspirin monotherapy was associated with an increase in major bleeding without any reduction in ais. malignant hemispheric stroke (mhs) represents between - % of all hospitalized ischemic stroke in the united states. pooled analysis of european studies has demonstrated that decompressive hemicraniectomy (dchc) for mhs reduces mortality compared with conservative medical management and may also improve functional outcomes. these trials however, excluded patients with major medical comorbidities that might confound clinical outcomes. apache ii and sofa scores are validated icu scoring systems to help characterize disease severity and estimated hospital mortality. this study aims to evaluate apache ii and sofa scores in predicting outcomes for patients undergoing dchc for mhs. this is a single center retrospective analysis of patients who underwent early dchc for mhs between may through january at unc chapel hill. apache ii and sofa scores were calculated for the date of admission or date of first presentation to neurologic care. outcomes included mortality at discharge, mortality at day, and functional outcome at last follow up, up to one year. multivariate analysis included timing of surgery, age, laterality, presence of midline shift, hemorrhage or multiple territory infarction. we identified patients who met inclusion and exclusion criteria. the median age was ( to ), -nine percent of patients received surgery by hospital day . full statistical analysis is pending. our hypothesis is a positive correlation between icu severity scores and mortality. given apache ii and sofa scores capture the effects of acute and chronic disease that would affect patient recovery, we hope to provide a more comprehensive prognostication of outcomes following surgery to help guide physicians and family members of these patients in their decision-making process. we conducted this study to investigate the effects of decompressive craniectomy (dc) combined with hypothermia on mortality and neurological outcomes in patients with large hemispheric infarction. within hours of symptom onset, patients were randomized to one of the following three groups: dc group, dc plus head-surface cooling (dcsc) group and dc plus endovascular hypothermia (dceh) group. we combined the data of the dcsc and dceh group to dch group during analysis. the primary endpoints were mortality and modified rankin scale (mrs) score at months. there were patients in the dc group, patients in the dcsc group and patients in the dceh group. for all patients, the mortality at discharge and after months was . % ( / ) and . % ( / ), respectively. the dch group had lower mortality, but the difference was not statistically significant (at discharge, . % vs. . %, p= . ; months, . % vs. . %, p= . ). after months, patients survived, and . % of the surviving patients had good neurological outcomes (mrs score of - ). the dch group had better neurological outcomes, but this difference was also not statistically significant ( / , . % vs. / , . %; p= . ). the total number of patients experiencing complications in the dc group and the dch group was ( . %) and ( . %), respectively. treatment with hypothermia led to decreased mortality and improved neurological outcomes in lhi patients who received dc. a multi-center rct is needed to confirm these results. destiny ii investigated hemicraniectomy in patients -years and older for the treatment of malignant cerebral edema. we sought to describe the treatment effect of early hemicraniectomy in destiny ii, using number needed to treat to benefit (nntb) and benefit per hundred (bph) treated at and months. as an mrs of is generally undesirable, we also present nntb and bph excluding this outcome. for all possible dichotomizations of the mrs, net nntb was derived by taking the inverse of absolute risk difference, and net bph by multiplying absolute risk difference by . for benefits simultaneously across all disability transitions on the mrs, nntb, and bph, estimates were derived using joint outcome tables: ) algorithmic minimum and maximum and ) four independent experts. the expert data is presented as geometric mean. the algorithmic nntb was . (range . - . ) at -months and . ( . - . ) at -months, while bph was . ( - ) and . ( - ). the expert nntb was . ( . - . ) at -months and . ( . - . ) at -months, and the bph was . ( - ), and . ( - ) respectively. excluding mrs the algorithmic nntb was . (range - . ) at -months and . ( . - . ) at -months, while bph was ( - ) and . ( - ). the expert nntb was . ( . - . ) at -months, and . ( . - . ) at -months, and bph was . ( - ) and . ( - ) respectively. early systematic hemicraniectomy improves outcome (including mrs ) for every - patients treated. excluding patients with mrs , hemicraniectomy improves outcome for every . patients treated. the algorithmic range provides bounds to the data, while the expert geometric mean provides the most accurate point estimate. these data provide a powerful tool to describe the potential treatment outcomes to families during the first day following a malignant middle cerebral artery infarction. background cerebral bypass surgery is performed to restore, or revascularize blood flow to the brain. previous studies have not shown whether emergency surgical reperfusion therapy may be effective in acute ischemic stroke patients with large artery occlusion and hemodynamic deterioration. objective to evaluate the effect of emergency sta-mca bypass surgery on the outcome of hemodynamic compromised patients who had progressive or fluctuating stroke despite best medical treatments. we retrospectively reviewed the clinical and radiological data of consecutive patients treated by both emergency bypass surgery ( cases, . %) and elective bypass surgery ( cases, . %) due to large artery occlusion at a single center. the effect of surgical therapy was measured with the modified rankin scale (mrs) at months. clinical severity was evaluated by the national institutes of health stroke scale (nihss) between pre-and post-operative state. major perioperative complications were defined as any hemorrhagic stroke, myocardial infarction and death. results occlusive sites were the cervical internal carotid artery in ( . %) patients and the middle patients in emergency surgery group and ( . %) patients in elective surgery group. emergency bypass surgery improved nihss (preoperatively, [ - ] ; weeks postoperatively, [ - ]). major perioperative complications in days were happened in three patients ( . %) after emergency bypass surgery, and four patients ( . %) after elective bypass surgery. emergency revascularization surgery may be effective alternative treatment for acute ischemic stroke patients with hemodynamic deterioration refractory to maximal medical treatments without significant complications. larger randomized clinical study is needed to evaluate the effect of emergency revascularization surgery in acute hemodynamic deterioration. multiple studies have reported lower mortality rates in obese patients with various cardiovascular disorders, a phenomenon called as the 'obesity paradox'. such relationship has been largely unreported in patients with neurological pathologies especially stroke. this study reports the effect of obesity on prognosis in patients with ischemic stroke. analysis of national inpatient sample data ( - ) showed a total of , , patients discharged with primary diagnosis of is, icd- code .xx and .xx. patients with obesity were identified using agency of healthcare research and quality (ahrq) criteria. we used binary regression to compare inhospital mortality between obese and non-obese patients with ischemic stroke. from - , , , patients with ischemic stroke were identified of which . % were found to be obese. obese patients with ischemic stroke were more often younger, female, and african american as compared to caucasian. after risk adjustment for demographics, and baseline comorbidities, obese patients with ischemic stroke had lower observed in hospital mortality as compared with non-obese patients with ischemic stroke ( . % vs %, or: . ci= . - . p< . ). from an eleven year nationwide cohort of patients with ischemic strokes, we observed a significant protective effect of obesity and better prognosis including a lower mortality rate. more prospective studies are warranted to further analyze this counter-intuitive trend. very early mobilization of critical care patients improves outcome, length of stay, and patient satisfaction. data for efficacy of very early mobilization for stroke patients have been mixed, and there is limited outcomes data for patients mobilized within hours of receiving intravenous alteplase (iv tpa). the objective of this retrospective observational study was to determine if patients receiving iv tpa who were mobilized earlier were more likely to discharge home. medical records of ischemic stroke patients who received iv tpa between and at two urban facilities were reviewed for mobility protocol activities. patients who received endovascular treatment, were placed on comfort care day zero or one, mobilized after the first hours, and transferred out or left against medical advice were excluded. multinomial regression was used to determine if there were significant differences in patients' discharge status by time first mobilized, adjusting for stroke severity using the national institutes of health stroke scale (nihss), age and gender. of the patients included, . % (n= ) were female, mean age was . (± . ), and the median admit nihss was . [iqr: . , . ]. the median time first mobilized was . hours [iqr: . , . ], . % (n= ) of patients were discharged to home, . % (n= ), a skilled nursing facility (snf), . % (n= ), an inpatient rehab facility (irf), and . % (n= ) hospice or expired. there was suggestive, but inconclusive evidence for a relationship between time first mobilized and discharged to snf versus home (p=. ). for every one hour increase in time mobilized, patients were . ( % ci= . - . ) times more likely to be discharged to snf than home. this study reveals very early mobility is potentially efficacious after iv tpa. longer time to first mobility was associated with discharge to skilled nursing facility, although this was not statistically significant. medical management of cerebral edema after large volume stroke varies greatly across institutions. hypertonic saline has emerged as a common treatment strategy to attempt to reduce edema and theoretically prevent the need for decompressive hemicraniectomy. there is no established protocol for hypertonic saline administration and there have been concerns regarding safety. in a single-center, retrospective analysis we identified patients who received hypertonic saline for malignant edema after an ischemic stroke involving the entire hemisphere or diffuse middle cerebral artery (mca) territory. we compared patients who received continuous infusions of % or % hypertonic saline to those who received continuous infusions with boluses of . %. the primary endpoint was time to goal sodium ( ). secondary endpoints included the need for surgical decompression and adverse events. we included patients who received only continuous infusions of hypertonic saline and patients who received a combination of continuous infusions and bolus doses. we found no significant difference between number of patients who reached goal sodium ( vs respectively, p= . ) or time to goal sodium ( hours vs . hours, p= . ). there was a significant difference in the number of patients who underwent surgical decompression ( vs , p= . ). there was not a significant difference in the rate of acute kidney injury or development of acidosis between groups ( vs. , p= . ). both hypertonic strategies appear to be safe. bolus dosing, on review, was more often instituted during clinical deterioration, accounting for the higher rate of surgical intervention. we feel we can safely be more aggressive earlier in the clinical course to potentially avoid surgical decompression. furthermore, we may need to look more closely at our target sodium, evaluating whether it should be based on the patient's baseline sodium or a universal value. even though recanalization is strongly associated with improved functional outcomes and reduced mortality, clinical benefit from thrombolysis is reduced as stroke onset to treatment time increases. in the recent study, endovascular treatment(evt) has been demonstrated to improve functional outcome in patients with acute ischemic stroke (ais) within the time window of onset to or hours. however, beyond usual thrombolysis time window, early neurologic deterioration(end) related with proximal artery occlusion is not uncommon in ais. with this, we report ais case series treated with evt because of end related proximal artery occlusion. from january through march , all patients underwent iat for ais with anterior circulation stroke. among them, twenty-four patients underwent evt due to end. at admission, all twenty-four patients showed near to complete occlusion of a proximal artery and had diffusion-perfusion mismatch. mean age was . initial median initial national institutes of health stroke scale (nihss) was and nihss after end was . all patients had diffusion-perfusion mismatch over %. seven patients treated with iv-tpa before evt. good recanalization (tici b/ ) was achieved in . %. the hemorrhagic complication was seen in the follow-up computed tomography scan in of cases: three were hemorrhagic transformation, another was the subarachnoid hemorrhage. the thromboembolic mortality case. in our report, evt in ais with end achieved safe and successful recanalization. and successful recanalization was associated with good clinical outcome. we think evt could be a useful method in case of end in ais patients with proximal artery near to complete occlusion, even beyond usual to hours time window for evt. jugular bulb venous monitoring can provide information about cerebral hemodynamics and metabolism. we investigated the feasibility and clinical application of jugular bulb venous monitoring in acute ischemic stroke patients at neurocritical care unit. from march to june , we conducted jugular bulb venous monitoring in patients in a tertiary referral hospital. five patients were excluded; without ventilator care and other diseases than stroke. jugular venous catheters were placed in internal jugular vein by ultrasound-guided method. lactate, venous oxygen saturation (sjvo ), and arteriovenous oxygen saturation differnece (avdo ) were monitored every hours. metabolic derangement was defined when lactate level was more than . mmol/l. patients were divided according to presence of clinical deterioration. for long-term prognosis, modified rankin scale - at months were defined as poor outcome. twelve patients ( . %) showed metabolic derangement and they experienced more frequent clinical deteriorations compared to patients without metabolic derangement (n= , . % vs. n= , . %, p= . ). clinical deterioration was noted in patients, and lactate level was significantly higher in the presence of clinical deterioration group ( . ± . vs. . ± . mmol/l, p= . ). adjusting other potential variables (age, baseline stroke severity, sjvo , and avdo ), metabolic derangement was an independent factor associated with clinical deterioration (or . , % ci . - . , p= . ). meanwhile, poor outcome group (n= ) showed no difference on lactate level, but avdo were higher in poor outcome group ( . ± . v. . ± . , p= . ). avdo remained an independent factor for poor outcome after multivariable logistic regression analysis (or . , % ci . - . , p= . ). this study showed that lactate was associated with clinical deterioration during neurocritical care, whereas venous desaturation contributed to long-term prognosis. jugular bulb venous monitoring is a feasible tool in patients with acute ischemic stroke at neurocritical care unit. swift recognition of stroke symptoms, immediate access to testing and timely treatment plays a vital role in functional outcomes (middleton et al., ) . delays can postpone treatment and complicate recovery. delays at this facility included registration, order entry times, and imaging. pi included evaluating and eliminating interruptions, with a goal of reducing the time to treatment. process improvement (pi) utilized an evidence-based algorithm to improve performance metrics and treatment of acute strokes. setting was a suburban, ancc magnet recognized primary stroke center with beds in the ed that experiences , ed visits and , admissions per year. patients included in the acute stroke protocol presented with signs and symptoms of stroke and last known well within hours of symptom onset. participation included ed staff, and staff working in areas impacted by stroke care. code stroke was initiated for patients who fit the criteria. an overhead page was implemented notifying the team throughout the hospital. radiology would prioritize ct and call the ed as soon as ct was ready. in the meantime, ed team continued assessments. with ct resulted, the physician would determine whether the patient was eligible for tpa. the acute stroke protocol included a list of inclusion/exclusion criteria for tpa administration. other treatment requirements included reminders for frequency of vital signs, neuro checks and assessments. implementation began in may and the team began to see a significant decrease in ct times and better compliance of dysphagia screening and nih assessments. ct tat completed within minutes increased from % to %. nih stroke scale completion rose from % to %. compliance with completing dysphasia screening increased from % to %. results stem from a commitment to excellence from the entire team. pi continues to further improve care for stroke patients. induced hypertensive therapy (iht) has used to enhance cerebral perfusion pressure in subarachnoid hemorrhage and stroke, but there is no established indication for iht in ischemic stroke. we report the usage of iht in acute ischemic patients with hemodynamic instability caused by steno-occlusive disease of a main cerebral artery. we reviewed acute ischemic stroke patients with cerebral perfusion deficit due to intracranial and extracranial steno-occlusive disease. iht was applied for early neurological deterioration and maintained until hemodynamic instability was stabilized over hours or neurointervention including angioplasty and extracranial intracranial arterial bypass surgery were performed. patients were analyzed. territories of stroke were of anterior circulation of intracranial vessels, of posterior vessels, and of extracranial vessels. mean duration of ih therapy was . minutes. pre and post nihss score of ih therapy was . and . , respectively. patients ( . %) were showed improvement and patients ( %) were stabilized without further aggravation. patients revealed bradycardia. there was no fatal complication of therapy. patients were performed further treatment include bypass surgery, angioplasty, and stenting after ih therapy. at months follow up, patients showed good outcomes (modified rankin scale , , and ). iht may be safe and effective for the neurologic deterioration or progression of acute ischemic stroke with hemodynamic instability due to severe steno-occlusive disease of major cerebral artery. large randomized trials are needed to confirm this result. most patients with progressive stroke have a poor prognosis. the aim of our study was investigate the factors related with progressive neurologic deficit (pnd) in the patients receiving recanalization therapy for acute ischemic stroke. -month period, were enrolled. blood pressures (bps) at , , and hours after admission and bp variation (bpv) for the first hours were collected. variables associated with pnd were analyzed. among enrolled patients, patients showed pnd. the patients with pnd had higher systolic bps at , , and hours after admission and higher bpv than the others (p < . ). posterior circulation stroke was more prevalent in the patients with pnd (p < . ). in logistic regression analysis, pnd was independently associated with posterior circulation stroke [odds ratio (or) = . , p < . ] and systolic bp at hours after admission (or = . , p = . ). pnd may be associated with elevated systolic bp for the first hours after admission in the patients receiving recanalization therapy for acute ischemic stroke. telestroke has revolutionized stroke care delivery in the modern era. massachusetts general hospital (mgh) uses the most common model, the hub and spoke. the demonstration of superiority of endovascular therapy (et) with intravenous tpa over tpa alone for acute stroke patients with large vessel occlusions prompts a thorough assessment of telestroke's role in the delivery of et, particularly in terms of transferring patients to hubs capable of et. our primary objective was to examine associations between transfer time and clinical outcomes. patients were selected from the get with the guidelines-stroke registry who were transferred to mgh from jan to oct who had nihss> and last known well< h on mgh arrival (n= ). we excluded patients for whom we could not calculate the primary predictor, transfer time (defined as the mgh arrival time minus the telestroke consult answered time, n= ). several clinical outcomes were explored by linear and logistic regression to determine association with transfer time. of the patients in the study, ( %) were transferred by ambulance, ( %) by helicopter, and ( %) underwent et at mgh. median transfer time was min, and median aspects decrease was during transfer. longer transfer time was associated with decreased likelihood of undergoing et (p= . ). however, transfer time was not significantly associated with aspects decrease during transfer. for those patients undergoing et, transfer times bore no association to day mrs. this study identifies an association between longer transfer time and decreased likelihood of undergoing et. reasons are varied, and are not clearly related to imaging progression alone. only % of transferred patients underwent et. more efficient spoke triage and transfer may improve the ratio of patients treated with et. these data provide an important perspective during this period of stroke triage evolution. intra-arterial thrombectomy (iat) has been approved for acute treatment of ischemic strokes (is). with the advent of several new devices for iat, this procedure has become more widely utilized with better outcomes. we performed this analysis to evaluate trends and predictors of utilization of iat over an year period. analysis of nationwide inpatient sample data ( to ) showed a total of , patients discharged with a primary diagnosis of is, icd- code .xx, and .xx. iat was ascertained by icd- procedure code . . independent predictors of iat were studied using binary logistic regression. the predictors included in the model were age, sex, race, teaching status, and insurance type. results or . % of is patients received iat. mean age of patients receiving thrombolysis was . years. percentage of is patients receiving iat has consistently increased from . % in to % in . we also observed significant year to year decrease in mortality among patients receiving iat. in , . % of iat patients died as compared to . % in . using binary logistic regression, the statistically significant independent predictors of iat utilization were age (or= . , p= . ), female gender (or= . , p= . ), insurance type as compared to medicare (private insurance or= . p= . , and self-pay or= . p= . ). as compared to caucasians, african americans were less likely to receive treatment (or= . p= . ). also, a teaching hospital was found to be more likely to administer iat as compared to a non-teaching hospital (or = . , p= . ). is patients with younger age, female gender, private insurance and patients admitted to teaching hospitals are more likely and african americans are less likely to receive iat. this study showed that iat utilization has increased significantly since with a steep decline in the in-hospital mortality. this may point to improved iat devices and better patients' selection. telestroke plays an integral role in stroke care. nationally the most common model is the hub and spoke, which is used at our institution. understanding telestroke's role in the transfer of candidate patients for endovascular therapy (et) is critical to minimizing delays. our primary objective was to evaluate predictors of transfer delay. patients were selected from the get with the guidelines-stroke registry who were transferred to mgh from jan to oct with nihss> and last known well< h on mgh arrival (n= ). we excluded patients for whom we could not calculate transfer time (the mgh arrival time minus the telestroke consult answered time, n= ). ideal time was calculated using google maps incorporating date/time information for ground transfers and straight line distance at mph for helicopter transfers. ideal time was subtracted from actual time to calculate delay, accounting for distance, mode of transport, weather, and traffic. analysis of covariance was used to explore possible predictors of delay (night vs. day, weekend vs. weekday, tpa delivery at spoke). of the patients in the study, ( %) were transferred by ambulance, ( %) by helicopter, and underwent et. a significant proportion of the variation in delay was explained by the predictors (f= . , p< . ). nocturnal transfer ( - hrs) was associated with significantly longer delay ( . additional minutes relative to daytime transfers, p< . ). weekend vs. weekday transfer and tpa delivery at spoke hospital did not contribute significantly to model variance. our findings highlight the importance of refining protocol approaches. nocturnal transfers were associated with substantial delay relative to daytime transfers. in contrast, delivery of tpa was not associated with delays, underscoring the impact of effective protocols that are in place. metrics and protocols for transfer, especially at night, may have a positive impact on transfer times. the use of anticoagulant therapy in the acute stage of ischemic stroke is controversial. novel oral anticoagulant (noac) is effective in preventing recurrent embolism in patients with non-valvular atrial fibrillation (nvaf), but the risk of hemorrhagic transformation is the major concern for its early use in ischemic stroke. we aimed to study the use of noac in patients with acute ischemic stroke and nvaf. patients with acute ischemic stroke and nvaf, who were admitted to our acute stroke unit from to , were recruited in this single-centre cohort study. the timing of initiation of noac is at the discretion of the treating physician based on the stroke severity and infarct size. nvaf attributed to . % ( / ) of all ischemic stroke cases. the early recurrent embolism rates were . %, . % and . % at one week, two weeks and one month respectively. noacs were prescribed in patients. noacs were initiated within one week in patients ( . %). the median time to noac initiation were five days (iqr . - . ), nine days (iqr . - . ) and days (iqr . - . ) for patients with no/small-sized infarct, moderate-sized infarct, and large-sized infarct respectively. at one month, two patients had recurrent ischemic stroke despite treated with noac. only one patient, who had a large-sized infarct, developed symptomatic hemorrhagic transformation. early use of noac in ischemic stroke appears to be safe. further large prospective studies are required to evaluate the risk and benefit of noac use in acute ischemic stroke. osmotherapy (hypertonic saline or mannitol) is the mainstay of available therapy to counter cerebral edema that can develop after large hemispheric infarction. in a post-hoc analysis of the games-rp trial, we hypothesized that patients with large infarction, treated with intravenous glyburide, might require less osmotherapy than placebo treated patients. games-rp was a multi-center prospective, double blind, randomized, placebo controlled study which enrolled patients with large anterior circulation infarction. patients were randomized to iv glyburide administration (biib ; n= ) or placebo (n= ) with target time from symptom onset to drug infusion decompressive craniectomy (dc), or both. total bolus osmotherapy dosing was quantified by an "osmolar load" (volume in l * osmolarity in mosm/l). of the subjects, the percentage of patients who received bolus osmotherapy did not differ between the glyburide and placebo treated subjects ( % v. %; p= . ). there was no difference in mean total osmolar load received (mosm) or hours from drug bolus to osmotherapy administration. overall, subjects received osmotherapy. the baseline dwi lesion volume (ml) was significantly larger in the osmotherapy treated group ( . ± . v. . ± . ; p= . ). the presence of adjudicated malignant edema on imaging was more common in the osmotherapy group ( % v. %, p= . ), as was dc ( % v. %; p< . ). among patients with adjudicated clinical neurologic deterioration from edema, % (n= ) did not receive osmotherapy. treatment with iv glyburide was not associated with less osmotherapy, possibly due to a ceiling effect resulting from the large infarct volumes. however, osmotherapy use was associated with larger infarct volumes, malignant edema, and higher incidence of dc. use of osmotherapy did not always follow the appearance of clinical or radiographic malignant edema. acute ischemic stroke patients receiving intravenous alteplase (iv-tpa) are placed on bedrest for hours or longer due to provider fear of worsening stroke symptoms from decreased cerebral perfusion. this is based on medical uncertainty and lack of robust studies, despite american stroke association (asa) recommendations for mobilization when hemodynamically stable. this retrospective observational study evaluates very early mobility in acute ischemic stroke patients post iv-tpa while evaluating for change in nihss. medical records of ischemic stroke patients who received iv-tpa between and at two urban hospitals were reviewed for mobility protocol activities. patients who were given endovascular treatment, placed on comfort care on day zero or one, mobilized after the first hours, transferred out or left against medical advice were excluded from the analysis. multiple linear regression was used to determine if those patients mobilized earlier saw a greater change between nihss at admit and hours post iv-tpa administration, adjusting for age and gender. of the patients included in the final analysis, . % (n= ) were female, mean age was . the multiple linear regression results showed no significant relationship between change in nihss from admit to hours post iv-tpa and earlier mobilization, after adjusting for age and gender (ß= - . change in nihss points per hour; p= . ). this study reveals early mobility does not worsen stroke symptoms or severity based on nihss. this suggests that very early mobility of patients after iv-tpa is safe as recommended by asa. interhospital transfers to a stroke center following iv-tpa administration are increasingly common. however, no studies have evaluated icu needs in these transfer patients and such understanding may have a significant impact on resource utilization. the aim of this study is to compare the frequency, timing, and nature of icu-level needs in post-iv-tpa patients that were transferred versus those who present directly to the admitting hospital. retrospective chart review of consecutive, tpa-treated ischemic stroke patients admitted to the icu at a comprehensive stroke center servicing a large telestroke referral network from / to / was performed. we evaluated patient demographics, stroke characteristics, and icu needs between transfer and non-transfer patients before and after icu admission. results patients were admitted to the icu post-tpa. patients ( . %) were transferred from an outside hospital, of which patients had icu needs ( . %). this frequency of icu needs was no different when compared to the non-transfer patients ( / , . %, p = . ). similar icu needs were observed for each specific icu intervention between transfer and non-transfer patients (iv antihypertensive, vasopressor requirement, iv rate control, respiratory support, ia therapy, icp monitoring, hypertonic therapy, and neurosurgical intervention, all p > association with icu needs (or . in transfer patients, or . in non-transfer; both p < . ). transferring post-iv-tpa patients is not associated with increased icu needs. about one-half of post-tpa patients do not have icu needs, and these patients typically have milder stroke severity. our data supports the safety of transferring post-tpa patients, and to potentially monitor a subgroup of these patients in a non-icu setting. the ability to appropriately triage post-tpa patients may lead to more efficient and cost-effective stroke care. stroke patients requiring decompressive craniectomy remain at high risk of prolonged mechanical ventilation as well as ventilator associated pneumonia (vap). early tracheostomy placement may provide a reduction in the duration of mechanical ventilation however prediction of those who ultimately require a tracheostomy remains a clinical challenge. a preoperative assessment of tracheostomy dependence may help to guide decision making. the authors compare key outcome data after early versus late tracheostomy and develop a preoperative decision-making tool to predict postoperative tracheostomy dependence. a subsequent validation utilizing a decision tree analysis applied prospectively is ongoing and will be presented. we performed a retrospective analysis of prospectively collected registry data and developed a propensity weighted decision tree analysis to predict tracheostomy requirement utilizing factors present prior to surgical decompression. outcomes include probability functions for icu los, hospital los, and mortality based on data for early ( day) tracheostomy. a subsequent validation of the decision tree is being applied prospectively to evaluate its predictive value. a total of surgical decompressions were performed on patients with acute ischemic or spontaneous hemorrhagic stroke between - . forty eight patients ( . %) required a tracheostomy, whereas ( . %) developed vap, and ( %) survived hospitalization. mean icu and hospital los were . and . days respectively. utilizing gcs, sofa score and hydrocephalus presence, our decision tree analysis provided a % sensitivity and % specificity for tracheostomy prediction. early tracheostomy conferred significantly fewer ventilator days (p< . ) and shorter hospital los (p= . ) with similar vap and mortality rates between groups. early tracheostomy shortens duration of mechanical ventilation and length of stay following surgical decompression for stroke, however without a demonstrable impact in mortality or vap rates. a preoperative decision tree awards a practical tool that may provide insight to guide preoperative decision-making with patient families. patients suspected acute stroke are critical in time delay of endovascular or intravenous thrombolytic therapy. prehospital notification from emergency medical services (ems) may shorten the door to recanalization time. the 'brain saver', web-based prehospital notification system could reduce the time interval from symptom onset to recanalization. beginning in march , stroke team consisted of stroke specialized doctors, nurses and radiologists of multi departments received direct alarms via smart phone application from paramedics of ems about transport information of patients with suspected stroke. we compared baseline characteristics and prehospital/ in-hospital delay time in stroke patients treated with intravenous thrombolysis or endovascular treatment for months with and without ems use brain saver protocol. patients ( patients with protocol and patients without protocol) were enrolled in this program. the patients who used brain saver had shorter median onset-to-arrival times ( minutes versus minutes, p < . ) and in in-hospital delay time ( minutes versus minutes, p<. ). prehospital notification by brain saver was associated with shorter median door-to-imaging time ( minutes versus minutes, p<. ), door-to-needle time ( minutes versus minutes, p <. ), door to puncture time ( minutes versus minutes, p < . ) we found that prehospital notification was associated with faster door-to-imaging time, door-to-needle time and door-to-puncture time in patients presenting within hours of symptom onset. close collaboration between stroke team in hospitals and the ems system gives stroke suspected patients an in-time emergency care system. infection is a common complication in the acute phase after ischemic stroke. furthermore, malnutrition is associated with unfavorable outcome in patients with stroke. therefore, we investigated that premorbid undernutrition identified by objective and quantitative method, nutritional risk index (nri) was related to the risk of infection after ischemic stroke. a consecutive patients who were admitted within days after ischemic stroke onset between october and october were included. we assessed initial nutritional status using nri, and nri formula as follows: nri = ( . × serum albumin, g/dl) + { . × present weight (kg)/ideal body weight (kg)}. the patients were categorized into three groups on the basis of nri [no risk (nri > . ), moderate risk (nri . - . ), and severe risk (nri < . )]. we compared the clinical characteristics and nri according to the presence of infection. among the included patients (mean age, . years, male, . %), ( . %) patients experienced infection during hospitalization. the rate of pneumonia was . % (n= ), and the rate of urinary tract infection was . % (n= ) among total infection. the proportion of lower nri patients (moderate risk and severe risk) was significantly greater in the infection group ( . % vs. . % and . % vs. . %, p < . ). moreover, higher nri patients were less likely to be admitted to the intensive care unit ( . % vs. . % vs. . %, p = . ). a multivariate analysis revealed that lower nri groups had a higher risk of infection [odds ratio ( % confidence interval); moderate risk . ( . - . ); severe risk . ( . - . ), p for trend = . ]. our study demonstrated that the lower nris predicted infection complications and severe infections after ischemic stroke. this suggests that assessment of nutrition depletion could be a useful predictor and a modifiable risk factor for infection following stroke. cyp c plays a major role in the metabolism of the clop[idogrel. cyp c generates an active oxidized metabolite of clopidogrel that exerts antipl;atelet activity by inhibiting p y reeceptor. the major alleles of the cyp c gene are * , * , * and * and approximately % of caucasians and % of asians have one or more loss of function alleles in this study, patients with at least two * or * allels were classified as poor metabolizer(pm), those with one * or * allele were classified as intermediate metabolizer(im), and those without a * , * or * alleles were classified as extensive metabolizer. in addition. those with (* /* or * /* ) were classified as unknown metabolizer. stroke patients were enrolled for this trial. the mean age was years, and % were women. % had a history of hypertension, % of dm and % of dyslipidemia. of the participants, % were classifies as em, % as um, % as im, % as pm and % as unknown metabolizer. % had good genotype for clopidogrel metabolism and % had poor genotype. there were no significant diffirences in the demographic and clinical findings between the good and poor genotype groups the prevalence of cyp c polymorphisms is different according to the ethnicity. the racial difference in platelet function may lead to diffrerences in the treatment as well as new targets for antiplatelet therapy the social brain hypothesis is an evolutionary theory proposing that the number of contacts in a primate's social network is proportional to neocortical volume. we tested the hypothesis in a patient population with social network data before and after vascular events. we studied whether social network indices would decrease after stroke, but not after myocardial infarction (mi), as anticipated by the theory. we examined trajectories of the lubben social network scale score (range - , higher values indicating larger network) before and after vascular events in participants from the cardiovascular health study. we used a repeated measures design with linear mixed models to compare the change in social network score before and after events in persons with ischemic stroke and with mi. over a mean of . years of follow-up for stroke and . years for mi, we examined an average of social network scores for each participant. we controlled for socio-demographics, baseline cognitive function, and comorbidities. social network scores declined significantly after stroke (an additional - . points every year, % ci - . , - . , p= . ), but not after mi (- . , % ci - . , . , p= . ) compared to the baseline slope in fully adjusted models. social network score declined more steeply after stroke than after mi, even after adjusting for potential confounders. these findings support the social brain hypothesis but do not address mechanism. shrinkage of the social networks may be a specific target for interventions to optimize recovery in vascular diseases, particularly stroke. emergency neurological life support (enls) protocols are an essential component to assessment and management of patients within the first hours of the neurological emergency. with increasing focus on emergent endovascular treatment for large vessel occlusion (lvo) in acute ischemic stroke our institution incorporated stroke van assessment as part of the enls acute stroke initial assessment protocol. stroke van screening tool was taught to all nurses in the emergency department (ed) who triage stroke. all patients who presented to the ed with suspected stroke had a van assessment completed prior to ed physician evaluation and ct imaging. patients with weakness in addition to visual changes, aphasia, or neglect were considered van + and triaged immediately to ct angiogram head/neck with immediate notification to the neurointerventionalist. a sample of patients presenting to the ed as a stroke alert over an month time period were utilized. using the stroke van assessment tool was found to improve time to identification of lvo by reducing time from arrival to cta for van positive patients from minutes pre-intervention (n= ) to minutes post-intervention (n= ). this was a significant decrease in time to identification of patients presenting with lvo (p< . ), improving time to endovascular treatment. incorporating stroke van as part of the acute stroke assessment protocol improved identification of patients presenting with lvo, decreased time to cta imaging and improved time to endovascular treatment which is well documented with improved neurological prognosis. time is essential in neurological emergencies. the van assessment is quick and easy to perform, requires no scoring or calculations, and is the only lvo screening tool tested in the ed by ed nurse and physicians. we suggest incorporating stroke van to the enls acute stroke protocol as a way to improve identification of lvo and improve time to endovascular treatment. elevated blood pressure (bp) is known to be related to hemorrhagic transformation (ht) after ischemic stroke. however, the effect of bp variation on the ht remains unclear, especially in patients with successful recanalization after mechanical thrombectomy. therefore, we investigated the relationship between bp and ht after mechanical thrombectomy following ischemic stroke. a consecutive patients with acute ischemic stroke and successful recanalization (tici b or tici ) were included for the analysis between january and november . the information on bp was obtained over the first hours using various parameters including mean, maximum (max), minimum (cv), and successive variations (sv) for systolic, diastolic bp, and mean bp. we defined major ht as a parenchymal hematoma type (ph ). among the included patients (age, . ; and male, . %), patients ( . %) developed major ht over the first hours after successful recanalization. systolic bp max-min was significantly increased in patients with major ht compared to those without major ht ( . mmhg vs. . mmhg, p = . ) while other bp parameters were not. in addition, systolic bp max-min was significantly associated with symptomatic ht (n= , . %, p = . ). after adjusting for confounders, systolic bp max-min was independently associated with major ht (odds ratio, . ; % confidence interval, . - . ). our results demonstrated that absolute change of systemic bp over the first hours was associated with major and symptomatic ht after successful mechanical thrombectomy after acute ischemic stroke. this suggests that maintaining stable systolic bp is an important factor in possibly preventing major ht after successful recanalization. the benefits of intravenous tissue-plasminogen activator in acute ischemic stroke are highly timedependent. however, there are so many cross-departmental tasks to eligible patent that many stroke centers have difficulty achieving the guideline recommended -hour door-to-needle (dtn) time. we have developed web based visual task management system called "task calc. stroke" (tcs) by using information and communication technology. herein, we performed a trial installation and preliminary evaluation of tcs. the application software of tcs was designed to run on the google cloud platform. tcs alerts the relevant hospital staff to the patient's arrival condition and time, and displayed tasks to be performed and its treatment status by changing color in real time on networked wall-mounted smart devices in the several relevant departments. we started a trial installation of tcs during the daytime from august . we compared lead times before (august to july ) and after (august to july ) trial installation of tcs. trial installation of tcs in our hospital showed successful information sharing. a total of patients included (pre: , post: ) . after the installation, significant reductions occurred in the median time from door to complete blood count time [ . vs. . min, p < . ] and a trend toward a reduction from door to needle time [ . vs. . min, p = . ]. tcs may be useful tool to reduce the lead times of acute stroke patients. tcs is a new approach that has the potential to promote efficiency for acute stroke care. prior history of intracranial hemorrhage (ich) has been considered a contraindication to administration of intravenous recombinant tissue plasminogen activator in acute ischemic stroke, per the original activase fda label and aha/asa guidelines. however, limited data are available on the risks of lysis in patients with prior ich. we performed a cross-sectional study of adult patients who received thrombolysis, using administrative claims data on admissions to acute care hospitals in california between - . diagnosis codes were used to identify patients who received thrombolysis, and to ascertain ( ) a prior diagnosis of ich, including intraparenchymal hemorrhage (iph), subarachnoid hemorrhage (sah), subdural hematoma (sdh), or epidural hematoma (edh); and ( ) relevant comorbidities, including hypertension, smoking, diabetes, heart failure, atrial fibrillation, renal disease, malignancy, and demographic data. we used univariable and multivariable logistic regression to model the odds of in-hospital mortality as a function of prior ich, after adjusting for potential confounders. , patients received thrombolysis during the study period (mean age [sd ], female count , [ %]). of these, patients ( . %) had a documented diagnosis of prior ich on admission. inhospital mortality was % overall, . % for patients without prior ich, and . % for patients with prior ich. in multivariable analysis, all prior ich subtypes remained independently associated with in-hospital mortality, including iph (or . , ci . - . , p < e- ); sah (or . , ci . - . , p < e- ); and sdh (or . , ci . - . , p= . ). only patients had edh and testing was not possible. . % of patients who received thrombolysis during the study period had prior diagnosis of ich. prior ich was found to be significantly associated with in-hospital mortality regardless of ich subtype. we evaluated the association between early neurological improvement (eni) after ert and time spent from symptom onset to recanalization, according to the degree of collateral circulation measured using multiphase cta. patients with anterior circulation occlusion who underwent ert based on a non-contrast brain ct and multiphase cta were evaluated. collateral status was evaluated using a pial arterial filling score, which was developed into a six-point scale. eni was defined as equal to more than %, or as an -point decrement in nihss from baseline. neurological statuses at day and at day (or discharge) were determined by a certified neurologist using nihss. the collateral circulation degree measured by multiphase cta was inversely correlated with baseline stroke severity (p= . ). the proportion of eni at day was significantly lower in patients with poor collateral status (score ~ ) according to the time from symptom onset to recanalization ( - , . %; - , . %; > , . %; p= . ). however, the proportion was similar in patients with a good - , . %; - , . %; - , . %; > , . %; p= . , day or discharge; - , . %; - , . %; - , . %; > , . %; p= . ). collateral status was the best predictor for eni after ert. eni was achieved in only ( . %) patients with poor collateral status, and their time from symptom onset to recanalization was more than minutes. the time window for ert might differ according to baseline collateral status measured by multiphase cta. the current time window for ert within hours from symptom onset to groin puncture could be atrial fibrillation (af) is the most common cardiac arrhythmia among adults. despite of the proven advantage in primary and secondary stroke prevention in patients with af, antithrombotic therapy has been reported to be still underused in many countries. however, there is a little data about the incidence of af and any changing pattern of antithrombotic therapy among patients with af over the past decade in korea. data source for this study were obtained from the nationwide sample cohort comprising , , individuals ( % of entire population in korea) which were established by nationwide health insurance system. during a -year follow-up period, there was , developed af ( . %). the incidence of patients with af remained relatively constant during study period ( . % in vs . % in ). the proportion of patients with antithrombotic therapy increased from . % in to . % in significantly (p for trends < . ). however, the proportion of patients with antiplatelet agents was higher than with oral anticoagulation. af steadily increased over recent years in korea. however, only . % of af patients were receiving antithrombotic therapy. our study demonstrated that there was huge gap between the clinical practice and treatment guideline in antithrombotic medication for af patients in korea over the past decade. ohiohealth (oh) possesses one of the nation's largest neuroscience programs and is the leading volume provider of stroke care in ohio. oh is comprised of hospital-based sites, primary stroke centers, comprehensive stroke center, and a virtual health (vh) stroke network that serves hospitals throughout the state. in august , stroke services at ohiohealth were restructured to enable dedicated clinical time for vh providers, require expertise, training, and quality review participation for stroke responders, streamline activation algorithms to limit hand-offs, and eliminate identified barriers to vh consultation. a month interim analysis was planned to assess the impact of these changes (termed "stroke . "). comparative analyses were performed between the first months of stroke . and the similar time period of the year prior to restructuring. pre-defined metrics included consultation volume, vh response time, iv-tpa time to treatment, research enrollment volume, endovascular referral rate and time to treatment, ischemic stroke (is) observed : expected (o:e) mortality data, and patient retention rate at associate vh sites. during the first months of stroke . , encounters were seen (historical ) with a mean activation to vh log in of . minutes. both volume of patients treated with iv-tpa ( vs. , p< . ) and mean treatment times ( vs. minutes; p< . ) were significantly reduced. mean time to endovascular intervention was less during stroke . ( vs. minutes, p < . ). system-wide o: e mortality was reduced after restructuring ( . vs. . , p< . ), accounting for additional lives saved. acute stroke research enrollment doubled ( vs. ) during this same period. transfer rates to vh hub were unchanged ( vs. %, p = . ). strategic changes in staffing, expertise, vh structure, and access can have profound and positive changes on a well-functioning stroke system. strokes due to cns fungal infections (scfi) are often misdiagnosed. retrospective study of electronically-extracted records in patients with strokes & positive fungal studies, from cerebrospinal fluid (csf) or brain biopsy. other stroke etiologies were excluded. thirteen patients had scfi by a priori exclusion & inclusion criteria. nine were males. mean age was + years. symptoms were mild [nihss ( , . ) (median and iqr)]. focal deficits & headaches (both . %) were common. seventy-percent were immuno-compromised (medications, malignancy, transplant recipients). clinical course was indolent in . %. seventy-percent had poor outcome ( -ltac, -snf, -dead). ninety-two percent had csf pleocytosis (range: - ) while % had csf glucose less than mg/dl (range: - ). seventy-five percent had lymphocytic predominance. seven strokes were from yeasts ( -cryptococcus, -coccidiomycosis, -histoplasma, -candida) and from molds ( -zygomycetes, -aspergillus). sixty-two percent had posterior circulation involvement ( . % yeast vs % molds). there was lepto-meningeal enhancement in % of yeast vs. % of molds infections (p= . ). the basal ganglia (bg) was involved in % of intravenous-drug users (ivdu) vs. % of non-ivdu (p= . ). one had abnormal cns vessel imaging directly attributed to the ischemic lesions. in this series, patients were young, immunocompromised or ivdu. stroke sizes & clinical deficits were modest with no angiographic evidence of vasculitis. majority had csf pleocytosis & hypoglycorrhachia. posterior circulation involvement was typical. lepto-meningeal meningitis was only seen in yeast infections. the bg was spared in non-ivdu but common in ivdu. mechanism of stroke in yeast infections is probably from meningitis & secondary involvement of small perforating branches. mechanism in mold infections in immuno-competent ivdu is probably direct angio-invasiveness in small vessels of the bg. outcomes are poor in spite of therapy. scfi should be considered in selected cases of cryptogenic (recurrent or progressive) strokes with clinical, csf and mri features described. life-threatening bleeding requires prompt reversal of factor xa (fxa) inhibitors. their anticoagulant effects can be reversed with the antidote andexanet alfa. the efficacy of andexanet to reverse bleeding in an apixaban anticoagulated porcine trauma model was investigated. after ethical approval, male pigs (n= ) were given apixaban for days ( mg daily); the sham group (n= ) received placebo. standardized polytrauma by blunt liver injury and bilateral femur fractures were inflicted. minutes post-trauma, animals were randomized (n= per group) to a single andexanet bolus ( , mg), a bolus ( , mg) + infusion ( , mg over hours) regimen, or vehicle (control). blood loss (bl) and hemodynamics were monitored over hours or until death and analyzed by anova (mean±sem). apixaban anti-fxa levels were ± ng/ml with no differences between anticoagulated groups prior to injury. bl in the sham animals was ± ml minutes after injury (total bl ± ml at "x" hours; % survival). anticoagulation with apixaban significantly increased bl minutes after injury ( ± ml; p< . ). controls exhibited a total bl of , ± ml with % mortality (mean survival time = minutes). treatment with a bolus or bolus+infusion of andexanet was associated with a significant reduction in bl versus sham (p< . ) and % survival. two hours after injury, apixaban anti-fxa levels in bolus animals were ± ng/ml, whereas the bolus+infusion regimen resulted in levels of ± ng/ml (p< . ). hemodynamic parameters (e.g., cardiac output) and markers of shock (e.g., lactate) recovered to pre-trauma levels in andexanet-treated groups. clinically and macroscopically, no adverse events were observed. in this study, andexanet effectively and safely reversed apixaban anticoagulation and reduced bl induced by severe trauma under anticoagulation. the bolus alone had a similar impact on survival and bl as the bolus+infusion regimen in this lethal porcine model. current guidelines for management of pain, agitation, and delirium in mechanically ventilated patients in the intensive care unit (icu) recommend an analgesia-first approach to sedation management. however, these guidelines are derived from non-neurologic patient populations leaving uncertainty in their generalization to this population. the purpose of this study was to evaluate implementation of an analgesia-first sedation clinical pathway in the neuroscience icu. a single-center cohort study was performed within the neuroscience icu including patients mechanically ventilated for greater than hours over a time period of three months before and after clinical pathway implementation. providers were educated on the pathway with emphasis on frequent assessment of richmond agitation-sedation scales (rass), critical care pain observation tool (cpot), and confusion assessment method-icu (cam-icu) scores and systematic de-escalation of sedatives through adequate pain and delirium management. outcome measures included frequency and magnitude of rass, cpot, and cam-icu scores, analgesic and sedative medication prescription/administration per day of mechanical ventilation (mv). a total of patients met inclusion criteria ( pre-pathway and post-pathway). there was no statistically significant difference in the median frequency of rass ( . vs. . ) and cpot ( . vs. . ) assessments per day of mv or in median rass (- vs. - ) and cpot ( vs. ) scores. mean acetaminophen usage increased from . % to % (p< . ) post-pathway implementation. there was no statistically significant difference in mean opioid or propofol usage, however a trend toward increased morphine and decreased propofol usage was observed post-pathway. analgesia-first sedation pathway implementation trended towards increased opioid analgesic and decreased sedative use, however only increased acetaminophen usage was significant. this highlights challenges in changing unit-based practices and future directions include focus on the frequency and reliability of pain, agitation and delirium assessment. interdisciplinary coordination and communication remains necessary for effective unit-based practice changes. andexanet alfa (andexanet), a modified, recombinant human factor xa (fxa) molecule, binds and sequesters fxa inhibitors. in a phase study of apixaban, rivaroxaban, edoxaban, and enoxaparin in healthy volunteers, andexanet rapidly reversed pharmacodynamic markers of anticoagulation. here, the ability of andexanet to reverse the anticoagulant activity of betrixaban was investigated. in a randomized, double-blind, phase study in healthy subjects, andexanet (n= ) or placebo (n= ) was administered intravenously following mg po qd betrixaban to steady state ( days). in cohort (andexanet bolus only), subjects (n= ) received a -mg andexanet bolus hours after the last betrixaban dose (day ) or placebo (n= ). in cohort (andexanet bolus plus -hour infusion), subjects (n= ) received a mg andexanet bolus hours after the last betrixaban dose, followed by a -hour infusion of andexanet ( mg/min) or placebo (n= ). endpoints included safety and pharmacodynamic markers of anticoagulation reversal. following treatment with betrixaban in cohort , andexanet rapidly decreased anti-fxa activity from . ± . to . ± . ng/ml, while the anti-fxa levels following placebo were largely unchanged ( . ± . to . ± . ng/ml). unbound betrixaban plasma concentration decreased from . ± . to . ± . ng/ml with andexanet, but remained constant following placebo administration ( . ± . to . ± . ng/ml). similar results were observed in cohort following andexanet bolus ( minutes after bolus), and the effects were maintained during the -hour infusion of andexanet. for cohort , thrombin generation was restored in / ( %) and / ( . %) of andexanet-administered and placebo subjects, respectively. for cohort , thrombin generation was restored in / ( . %) of andexanet subjects versus / ( . %) of placebo subjects. andexanet was well tolerated; there were no thrombotic events or serious/severe adverse events. andexanet was well tolerated and rapidly reversed anticoagulation effects of betrixaban in healthy subjects. these and other studies indicate that andexanet could be a universal antidote for fxa inhibitors. andexanet alfa (anxa), a recombinant human fxa molecule, reverses the anticoagulant activity of fxa inhibitors. in studies of healthy volunteers, anxa showed dose-dependent reversal of direct and indirect fxa inhibitors in tissue factor (tf)-initiated thrombin generation (tg). we compared rivaroxabaninduced inhibition of tg initiated via the extrinsic pathway (tf) versus intrinsic pathway (non-tf). tf-initiated tg was measured using a calibrated automated thrombogram (cat) and ppp-reagent. non-tf-initiated tg was measured using cat and actin fs. anti-fxa activity was measured using an anti-fxa chromogenic assay. pooled plasma was spiked with rivaroxaban or rivaroxaban+anxa; tg, anti-fxa activity, and clot formation were measured. for low tf-initiated clot formation, thromboelastography profiles were measured. anxa alone had minimal effect on endogenous thrombin potential (etp). anxa fully reversed rivaroxaban-induced anticoagulation in the actin fs assay, independent of anxa-tfpi interaction. modulation of tf activity was assessed by correlating etp versus anti-fxa activity with rivaroxaban or rivaroxaban+anxa. rivaroxaban dose-dependently inhibited tf-initiated tg as anti-fxa activity increased. at similar anti-fxa levels, rivaroxaban+anxa had higher etp than rivaroxaban alone, but not in the actin fs assay. clot formation was studied in plasma using thromboelastography without rivaroxaban. anxa did not affect thromboelastography parameters, with/without recombinant tissue plasminogen activator (rtpa). when low tf initiated clot formation without rtpa, anxa reduced the thromboelastography-r parameter, but not maximum amplitude. the fibrin clot was lysed at low rtpa, resulting in well-segregated coagulation and fibrinolysis. with the optimal rtpa, fibrin clots formed at each tf concentration were compensated by the fibrinolytic activity of rtpa. without a fxa inhibitor, anxa had minimal effect on tf or actin fs-initiated tg with no direct effect on rtpa function. anxa dose-dependently and completely reversed rivaroxaban-induced inhibition of tg initiated by intrinsic or extrinsic pathways, but had different effects on etp due to the anxa-tfpi interaction. there is a growing body of evidence relating poor outcomes to off-hour management. studies investigating the effect of overnight extubation (oe) have produced mixed results, and limited data is available for brain-injured patients. there may also be tendency to limit oe due to decreased staffing levels at night. we sought to determine the safety of oe and risk factor profiles associated with extubation failure (ef) in this cohort. we conducted a retrospective review of mechanically ventilated patients admitted to a single-center in-house database. exclusion criteria included limitations in care, tracheostomy placement, selfextubation, and death prior to extubation. the primary outcome was ef defined as non-elective endotracheal intubation within hours. ef rates were compared between daytime ( am - : pm) and overnight ( pm - : am) extubation cohorts. in-hospital mortality served as a secondary outcome. amongst identified patients, ( . %) underwent daytime extubation (de) and ( . %) oe. ef was indifferent between de and oe ( . % and . % respectively; p= . ). however, multivariable adjustment for clinical severity indicators suggests higher ef for oe (or: . , ci: . - . ; p= . ). compared to de, oe was more likely performed in elective post-operative patients ( . % vs . %; p= . ) with lower apache-ii scores (median vs ; p= . ), and shorter durations of mv (median . vs . days; < . ). higher apache-ii score, longer duration of mv, and admission diagnoses of acute vascular injury or neuromuscular disease were associated with ef. there was no difference in mortality (p= . ). in our cohort, oe was not associated with increased ef or mortality. our results suggest that oe can be performed safely if standard extubation criteria are met in low-risk patients. these data provide a basis for subsequent more robust studies. case series have reported reversible left ventricular dysfunction, also known as stress cardiomyopathy or takotsubo cardiomyopathy, in the setting of acute neurological diseases such as subarachnoid hemorrhage. the nature of the association between various neurological diseases and takotsubo remains incompletely understood. we performed a cross-sectional study of all adults in the national inpatient sample, a nationally representative sample of u.s. hospitalizations, from - . our exposures of interest were primary diagnoses of acute neurological disease, defined by icd- -cm diagnosis codes. our outcome was a diagnosis of takotsubo cardiomyopathy. binary logistic regression models were used to examine the associations between our prespecified neurological diagnoses and takotsubo cardiomyopathy after adjustment for demographics. we identified , , adults with a primary acute neurological diagnosis and , , patients admitted to the hospital without a primary acute neurological diagnosis. among neurological diagnoses, subarachnoid hemorrhage (odds ratio [or], . ; %ci, , status epilepticus (or, . ; % ci, . - . ), transient global amnesia (or, . ; % ci, . - . ), and meningoencephalitis (or, . ; % ci, . - . ) were most strongly associated with takotsubo cardiomyopathy. weaker associations were present for ischemic stroke (or, . ; % ci, . - . ) and migraine headache (or, . ; % ci, . - . ). intracerebral hemorrhage and guillaine-barre syndrome were not significantly associated with takotsubo cardiomyopathy. in our multivariable model, female sex was significantly associated with takotsubo (or, . ; % ci, . - . ). we found associations with takotsubo cardiomyopathy for several acute neurological diseases besides subarachnoid hemorrhage. gram-negative meningoventriculitis (gnmv) causes significant morbidity and mortality. in addition to intravenous antibiotics, intra-thecal (it) or intraventricular (iv) antibiotics may be used to treat central nervous system (cns) gram-negative infections, including multi-drug resistant gnmv. there are limited studies on the effect of direct cns administration on cerebrospinal fluid (csf) cultures, csf routine parameters and other clinical outcomes. we conducted a retrospective chart review of all patients who received it or iv antibiotics for gnmv since . demographics, source of illness, severity of illness (sofa), intravenous and it/iv antibiotic choice and csf microbiological, drug level and routine analysis were collected. time to pathogen clearance from csf culture was also measured. there were inpatient encounters where iv/it antibiotics were given for gnmv during our study period, of which were cared for in a neurosciences intensive care unit. antibiotics utilized were: gentamicin ( ), colistimethate sodium ( ), amikacin ( ), and tobramycin ( ). the most common pathogens were p. aeruginosa ( ), k. pneumoniae ( ), enterobacter sp. ( ) and e. coli ( ). prior to dosing, median csf white blood cell (wbc) count, protein and glucose was /ul, mg/dl and mg/dl, respectively. it/iv antibiotics were dosed a median of times per patient and clearance of csf culture occurred in a median of days. there were significant changes in csf wbc (p< . ), protein (p<. ) and glucose (p<. ) between the first and last dose of iv/it antibiotics. twenty-five ( . %) patients survived to discharge, ( . %) were confirmed alive at months. patients who survived to discharge went to rehabilitation ( ), home ( ), long-term acute-care ( ) and skilled nursing facility ( ). it and iv antibiotics significantly improve csf wbc, protein and glucose profiles and clear csf cultures in patients with gnmv. it and iv administration may provide additional benefit to systemic therapy. gram-positive organisms are the most common cause of meningo-ventriculitis. systemic antimicrobial therapy may fail to achieve adequate cerebrospinal fluid (csf) concentrations, particularly against organisms with higher minimum inhibitory concentrations, such as mrsa and vre. direct intraventricular (iv) or intra-thecal (it) administration may be beneficial as they can facilitate high csf levels at the site of infection. there are limited studies on the effect of direct central nervous system (cns) administration of antibiotics on csf cultures, csf routine parameters and other clinical outcomes. we conducted a retrospective chart review of all patients who received it/iv antibiotics for grampositive meningo-ventriculitis since . demographics, source of illness, severity of illness (sofa), intravenous and it/iv antibiotic choice and csf microbiological, drug level and routine analysis were collected. time to pathogen clearance from csf culture was also measured. there were inpatient encounters where iv/it antibiotics were given for gram-positive meningoventriculitis during our study period, of which were cared for in a neurosciences intensive care unit. antibiotics utilized were: vancomycin ( ) and daptomycin ( ). the most common pathogens were staphylococcus sp. ( ), enterococcus sp ( ), and streptococcus sp ( ). prior to dosing, median csf white blood cell (wbc) count, protein and glucose was /ul, mg/dl and mg/dl, respectively. it/iv antibiotics were dosed a median of times per patient and clearance of csf culture occurred in a median of days. there were significant changes in csf wbc (p< . ), protein (p<. ) and glucose (p=. ) between the first and last dose of iv/it antibiotics. twenty-nine ( . %) patients survived to discharge, ( . %) were confirmed alive at months. it and iv antibiotics significantly improve csf wbc, protein and glucose profiles and clear csf cultures in patients with gram-positive meningo-ventriculitis. it and iv administration may provide additional benefit to systemic therapy. use of prothrombin complex concentrate (pcc) for urgent reversal of anticoagulant associated coagulopathy is increasing, and at the university of illinois hospital (uih), an anti-thrombotic reversal guideline was developed in may in order to assist licensed practitioners in choosing the appropriate reversal agent, optimal dosing, and improve timely administration pcc. the current study examined the safety and efficacy of pcc used for the urgent reversal of anticoagulant associated coagulopathy before and after the development of the anti-thrombotic reversal guideline. this was a retrospective chart review of adult patients who received pcc as the only hemostatic agent at the uih from jan to april . the primary endpoint was hemostasis and secondary endpoints included thromboembolic events and time to pcc administration. there were and patients who received pcc before and after the anti-thrombotic reversal guideline, respectively. frequent cause of coagulopathy was warfarin ( % and %, respectively), and frequent indication for pcc was acute intracranial hemorrhage ( % and %, respectively). -factor pcc was more frequently used before the guideline and -factor pcc was more frequently used after the guideline. in patients presenting with warfarin induced major bleeding, target inr < . was achieved in % and % of these patients before and after the guideline, respectively. clinical assessment of bleeding cessation from direct oral anticoagulant (doac) therapy was difficult to assess. thromboembolic event was observed in % and % of the patients, respectively. median time to pcc administration from its initial order was minutes and minutes, respectively. hemostasis was similarly observed in the warfarin group before and after the development of reversal guideline, but more thromboembolic events were observed before the reversal guideline. in order to further reduce the pcc administration time, a change in workflow has been made to administer pcc in timely manner. dexmedetomidine, a selective alpha- adrenoreceptor agonist inhibiting sympathetic neuronal activity, is a mild sedation agent. two recent case reports showed reduced norepinephrine (ne) requirement in septic shock with clonidine, a less selective alpha- agonist. increased vasopressor responsiveness (vr) was also observed with dexmedetomidine in cardiovascular surgical settings. sympatholytic effects of the alpha- agonists reverse vascular desensitization due to high levels of sympathetic activity in sepsis. depletion of intra-neuronal catecholamines with reserpine has shown to increase vr. in septic sheep infused with escherichia coli, clonidine reduced renal sympathetic tone and restored vr. additionally, alpha- agonists have shown to decrease pro-inflammatory cytokines and reduce mortality, improve capillary perfusion deficit, and lower arterial lactate in animal sepsis models. a prospective trial in human septic shock is in the pipeline. we report decreases in vasopressor requirement with initiation of dexmedetomidine in two patients with brain injury. a -year-old woman presented with a high-grade subarachnoid hemorrhage and concomitant reverse takatsubo cardiomyopathy. her clinical course was complicated by septic shock secondary to aspiration pneumonia at admission. when dexmedetomidine was started after hours of ne infusion, a steady decrease in ne dosage was observed until its discontinuation. increased vr was also observed in a year-old man being treated for new onset refractory status epilepticus. on hospital day , the patient continued to have stimulus-induced seizures on ketamine, midazolam and pentobarbital infusions and required ne to maintain an adequate mean arterial pressure. when dexmedetomidine was added, a decrease in ne infusion was observed within an hour and continued for six hours until the patient no longer required vasopressor therapy. these findings are consistent with aforementioned reports of restored vr by alpha- agonists in septic shock, and warrant further investigation of possible beneficial effects of attenuated hyperadrenergic state conferred by alpha- agonists in various neurocritical care settings. decreasing the amount of time a patient remains intubated has been shown to reduce multiple negative outcomes. by extubating these patients earlier, risk of infection, prolonged immobility, and delirium are reduced. in early , this nsicu was chosen to participate in the society of critical care medicine's icu liberation collaborative. the collaborative was focused on implementation of the abcdef bundle or icu liberation. the successful implementation of the bundle led to a decrease in the amount of time neurocritically ill patients were intubated. the bundle elements began to be rolled out in june (end of st quarter). included in the bundle's roll out was the creation of a respiratory clinical specialist role to help the interprofessional team with the respiratory components of the bundle. this role was a full time respiratory care practitioner who was dedicated to the nsicu and helped to ensure standards were being met. additionally, as a part of the bundle's implementation, a spontaneous awakening trial and spontaneous breathing trial algorithm was developed and initiated. this algorithm relied on interprofessional collaboration between nursing and respiratory therapy with communication to the provider and was rolled out in september (end of rd quarter). ventilator o/e for : st quarter- . , nd quarter- . , rd quarter- . , th quarter- . ventilator o/e for : st quarter- . , nd quarter- . the bulk of the research conducted that proved the benefits of the bundle elements has been completed in medical and/surgical patient populations. the neurocritical care patient population is very specialized and has several nuances that may impact the way the various elements need to be implemented. through this process, we have found that the techniques suggested within each element can positively impact the neurocritical care patient population. the cognitive reserve hypothesis refers to inter-individual differences in the ability of patients to cope with brain pathology. cognitive reserve can be measured by surrogate markers such as education and occupation and has shown to be an important predictor of outcomes in alzheimer disease, multiple sclerosis and traumatic brain injury. in this prospective longitudinal cohort study we determined whether cognitive reserve measured as number of years of education and employment status predicted -month functional outcome of ncc patients. demographic and clinical data, including number of years of education and occupational status, were collected. at three months after discharge, glasgow outcome scales (gos) were collected via telephone from patients or surrogate respondents. gos scores were categorized into 'good' or 'poor' outcome (gos - ). from march to july , / patients with -month follow-up data were included. mean age was ± years, ( %) were male, with stroke as the predominant admitting diagnosis.the two groups with good vs poor outcomes did not differ in age, gender or race in univariate analysis although employment status was statistically different in the two groups. in multivariate logistic regression neither employment nor education was a significant predictor of good vs poor outcome (p = . , p = . ). prognostication in neurocritical care patients is difficult. the effect of cognitive reserve needs to be studied further. our current sample size is small and as enrollment continues, we will determine the relationship between cognitive reserve and -month functional outcome. fever commonly occurs in patients with spontaneous intracerebral hemorrhage (sich). however, it is non-infectious in the majority of cases. blood cultures (bcx) are often obtained as part of a fever workup, yet their utility may be limited and false-positive results may potentially compromise patient care. we hypothesized blood cultures in the first hours would more likely be false-positive. we performed a retrospective chart review of patients admitted to a tertiary medical center with a diagnosis of spontaneous intracerebral hemorrhage. patients with secondary causes of ich as well as institution of comfort measures only were excluded. data obtained included demographics, clinical parameters of ich and blood culture results. blood culture results and charts were reviewed for adjudication of false-positive and true-positive cultures. of included patients with sich, patients ( %) had blood cultures obtained. cultures were positive, of which were classified as false-positive and as true positive. false positive results were more common in the first days ( vs. ), while true positive results were more common after the first hours ( vs. ) (p= . ). early blood cultures in patients with sich are more commonly non-infectious. in line with prior published data, our results demonstrate the high cost and limited yield for blood cultures within the first hours. predictive energy expenditure (pee) equations are commonly used in lieu of indirect calorimetry (ic) due to cost and limited resources; however, these equations may not be as accurate as ic in estimating resting energy expenditure (ree) in critically ill patients. the purpose of this study is to compare pee and measured energy expenditure (mee) in critically ill adults with acute brain injury. this was a retrospective review of adult patients admitted with acute brain injury between may st, and april st, who had ic performed. three predictive equations (pe), harris benedict (hbe), penn state university, and mifflin st jeor (msj), were used in comparison to ic results. subgroup analyses included a modified aspen weight-based equation, stratifying patients based on bmi and type of acute brain injury. patients met inclusion criteria. comparing the pee estimated by the three predictive equations to the mee from ic found no significant difference. high degrees of interpatient variability were discovered in each anova analysis, with standard deviations ranging from - %. despite no difference found among pee and mee, pearson's correlations indicated weak associations when hbe, penn state, and msj were individually compared to mee (r-values = . , . , and . , respectively). in patients with a bmi < kg/m , a significant difference was found (p-value= . ) with pee underestimating the ree. additionally, in aneurysmal subarachnoid hemorrhage a significant difference was observed between pee and mee( p-value= . ). the results of this study highlight the importance of using ic whenever feasible due to the interpatient variability of the ree of critically ill patients with acute brain injury. although predicative equations appear to have similar estimations as ic, interpatient variability warrants more accurate measurement with ic to optimize nutrition in patients with acute brain injury. introduction -factor prothrombin complex concentrate (pcc) should be administered as soon as possible for reversal of anticoagulation in the setting of life-threatening bleeding or urgent procedures. limited information is available on the safety, efficacy, and time to administration of pcc when administered at high infusion rates. on march , grady health system implemented a rapid pcc administration strategy while attempting to reduce times from order entry to administration as a quality improvement initiative. this irb-approved, retrospective evaluation includes pcc administrations days pre-and post-protocol implementation. after protocol implementation, pcc doses were prepared in up to four, -ml syringes, dependent on the ordered dose. each syringe was administered over minutes, not exceeding a rate of iu/minute. the primary objective of this study is to evaluate the safety of a rapid administration strategy for pcc. secondary objectives include turn-around times and effectiveness of inr reversal in patients previously on warfarin. results unique pcc administrations were identified: administrations in the pre-cohort and in the postimplementation cohort. most pcc administrations were in the setting of spontaneous or traumatic intracranial hemorrhage. there were no infusion-related adverse events documented with the exception of a possible pcc infiltration post-implementation which resolved with supportive care only. the median order entry to administration time was higher in the post-implementation group ( vs. minutes). administrations in the pre-cohort and administrations in the post-cohort were for warfarin reversal. a greater percent of patients previously on warfarin reversed to an inr < . in the post-cohort compared to the pre-cohort, . % vs . %, respectively. this retrospective evaluation suggests that rapid intravenous push administration of -factor pcc is safe and effective. time to administration was longer after implementation of rapid pcc administration and may have been due to operational limitations. icu readmission is defined as a return to the icu during the same hospital admission. there are multiple studies related to medical and general surgical recidivism, however there is limited data on icu readmissions following spine surgery. the aim of this study was to evaluate factors associated with icu readmissions following spine surgery. patients requiring icu admission following spine surgery from june to june were studied. variables included age, gender, icu and hospital disposition, icu and hospital length of stay, bmi, comorbidities, surgical location, number of previous surgeries and vertebra manipulated, estimated blood loss, post op blood transfusions, and cause of readmission. a : matched control group based on age, bmi and location of surgery was identified. thirty-two patients required readmission following spine surgery during the study period. there was a higher prevalence of preoperative atrial fibrillation in the readmission group ( % vs. %, p= . ). ebl ( vs ml, p= . ) and lowest maps ( vs . mmhg, p= . ) were not significantly different in the two groups. we found a higher mortality rate ( % vs %, p= . ), longer icu ( . vs . hours, p= . ) and hospital los ( . vs . days, p= . ) in the readmission group. respiratory distress ( %) was the most common reason for readmission followed by cardiovascular instability ( %). discharge rates to inpatient rehabilitation and nursing facilities were similar for both groups; however % of the control group went directly home as opposed to % of the readmission group. complex spine patients who experience icu recidivism have a longer hospital stay and incidence of death within years of their index procedure. they are less likely to be discharged home. preoperative a-fib correlates with increased incidence of readmission to icu post-operatively. further studies are needed looking at post operative fluid and pain management. to demonstrate the feasibility of exenatide infusion for hyperglycemia following acute brain injury. adult patients with acute brain injury and having two blood glucose concentrations > mg/dl and was administered within hours of admission and continued per protocol for a maximum duration of hours. the primary endpoint was feasibility (< % of subjects experiencing severe hypoglycemia (< - mg/dl). descriptive endpoints were also collected. data is presented as medians [interquartile range] or percentages. a total of eight patients received exenatide (age . years [ . , . ], . % male, . % caucasian, . % history of diabetes, a c . % [ . , . ]). admitting diagnoses were intracerebral hemorrhage (n= ), acute ischemic stroke (n= ), subarachnoid hemorrhage (n= ), and subdural hematoma (n= ). glascow coma score was . [ . , . ] and sequential organ failure assessment was . [ . , . ]. based upon predefined criteria, feasibility was met with % of subjects experiencing severe hypoglycemia, . % achieving the blood glucose goal, and % experiencing nausea requiring discontinuation. blood glucose was controlled during the -hour exenatide infusion ( intravenous exenatide infusion is feasible for the treatment of hyperglycemia following acute brain injury. extubation failure remains a common complication in critical care patients, and is associated with increased intensive care unit and hospital length of stays, hospital costs, morbidity and mortality. the most common cause of reintubation is laryngeal edema, often identified by the presence of a high pitched inspiratory whistling sound known as post-extubation stridor (pes). providers in the neurocritical care unit (nccu) at a large urban academic medical center noted higher than normal rates of pes. to reduce the rates of pes and reintubation without delaying extubation, a clinical pathway was created by an interdisciplinary team. the purpose of the pathway was to aid in the identification of patients expected to develop pes and guide prophylactic treatment. prior to project implementation, all providers in the nccu completed hands on training with practice in completing the pathway in the form of a checklist. during the week implementation phase, checklists were completed on all intubated patients daily during rounds. during the week trial, there were a total of ventilator days. there were completed checklists, yielding an . % compliance rate for utilization of the clinical pathway. of the patients who were extubated during the trial, had a checklist completed, generating . % compliance on the day of extubation. a chi-square analysis was performed to evaluate outcomes following all non-palliative extubations during the week pre-implementation (n = ) and post-implementation (n = ) periods. implementation of the pathway was associated with a statistically significant reduction in rates of pes ( , n = ) = . , p< . , reintubation ( , n = ) = . , p< . and reintubation due to pes, ( , n = ) = . , p< . . the clinical pathway implemented in our nccu was safe and effective in reducing rates of pes, reintubation and reintubation due to pes. agency for healthcare research and quality (ahrq) identified postoperative deep vein thrombosis (dvt) or pulmonary embolism (pe), also commonly referred to as venous thromboembolism (vte), as one of the complications acquired in the hospital and thus developed a mechanism to report its rate using administrative data. postoperative vte rate reduction became top priority for the university of illinois (uih) due to its high yearly rate, especially among patients in the neurosciences intensive care unit (nsicu). therefore, a quality improvement team in the nsicu implemented vte bundle and analyzed its effect on the vte rate. the vte bundle was initiated on all neurosurgery and neurology patients admitted to the nsicu since march . vte bundle included lower extremity doppler ultrasound within hours of admission, vte education provided to patient or family member within hours of admission, and daily surveillance on proper use of mechanical sleeves and the mechanical device, low-dose heparin initiation and maintenance therapy, and documentation of activity status. the nursing staff were encouraged to follow the early mobilization protocol. mean vte rate was . per cases approximately -year before and . per cases approximately -year after the implementation of vte bundle. the rate of compliance was high on all aspects of vte bundle, especially on correct placement of ipc sleeve > %; functioning ipc device > %; low-dose heparin > %; documentation of activity status > %. no adverse effects were noted (i.e., skin breakdown, major bleeding) during the study period. this was the first time in years at uih, the postoperative vte rate was reduced among nsicu patients based on the ahrq reports. the reduction may partly be attributed to the implementation of vte bundle; however further evaluation need to be performed to determine the effect size of vte bundle. increasing evidence suggests that large volume infusions of . % sodium chloride (nacl) for resuscitation are associated with hyperchloremic metabolic acidosis and renal vasoconstriction leading to an increased risk of acute kidney injury (aki). in patients with neurologic injury, hypertonic ( . % or %) nacl or sodium acetate (naacetate) may be required for therapeutic hypernatremia, treatment of cerebral salt wasting or elevated intracranial pressure. the primary aim of this study was to determine the incidence of aki in neurologically injured patients receiving intravenous hypertonic nacl and in those who were switched to hypertonic naacetate based on provider preference. this single-center, retrospective study compared patients that received only hypertonic nacl to patients that were switched to naacetate. data was collected to assess renal function, hyperchloremia, and metabolic acidosis. a total of patients were screened and of those were included. the patients who were switched from nacl to naacetate (n= ) had a greater incidence of aki ( % vs. %, p< . ) and hyperchloremia ( % vs. %, p = . ) compared to patients who received only nacl (n= ). the incidence of metabolic acidosis was increased but not statistically significant ( % vs. %, p = . ). on average, hypertonic nacl was switched to hypertonic naacetate on day of treatment with a mean chloride of . meq/l at the time of the switch. there was no statistical difference in the administration of nephrotoxic antibiotics, mannitol, vasopressors, or contrast dye between the two groups. the receiver operating characteristic (roc) analysis demonstrated that if a patient received greater than meq of chloride over days they were more likely to develop aki (sensitivity %, specificity %, p= . , auc . ). neurologically injured patients receiving hypertonic sodium therapy requiring a switch to hypertonic naacetate had an increased incidence of hyperchloremia and aki. in-hospital complications following acute neurological injury has been a topic of extensive research to help reduce the morbidity and mortality among the patients. however, the incidence and prevalence of in-hospital infections following an acute neurological injury at the national level has never been studied. the aim of our study is to determine the frequency and prevalence of in-hospital complications among different patient groups admitted following acute neurological injury. we identified patients with primary diagnosis of ischemic stroke (is), subarachnoid stroke (sah), intracerebral hemorrhage (ich), status epilepticus (se), meningitis, encephalitis and traumatic brain injury (tbi) from nationwide inpatient database ( - ) through using the respective icd- codes. common in-hospital complications among the above-mentioned diagnoses through using their respective icd- codes patients with primary diagnoses of is (n= ), sah (n= ), ich (n= ), se (n= ), meningitis (n= ), encephalitis (n= ), tbi (n= ) were identified. in-hospital events such as myocardial infarction (mi), sepsis, pneumonia, deep venous thrombosis (dvt), pulmonary embolism (pe), urinary tract infections (uti), and gi bleed were identified and compared among different patient groups. patients with se were noted to experience higher systemic complications, mi ( . %), sepsis ( . %), pneumonia ( . %), dvt ( . %), uti ( . %), gi bleed ( . %). patients admitted with meningitis had a higher incidence of sepsis ( . %), pneumonia ( . %), dvt ( . %), pe ( . %) and uti ( . %) compared to the other groups. uti was the most common in-hospital complication observed. based on our analysis, we report a higher incidence of urinary tract infections among all patients admitted following acute neurological injuries. patients with primary diagnosis of status epilepticus experienced more systemic complications compared to the other diagnoses. macroglossia is a phenomenon that has been documented in association with prolonged neurosurgical procedures, brainstem injury, phenobarbital administration, and venous/lymphatic congestion of the tongue. however, exact causation of this condition in the neurocritical care population remains unclear. patients with macroglossia face significant risk for airway compromise. no interdisciplinary patient safety and management protocol exists. patients admitted to two neuro icu's within a single health system between - were reviewed. twenty-five patients with macroglossia were identified. an interdisciplinary patient management protocol was created, instituting airway safety standards, oral care directives, and interventions to promote symptom resolution. early consultation to oral and maxillofacial surgery and consideration of early tracheostomy was recommended. seventeen patients ( %) were women. age ranged from - years. the majority ( / ) of patients were african american. primary diagnoses included status epilepticus ( / ) and stroke ( sah, ais, ich). nineteen patients received antiepileptic medications before diagnosis. average gcs at symptom onset was . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] and at time of discharge was . [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] [ ] . median symptom onset was hospital day [ - ]. twenty patients ( %) required tracheostomy. nine ( %) experienced symptom resolution by hospital discharge. two patients received botulinum toxin injection; both experienced symptom resolution. lingual massage was performed in two patients; in both patients, tongue swelling resolved. tongue lacerations occurred in / patients ( %), although most were observed following macroglossia onset, ruling out trauma as an inciting event. chlorhexidine oral rinse was discontinued for all except five patients due to concern for angioedema. endotracheal tube was dislodged in two patients, complicating reintubation, although successful. no trend in pre-existing allergies or antibiotic regimen was apparent. macroglossia is a relatively uncommon but high-risk condition in the neuro icu that warrants further study. care of patients with macroglossia should be standardized in order to ensure airway safety. an interdisciplinary approach is recommended. one of the biggest challenges of magnetic resonance imaging (mri) examination is the acquisition of high-quality diagnostic images, as it requires the neurological intensive care unit (nicu) patients to keep still for a significant time. in situations with poor patient cooperation, unplanned sedation is inevitable, which can lead to complications such as desaturation and hypotension. we investigated the incidence and factors related to complicated mri examinations (mri-c) in patients admitted to the nicu. we designed a retrospective study to review the data of patients who had an attempt to undergo brain mri during stay in the nicu between july and august . the mri-c group was defined when a patient met one of following criteria: ) required sedation for mri examination due to irritability mmhg or required inotropic agents, ) developed cardiac or respiratory arrest. of patients, ( . %) developed mri-c. the most common cause of mri-c was unexpected irritability at the mri room. among patients with mri-c, ( . %) patients required unplanned sedation; , desaturation; , hypotension; none, cardiac or respiratory arrest. higher apache ii scores (p = . ) and lower gcs scores (p = . ) on admission and use of sedative agents during critical care in the nicu were associated with mri-c (p < . ). in addition, patients with mri-c had longer mri scan time than those without mri-c (p = . ). many of neuro-critically ill patients undergo unsafe mri scans. our findings suggest that severity of illness and use of sedative agents during management in the nicu were factors related to mri-c. introduction: fulminant hepatic encephalopathy (fhe) with diffuse cerebral edema has dismal prognosis if transplantation is not performed. novel therapeutic interventions may change this outcome. we reviewed all cases with fhe admitted to our hospital since . in , we developed a multidisciplinary management protocol, mandating transfer of patients entering grade from other icus to the neurosciences-icu (nicu) for intracranial pressure (icp) management. multiple interventions were utilized including coagulopathy reversal with factor vii and prothrombin complex concentrate (pcc, kcentra), icp device placement, osmotherapy, aggressive ammonia lowering regimen with lactulose and rifaximin, early renal replacement therapy, mild hypothermia for refractory icp, in conjunction with liver transplantation candidacy investigation. results: twenty-four patients ( women, mean age of all patients years) were admitted; seven were managed in the micu/sicu and in the nicu. the etiology of fhe was acetaminophen toxicity in % of patients. the model for end-stage liver disease (meld) admission scores and liver enzymes between the micu/sicu and the nicu were not different (mann-whitney test). although the nicu admission ammonia level was higher than the micu/sicu ( . vs . , p = . ), the lowest achieved ammonia was lower in the nicu ( . vs . , p = . , mann-whitney). patients received icp monitoring (all in the nicu plus in the sicu) and the highest icp recorded was mm hg. the preand post-coagulation reversal inr were . and . , p= . , wilcoxon test). seven patients in the nicu received hypothermic treatment. mortality in the micu/sicu was . % ( / ) and in the nicu . % ( / ), p = . (chi square test). conclusion: a multidisciplinary approach centered around anti-cerebral edema protocol-driven management based on novel interventions may improve the outcome of patients with fhe. catheter-associated urinary tract infections (cauti) are among the most common health-care associated infections (hcais), (gould, ) . neurological patients in the critical care setting are particularly at risk for cauti due to cognitive, motor, and sensory deficits. in the neuro intensive care unit, despite following recommended cauti reduction bundle guidelines, cauti rates continued to rise over the last five years with rates reaching . per catheter days. in january of , the unit implemented a cauti taskforce to perform a literature review of best practices and subsequent : peer training and education targeting cauti reduction. in an analysis of organisms causing the infections, e. coli and enterococcus bacteria accounted for more than % of cautis on the unit. the taskforce (comprised of staff nurses) focused on fecal management, proper cleaning technique, and proper indications of indwelling urinary catheter necessity. using training videos, indwelling urinary catheter care checklists, and real-time feedback on technique, the taskforce performed : training with bedside staff over four weeks. to ensure undivided attention, the taskforce worked in pairs enabling one trainer to teach and observe the staff member receiving training while the second trainer provided the necessary clinical duties for the trainee's patients. after implementation, the cauti rate decreased to . for january-march and . for april-june , lowering total cauti events to for fy compared to for fy . implementing a : training program focused on fecal management, cleaning techniques, and appropriately timed catheter removal can reduce cauti rates in the neuro critical care setting. brain aneurysms can be treated with coil embolization or flow-diverting devices. thromboembolism is a major complication of aneurysmal coil embolization, with an incidence as high as % . new flowdiverting devices have been designed to have a mesh with high coverage area and high flexibility to facilitate the redirection of blood flow. these features can induce blood stagnation and thrombosis. to reduce the risk of thrombosis, the common but unproven practice of dual antiplatelet therapy with aspirin and clopidogrel has been implemented from the cardiac literature. despite some favorable outcomes, clopidogrel, "non-responsiveness" has been reported to be present in as low as % to as high as % making this agent not optimal. this will leave practitioners with other oral p y alternatives such as prasugrel and ticagrelor that have not been studied widely in this setting. it is therefore likely that controversy exists among practitioners regarding the use of optimal antiplatelet agents in neurointerventional procedures. we hypothesized that practices in regards with the use of oral antiplatelets in neurointerventional procedures are likely heterogeneous and different from state to state. by using an electronic survey, we would like to identify different practices surrounding the use of oral anti-platelets in neuro-endovascular centers in the united states. an electronic survey will be distributed via the web using survey monkey (seattle, wa). the survey will be posted on the neuro-critical care society (ncs) web page. all practicing neuro icu or stroke physicians, pharmacists, physician assistants, or nurse practitioners are eligible to respond to this survey. this survey is approved by the johns hopkins hospital irb and the ncs research committee. centers have completed the survey at this point. the results will be analyzed after the closing date of survey ( / / ). to be completed myasthenia gravis (mg) crisis and guillain-barre syndrome (gbs) are immune mediated diseases that may require mechanical ventilation as part of their management if severe. comparative analysis of outcomes in terms of length of stay, disability, and mortality between these two disease entities at national level is not reported mechanically ventilated patients with primary diagnosis of guillain-barre syndrome and myasthenia gravis were identified from the nationwide in-patient sample (nis) database for the years to mechanically ventilated mg patients (n= , mean= +/- . years) were older compared to gbs patients (n= , mean= . +/- . years, p= . ). medical co-morbidities were significantly higher in mg patients (diabetes mellitus, congestive heart failure, coagulopathy, chronic lung disease and dyslipidemia) whereas significantly higher nicotine dependence and alcohol abuse were noted in gbs. significantly higher in hospital complications of pneumonia and urinary tract infection were noted in gbs. disease severity measured by apdrg severity index and rate of treatment with intravenous immunoglobulin and plasma exchange was comparable. length of stay ( . ± . days , p < . ); hospital charges ( $ . ± . vs . ± . p = . ) ; moderate to severe disability ( . % vs . % p < . ) were significantly higher for gbs patient compared to mg. inhospital mortality was comparable ( . % gbs vs . % mg, p = . ). in multivariate analysis after adjusting for confounders including treatment, myasthenia gravis patients had significantly less disability (or . ( % ci . - . ) and shorter length of stay (or . , % ci . - . ). mechanically ventilated gbs patients have higher in-hospital complications, length-of-stay, and disability compared to mg. this may reflect a delay in diagnosis of gbs at admission and poor response to immunotherapy in certain gbs variants. betrixaban is an inhibitor of factor xa (fxa) for prophylaxis of venous thromboembolism (vte) in at-risk patients hospitalized for acute medical illness. a phase trial (apex) compared extended-duration anticoagulation with betrixaban to enoxaparin in acute medically ill patients; the effect of patient characteristics on population pharmacokinetics and exposure-response relationships is analyzed here. patients received betrixaban ( - days; n= , ) or enoxaparin ( ± days; n= , ). the primary efficacy and safety endpoints were composite occurrence of vte events and incidence of major bleeding, respectively. betrixaban dose was mg po qd ( mg po qd for patients with severe renal insufficiency/requiring concomitant p-glycoprotein inhibitor). pharmacokinetic samples were collected - hours or - hours after the most recent dose of study medication. patient characteristics included age, sex, race, region, body weight, crcl category, and specific p-glycoprotein inhibitor. , pharmacokinetic samples were analyzed. at mg, the projected concentration was . ng/ml at hours post-dose and . ng/ml at hours post-dose, showing a stable daily concentration. coadministration of p-glycoprotein inhibitors on the day of sampling more than doubled betrixaban concentration to ~ ng/ml at hours post-dose. at mg, the projected concentration was . ng/ml at hours post-dose, indicating a greater-than-dose-proportional exposure relationship. patient age, sex, weight, crcl category, p-glycoprotein inhibitors, and region were significant covariates affecting betrixaban pharmacokinetics. the exposure-response relationship for the primary efficacy endpoint was not significant, but the relationship between betrixaban concentration and major/clinically relevant nonmajor bleeding was significant in multivariate testing (p= . ). the betrixaban pharmacokinetic profile exhibited stable serum concentrations with qd dosing. several covariates had a %- % effect on betrixaban concentration, but no effect on efficacy/safety. betrixaban dose should be adjusted to mg for patients taking amiodarone or clarithromycin, but not other p-glycoprotein inhibitors. andexanet alfa is being investigated for reversal of anticoagulation by factor xa (fxa) inhibitors. a pharmacokinetic/pharmacodynamics model, developed in healthy subjects, predicted the andexanet regimen required to reverse anticoagulation by fxa inhibitors. the current analysis validated the pharmacokinetic/pharmacodynamic model using interim data from the annexa- study in patients with acute major bleeding. in annexa- , an ongoing prospective, open-label study, bleeding anticoagulated patients received iv andexanet bolus ( or mg) followed by -minute infusion ( or mg/min). anti-fxa activity was measured before andexanet administration (baseline), at end of bolus (eob), at end of infusion, and at , , and hours after infusion. the relationship between baseline anti-fxa activity and reversal in healthy subjects was derived from the pharmacokinetic/pharmacodynamic model and used to predict percent reversal for patients with acute major bleeding. from the first interim analysis of annexa- , patients (apixaban, n= ; rivaroxaban, n= ) had plasma levels available for model qualification, although did not meet criteria for inclusion into safety and did not meet criteria for efficacy analysis. the mean observed percent reversal of anti-fxa activity for rivaroxaban and apixaban was well predicted by the healthy subject pharmacokinetic/pharmacodynamic model; the point estimates fell within the % confidence intervals of predicted values. the percent reversal at eob for rivaroxaban and apixaban were . [ . - . ] and . [ . - . ], compared with . and . predicted by the model. the predicted reversal closely fit the observed confidence intervals through the first hours for rivaroxaban and apixaban, and extended through all evaluated time points for rivaroxaban and slightly outside of post- -hour time points for apixaban, possibly due to higher baseline anti-fxa activity levels for apixaban. the pharmacokinetic/pharmacodynamic model in healthy subjects closely predicted the extent of reversal of anti-fxa activity for apixaban and rivaroxaban in patients with major bleeding. risk factors and methods to predict extubation failure are well established for patients in medical icus and surgical icus. literature on patients who fail extubations in neurological icus is limited. the intention of this study was to collect descriptive information from patients with neurological injuries who failed liberation from mechanical ventilation. retrospective review of all patients with acute neurological injury who were admitted to our neuro icu and who required reintubation within hours of discontinuation of mechanical ventilation between january -february . we identified patients intubated primarily due to neurological pathology who required reintubation within hours after initial extubation over a -year study period. the majority of reintubated patients (n= ; . %,) had a positive fluid balance prior to failed extubation. twenty-six of the reintubated patients had a concurrent underlying chronic cardiac and/or pulmonary disease. five patients were placed on noninvasive ventilation post extubation. low glascow coma scale and absence of basic brainstem functions (gag and cough reflexes) was only minimally predictive of extubation failure. most of our reintubated patients did not have significant supratentorial midline shift nor an insult to the posterior circulation or dominant hemisphere. in patients with primary brain injury who required reintubation, a positive fluid balance prior to extubation may confer a lower rate of successful extubation. lesion location and supratentorial midline shift may not be tightly associated with extubation success. overall, our reintubation rate is quite low. early tracheostomy may play a small but significant role in the low rate of reintubation. further studies may be useful in creating a scoring system to identify the likelihood of extubation success in patients with neurological injury. surgical prophylaxis guidelines for evd insertion recommend peri-procedural antibiotics rather than prolonged antibiotic administration for the duration of evd placement. several small studies have shown that prolonged systemic antibiotic use does not reduce the incidence of catheter related ventriculitis. prolonged use is also associated with a higher rate of multi-drug resistant (mdr) infections. this study aims to show that prolonged antibiotic administration following evd insertion is potentially harmful. this is a single center, retrospective, chart review. all patients admitted to our hospital who had an evd placed from january to march were identified. patients with preceding infections, incomplete data or uncertain infection diagnosis were excluded. sixty-nine patients were analyzed. documented variables included demographics, comorbidities, indications for evd, duration of antibiotic therapy, infections and organisms' sensitivities. eight patients ( %) did not receive any antibiotic therapy; the rest received cefazolin following evd insertion. infections occurred in of ( %) patients; of ( %) were mdr bacteria. ventriculitis occurred in ( %) patients, and of these were resistant to cefazolin (mdr). ventriculitis was not associated with the use or duration of antibiotic therapy. graphical analysis showed that the probability of any infection decreased during the first days of antibiotic prophylaxis. after days, the longer patients remained on prophylactic cefazolin, the higher the probability of infection (spearman rank correlati patients who received antibiotics for > days were . times as likely to develop mdr infections ( % ci, . to . ; p= . ). cefazolin may prevent infections for the first days after evd insertion. however, prolonged administration increased the risk of mdr bacterial infections. a randomized study comparing periprocedural ( hrs) antibiotic use is needed to resolve this controversy. each year more than , deaths are associated with urinary tract infections. eighty percent of all utis are associated with an indwelling catheter. neuroscience intensive care (neuro-icu) units have the highest rates of catheter associated urinary tract infections. catheter associated urinary tract infection (cauti) increases morbidity rates, length of stay, and costs among hospitalized patients. at an urban academic medical center, our neuro-icu had the highest cauti cases among our icus. the purpose of this project was to reduce our cauti cases by %. this quality improvement project used several strategies: ( ) formed a multidisciplinary cauti task force that included nurses, physicians, infection control, management and supply chain personnel; ( ) developed an action plan to update standard of practice by conducting a review of the literature and pilot testing new products; and, ( ) educated staff using huddles, a bedside guide, and email blasts with cauti facts starting in august . additionally, cauti prevention was discussed during patient handoffs among nurses and physicians. data were collected for all neuro-icu patients from fiscal year (fy) - . cauti cases are determined by utilizing cdc's national healthcare safety network. analysis included evaluation of trends across time. we reduced our number of cauti cases from in fy to in fy . as of the beginning of fy , we have not had a cauti for days. a comprehensive approach with a strong commitment by clinicians is critical for sustaining a reduction in cauti. we reduced our cases and exceeded our goal. our efforts to provide evidence-based care are ongoing as we continue to monitor the research and upcoming supplies aimed at making hospitalacquired cauti a never event. isophane insulin (nph) is a commonly prescribed basal insulin to manage hyperglycemia in critically ill patients on continuous tube feeding due to its intermediate duration of action. however, the incidence of hypoglycemia may be higher given the duration of nph can last between - hours and because of the potential for unexpected interruption in feeding. using scheduled regular insulin (ri) instead of nph may reduce this risk given its shorter duration of action. it may also improve glycemic control due to more frequent titration. this was a single-center, retrospective, observational, cohort study from december to may . patients on continuous tube feeding who were prescribed scheduled ri were compared to those prescribed nph. all patients continued to receive an insulin sliding scale. choice of agent was determined by the bedside team. the primary endpoint was incidence of hypoglycemia while secondary endpoint assessed efficacy. in our patient population, a higher incidence of hypoglycemia was seen in those that received nph. hypertonic saline bolus (hsb) is a proven intervention for neurological emergencies arising from cerebral edema and increased intracranial pressure. safety of hsb administered via central venous catheters is well established. however, infusion of hsb through peripheral intravenous access raises concern for complications related to caustic nature of the solution. we aim to assess the safety of peripherally administered boluses of hypertonic saline ( % sodium chloride) at a regional level trauma and comprehensive stroke center. we performed retrospective chart review of patients who received hsbs from january , to january , as part of a quality improvement project. we identified instances of hsb administration. the cases were individually reviewed for iv gauge, location of the iv, whether central access was present at the time of administration, documentation of iv removal, and volume of boluses. patients were excluded if there was concurrent central venous access catheter present at the time of hsb administration or unrelated death within hours after administration of hsb. adverse events were defined as line infiltration, erythema, or swelling at the site of hsb administration. charts were excluded from the study because of presumed administration of hsb through central venous access, not peripheral iv. two patients had adverse events ( . %). none of the patients progressed toward limb threatening complications. the majority of patients ( / ) did not experience erythema or infiltration of the iv. hsb administered through peripheral intravenous access does not pose significant risk of severe complications and may be safely used in emergency situations in the absence of central line access. routine screening of high risk asymptomatic trauma or surgical patients for venous thromboembolism(vte) is controversial. studies suggest against screening while others recognize that some patients at high risk may benefit. the purpose of this pilot study is to evaluate the outcome of routine screening in patients who underwent neuro-surgical interventions. all adult patients admitted to a neuro-intensive care unit with a primary diagnosis of brain injury requiring surgical interventions were included. data from april-june, were retrospectively collected on all subjects who had either spine or cranial surgery. data collected include: incidence of vte, number of times duplex ultrasonography and computed tomography of the chest was performed. on july st, prospective data collection began by screening for presence of deep vein thrombosis(dvt) on day , and from admission or surgery day. all patients received pharmacologic and mechanical vte prophylaxis within - hours post-operatively. a total of (pre-pilot, n= and post-pilot, n= ) subjects were included in the study. in the pre-pilot group, the ages ranged from - and most were male. majority, / ( %) had either craniotomy/craniectomy while / ( %) had spine surgery. about / ( %) were admitted with primary diagnosis of traumatic brain injury. of the subjects, had duplex screening for dvt and had screening for pulmonary embolism(pe). the incidence of vte was confirmed in / ( %); (dvt- % and pe- %). median hospital length of stay was (iqr - ) days. / ( %) were discharged home and / ( %) death rate was attributed to pe. in the post-pilot group, one incidence of pe was identified on day post surgery screening. the rest of the results are still pending. in this preliminary report, post surgical patients have a higher incidence of vte. routine screening might benefit to lower the incidence of mortality caused by pe. epsilon aminocaproic acid (eaca) is an antifibrinolytic agent that crosses the blood-brain barrier and has shown benefit in decreasing bleeding in patients acutely. its use in intracranial hemorrhage has uncertain benefit. we aimed to describe the administration and impact of eaca in a single-center neurosciences intensive care unit (neuroicu) over one year. we performed a single-center retrospective study of neuroicu patients undergoing intravenous eaca administration over a one-year time period. inclusion criteria included eaca administration over hours for a diagnosis of acute traumatic hematoma. the dose and duration of eaca infusion was collected. we additionally collected and compared pre-administration and post-administration prolonged thromboplastin time (ptt) hematology assays and neuroimaging. clinical outcomes were reviewed for survival at hospital discharge. over a -month period (april -may ), patients each received a -hour infusion of eaca. the most common indication for eaca was to prevent worsening of intracranial hemorrhage in patients in traumatic coma (gcs < ). % of patients underwent neurosurgical management. ptt assay values showed a significant difference before and after eaca administration. (ptt . +/-sd vs. . +/-sd; student's t test p< . , n= ). stability of the intracranial hematoma burden was evident following eaca in % of patients. % of patients who received eaca survived to discharge. patients receiving eaca showed a significant reduction in ptt assay values hours after completing their dose. ct neuroimaging demonstrated stable intracranial hemorrhage burden in most patients receiving eaca despite a high prevalence of acute operative neurosurgical management. however, only a modest number of patients receiving eaca survived to discharge. these results suggest that eaca may acutely reverse hematologic abnormalities and enable emergent neurosurgical management in patients with severe, acute traumatic hemorrhage, despite a limited role in affecting survival outcomes in these patients. prognostication is difficult for patients admitted to a neurocritical care unit (nccu). can serum biomarkers obtained as part of routine admission lab work help predict outcomes among patients in this prospective cohort study, the following biomarkers were measured at admission: c-reactive protein (crp), arterial lactate, neuron specific enolase (nse), lactate dehydrogenase (ldh), albumin, and brain natriuretic peptide (bnp). we collected information about demographics, comorbidities, hospital procedures and complications and -day mortality. we compared these serological biomarkers in patients who were alive versus those who had died at days. a total of patients were enrolled over months from june to september , of which whom ( . %) died within days of admission. there were no statistically significant differences in age or gender between the two groups. the -day mortality group had a higher mean charlson comorbidity index (cci) ( . vs . , p= . ) as well as mean nse ( . vs . ug/l, p= . ) and bnp levels ( . vs . pg/ml, p= . ). mean crp, lactate, and ldh were also higher in the -day mortality group ( . vs . mg/l, . vs . mmol/l, and . vs . u/l) while mean albumin was lower ( . vs . g/dl), although these differences were not statistically significant (p< . ). cci and serological biomarkers may have utility in predicting -day mortality among patients admitted to the nccu. as we continue enrollment, we plan to develop a predictive model for -day mortality on admission for patients admitted to the nccu using serological biomarkers, cci and admission characteristics. among hospitalized acutely ill medical patients, the risk for venous thromboembolism (vte) is high. the goal was to examine vte prophylaxis of at-risk patients and vte risk during hospitalization and in the outpatient continuum of care. acutely ill medical patients were identified from the marketscan commercial and medicare databases from / / to / / . inclusion criteria were hospitalization for heart failure, respiratory diseases, ischemic stroke, cancer, infectious diseases, and rheumatic diseases; months of continuous insurance coverage prior to (baseline period) and after (follow-up period) the index hospitalization. outcomes included the proportions of patients receiving inpatient and/or outpatient vte prophylaxis, and the risk for vte events. years, and . % were female. patients were hospitalized for infectious diseases ( . %), respiratory diseases ( . %), cancer ( . %), heart failure ( . %), ischemic stroke ( . %), and rheumatic diseases ( . %). mean hospital length of stay was . days. in total, . % (n= , ) of patients did not receive any vte prophylaxis, and . % (n= , ) received both inpatient and outpatient vte prophylaxis. during hospitalization, . % (n= , ) received vte prophylaxis (enoxaparin, . %; warfarin, . %; enoxaparin and warfarin, . %; a direct oral anticoagulant (doac), ~ %). following discharge, . % (n= , ) received outpatient vte prophylaxis (warfarin, . %; doac, . %; enoxaparin, . %; enoxaparin and warfarin, . %). among the entire study population, the vte event risk remained elevated up to - days after hospital admission. among hospitalized acutely ill medical patients, the risk for vte was present in both the inpatient and outpatient settings, with significant vte risk extending into the post-hospitalization period. only a small portion of at-risk patients ( . %) received vte prophylaxis in both the inpatient and outpatient continuum of care, suggesting an unmet medical need for vte prophylaxis in the post-hospitalization. brain edema is a good research target in various forms of neurologic injury. a real time measurement of brain edema is possible using thermal conductivity methods. however, this technique might be hard to apply in small rodents, which are commonly used as experimental brain edema models. we developed a new approach method for applying thermal conductivity methods in rodent brain edema model. a -week-old spraque-dawley rats were used for brain edema model. qflow probe was inserted through a suboccipital burr hole, located mm left from the midline, then was advanced anteriorly mm from the occipital bone margin until probe place assistance value indicates valid values (ranging from to . ). probe was fixated using adhesive glues and tagging suture. in vivo brain water content was continuously calculated using thermal conductivity values. for validation, calculated brain edema was compared with standard methods (dry/wet brain weight ratio) in water intoxication models (intraperitoneal injection of distilled water, % of body weight) and drying effect of mannitol was validated in streptokinase induced intracerebral hemorrhage (ich) models. calculated brain water content was . ± . % in thermal conductivity method and . ± . % using dry/wet weight ratio methods (p= . ). in water intoxication model, brain water content started to increase minutes after injection and reached up to . ± . % at hours post injection. on wet/dry weight method, edema was measured as . ± . % (p= . ). in ich model, brain water content started to drop minutes after administration of mannitol ( . mg/kg) and drifted back hours after injection of mannitol. thermal conductivity method in assessing brain edema is applicable in rodents using suboccipital approach through burr hole. this method may better reflect dynamic changes of brain edema. in patients with critical brain injury, alterations of brain physiology with dialysis initiation are poorly understood. from a consecutive series of brain-injured patients undergoing invasive multimodality monitoring between and , patients that underwent continuous veno-venous hemodialysis (cvvh-d) and patients that underwent intermittent hemodialysis (ihd) were identified. changes in mean arterial pressure (map), intracranial pressure (icp), and brain tissue oxygenation (pbto ), and microdialysis lactate-pyruvate ratio (lpr) were compared six hours prior to and twelve hours following dialysis initiation. high-resolution data was collected every seconds, with the exception of lpr collected hourly. data were normalized to patient maximum values, analyzed by fitted segmented regression, and checked for slope change-points by davies' test. values prior to dialysis initiation were averaged as a baseline for comparison. median values for patients undergoing cvvh-d were map +/- . , icp . +/- . , pbto . +/- . mmhg (n= ), and lpr . +/- . (n= ). normalized median values for patients undergoing ihd were map +/- . , icp +/- . . for the cvvh patient segmented regressions with normalized data, there was no change in map (slope . ) during the twelve hours. however, we found a change-point in icp at . hours (ci . - . , slope change . to . ) and pbto at . hours , slope change . to - . ). lpr increased through cvvh (slope . +/- . ). median values for patients undergoing ihd were map +/- . , icp +/- . . there was no identified change-points in map or icp in ihd patients, further parameters were limited by small sample size. initiation of cvvh in patients with neurologic multimodality monitoring showed change-points in icp and pbto in setting of stable map, with slight decrease in icp and pbto . initiation of hd in showed no change-points in icp. data on the cerebral effects of antihypertensive agents are limited but potentially important in patients requiring blood pressure reduction in neurological emergencies. our objective was to measure the effect of rapid-acting antihypertensive agents on cerebral blood flow (cbf) in patients with acute hypertension we conducted a prospective, quasi-experimental study of patients with a sbp > mmhg and planned rapid-acting antihypertensive treatment in the emergency department. patients < years or pregnant were excluded. non-invasive hemodynamic and transcranial doppler measurements of the middle cerebral artery mean flow velocity (mfv) were obtained prior to and post treatment. analysis included descriptive statistics and generalized linear modeling to test the effect of four categories of antihypertensive agents on mfv. categories included clonidine, iv labetalol, iv hydralazine and combination therapy. we enrolled patients ( % female) with a mean age of ± years. eight ( %) patients received clonidine, ( %) iv labetalol, ( %) iv hydralazine and ( %) combined therapy. the mean baseline sbp was ± mmhg and mfv ± cm/sec. the mean percentage fall in sbp by medication was: clonidine - ± %, labetalol - ± %, hydralazine - ± %, and combination - ± %. the overall change in mfv was - ± %, and by medication was: clonidine - % ( %ci - to - %), labetalol - % ( %ci - to - %), hydralazine + % ( %ci - to + %), and combination - % ( %ci - to - %). adjusting for baseline bp, hydralazine caused less change in mfv compared to other medications (difference between means + %, %ci - to + %, p= . ). in this study with modest bp reductions, rapid-acting antihypertensive medications had comparable effects on cerebral blood flow. these results hint that cerebral blood flow may be more stable with hydralazine administration, but further testing of hydralazine and infusions such as nicardipine is required. studies exploring correlations between non-invasive (oscillometric) blood pressure (nibp) and intraarterial blood pressure (abp) have excluded neurocritically ill patients with continuous infusion of vasoactive medications. compared to abp, nibp monitors generally tend to over-read at low values and under-read at high values. this study examines the relationship between simultaneously measured nibp and abp recordings in these patients. following informed consent, prospective observation of patients (n= ) admitted to a neurosciences icu, with simultaneous abp and nibp monitoring and continuous vasopressor (n= ) or antihypertensive (n= ) infusion. paired nibp/abp observations along with covariate and demographic data were abstracted via chart audit. analysis was performed using sas v . . , paired nibp/abp observations from subjects ( % male, % white, mean age years) receiving vasopressors (n= ) or antihypertensive agents (n= ). t-tests show significant difference between paired readings: ([sbp: m= vs mmhg respectively; p<. ], [dbp: m= vs mmhg respectively, p<. ], [map: m= vs m= mmhg respectively, p<. ]). the paired differences for specific medications were tabulated, with - % of the differences < mmhg, and - % of the values with < mmhg difference. bland-altman plots for map, sbp, and dbp demonstrate good intermethod agreement between paired measures (excluding outliers) and demonstrated marked nibp-abp sbp differences at higher blood pressures. pearson correlation coefficients for paired measurements show strong positive correlation for map (+ . ), sbp (+ . ), and dbp (+ . ). despite a statistically significant difference between nibp and abp readings for patients on vasoactive medications, there may be no clinical significance. the relatively positive and linear correlation between paired values guide providers towards not being forced to use one over the other. the final manuscript will aim to detail whether there is a clinical significance in particular vasoactive medications. pathological activity in continuous electroencephalogram (ceeg) data of icu patients is conventionally categorized into a small number of named rhythmic and periodic patterns. we aimed to develop a valid method to automatically discover a small number of homogeneous pattern clusters, to facilitate efficient interactive labeling by ceeg experts. we extracted time and frequency domain features from + hour ceeg recordings from different icu patients. after removing artifacts, we applied principal component analysis ( % variance retained), then separated the data into clusters (k-means). from each cluster we took random samples plus the most central one, rendering samples in total. three expert electroencephalographers independently categorized all samples into one of standard pattern categories (seizures, gpds, lpds, lrda, grda, burst suppression, other). we compared two methods for labeling clusters: ( ) "labor intensive labeling" (lil): assign the most frequent of expert-provided labels; ( ) "labor efficient labeling " (lel): assign the most frequent of the expert labels for the central sample. we compared interrater agreement (ira) among experts vs. between each expert and consensus labels using lil vs. lel. finally, we used laplacian eigenmaps (le) to visualize the data. this research suggests that large ceeg datasets can be automatically clustered into a small number of patterns described by standard icu eeg pattern labels. we demonstrated efficient cluster labeling by inspecting only the central-most representative of each cluster. furthermore, le visualizations support the hypothesis of an interictal-ictal continuum. real time measurement of cerebral oxyhemoglobin (oxyhb) and deoxyhemoglobin (deoxyhb) using near infrared spectroscopy (nirs) may help us better understand the status of cerebral oxygenation and possibly cerebral blood flow (cbf) in patients with acute brain injury. we developed multichannel functional nirs (fnirs) system and evaluated its role in patients with acute brain injury. a channel fnirs system (nirsittm) was used for measuring cerebral oxyhb and deoxyhb in patients with brain injury. measurement protocols were as follows; baseline measurement for minutes with activation stimuli (nipple pinching for seconds). patients groups were categorized as follows; ) global cerebral ischemia with profound cerebral injury (n= ), ) large ischemic stroke or decrease in cbf in the frontal lobe due to severe stenosis in the middle cerebral artery (mca) or internal carotid artery (ica) (n= ), ) high grade subarachnoid hemorrhage with a risk of vasospasm (n= ), control groups did not have either cerebral lesion or cbf abnormality (n= ). global ischemia with good functional outcome group had better oxyhb level (rso ) compared to those with poor outcome ( . % vs. . %, respectively, p = . ). patients with poor perfusion in the mca territory had low oxyhb level compared to mirror lead in the contralateral hemisphere. oxyhb level in patients with decreased vasomotor reactivity on diamox spect had improved after carotid stenting. three patients who underwent superficial temporal artery-middle cerebral artery bypass surgery had transient hyperperfusion syndrome. oxyhb and total hb were elevated in the affected area. patients with sah and vasospasm had blunted oscillation pattern of oxyhb compared to those without vasospasm. bedside multichannel measurement of oxyhb and deoxyhb using fnirs might be useful in understanding hemodynamic changes occurring in patients with acute brain damage at the real time. multimodality monitoring (mmm), brain tissue oxygenation (pbto ) and microdialysis (md) in sah may be important to the treatment of delayed cerebral ischemia (dci). our hypothesis was that concordance between pbto and md occurs in the tissue bed displaying angiographic vasospasm. this retrospective observational study includes patients with sah. the extent of angiographic vasospasm for each vessel was graded on angiography by the on call neuro-interventionalist and quantified as (no spasm) to (severe spasm). pbto and md probes were placed in the frontal lobe white matter. the severity of vasospasm was estimated by the weighted average of ( x aca + x mca + x ica) / . cases with score of or more were considered to have clinically relevant vasospasm. using a within-subjects design, epochs of baseline mmm were compared with during spasm using daily mean for pbto , lpr, glucose, icp and cpp. given the limited number of observations the simplifying assumption was made that the observations from all epochs are independent. the measurements from all patients were divided in the two groups with and without spasm and were compared using a twotailed non-paired student t-test. sixteen sets of baseline and vasospasm epochs were evaluated for pbto and for md. compared with baseline values, the average pbto was significantly lower ( . vs . mmhg, p= . ), lpr was non-significantly higher ( . vs . , p= . ), and glucose was similar ( . vs . mmol/l, p= . ) during vasospasm epochs. there was no difference in icp ( . vs . mmhg, p= . ). these differences were unaffected by induced hypertension, when cpp was augmented for treatment of dci ( . vs . mmhg, p= . ). mmm during angiographic vasospasm after sah suggests discordant changes in brain oxygenation and metabolism. these data suggests that dci may be related to metabolic factors other than tissue oxygenation. multimodal monitoring including brain tissue oxygenation (pbto ) is increasingly used for the management of acute tbi patients. the optimal management of pbto is not fully established. increasing fio is efficacious to correct pbto but may mask other oxygen delivery mechanisms which may be deficient. the objective of this study was to explore the clinical utility of a pbto /pao ratio to detect overtreatment by fio . retrospective cohort stud were collected simultaneously whenever an arterial blood gas was drawn (icp, cpp, hemoglobin, temperature, pco and pao ). causes of cerebral hypoxia (pbto < mmhg) were noted. pbto /pao ratio < . was considered abnormal and plotted over time for each patient individually. data sets were collected from patients (mean age . ± . , median gcs , mortality %). . % of the time and associated with a mean pao of mmhg. measures within the low pbto -low ratio category had significantly lower cpp ( vs mmhg), higher pao ( vs mmhg) than patients with normal pbto or normal ratio respectively. various causes of hypoxic pbto were reported when the ratio was abnormal: hypocapnia, low cpp, low cardiac index, long equilibration time... four patterns of evolution of the ratio over time were identified and associated with different mortality rate: . %, . %, . % and %. conclusions associated with increased pao and decreased cpp. this suggests clinicians often used fio to compensate for deficient cerebral oxygen delivery. indeed, various causes of hypoxia besides low pao were identified and corrected. pattern of temporal evolution of the ratio seems to correlate with mortality. pupillary light response (plr) evaluates cranial nerves ii, iii, and midbrain function. bedside quantitative infrared pupillometry provides reproducible assessment of the plr, reported as the neurological pupillary index (npi). increased intracranial pressure results in decreases in npi. intracranial hypotension (ih) can also cause brainstem distortion. we therefore hypothesized that similar changes in npi could be seen with ih. here, we describe sequential changes in npi in ih before and after treatment. we identified four patients monitored with pupillometry for clinical care during ih diagnosis and treatment. ih was diagnosed with a compatible history, exam, and characteristic neuroimaging findings. patients' npi at baseline, during symptomatic ih, and after treatment were compared using related samples friedman's two-way anova and wilcoxon signed ranks tests. two patients were male; causes of ih were csf leak following lumbar instrumentation (n= ) and basilar skull fracture (n= ). mean baseline npi was normal (defined as > ) and declined in one or both eyes concurrent with clinical deterioration in the - hours preceding definitive diagnosis. all patients underwent treatment for csf leak with epidural blood patch or fracture repair, with return of npi > within hours of treatment. the baseline, symptomatic and post treatment npi's differed significantly ( . ± . vs . ± . vs . ± . , mean +/-sd, pre-treatment vs nadir vs post-treatment, p= . ). both baseline and post treatment npi's differed from the npi nadir (p= . ) but there was no difference between baseline and post-treatment npi (p = . ). impairment of the plr, as measured by npi, occurred during symptomatic ih and resolved after treatment. because management of intracranial hyper-and hypotension differ markedly, our results emphasize the importance of evaluating the clinical context before attributing pupillary/npi changes to increased icp. automated pupillometry provides a non-invasive, bedside tool for monitoring progression and treatment of intracranial hypotension the correlation of optic nerve sheath diameter (onsd) as seen on ultrasonography (us) and directly measured intracranial pressure (icp) has been well described. nevertheless, differences in ethnicity and type of icp monitor used are obstacles to the interpretation. therefore, we investigated the direct correlation between onsd and ventricular icp and defined an optimal cut-off point for identifying increased icp (iicp) in korean adults with brain lesions. this prospective study included patients who required an external ventricular drainage (evd) catheter for icp control. iicp was defined as an opening pressure over mmhg. onsd was measured using a mhz us probe before the procedure. linear regression analysis and receiver operator characteristic (roc) curve were used to assess the association between onsd and icp. optimal cut-off value for identifying iicp was defined. a total of patients who underwent onsd measurement with simultaneous evd catheter placement were enrolled in this study. thirty-two patients ( . %) were found to have iicp. onsd in patients with iicp ( . ± . mm) was significantly higher than in those without iicp ( . ± . mm) (p . mm disclosed a sensitivity of . % and a specificity of . % for identifying iicp. onsd as seen on bedside us correlated well with directly measured icp in korean adults with brain lesions. the optimal cut-off point of onsd for detecting iicp was . mm. impaired cerebral autoregulation following neurological insult has been established as a strong predictor of clinical outcome. hypothermia may offer autoregulatory protection in these patients, although the effect of body temperature on autoregulatory status is unclear. retrospective analysis of data from an ongoing prospective study to evaluate multimodal monitoring using near infrared spectroscopy (nirs) for bedside measurement of autoregulation. ninety-one comatose patients (gcs < ) were continuously monitored for up to three days. nirs derived cerebral oximetry index (cox) was used as a marker of autoregulation. cox was calculated as a moving, linear correlation coefficient between regional cerebral oxygenation saturation and map. autoregulation improves as cox values approach , and is impaired as values approach . patients were grouped by trend in temperature seen over the monitoring period: no change (< oc temperature change, n= ), increase (n= ), decrease (n= ), increase followed by decrease (n= ), decrease followed by increase (n= ), and fluctuating (n= ). we performed multivariable logistic regression analysis to assess the association between temperature and outcomes. the association between hourly temperature and cox was assessed using mixed random effects models with random intercept. in patients showing a sustained increase or decrease in temperature, a linear relationship between temperature and cox was seen; for every oc increase or decrease in temperature, cox changed by . ± . (p< . ) and - . ± . (p= . ), respectively, after adjusting for pco , haemoglobin, map and temperature probe location. mean temperature changes over the monitoring period for these groups were . ± . oc and - . ± . oc, respectively. cox did not change significantly in other groups. there was no significant difference in mortality or poor outcome (mrs - ) at discharge and , , or months between patients in each group. in acute coma patients in the neurocritical care unit, increasing body temperature is associated with worsening cerebral autoregulation as measured by cox. the historical tradition of examining the pupillary light reflex (plr) required the examiner to score the size and reactivity of the pupil. a change in the plr from brisk to sluggish or fixed may be a marker of a pathological process and a need for intervention. the plr has been difficult to quantify and has poor inter-rater reliability. handheld pupillometry provides several novel measures, such as the neurological pupillary index™ (npi) and constriction velocity (cv) that may be more quantifiable than the plr. the purpose of this analysis is to examine the relationship between cv and npi in neurologically injured patients. the end-panic registry is a prospective registry of pupillometer values and variables associated with intracranial dynamics (e.g., icp). this analysis from adult (over years) patients from hospitals includes , pupillometer readings; left eye ( , ), and right eye ( , ). subjects had a mean age of . yrs and . % were male. the primary admission diagnosis included neoplasm ( ), ischemic stroke ( ), sah ( ), ich ( ), tbi ( ), and other ( ). the left eye mean/s.d. cv ( . / . ) npi ( . / . ) and size ( . / . ) were similar to the right eye cv ( . / . ) npi ( . / . ) and size ( . / . ); statistically significant difference related to large sample size. the correlation between left eye cv and npi (r = . , p< . ) was significantly improved after controlling for size (r = . , p< . ). the correlation between right eye cv and npi (r = . , p< . ) was significantly improved after controlling for size (r = . , p< . ). constriction velocity is highly dependent on size of the pupil. further studies need to be undertaken to determine the sensitivity and specificity of abnormal npi and cv in detecting pathological processes such as midline shift or rd nerve compression that effect pupillary reactivity. cerebral injury is increasingly described in adult recipients of extracorporeal membrane oxygenation (ecmo) therapy. we describe the association between regional brain tissue oxygenation (rso ) measured by near infrared spectroscopy (nirs), survival, and cerebral injury on neuroimaging. a single-center retrospective chart review was conducted of adult patients who underwent veno-arterial (va) ecmo from april to october . all patients had received nirs monitoring during ecmo therapy. baseline demographics, in-hospital complications, and mortality were recorded. desaturations of rso , defined as decline > % below baseline or absolute value < , were recorded and analyzed. desaturation burden was calculated by area under the curve analysis and measured by rso *seconds. eighteen va ecmo patients ( females) underwent nirs monitoring during the study period. eleven patients experienced desaturations, while did not. patients with desaturations tended to be younger ( . vs. . years old), more likely female ( vs. ), had lower ejection fraction ( . % vs. . %) and experienced liver dysfunction ( patients vs. ). patients with desaturations were more likely to have abnormalities on ct scan ( vs. ). eleven of the patients survived to discharge. survivors tended to be younger ( . vs. . years old) and had lower initial ecmo sweep ( . vs. . ). survivors had lower baseline rso values at the beginning of nirs monitoring (right - vs. , left - vs. ), fewer desaturation events ( vs. ), lower desaturation burden, and spent less overall time desaturating ( : vs. : hours). desaturation on nirs may be correlated with cerebral injury in the adult va ecmo population and may have utility in triggering clinical investigation or determining prognosis. further studies in larger patient populations are needed to determine its reliability and accuracy. pressure reactivity index (prx) is the most validated index to measure cerebrovascular reactivity in patients after traumatic brain injury. the aim of this study is to identify the natural history of cerebral autoregulation measured by prx in various forms of brain injury to monitor restoration or not of cerebral vasomotor reactivity in the acute phase. retrospective analysis of data from ongoing prospective study to evaluate multimodal monitoring using prx for the measurement of cerebral autoregulation at the bedside. thirty comatose patients (glasgow coma scal used as a marker of autoregulation. prx was calculated as a moving, linear correlation coefficient between icp and map. impaired cerebral autoregulation has been pre standard maximal medical therapy was implemented to treat elevated icp, cerebral edema, etc. patients with withdrawal of care in the first hours or brain death on neurological exam were excluded. thirty comatose patients from acute brain injuries ( intracerebral hemorrhage, tbi, aneurysmal subarachnoid hemorrhage, intraventricular hemorrhage, hypoxic ischemic encephalopathy) were studied. the average prx upon starting neuromonitoring using prx was . ± . (impaired), whereas the average prx at the end of day of neuromonitoring was ± . (restored). one third of the patients had icp crisis during monitoring. the average opening icp= . , average highest recorded icp= . . impaired cerebral autoregulation has been implicated as a predictor of clinical outcome. aggressive medical therapy instituted by the neurocritical care team (icp and cerebral edema management, blood pressure control, etc.) may result in restoration of cerebral vasomotor reactivity measured by prx by intensive care day - . restoration of cerebral vascular reactivity may be a necessary but not sufficient for favorable outcome. elevated intracranial pressure (icp) is an important cause of death following acute liver failure (alf). while invasive icp monitoring (iicpm) remains the gold standard, the presence of coagulopathy increases the risk of bleeding in alf. measurement of optic nerve sheath diameter (onsd) using optic nerve ultrasound (onus) may accurately detect elevated icp. our goal was to study the ability of onus to detect sustained intracranial hypertension following alf, and to predict death and therapeutic intensity level (til), a quantitative measure of the intensity of treatment required to control icp. consecutive patients with alf admitted to our institution in a -year period underwent onus. blinded measurement of onsd was performed from deidentified onus videos. patients underwent iicpm on the basis of an institutional protocol for selection of appropriate candidates, coagulopathy reversal and insertion of an intraparenchymal monitor. the til-basic for management of icp during the icu stay was recorded. the ability of highest onsd to predict concurrent icp> mmhg at the time of measurement, sustained icp elevation > mmhg at any time and til-basic> was assessed in patients who underwent iicpm, while prediction of death was assessed in all patients. receiver operating characteristic (roc) curves were constructed for the outcomes of interest. thirty-nine patients with alf were admitted during the study period, / ( %) underwent onus, / ( %) underwent iicpm and ( %) died. of patients who underwent iicpm, ( %) developed sustained icp elevation and ( %) had a til-basic> . the roc area under the curve (auc) of onsd for prediction of concurrent icp> mmhg was . ( % confidence-interval . - . , p= . for null hypothesis of auc= . ), sustained icp elevation at any time was . ( . - . ,p= . ), death was . ( . - . ,p= . ) and til> was . ( . - . ,p= . ). in patients with alf, onsd measurement performed poorly for detection of icp elevation, and was a poor predictor of til and death. limited literature exists regarding the neurochemical and physiologic events that occur as brain death develops. using intracranial multi-modality monitoring, we identify physiological changes that signal the onset of brain death. we measured intracranial pressure (icp), brain partial oxygen tension (pbto ), cerebral blood flow (cbf), and biochemical correlates of cerebral metabolism in patients with diffuse hypoxic ischemic brain injury after cardiac arrest during the development of brain death. monitoring probes were inserted into cerebral white matter through a burr hole using a ct compatible multi-lumen bolt. brain tissue energy-related metabolites (lactate, pyruvate, glutamate, glucose, glycerol) were measured using a bedside microdialysis analyzer. pbto and temperature were measured via a licox catheter. cerebral perfusion was measured with a hemedex bowman perfusion monitor. brain death was confirmed in accordance with institutional guidelines. a characteristic pattern of physiologic and neurochemical findings emerged as brain death occurred. absolute loss of cerebral autoregulation, with a near perfect correlation between icp and map was followed by equalization of map and icp resulting in progressive drop in cpp to zero, followed by a progressive decline in pbto that became unresponsive to a % fio challenge. cerebral perfusion decreased in tandem with pbto . lactate/pyruvate ratio (lpr), glutamate, and glycerol all increased precipitously, with lpr consistently > . brain temperature decreased despite maintenance of a normal core temperature. finally, intracranial compliance, while initially very low (evidenced by marked increase in the p component of the icp waveform), appeared to paradoxically re-normalize as the recording continued. continuous neuromonitoring reveals a characteristic pattern of cerebrovascular physiologic changes that accompany brain death. these changes are consistent with a progressive cessation of cerebral perfusion caused by diffuse cerebral edema. although not currently a part of the formal brain death determination process, such monitoring could be helpful to identify when brain death has truly occurred. automated devices that collect objective quantitative data on pupil size and reactivity are increasingly used for critically ill patients with neurologic disease. however, there is limited data on the normative range of pupillary reactivity in the critically ill, and the relationship between reactivity and traditional monitoring metrics. to determine pupil characteristics in this population, we prospectively collected quantitative pupillometry data in patients admitted to the neuro icu with an expected stay of at least hours. trained nursing staff measured pupillary reactivity with the neuroptics- pupillometer device every -hours. measurements included the neurologic pupil index, (npi) a composite metric ranging from - in which > is considered normal, resting and constricted pupil size, constriction velocity, dilation velocity and latency. these recordings were compared with averaged intracranial pressure (icp) and glasgow coma scale (gcs) assessments within the same hour. we used univariate and spearman's rank tests to explore associations between pupil characteristics and clinical variables, followed by multi-level linear regression to account for intra-and inter-subject variability. one-hundred patients underwent paired observations. fifty-five patients had at least one recorded episode of anisocoria, had low npis in more than % of recordings, and had normal pupil reactivity. average and minimum npi was correlated with average and minimum recorded hourly glasgow coma score (gcs) (p values < . ). increased asymmetry in both pupil size (p= . ) and dilation velocity (p= . ) was associated with increased intracranial pressure (icp). anisocoria was associated with hyperosmolar therapy (p= . ). the presence of low npis in more than % of total pupil measurements was associated with death at discharge (p= . ). the range of pupillary metrics varies among critically ill neurologic patients and correlates with gcs and icp. further study is needed to establish whether change in pupil metrics predict specific clinical events. near infrared spectroscopy (nirs) provides a non-invasive measurement of regional cerebral oxygen saturation (rso ) that may be able to detect seizure activity. in this study, we explored the hypothesis that rso is lower ipsilateral to seizures or epileptiform activity compared to the contralateral side in comatose patients. five patients ( men and women; mean age ) underwent continuous electroencephalography (ceeg) monitoring and nirs recording. ceeg data were classified as baseline, epileptiform activity or seizure, slowing, or burst suppression at hourly intervals over the course of the recoding period (mean duration . hours, range to hours). three patients had idiopathic status epilepticus, two had intracranial hemorrhage, and one had a temporal meningioma. the relationship between rso and epileptiform discharges was explored using scatterplots. the association was assessed using mixed random effects models with a random intercept. an independent within-subject residual structure was used. there were measurements with ceeg and nirs from patients. one patient was excluded as the nirs sensors were potentially reversed. epileptiform activity or seizures were observed in a median of % of the measurements (iqr - %). rso was significantly lower on the side ipsilateral to seizures - . , p < . ) after adjusting for map. all patients only had partial seizures with no generalization. partial seizures and/or epileptiform discharges were not associated with impaired autoregulation. we found a significant lower cerebral oxygen saturation ipsilateral to seizures and/or epileptiform activity. the association was observed in patients with various etiologies of coma, and with either convulsive and non-convulsive seizures. decreases of regional cerebral oxygen saturation at the bedside may alert the clinician of ipsilateral seizures. elevated intracranial pressure (icp) and cerebral edema are common causes of mortality in neurocritical-care patients. key monitoring techniques for icp-elevation include neuroimaging and invasive icp-measurement. examination of the pupils is routinely performed to determine disturbances within cerebral physiology but shows high inter-rater variability. portable infrared pupillometry is increasingly used for accurate measurements. the benefit of these technique remains to be established in patients with elevated icp. aim of this study was identify pupillary parameters associated with icpcrisis in neurocritical-care patients. we prospectively enrolled critically-ill patients (subarachnoid hemorrhage/intracerebral hemorrhage/stroke/bacterial meningitis) admitted to our neurointensive care unit( / - / ) who required placement of external ventricular drains. we recorded serial pupillometer readings [i.e. maximum/minimum apertures(mm), constriction/dilation velocities(mm/sec.), latency period(sec.)] and corresponding icp values every hours after admission. neurological pupil index(npi), an algorithm that compares above mentioned pupillary parameters to a normative model of pupil reaction to light, grades pupil-function on a scale of (nonreactive) to (normal). receiver operating characteristic(roc) curve analysis was performed to investigate associations between pupillary parameters and presence of icpcrisis(icp> mmhg). in our data suggest a relationship between non-invasively detected changes in npi, cv or mcv and icpcrisis. yet, clinical benefit of these parameters is subject to future studies. lung injury is frequently observed in patients with severe, acute brain injury. while these patients often require mechanical ventilation, a lung protective ventilation strategy has not been extensively studied. this may be due, in part, to concerns that elevated positive end-expiratory pressure (peep) could adversely affect intracranial pressure (icp) or cerebral perfusion pressure (cpp). we were interested in exploring this relationship as a first step towards understanding whether mechanical ventilation resulted in a transmission of pressure to the brain. ) and received both mechanical ventilation and icp monitoring were enrolled in this pilot study. an esophageal balloon was inserted to measure their transpulmonary pressure (ptp). fluid responsiveness was assessed prior to the intervention. subjects underwent a step-wise increase in peep (increments of five) from to cmh o. airway pressure, ptp and icp were measured at each peep interval. of the planned twenty, three patients have been enrolled to date. primary diagnoses included aneurysmal subarachnoid hemorrhage and intraparenchymal hemorrhage with a median gcs of . patients were ventilated using either volume control or pressure support ventilation; median fio was . . two patients were on vasopressors and the same two patients were determined to be fluid responsive. at baseline (peep ), mean icp, cpp, and ptp were mmhg, mmhg, and - . cmh o, respectively. when peep was increased to cmh o, the average change from baseline in icp and cpp was - . % and - . %, respectively. when increased to cmh o the change from baseline in icp and cpp was . % and . %. during the intervention icp did not exceed mmhg, nor did any patient experience hypotension. preliminary data suggests that intrathoracic pressure is not directly transmitted to the intracranial compartment. continued enrollment is needed to confirm these findings. neurocritical care after severe traumatic brain injury (stbi) is focused on detecting and preventing secondary brain injuries. in addition to intracranial pressure (icp), measures of brain tissue oxygen (pbto ), regional cerebral blood flow (rcbf), and electrocorticography (deeg) may provide critical clinical data. few studies have assessed the safety of such an approach and the reliability of data that is gathered. we describe here the placement, complications, and reliability of multimodality monitoring (mmm) data from a novel, single burr hole approach using a four-lumen bolt at our institution. we included consecutive adult stbi patients admitted to the neuroscience intensive care unit at the university of cincinnati from april to march who underwent mmm as part of standard clinical management per institutional protocol. data was obtained regarding device placement and complications. all data was visually inspected for errors and gaps in data. patients were included. the mean age was +/- and % were men. bolts were placed a median of . (iqr . - . ) hours from injury. no clinically significant complications occurred, although . % had minor complications (e.g. small tract hemorrhage or pneumocephalus). suboptimal placement of probes was noted in %. we monitored patients a median . (iqr . - . ) hours. icp data was the most reliable, with data available . % of the total monitoring time and only . % error time. pbto and deeg data were reliable for > % of total monitoring time with < % error time. rcbf provided data for % of total monitoring time and had . % error time. mmm in stbi may be carried out via a single burr hole without significant clinical complications and reliably yields continuous data to facilitate clinical decision making. this supports the feasibility of our approach as an alternative to icp monitoring alone. intracranial hemorrhage patients with non-compliant ventricles may have high intracranial pressure (icp) despite normal ventricle size. we aimed to assess the incidence of elevated icp among those with no radiographic evidence of intracranial hypertension. prospectively enrolled primary intracranial hemorrhage patients (sah, sdh and iph) admitted to two tertiary-care centers between / - / were retrospectively reviewed. among patients with external ventricular drainage (evd), admission head ct (hct) scans within h prior to evd placement were reviewed for evidence of elevated intracranial pressure (icp) including: ventricle size (bicaudate index, temporal horn size), basal cistern effacement, midline shift and global cerebral edema. when all of these features were absent, patients were classified as having normal-icp hct. the incidence of elevated icp (> mmhg) at the time of evd placement and during hospital stay were recorded. of intracranial hemorrhage patients enrolled, ( %) had evd. / ( %) had a normal-icp hct. of these, / ( %) had elevated opening pressure at the time of evd placement, and / ( %) had elevated icp during their hospital stay. among normal-icp hct patients with icp> mmhg, % had sah, and the median gcs and hunt-hess scores were (range - ) and (range - ). the positive and negative predictive values of normal-re % %, respectively (auc . , p= . ) the only radiographic feature that was associated with elevated icp was global cerebral edema (or . , % ci . - . , p< . ). approximately half of intracranial hemorrhage patients without radiographic features of elevated icp had icp> mmhg at the time of evd placement and additional patients had elevated icp during their hospital stay. radiographic findings should not be relied upon to exclude the possibility of elevated icp. the measurement of intracranial pressure (icp) is a cornerstone of intensive care management following severe traumatic brain injury (stbi). it has been only recently that the time integral of icp has been quantified in relation to outcome; the time integral of brain tissue oxygen (pbto ) has not been studied. we gathered time-locked intracranial monitoring data on s tbi patients at the university of cincinnati over years. clinical management of all patients followed national standards. raumedic pto probe was used to measure icp and pbto ; accuracy was verified by visual inspection with automated data cleaning. normalized data was mapped based on correlation with glasgow outcome scale scores at - months. we studied patients aged +/- years (mean+/-sd); % were male. initial post-resuscitation glasgow coma scale score was median (interquartile range: . - ). / underwent craniectomy prior to monitoring. among those with good (gos - ) and poor (gos - ) outcome, the average icp was . +/- . mmhg and . +/- . mmhg (p= . ); the average pbto was . +/- . mmhg and . +/- . mmhg (both n.s.). the correlation with outcome was dependent on both icp and time: an icp > mmhg for > minutes was associated with poor outcome, whereas an icp < mmhg was associated with poor outcome only after hours. in contrast, the pbto level, but not the duration, correlated with poor outcome in those without craniectomy at a pbto < mmhg, and particularly below mmhg. pbto burden was less reliable in those following craniectomy. we replicated the effects of icp/time in a cohort of patients with severe tbi, both with and without craniectomy and subsequently demonstrated the burden of brain tissue hypoxia in those without craniectomy. the time integral of multimodality monitoring data may provide more accurate measures of secondary insult burden with implications for clinical care and prognosis. neurologists who work in neurocritical care (ncc) as neurointensivists may have critical care (cc) charges rejected for payment unless they are classified per centers for medicare services (cms) taxonomy codes in their systems as critical care providers. the neurocritical care society and cms created a new ncc code a x to fix this issue. we polled the aan ccen section members for awareness of this problem. we conducted a six question google forms survey using the aan ccen synapse community website to assess knowledge of the ncc taxonomy code: we received anonymous responses by the time we closed the poll on / / . question (q ) and (answers, a ): are you a neurology or neurosurgery back grounded intensivist who does neurocritical care at your hospital? y/n (yes/no). a : % reported being neurologists. q : were you aware of the new cms neurocritical care taxonomy code a x ? y/n a : % were aware of the taxonomy code. q : are you aware why the ncc taxonomy code was created? y/n a : % of respondents were unaware why this code was created. q : what is your primary department for revenue collection? a : % reported neurology, % neurosurgery, % critical care, and % blend. q : are you aware that medicare can reject critical care charges ( and ) can be rejected unless you are listed as a cms 'critical care provider' or as a neurocritical care provider? a : % reported rejected charges at their centers. q : are you aware of rejection of critical care charges happening at your own institution due to this misclassification? y/n a : % of respondents reported rejected charges at their center. although limited in sample size, this survey revealed almost half of the respondents were unaware of the ncc code. we believe a larger study is warranted. arterial subdural hemorrhage (sdh) is a rare but potentially devastating neurologic entity. it has been associated with ruptured aneurysms. we report a case-series of five patients with arterial sdh and their outcomes. a retrospective chart review of our institute's vascular database was conducted using a pre-defined search strategy including the terms "aneurysm", "arterio-venous malformation", "subdural hemorrhage", and "dural arterio-venous fistula" (dural-avf). amongst patients in the database, five cases were identified with ages ranging from to (four females). four had sdh due to aneurysm (two internal-carotid, one middle-cerebral, and one posteriorcerebral artery; one had parieto-occipital dural av-fistula. no patient had preceding head-trauma or anticoagulation. of aneurysmal patients, one had no sah. on admission ct-head imaging, the mean-sdh size was . mm (sd . ; range . - mm), and mean midline-shift (mls) was . mm (sd . ; range - mm). the mean ratio between sdh-size and mls was . (sd . ). in a historic cohort of acute subdural hemorrhage of non-arterial etiology ; the mean size of sdh was . mm and the mean mls was . mm. ratio of mls: sdh size was . . in our series, three patients with aneurysms had decompressive-craniectomy, one had mini-craniotomy for sdh evacuation; the patient with dural-avf had coiling and mini-craniotomy for sdh evacuation. four patients had died during hospitalization, whereas patient with dural-avf recovered to baseline functional-status at -month follow-up. arterial sdh is a rare entity and may present without subarachnoid hemorrhage and any preceding head-trauma. the degree of midline-shift is usually out of proportion to sdh size. there should be a low threshold to obtain vessel imaging in cases of sdh with no clear trauma history. mls: sdh ratio may be a useful screening tool for possibility of arterial sdh especially in absence of trauma and may reflect rate of bleeding. neurostimulant medications (amantadine and modafinil) are sometimes prescribed after acute nontraumatic brain injury to facilitate wakening and rehabilitation participation; the safety and effectiveness of this practice is unknown. following a retrospective evaluation of our experiences, we characterized anticipated challenges to designing a prospective randomized trial of neurostimulant medications to promote rehabilitation participation after acute non-traumatic brain injury. retrospective chart review of patients over with subarachnoid hemorrhage (n= ), intracerebral hemorrhage (n= ) and ischemic stroke (n= ) who received neurostimulant medications over a period of months. data regarding clinical course and potential confounders to assessing response were collected. continuous data are reported as median and interquartile range. neurostimulant medications were initiated in patients at a median of ( - ) days after hospital admission, for hypersomnolence ( %), not following commands ( %), lack of eye opening ( %), and/or low gcs ( %). thirty-nine ( %) patients were receiving sedatives or opioids at the time of neurostimulant(s) initiation. twenty-two ( %) patients received newly prescribed sedatives or opioids after neurostimulant(s) initiation. potentially sedating antiepileptic medications were prescribed to ( %) of patients. twenty-two ( %) patients were intubated at the time of neurostimulant initiation confounding the gcs-v. potentially confounding clinical factors included hydrocephalus ( %), vasospasm ( %), and seizures ( %). twenty-eight ( %) of patients had temporary cerebrospinal fluid diversion in place at the time of neurostimulant initiation. initiation and titration of neurostimulant medications after acute non-traumatic brain injury was common, but timing and indications varied widely. confounders to assessing effectiveness included concomitant sedating medications, variable pathophysiology related to the type and location of the stroke, and clinical factors like seizures, vasospasm, and hydrocephalus. these confounders are likely to make prospective evaluation of neurostimulant medication effectiveness difficult in the period of initial therapy following acute non-traumatic brain injury. brain small vessel disease can cause cognitive impairment via ischemic or hemorrhagic mechanisms. current imaging modalities, specifically magnetic resonance imaging allow for easier detection of different intracranial pathological processes including cerebral microhemorrhages (cms). research demonstrated that the number and location of cms correlate with the type of cognitive impairment (memory, processing speed, executive function, and motor speed). a retrospective analysis of patients (age to ) seen at our neurology outpatient clinic from to who were identified by linguamatics software to have "microhemorrhage" in their radiology mri report. additional information included age, sex, cognitive examination, presence of cardiovascular risk factors, mri, and the number and location of cms. cognitive function was determined by mini mental state examination (mmse) score and diagnosis by a cognitive neurologist. patients were grouped by presence of cm or greater ( to ) and regression was used to determine a relationship with mmse and vascular risk factors. the number of microhemorrhages per patient were ( patients), ( patients), ( patients), ( patients), ( patients), ( patients) and ( patients). vascular risk factors included hypertension ( patients), diabetes mellitus ( patients) and smoking history ( patients). regression analyses indicated that the presence of more than cm correctly predicted mmse lower than at % (p= . ). age was the only factor that influences this finding and increased this prediction to %. this study provides novel evidence that the presence of multiple cms on brain images predicts the presence of cognitive impairment. this study raises the need for more investigations. point-of-care ultrasound is a valuable tool in critical care, allowing timely and frequent beside assessment of clinical questions. neurocritical care has long utilized transcranial doppler but is still early in the adoption of other critical care ultrasounds. this study looked at the comfort level and competency of the participants at the point-of-care ultrasound workshop at the neurocritical care society annual meeting. the workshop comprised of didactics and hands-on small group practice using live models. topics covered included ultrasound physics, lung, cardiac, optic nerve sheath ultrasounds, as well as case studies in neurocritical care. participants were asked to complete an anonymous pre-and postworkshop assessment on a volunteer basis. a total pre-workshop and post-workshop assessments were completed. the mean age of the participants was . ± . years. there were ( . %) attending physicians, ( . %) advance practice practitioners, ( . %) fellows, ( . %) residents, and ( . %) research scientist. participants had limited ultrasound experience prior to the workshop, with ( . %) reported none, ( . %) reported < year, and ( . %) reported to years. on a - scale on comfort using ultrasound with being very uncomfortable and being very comfortable, participants reported a median score of (iqr - ) pre-workshop with an improvement to (iqr - ) post-workshop. for matched pre-and post-tests, all participants had an improvement in their ultrasound knowledge. while the majority of the participants at this workshop had prior ultrasound experience, many are still uncomfortable with their ultrasound competency. the format of didactics and hands-on small group practice improved the comfort level as well as overall ultrasound knowledge of these participants. additional opportunities for point-of-care ultrasound training should be considered in neurocritical care fellowships and meetings. event related potentials (erps) allow assessment of cognitive processing in unconscious brain-injured patients. here we explored the diagnostic and prognostic value of erps obtained shortly after brain injury. we prospectively collected a comprehensive erp paradigm labeled "local global paradigm" from a consecutive series of unconscious patients with acute brain injury. this auditory paradigm allows the assessment of: ) cortical responses, ) unconscious cognitive processing, ) unconscious focusing of attention, and ) conscious processing of sounds. levels of consciousness assessed with the coma recovery scale-revised (crs-r) at the time of recording were correlated with the presence/absence of each erps component and functional connectivity/complexity measures. we tested the prognostic value of each measure for recovery of consciousness prior to discharge. we analyzed recordings from patients (median recordings per patients [iqr , ]). recordings were made [iqr . , . ] days after brain injury and all patients were unconscious at the time of the initial recording. underlying etiologies included ich(n= ), sah(n= ), tbi( ) and other (n= ). there were trends for higher crs-r scores in patients with preserved erp components. crs-r scores correlated with the functional connectivity indexed (rho= . ; p= . ) but not with complexity measures. five ( %) patients regained consciousness (within to days from brain injury). one of these patients had to be excluded due to poor quality recording. all the ( %) remaining patients had the three type of non-conscious responses preserved on at least one recording in comparison to only ( %) among patient who did not recover consciousness (fischer p-value = . ). similarly, connectivity was greater in patients who regained consciousness ( . vs . ; p= . ) but the complexity was similar. simple bedside erp responses indexing cognitive processing during the local global paradigm obtained shortly after brain injury correlate with the level of consciousness but, more importantly, the probability to recover consciousness. over a decade ago, the institute of medicine introduced family-centered care (fcc) as a vital aspect of quality health care by strongly recommending that family members of intensive care unit (icu) patients be actively involved in decision-making. while there are many resources to help icu staff conduct meetings and provide information to families, the latest society of critical care medicine guidelines for fcc recommend the implementation of communication and decision support tools for family members to use. electronic decision support tools such as my icu guide have been effective in pilot studies at allowing family members to customize information delivery and communicate their preferences to icu staff. we sought to integrate a decision support and communication tool for families into an electronic patient portal. we developed an electronic patient and family engagement checklist for the neurointensive care unit (nicu) using doctella (patient doctor technologies, sunnyvale, ca), an existing patient engagement application. checklist components included: identifying a spokesperson, developing an advance directive, understanding diagnosis and prognosis, access to helpful resources, and a family meeting guide and planner. we presented the checklist to our hospital's patient and family engagement steering committee for the icus and received useful feedback. the checklist will also be vetted by the hospital's patient and family advisory council. usability testing will also be conducted. a family engagement checklist using an electronic patient portal is a novel strategy to enhance communication in the nicu. further validation of the tool is needed. applying painful stimuli to brain injured patients is a time-honored practice assumed to provide valuable clinical information for diagnosis, prognosis, and potential guidance for therapeutic interventions. however, there is limited literature that has evaluated and discussed the benefits and potential adverse effects related to repeated painful stimulation during bedside neurological examinations. though providers intend to do no harm, the practice of repetitive painful stimulation can unintentionally damage patient's skin, muscle, and bone, as well as inflict emotional duress. in conjunction with basic ethical principles used to justify painful stimulation during patient examinations, we propose a revisiting of the practice of routine repetitive painful stimulation in neurologic bedside assessments. . discuss the current literature regarding the use of painful stimulation and its beneficial and damaging effects, . describe alternative strategies for neurologic assessments, . propose guidelines to optimize accurate neurologic assessments while avoiding unnecessary repeated painful stimulation, . propose the development of a graded methodology for delivering painful stimulation when necessary for neurologic assessments. a summary of the literature will be outlined and discussed focusing on the ethical considerations and justification for the use of painful stimulation in the neurologic patient and the perception of pain in coma and minimally unconscious patients, . alternative strategies will be presented to minimize bodily and emotional injury, . a proposed outline with a companion flow diagram "easing the pain guidelines" implemented in a tertiary care neurocritical care unit will be presented. there has been little attention paid to the burden of painful stimulation inflicted on patients in the neurocritical care unit. the guiding principle of nonmaleficence (do no harm) morally obligates clinicians to evaluate current practice standards using repetitive painful stimulation in routine neurologic assessments. implementing standardized guidelines will limit unintended harm to patients without compromising accurate neurologic assessments. plasmapheresis is utilized in anti-n-methyl-d-aspartate receptor (nmdar) encephalitis to remove autoantibodies. antiepileptic drugs (aed), such as valproate, are often used to control seizures which may complicate anti-nmdar encephalitis. it is important to prevent rapid reductions of aed levels to ensure proper seizure management in this setting. we obtained total and free (active drug, unbound to plasma proteins) valproate levels intermittently throughout two -day courses of daily plasmapheresis. during the first course, trough levels were obtained. during the second course, levels were obtained before, during, and after plasmapheresis. the patient was a year old female, weighing kg. albumin was . g/dl. her valproate regimen ranged from mg to mg every hours ( to mg/kg/day), given intravenously or enterally. prior to the first plasmapheresis, valproate dose was mg every hours, resulting in a total level of mcg/ml (reference range: - mcg/ml). free valproate was mcg/ml (reference range: - mcg/ml); free fraction was % (reference range: - %). four days later, prior to the th plasmapheresis, the total valproate level was . mcg/ml. two days after the th plasmapheresis the total level was unchanged at mcg/ml; free valproate was mcg/ml and free fraction was %. during the second course of plasmapheresis, valproate total levels, free levels, and free fractions were mcg/ml, mcg/ml, and % before, mcg/ml, mcg/ml, and % during (valproate dose given upon initiation of plasmapheresis), and mcg/ml, mcg/ml, and % after plasmapheresis, respectively. valproate serum levels were not markedly influenced by plasmapheresis. free valproate levels and the free fraction were highly elevated throughout the patient's hospital course, however. future studies should evaluate critically ill patients' clinical response and toxicity correlations as the free fraction of valproate appears to be elevated in this setting. the purpose of this study is to assess knowledge retention of emergency neurological life support (enls) after participation in the course via a prospective observational study. study subjects seeking enls certification consented for study participation (enls-vs) from the ncs website then took a closed-book, multiple-choice question pre-test within hours of enls course participation. after completion of the enls course, participants took the same closed-book, multiplechoice question test (post-test). these tests consisted of novel questions from material presented in the course. questions were not repeated from the enls certification exams. thirty participants enrolled in the study with completing both the pre-test and immediate post-test. all participants' scores improved on the post-test as compared to the pre-test. the mean percent correct on the pre-test was . % with a median of . % (range . - . %). of the participants who have completed both pre-and immediate post-test, the mean pre-test score was . % with a median of . % (range . %- . %). the mean post-test score was . % with a median of . % (range . %- . %). the improvement of scores was statistically significant on the post-test compared to the pre-test ( . % vs. . % %, p< . ). all participants in the emergency neurological life support course showed improved test scores immediately after participation in the standard enls course. this study will assess knowledge retention at -months following training, and is actively enrolling new participants. augmented renal clearance (arc, defined as a creatinine clearance of > ml/min) has been demonstrated in neurocritical care disease states such as traumatic brain injury, intracranial hemorrhage, and subarachnoid hemorrhage. arc may result in increased elimination of renallyeliminated medications, thereby reducing drug exposure with standard doses. the overall prevalence of arc is not well described. the purpose of this study was to estimate the overall prevalence of arc in a neurocritical care population. this was a retrospective cohort study of adults > years of age admitted to the intensive care unit on the neurosurgery service. demographic and pertinent laboratory data were collected for patients admitted from january , thru december , . an arctic score was calculated for each patient ( or greater suggests arc). parametric data was compared using one-sample student's t-test, nominal data was compared using fisher's exact test (alpha = . ). statistical analysis was conducted using ibm spss version . present in a total of . % of patients. a broad spectrum of neurocritical care diagnoses was present. the mean age in years was significantly lower in patients with arc [ . ( sd)] than without arc [ ( sd), p = . ], as was the serum creatinine [with arc . mg/dl ( . sd) vs without arc mg/dl ( . sd), p < . ]. mean hospital length of stay was greater in patients with arc than without [ . ( sd) vs . ( sd), p < . ]. arc occurs commonly in neurocritical care patients and likely merits proactive screening or direct measurement of creatinine clearance in select patients. pharmacokinetic studies of commonly used renally-eliminated medications may be needed to establish population parameters in the neurocritical care population. education surveys demonstrate gaps in resident neurocritical care education and training. we assessed junior residents' baseline knowledge of neurologic emergencies, procedural competency, knowledge of available resources, and the impact of pre-rotation orientations. junior residents (neurosurgery pgy s and neurology pgy s) who had not previously rotated in the neuroicu were surveyed. a three-part survey was administered: part i, knowledge of icu structure and personnel; part ii, procedural competency; part iii, comfort with common neurocritical care emergencies. the survey was comprised of selection responses. after the survey but prior to starting the rotation, each resident was oriented to the unit by a neuroicu attending and nursing director. this orientation reviewed rotation goals, icu structure, personnel and rounding expectations. a survey was repeated to evaluate the orientation. of residents who had not rotated in the icu, ( . %) responded. none of the residents understood their specific role within the icu team. % did not understand the role of the resource nurse and were unaware of where to find procedure equipment. % of residents were not comfortable placing an a-line; % were not comfortable performing a lumbar puncture. over half of respondents said they "didn't know and could not easily find" the indications for hemicraniectomy after malignant mca ischemia, the indications for icp monitoring, or the initial workup of autoimmune encephalitis. residents responded to post orientation surveys. % felt the orientation was helpful in explaining the roles of team members. % felt it was at least "somewhat helpful" in understanding the role of the resource nurse. % felt the orientation was "helpful" and % felt it was "somewhat helpful" in identifying the goals of the rotation. these baseline measures underscore the importance of structured interventions, both before and during the neuroicu rotation, to improve junior resident comfort and preparedness in managing neurologic emergencies. physician-staffed helicopter emergency medical services (hems) are a well-established component of prehospital care in japan. however, there has been no report on hems and neurocritical care patients. we studied characteristics of neurocritical care patients who were transported by hems. we retrospectively evaluated neurocritical care patients who were brought to our emergency and critical care medical center (eccmc) by hems between january, and march, . we excluded patients in whom the outcome was unknown, those who were transported to other hospitals or between facilities. of the most important role of hems is rapid transportation of a flight medical team to the scene to provide immediate, lifesaving medical treatment. we found that half of patients admitted to our hospital by hems were neurocritical care patients. as proposed in the enls of neurocritical care society, hems is considered useful to allow neuro-emergency patients to receive the best care in the first hour. optic nerve sheath diameter (onsd) measurement using ocular ultrasound has been shown to accurately detect elevated intracranial pressure (icp), but does require specialized training. variations in the optimal onsd threshold for detection of elevated icp in the literature limits clinical utility, and may reflect heterogeneity in manual measurement techniques. our objective was to develop, and validate against expert measurement, an image-analysis algorithm for onsd measurement to facilitate standardization and ease of use of this technique. consecutive patients with acute brain injury admitted to the neurointensive care unit underwent ocular ultrasound with a multipurpose point-of-care ultrasound machine. a -second video was recorded from each eye in the axial plane and downloaded in dicom format. the onsd measurement algorithm was as follows. an average of images was calculated using non-overlapped segments of the image sequence. a line integral was performed to estimate the border of the region of interest (roi), the globe. the roi orientation and globe point of the segmented region were established, then a point mm posterior to the globe point identified. the onsd was measured at this point. manual onsd measurement was performed separately from the dicom videos by an expert blinded to the algorithm measurement. an intraclass coefficient (icc) was calculated for absolute agreement between highest onsd measured by the algorithm and expert manual measurement. a total of patients with acute brain injury underwent ocular ultrasound. the icc for absolute agreement between algorithm (median . , interquartile range . - . ) and manual expert (median . , . - . ) highest onsd measurement was . ( % confidence interval . - . ). an algorithm for automated measurement of onsd was developed and demonstrated good inter-rater agreement with expert measurement, although further refinement is required. automated measurement may help standardize and simplify a promising noninvasive bedside tool for the detection of elevated icp. after transition to electronic health record (ehr), transition to inpatient hospice required a separate encounter to account for change in insurance payer in our neuroicu. this negatively affected completed transitions and hence patient-centered care. the focus of this quality improvement project was to define the new process, improve outcomes, and identify further opportunities. the quality improvement method "plan-do-study-act" was employed for this work within a -bed neuro-icu at a large academic medical center. we assessed the current state (not enabling transition to inpatient hospice) and the desired state (enrollment in hospice during inpatient stay). a new process was created using an ehr discharge navigator, coordinating all relevant stakeholder groups (patient/caregiver, nurse, pharmacist, bed control, physician,). in addition, standard methodology for unit-based education, in-service, just-in-time training, and booster education was employed to identify process, outcome, and improvement opportunities. after rollout of the new discharge navigator, % of all patient-facing staff successfully completed the inpatient hospice training. process improvements lead to increase in palliative care consults by % ( to annually) and inpatient hospice discharges up to % ( to annually). furthermore, there was a statistically significant improvement in the vizient mortality index r = . , f( , ) = . , p < . and length of stay index r = . , f( , ) = . , p < . within the study population and period. ability to transfer patients to inpatient hospice is often limited and complicated. this study shows how employing standard quality improvement as well as education and implementation methods can result in improved process and outcome measures with sustainable success. opportunities remain in further analyzing and optimizing 'time to palliative care consult', 'time to admission to hospice and withdrawal of artificial support'. arnp and pa's are a rapidly growing part of the critical care workforce. proper selection among a pool of app candidates for the job is necessary to ensure the "right fit" and optimize patient safety. conventional interview techniques may not be adequate when selecting critical care app's. we hypothesized that use of a simulation center could be used to help select app candidates based on their critical thinking skills in conjunction with contemporary interviewing skills. from to , we performed conventional interviews for app's to staff critical care and neurocritical care patients. in we changed to an interview process consisting of the conventional interaction with the interviewee followed by simulation. after narrowing down the initial candidate pool, each was taken to the simulation center where they participated in a simulation of a decompensating patient. proctors were able to view the simulation in a separate room and direct the simulation mannequin. during this time proctors were able to evaluate the interviewee's patient interaction, assessment and interventions. an evaluation tool was to grade app candidates for their decision making skills, communication and thought. from to , we screened candidates before selecting for interviews and finally of those for simulation. over this timeframe, our center hired app's. comparing the ratio of screen applicants to employment was . and ratio of interviewed to hired candidates was . . these ratios show the competitive process and potential use of simulation in selecting apps. compared to the time period of applicants prior to simulation to after, retention went from to %, and disciplinary action for practice deficiencies went from % to %. the use of simulation based interviews for critical care app's in our institution improved retention and decreased the number of disciplinary actions compared to conventional interview methods. the contraindications for lumbar puncture (lp) in the setting of cerebral mass effect remain debatable. limited retrospective data advocate its potential safety. yet, high-quality guidelines specifically addressing this topic are not available. specific patient populations (post-instrumentation & immunosuppressed) may benefit from csf studies. we reviewed consecutive patients who underwent lp and cerebral imaging a week before or after lp from - . all individuals with evidence of brain herniation, a component of midline shift, or mass effect were included. all subjects received a low volume lp ( - cc of csf). there were patients with radiological increased icp. midline shift (average = mm) was present in patients. we also observed herniation: uncal (n= ), subfalcine (n= ), and a combination of both (n= ) , ventricular effacement (n= ) and cisternal compression with partial occlusion: quadrigeminal cistern (n= ), cerebellar-pontine-angle cistern (n= ), ambient cistern (n= ), crural cistern (n= ), prepontine cistern (n= ), suprasellar cistern (n= ), basal cistern (n= ), suprachiasmatic cistern (n= ), cisterna magna (n= ), interpeduncular cistern (n= ), medullary cistern (n= ). all patients tolerated the lp without complications. most survived a week after the procedure (n= , %). notably, four individuals deteriorated for reasons unrelated to the lp and expired within a week because of withdrawal of care. as brain compliance cannot yet be accurately determined radiologically, we believe anatomical involvement should drive decision-making regarding lp safety. our data suggest that a low volume lp ( - cc) might be safe in individuals with subfalcine herniation, midline mass effect < mm at foramen of monro level, and partial cisternal effacement. we believe that while lps might be safer in patients with supratentorial mass effect, individuals with posterior fossa involvement may tolerate it as well. these promising findings need further verification in larger sample populations. the importance of neurocritical care has recently been recognized in japan. however, to date, there has been no neurocritical care training program. we developed the neurocritical care hands-on seminar as a proposed training module, and here we report the satisfaction of participants. we prepared a post-course questionnaire about participants' degree of satisfaction. the main concept of our seminar was "how to maintain cerebral oxygen demand and supply balance." beginning with a short lecture about this concept, participants joined four hands-on scenarios: post-cardiac arrest syndrome (pcas), subarachnoid hemorrhage (sah), traumatic brain injury (tbi), and states epilepticus (se). in the pcas scenario, participants learned how to trouble shoot regarding targeted temperature management, especially in regard to the management of shivering. in the sah scenario, they learned about perioperative management, including delayed cerebral ischemia. in the tbi scenario, starting with actual insertion of an intracranial pressure (icp) monitor in the simulator, they learned about icp management through a scenario-based simulation. in the se scenario, they learned about se management, with actual continuous electroencephalogram monitoring. this seminar was held twice in . most participants were middle-aged intensivists; % were in their twenties ( / ), . % were in their thirties ( / ), . % were in their forties ( / ), and . % were in their fifties ( / ). most of the participating physicians were specialists in emergency or intensive care medicine ( . %; / ); nurses ( . %; / ) and a clinical engineer ( . %: / ) also participated. most participants ( . %; / ) were satisfied with the seminar, and almost all ( . %; / ) improved their self-confidence in the ability to carry out clinical practice in neurocritical care. we received positive, satisfied reactions from the japanese intensivists who participated in our seminar. for further improvement, we need to collect objective data to assess the utility of our neurocritical care hands-on seminar. lumbar puncture in the presence of mass effect? ciro ramos-estebanez uhcmc, case western reserve university/neurology, cleveland, ohio, usa introduction ) we propose an international consortium that would prospectively confirm the safety of low volume lumbar puncture (lp) in the presence of mass effect in selected scenarios. ) welcome peers and advisors to join the effort. lp may be clinically necessary in the presence of cerebral mass effect. while empirical antibiotic therapy is generally successful, specific groups such as post-instrumentation patients and immunosuppressed individuals may benefit from cerebrospinal fluid (csf) studies. in the absence of high-quality clinical recommendations, uncontrolled retrospective literature suggests that a small volume lp ( - cc) might be without complications in specific situations. nevertheless, the ethical principle of non-maleficence and the liability risk prevent clinicians from performing lps. in this scenario, an extended length of stay, poor outcomes, or a higher cost of care are legitimate concerns. synthesize an external peer reviewed methodology to maintain rigour and transparency. . seek appraisal, approval and endorsement of national and international quality improvement committees. . generate and assimilate the most current clinical evidence through: a. systematic review and meta-analysis. b. prospective randomized controlled clinical trial. . construct a protocol to inform decision making amongst healthcare and non-healthcare personnel. . dissemination and implementation. . schedule updates and/or revision. centers across the globe (north america = , south america= , europe= , and asia= ) have agreed to establish an lp consortium so far. retrospective analyses suggest low-volume lp's relative safety in the presence of increased icp. thereby, an expert consortium trusted with prospective verification would potentially benefit specific patient populations. patient centered decision making in the nccu requires family members understanding of their loved one's preferences and values as well as the complexities of their medical condition and treatments. family-centered care (fcc) is essential so that family members are actively involved in decision-making. stakeholders have reported their preference to receive prognostic information in smaller packets and recapitulated in different venues including rounds, bedside and care conferences. we examine implementation of a multimodal communication strategy on clinician utilization, family engagement and satisfaction in the nccu. an interdisciplinary team convened to develop a plan implementing a multimodal communication strategy. pre-implementation survey of clinicians (mds, nps, rns, etc.) and patient families was completed to determine the level of family engagement already in place in the nccu. four interventions were implemented: family communication boards were installed in patient rooms; family engagement pamphlets developed; a script and schedule for family care rounds was developed; nursing and provider staff were educated on inviting families to participate in patient care team rounds. family involvement on patient care rounds and family conferences was compared before and after the implementation of the best practice initiatives. additionally, pre and post implementation patient satisfaction survey results were also compared to evaluate the project's success. pre-implementation data was collected from october -november . sixty-one clinician surveys and forty family surveys found that family more consistently participated on daily rounds. baseline and postimplementation surveys demonstrated families feeling supported during the decision-making process. the implementation of a multimodal communication framework to achieve consistent family engagement and communication has led to an appreciable change in utilization by clinicians. its use is supported by consistent positive family attitudes towards communication and availability of information in the nccu. neurocritical care society undertook initiatives to integrate social media in member engagement activities and initiated a twitter journal club (#ncstjc) in with the first journal club conducted in february . articles were chosen by a subgroup of the communications committee in consultation with dr. eelco wijdicks, chief editor, neurocritical care journal. these articles were chosen based on their overall importance and the interest bound to generate amongst the journal club attendees. the journal club occurs bimonthy over an hour and is unique in the participation of the authors. the journal club is registered with healthcare hashtag project. each article chosen for #ncstjc is made available free to download weeks before and after the scheduled date for the journal club courts springer. analytics data on usage on article discussed in #ncstjc was obtained from sean beppler, editor, clinical medicine. between feb and apr , sessions were held with data available from . the ncc articles discussed had higher than average altmetric scores (measuring social media activity). these articles represented % of all ncc articles discussed on twitter since feb but . % of all tweets. total usage (number of times an article html page is accessed, or a pdf is downloaded ) was , ( mean , n= ) representing . % usage of all neurocritical care articles, a total of citations and downloads ( mean ) . the upper bound of the audience as assessed by the publisher was total of , for all articles (mean , per article) twitter is becoming an emerging platform for dissemination of information in medical education and academic activities. while the exact impact of the initiative on member engagement or outreach in enhancing journal impact or citations is hard to determine, we saw trends in enhanced engagement. neurostimulant medications have been studied in patients with traumatic brain injury, but few studies describe their use in patients with acute non-traumatic brain injury. our objective was to describe neurostimulant medication prescribing patterns, clinical response, and potential adverse effects in this patient population. retrospective database review of patients with acute ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage who received amantadine or modafinil from december through june . neurostimulant selection, dosing regimen, and indication were recorded. patients were classified as responders if they met two of the following three criteria within days of neurostimulant initiation: ) increase in average daily gcs of greater than points, ) neurological improvement documented in provider progress notes, or ) increased participation in rehabilitation therapies documented in physical or occupational therapist progress notes. safety data included need for a new anxiolytic or sleep aid or seizure. continuous data are reported as median with interquartile range. eighty-eight patients received neurostimulants: intracerebral hemorrhage (n= ), ischemic stroke (n= ), subarachnoid hemorrhage (n= ). median age was ( - ) years and ( %) were male. amantadine (n= ), modafinil (n= ), or both (n= ) were initiated a median of ( - ) days after hospital admission. the median initial daily dose of amantadine and modafinil were mg and mg, respectively. reasons for initiation included somnolence ( %), not following commands ( %), lack of eye opening ( %), and low gcs ( %). forty ( %) patients were responders, occurring at a median of ( - ) days after neurostimulant initiation. twenty-three ( %) patients required new prescription of an anxiolytic or sleep aid. four ( %) patients developed seizure. neurostimulant medications may increase wakefulness and participation in rehabilitation therapies in patients with acute non-traumatic brain injury, with tolerable adverse effects. the role of neurostimulants in this population should be defined in prospective studies. difficulty in obtaining peripheral intravenous (piv) access often necessitates central venous access placement in many critically ill patients. central line placement exposes patients to potential complications such as pneumothorax, hemorrhage, catheter-related infection or deep venous thrombosis. ultrasound-guided piv placement has become common practice in emergency departments, but there is no systematic program to train and support routine use of ultrasound-guided piv access in icus. we have developed a systematic program to train and support icu nurses in becoming experts and clinical leaders in ultrasound-guided piv placement. we hypothesize that implementation of this program will increase nurse confidence and chances of successful piv placement subsequently decrease central line-related complications in -bed neurocritical care icus. we have developed a video didactic training program for the neurocritical care nursing staff. the program discusses use and maintenance of the ultrasound machine and guided-technique for piv placement including the short-and long-axis approaches. the training video is followed by a hands-on simulation session using mannequins. standardized-surveys are administered to nurses before training and then at and months post training. we are prospectively collecting data on nurse comfort level with ultrasound-guided piv placement, total iv attempts, patient central line associated bacteremia (clab) rates and total number of patient central line days. we will compare this data for months pre-and post program implementation. comparisons will be made using t-test and chi-square analyses or non-parametric equivalents depending on data distribution. central-line related complications are an important clinical problem in all icus. we have developed and implemented a systematic training program to support nursing-led ultrasound-guided piv placement. we will determine if this program reduces the overall number of central lines placed, duration of indwelling central lines, and clab rates in a neurocritical care, and subsequently expand to additional icus and beyond. ultrasound measurement of optic nerve sheath diameter (onsd) is a sensitive and specific non-invasive ultrasonographers. despite clinical applications in the icu, er and outpatient settings, neurology residents lack experience and training. the aim of our project was to provide neurology residents with foundational skills in ocular ultrasound and onsd measurement. we designed a two-part workshop for neurology residents covering ultrasound basics, measurement of onsd, and ultrasound appearance of papilledema. workshop was a minute lecture and demonstration followed by minutes of hands-on practice. two weeks later, workshop included additional minutes of practice to consolidate learning. the practical portions were facilitated by emergency medicine attendings and residents with experience in performing ocular ultrasounds. neurology residents tracked the number of practice ultrasounds performed. they also completed anonymous pre-and posttests to assess their knowledge of ocular ultrasound and their comfort level and likelihood to perform future procedures using a -point likert scale. prior to the workshop, the majority ( / ) of neurology trainees had never performed an ocular ultrasound. one ( / ) was able to answer two basic questions about the procedure correctly, which increased to % on the posttest (n= ). trainees performed an average of ultrasounds total during the workshops. resident self-assessment of comfort performing the procedure increased from a median of "very uncomfortable" to "moderately comfortable" on the -point likert scale (p= . ). resident likelihood to perform the procedure in the future increased from a median of "very unlikely" to "moderately likely" on the -point likert scale (p= . ). this session successfully increased basic knowledge, comfort, and likelihood to perform ocular ultrasound among neurology residents. future directions include follow-up to gauge magnitude of practice changes and accuracy of procedural skills. reaching patients by telephone is a common method of assessing functional outcome, cognitive function, and quality of life after hospital discharge. however, when patients do not answer the phone, missing data creates bias and warrants strategies to increase follow-up rates. we hypothesized that we would have less follow up with patients discharged to long-term care facilities and sought to examine other potential sources of lost data. between / and / , we identified all patients admitted to the university of cincinnati neuroscience intensive care unit (nsicu). we excluded those with recurrent admissions, boarders, and those admitted < hours or for uncomplicated post-op care. telephone follow-up was attempted for each patient. univariate analysis was used to identify associations with patients who did not answer the phone. critically-ill patients were included. average age was . +/- . and % were men. the average hospital length-of-stay was . +/- . days. major diagnoses were: ischemic stroke ( %), intracerebral hemorrhage ( %), traumatic brain injury ( %), seizures/status epilepticus ( %) and subarachnoid hemorrhage ( %). ( %) died in the hospital; ( %) died by follow-up. survivors were assessed . +/- . days following admission. calls were answered, were not. there were no associations between rate of answered calls and age, gender, race, hospital length-of-stay, diagnosis, or hospital disposition. there were no differences in between morning vs. afternoon calls. only the number of attempts differed: the probability of an answered call was % on the first attempt but declined to % by the third attempt (or . ; p< . ). our outcome assessment strategy captured data on % of neurocritically ill patients. those who answer the phone are most likely to answer with the first call; the probability of a patient answering after a second phone call may not justify resources needed to continue calling these patients. posterior reversible encephalopathy syndrome (pres) typically presents with vasogenic edema on neuroimaging. a subset of patient, however, can have "atypical findings" including restricted diffusion and intracranial hemorrhage. these atypical findings all suggest acute vascular injury, and may mark a distinct pathophysiological subtype of pres. however, it is unknown whether atypical imaging findings are associated with differences in precipitating factors or outcome. patients with evidence of restricted diffusion, frank hematoma, microhemorrhage, or subarachnoid hemorrhage were classified as having atypical imaging findings. the demographics, risk factors, clinical outcomes, and degree of vasogenic edema for patients with typical (n = ) vs atypical pres findings of vascular injury (n = ) were analyzed. patients with atypical pres had a longer hospital stay ( . vs . days; p = . ) and were less likely to be discharged home ( . % vs . %; p = . ). severity of vasogenic edema (graded using a standardized radiologic scale) was also higher in patients with atypical imaging findings (severe edema: . % vs . %; p = . ). restricted diffusion and hemorrhage are features of acute vascular injury that may mark a unique pathophysiological subtype of pres. pres patients with these atypical imaging features had longer hospital stays, greater degree of vasogenic edema, and were less likely to be discharged home. this may be due to the fact that bleeding and infarction lead to irreversible brain injury, prolonging hospital stay and contributing to overall disability. in , deaths occurred in the neuro-oncologic critical care unit (nccu). the impact of this event is significant for patients, families, and the staff that care for them. brain and spinal pathology can be incredibly debilitating causing a rapid and impromptu decline of the patient's status. in order to better support patients, family, and staff throughout the dying process, the nccu staff created formalized endof-life care interventions. these interventions include educational pieces and supportive approaches to aid all involved through the dying process. several interventions were created to help transition the family members during the dying process. these include the creation of: dnr-cc closet, homemade blankets, condolence cards, hygiene bags, educational packets, word clouds, and aromatherapies and massage items. once the patient's code status is changed to comfort care, a blanket is given to the patient. family members are provided with a bag of toiletries for those that remain at bedside. education on the dying process are given to family members. multidisciplinary resources are provided, such as religious support focused on patient/family beliefs, palliative care for symptom management, and dietary provision of light snacks to the family. education for the physicians, nurse practitioners, nurses, and patient care associates was provided for those who wished to attend to further understand this end of life care program. a item tool was created to collect before and after data on staff satisfaction and comfort with the end of life process. results from this process are currently in process. creating specific end-of-life care interventions for the nccu have enabled staff to better care for patients and families. through the creation of the interventions and utilization of the dnr-cc closet, this unit has been able to better provide comprehensive education and supportive pieces to patients and family members during such a difficult time. delirium is a neuropsychiatric syndrome, characterized by disturbance in awareness, with reduced ability to sustain attention, impaired cognition, perception, tends to fluctuate in severity during the day; in critical care is associated with longer stay and increase mortality. this study aimed to determine the incidence, prevalence, predictors, risk factors and outcomes of delirium in critically ill adult. a historical cohort study was conducted in adult patients hospitalized in a polyvalent icu from january until december . delirium was diagnosed using cam-icu. a bivariate and multivariable risk were analyzed and presented as odds ratio (or) and % confidence interval (ci). a total of patients were enroll. delirium developed in patients.the incidence was . %. three independent predictors for delirium were identified, sedation (or ( % ci, p < , ); alcohol dependence (or , ; %ci, p < , ) and glasgow coma scale < (or , ; % ci, p < , ). delirious patients had a significantly apache ii ( ( - ) vs ( - ), p < . ), higher sofa, ( ( - ) vs ( - ), p< . ) and higher saps iii ( ( - ) vs ( - ), p< . ). other risk factors were hyperlactatemia ( p< . ), and hypotension (map< mmhg),(p< . ). patients required prolonged mechanical ventilation, p< . ), and prolonged icu-hospital stay. the incidence of delirium in the period from january to december , was . % in a polyvalent intensive care unit. exposure to sedative medications, alcohol dependence, and decrease glasgow coma scale minor are independent predictors for the development of delirium. similarly, the icu stay was longer in the group that developed delirium; however, mortality was not affected by the presence of this condition. it has been previously reported that the course of hsv- in the cns is significantly more benign that hsv- , and that it rarely causes encephalitis or significant morbidity in immunocompetent adults. the aim of our study was to investigate the claim that hsv- cns infections are typically benign, and to assess for predictors of poor outcome in those patients who do suffer significant morbidity from hsv- cns infections. restrospective chart reviews were completed on patients with a positive hsv pcr at our institution from july until july . patients with a hsv pcr positive for hsv- were selected in our analysis. multiple clinical variables were evaluated in these patients and we assessed outcome in the patient population, dichotomizing outcome into two categories at the time of discharge: good outcome defined as home or inpatient rehabilitation versus those with poor outcome defined as death, hospice, or placement in a long term acute care facility. patients with hsv- positive pcrs were identified. their charts were evaluated for demographics, laboratory values (serum and csf), imaging results, and outcome. there were patients with poor outcomes. it was noted that they were all female, their mean age was . (vs . in the good outcome group) and two of the three were immunocompromised ( % vs % in the good outcome group). statistical analysis was performed however due to the small sample size no statistical significance was found. however, age, sex, clinical presentation consistent with encephalitis and immune status seemed to have a trend towards poor outcome in this pilot study. future study with larger sample size is warrented to further assess this trend, as hsv- may not be as benign as previously reported. there is a high prevalence of non-traumatic illness in patients presenting to emergency departments as trauma team activations (tta). we sought to determine the prevalence of neurologic emergencies within a population of patients receiving a tta. this was a retrospective review of prospectively-collected registry data capturing all ttas in a highvolume, urban, academic level i trauma center. records from june through june were reviewed to identify patients found to have a diagnosis of ischemic stroke, intracerebral hemorrhage (ich), subarachnoid hemorrhage (sah) or status epilepticus. further demographic, clinical, and outcomes data was then abstracted from the electronic medical record. a proportion of abstracted charts were reviewed by an independent reviewer to ensure data quality. there were , trauma activations in the registry during the study period. patients ( . %) were found to have a nontraumatic neurologic emergency and were included in the analysis. of these patients, there were ischemic stroke ( %), ich ( %), sah ( %), and status epilepticus ( %) patients. the mean age was , and patients ( %) were male. the mean gcs on presentation was . about half of these patients ( %) were intubated in the emergency department. all patients received a head ct scan. patients ( %) received intravenous thrombolysis. neurologic emergencies such as ischemic stroke, ich, sah or status epilepticus were common diagnoses in this population of trauma activation patients. clinicians caring for patients in these settings must maintain a high index of suspicion for non-traumatic illnesses, and act quickly to mobilize appropriate resources when a diagnosis is made to avoid delays in care. further research is needed to examine ways to improve both time to diagnosis and quality of care in this patient population. formalized communication strategies decrease post-traumatic stress disorder (ptsd) symptoms in caregivers in the intensive care unit (icu). in one study, only % of family meetings met all shared decision-making criteria. however, much of the research has focused on family meetings, ignoring less formalized communication. the decision maker (patient or caregiver) was interviewed for all patients admitted to the medical (micu), neurosciences (nsicu), surgical (sicu), and cardiothoracic icu (cticu) for greater than hours. subjects who stated significant decisions had been made were asked to report on aspects of shared decision making on a -point scale. they identified the lead provider, who was subsequently approached to complete the same questionnaire. overall, eligible decision makers were identified, ( %) in the micu, ( %) in the nsicu, ( %) in the sicu, and ( %) in the cticu. of these, ( %) were unable to be contacted, ( %) had insufficient english, and ( %) reported no decisions made, with ( %) enrolled. nineteen ( %) provider interviews were completed. topics most reported covered "well" or "thoroughly" by caregivers were assessment of understanding ( , %) and the nature of the decision ( , %), while those least covered were need for input from others ( , %) and the context of the decision ( , %). topics reported most covered by providers were the nature of the decision ( , %) and opinions about the treatment decision ( , %), while those least covered were patient's values and preferences ( , %) and their preferred role in decision making ( , %). eighteen ( %) caregivers and ( %) providers described all topics covered "well" or "thoroughly." these results demonstrate differences in perception of shared decision making by decision makers and providers. further qualitative investigation is underway to elucidate the nature of these inconsistencies. organ donation is a life-saving medical intervention. the effect of race, insurance and economic status on organ donation and recipients has not been studied at a national level. in our study, we analyzed nationwide in-patient (nis) database of years - to select donors and recipients. baseline demographics (i.e., age, gender, race), insurance status and socio-economic status was compared between two groups. we identified donors (n= ) and recipients (n= ) from - . recipients were significantly older (mean age ± sd, . ± . vs . ± . , p< . ). donors had higher ( . % vs . %, p< . ) proportion of women compared to recipients. both groups had a higher proportion of whites compared to other races ( % and . % respectively). insured patients were largely represented in both groups with private insurance predominating in donors ( %) and medicare in recipients ( . %). interestingly, self pay represented . % of donors but only . % of recipients. race, insurance and socioeconomic status seem to be evenly similarly represented in donors and recipients. interestingly self pay insurance has a higher distribution among donors than recipients. central line-associated bloodstream infections (clabsis) are a common health care associated infection accounting for , infections annually in the intensive care and acute care areas (cdc, ). according to the center for disease control, clabsis result in thousands of deaths yearly and upwards of billions of health care dollars spent on preventable hospital acquired infections. intensive care patients, especially the neurocritical care population, have an increased need for centrally placed catheters related to inadequacy of peripheral access, need for caustic iv medications, and fluid resuscitation. our neuroicu's goal was to decrease utilization and subsequently reduce number of clabsis. in february , we initiated a patient-centered quality improvement effort with this goal in mind. the neuroicu clinical nurse leaders conducted rounds daily to evaluate the necessity and management of central lines. the neurocritical care team and clinical nurse leaders collaborated in exploring alternatives if central lines were present. in addition to daily rounding, clabsi bundles based on cdc guidelines for clabsi prevention were initiated. our neuroicu developed checklist "buster cards" in september of , prompting staff to the bundle interventions. the intent of the cards was to enhance nurse to nurse dialogue of bundle elements. the cards were evaluated monthly for trends in care. from august -june , there was a % reduction in neuroicu utilization of central lines. in addition, the mean number of clabsis per month decreased from . to . . trending of unit buster cards did not show care variances during this time period. implementing daily clinical nurse leader rounds with enhanced team communication significantly reduced the neuroicu's utilization of central lines and thereby decreased the rate of clabsis. percutaneous dilatational tracheostomy (pdt) is one of the most commonly performed procedures on critically ill patients. many studies showed the safety and feasibility of pdt, but there is limited data of pdt in neurocritical care units. we have described our experience of pdt performed by neurointensivist. pdts were performed by neurointensivists at bedside using the griggs guide wire dilating forceps technique. to confirm a secure puncture site, pdt was done under fiberoptic bronchoscopic guidance. from september to may , procedural data were prospectively collected. the patients' demographic and clinical characteristics were retrospectively reviewed. we analyzed immediate complications of pdt as the primary outcome. pdts were performed for patients; the mean age was . years, ( . %) were male, and mean acute physiology and chronic health evaluation ii score was . ± . . overall, the procedural success rate was % and the mean procedural time was . ± . min. periprocedural complications occurred in patients; had minor bleeding and had tracheal ring fracture. there were no serious periprocedural complications of pdt. from our experience, pdt performed by neurointensivist was safe and feasible and was implemented without serious complications. the neurocritical care unit (nccu) is a fast paced setting with a multitude of providers and team members requiring optimal communication. it is also a high cost/high utilization environment, dictating the need for patients to be moved thru appropriate levels of care efficiently. all of this must be accomplished while providing support and opportunity for collaboration and decision making on the part of the patient/ family unit. there is great discussion in the case management world about the benefits of a unit based verses service based case management model. we looked at outcomes following the implementation of a unit based case manager in the nccu. a dedicated case manager (cm) was implemented in the nccu to maximize assessment, advocacy, communication, education, identification of resources, and facilitation of services. processes to support maximal contributions were created.interventions included use of a discharge planning worksheet, implementation of a morning huddle, and space for the case manager to be physically available on the unit. los of patients discharged from nccu decreased from . to . . alos for patients that passed thru the nccu during their hospitalization decreased from . days to . . there was a % increase in discharges from nccu from to . average time from admission to cm assessment decreased from hours to . hours. progress notes indicating intervention and/or communication of the plan increased from to . staff questionnaire indicated increased awareness of los and dc plan needs. in this midwestern, academic medical center, integrating a dedicated, unit based cm resulted in improved los, increased discharges and improved staff awareness of dc plans. high throughput genotyping technologies and large collaborative consortia have revolutionized the field of medical genetics. open data access is the final barrier to be overcome to capitalize fully on the opportunities currently available in stroke genetics research. the international stroke genetics consortium (isgc) has created the cerebrovascular disease knowledge portal (cdkp), a comprehensive web-based resource to explore and freely access genetic data related to cerebrovascular diseases. funded by the nih, the cdkp has been jointly developed by the isgc and the american heart association (aha) institute for precision cardiovascular medicine. the cdkp seeks to democratize access to genomic data and potentiate stroke genomics research by providing open access to genetic, phenotypic and imaging data on stroke. within the cdkp, data are aggregated, integrated, and harmonized according to a pre-specified standardized pipeline. any institution or investigator working with stroke genomic data is welcome to deposit their data or use available data. the cdkp houses two types of data, each meeting different regulatory and analytical needs: summary level data and individual level data. the cdkp offers three main features: ( ) a web-based graphical user interphase that allows the exploration of stroke genomics information through a wide menu of integrated tools for analysis and data visualization; ( ) a repository of full sets of genome-wide summary statistics produced by published landmark studies in the field, available with a single mouse click ; and ( ) a repository of individual level data, accessible through a secure cloud working space provided by the aha platform for precision medicine. the cdkp can be accessed at www.cerebrovascularportal.org. the cdkp advances the isgc's goal of liberal data sharing in stroke genomics and other areas of cardiovascular research that may benefit from genomic analyses. in the future, phenotypic datasets can be added to further enrich sharing of non-genetic data as well. hyperosmolar therapy using hypertonic saline is common in patients admitted to the neurocritical care unit (nccu) for the management of different type of cytogenic cerebral edema or increased intracranial pressure (icp). vancomycin is commonly prescribed in nccu as empiric antimicrobial therapy. the purpose of the study is to evaluate the effects of hypertonic saline therapy on the pharmacokinetic parameters of vancomycin in critically ill patients with generalized or compartmental icp. this was a retrospective, observational study of adult patient consecutively admitted in the nccu between february and february who received hypertonic saline ( % sodium chloride) and vancomycin dosing protocol managed by the pharmacist. patients with serum creatinine > . mg/dl were excluded from the study. the estimation of vancomycin trough levels was done by using published pharmacokinetic equations and then compared to the measured trough levels with the paired t test. the study protocol was approved by our institutional review board. of forty-four patients who met the inclusion criteria, twenty-one patients ( . %) were diagnosed with intracerebral hemorrhage, nine ( . %) ischemic stroke, seven ( . %) subarachnoid hemorrhage, four ( %) subdural hemorrhage, two with brain tumors, and one patient with chiari malformation. the mean dosing regimen was . ± . mg/kg every ( - ) h. the mean measured trough level was lower than the predicted trough level ( ± . vs. . ± . mcg/ml; p < . ). the mean serum sodium level was ± meq/l and the mean serum osmolality was ± mosm/kg. critically ill patients with cerebral edema or high icp who were treated with hypertonic saline achieved a subtherapeutic vancomycin level that may lead to lower through level and possibly poor clinical response. further research is warranted to evaluate the clinical response of vancomycin in this patient population. unnecessary telestroke activations are costly to emergency departments (ed), telestroke providers, and patients. therefore it is important that ed nurses are well trained to effectively recognize stroke symptoms, and decrease the rate of false-positive stroke code activations. the nursing-driven acute stroke care (nas-care) study aims to determine if implementing a standardized ed stroke program decreases door-to-needle times in emergency departments utilizing telemedicine. the nas-care intervention consists of ed nursing education including mock codes, nihss certification, and implementation of a standardized flow sheet. in this interim analysis from the first (of ) nas-care study hospitals, we examined ed admission and discharge diagnoses at each site for months of blinded baseline data collection ("control") and months after standardized training ("intervention"). false-positive encounters were defined as stroke code activations for which the patient diagnosis on leaving the ed was not stroke. although hospitals trended toward a reduction in false-positive stroke code activations after implementation of the standardized stroke education, mock stroke codes, and flow sheet, none of the values were statistically significant. further research is needed to determine whether intensive ed nursing education can improve telestroke resource utilization. pharmacist-driven intravenous (iv) to oral (po) conversion protocols result in greater compliance, improved cost-savings, and better patient outcomes related to length of stay, re-admission, and duration of intravenous therapy. this study aims to determine the cost-savings and patient impacts of such a conversion protocol for anti-epileptic drugs (aeds) including lacosamide, levetiracetam, phenytoin, and valproic acid. a retrospective, observational phase was conducted to determine usual practice patterns concerning conversion to oral therapy between / / and / / . the conversion protocol was approved in december and implemented in january . a second retrospective phase observed conversion practices beginning / / and ending / / . length of intravenous and oral therapy, date eligible for conversion, and date of conversion were recorded. hospital acquisition costs were utilized for medication expenditure calculations. this information was used to determine financial impact of the protocol and is presented as descriptive endpoints. adverse drug events were collected via an institutional incident reporting system. a total of encounters were identified, resulting in encounters in the pre-cohort and postcohort encounters. looking at the pre and post cohorts respectively, both cohorts had similar median lengths of stay ( days vs. days), -day readmission rates ( . % vs . %), and rates of conversion from oral back to intravenous therapy ( . % vs . %). the median length of intravenous therapy was days prior to protocol implementation and decreased to days in the post-cohort. the average cost per day of aed therapy was $ . in the pre-cohort but decreased to $ . in the post-cohort. median missed opportunity costs, defined as the cost savings if conversion occurred at the earliest possible date, also decreased between the cohorts from $ . to $ . . pharmacist involvement in aed conversion had a positive financial impact without compromising patient care. the national institute of neurological disorders and stroke (ninds) established the nih strokenet to facilitate the rapid initiation and efficient implementation of multi-center exploratory and confirmatory clinical trials focused on promising interventions in stroke prevention, treatment, and recovery. strokenet was initiated in the fall , and involves over hospitals across the us. the network is anchored by regional coordinating centers (rccs), along with the national coordinating center (ncc) at the university of cincinnati and national data management center (ndmc) at the medical university of south carolina, as well as active participation by the ninds. one of the primary goals of the strokenet is to serve as the primary infrastructure for conducting stroke clinical trials and pipeline for new potential treatments. to maximize the impact of nih strokenet, it is important for the larger community of stroke researchers and clinicians, including the neurocritical care specialists, to know its structure and the process and timeline by which stroke trials are developed and implemented. since the inception of the network, * proposal concepts have been submitted to the strokenet and are in different development stages. among those evaluated to obtain ninds permission to submit a grant application, have submitted and are in the process. every application has been prepared and submitted for peer review within months of the ninds permission. two* funded strokenet trials are now underway with brisk enrollment rates, and another is awaiting study initiation. (*as of abstract submission date) the nih strokenet has become a stable infrastructure and offers several distinct advantages to developing competitive clinical trial proposals, including scientific input from the strokenet working groups, comprehensive feasibility assessments (including site enthusiasm and patient availability), assistance with grant budgeting, and other requirements for grant submission that are likely to help refine and improve the application. the modified early warning score (mews) is a physiological scoring system, validated in adult medicalsought to determine the value of mews to identify clinical deterioration or occurrence of sepsis in neuroicu patients. we retrospectively reviewed all patients admitted to the neurological intermediate care unit (imc) or neuroicu of a large tertiary care center from / presentation/during admission. baseline characteristics, diagnoses, physiologic parameters, infections, treatment with antibiotics, neurological worsening and mortality were abstracted from the electronic medical record. outcomes were defined as escalation of care and discovery of a new infection or sepsis. of p were male. % were intubated, and in-hospital mortality was % (versus % for all admissions). ( %) were already treated with antibiotics for a known infec diagnosed in %. in reaction to the elevated mews score, antibiotics were added or broadened in %, and level of care was escalated in . % from imc to icu. in . %, there was neurological worsening, most frequently associated with increasing cerebral edema ( %) and midline shift/herniation ( %). the mews score is not a valuable screening tool in the neuroicu population. it preferentially was triggered in known high acuity patients with ongoing or present infections with no change of management in the majority of patients. while associated with high mortality, its ability to indicate new infections or sepsis was poor. in out of patients, the mews score was associated with neurological worsening known at that time of the score. other screening tools should be explored for early warning in the neuroicu. introduction: it is challenging to maintain neurosciences critical care nursing expertise in an environment of a rapidly expanding knowledge, changing evidence-based practices and technological advancements. to address the needs for neuroscience nursing expertise in a mixed critical care unit, our institution developed a core group of nurses, known as "neuro champions", who have additional training and expertise in neurocritical care. methods: nursing participation was voluntary and recruitment was via unit-wide announcements. the goal was to improve patient care by developing a core group of nurses who serve as resources and educators for all things neurosciences related. to develop content expertise, the nurses initially completed a set curriculum including: neuro anatomy and pathophysiology, cerebral hemodynamics and multimodal monitoring, pupillometry, eeg interpretation, temperature management, evds, and quality indicators. bi-monthly meetings continued ongoing education, with content including clinical case studies and review of processes and protocols. additionally, beds staffed by neuro champions were designated as critical neurological care unit ("cncu") beds to co-localize the highest acuity neurosciences patients. the neuro champions are responsible for educating and sharing neuro related practices with the entire icu nursing staff. results: as a result of the implementation of the neuro champion role, our icu has benefited from: ) dedicated co-localized beds for the highest acuity neuro patients; ) increased number of enls certified nurses; ) improved collaboration between the medical team and nurses; ) promoting care uniformity to maintain comprehensive stroke center certification; ) integration of multimodal monitoring advancements, all of which supports advances in patient care and research. conclusions: the neuro champion role has provided a platform for neurosciences-specific nursing expertise in a mixed critical care unit and has facilitated education dissemination to the entire staff via a core group of nurses. this expanded knowledge has improved the care of the neurologically critically ill patients. the rate of cerebrovascular complications in patients treated with extracorporeal membrane oxygenation (ecmo) is about %. transcranial doppler (tcd) can be used to noninvasively monitor cerebral blood flow velocities (cbfvs) in patients undergoing ecmo. the aim of this study is to describe tcd-cbfv patterns in patients undergoing venovenous (vv) and venoarterial (va) ecmo. a neuro-surveillance protocol among ecmo patients was initiated as part of a quality improvement project at our institution. daily neurological exam, daily tcd, brain-ct on days one and three and -hr continuous eeg were performed in all patients undergoing vv and va-ecmo. demographics, clinical and imaging data were collected for the duration of ecmo support. cbfvs, lindegaard ratios (lr), pulsatility index (pi) and resistance index (ri) on tcd were collected. total of patients were included in the study [ female ( %); caucasians ( %)]. mean age was years. ( %) patients received va-ecmo; ( %) vv-ecmo; ( . %) received both va and vv-ecmo. median days on ecmo was days. median number of tcd studies performed was (mean, . we observed an overall pattern of low-normal flow cbfvs and reduced pulsatility in patients on va-ecmo. nurse practitioner (np) and physician assistant (pa) roles continue to expand in the critical care setting. single and multisite studies have examined various aspects of app practice, but none have focused on role implementation within the neurologic critical care unit (nccu). the purpose of this study was to obtain foundational knowledge about how nccu apps are implementing the role nationally this was a voluntary, cross-sectional, descriptive study of nurse practitioners (np) and physician assistant (pa) practicing in the us. apps were invited to participate in this voluntary, item survey. distribution occurred initially through email inquiry via multidisciplinary, professional organization listservs (ncs, aacn, aann) followed by snowball effect circulation. enrollment occurred from march to june . data was collected in redcap and analyzed using spss with descriptive statistics for demographic, institutional, practice, role characteristics of the sample and for each survey data element app participants completed the survey: % np, % pa, % other. the majority of respondents were master's prepared ( . %) acute care trained, ( . %) and hospital employed ( . %). participants were either early in their career ( . % - years as app) or experienced ( . % > years). % work in a direct care role with % providing total care for their patients with an average daily caseload of . + . patients. % of providers believed - patients was a reasonable caseload for total care. in addition to the nccu, % of participants care for patients in step-down or emergency department ( %) with % routinely bilingl for their work. this study is the first to provide information regarding how ncc apps are implementing the role in the united states. this study provides benchmarking data which may guide future research with this population as well as serve as a template for evaluation of other app specialty roles. despite advances in treatment, the median survival for high grade gliomas (hgg) remains poor. there is a growing body of research showing that palliative care improves quality of life and survival in patients with advanced malignancies. we sought to examine our own practices in the neurologic intensive care unit (nicu) regarding palliative care consultation in this population. we hypothesized that the incidence of palliative care consultation is low and associated with a clarification of patient's wishes, measured by a change in code status. we conducted a retrospective cohort review of patients with previously diagnosed hgg admitted to the nicu from - with a length of stay (los) greater than hours. the primary outcome was the incidence of patients with an advanced directive or inpatient palliative care consult (pcc). secondary outcomes included intensive care unit los, change in code status and location of death. patients were identified with hgg. the mean age was . years ( - years), % were male, % were white. zero patients were admitted with an advanced directive on admission. pcc was obtained in patients ( %). pcc was associated with increased nicu stay ( hrs vs hrs p= . ), a change in code status to do not resuscitate ( % vs % p= . ), and an increased likelihood to not die in the hospital ( % vs % p= . ). at our large academic tertiary care facility intensivists underutilize palliative care services for hgg patients. patients with fatal brain tumors are not having end of life discussions prior to admission, indicating a need for early palliative care intervention. patients are six times more likely to change their code status and there is a trend towards dying outside of the hospital if they receive a palliative care consult. hypertonic saline (hts), a hyperosmolar solution, is typically administered using a central venous catheter (cvc) due to concerns of extravasation, but a cvc is rarely readily available. in emergent situations, intraosseous (io) access is used when peripheral intravenous access is not available. existing literature does not address the administration of hypertonic saline using io access for adult patients with brain injury. the administration of hts is often delayed due to the time taken to obtain a central venous access. insertion of an io needle is typically much faster than a cvc. we report the safety and tolerability of hts using io route. a prospective pilot study on the safety and tolerability of % hts via io is currently underway. data on local complications at the site of injection, pain during insertion and during infusion, and serial serum sodium levels were collected. additionally, we report a case of successful administration of . % hts using the io route. preliminary data demonstrated that % hts was well-tolerated, with no reports of severe pain, infections, extravasation, soft tissue injury or local infectious complications in our sample of patients with brain injury. indications for use of hypertonic saline included patients with cerebral edema and mass effect from intracerebral hemorrhage. an appropriate rise of serum sodium levels by approximately mmol/l/hr in was observed. in the case where ml of . % hts, no local complications were observed and serum sodium levels rose appropriately. administration of hts using io route appears to be safe and feasible. utilizing io access for urgent administration of hts may reduce the lag time to administration of the initial bolus, reduce the need for emergent placement or eliminate the placement of cvc in certain cases. optic nerve sheath diameter (onsd) measurement is an emerging bedside tool to assess intracranial pressure (icp) non-invasively in brain injury patients. multiple studies demonstrate onsd width from . mm to . mm correspond to an external ventricular device (evd)-measured icp > mmhg. we sought to create a low cost, -d constructed, re-usable osnd teaching model to train neurology, neurosurgery, and critical care advanced practice providers and physicians. we searched the national library of medicine using terms "optic nerve sheath diameter ultrasound" with combinations of "simulation" and "model." the literature was used in conjunction with a human non-contrast head ct head model to make an eye ball model which was then tested in our simulation center and compared to a live human model. we identified articles, of which were associated with models and two with simulation. one gelatin model was reported, upon which we based our initial design. we could not validate the visual findings of this model. however, following construction of multiple beta models, the design most representative of human eye anatomy was a globe made of ballistics gel with either a mm, mm or mm -d printed "optic nerve" attached to a platform composed of ballistics gel and psyllium powder with a hollowed out core for ultrasound gel the globe rests upon. this model was taught to learners at a continuing medical education event prior to teaching osnd on a live human model. a -d printed skull from ct head data is being created to incorporate this model. a simple -d ballistic onsd model allows learners to learn proper hand placement, basic landmarks, onsd measurement, and practice proper pressure on human eyes. this model can be replicated and utilized in a sustainable fashion given that the globe and platform are composed of ballistics gel. pressure measurements using pressure guide wires is an invaluable diagnostic tool in the management of many endovascular revascularization therapies. its role is well established in coronary artery disease management such as use of fractional flow reserve (ffr) as a standard diagnostic tool to determine need for stenting, angioplasty or bypass. renal fractional flow reserve remains an integral physiologic parameter used in endovascular revascularization therapy of renal artery stenosis. despite the wide spread use of pressure wires in endovascular therapies, its application in the management of cerebral venous diseases remains vastly unexplored. we sought to evaluate the safety and applicability of pressure guide wires in several cerebral venous diseases. patients undergoing diagnostic angiography for possible venous outflow obstruction had pressures measured by pressure guide wires (volcano verrata® or prestige primewire®) across the following vessels: superior sagittal sinus, torcula, right and left transverse sinus, right and left sigmoid sinus, and right and left internal jugular vein. venous pressures were also collected from patients undergoing venous thrombectomy, stenting, or an arteriovenous malformation embolization (avm). five patients who underwent diagnostic angiography for pseudotumor cerebri showed no major variability in their pressures across the cerebral venous architecture which was confirmed by lack of stenosis or thrombi on intravascular ultrasound (ivus). four patients had a pressure difference above which was suggestive of a stenosis and later confirmed by ivus. patients undergoing pressure measurements that had evidence of stenosis or thrombosis by ivus showed improvement in pressure gradients post stenting or thrombectomy. no variability in pressure gradients were noted in a patient that underwent avm embolization. pressure measurements using pressure guide wires can improve diagnostic accuracy and guide management of several diseases of the cerebral venous system. further studies are necessary to understand the applicability of this approach in the management of venous disease. monitoring metrics is imperative for quality assurance and ongoing improvement in a developing clinical unit. a new neurocritical care unit (nccu), specializing in the treatment of critically ill, neurologicallyinjured patients opened in july . this study examined quality metrics that correlate with the development and growth of a neurocritical care program. data from patients with principle diagnoses of ischemic stroke (isc), subarachnoid (sah) or intracerebral (ich) hemorrhage, seizure, or brain tumor, admitted to nccu in and were used in the analyses. quality metrics included overall and individual complication rates per , patient days of pneumonia, venous thromboembolism, pulmonary embolism, sepsis, septic shock, pulmonary edema, gastrointestinal bleeding, and catheter associated urinary tract infection, as well as hospital mortality and length of stay (los). chi-squared and mann-whitney tests and poisson regression were used to compare metrics between and . patient volumes increased by . % ( to ) from to . the overall complication rate declined significantly from . to . per , patient days (p= . ). the highest complication rate in and was pneumonia ( . and . per , patient days, respectively). the proportion of patients who expired decreased from . % (n= ) in to . % (n= ) in , though not significantly (p= . ). there were no significant differences in los among patients with isc, brain tumor or seizure. however, those with sah or ich had significantly shorter stays in (median [interquartile range] = . [ . , . ]) versus ( . [ . , . ]) (p= . ). data suggest that over the initial -year period, complication rates among patients in the nccu improved. los did increase for hemorrhage patients; however, this may be related to greater severity of illness in the patient population over time. further analyses will be conducted to account for severity and other factors. delirium is a frequently seen but underestimated problem in critical care settings. delirium screening is considered time consuming, which is one of the factors leading to under diagnosis. the cam-icu screening tool for delirium has been validated in medical and surgical icus. among neurological patients, it has been validated in stroke patients but not in general neurocritical care population. this study was designed to validate cam-icu flow sheet in neurointensive care unit. a prospective cohort study was conducted in a bed neurointensive care unit of a university hospital. patients meeting the inclusion criteria (all nicu patients) and exclusion criteria (comatosed, aphasic, psychotic, prior diagnosis of neurocognitive disease, persistently vegetative state, sedated) were screened for delirium by ( ) a nurse practitioner using confusion assessment method (cam-icu) and ( ) a physician reference rator using delirium screening criteria in diagnostic and statistical manual of mental disorders- . assessments were done daily monday through friday for the icu stay. paired assessments were done less than hours apart. the study enrolled patients ( male, female). daily assessments were done. mean age of the patients was . and mean sap score was . admitting diagnoses were ich ( ), sah ( ), ischemic stroke ( ), tumor ( ), spinal surgery( ), neurological infections( ), seizures( ),elective angiograms( ), hydrocephalus( ), transverse myelitis( ) and av dural fistula( ). using dsm- criteria, the reference rator identified delirium in out of ( %) patients during the icu stay. out of assessments were positive for delirium according to dsm- and according to cam-icu. cam-icu flow sheet had sensitivity of . % ( %ci . % - . %) and specificity of . % ( %ci . %- . %). cam-icu has high sensitivity and specificity for diagnosing delirium in critically ill neurological population. it is a valid tool for diagnosing delirium. a value stream mapping event (vsm) for general neurology inpatients, revealed multiple barriers related to videofluoroscopy swallow studies. there was a high volume of patients requiring instrumental swallow assessments, a limited number of radiology appointments, and transportation delays that were delaying feeding plans, discharge recommendations and goals of care discussions. an operations engineer involved in the vsm event started the process by collecting observational data regariing timing. after meeting with the chief operating officer, director of patient transport, director of radiology, speech pathology manager, neuro intensive care unit manager and the operations engineer, a pilot program was agreed upon. the results for the three week pilot program were successful, and resulted in a permanent change in procedure. the pilot data showed a decrease in test time by minutes, a decrease in transport delays by minutes, and a decrease in length of stay by . days. the number of patients waiting for the study dropped from . to . per week. by annualizing this data, the change has created new available bed days, additional patient encounters and an incremental annual contribution margin of $ , . with the appointment time consistent, the nurse is able to plan patient care around the study, and ensure the patient is prepared and not delayed for the study. it has also allowed, if deemed safe for the patient to swallow, medications to be changed from the intravenous route to the oral route earlier, and earlier determination of safe feeding and diet restrictions. we previously reported outcome for children with refractory and super-refractory status epilepticus in a cohort of patients. mortality was %. % of survivors required new tracheostomy and/or gastrostomy tubes. the majority of surviving patients experienced some degree of disability at discharge as determined by the pediatric cerebral performance category scale (pcpc). here, we aimed to identify patient factors in this cohort that were associated with a decline in functional neurologic outcome at discharge. retrospective chart review of children age - years who received pentobarbital infusion for status epilepticus in the pediatric intensive care unit of a large tertiary children's hospital from - . outcome was defined using pcpc at admission and discharge. potential factors associated with outcome were evaluated using fisher's exact test and wilcoxon rank sum test. children were included. pcpc score at admission (p= . ), etiology of status epilepticus (p= . ), new tracheostomy (p= . ), and new gastrostomy tube (p= . ) were all significantly associated with children were more likely to have normal baseline neurologic function and more likely to have febrile encephalitis, stroke/trauma, or hypoxic ischemic encephalopathy as the etiology of status epilepticus. duration of pentobarbital infusion (median = days vs. days) (p= . ) and duration of hospital admission (median = . months vs. . months) (p= . ) were both longer in patients who had an admission pcpc score, etiology of status epilepticus, new tracheostomy and gastrostomy tube as well as longer duration of pentobarbital infusion and longer hospital stay were significantly associated with a decline in functional neurologic outcome at hospital discharge in children with refractory and superrefractory status epilepticus. status epilepticus (se) is the most common pediatric neurological, and super-refractory se is a lifethreatening form of se that continues or recurs for more than hours despite multiple therapeutic interventions. this population-based study investigated pediatric se and srse admissions in germany. pediatric (age - years) admissions between - were identified in the arvato health analytics database. se, epilepsy, and febrile seizure cases were identified using a modification of a previouslypublished algorithm based on icd- diagnosis codes (g , g , and r ) and coding for ventilator and intensive care unit use. based on primary diagnosis, prior epilepsy status, and ventilation se was subclassified as non-refractory, refractory (rse), and super-refractory (srse). inpatient mortality, costs, length-of-stay (los), and discharge disposition were assessed overall and for rse and srse. the algorithm identified , seizure-related admissions and classified % as se, of which . % were rse and . % were srse. the rse frequency was highest among ages - . the incidence of cases classified as srse peaked among newborns (age< year), decreasing between ages - years. cases classified as se accounted for . % of total costs associated with seizure-related hospitalizations. srse exhibited the highest per case cost (mean € , ), amounting to . % of all se costs, and these costs correlated with the highest los (median . days). srse was associated with greater mortality ( . %) cases classified as srse accounted for . % of all pediatric seizure-related costs, despite representing only . % of admissions. srse was associated with the highest los and mortality rate. these results highlight the burden of illness associated with srse and suggest that optimization of srse management has the potential to improve outcomes and reduce costs. despite its more routine use and the recognition that mri provides superior detection of traumatic brain injuries, there has been little written about how mri might affect the acute management of trauma patients. we sought to describe mri findings in a cohort of children admitted to the picu with tbi and to extend comparisons between ct and mri in acute trauma. a secondary aim was to quantify in what ways mri findings influenced clinical management in this cohort. we retrospectively identified patients admitted to the picu with an acute head injury between september and may who underwent head mri within the first hrs. we compared mri with ct findings, using the nih common data elements definitions of injury type. we determined by chart review the indication for mri and if there was documentation that mri led to a change in management, defined as either an escalation or a de-escalation of care. seven patients had mri only, and mri identified additional lesions in of the patients who had first undergone head ct. of these, patients had new intra-parenchymal lesions, had new extra-axial lesions, and had both a new intra-parenchymal and a new extra-parenchymal lesion identified. the most frequent new lesions were contusions and traumatic or diffuse axonal injury. acute management was influenced by mri in a majority of patients, leading to an escalation of medical or surgical management in nearly one third and a de-escalation of care in half. early mri may have a beneficial role in the acute management of pediatric traumatic brain injury. mri frequently identified clinically important lesions not appreciated on ct, and findings influenced management decisions. future studies will assess whether early mri improves patient outcomes or provides cost/benefit by reducing length of stay. while adverse outcomes of decompressive hemicraniectomy (dh) including infection, disturbances of the csf compartment, and sunken flap syndrome are well documented, there is a dearth of literature assessing outcomes related to the timing of cranioplasty. while adverse outcomes of decompressive hemicraniectomy (dh) including infection, disturbances of the csf compartment, and sunken flap syndrome are well documented, there is a dearth of literature assessing outcomes related to the timing of cranioplasty. we identified patients who received dh, of whom underwent reconstructive cranioplasty at our institution. the post-cranioplasty complication rate was %, which was due in part to hemorrhage, infectious complications, or csf compartment disturbances. patients receiving early cranioplasty developed an increased rate of hemorrhagic complication ( % vs %; p = . ), increased median hospital length of stay (los) ( vs days; p = . ) and increased median icu los ( vs days; p = . ). of the patients who received dh surgery related to malignant cerebral edema from an acute ischemic stroke, total complication rates trended down for early compared to late cranioplasty surgery ( % vs %; p = . ). patients receiving dh surgery for any cause who underwent early reconstructive cranioplasty, experienced higher rates of hemorrhagic complications and increased hospital and icu los. however, among those patients receiving dh surgery for the specific indication of malignant cerebral edema from acute ischemic stroke, significant differences did not exist between the early and late cranioplasty groups. the total complication rates in these patients trended lower in the early group. another important and mainly unpublished finding is that a majority of dh patients are lost to surgical follow up and may therefore impact the complication rate of this not so benign surgery. postoperative antibiotics (pa) are often administered to patients after instrumented spinal surgery until all drains are removed to prevent surgical site infections (ssi). this practice is discouraged by numerous medical society guidelines, so our institutional neurosurgery quality improvement committee decided to discontinue use of pa for this population. we retrospectively reviewed data for patients who had instrumented spinal surgery at our institution for seven months before and after this policy change and compared the frequency of ssi and development of antibiotic related complications in patients who received pa to those who did not (non-pa). we identified pa patients and non-pa patients. discontinuation of pa did not result in an increase in frequency of ssi ( % of pa patients vs. . % of non-pa patients, p= . ). growth of resistant bacteria was not significantly reduced in the non-pa period in comparison to the pa period ( % vs. %, p= ). the cost of antibiotics for pa patients was $ , . , whereas the cost of antibiotics for the non-pa patients was $ . on a per patient basis, the cost associated with antibiotics and resistant infections was significantly greater for patients who received pa than for those who did not (median of $ . with iqr $ . -$ . vs. median of $ with iqr $ -$ ; p< . ). after discontinuing pa for patients who had instrumented spinal procedures, we did not observe an increase in the frequency of ssi. we did, however, note that there was a non-significant decrease in the frequency of growth of resistant organisms. these findings suggest that patients in this population do not need pa, and complications can be reduced if pa are withheld. the development of flow-diverting stents has allowed for new treatment options for giant vertebrobasilar aneurysms. however, the expertise required to perform these procedures safely and concerns about complications continue to limit their use. we sought to identify common complications of this treatment that can be anticipated by neurointensivists, to optimize management in the postoperative period. we retrospectively reviewed our hospital database of treated aneurysms to identify those with giant vertebrobasilar aneurysms. medical and neurological complications were recorded. six patients ( male, female) underwent treatment of giant vertebrobasilar aneurysms with pipeline embolization devices. five received adjunctive coiling. frequently reported pre-procedure symptoms were dysphagia (n= ), diplopia (n= ), dysarthria (n= ), facial weakness (n= ), hemiparesis (n= ), gaze palsy (n= ), and nystagmus (n= ). five patients ambulated normally. due to concerns about necessary procedures after stenting when on antiplatelet therapy, three patients received prophylactic ventriculoperitoneal shunts, two underwent gastrostomy, and two underwent tracheostomy. angiography confirmed successful aneurysm embolization in all patients. postoperatively, all patients developed new or worsened symptoms attributed to brainstem edema, including hemiparesis (n= ), facial weakness (n= ), dysphagia (n= ), diplopia (n= ), nystagmus (n= ), gaze palsy (n= ), and dysarthria (n= ). neurological symptoms were treated with steroids, with most symptoms subsiding by discharge. five patients had medical complications, including pneumonia (n= ), respiratory failure (n= ), gastrointestinal bleeding (n= ), arrhythmia (n= ), urinary tract infection (n= ), and myocardial infarction (n= ). two patients were re-intubated, three underwent gastrostomy, and one underwent tracheostomy. functional status at -months was available for five patients. three achieved modified rankin scale scores between - , one regressed to a , and one died. the treatment of giant vertebrobasilar aneurysms presents significant challenges. practitioners should anticipate temporary postoperative neurological worsening and various medical complications. prophylactic shunt placement, gastrostomy, and/or tracheostomy should be considered in patients anticipated to likely need these procedures after treatment. ventriculostomy-related infection (vri) remains a major complication of external ventricular drain (evd) placement. historically, prophylactic antimicrobials are utilized to decrease the incidence of vri after evd placement. recent guidelines for the insertion and management of evds recommend a single preoperative dose prior to evd insertion and urges against the use of duration antibiotic prophylaxis. prior to the publication of this guideline, we hypothesized that significant variations existed among institutions with respect to antibiotic prophylaxis practices in this setting. the purpose of this practice survey was to determine trends in antimicrobial prophylactic strategies utilized by various healthcare institutions for evd placement prior to publication of the neurocritical care society (ncs) evidence-based guidelines for the insertion and management of evds. a seven-question practice survey on antimicrobial prophylaxis for evd placement was distributed to active pharmacist members of the ncs by email and open for response from / / to / / . the following information was collected: antimicrobial prophylaxis regimen utilized, pharmacologic class, utilization of impregnated catheters, and institution guidance. survey results were analyzed for trends in antimicrobial prophylaxis in the setting of evd placement. respondents ( / , % response rate) from institutions completed a seven-question evd management survey. most institutions initiate a single dose of antibiotics prior to evd insertion ( / , %). periprocedural antimicrobial therapy is the most common prophylactic strategy utilized by respondents ( / , %). of respondents who do not continue antimicrobial prophylaxis for the duration of evd placement, % ( / ) utilize antimicrobial-impregnated catheters to reduce incidence of vri. the importance of antimicrobial prophylaxis to prevent infectious complications associated with evd placement is widely accepted. prophylactic strategies vary between institutions. periprocedural antimicrobial therapy is the most common prophylactic strategy utilized by survey respondents. antimicrobial-impregnated catheters are commonly utilized in institutions using periprocedural antimicrobial prophylaxis. the postoperative course seen in critically ill neurosurgical patients is known to vary depending on the timing of the surgical procedure. this study seeks to compare the clinical characteristics, complications, and outcomes between elective or urgent surgery patients admitted to the intensive care unit (icu). retrospective review of a two-year neurosurgical patients' cohort. the pre and postoperative conditions and outcomes were compared between elective (group a) and emergency (group b) surgery patients. a total of patients were evaluated, in group a and in group b. the most common diagnosis was intracranial tumor. the mean american society of anesthesiology (asa) score was significantly higher in group b than in group a ( . vs. . , p< . ). mean sequential organ failure assessment (sofa) score on admission was higher in group b ( . vs. . , p< . ). these patients were more likely to require mechanical ventilation (or . , p< . ) and vasopressors (or . , p< . ) . group b had a higher probability of rebleeding (or . , p< . ), intracranial hypertension (or . , p< . ), hydrocephalus (or . , p< . ), and reintervention (or . , p= . ). post-operative nausea and vomiting were less likely in group b ( . % vs. . % and vs. . %, respectively). mean hospital and icu los were shorter in group a than in group b ( . vs. . and . vs. . , p< . respectively). mortality rate during icu stay was higher in group b ( . % vs. . %; or . , p< . ). the preoperative glasgow coma scale (gcs) in patients who died, was below in only a minority of them ( . % in group b; % in group a). in this cohort of neurosurgical patients, emergency, compared to elective operations, were associated with higher post-operative complications and mortality rates. emergency surgery was associated with a higher severity of illness measured by the sofa and asa scores. intraprocedure rupture (ipr) is a rare but potentially serious complication of endovascular coiling of intracranial aneurysms. potential complications include hemorrhage, ischemic stroke, vasospasm and hydrocephalus which can lead to increased morbidity and mortality. the clinical course for these patients is not well studied and characterized. we performed a retrospective review of prospectively collected data for all unruptured aneurysms treated with endovascular coil embolization between july and march at a large universitybased hospital. out of cases of all unruptured aneurysms coil embolizations, ( . %) patients had ipr. we reviewed baseline data, procedure notes, clinical course, and outcomes at discharge and at , and months. among the ten patients, the location of the aneurysms included: basilar apex, internal carotid artery anterior communicating artery, posterior cerebral artery, and posterior communicating artery aneurysm. patients were monitored in the icu for variable lengths of time and daily transcranial doppler ultrasound detected no significant sonographic vasospasm. the large majority of the patients ( / ) were discharged to home at their baseline functional status assessed by modified rankin scale. one patient was discharged to inpatient rehabilitation for cognitive deficits from ipr of a basilar apex aneurysm. they were subsequently discharged home with supervision. there was a single mortality in a patient receiving retreatment of a proximal ica aneurysm with prior stenting and coil embolization who developed massive subarachnoid hemorrhage with diffuse intraventricular hemorrhage with external ventricular drain placement. the incidence of ipr is very low and potentially serious complications occur rarely in these patients. the location and factors associated with ipr are highly variable and without clear associations. outcomes of such complications are overall favorable. a short observation period in the hospital is likely warranted with a benign clinical course the most likely outcome. the standard treatment of cerebral venous-sinus thrombosis (cvst) is anticoagulation. however some patients clinically deteriorate secondary to mass-effect from infarct or intracerebral-hemorrhage (ich). the role of decompressive-craniectomy (dc) in this patient population is unknown. we elucidate the baseline characteristics of patients treated with dc, and report their outcomes. a retrospective chart review of our institutional database identified patients with cvst who were treated with dc. demographic and clinical data were collected. imaging variables collected from ct-head or mri-brain immediately before dc were intracerebral-hemorrhage volume (ich-v), combined volume of mass-effect from infarct/ich and peri-lesional edema (me-v), midline-shift at level of pinealgland (mds-p), midline-shift at cranial-most portion of corpus-callosum (mds-cc), and herniation-type. favorable outcome was defined as glasgow-outcomes scale of - upon last-known follow-up. a total of patients (females= ) treated with dc were identified with mean-age . (+/- . ), mean glasgow-coma scale (gcs) before surgery (+/- . ), mean-ich-v . ml (+/- . ), mean-me-v . ml (+/- . ), mean-mds-p . mm (+/- . ), and mean-mds-cc . mm (+/- . ). transverse-sinus was most commonly involved (n= ). / patients had any herniation, most commonly cingulate (n= ). meanchange in gcs from admission to before-surgery was - . (+/- . ). ten patients were anticoagulated before surgery. on last-known follow-up, / patients had a favorable outcome. four had died. on chisquare analysis, superior-sagittal sinus thrombosis was associated with unfavorable outcomes (p= . ), and mortality (p= . ). on univariate binary-logistic regression, there was a non-significant trend towards unfavorable outcomes (p= . ) and mortality (p= . ) with every-point decrease in mean-gcs before surgery. the predictive-value of other factors towards outcomes is unknown given limited sample-size. decompressive-craniectomy might improve outcomes even in patients with cvst who have developed coma, cerebral herniation, have failed treatment with anticoagulation, and have large-volume masslesions causing midline-shifts of > mm. a prospective multi-institutional observational-cohort would poster presentations better delineate outcomes in comparison to matched-patients who are not treated with decompressivecraniectomy. meningiomas are often benign and mostly asymptomatic, and the treatment approaches may include open surgical resection, radiosurgery, and/or watchful waiting. reported morbidity and mortality rates for elderly patients undergoing meningioma resection vary widely. we sought to investigate mortality rates for elderly patients undergoing craniotomy for meningioma resection using the nationwide inpatient sample (nis). the nis datasets from to were used to identify patient admissions for meningioma resection based on the icd- -cm code . . age categories were defined as years of age. primary outcomes were in-hospital mortality, poor outcomes (defined as death or discharge to a facility other than home), cost and length of hospitalization. a total of , patients were identified who underwent meningioma resection during - of which . % were elderly (> years). each of the primary outcomes was heavily influenced by the advancing age. in-hospital mortality was higher in the elderly as compared to the younger patients ( . % vs % p< . ), as was the rate of a poor outcome ( . % vs . %, p< . ). elderly patients also had a higher cost ($ vs $ , p= . ) and increased length of hospitalization ( . vs . days, p< . ). in our study, age > was strongly associated with adverse outcomes after meningioma resection. this increased risk should be taken into account when considering surgical intervention in this subgroup. based on this study, closer perioperative monitoring may be warranted in the elderly patient subgroup. treatment with anticoagulation improves outcomes in cerebral venous-sinus thrombosis (cvst). however patients who develop extensive infarcts and/or intracerebral-hemorrhage with mass-effect resulting in comatose-state are at risk of poor outcomes, and may benefit from decompressive craniectomy (dc). we evaluated the role of dc in the management of malignant cvst and its impact on outcomes. literature-search was conducted on pubmed and google-scholar using terms "craniectomy", and "cerebral venous-sinus thrombosis". we included studies that described any number of patients with cvst who underwent dc after clinical deterioration and reported their outcomes. a similar search strategy identified patients from our institute. outcomes were reported as modified-rankin scale (mrs) or glasgow-outcomes scale (gos) and were classified as favorable (mrs - ; gos - ), or unfavorable (mrs - ; gos - ). a total of patients (females= ; males= ; unknown= ) who underwent dc for malignant-cvst were identified from studies (n= ) and our institute (n= ). age and gcs (before-surgery) were only available from patients, with mean-age . (+/- . ) and mean-gcs . (+/- . ). patients ( . %) had favorable-outcomes, while patients ( . %) died. in the multi-variate binarylogistic regression-model, every point-drop in gcs decreased the odds of favorable-outcomes by . times (p< . ; %ci= . - . ), and survival by . -times (p= . ; %ci= . - . ). thrombosis in internal-jugular vein (ijv) (or= . ; %ci= . - . ; p= . ) and deep-cerebral veins (dcv) (or= . ; %ci= . - . ; p= . ) predicted unfavorable-outcomes. ijv-thrombosis (or= . ; %ci= . - . ; p= . ) and dcv-thrombosis (or= . ; %ci= . - . ; p= . ) also predicted mortality. interestingly, cortical-vein thrombosis was associated with lower odds of unfavorable outcomes (or= . ; %ci= . - . ; p= . ). data regarding anticoagulation and long-term follow-up were not uniformly available. for patients with malignant-cvst, craniectomy could potentially improve outcomes. factors such as gcs before-surgery and cvst location can help predict outcome following dc and aid the decision-making process. a multi-institutional observational cohort should be designed to prospectively evaluate predictors for, timing of, and outcomes after craniectomy in cvst. the external ventricular drain (evd) is commonly used in the neurocritical care unit to help monitor intracranial pressure (icp) with the added advantage of therapeutically treating elevated icp by diverting cerebrospinal fluid (csf). placement of an evd can be complicated by hemorrhage surrounding the catheter insertion tract, which in some cases may prove to be fatal. this retrospective study was designed to look at the rate of tract hemorrhages after evd placement that were performed at our institution as well as associated outcomes. we conducted a retrospective review of all patients who underwent evd placement during a year period using our institutional database. postinsertion computerized tomography (ct) scans of the head were analyzed independently by physicians to identifying tract hemorrhages. data on primary diagnosis, age, sex, length of icu stay and mortality were collected and analyzed. a total of patients were identified as having had an evd placed during their hospital course. patients were excluded as there were no images of evds present in their records. patients were analyzed, of which % were male. mean age was . years. % of patients had a diagnosis of subarachnoid hemorrhage, % with intraparenchymal hemorrhage and % with ischemic stroke. mortality was % among all evd patients. the rate of tract hemorrhages among all patients with evd images was %. asymptomatic tract hemorrhages occurred in patients ( . %) with patient ( . %) dying due to the tract hemorrhage itself. among patients with tract hemorrhages mortality was . %. the rate of tract hemorrhages was noted to be % with the majority being asymptomatic. there was no difference in mortality among patients with evds who developed tract hemorrhages compared to patients with no tract hemorrhages. verapamil is a phenylalkylamine calcium channel blocker that blocks the calcium ion influx through slow channels into conductile and contractile myocardial cells and vascular smooth muscle cells resulting in vascular relaxation and vasodilatation. symptomatic hypotension and/or extreme bradycardia/asystole are often seen with intravenous verapamil administration requiring pharmacologic treatment. in neuroendovascular field verapamil is mainly being used as a vasodilator agent. current lack of pharmacokinetic/pharmacodynamics data of intra-arterial verapamil often makes very challenging to neurointerventionalists during endovascular procedures. the purpose of this study is to observe acute hemodynamic effects of intra-arterial verapamil administration as well as the safety of higher dose of the medication during endovascular treatment. ten patients who underwent endovascular treatment for acute ischemic stroke were evaluated pre and post procedure with vital signs. the dosage of intra-arterial verapamil was documented and tabulated along with the pre and post heart rate and systolic blood pressure. the dose of intra-arterial verapamil varied from to mg in each internal carotid or vertebral artery, total dose per patient per procedure varied from . to . the average dose of intra-arterial verapamil administered was . ± . mg or . ± . mcg/kg that were infused over to minutes. at the baseline before administration of intra-arterial verapamil, the mean systolic blood pressure (sbp) was . ± . mm hg and the mean heart rate (hr) was . ± . bpm. after administration of intraarterial verapamil, sbp decreased by mean of . ± . mm hg but we observed no symptomatic hypotension requiring any pharmacologic treatment. hr changed only by mean of . ± . bpm post intra-arterial verapamil. we observed no acute significant changes in hemodynamic parameters with administration of verapamil in carotid or vertebral arteries. this may represent its safe use during neuro-endovascular therapy. growing evidence suggests inflammation is critical in epileptogenesis. endogenous brain apolipoprotein e protein (apoe) modulates neuroinflammatory responses to injury through downregulation of glial activation and secondary neuronal injury. we created a amino acid peptide (cn- ) mimicking the binding face of apoe. cn- downregulates the inflammatory response in vitro and in vivo and improved histologic and clinical outcomes across several injury models in mice. we hypothesized that downregulation of inflammation by administration of cn- will reduce the development of epilepsy after pilocarpine induced status epilepticus in mice. c bl/ mice were intraperitoneally injected with pilocarpine to induce status epilepticus. following induction of status, animals were randomized to receive two doses of cn- or vehicle at minutes and hours. status was terminated by injection of benzodiazepine at minutes. epidural eeg leads were surgically placed at weeks and continuous video-eeg (cveeg) monitoring was performed for several days in a row at - weeks post status to determine spontaneous seizure development and frequency. at - weeks following induction of status epilepticus, administration of . or . mg/kg cn- reduced the development of epilepsy by approximately % compared to vehicle treated animals. further, cn- treated animals that did develop seizures had significantly fewer seizures than vehicle mice. similar results were seen with daily doses of mg/kg starting at minutes. importantly, cn- is not an anticonvulsant as cveeg monitoring during status induction clearly demonstrated that seizures were not stopped or reduced by injection of cn- . these results are consistent with the hypothesis that inflammation plays an important role in the development of epilepsy after injury and demonstrates treatments that target inflammation, like cn- , can prevent and/or reduce the development of epilepsy. this represents the first therapy to prevent the development of epilepsy that has entered into clinical trials. to determine the speed of brain entrance of the antiepileptic drugs (aeds) brivaracetam (brv) and levetiracetam (lev) after single intravenous dosing in humans. brv and lev both bind to synaptic vesicle protein a (sv a), but brv has more rapid brain entry than lev in mice and monkeys [ ] . sv a can be quantified in the living human brain using pet imaging with [ c]ucb-j[ ]. pet scans (n= ) were performed with [ c]ucb-j administered by a bolus-infusion protocol in healthy volunteers (n= ). therapeutic dosages of brv ( mg, n= ; mg, n= ; or mg, n= ) or lev ( mg, n= ) were administered as -minute intravenous infusions minutes after the start of the first pet scan. tracer displacement half-times were determined by subtracting the radioligand clearance halftime from the radioligand displacement half-times estimated by exponential fitting of the post-aed drop in distribution volumes (vt). data were also analyzed using an advanced mathematical model that described the relationship between brain [ c]ucb-j pet data and time-varying aed plasma curves to directly estimate brain entrance (k ) of both aeds and [ c]ucb-j, free fraction of [ c]ucb-j in the brain, and vt values. the radioligand clearance half-time was minutes. tracer displacement half-times were . and . minutes for brv mg, and ± minutes for lev mg. lower brv doses had longer half-times, but values were misleading as they assumed % sv a occupancy. the advanced compartment model described well -dose scans. using the advanced model, the brv uptake rate (~ ul/min/cm ) was found to be at least -fold higher than that of lev (~ ul/min/cm ). the results demonstrate that brv enters the human brain faster than lev. the potential therapeutic benefit of this has yet to be determined. while intravenous anesthetic therapy (ivat) represents the gold-standard for treatment of refractory status epilepticus (rse), the optimal depth and duration of therapy is not known. the goal of this retrospective observational study was to describe the relationship between the depth of burst suppression and the ability to successfully wean ivat during rse treatment. fifty patients were identified with rse who underwent continuous electroencephalography. using persyst, the suppression ratio (sr) was calculated up to hours prior to weaning ivat. the type and duration of ivat was recorded, as well as complications. we compared these variables between successful and unsuccessful weans. the mean sr for all patients was . ± . %, with a mean treatment duration of . ± . hours. there was no difference in treatment duration between successful and unsuccessful weans(p= . ), but sr was significantly lower in successful weans ( . ± . % vs . ± . %, p= . ). the receiver operating curve (roc) for the sensitivity and specificity of the mean sr to predict a successful weaning attempt did not identify a threshold to predict weaning success. the use of pentobarbital was associated with a significantly higher sr when compared to midazolam ( . ± . % vs . ± . %, p < . ). patients failed ivat weaning a mean . ± . hours after initiating the ivat wean, which occurred after a mean decrease in the midazolam infusion rate of ± %. depth of sr was not associated with infection risk (p= . ), but was associated with the need for tracheostomy ( . ± . % versus . ± . %, p= . ). vasopressors were required in . % of patients while on ivat. unsuccessful weaning of ivat was associated with a higher depth of sr, which is likely a marker of disease severity. depth of sedation was not associated with increased risk of infection, but was associated with the need for tracheostomy. vasopressor requirements are common. the primary objective of this study was to determine the sensitivity and specificity of real-time neuro icu nurse interpretation of quantitative eeg (qeeg) trends in the identification of recurrent nonconvulsive electrographic seizures in adult patients admitted to the neuro icu. thirteen adult patients admitted to the neuro icu that had nonconvulsive seizures on continuous eeg (ceeg) monitoring were included in the study. neuro icu nurses consented for their participation and underwent a brief, standardized qeeg training session. a -hour qeeg panel (rhythmicity spectrogram, left/right and amplitude-integrated eeg, left/right) printout containing the marked sentinel seizure(s) was displayed next to the bedside ceeg/qeeg monitor. at one-hour intervals, the nurses logged the number of seizures seen in the past hour based on their qeeg interpretation for the duration of their shift. their answers were compared with the gold standard of neurophysiologist interpretation of seizure occurrence on raw eeg. a total of hours of qeeg data was reviewed for patients. average length of data collection was . hours. for the neuro icu nurses' ability to detect the presence of seizures on real-time qeeg the sensitivity was . % ( % ci, . - . %) and specificity was . % ( % ci, . - . %). the positive predictive value for seizure detection was . % ( % ci, . - . %) and the negative predictive value was . % ( % ci, . - . %). the false-positive rate was . /hr. a simplified panel of qeeg trends can be used by neuro icu nurses to screen for recurrent electrographic seizures in critically ill patients with a reasonable sensitivity, an excellent specificity and a very low false-positive rate. this may facilitate earlier identification of recurrent electrographic seizures by notifying the neurophysiologist who is not present in the icu and not able to perform real-time ceeg interpretation. nonconvulsive status epilepticus (ncse) is an indicator of poor outcomes in neurocritical care settings. however, because of unfamiliarity with continuous electroencephalography monitoring (ceeg), the diagnosis and treatment of ncse remains challenging, and its clinical impact and prognostic factors have not been sufficiently reported in japan. we performed ceeg for adult patients in our neurocritical care unit with coma or unexplained altered mental status from april to september . we reviewed all ceeg records according to the american clinical neurophysiology society's terminology ( version), and diagnosed patients with ncse when the ceeg revealed spatiotemporally evolving or fluctuating periodic or rhythmic discharges and after considering clinical information based on the modified salzburg consensus criteria. patients with ncse were aggressively treated with benzodiazepines, fosphenytoin, and levetiracetam. they were divided into a generalized convulsive status epilepticus (gcse) group and a non-gcse group. we compared mortality and outcomes between the two groups after months using fischer's exact test. outcomes were defined as poor when the glasgow outcome scale score was worse at the -month follow-up than at admission. we excluded cases undergoing supportive care or lacking of follow-up. of cases in the study, cases were diagnosed with ncse, including cases with accompanying gcse and cases without. mortality rates at the -month follow-up were significantly higher in the non-gcse group than the gcse group ( % vs. %, respectively; p = . ). the rate of poor outcomes was significantly higher in the non-gcse group than in the gcse group ( % vs. %, respectively; p = . ). this study suggests that the absence of gcse is associated with increased mortality and poor outcomes among ncse patients. limitations of this study include its retrospective design and small number of ncse patients. further studies are necessary to identify additional prognostic factors. super-refractory status epilepticus (srse) is a life-threatening condition in which status epilepticus recurs or continues for over hours despite first-, second-, and anesthetic third-line agent (tla) medications. no treatments are currently approved for srse. a randomized, double-blind, multi-center, placebo-controlled phase trial evaluated brexanolone (usan; formerly sage- injection), a synaptic and extrasynaptic gabaa receptor positive allosteric modulator as adjunctive therapy for srse (nct ; "status trial"). enrolled subjects underwent a qualifying tla wean after at least hours of seizure-or burstsuppression. srse subjects failing the qualifying wean were randomized : to a blinded infusion of brexanolone or placebo as adjunctive therapy following resumption of one or more tla infusions. subjects were administered the blinded infusion for days, during which attempts were made to wean off tla infusions. clinical standardization guidelines (csgs) facilitated standardization across sites by outlining eeg patterns for which tla weaning should be continued, paused, or discontinued. an on-call clinical standardization team provided real-time support. safety was assessed via adverse events, laboratory testing, vital signs, and ecg parameters. the primary endpoint was defined as successfully super-refractory status epilepticus (srse) is a life-threatening neurological condition characterized by status epilepticus persisting over hours despite treatment with first-, second-, and third-line agents (tlas) or upon the weaning of tlas. currently, there is no consensus around treatment protocols for srse. this study aims to describe srse treatment patterns and related outcomes in a us population. we retrospectively identified srse cases in cerner healthfacts®, a large, de-identified, us electronic health record database, using records from - . cases were classified as srse using a modified version of a previously published algorithm using icd- and procedure coding for status epilepticus ( . , . , . x, . , . , . , and . ) , ventilator support, pharmacotherapies. descriptive and univariate statistics were used to evaluate anesthetic treatment, anti-epileptic medications, and the association between glasgow coma score (gcs) and mortality. using our algorithm, srse cases ( patients) were classified. multiple tlas were received in % of cases, and in %, > concurrent tlas were received. the first post-admission tlas were propofol, lorazepam and midazolam, respectively, in %, % and % of cases. median anesthetic duration was . days. mortality was higher in - ( . vs. . days; p< . ). srse patients identified in our analysis underwent variable treatment patterns, reflecting lack of co days of tla treatment. nonconvulsive seizures (ncs) and nonconvulsive status epilepticus (ncse) occur in approximately % of neurologically critically ill patients. the most effective antiepileptic drug (aed) regimen to treat ncs and ncse is unknown. this study was designed to determine the efficacy of add-on clobazam, a unique , -benzodiazepine with favorable pharmacokinetic properties, in the treatment of ncs and ncse. a retrospective chart review was performed on adult patients who were admitted to the neurological intensive care unit between january , and june , , were diagnosed with ncs or ncse by continuous eeg monitoring and received clobazam as add-on therapy. the primary efficacy endpoint was defined as clobazam being the last aed added before ncs/ncse cessation, regardless of latency between dosing and ncs/ncse cessation. of the patients included in this study, ( %) had ncs vs. ( %) with ncse. the most common etiologies were autoimmune (n= ) and cns tumor (n= ), with patients ( %) having pre-existing epilepsy. clobazam was the last aed added before cessation of ncs/ncse in of ( %) subjects. clobazam was chosen as the rd to th line agent. clobazam was started at a median of days from the onset ncs/ncse (range - days). the median total daily dose of clobazam was mg (range - mg). this study suggests that clobazam may be effective at various time points in the treatment of ncs/nsce and may prevent the need for addition of intravenous anesthetic drugs to control seizures. however, a prospective study is warranted to determine efficacy and optimal dosing. continuous electroencephalography monitoring(ceegm) with international - system is essential for detect nonconvulsive status epilepticus (ncse). in japan, both ceegm systems and human resources are lacking, and few facilities are able to conduct such advanced monitoring. the ceegm headset, described in this report, is a novel and easy-to-use technology. we attempted to validate the novel ceegm headset by comparing it with a conventional, international - ceegm system (conventional ceegm). we completed this study at a single center, eight-bed neurocritical care unit, between january and june . the new, ceegm headset features eight electrodes (f, c, t, o), and is capable of simultaneously transmitting eeg data by bluetooth. patients with disturbed consciousness, of unknown etiology, underwent ceegm headset followed by conventional ceegm. we verified the concordance rate of the two systems for detecting eeg morphologies (e.g. periodic discharges, rhythmic delta activity, spikes and waves), and diagnosing ncse. eeg morphologies were appreciated according to "american clinical neurophysiology society's standardized critical care eeg terminology: version" and diagnosis of ncse were done according to modified salzburg consensus criteria. among this period, we enrolled thirty patients. three patients were excluded because of not satisfying protocol. final analyses included verified data from patients. the mean age was years old (range: - ), % were male, mean acute physiology and chronic health evaluation (apache) ii score was (range: - ), and mean full outline of unresponsiveness (four) score was (range: - ). we appreciated concordant eeg morphologies, and ncse, in % ( / ), and % ( / ) of patients, respectively. this easy novel ceegm headset may be useful in settings with limited resources or access to conventional ceegm technology. further study is needed to validate the actual diagnostic ability of this novel headset. the traditional approach to interpreting eeg requires physicians with formal training to visually assess the waveforms. this approach is less practical in critical settings when a trained eeg specialist is not readily available to diagnose subclinical seizures, such as non-convulsive status epilepticus, in patients with altered mental status. we have recently invented an algorithm for sonifying eeg, and in the current study, we explored whether individuals without eeg training can detect ongoing seizures by simply listening to one channel of sonified eeg. we sonified eeg samples ( -second long) that represented various conditions commonly seen in the icu ( seizures; lpd, gpd, or burst suppression, and normal or slowing). medical students and nurses were asked to indicate each audio sample as "seizure" or "non-seizure". we then compared their performance with that of eeg experts [epilepsy attendings with > years of experience (n= ) and epilepsy fellows (n= )] and some of the medical students (n= ) who also diagnosed the same eegs on visual display. non-experts listening to single-channel sonified eegs detected seizures with remarkable sensitivity (students: ± %; nurses: ± %) compared to experts or non-experts reviewing the same eegs on visual display (attendings: %; fellows: ± %; students: ± %). if the eegs contained seizures or seizure-like activity, non-experts listening to sonified eegs rated them as seizures with high specificity (students: ± %; nurses: ± %) compared to experts or non-experts viewing the eegs visually (attendings: ± %; fellows: ± %; students: ± %). our study confirms that individuals without eeg training can detect ongoing seizures or seizure-like rhythmic periodic activity by merely listening to short duration of sonified eeg. while sonification of eeg cannot replace the traditional approaches to eeg interpretation, it provides a meaningful triage tool for fast assessment of patients with suspected subclinical seizures. super-refractory status epilepticus (srse) is a life-threatening form of status epilepticus (se) that continues despite, or recurs after, hours of therapeutic interventions, including continuous intravenous anesthetic third-line agents (tlas). no therapies are approved for srse, leading to substantial variation in both management and determination of treatment response. for the phase trial of brexanolone as adjunctive therapy for srse involving up to international sites, we developed and implemented clinical standardization guidelines (csgs) for real-time support of tla administration, weaning, and outcome assessment under eeg neuromonitoring. a clinical standardization team (cst), including investigators and se experts, developed consensus csgs defining acceptable eeg patterns for continuation, termination, or pausing the weaning of tlas. csg implementation was facilitated by training and cst call centers staffed internationally by physicians with critical care eeg expertise. in cases of disagreement, the local site retained final decision-making authority. a "traffic light" system defined: )"green" tolerated eeg patterns (improving background, seizures within hours, discharges > hz, or discharges - . hz with evolution and no improvement over hours), and )"amber" eeg patterns not meeting the above, for which tla weaning should be paused while optimizing anti-epileptic medications and monitoring for transitions to green/red eeg patterns. the initial cst consultations yielded % csg compliance; % of eegs underwent cst review. few cst consultations lasted > minutes ( %); most lasted < minutes ( %). this phase trial demonstrates the feasibility of applying neuromonitoring csgs for tla weaning in srse patients, to ensure better consistency of clinical care and reliability of the primary outcome measure in clinical trials. csgs were well accepted by investigators and may serve as a framework for future clinical trials or clinical therapies in srse. severe brain trauma is a leading cause of death and disability worldwide. post-traumatic epilepsy (pte) is a chronic complication that occurs in up to % of cases (frey, ; najafi et al., ) . drugs and other interventions to prevent epileptogenesis would likely be most effective early after traumatic brain injury (tbi), but cannot be given indiscriminately. there is a critical need for tools that quantify those at high risk for pte. abnormal neural activity, in the form of ictal-interictal continuum abnormalities(iicas) are increased acute brain injuries, and appear to differentiate patients at risk for secondary brain injury (e.g. kim et al., ) . we hypothesized that iicas acutely following tbi may be a marker of posttraumatic epilepsy risk. we evaluated continuous eeg data from moderate to severe tbi patients who did and did not develop pte, (any seizure - months post-tbi; n= ). seizures < month post-tbi were classified as symptomatic, not pte. conventional - scalp electrode placement was used and eegs were reviewed by standard visual analysis, by the mgh neurophysiology service. daily eeg reports were scored for the presence of iicas and seizures. demographic data including gender, age, tbi severity and type of brain injury were recorded. univariate and multivariate regression analyses were performed to determine which iica and demographic features correlated with pte. gcs (p= . ) and tbi severity (p= . ) were significantly associated with pte, as expected. seizures (p= . ), epileptiform discharges (p= . ), generalized periodic discharges ( . ) and lateralized rhythmic delta activity (p= . ) independently predicted risk for post-traumatic epilepsy. epileptiform discharges, in particular, were more prevalent acutely post-tbi in pte patients. increased iica prevalence is significantly associated with pte and may be a predictive marker for identifying patients who may benefit from anti-epileptogenesis trials. rapidly obtaining eeg signals in the ed and icu for at-risk patients can enhance diagnosis accuracy and speed, while cutting down time until treatment. ceribell inc has developed a portable eeg data recorder and electrode headset with rapid setup (~ min) technology without any eeg technician required to overcome the inaccessibility of eeg in urgent situations when seizures are suspected. the purpose of this study is to evaluate the signal quality and performance of the ceribell system compared to a reputable clinical eeg system. we collected eeg samples in the laboratory and at stanford university medical center. laboratory collections on healthy volunteers included simultaneous collection of eeg using ceribell and nihon kohden systems, and a split-signal that recorded eeg to both data recorders from the same electrodes. in the icu, eeg was recorded with the ceribell system on patients and subsequently with the clinical eeg system. data was filtered and spectral densities, mean frequency (mf), spectral entropy (se), and % spectral edge frequency (sef ) were computed. in the split-signal test, the waveforms consistently appeared similar by visual inspection. the analysis of ceribell data revealed (mf = . hz, se= . , sef = . ) similar to the commercial system (mf = . hz, se = . , sef = . ). in the simultaneous test, the ceribell system produced (mf = . hz, se = . , sef = . ) similar to the commercial system (mf = . hz, se = . , sef = . ). in the clinical setting, the ceribell system showed spectral density distributions comparable with the commercial system. our results indicate that the signal quality of the ceribell system is similar to a commercially available eeg used widely in the clinical setting, while requiring less setup time and allowing more portability. status epilepticus (se) is a life-threatening condition characterized by prolonged seizures without regaining consciousness between seizure events. when se continues or recurs hours or more after treatment with third line anesthetic agents, it is considered super-refractory se (srse). there are few population-based studies on the descriptive epidemiology of srse at a national level. the objective was to estimate the incidence of srse in canada in - . we analyzed standardized national administrative record-level data covering all provinces across canada as provided by the canadian institute for health information. srse episodes were classified from two databases for acute care admissions (discharge abstract database) and emergency visits (national ambulatory care reporting system) over fiscal years ( / to / ). cases were identified as srse using a modification of a previously published algorithm using icd- -ca diagnostic codes for epilepsy (g ), status epilepticus (g ), or convulsions (r ) plus an intensive care unit stay of days or more with mechanical invasive ventilation. using our algorithm, from - , the mean annual number of cases classified as srse was , ( . / , persons per year). the annual incidence was higher in males ( . / , per year) than females ( . / , per year). the highest rates were in the age group - years: . and . per , per year for females and males, respectively. the mean age of srse patients was years (sd= years), with % males. the most common comorbidities for srse included metabolic disturbances ( %), sepsis ( %), toxic withdrawal state ( %), cardiovascular disease ( %), and head trauma ( %). in-hospital mortality for srse was %. this is the first study reporting estimates of srse incidence in canada. these results suggest that srse is associated with a substantial disease burden. interventions that improve patient outcomes and reduce mortality are required. new-onset refractory status epilepticus (norse) is a condition characterized by prolonged pharmacoresistant seizures in a previously healthy individual with no identifiable etiology during initial evaluation. typical magnetic resonance imaging (mri) findings include bilateral limbic and neocortical t -weighted hyperintense lesions. fluorodeoxyglucose (fdg)-positron emission tomography (pet) findings have not been previously reported. this study sought to describe fdg-pet and mri characteristics in patients with norse. methods patients were retrospectively identified amongst a database of autoimmune-mediated encephalitis from - , meeting diagnostic criteria for norse and having undergone mri and pet over the course of their illness. imaging findings were confirmed with a board-certified neuroradiologist. nine patients were autoantibody positive: three n-methyl-d-aspartic acid (nmda) receptor, two glutamic acid decarboxylase (gad), three voltage-gated potassium channel (vgkc)-complex with two having leucine-rich glioma-inactivated protein igg positivity, and one gamma-aminobutyric acid (gaba) b receptor. all patients had identifiable abnormalities on fdg-pet. hypometabolism was most common, with of patients having diffuse, bilateral, or unilateral frontal, parietal, or occipital cortical hypometabolism. nine patients also had bilateral ( ) or unilateral ( ) mesial temporal hypermetabolism. two patients had multifocal hypermetabolism with bilateral or unilateral frontal abnormalities in addition to mesial temporal findings. of the nine patients with fdg-pet hypermetabolism, concurrent mri scans failed to show corresponding t -weighted hyperintense lesions in the mesial temporal and medial frontal regions in two patients. fdg-pet findings in norse include bilateral or unilateral mesial temporal or mesial frontal hypermetabolism with diffuse, bilateral, or focal cortical hypometabolism. hypermetabolism may reflect regions predominantly involved in acute epileptogenesis. fdg-pet may improve sensitivity when compared to mri alone. while seizures are uncommon but reported in primary intraventricular hemorrhage (ivh), little evidence is available on the prevalence of hyperexcitable patterns on long term eeg monitoring. we sought to determine the prevalence of hyperexcitable patterns and seizures in patients with primary ivh who were extracted from a cohort consisting of patients with spontaneous intracerebral hemorrhage (sich) who underwent continuous electroencephalogram (ceeg) monitoring between january and december at yale-new haven hospital. indications for ceeg monitoring included fluctuation of or depressed mental status, abnormal movements and a limited clinical exam. we recorded demographics, radiologic hydrocephalus, duration of eeg recording and eeg findings. hyperexcitable patterns comprised generalized, bilateral independent or lateralized periodic discharges (pds), lateralized rhythmic delta activity (rda), brief potentially ictal rhythmic discharges (b(i)rds), and spike-and-wave discharges (sw). of adults with sich who had ceeg performed, patients had primary ivh. hydrocephalus was present in patients ( %). patients were monitored for a mean duration of . (± . ) hours. patients had hyperexcitable patterns and/or electrographic seizures ( %): electrographic seizures and co-existent hyperexcitable patterns were captured in of patients ( %) and hyperexcitable patterns without seizures in of patients ( %). hyperexcitable patterns included periodic discharges (pds) ( ) (generalized, lateralized and bilateral independent, with and without rhythmicity), rhythmic delta activity (rda) ( ) (both lateralized and generalized, with and without sharps), brief potentially ictal rhythmic discharges(b(i)rds) ( ) and spike-and-wave discharges (sw) ( ). there was no significant difference between patients with and without hydrocephalus and hyperexcitability or electrographic seizures (p= . ). both electrographic seizures and/or patterns of hyperexcitability on eeg are common in our selected cohort of primary ivh patients. this underscores the importance of continuous eeg monitoring in this patient population, since the detection of non-convulsive seizures may offer an opportunity for therapeutic intervention. patients with aneurysmal sah (asah) frequently have ictal-interictal continuum (iic) eeg patterns. while seizure burden can worsen outcomes, less is known about iic burden. we investigated the impact of iic burden and anti-epileptic drug (aed) treatment on asah outcomes. we included patients with asah undergoing continuous eeg (ceeg) from - . patients with nonaneurysmal sah or %, - %, - %, - %, < %. age gender, admission gcs, apache ii score, fisher and hunt and hess (hh) scores, aed dosing and discharge gos were ascertained by chart review. presence of iic patterns in asah independently predicts worse neurologic outcome, although maximum burden does not. although nearly half of these patients receive aed treatment, our data suggest that aed treatment may not influence outcome. prospective studies may further delineate the clinical risks and benefits of aed treatment. refractory status epilepticus (rse) is defined by failure to control epileptic activity after the administration of st and nd line antiepileptic agents. mortality associated with rse has been estimated to be around - % at hospital discharge. we conducted this study to analyze trends in the frequency and management of rse. we conducted a cross-consortium (uhc) database from to . this is a database from academic medical centers and their affiliated hospitals in the united states and consists of a sample of , , patients. data including age, sex, antiepileptics (aed) and length of stay was collected. total mean age was . years and females were . %. there was an increasing trend of using lorazepam as the first line aed ( . % in to . % in ) and a decreasing trend was noted of using midazolam as the first line aed ( . % in aed ( . % in to . % in . leviteracetam was the most common second line aed used throughout all years which was followed by propofol followed by phenytoin/fosphenytoin. mean length of hospital stay was . days. between to , the proportion of hospitalized patients in the united states diagnosed with rse has increased. lorazepam and leviteracetam have been the most common aeds used. mean length of hospital stay has not changed. status epilepticus is associated with high risk of multi-organ dysfunction. ketamine for the treatment of super refractory status epilepticus (srse) has the benefit of a different mechanism and lack of cardiac depression when compared with other anesthetic agents. this study evaluated the improvement in sequential organ failure assessment (sofa) score in patients treated with ketamine for srse. this is a retrospective study of patients with srse from to . the timing and dosage of anesthetic agents used in their treatment were abstracted. sofa scores at admission and for the first days after initiation of ketamine were calculated. the presence of shock prior to initiation of ketamine included septic shock and cardiogenic shock. outcomes including mortality, organ failure, and hospital associated infections (hais) were also recorded. a total of patients were treated with ketamine after failure of seizure control using other anesthetic agents. seventeen ( . %) had an improvement of their sofa score while ( . %) did not. the median sofa score on admission was (iqr - ) for those who had an improvement and (iqr - ) for those who did not (p= . ). cardiac arrest was the etiology of srse for ( . %) patients who improved vs. ( . %) patients who did not (p= . ). patients required to vasopressors for hemodynamic support, with less needed for those who had an improvement (p= . ). there was a higher rate of hais in patient who did not have an improvement of their sofa score (p= . ). there is a subset of patients treated with ketamine for srse who have an improvement in their sofa score, require less vasopressor support, and have a lower rate of hais. further studies are needed to better understand which patient population may most benefit from the use of ketamine for treatment of srse. the ceribell eeg system (ces) is a novel channel eeg device with instant sonification and visual display capability that can be set up quickly without an eeg technician. we hypothesized that by using ces, we can decrease time to eeg acquisition and improve diagnosis and treatment decisions in suspected nonconvulsive seizures (ncs). adult icu patients (gcs < ) who had continuous eeg (ceeg) as part of clinical care were enrolled. once ceeg was ordered, consent was obtained and ces was placed by the treating physician (n= ) who listened to the left/right hemisphere signals for seconds each. suspicion for seizure ( =low, =high) and decision to treat (yes/no/not sure) were rated pre-and post-sonification. three blinded epileptologists compared accuracy of sonification with visual ces eeg. outcomes were difference in time to eeg acquisition, change in suspicion for seizure and decision to treat, and ease of use ( =challenging; =easy). patients (mean age +/- , median gcs of (iqr - . ) were enrolled from : am to : pm. start of eeg acquisition was significantly faster for ces ( minutes (iqr - ) vs minutes (iqr - ) p< . ), median difference minutes (iqr - ). one patient had ncs during sonification and this was accurately identified and treated. low suspicion for seizure ( ) was more likely postsonification ( % vs %, p= . ). treatment decision changed in % after sonification, and this was in the correct direction % of the time. inappropriate decision to treat decreased from % to % (p= . ). negative predictive value was % ( % ci - %). ces was consistently rated easy to use. the ceribell eeg system is easy to use, speeds eeg acquisition, accurately identifies ncs, and enables appropriate treatment decisions. it has the potential to greatly enhance timely diagnosis and treatment of ncs in critically ill patients. the aim of the study was to understand the efficacy of ketamine in refractory status epilepticus and identify the underlying factors affecting the effectiveness of ketamine. moreover, we also studied the rate of complications in patients who underwent continuous midazolam ketamine dual therapy for treatment of refractory status epilepticus. this is retrospective cohort study evaluating the efficacy of ketamine in patient with refractory status epilepticus in total of patients admitted to university of maryland medical center in either neuro intensive care unit /micu during the last five years between ( - ). we established a standardized algorithm for managing refractory status epilepticus. electrographic and clinical control of seizures was classified into four groups: likely response, possible response, permanent response and no response reviewed by a team of epileptologist and neuro intensivist. the effective doses of ketamine to abort rse were studied. complications intensive care unit stay while on therapy were reviewed. of the patients, were male, were female. % of the patients had cardiac arrest as an etiology of seizures. median loading dose was . mg/kg, median maintenance dosage was mg/kg/hr. % of the patients had no response to ketamine. % were responsive to ketamine of which, patients had likely response to ketamine, patients had possible response. . % of the patients had permanent response to ketamine. % patients had hospital acquired infections, % patient had metabolic acidosis, % had ards. this is one of the largest single center study illustrating the efficacy of ketamine in aborting rse. further study should address the difference in incidence of complications in patients with usage of ketamine versus groups alternative therapies. this study also demonstrates the etiology of seizures and its influence on efficacy of ketamine in aborting rse. acute cardiopulmonary complications are frequently observed in convulsive status epilepticus but mechanism is poorly understood. complications include tachy-arrhythmias, myocardial ischemia, takotsubo cardiomyopathy and neurogenic pulmonary edema. herein, we mapped evolution of cardiac dysautonomia as function of sequential electrographic stages of se in four subjects admitted to icu. we hypothesize pathological co-activation of both arms of autonomic system contributes to cardiac complications. heart rate variability (hrv) is considered a proxy for ans tone on heart. we analyzed hrv in time and frequency domain, complexity measure (lempel ziv-lz) during se and mapped changes as function of stages of se as determined by scalp eeg. conventional scalp eeg recording and lead i-ekg (sampled at hz) were analyzed using kubios hrv software . . cardiac vagal index (cvi) and cardiac sympathetic index (csi) were calculated using geometric lorenz-plot method. parasympathetic activity is expressed in rmssd, pnn, cvi, and hf power four adults (range - ; m= ) were admitted to icu following convulsive se. ictal hrv changes initially reflected high sympathetic system activation (high csi) and reduced vagal tone (low hf, rmssd) as reported previously with convulsive seizure. earlier stages of se (stage i and ii) were marked by dual activation of the ans with sympathetic predominance (lower cvi/csi ratio). later stages of se (stage iv and v), demonstrated progressive increase in parasympathetic activity (hf power, rmssd, cvi, cvi/csi ratio). hf power and rmssd at stage v se was three times higher than during discrete seizure. lz complexity measure downtrended with the loss of fluctuations in late stages of se. in one subject se terminated with asystole this case series highlights dynamic changes in sympatho-vagal imbalances with progressive se. dual activation of sympatho-parasympathetic system and loss of complexity measures are associated with increased cardiac complications. therapies directed towards stabilization of cardiac dysautonomia might minimize complications super-refractory status epilepticus (srse) is a life-threatening neurological condition that is characterized by status epilepticus that persists for hours despite treatment with first-, second-, and third-line agents (tlas) or upon the weaning of tlas. srse is associated with limited treatment options, and high morbidity and mortality. this study aims to describe and quantify inpatient srse treatment and its associated outcomes in the us. srse cases were classified retrospectively using a modified version of a previously published algorithm applied to a large, de-identified, us electronic health record database (cerner health facts®) covering > hospitals ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) . cases were classified utilizing icd- and procedure coding for status epilepticus ( . , . , . x, . , . , . and . ) , ventilator support or with los> days or missing age were excluded. univariate statistics were used to describe mortality, hospital los, icu los, and discharge disposition. our algorithm classified cases as srse ( patients). most cases ( %) were to large ( + beds) and/or teaching hospitals ( %). mean hospital los was . days, and icu los was . days. both los and icu los were significa average mortality rate was . %. mortality rates increased with number of tlas used ( - tla= . %; -rged home ( % with tracheostomy), while % (n= ) were discharged to another facility. treatment of srse requires acute, intensive management in the hospital setting. los and mortality rates were high and increased with increasing use of tlas. while good outcomes remain possible even after srse, additional interventions are needed that enable seizure control, liberation from anesthetic and ventilator management, and improved mortality. refractory status epilepticus (se) carries an exceedingly high mortality and morbidity, often warranting an aggressive therapeutic approach. initially used in childhood epilepsies, ketogenic diet (kd) has also accumulated supporting evidence in the treatment of pediatric se. recently, the implementation of kd in adults with refractory and super-refractory se has been shown to be feasible and effective. we describe our recent experience with a new onset refractory status epilepticus (norse) patient and the unexpected challenge of achieving and maintaining a ketotic target. practical advice, a comprehensive review of offenders jeopardizing ketosis commonly used in the neurocritical care unit and alternatives is provided. a previously healthy -year-old woman was admitted with cryptogenic norse following a febrile illness with a course complicated by prolonged super-refractory se. a comprehensive work-up was notable only for mild cerebral spinal fluid (csf) pleocytosis, elevated non-specific inflammatory serum markers, and edematous hippocampi with associated diffusion restriction on magnetic resonance imaging (mri). repeat csf testing was normal and serial mris demonstrated resolution of edema and diffusion restriction with gradually progressive hippocampal and diffuse atrophy. she required an aggressive approach including high anesthetic infusion rates, anti-seizure drug trials (in various combinations), empiric partial bilateral oophorectomy, and immunosuppression. enteral ketogenic formula was started on hospital day , however, sustained beta-hydroxybutyrate levels > mmol/l were only achieved days later following a careful comprehensive adjustment of the care plan. notably, a significant response to kd was only achieved with beta-hydroxybutyrate levels > . mmol/l. there are hidden carbohydrates in commonly administered medications for se, antibiotics, and even electrolyte repletion formulations and solutions used for oral care -all challenging the use of kd in this setting. tailoring comprehensive care and being aware of possible complications of kd are important for the successful implementation and maintenance of ketosis. early seizures are estimated to occur in - % of patients with moderate to severe traumatic brain injury (tbi) (herman , vespa ). continuous eeg (ceeg) is essential for detection of nonconvulsive seizures (claassen ) the university of california davis protocol for tbi includes ceeg on a case by case basis, which we reviewed. a retrospective review of patients admitted to icu for tbi from / / - / / was performed for demographics, icu length of stay (los), and ceeg. patients with ceeg were assessed for demographics, tbi severity, gcs, ceeg indication and findings. patients were identified. twenty-one were monitored on eeg. median age was , % were female. indications for ceeg included seizure prior to admission (n= ), altered mental status (ams) (n= ), ams with paroxysmal events (n= ). seizures were recorded in patients. median duration of ceeg was . , . , and . hours among the groups. those with seizures prior to hospitalization were connected to ceeg earliest (median . hours) but had the longest median icu los ( . hours), followed by ams ( . and . hours) and ams with paroxysmal events ( . and . hours). median gcs was , , and respectively. median los for patients without seizures or interictal epileptiform activity (iea) was . hours, . for those with iea only, and . for those with seizures. median gcs was . , , and among the eeg groupings. our data suggests seizures prior to hospitalization, ceeg recorded seizures, and iea predict longer icu los. associated lower gcs likely indicates more severe injuries. tbi patients with ams may have delay to seizure detection and treatment. our rate of seizure detection is lower than expected. a more consistent protocol for ceeg will likely improve seizure detection. prospective studies are needed to determine if ceeg can predict and influence outcomes. status epilepticus is a serious neurologic emergency. although many studies have been published on incident status epilepticus, there are few data on the risk of recurrent status epilepticus. we performed a retrospective cohort study using administrative claims data to identify all patients hospitalized with status epilepticus in california, new york, and florida between - . our primary outcome was a recurrent hospitalization for status epilepticus. survival statistics were used to calculate the cumulative rate of recurrence at days, year, and years. in subgroup analyses, we compared rates of recurrence according to age, gender, race, and etiology (stroke, traumatic brain injury, acute and chronic central nervous system (cns) infections, brain tumors, dementia, autoimmune cns disease, or unspecified etiology). we identified , patients with status epilepticus. during a mean follow-up of . (± . ) years, , ( . %; % ci, . - . %) developed recurrent status epilepticus. the cumulative rate of recurrence was . % ( % ci, . - . %) at days, . % ( % ci, . - . %) at year, and . % ( % ci, . - . %) at years. the -year cumulative rate of recurrence was . % ( % ci, . - . %) in women versus . % ( % ci, . - . %) in men, . % ( % ci, . - . % ( % ci, . - . %) in patients < , and . % ( % ci, . - . %) in white patients versus . % ( % ci, . %- . %) in non-white patients. the -year cumulative rate of recurrence was highest for status epilepticus associated with autoimmune cns disease ( . %; % ci, . - . %) and chronic cns infection ( . %; % ci, . - . %). approximately in patients with status epilepticus experienced a recurrent episode within years. recurrence was most often seen in younger patients, non-white patients, and patients with underlying autoimmune cns disease or chronic cns infection. super-refractory status epilepticus (srse) is a rare, life-threatening form of status epilepticus (se) refractory to multiple therapies including anesthetic third-line agents (tlas). enrollment in a srse clinical trial is challenging because patients may present urgently before srse is confirmed or may dynamically improve before randomization. pivotal clinical trials in srse require patient selection criteria accurately identifying srse at randomization. in this phase trial of brexanolone as adjunctive therapy for confirmed srse, the enrollment scheme enabled operationally confirming srse prior to randomization during a qualifying wean (qw) under real-time eeg neuromonitoring. informed consent was obtained for all subjects ) admitted in se having failed first-and second-line therapies; ) transferred on tlas in seizure-or burst-suppression; or ) transferred without seizure-or burst-suppression or not receiving tlas. subjects were required to achieve seizure-or burst-suppression for hours through continuous administration of one or more tlas, followed by a post-enrollment qw of tlas. enrolled subjects failing the qw were randomized to concomitant brexanolone or placebo following reinstitution of one or more tlas. subjects not randomized after a successful qw underwent a -week follow-up. the qw protocol and criteria for qw failure were developed and implemented utilizing eeg neuromonitoring to confirm srse after enrollment using the definition of shorvon and colleagues. a qw was performed on over evaluable subjects across international sites to enable enrollment of patients with confirmed srse. subjects with a successful qws who were not randomized provided insight into outcomes associated with se and avoided the randomization of patients who did not meet srse criteria following enrollment. the use of neuromonitoring-guided diagnosis during a structured qw helped confirm srse, facilitating the enrollment of appropriate patients into this phase trial in a rare, critically ill, and dynamic srse patient population. autoantibodies to the kda isoform of gulutamic acid decarboxylase (gad ab), commonly found in t dm patients, have been associated with drug resistant epilepsy. ketosis prone diabetes is a heterogenous syndrome encompassing various forms of beta cell dysfunction culminating in diabetic ketoacidosis. rates of epilepsy in patients with ketosis prone diabetes are not known. we compared the prevalence of epilepsy in patients with ketosis prone diabetes in a multi-ethnic population with the prevalence of epilepsy in the type diabetes population as well as the general population in a metropolitan medical center. our study design is prospective review of retrospectively collected sera of patients admitted for diabetic ketoacidosis (defined as ph < . , bicarb < , with ketonemia or ketonuria) for the presence of gad ab. all these sera were assessed separately for autoantibody presence or absence at dr hampe's lab in washington, seattle. we also reviewed patients medical records for neurological diagnoses. this done in a blinded fashion by two separate reviewers. out of our patients with ketosis prone diabetes, . % also had epilepsy. this is higher than the published rate in type diabetics ( . %) and the general population in the surrounding area (< . %). antibody testing revealed % of patients with ketosis prone diabetes were gad ab positive with a rate of epilepsy of %. a two-tailed t test between the gad ab + group and gad ab -group showed no statistically significant difference in prevalence of epilepsy in these two groups. while prevalence of epilepsy is higher in the ketosis prone diabetes population than the general population of houston, the difference is not related to titers of gad ab, and must be due to some other unknown factor in these patients management of refractory status epilepticus commonly involves the induction of seizure-or burstsuppression using anesthetic agents. however, the duration and endpoints of these therapies are not well defined. specifically, weaning anesthetic agents is complicated by the emergence of eeg patterns on the ictal-interictal continuum (iic), which have uncertain significance, given that iic patterns may worsen cerebral metabolism and oxygenation, have a dissociation between scalp and depth eeg recordings, and indicate a late stage of status epilepticus itself. determining the significance of iic patterns in the unique context of anesthetic weaning is important to prevent the potential for unnecessarily prolonging anesthetic coma. we identified a series of patients who underwent over hours of burst-suppression therapy, multiple weaning attempts, and continued weaning despite the initial emergence of iic patterns. patients who experienced anoxic brain injury were excluded from the series. we report cases of patients who underwent successful weaning despite initial emergence of iic patterns. eeg patterns following anesthetic weaning (including lateralized periodic discharges approaching hz frequency and lateralized rhythmic delta activity) as well as terminal eeg patterns are described in detail. in these patients, continuing weaning of anesthetic agents despite the emergence of iic patterns did not result in relapse to status epilepticus. while the metabolic impact of these patterns on brain activity is uncertain, weaning strategies that treat iic as a surrogate of recurrent status epilepticus risk further prolonging anesthetic management and its known toxicity. we speculate that iic patterns are transitional and may have a context-specific association with status epilepticus relapse, with less risk conferred when these patterns are observed during the weaning of anesthetic agents after prolonged burst-suppression therapy. other electrographic features aside from this clinical context may discriminate the risk of status epilepticus relapse, such as eeg background activity. brivaracetam (brv) is approved as adjunctive therapy for focal (partialyears) with epilepsy. brv is available as oral tablets, oral solution, and an intravenous (iv) formulation. the formulations are interchangeable. this abstract reports the safety and tolerability of iv brv. during clinical development, participants received iv brv. we report pooled safety findings from participants receiving brv - mg doses. the therapeutic range of brv is - mg twice daily. in n , healthy volunteers received iv brv as a -minute infusion or mg/min bolus ( , , , or mg single doses; n= in all groups). in ep (nct ), healthy volunteers received iv brv mg as a single -minute bolus injection or oral tablets. in n (nct ), patients received days of brv oral tablets mg twice daily or placebo, and then . days of iv brv mg twice daily either as a -minute bolus or -minute infusion for nine doses in total. treatment-emergent adverse event (teae) data were pooled. data reported are for iv brv - mg (n= ). most frequent teaes were somnolence . %, dizziness . %, fatigue . %, headache . %, dysgeusia . %, euphoric mood . %, feeling drunk . %, and infusion-site pain . %. infusion-site pain was specific to administration route. most teaes were mild or moderate and occurred mostly in healthy volunteers. iv brv was well tolerated, with an ae profile consistent with oral administration except for routespecific injection-site aes, dysgeusia, euphoric mood and feeling drunk. the interpretation of these data was complicated by the difficulty of pooling disparate studies involving healthy volunteers and epilepsy patients with heterogeneous medical histories and concomitant antiepileptic drug use. further clinical trials or real-world experience are needed to understand potential clinical impact. ucb pharma funded refractory status epilepticus (rse) is a challenging condition that requires multiple antiepileptic drugs (aed) to treat. during rse, the brain is under excessive excitation, which results in an increase in glutamate receptors such as alpha-amino- -hydroxy- -methyl- -isoxazolepropionic acid (ampa) and nmethyl-daspartate (nmda).. perampanel (per), a novel, noncompetitive ampa-receptor antagonist, may have a role in the treatment of rse and there are positive results in different animal models with rse. we identified adults patients over a month period who were treated with per for different forms of rse. one was excluded as the etiology of rse was anoxic brain injury and care was transitioned to comfort only within hours of initiating per. three patients had a definite response to per, which we defined as resolution of ictal patterns on electroencephalogram (eeg) within hours of per without adding a new aed. one had a possible response with significant improvement in eeg findings; however, there was some eeg improvement predating the initiation of per. in observed several treatment factors that may have increased response to per. those who responded had it used earlier in the treatment cascade (sixth or seventh vs. ninth or tenthaed ), higher initial dose ( mg vs mg), and were escalated to maximum dosage within hours. they were also more likely be receiving continuous ketamine and midazolam, suggesting a possible synergy with per. there were no documented adverse effects in any patient prior to discharge. one patient did experience a decline in phenytoin levels, which could be related to per as there are reports of enzyme-inducing properties. we observed efficacy of per in several patients with focal and generalized rse without a significant adverse effect profile. further studies are needed to clarify the dosing, timing and appropriate indications in rse treatment. topiramate is a potent broad-spectrum anti-epileptic drug (aed) with several mechanisms of action including blockage of the inotropic glutamatergic ampa receptor, voltage-gated sodium channels, antagonism of non-nmda glutamate receptors and enhancement of gaba mediated chloride conductance. we hypothesize that topiramate is an effective adjunctive therapy in rse and srse due to multiple mechanisms of action. we performed a retrospective analysis of patients admitted to the intensive care unit with status epilepticus (se) at a tertiary referral center from - . we reviewed demographics, age, seizure type, etiology, prior aed/topiramate exposure, time to response to treatment, eeg reports and neuroimaging results. rse was defined as failure of benzodiazepine and another conventional second line aed to stop se. srse was defined as se that continues or recurs hours after being treated with an anesthetic agent. ( %) were male, ( %) had a history of seizures; mean age of patients with se was . years. of treated patients, ( %) had focal non-convulsive se (ncse), ( %) had myoclonic se, had myoclonic, followed by generalized ncse, ( %) had generalized ncse, and ( %) had focal and generalized nonconvulsive se, prior to administration of topiramate. ( %) patients were treated with aeds, ( %) patients with aeds prior to topiramate. electrographic seizures improved in ( %) patients after receiving topiramate. resolution of electrographic seizures occurred within hours in ( %) patients, hours in ( %) patients, hours in ( %) patients and hours in ( %) patients. our findings suggest that topiramate could be an effective adjunctive treatment in rse and srse. however, prospective studies, including larger number of patients are needed to confirm these findings. patients with refractory status epilepticus (se) require multiple antiepileptic drugs (aeds) to abort seizures, and often barbiturates. there is a paucity of data on how to wean aeds safely once seizures are controlled while minimizing medication side-effects or withdrawal symptoms. a retrospective review of patients admitted to mayo clinic in rochester, minnesota for se between and was performed. patient demographics, se type (focal versus generalized, convulsive, and refractoriness), seizure etiology, aeds in admission and at outpatient follow-up, aed side effects from use and withdrawal, and functional outcomes in terms of modified rankin scale were recorded. of ( . %) patients had refractory se, ( . %) patients had refractory non-convulsive status epilepticus (ncse), ( . %) patients had convulsive se, ( . %) patients had ncse, and ( . %) patients had epilepsia partialis continua. of the patients with outpatient follow-up (ranging to weeks following hospital discharge with . % patients following-up within one month), patients were on an aed regardless of etiology. patients were on a median of aed in both refractory and nonrefractory se at follow-up. ( . %) patients had withdrawal seizures after aeds were weaned ( had a prior stroke, traumatic brain injury, idiopathic, multifactorial). none of the patients completely weaned off a barbiturate had seizure recurrence at follow-up. -month mortality in refractory se was / ( . %) and / ( . %) in non-refractory cases. favorable functional outcome at follow-up was achieved in / ( . %) patients with refractory se versus / ( . %) in non-refractory se. we found a low rate of late seizure recurrence after weaning aeds in refractory and non-refractory se, particularly in the case of barbiturates. spreading depolarizations (sd) are strongly associated with secondary brain injury after aneurysmal subarachnoid hemorrhage (sah). however, studies to understand whether sds play a causal role in secondary injury are hindered by existing sd induction methods which are invasive, cumbersome, and cause primary tissue injury. we developed a method to study the role of sds after experimental sah using commercially available transgenic optogenetic mice which express channelrhodopsin (chr ) in cortical neurons. we used in vivo laser speckle and doppler flowmetry, intrinsic signal imaging, and local field potential (lfp) and extracellular potassium shifts to detect sds. we optogenetically induced sds with light through intact and unaltered skull in multiple regions without causing primary brain injury. we found regional differences in thresholds for optogenetically-induced sds (from lowest to highest threshold): ( ) whisker barrel, ( ) motor, ( ) sensory, and ( ) visual cortex. lower thresholds were associated with higher chr tissue expression. changes in lfp and increased extracellular potassium concentrations at the site of stimulation preceded precipitation of an sd. finally, we induced and detected sds in the setting of sah over several days through chronically implanted glass coverslips non-invasive optogenetic light stimulation can reliably induce sds in the setting of sah. longitudinal optogenetic induction of sds in chr transgenic mice is a potentially useful tool to study the role of sds in the pathogenesis of secondary brain injury after sah. aneurysmal subarachnoid hemorrhage is a devastating neurologic injury with significantly prolonged hospital courses and high morbidity and mortality. when aneurysms are detected, they often require securement either via surgical clipping or endovascular techniques. a subset of intracranial aneurysms, given location, poor surgical approach, and wide neck are amenable to flow diversion which promotes thrombosis through redirecting of blood flow within an aneurysm leading to slow obliteration. approximately % of treated aneurysms with flow diversion do not obliterate after months, but currently there is no validated way to predict treatment failure. computational models of blood flow of flow diverted aneurysms predict a significant difference in the hemodynamic energy loss across aneurysms between cases that resolve and those that do not. energy loss could be estimated clinically during angiography, however, this hypothesis needs to be validated experimentally because computer models often over estimate hemodynamic parameters, poorly predict flow through stents, and may not have the resolution to fully describe intra-aneurysmal blood flow. in this pilot study, four cases of giant fusiform intracranial aneurysms will be selected --two with resolution following flow diversion treatment, and two without resolution. models of each vessel geometry will be fabricated using additive manufacturing techniques. under fluoroscopy, within the model vessel, flow diverting stents will be placed within the aneurysm in the same configuration that was achieved clinically. model blood, containing tracer particles will be pumped through model aneurysms and using particle image velocimetry, energy loss will be calculating within model vessels following treatment. energy loss between aneurysms successfully and unsuccessfully treated with flow diversion will be compared experimentally. hemodynamic energy loss may be a clinically measurable value which could predict treatment failure after flow diversion. additive manufacturing techniques can be used to test patient specific hemodynamics to improve understanding of flow-diversion treatment success or failure. the national institute of neurological disorders and stroke (ninds) and the national library of medicine (nlm) initiated development of unruptured cerebral aneurysms and subarachnoid hemorrhage (sah)specific common data elements (cdes) in as part of a joint project to develop data standards for funded neuroscience clinical research. through the development of these data standards, the ninds and nlm sah joint cde initiative strives to improve sah data collection by increasing efficiency, improving data quality, reducing study start-up time, facilitating data sharing/meta-analyses and helping educate new clinical investigators. the sah cde working group (wg) consisted of international members with varied fields of sahrelated expertise and was divided into domains such as subject characteristics and assessments and exams. the wg developed a set of sah-specific cde recommendations by selecting among, refining and adding to existing field-tested data elements, especially established stroke cdes. wg cde recommendations were drafted into the nih cde repository. following an internal review of recommendations, the sah cdes were vetted during a public review on the ninds website for weeks and later posted on nlm and ninds websites. version . of the sah cdes was available on the ninds cde website in april . these new sah cdes and recommendations include those developed for unruptured intracranial aneurysms and long-term therapies. the website provides uniform names and structures for each data element, as well as guidance documents and template case report forms using the cdes. the ninds encourages the use of cdes by the clinical research community in order to standardize the collection of research data across studies. the ninds cdes are a continually evolving resource, requiring updates as research advancements indicate. these newly developed sah cdes will serve to be a valuable starting point for researchers and facilitate streamlining and sharing data. subarachnoid hemorrhage (sah) represents % of stroke admissions in the us. aneurysmal hemorrhage represents the most dangerous etiology, however - % of sah have negative digital subtraction angiography (dsa). there is variation in practice with regards to repeat diagnostic studies and timing of such studies. it is not uncommon to repeat dsa in - days of the initial assessments. this study aims to describe the costs associated with prolonged icu stay and repeat diagnostic studies this patient cohort. retrospective review of all patients admitted for spontaneous sah between january and april at our single institution. patients with at least one negative initial angiogram for suspected spontaneous sah were included. patients were categorized into diffuse patterns of sah and nondiffuse. cost estimates were based on standard costs as provided by our financial department and cdc estimates for costs of hospital acquired infections. one hundred fifty-four patients were identified with initial negative dsa. second angiograms were performed in % of patients, and potentially positive causal findings in / ( . %). icu los for angiogram negative diffuse sah and non-diffuse were . and . days respectively. other indications for icu stay included vasospasm ( . %), evd placement ( . %), and intubation ( %). the excess cost estimates per patient for angiogram negative diffuse and non-diffuse sah were $ , and $ , respectively. hospital acquired complications were an additional total $ , for the cohort. this is the first study to our knowledge attempting a cost analysis of the diagnosis and management of patients with angiogram negative sah. we had a high frequency of patients requiring icu admission for other indications, which should continue to dictate the level of care. however, there may be a cohort of lower risk patients in which de-escalation would not harm, and be of benefit in the reduction of morbidity and cost. purpose: to evaluate the feasibility and potential role of bedside optical coherence tomography (oct) as a diagnostic protocol in terson's syndrome (ts) in patients with acute subarachnoid hemorrhage (asah). background: % of sah patients become permanently legally blind. the average cost of lifetime support and unpaid taxes for each blind person is approximately $ , . ts presents as ocular bleeding commonly associated with asah. it can be diagnosed by fundoscopy, yet retinal haemorrhages, detachments and macular holes may be undetected. early ts identification is critical since untreated it may lead to legal blindness, limit rehabilitation and impair quality of life. pilot study: sah patients were screened for ts with dilated fundoscopy and then with oct. mood assessments (phq- , hds), quality of life measures (nih-promis) and subjective visual function scales (vfq- ) were performed. there was a . % (n= ) incidence of ts. dilated retinal fundoscopy significantly failed to detect ts (n= , . % missed cases). ivh was significantly more in ts ( . % vs. %). no participants experienced any complications from oct examinations. neither decreased quality of life visual scores nor a depressed mood correlated with objective oct pathological findings at weeks follow-up after discharge. there were no significant mood differences between ts cases and controls. oct is the gold-standard in retinal disease diagnosis. this pilot study showcases its bedside feasibility in asah. in our series, oct was a safe procedure that enhanced ts detection by decreasing false negative/ inconclusive fundoscopic examinations. it allows early diagnosis of macular holes and severe retinal detachments, which require acute surgical therapy to prevent legal blindness. besides, oct aids ruling out potential false positive visual deficits in individuals with a depressed mood at follow up. a comprehensive study is underway to understand the impact oct might exert on blindness prevention and quality of life. fever is common in patients with aneurysmal subarachnoid hemorrhage (asah), and blood cultures are commonly sent to diagnose etiology. several studies have shown a low incidence of positive blood cultures, but no studies have assessed blood cultures in patients with asah. we performed a retrospective analysis of patients admitted with asah between january to december . blood cultures were adjudicated as true positive (tp) or false positive (fp) based on speciation, time to positivity, number of cultures positive, and repeat culture results. tp patients were compared to all other patients. age, gender, hunt hess, modified fisher, aneurysm treatment, incidence of delayed cerebral ischemia (dci), length of stay (los), and neurological outcomes were analyzed. patients with asah were included. blood cultures were sent on ( %). sixteen were positive. eleven were adjudicated tp and fp. thus, . % ( / ) of patients had true bacteremia, and blood culture yield for true infection was . % ( / ). fp rate was . % ( / ). eight tps were gram negative ( %), and all contaminants were staphylococcus non-aureus. median post-bleed day for tp results was . only patients were tp within the first week of admission ( . %). tp patients had higher admission wfns (p=. ) and ivh score (p=. ), but age, gender, aneurysm treatment, and fisher score did not differ. tp patients had longer icu and hospital los and higher incidence of dci ( % vs %, p=. ). mortality did not differ in the two groups either. the yield of blood cultures in asah patients is low. even with a contamination rate under %, % of positive blood cultures are fp. future studies should evaluate factors to identify patients at higher risk of bacteremia to reduce costs and improve care. intra-arterial verapamil therapy reduces cerebral vasospasm after aneurysmal subarachnoid hemorrhage (sah). there is little literature that quantitatively describes its safety, required dosing, or efficacy. as a result, therapeutic outcomes need to be subjectively analyzed by experienced radiologists during the intervention and clinically correlated by cerebral perfusion pressure, intracranial pressures and transcranial dopplers. we present a novel imaging analysis to quantify cerebral perfusion in realtime and apply this technology to patients undergoing therapy for vasospasm. we developed software to evaluate changes in contrast flow dynamics for digital subtraction angiography (dsa) scans performed pre-and post-intra-arterial therapy for vasospasm. performing signal intensity curve deconvolution on a voxel by voxel basis provides quantitative d perfusion parameters including: time to peak, time to drain, area under the curve, root mean transit time, arrival time, tissue concentration, arterial input functions and cerebral blood flow at each voxel. after aligning perfusion studies, our software then displays and automatically creates regions of interests for changes in perfusion to visualize the effects of interventions. our software quantitatively measures perfusion from dsas and can normalize two dsas accounting for differences in volume and speed of contrast administration. two applications of this technology are demonstrated. the first subtracts perfusion from pre-and post intra-arterial interventions quantifying exact changes in perfusion at each voxel. the second compares two dsa studies of the same patient at different dates to contour the territories susceptible to delayed cerebral ischemia. we compare this analysis to mri imaging when applicable demonstrating ischemic changes aligning to the susceptible territories outlined by our analysis. dsa based perfusion is an effective study to quantify the need for and the precise effects of endovascular interventions. quantitative thresholds and analysis based on dsa perfusion may assist with real-time assessment of treatment efficacy for patients undergoing intra-arterial verapamil therapy. we aim to characterize the clinical predictors of ventriculoperitoneal shunt (vps) placement in aneurysmal subarachnoid hemorrhage (asah) patients. there has been no clear consensus as to effective measures of predicting vps placement in these patients. we reviewed the clinical data of patients with aneurysmal subarachnoid hemorrhage (asah) who were treated at our institution between - . we eliminated patients who died or had withdrawal of care during admission. we recorded patient demographics and clinical predictors including admission/discharge glasgow coma scale (gcs), hunt hess score, aneurysm size/location, modified fischer score, modified rankin scale (mrs), intracranial pressure (icp) values during evd clamp trial, and incidence of vasospasm requiring intra-arterial therapy. there were patients included in this study and % of patients required vps (n= / ). vps patients had significantly worse mrs functional scores at discharge ( . vs . ; p= . ), but this began to balance at year ( . vs . ; p= . ). aneurysms were significantly larger in vps patients ( . cm vs . cm; ci: . to . ; p= . ). a greater percentage of vps patients had posterior fossa aneurysms, but this was not found to be statistically significant ( % vs %; p= . ). vps patients had significantly lower gcs scores at admission ( . vs . ; p= . ), and discharge ( . vs . ; p= . ). there was no difference in modified fischer score (p= . ) or hunt hess (p= . ), but both variables were higher in the vps cohort. there was no difference in the frequency of vasospasm in the vps cohort (p= . ), or icp values (p= . ). patients presenting with large aneurysms and poor gcs scores had a significantly higher likelihood of requiring vps during admission. these patients had significantly poorer mrs scores at discharge but not at year. subarachnoid hemorrhage (sah) affects a young population and results in death or disability in the majority of those who experience it. this epidemiology is very different from other forms of stroke. consequently, patients with sah and their families may have different priorities for recovery. involving patient perspectives is encouraged in research and is often accomplished using patient-reported outcome measures (proms). however, whether proms reflect patient and family priorities is unclear given that (a) proms are often developed without their input; and (b) generic proms may not apply to specific conditions. we aimed to systematically review the sah literature that has: a) involved patient, family or caregivers in evaluating existing outcome measures, b) developed novel outcome measures by incorporating their perspectives (including co-development), or c) described outcomes important to patients, families, or caregivers. we searched embase and ovid medline from inception to december , . study eligibility and data extraction was performed independently and in duplicate. for each eligible citation, we abstracted the following: study population, design, type of patient involvement, and outcome measure(s), as applicable. we planned a qualitative summary of all included studies. our search yielded unique citations. only four articles have met our eligibility criteria. in each, patients (n= ) self-report impairments resulting from sah and their impact on their lives (aim c). none involve the evaluation of prom applicability. additionally, we found articles that, although they did not meet our a priori eligibility criteria, discuss collecting proms (n= ), using proms to predict health outcomes (n= ), and comparing prom applicability without patient perspectives (n= ) in sah populations. based on our findings, there is alack of patient, family, or caregiver involvement in selecting or identifying outcomes after sah with direct relevance to them. sah research may be overlooking outcomes that are important to patients. early brain injury (ebi) after aneurysmal subarachnoid hemorrhage (asah) is defined as brain injury occurring within hours of aneurysmal rupture. although ebi is the most significant predictor of outcomes after asah, its underlying pathophysiology is not well understood. we hypothesize that ebi after asah is associated with an increase in peripheral inflammation measured by cytokine expression levels and changes associations between cytokines. methods asah patients were enrolled into a prospective observational study and were assessed for markers of ebi: global cerebral edema (gce), subarachnoid hemorrhage early brain edema score (sebes), and huntassays to determine levels of pro-and anti-inflammatory cytokines. pairwise correlation coefficients between cytokines were represented as networks. cytokines levels and differences in correlation networks were compared between ebi groups. of the patients enrolled in t associated with high grade sebes. correlation network analysis suggests higher systematic inflammation conclusions ebi after sah is associated with increased levels of specific cytokines. peripheral levels of il , il and ession levels of individual cytokines may offer deeper insight into the underlying mechanisms related to ebi. few recent studies have evaluated health resource utilization and patient outcomes in aneurysmal subarachnoid hemorrhage (asah) in the united states. empirical evidence implicates asah as one of the highest cost diseases treated in the hospital. we identified asah patients to determine hospital charge, length of stay (los) and patient disposition associated with care in u.s. hospitals using claims data from the national inpatient sample (nis). patients within the international classification of disease, th revision (icd- ) diagnosis code were identified; a secondary analysis of the nis ( ) was conducted utilizing icd- clinical modification codes excluding patients with traumatic and non-aneurysmal sah. population size, patient outcome, average charge and average los were calculated using subgroups including: aneurysmal clipping or endovascular coiling (n= , ), aneurysmal clipping or coiling with external ventricular drain (evd) (n= , ), use of evd only (n= , ), other surgical procedures (n= ) and medically managed (n= , ). analyses were survey-weighted and adjusted for patient and hospital characteristics. in , asah resulted in an average per patient hospital charge of $ , , an average los of days, an average mortality of % and total, annual hospital charges of $ . billion. the highest average charge per patient ($ , ) and hospital los ( days) were attributed to clipped or coiled patients with evd, and highest mortality ( %) found in medically managed patients. these data support the conclusion that asah is a high cost illness managed in u.s. hospitals, and help raise awareness to the potential economic benefits resulting from developing safer, more effective therapies. additional analyses with updated datasets including lifetime burden of asah (e.g. physician fees, long term medical and care costs, hospital re-admission impact, quality of life, productivity loss, caregiver burden) should be explored to understand the full economic burden of asah and the potential cost effectiveness of new therapies. external ventricular drain (evd) placement is a mainstay of treatment for patients with aneurysmal subarachnoid hemorrhage with hydrocephalus or elevated intracranial pressures, but the optimal strategy for evd management is still unclear. the goal of this study was to compare the impact of evd clamping at three different levels on the duration of drain placement and the intensive care unit (icu) length of stay. we performed a retrospective analysis of patients admitted with aneurysmal subarachnoid hemorrhage to the neurological icu from december to january and included all patients who had an evd placed. patients who died were excluded from the study. patients were divided into three groups: patients whose evd was clamped at mmhg, patients whose evd was clamped at mmhg, and patients whose evd was clamped at mmhg. duration of drain placement in days and icu length of stay in days was compared among the groups using an analysis of variance (anova). outcomes were adjusted for presenting hunt-hess score, modified fisher grade, gender, and age. there were patients who had their evd clamped at mmhg, who had their evd clamped at mmhg, and who had their evd clamped at mmhg. there was no difference in duration of evd placement among the three groups (adjusted p-value . , unadjusted p-value . ) nor in icu length of stay (adjusted p-value . , unadjusted p-value . ). evd clamping at three different levels did not affect drain duration nor length of stay in icu. this study was limited by the small number of patients enrolled. further studies are need to clarify optimal strategies for evd management in the icu. headache is a presenting complaint in majority of patients with asah and is known to persist long after initial icu care. various medications have been used for control of headache with major emphasis on opiate use. history of a prescription for an opioid pain medication increases the risk for overdose and opioid use disorder. we looked at prevalence of opiate use at discharge and its associated factors. chart review of all patients admitted in a tertiary care center between jan and march was carried out. along with baseline demographic data, information about use of pain scores, csf diversion, use of opiates, average morphine equivalent doses, use of opiates at discharge and destination at discharge was collected. analysis was carried out using microsoft excel. the study was approved by hospital irb. patients were admitted with asah in above period ( % female, average age: yrs). ( % home, % snf) survived to discharge. among survivors, % required csf diversion for hydrocephalus. all people complained of pain on presentation and were prescribed opiates during hospital stay. average oral morphine equivalent doses used was mg per day. ( %) patients were prescribed opiates on discharge. alternative regimens included ( patients: tricyclic antidepressant (tca), opiate + tca, acetaminophen, dexamethasone, tca and opiates). most common prescribed form of opiate was oxycodone. there was no significant association between opiate use/morphine dosing and age, gender, final disposition and csf diversion, opiate prescription at discharge is common in patients with asah. no clinical characteristic seem to predict analgesic need at discharge. little data exists about better alternatives leading to variety of treatment approaches. further controlled trials are needed to decrease opiate use and prevent adverse effects delayed cerebral ischemia (dci) in sah has been associated with vasospasm-dependent and vasospasmindependent phenomena. for more than years isolated hemostasis disorders have been reported in these patients. the objective of this systematic review is to describe the natural history of hemostasis in sah. we systematically reviewed the medline, embase, cochrane and lilacs databases using controlled language and the prisma statement and included studies on spontaneous sah analyzing any hemostasis parameter. we screened titles, of which observational were included. evidence was evaluated following the strobe statement. no meta-analysis was attempted because of the methodological nature and heterogeneity of the studies. hemostasis is profoundly altered during the first hours after bleeding, with several alterations noted including a hypercoagulable state concomitant with increased fibrinolysis activation and reduced clot stability. direct and indirect coagulation markers show a trend towards normalization of hemostasis in the first to days. platelet count decreases with a nadir to days after bleeding and a recovery in the following weeks. a later nadir is associated with dci. platelet aggregability is consistently decreased in the first few days, regaining its normal function around the second week after bleeding. in addition, the persistence of these alterations or the presence of a second peak in pro-coagulatory activity is associated consistently with dci and worse functional outcomes. the hyperacute phase of sah is characterized by a profound activation in hemostasis with reduced clot stability, probably due to an increase in the fibrinolytic pathways. on the second day post-bleeding, a slow trend towards normalization takes place, except in patients evolving towards dci. further research on the pharmacologic manipulation of hemostasis in sah might be warranted to decrease dci and improve outcomes in this population. hypertonic saline(hts) is a treatment for sah-related cerebral edema, administered to improve cerebral perfusion and reduce brain injury. hts a supra-physiological chloride concentration that can contribute to acute kidney injury which can lead to a poor outcome. in a previously published single-center cohort of , l sah patients, . % developed acute kidney injury (aki). hyperchloremia, but not hypernatremia, was correlated with an increased risk to develop aki (o.r. . ). aki was correlated with increased mortality. a secondary analysis of the aforementioned sah patient cohort ( ) ( ) ( ) ( ) ( ) ( ) , was analyzed. trends of acute kidney injury were evaluated in relation to the burden of exposure to intravenous chloride, as well as serum levels of sodium and chloride. the proportion of patients developing aki with a maximal serum chloride concentration of (p , will be randomized into one of two treatment groups: standard hypertonic saline solution (nacl . %) versus a solution of nacl/na-acetate. we hypothesize that by reducing the iv chloride burden(baseline compared to post randomization exposure), the delta serum chloride level will decrease, and will subsequently reduce aki occurrence (acetate trial, clinicaltrials.gov nct ). aki is common in sah patient population, and associated with worse outcomes. serum chloride concentrations are a significant risk factor for the development of aki. a prospective randomized clinical trial now underway examining the relationship between the hypertonic solution composition and serum chloride concentration, and to the development of acute kidney injury in aneurysmal sah. spontaneous spinal subarachnoid hemorrhage (ssah) is a rare but serious condition that can lead to a variety of medical complications. literature to this point primarily includes isolated case reports, and none have looked at hyponatremia as a complication. patients were identified from the electronic medical record database at the mayo clinic in rochester, minnesota. the advanced cohort explorer tool was used, searching from january to december . inclusion criteria were spinal subarachnoid blood products due to hemorrhage into the spinal subarachnoid space not due to ( ) redistribution of blood from intracranial subarachnoid hemorrhage, ( ) trauma, ( ) medical procedures, or ) predominant hematomyelia who experienced symptoms and received treatment at our facility. eight patients (median age years, range - ) were identified as meeting the study criteria. five of these eight patients experienced hyponatremia during hospitalization with a median value of meq/l. all of these patients were treated with free water restriction and one patient briefly received . % sodium chloride solution; in all cases the hyponatremia improved after free water restriction. in all cases the hyponatremia improved with fluid restriction, and there was no documentation of increased urine output, suggesting that it was likely due to siadh. cord compression and hyponatremia were present together in two patients, and in these cases treatment of the hyponatremia was particularly useful to avoid worsening edema. to our knowledge this is the first compilation of cases of spontaneous ssah highlighting hyponatremia as a complication. there is significant morbidity and mortality associated with aneurysmal subarachnoid hemorrhage (sah) and only about % of patients survive and resume their previous lifestyle after - months. many randomized clinical trials (rcts) have been conducted yet no treatment definitively improves outcome from sah. outcome is strongly related to baseline factors, yet imbalances are common in early trials. we developed a technique to identify promising treatments at early phase using a pooled control arm model (ppredicts: kent, shah, mandava neurology ) that compares early studies at their own baselines. we applied this method to sah to develop a multi-dimensional model (ppredicts-sah). models for functional outcome and mortality (dependent variables) were developed based on baseline variables (eg: wfns grade - % and age) using methodology developed for ischemic stroke (mandava, kent, stroke ). the outcome model is a -dimensional surface bounded on either side by +/- . prediction interval surfaces. these prediction interval surfaces incorporate statistical variability to assess whether a treatment differs from expected outcome. treatment arms from rcts and single arm trials, of various treatments of sah were compared against the pooled controlled arm. the best model fit was for good outcome (modified rankin score - equivalents) based on % patients with wfns - and age (r = . ; p< . ). seven trials of known negative drug tirilazad were superimposed on the model and fall within the +/- . prediction interval surfaces confirming futility. three trials were neutral and within the prediction interval surfaces while case series using implanted prolonged release nicardipine and a low dose heparin study were above the +p= . surface showing promise. models were also developed for mortality (r = . , p=. ). outcome models based on percentage of high grade wfns and age were successfully developed. this approach may be useful to prioritize treatments worthy of further study. oral nimodipine is recommended to improve outcome in treatment of aneurysmal subarachnoid hemorrhage (asah). fda approved nimodipine liquid oral solution (nos) in to reduce complications associated with administering nimodipine capsules (nc) to patients with impaired swallow. experience with nos at our center has been complicated by increased liquid bowel movements (lbm) prompting unnecessary testing for infectious diarrhea and exposure to invasive fecal management devices. study approved by local qualtiy improvement review committee. data was collected prospectively in consecutive patients diagnosed with asah during intensive care unit (icu) course. formulations of nimodipine available were generic nc (heritage pharmaceutical) and nos (arbor pharmaceuticals). we examined total icu days exposed to nos, icu days with lbm, infectious diarrhea investigations, and fecal management device use. all statistical tests were performed using minitab. patients were studied from / / to / / ; patients exposed to nos for icu days, icu days with lbm, infectious diarrhea investigations, and required fecal management devices. patients exposed to nc for icu days, icu days with lbm (all cases were also received nos), no infectious diarrhea investigations, and no fecal management device requirements. odds ratio for lbm with exposure to nos was . ( % ci . to . , p < . ). the high incidence of lbm with nos resulted in more infectious diarrhea testing and fecal management device use. uncontrolled diarrhea may increase risk for dehydration and delayed cerebral ischemia, although this is not explored in the current study. nos can mitigate risks associated with needle aspiration of nc, however these issues coupled with higher cost may limit benefit of its use. possible solutions may include compounding nc into a liquid formulation by pharmacists or pharmacy technicians. possible safety and cost benefits require further investigation. headache (ha) management after subarachnoid hemorrhage (sah) is challenging and lacks standardization. we hypothesized that inadequate inpatient ha pain management leads to the development of chronic ha (cha) after sah. prospective, observational study of non-traumatic hunt and hess (hh) grades i-iii sah patients admitted from / to / . after informed consent we recorded demographics, clinical and radiographic features, analgesic and steroid doses, hospital course and inpatient pain scores using numeric rating scale (nrs, - ) before (nrs-pre) and after each analgesic administration over post-bleed days - . a phone survey administered - months after admission evaluated cha burden. inpatient ha control effectiveness was evaluated by percent pain resolution from initial pain score, using nrs-pre. the percentage of administrations yielding full pain resolution was compared between those with and without cha. chi-square and t-tests were used for statistical analyses. patients, % female, mean age . ± . years with hh grade i ( / ), ii ( / ), and iii ( / ) sah were enrolled with lost to follow-up. at follow-up, . % patients ( / ) reported daily ha, . % ( / ) occasional ha, and % ( / ) no ha. full pain resolution after analgesic administration was associated with less cha ( [ . %] vs. [ . %], p= . ). mean daily inpatient opioid dose (morphine equivalents) for patients with and without cha was . mg and . mg, respectively (p= . ). mean nrs-pre were . vs . for patients with vs without cha, respectively (p= . ). inpatient analgesia for sah-related ha is inadequate and may be associated with the development of chronic ha. patients with cha had higher mean inpatient pain score and fewer analgesic administrations resulting in complete pain resolution. inpatient opioid dose per day was higher in cha group, although not statistically significant. additional research is needed to characterize the relationship between inpatient headache management and chronic headache after sah. subarachnoid hemorrhage (sah) remains a significant cause of neurological morbidity and mortality with few interventions to prevent delayed cerebral ischemia. hypocapnia has been associated with worse outcomes in brain injury. sah patients may be particularly susceptible to hypocapnia induced vasoconstriction. this study aims to describe the incidence of iatrogenic and spontaneous hyperventilation in sah patients. a descriptive analysis was performed on a retrospective cohort of adult sah patients admitted to beth israel deaconess medical center icus between and with gcs < who were treated with mechanical ventilation and an extraventricular drain, and had at least one abg. patients on chronic ventilator support were excluded. the lowest paco per icu day was analyzed. patients were included with days with at least one documented paco . mean gcs on admission was . (sd . ). . % of patients survived to hospital discharge. . % of patients were exposed to severe hypocapnia (paco mmhg, those with severe hypocapnia had similar pao and pao /fio ratios, but mildly increased leukocytosis ( . vs . ). . % of paco s < mmhg occurred during spontaneous ventilation or over-breathing. prior studies have shown that hypocapnia causes decreased brain tissue perfusion and is associated with worse outcomes in sah patients. these recent data demonstrate that severe hypocapnia is common in patients with sah severe enough to warrant intubation, and is associated with both iatrogenic and spontaneous hyperventilation. hypocapnia is not primarily compensatory or hypoxia driven, as suggested by mean ph and pao . confirmation of this association and potential future interventions require further study. although delirium is associated with higher rates of hospital complications among critical care patients, limited data exist on risk factors for delirium in aneurysmal subarachnoid hemorrhage (sah). a previous study identified older age, high hunt hess grade, intraventricular hemorrhage (ivh), and hydrocephalus as risk factors for delirium. we sought to identify risk factors for delirium during admission after sah. retrospective review was performed of prospectively collected data for consecutive sah patients enrolled into the university of maryland recovery after cerebral hemorrhage (reach) study. baseline data and clinical complications during each admission, including delirium, were recorded. statistical analysis was performed using univariate and multivariate logistical regression. sah patients from july to january were reviewed. while age was not singly associated with delirium during icu admission, higher hunt hess grade, ivh, hydrocephalus, hospital-acquired infection, elevated troponin, and intubation were significantly associated with delirium on univariate analyses. upon stepwise multivariate logistic regression, ivh (or . , p= . ) and intubation (or . , p= . ) remained significantly associated with delirium. ivh and intubation predicts delirium during icu admission for sah. further analyses are needed to determine if the relationship between ivh and delirium is primarily explained by risk of hydrocephalus, risk of fever, medication exposure, or through independent mechanisms. stroke triage scales are very important in order to expedite acute evaluation, assure quick door to neuroimaging time and decrease door to needle time in patients with ischemic stroke eligible to intravenous thrombolysis. subarachnoid hemorrhage (sah) is associated with a high mortality in the acute phase due to a particular risk of early and devastating re-bleeding. therefore patients with sah also need urgent assessment. the performance of classic triage stroke scales in the identification of patients with sah was not previously evaluated. the objective of our work was to evaluate the performance of the los angeles prehospital stroke screen (lapss) in identifying patients with sah admitted to a tertiary hospital. we evaluated consecutive patients admitted to a tertiary hospital with sah from january to may . at hospital admission, lapss was applied by trained nurse personnel to all noncomatose patients with complaints suggestive of neurological disease. a total of with sah patients were evaluated (mean age . +/- . ), . % females). lapss was applied to patients. lapss was positive in only patients ( . %). patients with a positive lapss had higher nihss stroke score at admission ( , [ , ] versus , p< . ), lower glasgow coma scores ( [ , ] versus , p< . ) and a significant shorter door to neuroimaging time (p< . ). in patients with sah and mild symptoms, lapss was not a sensitive screening tool in our series. hospital and pre hospital services using lapss for triage of patients with stroke should be aware of this limitation and include in triage flowcharts specific questions evaluating sah specific symptoms. spontaneous subarachnoid hemorrhage (sah) is a neurological emergency, which despite current advances in management strategies and advent of institutional protocols, remains with significant rates of mortality due to poorly understood causes. our objectives were to characterize in-hospital mortality by evaluating the primary cause of death and externally validate the hair score, a clinical score that prognosticates mortality. in this retrospective cohort study, we reviewed all sah patients admitted to our neuro-icu between april , and march , . univariate and multivariate logistic regressions were performed to identify predictors of in-hospital mortality, our primary outcome. to validate the hair score, the model's predictors were hunt and hess score at treatment decision, age, intraventricular hemorrhage, and re-bleeding within hours. discrimination was assessed by visualizing the receiver-operating curve and calculating the area under the curve (auc). among sah patients with a median age of years (interquartile range, - ), . % females, inhospital mortality was . % (n= ). of those, ( . %) had a neurological cause for death or withdrawal of care and ( . %) had a cardiac death. median time from sah to death was days. the main causes of death were the primary effects of the initial hemorrhage, re-bleeding and refractory edema. factors significantly associated with in-hospital mortality in the multivariate analysis were age, hunt and hess score, and intra-cerebral hemorrhage. maximum lumen size was also a significant risk factor among aneurysmal sah patients. the hair score had a satisfactory discriminative ability, with an auc of . . our in-hospital mortality is lower than previous reports, attesting to the continuing improvement of our protocolized subarachnoid hemorrhage care. the major causes are the same as previous reports. the hair score showed good discrimination and could be a useful tool for predicting mortality. so far, scientific and therapeutic efforts mainly focused on the prevention of rebleeding and ischemic complications(dci) in patients with subarachnoid hemorrhage(sah). however, data regarding the impact of parenchymatous hemorrhage(ph) on longterm outcome in these patients is limited. all consecutive patients with atraumatic sah admitted to our hospital over a -year-period( - ) were retrospectively analyzed. extent of sah as well as presence, localization and volume of ph were evaluated. functional and health outcome were assessed after months using the modified rankin scale (unfavorable: - ) and the eq- d. propensity-score(ps)-matching was performed to minimize potential bias due to confounding variables between sah-patients with and without ph. of overall patients with atraumatic sah, ( . %) patients had ph on initial imaging. ph-patients had a worse clinical condition on admission (wfns: ph ( - ) vs. Øph ( - );p< . ) and a greater extent of sah (modified fisher: ph ( - ) vs. Øph ( - );p= . ). median ph-volume was . ( . - . )ml with largest volumes in patients with ruptured )ml). after successful ps-matching (parameters: age, wfns, modified fisher and graeb score) patients with ph had worse functional and health outcome after months compared to those without ph (mrs - : ph / ( . %) vs. Øph / ( . %);p= . ; eq- d: ph ( - ) vs. Øph ( - ); p< . ). in multivariate analysis presence of ph was the strongest independent predictor of unfavorable outcome after months followed by the occurrence of dci (risk-ratio( %ci): ph . ( . - . ); p< . ). parenchymatous hemorrhage is frequent and associated with functional and subjective impairments in patients with atraumatic sah. aneurysmal subarachnoid hemorrhage (asah) is associated with early and delayed brain injury. insulin growth factor (igf ) is a potent cellular growth-promoting factor with demonstrated independent neuroprotective actions in stroke and neurologic disease but has not been well characterized after asah. this study sought to examine the relationship between plasma igf levels and outcomes after asah. this cohort of asah patients was . years (sd . ) and female ( %) with a mean hh ( %), wfns ( %) and fisher ( %). initial and peak plasma igf concentrations were measured in plasma samples from a banked biorepository using a commercial sandwich solid-phase elisa kit. delayed neurological deterioration (dnd) and delayed cerebral ischemia (dci) were determined using radiologic and clinical information. igf levels were log transformed due to non-normality. anova, t-tests, pearson correlations and logistic regression analyses were completed using spss and sas. older age was significantly associated with lower initial and peak plasma igf levels (r=. , p<. ; r=. , p<. ). men had higher initial and peak plasma igf levels than women (p<. ; p=. ), and premenopausal women had higher initial and peak plasma igf levels than post-menopausal women (p=. ; p=. ). lower peak plasma igf levels were associated with increased clinical severity by wfns (p=. ) and fisher grade (p=. ) as well as the development of dnd (p=. ; p=. ). lower peak igf levels were associated with the presence of dci (p=. ). controlling for age and fisher grade, log peak plasma igf levels remained significantly associated with the presence of dnd (p=. ; or . ; ci: . -. ) and dci (p=. ; or . ; ci: . - . ). igf levels have not been well characterized after asah. these results suggest lower plasma igf are associated with clinical severity and outcomes after asah and provide impetus for future work to further examine these relationships. induced hypertension (ih) is the mainstay of medical management for delayed cerebral ischemia (dci) after subarachnoid hemorrhage. however, using vasopressors to raise systemic blood pressure well above normal levels may be associated with systemic and neurological complications, of which posterior reversible encephalopathy syndrome (pres) has been increasingly recognized. however, the frequency and risk factors for ih-induced pres have never been systemically evaluated we identified patients treated with ih from sah patients admitted over a three-year period. pres was diagnosed based on clinical suspicion (i.e. unexplained deterioration), confirmed by imaging. we conducted retrospective extraction of data on ih therapy, including baseline and highest target mean arterial pressure (map) and vasopressor dose/duration. we compared those with pres to ihtreated controls and also described the clinical features and sequelae of all pres cases. five sah patients were diagnosed with pres, with median time from initiation of vasopressors to diagnosis of . days (range - days). baseline map did not differ between pres and ih controls, but highest target map was greater ( vs. mm hg, p= . ). magnitude of ih was similarly greater ( vs. mm hg above baseline, p= . ). all cases presented with lethargy, three had new focal deficits, and one had a seizure. one died from cardiac complications but the other four patients had complete resolution with ih discontinuation, without infarction or residual disability. pres was diagnosed in % of patients undergoing ih therapy and was most likely when map was raised well above baseline to levels exceeding the traditional limits of autoregulation ( - mm hg). high clinical suspicion for this reversible disorder appears warranted when aggressive ih targets are maintained for several days or in the presence of unexplained neurological deterioration. other interventions may be preferable for refractory dci when moderate degrees of ih have been attempted. patients with aneurysmal subarachnoid hemorrhage (asah) may receive significant exposure to potentially harmful ionizing radiation exposure (phire) from diagnostic tests and therapeutic procedures during their initial hospitalization. we hypothesized that risk factors to detect excessive phire are present at the time of admission. following irb approval, all patients admitted to our institution with documented asah over a -year period were retrospectively evaluated for inclusion and exclusion criteria. patients were excluded if they died prior to discharge. all study data, including sah-specific and patient-specific risk factors, were obtained from the electronic medical record. the total effective dose of ionizing radiation (tedir) per patient was calculated from previously published radiation exposure data. phire was considered to have occurred if tedir was greater than msv, the annual phire limit for radiation workers. logistic regression models were then fit to the dataset to evaluate clinical variables that significantly the risk of phire in these patients. data were collected from patients ( . % of all asah patients evaluated). the mean tedir in these patients was . msv. forty-two ( . %) of patients met criteria for phire. in multivariate logistic regression modeling, male gender (or= . , ci= . - . ), posterior circulation aneurysms (or= . , ci= . - . ) and ventriculostomy (or= . , ci= . - . ) were significantly associated with an increased risk of phire. in this study, approximately % of asah patients received phire. male gender, posterior circulation aneurysms and ventriculostomy were significantly associated with increased risk of phire. these factors may serve as important predictors of patients who require additional or complex care necessitating repeated diagnostic or therapeutic procedures during their hospitalization. alternative diagnostic or therapeutic modalities should be considered for patients with these risk factors to limit the risk of phire. future research should also evaluate the effect of phire on neurologic outcomes in these patients. it remains unclear whether patients with unruptured intracranial aneurysms (ica) should be treated. vessel wall enhancement (vwe) in high-resolution magnetic resonance vessel wall imaging constitutes a promising marker of aneurysm instability in this population. to find risk factors for aneurysm instability, we sought to identify predictors of vwe in patients with unruptured icas. we conducted a retrospective analysis of prospectively collected data on patients with unruptured ica evaluated by a single provider. all patients were evaluated using a previously validated algorithm to ascertain vwe using high-resolution magnetic resonance vessel wall imaging. two different raters, blinded to the study data, categorized all observed aneurysms as vwe-positive or vwe-negative. kappa statistics were used to evaluate the reproducibility of this approach. univariable and multivariate logistic regression modelling was utilized to identify factors associated with vwe after adjusting for potential confounders. patients with unruptured ica were included in the analysis (mean age [sd ] , female sex [ %]). of these, ( %) were vwe-positive and ( %) were vwe-negative. inter-rater reliability for vwe ascertainment was excellent (kappa . , %ci . , . ). out of ( %) patients presenting with cranial nerve palsy were vwe-positive. in univariable analysis, age (p= . ), headache on presentation (p= . ), and size (p< . , per additional millimeter) were associated with vwe-positive status. in multivariable analysis, headache on presentation (p= . ) and size (p= . ) remained independently associated with vwe. cranial nerve palsy is an established clinical marker of aneurysm instability; consequently, our results confirm the role of vwe as a marker of aneurysm instability. headache on presentation and aneurysm size are independently associated with vwe; these risk factors for aneurysm instability could be used to select patients with unruptured icas that may benefit from vessel wall imaging. prognostication in subarachnoid hemorrhage (sah) patients presenting in coma is crucial for surgical decision making. indications for aggressive aneurysmal treatment are unlikely for those not demonstrating signs of neurological improvement chronologically or after ventricular drainage. early neurological evaluation is, however, challenging in critically ill sah patients requiring anesthesia and intubation for airway protection. in this single-center retrospective study, we applied continuous amplitude-integrated eeg (aeeg) monitoring using a subhairline montage for wfns grade v patients who did not undergo emergency aneurysm treatment. monitoring was initiated soon after admission to the icu. patterns of aeeg findings were classified according to rundgren, et al. as follows: flat (f); suppression-burst (sb); electrographic status epilepticus (ese); and continuous (c). based on the aeeg findings, indications for aneurysm treatment were reevaluated. outcome was assessed at six months using the glasgow outcome scale. twenty-three patients, men and women, aged . ± . years (mean ± sd), were eligible since december . all patients underwent prophylactic intravenous sedation. the population represented % of all grade v patients including those resuscitated after cardiac (n= ) or respiratory (n= ) arrest. the glasgow coma scale scores were (n= ), (n= ), and (n= ), respectively. aneurysms were located in the posterior fossa in patients ( %). aeeg monitoring was initiated . ± . hours median . , . - . hours after arrival. all patients showing early f (n= ) or sb patterns (n= ) died. one patient demonstrated ese remained in a persistent vegetative state. five out of patients with a c pattern underwent aneurysm treatment; clippings and coil embolization. moderate disability was attained in and severe disability in . two patients undergoing conservative therapy died. continuous aeeg provided useful prognostic information for identifying salvageable sah patients undergoing sedation in the early phase. delayed cerebral ischemia (dci) may result in focal neurological deficits and cerebral infarction after subarachnoid hemorrhage. while global cerebral blood flow (cbf) may be variably reduced, dci is more likely related to regional impairments in cbf below critical perfusion thresholds. we applied volumetric methods to assess the proportion of brain exhibiting hypoperfusion (pbh) in those with clinical dci and in the symptomatic hemisphere of those with focal deficits. methods patients with aneurysmal sah underwent o-pet and ct imaging during period of risk for dci (median days after sah, iqr - ). we measured pbh as proportion of voxels with cbf < ml/ g/min, after excluding regions of infarction/hematoma on ct. we compared pbh in patients with vs. without dci at time of pet and, in those with focal deficits, we compared hypoperfusion between affected and unaffected hemispheres. pbh was greater in the ( %) with dci compared to those without dci ( %, ( ) ( ) ( ) ( ) ( ) ( ) ( ) ( ) p= . ) despite higher mean arterial pressure (map) and most being on active hemodynamic therapies. global cbf was also lower in those with dci ( . vs. . ml/ g/min, p= . ) but did not differ between those remaining symptomatic and those whose deficits had resolved. while mean hemispheric cbf was not lower in the affected hemispheres of with lateralizing deficits ( . vs. . ml/ g/min, p= . ), there was greater pbh in the symptomatic hemisphere ( % vs. %, p= . ). sah patients with dci have a greater proportion of brain with hypoperfusion despite active hemodynamic therapy and higher map. there was also larger proportion of the symptomatic hemisphere with hypoperfusion despite no asymmetry of hemispheric cbf. such measurements of hypoperfusion may better reflect the regional pathophysiology of dci than global averaged measures of cbf. further studies should determine whether burden of hypoperfusion correlates with tissue and patient outcomes. patients who survive aneurysmal subarachnoid hemorrhage (asah) are often burdened with lasting cognitive impairment due to a combination of sequelae including neuro-cardiac injury. the impact of neurocardiac injury after asah is poorly understood. this study sought to examine if neurocardiac injury detected by global longitudinal strain (gls) is associated with poor performance in neuropsychological np memory impairment after asah. we studied asah patients at months and at months (sahmii study r nr ) after hemorrhage. speckle tracking gls from apical views were assessed days - from bleed from transthoracic echocardiograms. neuropsychological (np) outcomes covering domains were completed at and months after hemorrhage by trained personnel. memory tests included controlled oral word association (cowa), wechsler memory scale (wms) and rey auditory (r-aud) and complex figure (reyc). anova and kruskal-wallis, pearson and spearman correlations and logistic regression were completed using spss and sas. there were ( %) patients with abnormal gls (defined as >- %) and ( %) in the and months groups respectively. gls groups had similar age, gender and fisher grade. abnormal gls was associated with higher hh at (p=. ) and (p=. ) months. abnormal gls was significantly associated with decreased performance in r-aud memory domains at months (p=. ) and months (p=. ) after asah and even when controlling for age and hh at months (p=. ). gls<- was associated with poor memory performance months after asah in cowa (p=. ) and the wms (p=. ) even after adjusting for age and hh, cowa (p=. ) and wms (. ). neuro-cardiac injury detected by gls was associated with decreased performance in memory domains of np function at and months after asah. while these relationships require further examination, neurocardiac injury may contribute to long term np impairment after asah. delayed cerebral infarction (dci) is a frequent complication following high-grade aneurysmal subarachnoid hemorrhage (asah). management of dci includes maintaining hypertension, which is challenging in heavily sedate patients. ketamine is a hemodynamically stable, analgesic sedative not studied in this population. we hypothesize that ketamine infusion (k), as compared to traditional sedatives (control), will safely improve the hemodynamic profile in high grade ventilated asah patients retrospective review of asah patients admitted / to / requiring mechanical delayed cerebral infarction (dci) is a frequent complication following high-grade aneurysmal subarachnoid hemorrhage (asah). management of dci includes maintaining hypertension, which is challenging in heavily sedate patients. ketamine is a hemodynamically stable, analgesic sedative not studied in this population. ventilation > hrs, and without dnr within hrs from admission. we assessed demographics, hemodynamics, pressor, dci at weeks, ventilator and icu los, and mortality. fisher exact, wilcoxon, and paired t-test applied. comparing k (n= ) vs control (n= ), median (q , q ) results for: age ( , ) vs ( , ); hunt and hess ( , ) vs. ( , ); mpm- day estimated mortality . % vs. . %; and gcs ( , ) vs ( , ) . ketamine initiated on day ( , ); icu los ( , ) vs. ( , ); and vent los ( , ) vs. ( , ) . mean (sd +/-) for hours before and after ketamine: map ( ) vs ( ), p . , except where noted. ketamine infusion, as a second line sedative, had no effect on mortality or icp, and improved map. however, there was a nonsignificant increase in dci as well as vent los, without a greater rate of tracheostomy. prospective studies are needed to study the effect on dci and long term outcomes. seizures are a well-known complication of aneurysmal subarachnoid hemorrhage(asah) and occur most commonly in the immediate post-hemorrhagic period. most commonly used antiepileptic drugs (aeds) for seizure prophylaxis in asah include phenytoin and levetiracetam. there is no reliable data available on the safety and efficacy of restricting aed prophylaxis only till the aneurysm is secured. we retrospectively chart reviewed patients admitted to our neurosciences intensive-care-unit with asah during the last two years. seizure incidence was studied in patients treated with phenytoin versus levetiracetam and in patients treated for to days versus those where aed was discontinued immediately after aneurysm was secured. in patients aed prophylaxis was discontinued immediately after the aneurysm was secured, and in patients it was continued for to days. of th phenytoin was used in patients and levetiracetam was used in patients. in patients receiving aed prophylaxis for to days, phenytoin was used in cases and levetiracetam was used in cases. none of these patients had seizures reported during hospitalization or at three month follow-up. stopping the aed prophylaxis immediately after aneurysm coiling is not associated with increased risk of seizures. seizures at presentation in patients with asah are not associated with development of epilepsy at months. both phenytoin and levetiracetam are well tolerated in patients with asah when limited to the immediate post-hemorrhagic period. the main preceding factor of delayed cerebral ischemia (dci) in asah is cerebral vasospasm (cvs). anticipating dci can have major impact on patient outcomes. studies have attempted to predict dci in patients with asah by using various imaging modalities that measure cvs, ranging from transcranial doppler ultrasonography, ctp, and mr perfusion. few compare these imaging modalities to the accepted gold standard of dsa. we propose that mri using asl imaging can be used as a sensitive and specific measure of cvs and can be used as a marker to identify patients with asah who are at risk for developing dci. to support our hypothesis, we compare asl results in patients with documented cvs on dsa who developed dci. patients in the academic years to with the diagnosis of asah were admitted to our nicu. the inclusion criteria for the patient population was the presence of asah confirmed by dsa, diagnosis of dci by a neurointensivist, mri with asl, and a repeated dsa during the hospitalization after dci was suspected. all patients underwent mra with asl on day in an attempt to capture the peak time of cvs. nine patients were included in this study. all cases with perfusion defects on asl sequences had confirmed cvs on dsa except for one. the outlier in our cohort developed dci with asymmetry on asl that was not demonstrated on dsa. to our knowledge, no studies have compared the specificity of asl with dsa in detecting cvs. this study highlights the utility of asl in detecting cvs in patients with asah. our limited data suggests asl can be utilized for detection of dci and cvs with greater confidence than the conventional modalities. we also suggest that asl approaches the utility of dsa in the detection of cvs. blood glucose dysregulation following aneurysmal subarachnoid hemorrhage is associated with serious complications and poor clinical outcome. an influence of hyperglycemia on the occurrence of delayed cerebral ischemia (dci) is assumed, nevertheless the exact mechanism remains unclear. the goal of the present study aims to investigate the influence of systemic blood glucose level on cerebral perfusion measured by dynamic perfusion computed tomography (pct) and outcome. daily serial blood glucose levels and pct data sets of patients treated at our neurointensive care unit after asah were retrospectively analyzed. serial pcts were performed between six hours and days after aneurysm repair. mean average of mean transit times (mtts) was calculated for each perfusion scan. the maximum mean transit time (maxmtt) and outcome assessed with glasgow outcome scale were correlated with defined blood glucose ranges as followed .) > mg/dl (hyperglycemia) .) - mg/dl (elevated glucose level) .) - mg/dl (strict glucose control) and < mg/dl (low glucose level). hyperglycemia (> mg/dl) was associated with prolonged maxmtt (p< . , rs = . ) and was linked to an increased risk of infarction (p < . ) whereas strict glucose control ( - mg/dl) correlated significantly negative with maxmtt (p < . , rs = -. ). strict glucose control was also associated with a lower occurrence of cerebral infarction and good outcome (p < . , rs = . ). in contrast, elevated blood glucose levels ( - mg/dl) and hyperglycemia showed a negative correlation with good outcome (p < . , rs = -. , rs = -. ). the present analysis supports for the first time the assumption that dysregulation of blood glucose balance influences cerebral perfusion and thus may contribute to the occurrence of dci and poor outcome. therefore careful monitoring and prompt treatment of blood glucose levels after asah should be highly valued to avoid cerebral perfusion deficits correlated with poor outcome. the aim of this study was to determine the correlation between transcranial doppler (tcd) velocities and angiographic vasospasm after subarachnoid hemorrhage (sah). methods patients with sah were evaluated with spencer technologies tcd power m mode from - days, following the sah. both the temporal windows were insonnated to determine flow velocities in the middle (mca) and anterior cerebral arteries (aca) and the suboccipital widow was used to determine flow velocities in the vertebral (va) and basilar arteries (ba). the middle cerebral artery/ipsilateral extracranial internal carotid artery velocity ratio (lindegaard ratio) was also correlated with vasospasm ct angiography and conventional cerebral angiography was used to confirm tcd findings suggestive of vasospasm. the sensitivity, specificity, likelihood ratios for positive and negative tcd results, positive there was males and females and with mean age . +- . years. % were aneurysmal sah. delayed ischemic neurological deficits (dind) developed in / patients ( . %). interobserver ue of cm/s were useful (likelihood ratio for negative result = . , likelihood ratio for positive result = . ). lindegaard ratios correlated well with vasospasm. tcd diagnosis of vasospasm was more often present in the mca, followed by aca and basilar arteries. tcd is a good non invasive method to detect vasospasm and predict the occurrence of dind. very high angiographic vasospasm. tcd is also useful to follow up patients with angiographically proved vasospasm. aneurysmal subarachnoid hemorrhage (asah) is a significant cause of morbidity and mortality. the mortality rate approaches %. nearly half of the survivors remain unable to care for themselves . dci occurs in % of these patients . when present, it doubles the risk of poor outcome. -several methods have been used to treat cerebral vasospasm and dci, which is a major cause of morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (sah). milrinone safe and, potentially, effective treatment of dci as reported in low level of evidence literature . however, the efficacy not compared in a randomized way to placebo. we will examine the effectiveness and safety of intra-venous injection of milrinone for the treatment of dci following aneurysmal sub-arachnoid haemorrhage. our intension is to study the outcome of using milrinone as an addition to current therapies such as hypertensive therapy are not effective enough, yet can not be replaced as it is standard of care. as intravenous milrinone was not yet shown to have an affect in dci in a randomized controlled trial. this pilot trial is a step towards that study. the study is a pilot trial of a randomized placebo-controlled double blind trial testing the potential beneficial effect of milrinone, a phosphodiesterase inhibitor, on clinical neurological outcome in patients with dci after aneurysmal subarachnoid hemorrhage. the study drug will be given along with the standard therapy when dci occurs. the administration of milrinone increases cerebral blood flow most likely as a result of cerebral vasodilation. as intravenous milrinone was not yet shown to have an affect in dci in a randomized controlled trial. this pilot trial is a step towards that study. milirinone promising treatment for delayed cerebral ischemia following aneurysmal sub-arachnoid haemorrhage .particulary by using standardized protocol as a finding suggestive of good prognosis fever in the neurocritical care population is very common and is strongly associated with increased mortality and poor outcome. fever is aggressively treated in the icu due to its deleterious effects. yet despite best efforts with standard antipyretic agents and even with aggressive cooling measures with endovascular cooling catheters some patients may still have refractory fevers. celecoxib, a cyclooxygenase- (cox- ) inhibitor, has been used as an adjunctive antipyretic agent. this is a retrospective analysis to evaluate the effectiveness of celecoxib in lowering temperatures in patients with refractory fevers. this is a retrospective chart review of patients admitted to a neurointensive care unit at a single institution with fevers (> . c) that do not respond to convention treatment with acetaminophen, endovascular cooling catheters and ibuprofen. patients with severe traumatic brain injury, subarachnoid hemorrhages and intracerebral hemorrhages were included. patient temperature recordings were obtained in the period of hours before and hours after administration to the first dose of celecoxib. the mean temperature of the before and after periods were compared and temperature difference was calculated. patient records were included. the average of the mean temperatures in the before periods and after periods were . c (+/-sem . ) and . c (+/-sem . respectively. there was a significant difference on mann-whitney-wilcoxon rank sum test (p< . ). one average there was a drop of . (+/-sem . ) degree celsius of the mean temperature after the start of treatment. in neurocritically ill patients with fevers that are refractory to conventional treatments adding celecoxib, a cox- inhibitor seems to be effective at lowering the core body temperature. further study is warranted to evaluate for adverse effects such as risk of cardiovascular events. achieving and maintaining normothermia (nt) after subarachnoid hemorrhage (sah) or intracerebral hemorrhage (ich) often requires temperature modulating devices (tmd). shivering is a common adverse effect of tmd's that can lead to further costs and complications. we evaluated a new esophageal tmd, the ensoetm (attune medical: chicago, il), to compare nt performance, shiver burden, and cost of shivering interventions with existing tmd's. patients with sah or ich and refractory fever were treated with the ensoetm. patient demographics, temperature data, shiver severity, and amount and costs of medication used for shiver management were prospectively collected. control patients who received other tmds were matched for age, gender, and body surface area (bsa) to ensoetm recipients and similar retrospective data was collected. all patients were mechanically-ventilated. fever burden was calculated as areas of curves of time spent above . or c. demographics, temperature data, and costs of ensoetm recipients were compared to recipients of other tmd's. eight ensoetm recipients and controls between october and november were analyzed. there were no differences between the two groups in demographics or patient characteristics. no difference was found in temperature at initiation (p = . ) and fever burden above °c (p = . ). ensoetm recipients showed a non-significant trend in taking longer to achieve nt than other tmd's (p = . ). ensoetm recipients required fewer shiver interventions than controls (p = . ). ensoetm recipients incurred fewer costs than controls per day (p = . ). the ensoetm achieved and maintained nt in sah and ich patients and was associated with less shivering and lower pharmaceutical costs than other tmd's. further studies in larger populations are needed to determine the ensoetm's efficacy in comparison to other tmd's. targeted temperature management is an important aspect of care in neurologically impaired patients. however, achieving optimum temperature for a specific patient can be challenging; a patient's size, body composition, metabolism, and hypothalamic function contribute to his or her response to a given temperature management modality. the purpose of this study is to evaluate patient response to esophageal temperature management when continuously applied for at least h. deidentified core temperature data for patients (a total of measurements) were obtained from three hospital sites where esophageal temperature management was used for at least h (range - h). indications for active temperature management included: cardiac arrest ( ), refractory fever ( ), subarachnoid hemorrhage ( ), intracranial hemorrhage ( ), and traumatic brain injury ( ). goal temperatures ranged from - °c and initial patient temperatures ranged from - °c. deviation from goal was calculated by subtracting target temperature from actual temperature for each measurement which allowed the calculation of the mean and standard deviation for each time point across all temperature management protocols. across time points, representing an average treatment time of . h, . % of mean deviations from goal were within ± °c and . % were within ± . °c. in interpreting these results, several limitations must be considered. this dataset reflects a wide range of temperature management protocols and clinical scenarios. for example, a larger than average deviation in measurements recorded in the - h period was related to rewarming in cardiac arrest patients who rewarmed slowly. also, the later time points were dominated by sah, ich, and refractory fever patients who often experience more pronounced fever spikes. this analysis indicates that esophageal temperature management is a feasible option for patients who require active temperature management for or more hours. the role of therapeutic temperature management (ttm) in neurocritical care is uncertain. one question that has been inadequately addressed is the diversity of practice across multiple neurocritical care units (nccu) throughout the world. a barrier to understanding this practice variance is a data collection method that would provide adequate understanding of how ttm is implemented in various nccus. the purpose of this pilot study is to test the efficacy of a data collection method that would provide unitlevel data on ttm practice. the design of this study was prospective, observational, and cross-sectional study using quality assurance methodology. the study received institutional review board approval. to reduce the risk of loss of confidentiality and promote privacy, individual patients were not consented. data on temperature management was collected each day for consecutive days. completed data was available for days. mean daily census of patients included the following mean number of patients with sah ( ), ich ( ), ischemic stroke ( ) and other ( ). of those, ttm was provided to at least one patient during of days ( . %). the most common ttm method (tylenol) was used on patient days; surface cooling was used on patient days. ttm was initiated for fever management ( patient days) and normothermia ( patient days). the most common associated complication was hypocalcemia ( ) and hypokalemia ( ). the data collection form was easily and quickly filled completed on a daily basis, but provides limited data. although the form captured a significant number of events surrounding the use of ttm, the primary limitation noted is the inability to link specific events (e.g., hypokalemia) to specific patients or diagnoses. this pilot study demonstrates the efficacy of data capture and provides insight towards refining a prospective observational study to describe ttm practice. brainstem tumors are exceedingly dangerous due to its proximity to the structures responsible for basic human survival in the neurocritical care setting. these lesions may cause autonomic dysregulation. we report on a rare case of a female with a past surgical history of ventriculoperitoneal shunt with a brainstem mass of müllerian type epithelial tissue. methods year old caucasian female presented to our hospital status-post fall after episodes of lightheadedness, as well as, episodes of decreased respirations in her sleep. mri showed a medullary contrast enhancing mass with calcifications measuring . x . x . cm and a small calcified lesion in the right lateral ventricle. suboccipital craniectomy for biopsy and decompression was performed. intraoperatively, the heart rate and blood pressure dropped transiently due to the mass being firmly adhered with calcification to the medulla. the neuropathologist diagnosed the tissue as mullerian type epithelium with estrogen receptors. post-operatively, our patient encountered several instances of cardiac pauses on monitoring that required the need for cardiology to place a permanent pacemaker. the above is a rare case of a calcified heterogeneously contrast enhancing brainstem mass that underwent neurosurgical biopsy. histopathology results indicated müllerian type epithelial tissue which is tissue that gives rise to female reproductive organs. the origin of a brainstem lesion from an embryologically gynecological site could be speculated to have traveled retrograde via the ventriculoperitoneal shunt catheter. patient required postoperative cardiac management and intervention with a pacemaker for encroachment or mechanical conflict of the mass onto the rostral ventrolateral medulla. oncology recommended pet ct scan and further consideration for tamoxifen chemotherapeutic regimen. this case is a reaffirmation of the importance of brain tumor location and tissue diagnosis for the purpose of adjuvant treatment of neurosurgical lesions in the neurocritical care setting. tranexamic acid (txa) has been used off label in cardiovascular and orthopedic surgery, as well as in trauma resuscitation. the use of txa has increased since the publication of crash- ( ) and matters ( ), demonstrating its efficacy in trauma patients to reduce bleeding. there remains concern about the thrombotic risk as well the reduction in the seizure threshold after txa administration. case description: we present a case of a -year-old female admitted to the surgical icu after a motor vehicle accident with multiple traumatic pelvic and extremity fractures and soft tissue injury. she subsequently developed extensive arterial and venous thromboses with bilateral acute ischemic strokes with superimposed posterior reversible encephalopathy syndrome after txa administration. a second case involved a -year-old female who had a fall from standing and given txa in the field by ems. shewas admitted to the neurocritical care unit with status epilepticus and suffered a complicated course with cardiogenic shock due to stress induced cardiomyopathy. discussion: the risk-benefit balance of txa administration is generally considered acceptable in severe bleeding. the cases presented here suggest the neurological risks of txa administration may be poorly understood and demonstrate the need for better patient selection and heightened awareness for early identification and management of complications given the possible severity of neurologic sequelae. conclusion: txa is an anti-plasmin drug that is increasingly used in the areas of trauma and postoperative bleeding. we aim to educate clinicians in the potential neurological complications that can arise with its use. cryptococcus neoformans is normally an opportunistic infection known to cause meningoencephalitis and can present with stroke like symptoms. in imaging, cns vasculitis can be identified, which can lead to cerebral infarcts. when involved, these cerebral vessels are small sized leading to lacunar infarcts. we present a case that involved a large vessel territory leading to patient mortality. initial treatment with glucocorticoids, though beneficial in other meningoencephalitidies, may actually be harmful in fungal cns infections. case: a year old male with a presents with weeks slurred speech and worsening headache. an enhancing lesion on brain mri in left temporal lobe was concerning for vasculitis. patient was treated with glucocorticoids, with a negative rheumatologic workup and discharged home. patient subsequently presented days later with worsening symptoms, with ct imaging showing completed infarcts. blood cultures were positive for cryptococcus neoformans; patient died due to diffuse right mca territory edema and brain herniation syndrome. discussion: it is important to consider cns infection even in immunocompetent patients who present with any of the following: fever, nuchal rigidity, mental status change, and headache. cns vasculitis in association with infection is caused by basilar meningeal exudates. these cause traversing vessels to become inflamed, leading to distal inflammation and subsequent thrombus and infarction. we present a right mca territory infarct , presumed to be based on the aforementioned vasculitic process. when acute infarcts are associated with opportunistic cns infections, they are usually not associated with large vessel infarction. we also examine the adjunctive use of glucocorticoid therapy for treatment of fungal cns infections. this is an infrequent case of cryptococcus neoformans causing a cns infection in an hiv-seronegative patient not on chronic immunosuppressive medications. this case presents a unique complication of cryptococcal infections, a cns vasculitis leading to infarction in a large vessel territory. we describe the baseline characteristics, continuous intravenous midazolam doses, seizure control, hospital course and outcomes in patients who received high dose continuous midazolam infusion for refractory status epilepticus in this retrospective case series study, we evaluated adult patients with refractory status epilepticus treated with high continuous intravenous midazolam doses in an academic neurocritical care unit between august and june . four patients were identified. the maximum midazolam dose for each patient was: withdrawal seizures (occurring within hours of discontinuation of continuous iv midazolam) occurred in patient b. "ultimate continuous iv midazolam failure" (patient requiring change to a different continuous intravenous antiepileptic drug despite maximum optimized dose) was not observed in any of the four patients. hospital complications occurred in patient a and b due to infections. hypotension related to continuous infusion midazolam occurred in patient a. three out of four patients discharged alive to a skilled nursing facility; after a goals of care discussion with the family, the fourth patient had withdrawal of care due to the severity of his brain injury. in this case series, we report the use of high dose continuous iv midazolam for treatment of refractory status epilepticus. there were no midazolam-related deaths. neurologic complications in infective endocarditis (ie) occur up to % and are independent predictors of mortality. infectious intracranial aneurysms known as "mycotic aneurysm" (ma) are rare constituting - %. hemorrhaging rate is %. mortality is % with rupture. ruptured ma poses significant management conundrum due to lack of available solid prospective data guiding the order (cardiac vs neurosurgical) or timing (early vs delayed) of surgery. a y/o male iv drug abuser presented with acute hypoxemic respiratory failure secondary to pneumonia and suspected meningitis. gsc intubated on iv antibiotic. hemodynamic instability prompted tee showing large aortic valve vegetation. blood cultures positive mssa fulfilled criteria for ie. tests showed kidneys infarctions. ct brain showed r mca territory infarct with sah.cta head revealed small ma along the distal r mca m branch confirmed with cerebral angiogram. acute heart failure and arrhythmia led discussion on cardiothoracic surgery for valve replacement. due to ruptured ma, decision to secure it was made prior to cardiac surgery. after failed endovascular intervention, patient underwent surgical clipping. post operative mri brain showed new infarcts suggesting recurrent embolization. due to risk of intracranial bleeding, cardiac surgery was postponed for at least weeks initially then to weeks. patient underwent avr after completed weeks of antimicrobial therapy with st jude mechanical valve and discharged on anticoagulation with a modified rankin scale of . this case reflects on how urgent surgical intervention should take place.safety period between neurological event and cardiac surgery is largely debated because of lack of controlled studies. there has been no consensus on how to approach those cases as paucity of robust evidence. given their rarity the best management modality remains unclear. this case stress the importance of multimodal therapy in achieving good outcome although the timing of surgery remains a matter of debate. we present a patient with vertebral cerebral artery embolism (cae) following blunt trauma. case presentation: a year-old male was admitted with a right vertebral artery dissection and occlusion with intraluminal air, widespread pneumocephalus, bilateral pneumothoraces, a pulmonary laceration, and multiple fractures including ribs, c transverse foramen (with normal alignment), and femur following a motor vehicle collision. his pupils were initially nonreactive, and he experienced one hour of witnessed generalized seizure activity on arrival despite aggressive treatment. management: midazolam infusion, levetiracetam, and fosphenytoin were initiated for seizure control. targeted temperature management to celsius was initiated on arrival out of concern for hypoxic brain injury. computed tomography at hours demonstrated resolution of vertebral and intracerebral air, diffuse edema, and diffuse loss of gray-white matter differentiation, thus a hypertonic saline infusion was initiated. the following day, an mri demonstrated diffusion restriction in the areas adjacent to the air, including c - and diffusely throughout bilateral cerebral hemispheres. prognosis was thought to be poor. however, the following day, the patient awoke. by day four he followed commands. he was discharged to skilled nursing on day . at three months he had only minimal residual right hip weakness. discussion: there are only three case reports of cae following blunt trauma, and only one involving the vertebral artery. air migrates to the arterial circulation due to a positive gradient from low central venous pressure or high airway pressure. pulmonary venous air then embolizes to cerebral vasculature. as little as ml of arterial air emboli can be fatal with the major cause of death being circulatory obstruction and arrest from air trapped in the right ventricular outflow tract. conclusion: this patient developed pneumocephalus and cae due to a pulmonary laceration. as the cerebral air reabsorbed, his seizures resolved and his exam improved. petrous ica aneurysms are extremely rare - and difficult to treat surgically, due to the inherent challenges of microsurgical access to the carotid canal of the petrous bone - . endovascular approaches may also prove challenging, typically as the consequence of therapeutically-unamenable morphology, but occasionally due to size considerations as well. a -year-old male presented with headache and vertigo for the past weeks. the patient was hivpositive with medication noncompliance and denied any history of trauma or head injury. head ct identified a . x . cm heterogeneous soft tissue density lesion in the right petrous bone. ct angiography revealed a . x . x . cm lobulated giant aneurysm of the right petrous ica. mri/mra was performed to rule out thrombosis and showed giant partially thrombosed right petrous ica aneurysm. the decision was made to treat using flow diversion. the patient underwent catheter angiography, confirming a giant x . cm right internal carotid artery petrous segment aneurysm. we proceeded with flow diversion pipeline endovascular device, placement of two pipeline endovascular devices (flex x and x ) successfully. final angiographic runs showed significant stasis within the aneurysm and demonstrated the flow-diverter construct was well placed both proximal and distal to the aneurysm neck with no sign of endovascular leak. the patient was discharged home well. we suggest that flow diversion is an ideal treatment for petrous ica aneurysms, specifically un-ruptured lesions of complex morphology. other options for treating petrous ica aneurysms challenging, not possible, less effective, and/or carry substantial risks. second, several of the disadvantages of pedocclusion of side vessel branches and preclusion of future coil embolization, do not apply to the petrous segment of the ica. lastly, use of ped in petrous ica aneurysms has proven effective in the vast majority of reports. the spot sign is a focus of enhancement within the hematoma on ct angiogram (cta) with unique characteristics. it has a spot-like appearance within the margin of a parenchymal hematoma without connection to an outside vessel. it should measure greater than . mm in diameter in at least one dimension. its contrast density (hounsfield units, hu) is at least double that of the background hematoma. finally, there should be no hyperdensity at the corresponding location on non-contrast ct. it is a strong predictor of hematoma expansion and poor prognosis in intra-parenchymal hemorrhage. the pathogenesis of spot sign remains unclear. some studies showed an association with faster rates of contrast leakage which indicates continued bleeding. a spot sign has not been reported with isolated intraventricular hemorrhage (ivh) before. a case report of a -year-old man with a past medical history of hypertension who got admitted to the er with acute encephalopathy and right-sided weakness. head ct-scan (hct) revealed isolated ivh. cta was notable for a spot sign. it measures . mm in diameter and hu in density (surrounding hematoma measures hu). it lies within the hematoma without connections to any adjacent vessel. a follow-up hct after four hours showed expansion of the ivh. although seems uncommon, looking for a spot sign in isolated ivh can also anticipate expansion of the hemorrhage. a further study is needed to validate this observation and calculate the prevalence of the spot sign in isolated ivh. west nile neuroinvasive disease may present with nonspecific physical exam and imaging findings. to our knowledge, this is the first report of wnnd involving the temporal lobe in adults with neuroimaging suggestive of limbic encephalitis. our patient presented in winter and developed autonomic instability and sensory deficits, which are all rare findings in wnnd. -year-old texan with dm presented with acute confusion and seizure in november. patient complained of headache, fever, diarrhea and lower extremity weakness after a fishing trip. patient was febrile with mosquito bites on his arms. neurological exam was significant for comatose state, absent brainstem and deep tendon reflexes, and flaccid paraparesis. he developed autonomic instability with labile blood pressures. lp revealed wbc/mm (monocyte predominance), rbc/mm , glucose mg/dl, elevated protein of mg/dl, and a positive west nile virus (wnv) igm antibody; gram stain, hcv pcr, and the paraneoplastic and autoimmune panels were negative. eeg showed severe diffuse brain slowing. mri brain had t flair and dwi changes in right hippocampus and posterior limb of internal capsule. emg described severe subacute sensorimotor axonal polyneuropathy without prolonged distal latencies and normal conduction velocities. he received days of ivig without improvement and was terminally extubated. our patient presented with both clinical entities of west nile: wn fever and wnnd (present in less than % of cases). our patient had axonal polyneuropathy with paralysis which is due to inflammatory changes in the white matter tracts affecting spinal sensory pathways. sympathetic ganglia involvement caused the autonomic instability, another very rare manifestation of wnnd. november presentation was due to warmer texas winter. recognize that west nile fever and west nile neuroinvasive disease may present together in winter. recognize that west nile neuroinvasive disease can present with rare temporal lobe neuroimaging, sensory involvement, and autonomic instability. intracerebral hemorrhage (ich) is a common pathology seen in the neurocritical care setting that can be associated with significant morbidity and mortality. the use of sympathomimetic agents containing phenylpropanolamine (ppa) have been associated with ich in the past which lead to the drugs' removal by the fda as an over the counter medication in . we report a case in which ppa was the etiology for a spontaneous ich in a patient who was taking an appetite suppressant. case report and review of the literature we report a case of a year old female with no prior medical history, who presented with sudden onset left sided hemiparesis and hemianesthesia found to be due to a right striatocapsular intraparenchymal hematoma. systolic blood pressures at presentation and throughout the hospital course were normal. extensive work up including multiple ct scans of the head, mri brain, ct angiography, mr angiography and digital subtraction angiography were performed with no evidence of any vessel abnormality. etiology of the ich was attributed to the use of ppa. in young patients with no known comorbidities, ppa use should be considered a primary etiology of ich when no intracranial vessel abnormality can be detected. seizures have been known to cause sudden death, but reports in the literature of only cardiopulmonary failure in cases of sudden unexpected death in epilepsy (sudep). we present the case of a patient who presented post-seizure and developed sudden progressive and fatal cerebral edema within hours after a second seizure. a year old female with a history of down syndrome and epilepsy presented to the emergency department after a prolonged convulsive seizure. she received doses of mg lorazepam and levatiracetam . mg/kg with cessation of seizure activity and return to baseline neurologic status within hours of the initial event. head ct showed lack of sulci throughout the cerebral hemispheres and basilar cistern effacement despite being at her baseline neurologic status. hours after presentation the patient had another seizure, vomited, was intubated and an additional mg/kg of levatiracetam given. hours after presentation, the patient was admitted to the neuroicu with absent brainstem reflexes and repeat head ct with worsened cerebral edema and tonsillar herniation. formal brain death testing was performed approximately hours after the patient's initial presentation. seizures are known to cause a hypermetabolic state in the brain. uncontrolled neuronal firing leads to hyperemia, failure of na+/k+ atp pump, increased levels of neuronal chloride, and inability for cells to maintain homeostasis. in this case, the patient's initial head ct showed cerebral edema, likely from prolonged seizure activity. once the second convulsive seizure occurred, a period of pre-intubation hypoxemia coupled with post-intubation hypotension allowed for progression of cerebral edema in an already compromised brain; similar to what is seen in post-cardiac arrest and traumatic brain injury. this case illustrates the importance of controlling for factors that can contribute to secondary brain injury in seizure patients. posterior reversible encephalopathy syndrome (pres) is a clinico-radiographic syndrome characterized by seizure, headache, encephalopathy and neuroimaging findings of symmetric white matter edema in the posterior cerebral hemispheres. cerebellar and brainstem involvement occurs rarely. here, we report a patient who presented with severe pres complicated by diffuse cerebellar edema and obstructive hydrocephalus requiring decompression with ventriculostomy placement. this is a case report from a tertiary medical center. a -year-old woman with a history of migraine presented to the emergency room with -day history of fever, right upper quadrant abdominal pain, nausea and vomiting. on day two of hospitalization, the patient developed worsening headache, dizziness and lethargy and her blood pressure was elevated to / mmhg. ct of the brain showed cerebellar edema and bilateral occipital lobes with effacement of the fourth ventricles and associated hydrocephalus involving the lateral and third ventricle. mri obtained post-operatively revealed t -weighted/flair diffuse hyperintensities in the parietal, occipital lobes and cerebellum. there was no mass lesion or restricted diffusion in diffusion weighted images (dwi) suggestive of acute infarction. cerebellar edema with compression of the fourth ventricles with hydrocephalus was slightly improved status post interval ventricular drain placement. ventriculostomy was weaned off over the course of seven days. follow up mri showed improvement of the hydrocephalus with decreased in t -weighted hyperintensities in posterior parietal and occipital lobes as well as within the cerebellum. severe cerebellar edema with obstructive hydrocephalus is an exceedingly rare complication of pres; however, prompt recognition and surgical decompression in addition to usual medical management is critical to achieve a favorable outcome. while obstructive hydrocephalus may be successfully treated with medical management and blood pressure reduction, this case emphasizes that clinical evidence of brain herniation should prompt immediate consideration for emergent ventriculostomy placement or surgical decompression to redirect cerebrospinal fluid and reduce intracranial pressure. one of the biggest uses of qeeg is the alpha delta ratio (adr). adr drops of % from baseline are associated with vasospasm (vsp/dind). we describe a case in which subtle qeeg adr change occurred in a poor grade sah patient over a number of days, making it challenging to detect an acute adr drop. this is a case report and literature review. this study also compared hemispheric adr values against the mca values by tcd, dsa, cta and clinical exam. a year old female with hunt hess iii, wfns iv, came in comatose with a ruptured ica aneurysm. over six days, she developed refractory vsp/dind. the patient's adr was gradually declining but their increased icp required propofol sedation, which itself lowers adr. re-analysis over multiple days had to be performed, and that re-analysis showed a gradual adr decline preceding the vsp/dind. when looking at our cases, we found a sensitivity and specificity of ( , %) when using the adr nadir compared to cta/dsa. recent publications have shown the adr method has less than ideal sensitivity and specificity of ( , %). qeeg adr is a useful multimodal monitoring parameter in neuroicu patients with relatively good baseline adr. however, its ability to detect vsp and dind in poor grade sah patients who have adr values that are already low (< . ) is challenging, particularly given the confounders in this population, such as eeg artifact which artificially raise adr values, and sedation (e.g., propofol) which suppress adr values. based on this information, we would suggest neuroicu centers carefully use continuous eeg monitoring for other indications such as nonconvulsive seizures, unless they have sophisticated bedside protocols about sedation vacation (baseline daily adr that is not) and eeg department resources (technicians who can fix eeg electrode artifacts). hypoxic-ischemic brain injury is a severe consequence of global cerebral hypoperfusion following cardiac arrest. brain ct findings may include diffuse sulcal effacement, loss of cisternal spaces, poor differentiation of grey/white matter, and decreased densities in the basal ganglia and watershed territories. the connection between aggressive resuscitation, as seen with in-hospital cardiac arrest, and cerebral edema is unclear. here we present the case of a hemodynamically unstable patient who developed transient reversible cerebral edema believed secondary to aggressive resuscitative efforts and pressor therapies. a year old female with a past medical history significant for diabetes and hypertension presented to the emergency department with headache and non-bilious vomiting. workup revealed isolated ventricular hemorrhage secondary to a ruptured left posterior inferior cerebellar artery (pica) aneurysm and cerebellar arteriovenous malformation, which underwent subsequent embolization. during her early hospital course she remained intubated due to pulmonary factors, but awake and alert with a non-focal neurologic examination. her course was subsequently complicated by a severe metabolic acidosis requiring several doses of bicarbonate boluses and continuous infusion, cvvhd, intravenous crystalloids, hydrocortisone and multiple pressors to maintain stability. over a hour period she received liters of volume while maintaining a mean arterial pressure above mm hg and o saturations above %, without requiring cpr. subsequent progressive encephalopathy developed, with a ct brain revealing diffuse sulcal effacement prompting hyperosmolar therapy. gradually her encephalopathy began to improve, with repeat imaging showing improvement of cerebral edema and return of grey/white matter differentiation. this case highlights a potential etiology of reversible cerebral edema that may confound early prognostication in patients with hemodynamic instability such as multi-organ failure and in-hospital cardiac arrest. further investigations are warranted. langerhans cell histiocytosis (lch) is a rare disease with an incidence of . - . cases per , children under years of age. frequency in adults is unknown. the hypothalamic-pituitary manifestations of lch (commonly diabetes insipidus) and hypernatremia are well known complications. here we present a case where a patient presented with poor mental status and the etiology remained unknown initially despite extensive testing. electronic medical record was reviewed regarding hospital course, sodium trends, and radiology images. this patient is a year old female with history of langerhans' cell histiocytosis with biopsy-confirmed suprasellar metastases (complicated by pan-hypopituitarism) who was transferred to our institution for hypernatremia and hydrocephalus. she had undergone two cycles of chemotherapy, most recently one week prior to presentation, and five rounds of radiation completed three months earlier. her presentation to the community hospital from a nursing facility was with unresponsiveness and she was intubated on arrival. her sodium was at that time; and had been three days prior. sodium was corrected from to over the course of four days with a drop from to within the first ten hours. her mental status improved to the point where she was awake and following commands; however still remained intubated. when she presented to our institution her sodium was and subsequently became unresponsive with a poor neurological exam limited to cranial nerve function only. she was evaluated with eeg monitoring and mri brain; however both were unrevealing for a cause. she had an external ventricular drain placed for concern for hydrocephalus that did not change her exam. one week later repeat mri brain revealed extrapontine myelinolysis. this case highlights the complications associated with intracranial lch and the need for repeat imaging in patients with rapid sodium correction to identify effects of osmotic demyelination. cangrelor is a rapid-acting, intravenous p y platelet receptor inhibitor with a plasma half-life of - minutes and full platelet recovery achieved within one hour after discontinuation. because it is rapidly reversible, cangrelor is commonly used to bridge patients with recent coronary stents to cabg surgery. oral p y inhibitors, such as clopidogrel, have a delayed onset and offset with platelet recovery occurring over - days, making their use challenging perioperatively or in the setting of an acute bleed. safety and efficacy data of cangrelor in noncoronary stents are lacking. we present two patients in whom cangrelor was used to maintain internal carotid artery (ica) stent patency acutely. both patients presented with an ischemic stroke secondary to acute occlusions of the left ica and left middle cerebral artery (mca) and were taken emergently to the neurointerventional suite for carotid artery stenting (cas) and mechanical embolectomy of the mca clot. heparin and eptifibatide were administered intraoperatively. post-procedure dynact demonstrated intracranial hemorrhage complications. dual antiplatelet therapy (dapt) with clopidogrel and aspirin, typically initiated following cas, was deferred given the difficulty of reversing their antiplatelet effect in hemorrhage expansion. instead, cangrelor was initiated to maintain carotid stent patency at . mcg/kg/min in one patient and . mcg/kg/min in the other patient and infused for . and hours, respectively. platelet reactivity was trended with the verifynow® assay and used to adjust cangrelor dosing. serial imaging was obtained to monitor hemorrhage expansion. one patient was transitioned to oral dapt and discharged while the other patient deteriorated neurologically from malignant cerebral edema and expired. cangrelor may be useful following cas complicated by intracranial hemorrhage when the need to maintain stent patency must be balanced with the risk of hemorrhage expansion. further research is warranted to determine its safety and efficacy in noncoronary stents. cerebral amyloid angiopathy (caa) although has been described in the literature, the different categories of this entity and its recognition and subsequent treatment are still elusive. it is important for neuro intensivists to recognize its variable presentation . we describe a single case report and perform a systemic review. caa depending on pathology can be categorized as inflammatory-caa where perivasculitis is seen on biopsy. this causes a non-destructive perivascular inflammatory infiltration and amyloid deposition pattern. on the other hand, amyloid beta related angitis (abra) results in a vasculitis and there is predominantly granulomatous angio-destructive inflammatory mediated disease affecting leptomeningeal and cortical vessels characterized by meningeal lymphocytosis and abundant amyloid-beta deposition within the vessel walls. caa on the other hand results in no inflammation of vessels but rather just deposition of amyloid deposition in the walls of vessels. we report a case of a year old man with an extensive cardiac history, who presented with syncope. initial computed tomography (ct) of head was negative. during admission, he acutely started having trouble answering questions including his name, and was unable to communicate his needs. repeat ct head showed hypodensity in left frontal region which was attributed to a stroke. he than developed complex partial seizures requiring intubation and seizure management. lumbar puncture showed mild pleocytosis. mri brain showed edematous changes of the left subcortical and deep white matter frontal lobe region which on repeat imaging subsequently worsened. biopsy was eventually performed which confirmed inflammatory cerebral amyloid angiopathy. he was treated with steroids and immunosuppression with gradual improvement. month follow up in clinic with continued improvement to independence. recognize the various subtypes of caa in their pathology, presentation and potential treatment. in acute emergency situations, intraosseous vascular access represents an alternative route of vascular access when peripheral vein insertion is difficult. we present the first documented case of intraosseous alteplase (tpa) administration in a patient with acute ischemic stroke symptoms. methods year old male with past medical history of hypertension, end stage renal disease, and diabetes mellitus presented to the hospital with sudden onset expressive aphasia and right sided numbness minutes prior to ed arrival. nihss was and code stroke was activated. patient blood pressure was / . ct head did not show any acute intracranial hemorrhage. it was decided to proceed with thrombolytic therapy. one peripheral venous access was obtained through which nicardipine drip was started to lower the blood pressure however second peripheral venous access was attempted multiple times but was unable to be obtained. tpa is more effective the faster it is administrated, and there was no known contraindications to administering tpa via intraosseous access (io). we report the first known case of successful and safe administration of fibrinolytic therapy through the intraosseous route in a patient with acute ischemic stroke symptoms. intraosseous access has been considered to be more invasive than intravenous (iv) and carries theoretical risk of bleeding however we were able to demonstrate tpa administration through io without any local or systemic complications. the bioavailability of alteplase through io access has not been studied however it is considered to be close to iv infusion in case of morphine and vasopressors. no studies negate or support the use of intraosseous access in stroke patients. contraindications are few and complications are uncommon. the findings of our case report suggest that intraosseous cannulation may be safely used for fibrinolysis in acute ischemic stroke patients with difficult peripheral venous access in in-hospital or out-of-hospital setting. tufts medical center, boston, massachusetts, usa we report a case of a pregnant patient with bilateral ovarian teratomas who presented with treatment refractory nmda receptor encephalitis despite removal of bilateral teratomas, successfully treated with rituximab. case report and discussion of treatment and outcome. year old weeks pregnant female with known ovarian cysts who presented with one week of confusion and subsequent status epilepticus. she was started on empiric treatment with ivig while undergoing workup. nmda receptor antibody was confirmed. left oophorectomy and right ovarian cystectomy were performed, both of which confirmed ovarian teratoma. she was given high dose steroids. her worsening condition prompted consideration of additional agents. plasma exchange and rituximab were initiated and then she was continued on rituximab alone. she improved dramatically over six weeks and delivered at full term via spontaneous vaginal delivery. at one year follow up, the child was healthy and meeting appropriate milestones. we report the use of rituximab for safe and successful treatment of nmda receptor encephalitis in a gravid female. neovascular glaucoma (nvg) is a known complication of carotid endarterectomy in patients with carotid stenosis. there are no previous reports of acute nvg refractory to medical treatment following carotid artery stenting (cas). we report a patient who needed surgical treatment for acute exacerbation of nvg following cas. a -year-old man with hypertension, diabetes, and hypercholesterolemia presented with recurrent transient weakness in his right hand. fifteen days before presentation, he had experienced acute loss of vision on the left side because of central retinal artery occlusion. magnetic resonance imaging of the brain was unremarkable. conventional angiography showed an occlusion of the left proximal internal carotid artery. ophthalmological evaluation before cas showed neovascularization of the iris and a normal intraocular pressure (iop) of mm hg in the left eye. cas was uneventful, but the following morning, the patient developed pain in the left eyeball with an iop of mm hg. anterior chamber paracentesis followed by intraocular injection of bevacizumab, panretinal photocoagulation, and medical treatment failed to reduce the iop below - mm hg. eighteen days following cas, an ahmed glaucoma valve was implanted in the left eye to treat the refractory nvg. iop decreased to mmhg and his ocular pain resolved completely post implantation. although nvg is a rare complication of cas, it should be suspected in patients who develop acute ocular pain following cas. nvg may respond to anterior chamber paracentesis, panretinal photocoagulation, and bevacizumab, but surgical treatment, such as implantation of an ahmed glaucoma valve, should be considered in cases with refractory nvg. background: cerebral amyloid angiopathy is a common cause of spontaneous lobar intracerebral hemorrhage. convexal subarachnoid hemorrhage can be a manifestation of cerebral amyloid angiopathy. whether focal amyloid burden predicts future hemorrhage is unclear. case: an -year-old man presented with transient left arm weakness and paresthesias in the setting of previous cognitive decline. mri showed a convexal subarachnoid hemorrhage of the right central sulcus, as well as susceptibility weighted imaging findings consistent with superficial siderosis. lumbar puncture revealed normal cell count with a mildly elevated protein. he had spontaneous resolution of his symptoms after several hours. one year later he presented with sudden onset confusion and imaging again showed a convexal subarachnoid hemorrhage over the posterior right frontal lobe. susceptibility weighted mri revealed hemosiderin over the right posterior frontal and anterior parietal lobes. an amyloid-pet, obtained one year prior to his first spell as a research participant, demonstrated asymmetric amyloid deposition in the right temporo-parietal region. years after his initial episode he presented again with confusion, headache, and decreased level of alertness. a ct scan demonstrated a right-sided temporo-parietal intracerebral hemorrhage in the area of asymmetric amyloid deposition on pet. his family opted for comfort measures only, and he was discharged to hospice. autopsy revealed severe amyloid angiopathy, as well as alzheimer disease, braak stage vi. discussion: this case illustrates the clinical course of a patient with amyloid angiopathy, including recurrent convexal subarachnoid hemorrhages, and superficial siderosis. of importance, the amyloid pet scan predicted the location of his intracerebral hemorrhage years later. the case of a -year-old man, presenting with a past medical history of migraine headaches, dipola, vertigo, with symptoms later progressing to lethargy and confusion for days. brain mri revealed a peripherally enhancing mass within the left thalamus with central restricted diffusion, which is consistent with a cerebral abscess. case report of congenital heart disease when discovered in adulthood is an interesting entity, especially when it is the source of brain abscesses. detailed history taking, physical examination and appropriate imaging can usually reveal the anomaly. the diagnosis of brain abscess should promote the clinician to consider right to left shunts as a possible predisposing condition for brain abscess management of acute cerebral embolism in patients with implanted ventricular assist devices (vads) is particularly challenging, since chronic anticoagulation often precludes the use of intravenous tissue plasminogen activator (iv-tpa). we describe a vad patient who suffered cerebral embolization, and was successfully treated with thrombectomy, emphasizing the nuances particular to this clinical scenario in the context of limited historical experience. a year-old man with heart failure (ejection fraction %) and heartware ii vad implantation about months prior, was found at the scene of a car accident with expressive aphasia, right homonymous hemianopia, extinction and right hemiplegia, with a national institutes of health stroke scale (nihss) score of . upon arrival, his ct was unremarkable, but cta revealed occlusion of the left middle cerebral artery (m segment). since his inr was . , he underwent emergent thrombectomy with the solitaire device, resulting in complete revascularization (tici = ) minutes from onset, with rapid deficit resolution (nihss = ). the procedural and clinical success was accompanied by lack of evidence of infarction in subsequent ct studies, and a modified rankin score of upon discharge. the removed thrombus displayed early organization, suggesting unexpected firmness, and underscoring the potential importance of mechanical removal rather than chemical lysis in vad patients. our case has attributes that set it apart from those previously reported: ) the use of a hybrid (i.e. retrieval plus aspiration) endovascular retrieval technique, ) the lack of concurrent use of thrombolytic drugs, and ) the rapid, sustained and optimal clinical improvement. the utilization of vads continues to grow, yet the literature regarding endovascular techniques for managing these types of patients remain scarce. however, the increasing availability of centers capable of delivering this type of treatment, suggests that thrombectomy should be strongly considered in vad patients with acute cerebral embolism. extreme cerebral oxygen changes has not been reported via monitoring of partial brain tissue oxygen levels. here we present an asah patient with brain tissue oxygen (pbto ) monitoring, who developed cerebral hypoxia due to cerebral vasospasm, then went on to develop cerebral hyperoxia with associated cerebral infarction. methods yo female with hh fg sah with initial gcs of t underwent coiling of a ruptured basilar tip aneurysm. a pbto monitor was inserted to guide therapy. this patient had multiple episodes of low pbto ( mmhg). this corresponded to infarction on follow up head ct and mri with preservation of local arterial vessels on mra, consistent with diagnosis of dci. in the present case, high pbto is more likely resulted from a combined effect of ) increased cbf from co-administration of ketamine at the time of milrinone infusion; ) decreased cerebral metabolic demands in already infarcted left frontal lobe, resulting in reduced oxygen uptake; ) accelerated reperfusion and thus hyperemia with milrinone. restoration of flow with milrinone may have been too late to reverse the prolonged period of vasospasm induced ischemia, resulting in perfusion of infarcted tissue, or luxury perfusion. clinicians utilizing pbto monitoring for dci management should be cautious of high pbto values, as it may herald cerebral infarction. further studies are needed to better elucidate the mechanism of reperfusion injury and potential treatments. patients with acute brain injury, especially those with intracranial hemorrhages are at a higher risk for hemorrhage while on therapeutic anticoagulation. unfractionated heparin (ufh) is frequently used as it is easily reversible and has a short half-life. activated partial thromboplastin time (aptt) is traditionally used to monitor its effect. several disadvantages with aptt monitoring include inability to reach therapeutic goal, over-or under-dosing and its associated complications. anti-xa level is reported to have better correlation with actual degree of anticoagulation using ufh. retrospective chart review of patients with acute brain injury who required initiation of early therapeutic anticoagulation and monitored with anti-xa level. case - year-old-man with intracerebral hemorrhage (ich) developed lower extremity deep vein thrombosis (dvt) and required therapeutic anticoagulation. patient became therapeutic within six hours of titrating infusion based of anti-xa levels and remained therapeutic. asymptomatic rectal bleeding associated with fecal management system was noted. case - year-old-man with cerebral venous sinus thrombosis presented required therapeutic anticoagulation. ufh infusion was initially monitored using aptt levels which had widely varied lab results, thus monitoring was switched to anti-xa levels which provided a more consistent therapeutic range. however, patient developed thrombocytopenia in the setting of inflammatory bowel disease. therefore, ufh infusion was changed to argatroban infusion. case - year-old-man with lower medullary acute ischemic stroke due vertebral artery dissection required therapeutic anticoagulation to prevent recurrence. patient became therapeutic within hours of titrating based of anti-xa levels. to monitor therapeutic anticoagulation, anti-xa level appears to achieve target anticoagulation level faster and without serial variation as compared to aptt. however, anti-xa level estimation is costlier as compared to aptt and not widely available. by restricting it to special populations like those with acute brain injury might justify its use and underscore cost-effectiveness. neurological admissions presenting to the icu benefit from a dedicated neurocritical care team but many community hospitals lack this subspecialty expertise. with an aging population and a neurointensivist shortage, more patients are transferred to designated neurocritical care units which increases healthcare spending and resource utilization. recognizing this obstacle, we describe the management of a patient in status epilepticus via our novel "eneuro-icu" consult program in which a 'sub-hub' of the northwell health tele-icu was set up at the only hospital out of in our health system that is staffed / by neurointensivists. a -year-old man with history of a left frontal meningioma presented with multiple seizures to a hospital within our healthcare system. he received mg of lorazepam and levetiracitam in the emergency department and was admitted to the icu for further monitoring. there he was witnessed to have recurrence of clinical activity concerning for ongoing seizure. levetiracitam was increased and phenytoin was added. neither immediate neurological consult nor continuous eeg was available, thus an "eneuro-icu" consult was obtained. in this model, the bedside provider contacts the tele-icu that facilitates a conference call with the neurointensivist. av technology was used to provide consultations and follow ups. the neurointensivist determined the patient was rapidly returning to baseline and recommended a head ct, lab studies and continuation of the anti-epileptic drugs. the eicu team monitored the patient overnight. by leveraging the infrastructure in place for management of critically ill patients remotely, an additional level of subspecialty care was offered in a timely manner and allowed the patient to remain at their local facility. based on the success of the initial program we are currently in the process of extending the virtual consult service to various community hospitals' eds/icus to improve outcomes for patients who would benefit from neurocritical care services. hypoglycemic encephalopathy is a potentially life-threatening manifestation of hypoglycemia, it is usually caused by metabolic change, hypoglycemic agents, and malignancy. here, we report a patient with hypoglycemic encephalopathy caused by sleeve gastrectomy a -year-old woman was admitted due to unconsciousness of acute onset. she showed normal corneal and vestibulo-ocular reflex but sluggish pupil light reflex and decerebrated posture by painful stimulation. she has taken severe medications for weight control including orthosiphon powder and hydrochlorothiazide after bariatric surgery. laboratory studies showed significantly low blood glucose level ( mg/dl) with normal liver enzyme and creatinine. there was no evidence of adrenal insufficiency. electroencephalography showed no epileptiform discharge. initial and follow-up brain magnetic resonance imaging revealed diffuse high signal intensity on white matter expanded to cortex, corpus callosum and posterior limb of the left internal capsule, suggesting hypoglycemic encephalopathy. in abdomen-pelvic ct, there is no mass lesion like carcinomas or insulinoma. the clinical diagnosis of hypoglycemic encephalopathy followed by sleeve gastrectomy was made by given history of bariatric surgery and the lack of evidence of hypoglycemic agent overdose, adrenal insufficiency, endogenous hyperinsulinism or malignancy. there are several hypotheses that sleeve gastrectomy can encourage hypertrophy of beta cells, hypersecretion of glucagon-like peptide, glucagon abnormality and increased insulin sensitivity, that may induce hypoglycemia. we suggest that clinicians should consider sleeve gastrectomy itself as a possible cause of profound hypoglycemia pulmonary embolism (pe) is a fatal complication in neurological conditions with plegic extremities. clinical presentations and supportive testing can be variable. we present a case of pe which presented with st segment elevations weeks after spontaneous intracerebral hemorrhage (sich). case report and review of the literature we present a case of a year old female with a history of a recent sich with resultant left hemiplegia who presented with a syncopal episode and chest pain. on physical examination, she was noted to be tachypneic and tachycardic with an unchanged neurological exam. pulmonary embolism can present with a variety of ekg abnormalities including st elevations after sich and the treating physician should be aware of these idiosyncrasies. anticoagulation should be cautiously initiated in such cases. infectious intracranial aneurysms (iia) are rare neurovascular lesions associated with infective endocarditis. we present a case of a large iia which developed within hours of a negative ct angiogram and ruptured despite weeks of appropriate antibiotic treatment. a year-old woman presented with fevers and malaise. her initial workup revealed an aortic valve mass and blood cultures grew out streptococcus. three days after intravenous penicillin therapy was initiated for bacterial endocarditis, she developed a new headache and right hemianopsia. a head ct demonstrated a left occipital lobe stroke with hemorrhagic transformation. further workup with ct angiography revealed a mm outpouching along of the distal branch of the left pca, consistent with an infectious intracranial aneurysm. on repeat imaging, this aneurysm demonstrated growth despite medical treatment, and required coil embolization/occlusion. aortic valve replacement was planned after weeks of antibiotic therapy because of continued severe aortic insufficiency and persistent valve vegetation. on the day of surgery, she developed acute word-finding difficulty followed by a rapid neurologic deterioration resulting in coma. a head ct demonstrated a new left frontal intraparenchymal and subarachnoid hemorrhage associated with the rupture of an mm x mm irregularly shaped aneurysm in the region of the left mca bifurcation, which had been absent on a prior surveillance ct angiography just hours prior. she underwent emergent coil embolization, extraventricular drain placement, and decompressive hemicraniectomy. despite these measures, her exam did not improve. she was transitioned to comfort measures and life-sustaining therapies were withdrawn. the development of iia can occur despite appropriate medical treatment. these aneurysms may rapidly expand and rupture within hours, as shown by our case. even with prior exonerating imaging, clinicians should have a high suspicion for iia development in all infective endocarditis patients. the corneomandibular reflex, also known as wartenburg reflex or von solder phenomenon, is a rare pathological reflex signifying severe supranuclear trigeminal injury. it presents as contralateral jaw deviation to corneal stimulation. etiologies include upper brainstem lesions, large hemispheric lesions with brainstem compression, as well as advanced amyotrophic lateral sclerosis and multiple sclerosis when corticobulbar pathways are affected. this clinical finding is useful in differentiating structural and metabolic causes of coma, as this examination finding would not be present in metabolic phenomena. a middle aged man presents with a hypertensive right thalamic hemorrhage and a four score of e m b r . the patient's cornea was stimulated with a cotton swab. the cornea was tested bilaterally to determine any lateralizing features. recording on video was performed with patient's family written consent as patient was comatose. upon stimulation of the patient's cornea a contralateral jaw jerk was appreciated. this was replicated contralaterally. this case describes a common patient with a rare physical examination finding. there is utility in recognizing this finding as it will aid in determination of the underlying cause of a comatose state. the corneomandibular reflex present at presentation rules out a metabolic cause. a structural cause was validated by imaging studies (shown). the reflex arc was researched and has been independently artistically rendered (shown), which demonstrates the pathway beginning with the afferent limb of the corneal stimulus (v ) which travels to the main trigeminal sensory nucleus via the trigeminal ganglion. severe supranuclear trigeminal lesions will inhibit inhibitory interneurons within the mesencephalic nucleus, leading to activation of the motor nucleus of the trigeminal nerve. this causes activation of the ipsilateral external pterygoid muscle which produces a contralateral jaw jerk. overall this patient fared poorly and expired several days after admission. pneumocephalus is when air enters and is contained inside the intracranial compartment. when intracranial pressure increases causing neurological decline, patients can experience nausea, vomiting, seizures, dizziness, and altered mental status. here we present three cases of postoperative pneumocephalus which resolved quickly with humidified oxygen delivery via high-flow nasal cannula. we follow the cases with a review of the mechanisms and pathophysiology of pneumocephalus and its treatment, as well as future directions in management. case series of patients with post-operative pneumocephalus who were treated with high-flow nasal cannula. case describes a -year-old woman who underwent hemicraniotomy for removal of meningiomas, with focal postoperative neurological signs and mm of midline shift on head ct due to pneumocephalus. case describes a -year-old woman who underwent right anterior temporal lobectomy for seizures, who developed postoperative focal prefrontal lobe signs and mount fuji sign on head ct. case describes a -year-old man with bilateral subdural hematomas, status post bilateral burr hole evacuation. he was excessively somnalent postoperatively with bilateral pneumocephalus. with high-flow nasal cannula, they all returned to clinical, and near radiographic baseline within , , and hours, respectively. recognizing the limitations of a small case series, we believe these cases support use of high-flow nasal cannula when treating patients with symptomatic pneumocephalus. thsee patients showed more rapid clinical and radiographic improvement after implementation of hfnc oxygen therapy than previously described using other methods. high-flow nasal cannula may help washout nitrogen from the lungs, allowing a downward gradient from the nitrogen in the intracranial air bubble out the lungs. in addition, high-flow nasal cannula is more comfortable for the patient, allowing for more consistent treatment. randomized studies are needed to confirm our findings. the neurotoxin produced by clostridium botulinum is the most lethal toxin known by weight. early recognition and treatment of botulism are crucial for full recovery. we present a case of progressive paralysis secondary to botulism toxemia following a gunshot wound (gsw). a -year-old man suffered a gsw to the right lower extremity. he was treated in the emergency department where the wound was irrigated and closed. some bullet fragments could not be retrieved due to close proximity to popliteal vessels and surrounding nerves. he returned ten days later with diplopia and nausea. he denied consumption of canned foods or illicit substances and had no preceding upper respiratory or gastrointestinal illnesses. on examination, he exhibited ptosis and symmetric bilateral motor weakness with diminished deep tendon reflexes. the gsw showed no signs of infection. progressive respiratory insufficiency resulted in intubation and mechanical ventilation. a lumbar puncture revealed normal opening pressures and cerebrospinal fluid analysis was unremarkable. titers for acetylcholine receptor and anti-muscle specific kinase antibodies were negative, as was a tensilon test. blood toxicology analysis showed no evidence of illicit substances or heavy metal poisoning. a high suspicion for wound botulism led to consultation with the regional poison center and cdc. blood and anaerobic wound samples were obtained for toxin bioassay and culture. empiric intravenous penicillin g therapy was started. equine heptavalent antitoxin (h-bat) was obtained and administered on hospital day . serum toxin bioassay tested positive for botulinum neurotoxin type a. the patient required a gastrostomy tube due to persistent dysphagia. after one month of hospitalization, he was discharged home and continues outpatient physical therapy. wound botulism from traumatic injury is exceedingly rare with only one to two cases reported annually. our case is the first reported incidence of wound botulism from a single gunshot wound. hyperammonemic cerebral edema (hce) with brain herniation carries a dismal prognosis historically despite aggressive treatment. however, we report a case where a patient with severe hce and herniation returned to her neurological baseline after aggressive medical management. a -year-old woman became acutely comatose with a blown left pupil and required intubation several days after admission for encephalopathy. head ct demonstrated diffuse cerebral edema with central and bilateral uncal herniation. profound hyperammonemia ( ug/dl) was implicated, though hepatic function was normal. her intracranial hypertension was ultimately controlled using hyperventilation, sedation, and osmotherapy, resulting normalization of her brainstem reflexes and improvement in her coma and imaging. continuous veno-venous hemodialysis (cvvhd) normalized her ammonia and encephalopathy that was initially refractory. multiple porto-hepatic shunts were identified on hepatic ct angiogram as the cause of her hyperammonemia, and were embolized. she was eventually weaned off cvvhd and extubated, without residual neurological deficits. our case demonstrates that, with contemporary management, clinical and radiographic reversal of hce and herniation is possible and prognosis is not uniformly poor. therefore, neurological prognostication in these patients should only be performed after assessing the clinical trajectory following cerebral resuscitation and ammonia reduction. furthermore, our case provides an example of how cvvhd can be used to reduce refractory hyperammonemia quickly until the cause of the hyperammonemia can be ascertained and addressed. finally, this is the first case reported of hce secondary to primary portosystemic shunt in absence of hepatic disorder; vascular imaging of the liver should be considered in the work-up of patients with hyperammonemia. a good neurological prognosis is possible for patients with hce and cerebral herniation with aggressive management that includes reduction of icp and ammonia. ccvhd is a useful adjunct to treat refractory hyperammonemia. a porto-systemic shunt should be considered as an etiology for hyperammonemia. cerebral venous sinus thrombosis (cvst) often presents with intracerebral hemorrhage and seizures. extensive involvement of the cerebral sinuses can lead to comatose state due to cerebral edema and associated intracranial hypertension. if not reversed with early therapeutic anticoagulation, then mechanical thrombectomy and decompressive hemicraniectomy (dhc) may be necessary as life-saving measures. however, etiological diagnosis of associated hypercoagulable state is needed for successful long-term treatment. case report of a patient presenting with cvst requiring anticoagulation, dhc and total colectomy (to treat underlying ulcerative colitis) as treatment with full anticoagulation was associated with lifethreatening hematochezia. twenty-five year old man with one week history of diarrhea presented with left sided weakness. imaging studies confirmed extensive cvst with minimal venous drainage through bilateral cavernous sinuses as well as right hemiparesis secondary to left post cingulate intracranial hemorrhage. patient subsequently developed loss of vision and became encephalopathic, despite initiation of anticoagulation with heparin. hence, mechanical thrombectomy was attempted but was unsuccessful. he also developed consumptive thrombocytopenia for which his anticoagulation was switched to argatroban. progressive neurologic deterioration necessitated dhc. his neurological examination progressively improved upon re-initiation of anticoagulation resulting in restoration of vision and resolution of left hemiparesis. later in the disease course, he developed symptomatic hematochezia associated with his primary disease, ulcerative colitis and required total colectomy. subsequently he was transitioned to oral anticoagulation and transferred to inpatient rehabilitation facility due to deconditioning from prolonged hospitalization. cvst can be life-threatening unless early treatment is initiated. appropriate and timely treatment including etiological diagnosis can lead to favorable patient outcomes. adverse effects of intrathecal non-ionic contrast during myelography are rare but can include seizures and encephalopathy. to our knowledge, cerebral edema has only been reported in the literature in two previous cases. we report a case of malignant cerebral edema following intrathecal administration of non-ionic contrast who developed seizure like activity with radiographic evidence on a head computerized tomography (ct) scan of acute diffuse cerebral edema. an year-old male underwent an elective spinal ct myelogram using mm of isovue m non-ionic contrast to evaluate chronic lumbar pain related to spinal stenosis. no complications were reported intra-procedurally and the patient was discharged home. the patient began to complain of progressive worsening headaches. the following morning he started complaining of nausea/vomiting, lost consciousness with posturing vs seizure like activity. a head ct revealed extensive brain edema and swelling with crowding of the brainstem and herniation ( fig. ). this patient was intubated and given an iv mannitol, . % hypertonic saline followed by an infusion of % hypertonic saline infusion. serial cts revealed complete resolution of his cerebral edema hours after admission ( fig. and ) . the patient's mental status improved, was extubated, and then was discharged home days after admission. while significant adverse effects of non-ionic contrast following spinal myelography are rare, the potential life threatening severity of these incidents warrants further patient education following this routine outpatient procedure. we recommend close neurological monitoring after intrathecal administration of contrast media. patients should be provided with detailed instructions about the potential side effects of non-ionic contrast and how to seek medical attention if symptoms of cerebral edema are noted post procedurally. a large acute traumatic subdural hematoma with brain compression and midline shift is typically considered a neurological emergency necessitation surgery. spontaneous resolution of a large subdural hematoma is considered a rare phenomenon with a few case reported in the literature. to our knowledge, we present the first case of spontaneous resolution of a traumatic acute subdural hematoma with brain compression and midline shift on dual antiplatelet therapy. a year-old patient initially presented after being found down and unresponsive in his home. the patient was on aspirin and clopidigrel. he was found to have altered mental status, wasn't following commands, and had a glascow come scale score of < . the patient's initial head ct revealed a large left acute subdural hematoma (sdh) measuring . cm in diameter. neurosurgery was consulted upon arrival for possible emergent evacuation. the patient's repeat head ct showed a decreased sdh to . cm in diameter. given the rapidly resolving sdh, surgery was postponed. another repeat head ct the following day revealed a decrease in size of the sdh to mm in diameter. several theories have been proposed for the rapid resolution of an acute sdh including csf leaking into the sdh through a tear in the arachnoid membrane with rapid reabsorption, redistribution of the hematoma in the subdural space, and acute fluctuations in icp driving the spontaneous resolution of the sdh. close neurological and repeat imaging may be helpful in managing these patients. as seen in our patient and others, a low density band in the subdural hematoma may indicate csf and be a predictor for spontaneous resolution of an acute sdh. the features of this atypical case offer points of discussion regarding the surgical or non-surgical approach of these patients. early post-hypoxic myoclonus -or myoclonic status epilepticus -develops within hours of the initial anoxic injury and is associated with poor outcomes per current aan practice guidelines. late posthypoxic myoclonus -or lance-adams syndrome -develops > hours after the anoxic injury, consciousness is regained, and is associated with relatively good outcomes. the patient is a yo man with a history of alcohol and cannabis use disorder, bipolar disorder, pnes who presented after attempted hanging for up to minutes. intial rhythm was pea; he had rounds of cpr, received mg epinephrine, and was intubated prior to rosc. myoclonic jerks were noted within hours post arrest. hypothermia protocol was initiated as gcs was t. ct head showed subtle loss of grey-white differentiation. eeg initially showed that his generalized myoclonic jerks correlated with cortical activity. he was started on versed gtt, keppra, vpa with improvement in the frequency of jerks. on post-arrest day , mri brain showed mild cerebellar edema. mri c-spine was negative for significant myelopathy, arguing against myoclonus as a spinal reflex. mentation gradually improved; on post-arrest day he opened his eyes to command. eeg evolved to show gpeds and sirpids and oxc and tpm were added. on post-arrest day a paralytic challenge resolved electrographic spikes, suggesting subcortical origin of myoclonus. he continued to improve cognitively, but despite clonazepam, vpa, home oxc he continues to have severe intention myoclonus. despite the presumed poor prognosis, the patient's family pursued aggressive measures and his mentation gradually improved. early post-hypoxic myoclonus carries a poor prognosis, however, in this case, the patient survived with a good cognitive outcome likely owing to his age and relatively few comorbidities. further studies are needed to differentiate early-onset lance-adams from myoclonic status since prognosis differs greatly. posterior reversible encephalopathy syndrome (pres) can occur from multiple etiologies and often presents with rapid-onset headache, altered consciousness, seizures and/or visual disturbances. vasogenic edema involving predominantly cerebral white matter is a key finding on imaging studies. although seizures are a frequent presenting symptom of pres, refractory status epilepticus (rse) requiring multiple antiepileptic medications is very rare. a case report of a patient presenting with pres and clinical course complicated with rse necessitating use of intravenous anesthesia, ketamine, and newly-available brivaracetam. -year-old woman with history of congestive heart failure, chronic iron deficiency anemia and uncontrolled hypertension was admitted for severe encephalopathy and convulsive status epilepticus (cse) for longer than minutes necessitating propofol and midazolam infusions. her admission systolic blood pressures were in the s, and mri brain revealed bilateral parieto-occipital t /flair hyperintensities consistent with pres. despite adequate control of hypertension following admission, patient remained encephalopathic and continuous electroencephalography (eeg) demonstrated nonconvulsive status epilepticus (ncse). the patient's ncse continued despite use of maintenance antiepileptics (fosphenytoin, lacosamide, levetiracetam) and high-dose infusions of midazolam and propofol. ketamine infusion was started to maximize nmda receptor blocking properties, and burstsuppression pattern on eeg was easily achieved with bolus infusions followed by continuous infusion. addition of brivaracetam was used to replace levetiracetam and allowed patient to remain seizure-free when iv anesthetics were weaned off. patient required prolonged hospitalization with gastrostomy tube placement and tracheostomy, which was later decannulated prior to patient's discharge to home with family. high index of suspicion is necessary to identify patients in ncse with prolonged encephalopathy that have pres. early use of ketamine along with a benzodiazepine may result in rapid achievement of burstsuppression to treat se. brivaracetam may be a useful agent to treat rse. diagnosis of diabetes insipidus(di) includes polyuria, hypernatremia and low urine specific gravity. we present two patients, receiving hyperosmolar therapy for intracranial hypertension (iht), in whom using low urine specific gravity to diagnose di lead to delayed treatment. this is a retrospective case series. criteria used to diagnose di at our institution include polyuria, sodium < mosm/kg and urine to plasma osmolality ratio < . case : -year-old male with subdural hematoma, iht on hyperosmolar therapy, developed polyuria. sodium rose from to meq/l. urine specific gravity was . excluding di. eventually, sodium rose to meq/l. specific gravity remained . but urine osmolality was mosm/kg and urine/plasma osmolality ratio was . , consistent with di. vasopressin was initiated, however the patient had already developed lactic acidosis and renal failure due to hypovolemia. case : -year-old female with intracerebral hemorrhage and iht on hyperosmolar therapy, developed polyuria. sodium rose to meq/l, specific gravity remained > . but urine osmolality was mosm/kg and urine/plasma osmolality ratio was . consistent with di. vasopressin was initiated. hyperosmolar therapy increases urine osmoles and raises urine specific gravity. this interferes with diagnosis of di which requires low urine specific gravity. while specific gravity measures the weight of particles, osmolality measures particles independent of their weight and thus accurately measures urine tonicity in the presence of heavy particles like mannitol. moreover, urine/plasma osmolality ratio is able to demonstrate relative hyposmolarity of urine when compared to serum assisting with diagnosis of di even when urine specific gravity is elevated. we conclude that urine specific gravity does not reliably detect di in patients receiving hyperosmolar therapy. urine osmolality and urine/plasma osmolality ratio may detect di earlier and prevent dehydration and kidney injury. these findings should be validated prospectively. endovascular intervention in the treatment of cvt(cerebral venous thrombosis) is an alternative strategy when cases deteriorate despite best medical management or develop refractory intracranialhypertension. we present a patient with cvt due to heparin-induced thrombocytopenia(hit), with intraparenchymal hemorrhage(iph) and refractory intracranial-hypertension, who was managed with systemic anticoagulation, continuous intra-sinus infusion of rtpa and mechanical thrombectomy(mt) resulting in excellent outcome. case report: a -year-old woman with left parafalcine meningioma s/p cyberknife was started on subcutaneous heparin for radiation necrosis days prior to admission. she presented to the hospital with new onset headaches and nausea. ct head showed increased edema with mid-line shift around the meningioma, for which steroids were started. within days her headaches worsened and repeat imaging demonstrated right temporal iph. emergent hematoma evacuation was performed. mri brain showed right cerebellar infarct and mra head showed extensive cavernous sinus thromboses, from right internal jugular vein and into sigmoid and transverse venous sinuses. she tested positive for hit and was switched to argatroban drip. patient however continued to deteriorate due to refractory intracranial-hypertension. intra-cavernous rtpa injection and mt was done but the thrombosis was noted to recur on repeat angiogram hrs later. an intra-sinus catheter was left in place for continuous infusion of rtpa at mg/hr. for hrs was done while argatroban drip was continued. the patient's intracranial pressure returned to normal. repeat venogram showed resolution of cvt. patient tolerated the therapies well, without any further hemorrhagic complications. modified rankin score at month follow-up was . this case features successful aggressive endovascular interventions including in-situ rtpa infusion, mt and concomitant systemic anticoagulation for cvt due to hit, complicated by intracranial hemorrhage and refractory intracranial hypertension. the paucity of high quality evidence related to safety, efficacy and modality of endovascular treatment lead to making therapeutic decision on individual basis. acute brain injury may be followed by encephalopathy marked by electroencephalographic features along the ictal-interictal continuum (iic). the use of perfusion imaging to co-localize radiographic features of known malignant eeg patterns may add an important context to guide treatment escalation or de-escalation. this is only the second report in which widely available ct or mr perfusion techniques were favored for this application over more cumbersome metabolic imaging such as pet. retrospective analysis was performed on records for patients admitted to a neurosciences icu, exhibiting encephalopathy, with eeg features on the iic, who underwent perfusion imaging. studies included ct perfusion, mr perfusion, arterial spin labeling, or spect. these studies were obtained for unrelated purposes. escalation or de-escalation of anti-convulsant and sedative medication, hospital course, and patient outcomes were extracted. perfusion imaging data was juxtaposed with eeg patterns along the iic, and patient outcomes are described in narrative form. seven cases were identified. four cases occurred in the context of intraparenchymal hemorrhage, of which one was secondary to meningioma resection. two cases occurred after treatment for subdural hematoma, and one case was related to ischemic stroke. anti-convulsant and sedative management was escalated or de-escalated relative to the presence or absence of radiographic co-localization of hyperperfusion in all but one case. emerging data indicates that some iic eeg patterns may merit aggressive treatment. metabolic signatures of secondary brain injury as measured by cerebro-oximetry or microdialysis have associated these patterns with unfavorable outcomes. we report case studies in which information gleaned from basic perfusion imaging may suffice to distinguish between benign iic patterns and those that should be regarded as near-ictal. the cases hint at novel ways to conceptualize treatment of encephalopathy following acute brain injury and suggest a dimensional shift in thinking towards electroperfusive status epilepticus. sudep has classically been a diagnosis of exclusion. recent studies have shown, however, that similar genes -and even genes within the same family -are associated with sudep and brugada. this suggests that perhaps the cardiac irritability of brugada syndrome exists on a spectrum with epileptic sudden death. a yo man with a history of presumed seizure disorder presented as a transfer from another hospital after being found to have anoxic brain injury following cardiac arrest. he had been shopping with his wife when he was thought to have one of his typical seizures. he was non-responsive for about minutes. on arrival ems found him pulseless. cpr was started en route and continued for minutes in the ed where he was defibrillated three times before achieving rosc. he completed the therapeutic hypothermia protocol. cardiac catheterization was clean. eeg showed diffuse slowing with no epileptiform discharges. imaging showed diffuse anoxic brain injury. after nearly two weeks without clinical improvement he was made comfort care. . of note, previous seizure workup failed to identify epileptiform activity. he was given an aed prescription which he never filled. further chart review showed that he had previously presented to the ed after a "seizure" episode which lasted minutes. his neuroexam was non-focal. ct head was negative. review of his ekg at that time showed type brugada syndrome pattern with an elevated jpoint and t-wave inversions in v and v . his sudden cardiac arrest is most likely a result of symptomatic brugada symptomatic brugada is important to identify early since deaths such as the one discussed above may be prevented by an implanted defibrillator. this case highlights the need for heightened awareness and more effective testing for brugada in the setting of seizure or pseudoseizure. patients with cerebral air embolism (cae) often exhibit more severe symptoms than those typically associated with the number of air emboli and size of infarcts on brain images. however, this discrepancy between symptoms and imaging findings has not been sufficiently explained. we report a case of cae in which disruption of the blood-brain barrier (bbb) and perfusion defects were identified via brain magnetic resonance imaging (mri). a -year old man with a lung mass was admitted to our hospital. percutaneous needle aspiration of the mass was performed in the left lower lobe of the lung. the patient developed sudden confusion and irritability after the procedure. during neurological examination, he could follow only simple commands and exhibited symptoms of left-sided weakness and neglect (medical research council grade ). noncontrast computed tomography (ct) of the brain revealed a few small air emboli in the right frontal subcortical area. multimodal mri of the brain was performed minutes after the onset of symptoms. t -weighted gradient-echo imaging revealed only a few small air emboli in the right frontal area, and diffusion-weighted imaging findings were unremarkable. in contrast, time-to-peak imaging revealed widely distributed perfusion defects in the right hemisphere, while contrast-enhanced t -weighted imaging revealed prominent leptomeningeal enhancement, suggestive of bbb disruption in the right hemisphere. magnetic resonance angiography revealed no steno-occlusive lesions. the patient was treated with % oxygen via a high-flow nasal cannula. his weakness subsided the next day, although his confusion persisted for days. follow-up mri performed five days after the onset of symptoms revealed resolution of the abnormal findings. our findings suggest that disruption of bbb and perfusion defects may develop in patients with cae. extensive impairments of the bbb and perfusion may explain the mismatch between severe neurological symptoms and small air emboli/infarcts. co-existence of cerebral salt wasting and diabetes insipidus is an extremely rare entity that has only been described in adult case series and a paediatric series. due to the complex nature of diagnosing this entity, mistreatment may ensue and lead to high morbidity and mortality rates. we report a case of a patient who was admitted to the neurosurgical intensive care unit after sustaining a subarachnoid haemorrhage secondary to a ruptured anterior communicating artery aneurysm. a -year old lady presented with sudden onset of severe headache and nausea. gcs was (e v m ) with no focal neurological deficits. she underwent endovascular coiling and embolisation of the aneurysm under general anaesthesia and had a left external ventricular drain inserted. in the immediate postoperative period, she was found to be polyuric, with the initial workup suggestive of diabetes insipidus. desmopressin was administered with initial good effect. however, her polyuria recurred and persisted despite desmopressin. the repeat workup revealed the presence of concomitant cerebral saltwasting. she was then treated with fludrocortisone and sodium chloride supplementation. careful monitoring of her serum sodium levels and overall fluid balance allowed close titration of the desmopressin, fludrocortisone and sodium chloride supplementation. she was eventually weaned off treatment and discharged well with normal sodium levels and with no neurological deficits. this case highlights the difficulty encountered in managing concomitant cerebral salt wasting and diabetes insipidus in critically ill neurosurgical patients and the need to for a high index of clinical suspicion, early intervention and close monitoring. levetiracetam is a commonly used antiepileptic drug (aed) used to treat epilepsy. this agent was approved by the fda in , is available in oral and intravenous formulations, and offers advantageous pharmacokinetics, minimal drug interactions, and a favorable side effect profile. the purpose of this case report is to describe a case of severe, asymptomatic rhabdomyolysis exacerbated by levetiracetam administration. the medical record was reviewed and data was collected to describe a case with a pertinent review of the literature. a -year-old african-american male with a history of hypertension presented to the emergency department following a tonic-clonic seizure. baseline labs were drawn and revealed a ck level of , iu/l, negative urine myoglobin and normal renal function. levetiracetam therapy was initiated and no further seizures were noted. the patient's ck continued to trend up throughout his stay despite aggressive fluid resuscitation with a positive myoglobin on hospital day . the ck reached a peak of , iu/l on hospital day . after a literature review and evaluation of his medication list, six casereports were identified linking elevated ck and rhabdomyolysis to levetiracetam administration. at that time levetiracetam was discontinued and the ck rapidly declined to , iu/l on hospital day . the patient never had muscle pain or kidney injury and was discharged on hospital day . this case-report describes rhabdomyolysis associated with levetiracetam administration with a naranjo probability scale score of indicating a probable adverse drug reaction. the adverse effects of generalized pain and neck pain are described in the package insert with an incidence of - %; however, it is not reported that ck levels were monitored. due to the frequent use of this aed and given the rare yet serious adverse effect of rhabdomyolysis, ck levels should be monitored upon initiation. acute toxic leukoencephalopathy (atl) is a potentially reversible disturbance to white matter caused by exposure to toxins. we report the first case of a patient with atl in the setting of a fentanyl overdose and reviewed the literature. a year-old man with a history of opiate abuse was found unconscious, last seen well nine hours prior. he was known to have purchased mg of fentanyl that day. he was intubated and briefly required blood pressure support. he was initially hypoglycemic and suffered fulminant liver damage, acute kidney injury, rhabdomyolysis, and stunned myocardium. comprehensive toxicology screen was positive for cannabis and fentanyl. mri of the brain showed pronounced bilateral restricted diffusion in the high frontoparietal subcortical white matter with radiographic stability five days later. he remained intubated and neurologic exam poor with fluctuating brainstem reflexes and posturing despite improvement in end-organ function. atl has been reported in a -month-old girl and an -year-old man with exposure to transdermal fentanyl, both of whom had favorable outcomes ( , ). one case has been reported following oral oxycodone ingestion ( ). of cases of atl secondary to inhaled heroin, % were fatal ( ). preferential white matter injury has been seen in cases of hypoxic ischemic encephalopathy (hie) ( , ). it was initially thought to be secondary to wallerian degeneration following grey matter damage, but post-mortem pathology has shown direct insult to axons ( ). atl has been reported in one case of hypoglycemic coma ( ) and one case of uremia ( ). it has never been reported in isolated hepatic encephalopathy, secondary to seizure, or with cannabis use alone. based on our review of the literature, the most likely causes of this patient's atl are fentanyl or hie. fentanyl should remain on the differential as a previously unreported cause of atl. autonomic dysregulation is a common complication of acute spinal cord injury (sci). subsequent hypotension may worsen central nervous system injury as well as neurologic and mortality outcomes. to help mitigate this occurrence, consensus guidelines recommend maintaining patients' mean arterial pressure (map) > mmhg within the first seven days based on evidence from limited clinical trials. limited data exists describing the use of midodrine, an alpha- agonist and the previously only available enteral vasopressor, for blood pressure (bp) augmentation in this setting. the use of midodrine is limited by cardiovascular side effects such as bradycardia. droxidopa, a novel enteral precursor of norepinephrine that works independently of the central nervous system, may serve a role in sustaining map in acute sci. we describe a novel case of droxidopa use in a -year old male who sustained a spinal cord contusion secondary to severe stenosis at the fourth cervical vertebrae following a ten-foot fall. droxidopa was used to facilitate vasopressor wean in the setting of neurogenic shock as a complication of acute spinal cord injury. to sustain adequate cns perfusion (map goal > - mmhg) and facilitate patient transfer to a lower level of care, droxidopa mg three times daily was initiated after five days of continuous infusion of intravenous norepinephrine. daily assessments of hemodynamic parameters were performed, including blood pressure, heart rate, map, and an electrocardiogram. successful wean of norepinephrine was achieved within hours of droxidopa initiation, with an average map sustained above mmhg. the patient was transferred to a lower level of care within hours of droxidopa initiation. no cardiovascular side effects were observed. droxidopa was well tolerated and facilitated transition from norepinephrine infusion to an enteral option. droxidopa may be a viable option in stable neurocritical care patients who require vasopressors to sustain adequate cns perfusion. traumatic brain injury is acute and sometimes rapidly aggravated during or after surgical treatment. imaging study is most important and computed tomography (ct) is the golden standard in tbi. however the patient should be transfer to ct room or relatively high cost mobile ct scanner may be used. ultrasound is not expensive and also does not produce radiation exposure. we studied the effectiveness and advantages of intra-operative ultrasound examination in traumatic brain injury patients intra-operative ultrasound was used after decompression of injured brain from june to april . the ultrasound device was the affiniti (philips ultrasound inc, usa) and . mhz transducer was used. the transducer was covered by thin transparent sterilized vinyl with ultrasonic gel with aseptic manner. to protect brain injury by the ultrasonic probe, a saline soaked gauze was applied on the cerebral cortex. the axial images were captured and then stored in pacs system promptly. ultrasound images were compared to postoperative ct scan. there were male and female patients were examined by ultrasound during there surgery. ipsilateral hemisphere, especially cortical layer was slightly distorted to identification. brain stem area was visible in most cases. contralateral hemisphere was seen in unilateral craniotomy and craniectomy cases. in bilateral craniectomy cases, both hemispheres were observed well. parenchymal hemorrhage was also identified and confirmed for removal using ultrasound. in severe brain swelling cases, arachnoid space was seen increased echogenicity. ultrasound image was compared to postoperative ct scan. intra-operative ultrasound is effective in real time inspection of brain during surgery and may helpful detect opposite or parenchymal hemorrhage before closure and leaving operation room. to describe a rare case of a varicella zoster virus (vzv) meningitis with progressive multiple cranial nerve deficits in the absence of cutaneous zoster rash. a young woman with idiopathic thrombocytopenic pupura on steroids presents with horizontal diplopia in the setting of seven days of intractable headache. she had no meningeal signs, fever, leukocytosis or cutaneous rash. within three days into hospitalization, she developed bilateral cn vi, cn iii, right cn v and right cn vii palsies in a progressive fashion. csf analysis revealed cell count of , /mm , a protein of mg/dl and glucose mg/dl. cytology, tuberculosis, bacterial and fungal cultures, ace and hiv testing were negative. vzv-dna was detected in csf in high titers vzv quant: . million. contrasted brain mri revealed mild diffuse leptomeningeal enhancement in the basilar region. she recovered almost all cranial nerve function within days of treatment with acyclovir and high dose steroids. a diagnosis of polyneuritis cranialis with zoster sine herpete (zsh) was made given pcr positive vzv-dna in csf. vzv reactivation with a wide array of neurological deficits can present without rash making diagnosis challenging. zsh should be in the differential for acute cranial nerve deficits as prompt treatment with acyclovir can lead to rapid recovery. stress-induced cardiomyopathy or neurogenic stunned myocardium is a well-documented cardiac complication following aneurysmal subarachnoid hemorrhage (sah). onset is usually immediate, within hours after aneurysm rupture, and is characterized by left ventricular dysfunction with pulmonary edema and elevation in cardiac biomarkers. this can often be mistaken for an acute myocardial infarction or ischemia. the pathogenesis appears to be the result of elevated catecholamine levels following injury leading to myocardial contraction band necrosis and cardiac dysfunction. this syndrome occurs more commonly in patients with severe or "high-grade" sah. we review a case of delayed cardiac dysfunction coinciding with the onset of vasospasm. a -year-old female presented with a h&h , mf sah. she appeared to have lost consciousness prior to arrival and was reporting worst headache of life. she had an evd placed upon arrival with opening pressure at . she underwent endovascular coiling of a ruptured aneurysm of her anterior communicating artery aneurysm. initial echocardiogram demonstrated normal wall motion with ef of %, and minimal troponin i elevation at . ng/ml. on post-bleed day the patient became more somnolent and developed chest pain with an ecg demonstrating st-elevation in all anterolateral leads concerning for acs. she was taken for cardiac catheterization where she had non-obstructive vessels with no vasospasm seen. her ef was reported at - % with apical ballooning present. her repeat echocardiogram also demonstrated a new apical akinesis with ef %, and troponin peaked to ng/ml. her tcds at the time were suggestive of vasospasm with bilateral lr > , but no focal deficit present. it appears that regardless of timeline, stress-induced cardiomyopathy or neurogenic stunned myocardium occurs after sympathetic or catecholamine surge and may occur after the onset of vasospasm in patients with aneurysmal sah. the rapid neurological assessment of critically ill patients with neurologic disease is paramount when determining a course of action. neuromuscular blockade is often used during critical care transport and in the emergency department. unfortunately, this can delay examination and assessment leading to unnecessary testing and procedures. historically, neuromuscular blockade reversal was accomplished using a combination of neostigmine and glycopyrrolate. however, this can lead to incomplete reversal and unwanted side effects from these medications. sugammadex is a cyclodextran injectable compound that has been fda approved in the united states since for rapid reversal of rocuronium induced neuromuscular blockade. sugammadex works by forming a complex with rocuronium and rendering it unable to bind to nicotinic cholinergic receptors at the neuromuscular junction. sugammadex can reverse neuromuscular blockade without the unwanted side effects of cholinesterase inhibitors. this is a case report of the successful use of sugammadex to reverse the effects of neuromuscular blockade in an intracerebral hemorrhage patient. a year old male with a history of atrial fibrillation and a supratherapeutic inr presented via aeromedical ambulance with a ml left frontal intracerebral hermorrhage causing a mm midline shift. he received a mg bolus of rocuronium prior to arrival and had a gcs of upon presenting to the neurosciences icu. a train-of-four revealed / twitches. he was given mg/kg of sugammadex with a return of / twitches within seconds. a more accurate neurological examination was then obtained demonstrating that his brainstem reflexes were intact, he could open his eyes spontaneously and reacted purposefully to painful stimulation. this allowed a non-operative course to be taken. sugammadex can reliably and quickly reverse neuromuscular blockade allowing for the immediate assessment of the neurocritical care patient. it is a useful tool with minimal side effects. piperacillin-tazobactam is commonly deployed as empiric antibiotic therapy. piperacillin-induced hematologic laboratory test abnormalities were rare in pre-marketing studies, and whether these alterations are of clinical significance has been studied little. aberrations in platelet function have not been implicated. in the present case, we discuss a patient presenting with hypertensive intracerebral hemorrhage (ich) who sustained two additional hemorrhages in distinct locations after routine removal of intracranial monitors and an external ventricular drain (evd). these significant bleeding events occurred exclusively during piperacillin-tazobactam therapy and were correlated with new abnormalities in the patient's platelet function assay (pfa) results. a -year old vietnamese male with hypertension presented for treatment of a left basal ganglia ich. epinephrine/collagen and adenosine diphosphate/collagen pfas at the time of evd and quad-lumen bolt placement were normal, and imaging showed no hemorrhage after placement. hospital course was complicated by aspiration pneumonia requiring empiric piperacillin-tazobactam administration. after removal of the quad-lumen bolt and evd on separate days, both follow-up ct scans showed new hematomas in the devices' tracts, with significant intraventricular hemorrhage. repeat pfas were abnormally prolonged, representing a distinct change from baseline. a trend toward normalization of pfas was observed after discontinuation of piperacillin-tazobactam with progression toward baseline thereafter. the present case is unique in that the significant bleeding that occurred was attributable to objectively confirmed platelet dysfunction rather than thrombocytopenia. other possible innate causes of bleeding were less likely as the patient demonstrated normal platelet count, von willebrand multimers, platelet morphology, and clotting factors. this is the first reported case of intracranial (periprocedural) hemorrhage potentially related to piperacillin-tazobactam; further research into this drug's impact upon qualitative platelet function is needed. the life-saving potential of extracorporeal membrane oxygenation (ecmo) has been well recognized since the s. modern advancements of research and technology have allowed ecmo to be accepted as a dependable intervention for patients with severe pulmonary or cardiac failure. however, with increased use, associated complications that detract from the benefit of ecmo are surfacing as well. this case report describes a case of diffuse intracerebral hemorrhage (ich) after prolonged ecmo resulting in cerebral edema, mass effect, and eventual brain herniation. the patient is a previously healthy year old female who presented with fever, chills, and myalgia. when evaluated at urgent care, she was noted to be hypoxic and was sent to an outside hospital where her monospot test was positive. upon arrival, the patient was placed on venovenous ecmo (vv-ecmo) due to severe hypoxia. she was also in acute renal failure requiring continuous renal replacement therapy (crrt). she had an episode of hypotension with bradycardia. subsequently, her pupils were noted to be fixed and dilated. a stat ct head then showed diffuse bilateral hemorrhages at the graywhite junction as well as diffuse edema. labs showed thrombocytopenia likely due to disseminated intravascular coagulation (dic). her exam was consistent with brain death. it has been estimated that up to % of patients who were placed on ecmo as a last resort for respiratory failure have neurological complications including ich. there is no stereotypical pattern of bleeding but diffuse hemorrhage has been seen, which is consistent with the pattern seen in our patient. notably, those with ich have significantly higher rates of mortality. thrombocytopenia, dic, and platelet dysfunction that develop as a result of ecmo are thought to play a role in the development of ich. to present a case report of syndrome of the trepheined (sot) and paradoxical herniation without craniectomy. sot is reported when a constellation of positional neurological symptoms arise following large craniectomy, resolving in a delayed fashion following cranioplasty. paradoxical herniation may occur in extreme cases.the pathophysiology is incompletely understood however proposed mechanisms include compression of underlying brain by the flaccid skin flap due to the gradient between atmospheric and intracranial pressure exacerbated by upright pressure, changes in cerebral blood flow, and csf fluid. a middle aged woman with a history of mood changes eight months preceding admission presents with worsening left hemiplegia over one week. mri revealed a x mm right frontal cystic mass. hyperosmolar therapy and steroids were initiated for midline shift and brainstem compression. her immediate post operative course after tumour excision was uncomplicated. on post-operative day two, she developed uncontrolled hypertension, worsening anisocoria, and decerebrate posturing requiring urgent intubation. head ct revealed uncal and subfalcine herniation despite a large resection cavity. an external ventricular drain was placed and removed due to lack of drainage. within hours of trendelenburg positioning, she improved both clinically and radiographically. she did not undergo an intraoperative csf reduction and no preadmission history (back pain, orthostatic headache, trauma) to support an occult csf leak. she had a recurrence of symptoms on post-operative day eight which also resolved upon lying flat for hours. she was ultimately discharged to acute rehab and tumor pathology returned as glioblastoma (who grade ). this novel case of sot in the absence of craniectomy demonstrates the complex and poorly understood consequences of slow growing massive tumors, csf dynamics and exertional force on static cns structures. this case also illustrates the benefits of a collaborative, multidisciplinary approach to patient care in the neuroicu. to present a lesser known leukoencephalopathy that occurs when patients overdose on inhaled heroin vapor 'chasing the dragon" is a method of inhaled heroin vapor that is different from smoking or snorting heroin. heroin powder is placed on aluminum foil, which is heated by placing a flame underneath. the white powder turns into a reddish-brown gelatinous substance that releases a thick, white smoke, which resembles a dragon's tail. the fumes are "chased" or inhaled through a straw or small tube. currently the us is facing a growing epidemic of heroin use making this leukoencephalopathy more pronounced. a -year-old female with history of drug abuse presented to the emergency department with altered mental status. the boyfriend informed staff that she likely smoked heroin. on arrival, she was drowsy but easily arousable. her brainstem reflexes were intact but she was grossly dysmetric. urine drug screen was positive for opiates only. initial ct of the brain demonstrated extensive loss of gray-white differentiation within the cerebellar hemispheres and bilateral lucency in the globus pallidus and developing hydrocephalus. patient was placed in the neurointensive care unit to monitor and was managed medically with hypertonic therapy to combat her cerebral edema. an mri was done which demonstrated a distinctive pattern of symmetrical white matter t hyperintensities in the cerebellum, hippocampus and internal capsule bilaterally characteristically known as "chasing the dragon" sign. the patient gradually improved with supportive treatment, but continued to have mild ataxia upon discharge. we present a case of leukoencephalopathy that was generally rare to see, but now that heroin use is now at a year high within the us, this phenomenon may become more prominent. heroin inhalation leukoencephalopathy should be suspected in all patients with a history of chasing the dragon when they present with neurological abnormalities. the use of intra-venous (iv) thrombolysis for the treatment of acute ischemic stroke is now the standard of care. this is typically followed by endovascular thrombectomy if patient is eligible does not improve . we present a rare acute ischemic posterior circulation stroke that had progression of the stroke despite receiving both intra-venous thrombolysis and endovascular thrombectomy. case report: a years old african-american gentleman with past history of obesity, sleep apnea and prostatic hyperplasia, presented with acute onset left hemiparesis, with limb ataxia, who then progressed to altered sensorium in the emergency room needing endotracheal intubation. his initial nihss was . he was given iv thrombolysis, with subsequent vascular imaging that showed a top of the basilar clot, that was removed via endovascular intervention. a sister and one of the aunts reported a history of 'clots' when asked about family history. despite initial improvement, the patient deteriorated clinically after about hours from symptom onset, and was found to have extension of stroke into the brainstem, with simultaneous acute loss of brainstem reflexes . the patient was started on palliative withdrawal of care by the family about days from the initial onset of symptoms. his thrombophilia work-up revealed later that he was homozygous for methylenetetrahydrofolate reductase (mthfr) gene mutation, c >t. this case with a poor outcome due to extension of the ischemic stroke despite receiving the standard of care therapy, highlights the need for considering the use of anticoagulation within hours postthrombolysis and thrombectomy in cases with underlying thrombophilia. the current guidelines do not support this aggressive approach. there is a dire need for randomized controlled trial about such cases to provide evidence based care to avoid a repetition of a similar poor outcome. barbiturate therapy has shown benefit in reducing intracranial pressure (icp) in patients who are refractory to other treatment modalities. however, severe adverse drug effects can accompany barbiturate use when used at the high doses required for icp management, such as hypotension, hepatic/renal dysfunction, and infection, among other deleterious consequences. dyskalemia has been reported infrequently in the literature with most of the cases involving patients on thiopental. there remains little guidance for management of this adverse effect. we present a case of severe dyskalemia induced by high-dose pentobarbital therapy and experience with management of this rare but life threatening effect. the patient was a -year-old male with traumatic brain injury and subdural hematomas complicated by refractory icp elevations. after hyperosmolar therapy, sedation, and csf drainage failed to control icp, and he was deemed to not be a candidate for surgical decompression, high-dose pentobarbital was started. after initiation of pentobarbital, his initial potassium of . mmol/l decreased to a nadir of . mmol/l over the next hours despite aggressive repletion with a total of meq of oral and intravenous potassium chloride. upon down-titration and discontinuation of pentobarbital, the serum potassium rapidly rebounded to . mmol/l with st-segment elevations on ekg. pentobarbital was restarted in an attempt to stabilize escalating icps and elevated serum potassium. subsequently a slow taper was utilized to mitigate dyskalemia during barbiturate discontinuation. dyskalemia associated with high-dose barbiturate therapy presents a significant dilemma to practitioners as both severe hypo-and hyperkalemia can be life threatening. published literature provides little guidance on how to safely manage patients who experience this adverse effect. patients receiving barbiturate therapy should have frequent potassium monitoring especially in the initiation and discontinuation phases. potassium repletion should be approached with caution, especially preceding discontinuation of barbiturate therapy. diffuse astrocytoma (formerly known as 'gliomatosis cerebri') may present with seizures or symptomatic raised intra-cranial pressure. this is typically followed by a few months of relatively stable phase (with treatment) and then possible subsequent development of glioblastoma multiforme. we present a rare case of a previously healthy caucasian lady who had new onset seizures, that showed glioblastoma multiforme already present on a background of diffuse astrocytoma. case report: a years old caucasian lady with no significant past medical history was admitted with new onset focal seizures with secondary generalization, needing intubation and propofol for airway protection. brain imaging showed left frontal ring-enhancing mass, with a smaller satellite lesion in the left insular cortex, on a background of diffuse infiltrative lesion involving left fronto-temporal lobe and a smaller area of right parafalcine frontal lobe. biopsy of the left frontal mass revealed it to be glioblastoma multiforme. this is a rare situation when a previously healthy patient presents with new onset seizures and already has glioblastoma multiforme on a background of diffuse astrocytoma (or 'gliomatosis cerebri'). her post operative imaging revealed disease progression with increase in the size of the left insular cortical lesion. she was discharged home with plan for radiotherapy and chemotherapy. diffuse astrocytoma with glioblastoma multiforme within can remain asymptomatic till late in the disease course. diffuse astrocytoma (or 'gliomatosis cerebri') is a rare disease and even more rare is to have this remain asymptomatic till the development of glioblastoma multiforme within. this particular case highlights the need for vigilance about such a possibility, as this aggressive brain tumor carries a grave prognosis, especially when it develops on background of a diffuse astrocytoma. subdural hygromas (sdg) are cerebral spinal fluid collections in the subdural space that may occur following trauma. decompressive craniotomy may increase the risk for acute sdg or other forms of external hydrocephalus along the surgical plane. while these are traditionally benign and resolve spontaneously, they may in rare cases cause clinical deterioration. we report three cases. cases and were alcoholic men aged and , respectively, who suffered severe traumatic brain injury (tbi) following falls while intoxicated. they had early clinical deterioration prompting emergent hemicraniectomy for left-sided sdh with midline shift (mls). case clinically worsened on postoperative day (pod) with posturing, decreased pupillary responses, and new-onset seizures. new bilateral, extensive subdural hygromas were noted, enlarging over serial ct scans up to -cm with progressive mass effect. uncal herniation and downward brainstem displacement occurred by pod despite external ventricular drainage. case deteriorated on pod with fluctuating exam and newonset seizures. imaging revealed new subgaleal fluid collection measuring . -cm and a contralateral sdg. on pod , hemicraniectomy was performed for new mls from enlarging fluid and hemorrhage in extradural component. both died shortly after withdrawal-of-care. case was a year-old man with dural arteriovenous fistula who presented with spontaneous left-sided sdh and underwent left hemicraniectomy. on pod , he had new-onset seizures and new bilateral sdg measuring . -cm on the left and . -cm on the right without mass effect. two days later; the right sdg grew to . -cm causing significant mass effect. he recovered after burr-hole evacuation and temporary subdural drain placement. sdg following sdh evacuation can have a malignant course, causing clinical deterioration without prompt recognition and csf diversion. all patients had large volume sdh and two were alcoholic; larger prospective cohorts are required to identify risk factors. seizures may be an early clinical sign. moyamoya disease is an intracranial vasculopathy that results in stenosis of bilateral internal carotid arteries with subsequent development of extensive collateralization. the diagnostic criteria for moyamoya disease are well established and generally accepted, yet reaching the diagnosis can be challenging in some cases. herein, we present an unusual case of progressive cerebral vasospasm triggered by pituitary apoplexy that led to a delay in the underlying diagnosis of moyamoya disease. case report. a -year-old female with hyperlipidemia presented to the emergency department with a bifrontal headache, right-sided weakness, and dysarthria. ct angiogram showed extensive multifocal narrowing of the bilateral supraclinoid icas, proximal aca/mcas, and posterior circulation. mri brain revealed a left insular stroke as well as a sellar mass with a central hemorrhagic component. mr perfusion demonstrated decreased perfusion in the right hemisphere. lumbar puncture and extensive vasculitic workup was unremarkable. endocrine studies were notable for elevated prolactin with low fsh and lh levels. despite protracted blood pressure augmentation strategies, the patient continued to experience progressive infarcts in the left mca/aca territory. repeat ct angiogram showed progression of vasculopathy, and transcranial doppler studies demonstrated worsening vasospasm of the right mca and left pca arteries. the patient received corticosteroids given concern for apoplexy, and was maintained on aspirin and verapamil. given the aggressive nature of her vasculopathy, the patient underwent conventional angiography two weeks later, which revealed bilateral suzuki grade iii moyamoya. following this diagnosis, she received bilateral sta-mca bypass surgeries. it is important to revisit the differential diagnosis of cerebral vasospasm when the clinical course does not conform to expectations. this case highlights moyamoya as the causative agent in progressive vasculopathy likely masqueraded by pituitary apoplexy and concomitant vasospasm. moyamoya is an important diagnosis to consider in patients with a fulminant vasculopathy refractory to traditional treatment of vasospasm. visualization of intracranial structures by ultrasound in adults is limited by the presence of skull, though ultrasound imaging can occur through temporal windows. point of care ultrasound allows assessment of midline shift, brainstem, and ventricles. doppler allows visualization of cerebral perfusion patterns. patients with a hemicraniectomy have better temporal windows available since a portion of their skull has been removed. in such patients, ultrasound can provide a non-invasive method to serially assess midline shift, intracranial hematomas, and focal ischemia at the bedside. we present images of a cranial ultrasound that shows remarkable anatomical details that correlate well with computed tomography (ct) head. a year-old male presented with right-sided weakness and confusion and was found to have a left parietal intraparenchymal hemorrhage with cerebral edema and left-to-right midline shift on ct head. increase in cerebral edema and expansion of the hematoma caused clinical neurological decline necessitating a left-sided hemicraniectomy with clot evacuation. a cranial ultrasound was performed two days after surgery to assess for progression of cerebral edema and intracranial hemorrhage. a transtemporal approach in axial plane was used to visualize intracranial structures through the craniectomy window. physiological structures like the falx cerebri, lateral ventricles, midbrain, mammillary bodies, choroid plexus, splenium of corpus callosum, thalami, and circle of willis were visualized with incredible anatomical detail. pathology such as intracranial hemorrhage, focal ischemic areas, vasogenic edema as well as encephalomalacia were identified with close correlation to the noncontrast head ct. the patient is currently recovering in the neurocritical care unit with supportive care. cranial ultrasound has potential applications in point of care assessment of intracranial pathology in neurocritical care patients. this application has promising use in directing therapy in patients who are otherwise unstable for transport or are unable to undergo neuroimaging secondary to positioning needed for management of cerebral edema. cerebral mucormycosis is a rare infection caused by fungi found in soil and decaying vegetation. the rhino-orbital-cerebral type is classically associated with aids, diabetes, malignancy and immunosuppression. we observed a series of young immunocompetent patients who presented with a fulminant form of isolated cerebral mucor associated with severe meningoencephalitis, parenchymal necrosis and symptomatic cerebral edema. six patients with histopathological diagnosis of cns mucormycosis admitted to the university of cincinnati neurocritical care unit between and are presented. patient ages ranged from - (median ). none had diabetes or hiv. drug use (intravenous and intranasal) was confirmed in patients. they presented with altered mental status ( ) and focal neurologic deficits ( ). four patients presented with fever and leukocytosis. mri revealed lesions in the basal ganglia ( ) or cerebellum ( ) which were characterized by t hyperintensities with patchy restriction and susceptibility signal. contrast enhancement was present in patients. mass effect ( ) and midline shift ( ) were prominent. mechanical ventilation was required in four patients. all but one patient received amphotericin b. three died from intractable intracranial pressure (icp). one patient eventually gained functional independence, one still requires high level of care, and one was lost to follow-up. csf analysis was negative for mucor in all cases. fulminant cerebral mucormycosis should be considered in every young patient presenting with rapid onset meningo-encephalitis and necrotized cerebral lesions, especially if located in the basal ganglia. history of ivdu should raise further suspicion. these patients should be monitored in intensive care settings as they can rapidly develop malignant cerebral edema and increased icp. antifungal therapy should be initiated upon presentation as it has been shown to improve morbidity and mortality. the incidence of acute ischemic stroke in the immediate post-partum period ranges between - % and is considered a serious cause of morbidity and mortality. pregnant or postpartum women are less likely to receive iv tissue plasminogen activator (tpa) primarily because of pregnancy, ongoing peripartum bleeding and/or recent delivery. the fda classifies tpa as a category c drug and current recommendations consider pregnancy a relative contraindication for receiving tpa. we present two cases of peripartum ischemic strokes with varying ischemic stroke time windows requiring aggressive revascularization therapy (endovascular and pharmacologic). a y g p presented to an outside hospital days post-partum with new onset of facial droop and left upper extremity weakness (nihss ). imaging showed right m cutoff and occlusion of several m branches. the patient was not a candidate for tpa given ongoing vaginal bleeding. the decision was made to proceed with mechanical thrombectomy when her exam worsened to nihss . the thrombectomy was successful with tici c reperfusion. she was discharged home days later with a nihss of zero. a y g p presented days post-partum with new onset of left facial droop and slurred speech (nihss ). imaging showed right m cutoff with reconstitution, but with significant associated penumbra. acute worsening of exam post tpa triggered a push for mechanical thrombectomy achieving a tici recanalization. post procedure the patient's only symptom was decreased sensation in left fingertips. at -day follow up the patient had returned to her baseline with a nihss of zero. endovascular and pharmacologic revascularization therapy should be considered on an individual basis in the peripartum population. current literature is limited to case reports /case series. larger multicenter trials are warranted and anticipated in the near future. while the optimal duration of burst suppression for status epilepticus (se) has not been established, burst suppression poses significant morbidity that may be dependent on the amount of time spent in burst suppression. herein, we report a case of se that resolved after ultra-short burst suppression. case report. a year-old female was admitted to the neuro-intensive care unit after experiencing several brief tonic-clonic seizures characterized by right-sided shaking and left-sided head turn. despite lorazepam and levetiracetam administration, the patient did not return to baseline and was transferred to our unit. on presentation, her workup revealed a leukocytosis and a glucose level > mg/dl. lumbar puncture showed a mild pleocytosis for which broad spectrum antibiotics were initiated. on initial examination, she was unresponsive and was not following commands. electroencephalogram (eeg) demonstrated frequent sharp and slow discharges in the right posterior quadrant with generalization (~ seizures/hour) with minimal improvement following levetiracetam and phenytoin administration. given the refractory nature of seizures, the patient was intubated and treated with general anesthetics. using propofol, burst suppression was achieved (consisting of - s bursts with intermixed suppressions) and was continued for < hours. following weaning, the patient had no further evidence of seizures, and eeg showed lateralized periodic discharges in the right occipital lobe. mri did not demonstrate an occipital focus, but did reveal cortical diffusion restriction in the bilateral posterior hemispheres. the patient was extubated the following morning, and was transferred to the neurology floor two days later. this case provides evidence that in certain situations, relatively brief periods of burst suppression in se can serve as a "reset switch", allowing for resolution of seizures while minimizing toxicities associated with prolonged burst suppression. further studies to determine which patients may benefit from ultrashort burst suppression are warranted. there are two systems of facial control, voluntary and emotional; these are independent up to the level of the facial nucleus. we described a case of a patient who presented with isolated emotional facial palsy after intracerebral hemorrhage (ich). retrospective review of a case admitted to the neurocritical care unit (nccu) of the johns hopkins hospital. a year-old woman with history of migraines who presented to the emergency room after a colleague noticed she was not moving the left lower side of her face when she smiled. head ct showed a large right frontal ich involving the medial frontal lobes and anterior thalami. on review of an old mri done, an underlying developmental venous anomaly with an associated cavernoma was seen. her exam was notable for a flattened emotional affect, no facial palsy when asked to activate on command, but a facial droop that occurred in the context of her smiling to jokes and other humor. her nccu course was complicated with significant brain edema requiring osmotherapy up to weeks out from the initial insult with self-limited episodes of brain herniation characterized by extensor posturing, dilated pupils, hypertension, hyperventilation and tachycardia. these were initially dismissed as sympathetic storming vs seizures as she will come out of those to her baseline (awake with mild left sided weakness) many times without therapy. she eventually required a hemicraniectomy two weeks after presentation. conclusions solated emotional facial palsy can be the presenting sign after ich when the hemorrhage involves the contralateral thalamus, of the striato-capsular region or the medial frontal lobes. in this case, transient icp elevations were leading to dilated pupils, tachycardia and hypertension -highlighting that heart rate changes can be variable with elevated icps and that in young patients, brain herniation episodes can be self-resolved with hyperventilation. yo female with no pmh developed fever, headache, and neck pain. she presented to outside hospital day after ct head was negative, patient was discharged. symptoms did not improve and she went to her pcp on day and was instructed to go to the ed. she presented to osh and underwent a lp that was indicative of viral meningitis with wbc cells/mm and protein mg/dl. patient admitted and treated with acyclovir. on day , she developed generalized body aches. on day , she was trying to stand with assistance and she became rigid. parents report a total of seizures and was intubated for airway protection. she underwent another lp on day with an opening pressure of cm h o. csf was sent for paraneoplastic panel. csf analyses and blood cultures were negative. evd placed for icp pressures of - cm h o. history obtained from mother and father who reported the patient had been hiking weeks prior. results mri brain showed meningeal enhancement scattered throughout the supratentorial and infratentorial brain and most compatible with inflammatory sequela of meningitis. patient continued on keppra, high dose steroids, antibiotic, antiviral, antifungal therapy until cultures resulted. additional treatments included ivig therapy followed by plasmapheresis, and finally rituximab. continued workup with brain biopsy showed demyelinating process and possible necrotizing encephalitis. mri four weeks after initial presentation showed white matter demyelination and deep gray nuclei lesions consistent with adem. four score of on admission improved to (e , m , b , r ) weeks after patient presented from osh. diagnosis of adem vs ms variant made based on the above data. case provides information for the clinician diagnosing and treating adem. potential for further studies with treatments described above and their effect on meaningful neurological outcomes. dengue is a flaviviruses transmitted via mosquitos and prevalent in south east asia. neurological complications are rare but can involve encephalitis, myelitis, neuromuscular dysfunction and neuroophthalmological problems. we describe an interesting case of dengue encephalomyelitis. retrospective review of a case admitted to the neurocritical care unit (nccu) of the johns hopkins hospital a year-old ship filipino captain with no significant past medical history but an extensive exposure to heavy metals, travel throughout the pacific, who presented with progressively worsening fevers, encephalopathy, urinary retention and tremors. he was transporting iron ore and other metals in a cargo ship from russia through south-east asia through to bermuda. while passing through the pacific, he began to experience malaise, myalgia, and fever. he was treated with amoxicillin but became worse, developing urinary retention, periods of confusion, and word finding difficulties. he was initially hospitalized in bermuda and then transferred to our hospital for further workup. given his rapid deterioration, he was initially in the nccu. his exam was notable for mild expressive aphasia, paratonias, right-sided weakness with hyper-reflexia, and a low amplitude tremor. his csf was notable for lymphocytic pleocytosis, elevated protein, low glucose. mri brain showed flair hyper-intensities in the frontal lobes, and diffusion restrictions in the bilateral basal ganglia and thalami. mri spine showed extensive flair hyper-intensity lesions. an extensive workup evaluated for heavy metal toxicities, autoimmune disorders and infectious workup. csf analysis came back positive for dengue igg and igm, leading to a diagnosis of acute dengue fever and encephalomyelitis. with supportive care in the nccu, he improved considerably over - weeks and was discharged home to the philippines. dengue encephalomyelitis is a rare infection but should be considered in patients living in endemic areas. treatment includes supportive care with fluid resuscitation, neurological monitoring and monitoring for hemorrhage. posterior reversible encephalopathy syndrome (pres) is known to cause altered mental status and leukoencephalopathy in the setting hypertensive emergency. we present a novel case of severely asymmetric pres due to a concurrent right transverse sinus dural arteriovenous fistula (davf). a year-old woman with hypertension, non-compliant on medication, had fatigue and weeks of intermittent left sided weakness when she presented to an outside hospital for evaluation. initially upon arrival her glascow coma scale (gcs) was . her mental status deteriorated over hours, eventually requiring intubation. her peak blood pressure was / . outside ct demonstrated scattered intracerebral hemorrhage (ich) and she was transferred for higher level of care. on admission her gcs was . review of her outside ct was remarkable for extreme right-sided white matter hypodensity, moderate left white matter hypodensity, and small scattered ich. workup including infectious, inflammatory, and neoplastic processes were excluded through serum, csf studies, and mri. conventional angiogram demonstrated a right transverse sinus davf with reflux into cortical veins, which was subsequently embolized. her white matter t -weighted hyperintensities improved on follow-up mri, and her gcs was at the time of discharge. our case highlights the possibility of asymmetric pres due to abnormal venous congestion due to the right-sided davf. venous hypertension likely caused the patient's intermittent left sided symptoms in the weeks prior to admission. few cases of unilateral or asymmetric pres have been reported following induced hypertension for treatment of subarachnoid hemorrhage or in the setting of vascular malformation. to our knowledge, this is the only case of severely asymmetric pres and preceding stroke like symptoms due to a davf. the most common pathology associated with an intraluminal carotid thrombus is underlying atherosclerosis. in rare cases it may be associated to thrombocytosis. currently there are no clear recommendations for the treatment of ischemic stroke associated with thrombocytosis. our case describes the use of plateletpheresis for the acute management of thrombocytosis complicated by an internal carotid artery thrombus resulting in a right mca stroke. a -year-old female with past medical history of menorrhagia who presented complaining of left face, arm and leg weakness with associated shortness of breath. upon arrival her nihss was and the initial head ct was unremarkable. laboratory results revealed a hemoglobin . mg/dl, hematocrit mg/dl, and platelet count of x /ml. she was not a candidate for thrombolytic therapy due to the time window. soon after admission she had acute worsening of symptoms with an nihss of . a cta of the head and neck showed acute ischemic infarction involving the right mca territory with non-occlusive intraluminal thrombus within the right carotid bulb. asa mg and heparin infusion were initiated promptly. after a thorough work-up for thrombocytosis, reactive thrombocytosis secondary to iron deficiency anemia was diagnosed. plateletpheresis as well as oral ferrous sulfate were started. after one plateletpheresis cycle the platelet count stabilized at x /ml. complete thrombus resolution was confirmed on follow-up cta on day of admission without need for surgical revascularization. the role for plateletpheresis is not well established in secondary thrombocytosis. in cases with extreme thrombocytosis immediate surgical thrombectomy may be contraindicated due to high risk of rethrombosis. urgent cytoreduction with correction of the putative mechanism for thromboyctosis should be undertaken for optimal management. plateletpheresis is safe and efficient in reducing the platelet count to decrease the risk of clot progression or further clot formations which could worsen patient outcome. hyperpyrexia is an elevated core body temperature secondary to an elevated hypothalamic set temperature. hyperthermia is an elevated core body temperature beyond the normal hypothalamic set temperature. intracranial hypotension can present with a wide variety of symptoms ranging from orthostatic headache up to coma. it has never been reported to present with fever, namely hyperpyrexia. a case report of a year old female patient with a history of depression, diabetes mellitus, hypertension, and angiogram negative subarachnoid hemorrhage status post ventriculo-peritoneal (vp) shunt placement six years ago who was complaining of worsening headaches and slurred speech for the past three months but acutely decompensated one morning. she suddenly became confused and agitated but became obtunded. initially, she was given haldol. she was found to be febrile (rectal temperature of . f). she was given dantrolene and bromocriptine for suspected malignant neuroleptic syndrome with no effect. creatine phospho-kinase was not elevated. she underwent infectious work up which later came negative. cooling measures like external cooling, peripheral iv cooling, tylenol and nsaids were also not helpful. fever responded to central intravascular cooling but encephalopathy did not. several expert attempts of lp and shunt tapping failed to obtain csf. brain imaging showed bilateral chronic symmetrical hygromas, diffuse pachy-meningeal thickening and enhancement, slit-like ventricles and slumping of the midbrain with closure of the mammillary pontine distance. following shunt setting adjustment, the encephalopathy markedly improved and the fever did not recur after stopping the cooling measures and antimicrobials. intracranial hypotension might present with hyperpyrexia, likely secondary to hypothalamic dysfunction. in our case, hyperpyrexia was reversible as the intracranial hypotension was emergently treated. nevertheless, spontaneous intracranial hypotension might be difficult to diagnose especially if it presented with non-classical symptoms like fever. complex emotions about critical illness can affect families in the icu. rightfully, we put focus on how they are impacted, but we also need to pay attention to how it can affect providers and our decision making. a poignant case from my training was a -year-old girl struggling with lupus. she had now developed lupus cerebritis and had massive intracranial hemorrhages. despite aggressive efforts to manage cerebral edema, she repeatedly herniated brain matter out of old craniotomy scars with incredible force. it was the most horrifying thing i've ever seen. other organs were also failing, with four consulting services working to salvage them unsuccessfully, prompting numerous procedures. this went on for a month. the therapies that we can offer have limits from a physiological standpoint which we must recognize and respect. we struggle with reconciling the interventions we feel compelled to implement versus what is realistic. i remembered the most valuable advice that i once received: "only do something to someone if it does the complexity of the neuro icu is amplified by the nature of intracranial catastrophes and poor recovery (in contrast to pure medical illness). providers cling to what is technically indicated while families cling to hope, but neither is enough and concurrently too much. we lose our autonomy to grieving families telling us to "do everything" losing sight of the bigger picture. we lose our autonomy to one another by pushing onwards, which can unintentionally push each other into the territory of doing more harm than good. something for them". all services began to share this view, thus slowly dialysis, steroids and immunosuppression stopped. eventually, her heart stopped. my experiences have reiterated a simple paradigm: to do no harm. through this, i can empower myself to take control of each situation by first taking control of myself. we report a case of an hiv positive patient who presented with cryptococcus gattii meningitis who then developed acute respiratory distress syndrome (ards) secondary to pneumocystis jirovecii pneumonia (pjp) that required ecmo support. ards in immunocompromised hiv positive patients is associated with extremely high mortality. ecmo can improve oxygenation in patients without increasing alveolar pressure and therefore avoid mechanical lung damage with ventilation. we present a patient with newly diagnosed aids with cryptococcus gattii meningitis and course complicated by pjp that progressed to severe acute respiratory distress syndrome (ards) for which veno-venous ecmo was initiated. patient is a year old male who presented to the emergency department with new onset seizures. lumbar puncture in the ed overflowed the manometer and demonstrated wbc , rbc , protein , glucose , positive yeast gram stain positive for yeast with pcr and ag positive. his cultures later grew out cryptoccoccus gattii. he was admitted to the nsicu and we placed a lumbar drain and an intraparenchymal ipc monitor that demonstrated elevated icps to the - mmh but improved with drainage. the day of admission he acutely desaturated and required emergent endotracheal intubation. chest x-ray demonstrated bilateral infiltrates. bal was positive for pj. five days following presentation and respiratory failure he was started on veno-venous ecmo. two days following initiation of pjp treatment with bactrim his chest x-rays and lung compliance began to improve. he remained on ecmo for a total of days before decannulation. he underwent induction chemotherapy for four weeks for meningitis. this case report demonstrates the use of ecmo in a complicated and critically ill patient with aids, pjp, and cryptoccous gattii meningitis. to our knowledge, few cases of ards secondary to pjp are reported and none are reported with concurrent cryptococcus gattii infection. sympathetic storming occurs during the acute care of patients following severe brain injury. cannabinoid cb receptors (cb r) mediate the effects of delta( )-tetrahydrocannabinol (thc), the psychoactive component in marijuana. expression of cb r is widespread in the central nervous system and includes the hypothalamus, which is thought to mediate the hypothermic inducing effects of cannabinoids. dronabinol is a synthetic analogue of thc we present a novel therapeutic use of cannabinoids in a case of super-refractory sympathetic storming following coccidioidal meningitis and extensive bilateral subcortical stroke a -year-old previously healthy man was transferred from an outside hospital for treatment of meningitis, vasculitis, and hydrocephalus requiring placement of a ventriculostomy. workup subsequently revealed coccidioidal meningitis. during hospitalization the patient had severe vasospasm, elevated intracranial pressure, diabetes insipidus, cerebral salt wasting, and severe sympathetic storming. intermittent storming episodes with high fever persisted for over weeks despite treatment with bromocriptine, dantrolene, tylenol, ibuprofen, phenobarbital, and sinemet. due to its mechanism of action, a trial of dronabinol mg divided twice daily was tried. the storming episodes ceased and within hours the average temperature decreased by about . degree centigrade. temperature over the next several days was better controlled with a substantial reduction in use of anti-pyretics, surface cooling measures, and other storming medications our case highlights a novel therapeutic use of cannabinoids in super-refractory sympathetic storming related to brain injury. dronabinol may be an alternative pharmacotherapy with unique mechanism of action in difficult to control sympathetic storming patients with poor grade subarachnoid hemorrhage(sah) commonly present with significant mental status changes that preclude reliance on neurologic exam for screening for neurologic deterioration. jugular venous oximetry monitoring has been suggested for use in guidance of hyperventilation therapy, barbiturate coma, and vasospasm monitoring. no studies are found in literature validating its use in sah. milrinone has been using for the treatment of vasospasm in sah in an established protocol in the montreal neurological hospital. this study was performed using multiple methods of monitoring, but not jugular bulb oximetry. we report one case with high grade subarachnoid hemorrhage complicated by vasospasm treated with milrinone using jugular bulb monitoring for dose titration. methods years old female presented with thunderclap headache and subsequently became comatose. noncontrast head computer tomography showed posterior fossa subarachnoid blood. she was intubated, external ventricular drain (evd) was placed and she was admitted to neurosurgical intensive care unit (nsicu). angiogram showed left posterior inferior cerebellar artery aneurysm and was successfully coiled. her hospital course was complicated by refractory symptomatic vasospasm. angiogram showed basilar artery vasospasm treated with intra-arterial verapamil. post procedure patient was not able to tolerate norepinephrine due to tachycardia and could not maintain hypertension on phenylephrine. milrinone was then started. jugular bulb catheter was place because the area at risk was not amenable to invasive multimodality monitoring. oximetry was monitored and her milrinone rate was titrated to goal of venous oximetry in the range of - %. on day , angiogram showed no more evidence of vasospasm. her exam was back to her prior poor baseline. subsequently, she was discharged to long term care facility. our case demonstrates the benefit of using jugular venous oximetry monitoring guidance for milrinone dose titration. further, it may be an effective tool is research studying treatments of cerebral vasospasm repetitive transcranial magnetic stimulation (rtms) is increasingly used in treatment of various conditions including depression, chronic pain, and movement disorders. the use of rtms for chronic management of medically refractory epilepsy has grown substantially in the last years. however, little literature exists on use of rtms for acute status epilepticus. the exact antiepileptic mechanism of rtms remains unclear, but may be secondary to inhibition of cortical excitability. we report promising response to rtms in a case of super-refractory focal status epilepticus. the study is a case report. a daily dose of pulses of hz rtms was applied to the left occipital lobe. treatment course was divided into periods of - consecutive days each for a total of days of treatment over days. a -year-old woman with recent hemiarthroplasty complicated by wound infection presented with acute unresponsiveness and right gaze deviation, evolving into fluctuating encephalopathy, word finding difficulty, and right hemineglect. eeg revealed persistent left posterior quadrant lateralized periodic discharges (lpds), at times evolving into electrographic seizures, and positron emission tomography demonstrated a co-localized hypermetabolic focus. mri revealed subtle bilateral occipital t hyperintensity without diffusion restriction, which later resolved; cerebrospinal fluid was noninflammatory. seizures continued despite treatment with multiple aeds, burst suppression, and empiric trial of high dose corticosteroids. the patient demonstrated abrupt electrographic and clinical improvement after rtms initiation. previously unseen brief periods of lpd resolution were observed within minutes after first tms session with further improvement in eeg background correlating with improvement in encephalopathy and clinical findings over subsequent days. given excellent safety profile, rtms may be useful transitional therapy in management of some cases of status epilepticus. durability of efficacy, patient selection, and optimal treatment schedules remain important unresolved questions. further study is required. central pontine myelinolysis (cpm) occurs due to rapid osmotic shifts causing demyelination in white matter, typically due to rapid correction of hyponatremia mostly in setting of alcoholism, malnutrition, and/or liver/renal dysfunction. sequelae may include cranial neuropathies, quadriparesis, seizures, and encephalopathy. no specific treatment exists; literature reports indicate favorable outcomes in only - % of patients. our patient is a year old male with hypertension, tobacco and alcohol abuse, admitted with severe aortic stenosis, complicated by alcohol withdrawal, pneumonia, and acute kidney injury. he was treated with benzodiazepines, broad spectrum antibiotics, and fluid resuscitation. on hospital day (hd) , he had to be intubated for airway protection due to acute confusion and quadriparesis. his blood work was notable for wide fluctuations in serum sodium, from on admission to on hd to on hd . otherwise, laboratory evaluation was remarkable only for mildly elevated ast and serum creatinine. mri brain days after symptom onset (hd ) showed dwi and flair hyperintensities around central pons bilaterally crossing midline. eeg showed severe generalized slowing. diagnosis of cpm was made and intravenous immunoglobulin (ivig) ( . g/kg/day for days) was initiated within days of symptom onset, on hd . after initiation of ivig, patient showed rapid improvement, first noted in the bilateral upper extremities. by hd i.e., days after initiation of ivig, he was able to be successfully extubated; and he had regained - / strength in all extremities. neuropsychology testing at month demonstrated intact cognition. we describe a case of rapid clinical improvement in cpm following treatment with ivig. in addition to ours, about similar cases have been reported, in which beneficial outcomes were demonstrated following prompt initiation of ivig. one proposed theory would be through reduction of myelinotoxic antibodies, thus promoting remyelination. few cases have reported central neuronal hyperventilation (cnh) secondary to infiltrative malignancy or autoimmune disease. the lesion is usually located at the pontine tegmentum and interrupts the fibers between the respiratory centers in the pons and those in the medulla. we report a case of a year old female with multiple comorbidities who was admitted to the neurocritical-care unit after intra-operative rupture of a mm distal basilar aneurysm while being electively coiled. an external ventricular drain (evd) was placed due to early signs of ventriculomegaly. the postoperative exam showed progressive encephalopathy, left > right hemiplegia progressive tachypnea (rate and depth) despite being on assisted mode ventilation leading to severe hypocapnia ( . mmhg) and compensatory renal acidosis (bicarbonate = . mmol/l) to maintain normal ph. attempt to sedate the patient led to severe metabolic acidosis. intraventricular nicardipine was started and the patient ventilator settings were changed to bi-level pressure control. transcranial doppler (tcd) showed markedly improved vasospasms. the patient respiratory rate and, to a lesser extent, the tidal volumes improved after several days. sedation was weaned off successfully. evd was successfully weaned off and removed. tcd and ct angiogram showed severed basilar artery vasospasm while mri done later showed bilateral tegmental midbrain ischemia. one case has reported acute central neuronal hyperventilation following left thalamic bleed while another reported chronic neuronal hyperventilation that was attributed to old bilateral lacunar thalamic strokes by exclusion. our case is the first to report central neuronal hyperventilation following aneurysmal subacrachnoid hemorrhage that got complicated by bilateral tegmental midbrain strokes. while respiratory centers are known to exist in the medulla and the pons, more recent articles have described networks that regulate breathing extending to the midbrain peri-acquiductal grey and possibly the thalami. our unique case supports this hypothesis. serotonergic and atypical antipsychotic drugs are often used in the critically ill in the treatment of posttraumatic depression and anxiety disorders. hyperactive delirium may mask serotonin syndrome, which carries high morbidity and mortality if left untreated. we describe a case of serotonin syndrome in a critically ill patient in the setting of surgical and neurocritical intensive care unit. a -year-old male with remote trauma presented with left upper abdominal pain. a ct-scan of abdomen showed left diaphragmatic hernia. he underwent left thoracotomy and repair of diaphragmatic hernia. his postoperative course was complicated by sepsis, ileus, and aspiration pneumonitis. he was started on sertraline and quetiapine for stress-induced anxiety disorder, depression and agitation. despite increasing doses of sertraline, patient became agitated, tremulous, and confused. physical examination included fever, tachycardia, hypertension, diaphoresis, dilated pupils, hyperactivity, and clonus. initially considered to be due to hyperactive delirium, these manifestations did not improve with haloperidol. neurocritical care was consulted. due to presence of hyperactivity, fever and clonus, serotonin syndrome was strongly suspected. sertraline and quetiapine was discontinued and cyproheptadine added. within -hours his symptoms improved and cyproheptadine was tapered over days. serotonin syndrome, a potentially life-threatening syndrome, is manifested by triad of mental status changes, neuromuscular and autonomic hyperactivity. a multitude of drug combinations can result in serotonin syndrome. serotonin syndrome is a diagnosis of exclusion, based on history and neurological examination in a patient taking serotonergic drug. ht- a receptors are most commonly incriminated along with high levels of norepinephrine.the keys to management include discontinuation of all serotonergic agents, supportive care, and cyproheptadine. cyproheptadine, a potent ht- a antagonist, is effective in ameliorating symptoms. a high suspicion for diagnosis is important for reducing morbidity and mortality associated with this neurologic syndrome in the critically ill. ruptured cerebral mycotic aneurysm as consequence of infective endocarditis (ie): a management qeeg adr in poor grade sah: is it really useful? recognize the various subtypes of cerebral amyloid angiopathy bilal butt baylor college of medicine -hour development of a giant infectious intracranial aneurysm: a case report catherine albin intra-operative ultrasound in traumatic brain injury patients namkyu you syndrome of the trepheined (sot) and paradoxical herniation without craniectomy elysia james spectrum health neurosciences -icu division stephen a. trevick , andrew naidech , leah tatebe patients were included. median age was years. % were female, % smokers, % hypertensive and % diabetic. % had a history of cad or mi and % had hyperlipidemia. in the multivariable analysis, the odds ratio for unfavorable outcome, defined as mrs score of - , was . ( %c.i: . - . ) and . ( %ci: . - . ) for the intermediate-grade(iii) and high-grade(iv and v) hh groups respectively, when compared to the low-grade(i and ii) hh group. age, hypertension and diabetes were found to be negatively associated with mrs, while hyperlipidemia was positively associated. gender, race, smoking and history of cad/mi were not significantly related to mrs. a positive trend for better mrs outcome was observed across years (p= . ). this trend was not related to hh grade on admission, (p= . for interaction between hh grade and year). hh scale on admission is associated with the mrs outcome upon discharge for patients with nontraumatic sah. models predicting the probability of a good mrs outcome could be created based on the hh grade on admission, age, hypertension, diabetes and hyperlipidemia status. the data suggest a trend toward improvement in medical and surgical care for this patient population across years. ciro poor-grade subarachnoid hemorrhage (sah) is associated with high mortality rates. although death rates have decreased in the last three decades, the exact mechanisms of demise are still to be determined in this patient population. a retrospective study of consecutive poor-grade sah patients (world federation of neurosurgical societies grades iv and v) aggressively treated in two academic high-volume centers, one in the netherlands (amc) and one in canada (smh). the primary outcome was in-hospital mortality. the main reasons of death were evaluated. a total of poor-grade sah patients were admitted between and , to amc and to smh. ( %) patients died, and ( %) of those patients died before having the culprit aneurysm treated. the median interval between hospital admission and death was three days (iqr - ).withdrawal of life support was the main reason of death in both centers (total of deaths - %), cardiopulmonary causes, aneurysm rebleeding, refractory intracranial hypertension, and other extracranial causes), represented less than %. extensive review of patients chart for all the data collection including literature search for similar cases if reported before. although rare, there are multiple case reports and series of nkh and clinical findings of hemichorea-hemiballism (hc-hb). there are few case reports of nkh with unilateral signal changes in the caudate and putamen. our patient presented with acute right basal ganglia ich. despite the typical imaging findings of nkh, work-up and management of ich took precedence over control of bg. mri findings were different in our patient given presence of positive gre and dwi/adc in areas other than t hyperintensity, which is known to be associated with nkh. we hypothesize an association between ischemia and hemosiderin deposition with hyperglycemia. the selective vulnerability of unilateral involvement of basal ganglia and caudate is unclear and needs more research. identification of neuroimaging findings in nkh in absence of focal neurological deficits (hc-hb) is important, especially for a first responder. early recognition can prevent icu admission, provide efficient patient care and allocation of resources. although most metabolic diseases affect basal ganglia bilaterally; nkh is associated with specific unilateral neuroimaging findings even in absence of movement disorders or focal neurological deficits. a year old male with a history of seizure disorder due to mesial temporal lobe sclerosis, presented with altered mental status after a lamotrigine overdose. he had consumed . gm of the drug. he was awake and alert at presentation. urine toxicology was negative. initial creatine kinase (ck) was iu/l and peaked at iu/l; his creatinine was . mg/dl. lamotrigine level went from mcg/ml to . mcg/ml after hours. four days after admission it was mcg/ml. a head ct at admission was negative. despite initial alertness, he developed profound encephalopathy with agitation and rigidity, requiring heavy sedation, induced paralysis, and intubation. this in turn lead to hemodynamic instability, which along with persistently elevated lamotrigine levels, prompted initiation of continuous veno-venous hemodia-filtration (cvvhdf) on hospital day . the lamotrigine level declined to . mcg/ml within hours, the encephalopathy and rigidity resolved, and he was extubated. to our knowledge, this is the first reported case of lamotrigine toxicity managed with cvvhdf. overdoses up to g have been reported and can even result in death. while cleared hepatically, the half-life of lamotrigine is approximately twice as long when patients have chronic renal failure. in a small series of patients with renal failure, approximately % of lamotrigine was reported to be removed by hemodialysis. we applied this principal to our patient. our experience suggests that augmenting drug clearance with dialysis may help reduce the time on mechanical ventilation, need for higher doses of sedatives, and improve time to discharge. cvvhdf should be considered a supplemental treatment option for lamotrigine toxicity. traumatic brain injury (tbi) complicated by percutaneous coronary intervention (pci) remains a significant clinical dilemma. dual anti-platelet therapy (dapt) is standard after pci, but may contribute to progression of tbi. novel antiplatelet drugs with ultra-short half-lives, such as the p y -adenosine receptor antagonist, cangrelor, may provide added clinical flexibility in avoiding tbi-associated hematoma progression, particularly in the absence of reversibility options. case report. we report a year-old female who presented to the ed after a syncopal episode with a fall down a flight of stairs. an ekg was obtained demonstrating inferior wall stemi. signs of head trauma included facial and scalp contusions, and bloody otorrhea. initial gcs was . a non-contrast head ct demonstrated tsah and contusions of bilateral frontal lobes and left temporal lobe, and a non-displaced fracture of the left temporal bone. neurosurgery, interventional cardiology and critical care were consulted. the patient developed signs of cardiogenic shock related to stemi and was taken emergently to cath lab. successful revascularization of proximal rca occlusion was achieved. heparin was given per protocol, and aspirin and cangrelor administered post-pci. cath lab was complicated by tonic-clonic seizures requiring intubation. repeat head ct demonstrated blossoming of bifrontal contusions, trace subdural hematoma development and increased tsah conspicuity. dapt infusion was continued, and subsequent imaging was stable, allowing transition to asa and clopidogrel. she survived with only minor disability. newer generation p y inhibitors can be administered intravenously with reliable platelet inhibition similar to older p y receptor inhibitors. with rapid reversibility upon discontinuation, their utilization should be considered any time pci complicates tbi. cerebral air embolism (cae) is a rare but potentially fatal entity with high morbidity and mortality, commonly seen secondary to iatrogenic causes like neurosurgical procedures, vascular surgeries, etc. as also deep sea diving. cae after esophagogastroduodenoscopy (egd) is extremely uncommon. we present a rare case of cae post egd resulting in diffuse cortical infarction. an year old man underwent an elective (egd) for esophageal stricture with biopsy and balloon dilatation. patient did not wake up after procedure. on initial exam, patient was comatose, glasgow coma scale t with decerebrate posturing. computed tomography (ct) revealed multiple foci of cerebral air embolism. ct angiogram of the brain was negative. diffusion weighted imaging and apparent diffusion coefficient imaging sequences in magnetic resonance imaging (mri) showed diffuse, global bi-hemispheric cortical infarction. ct chest showed pneumomediastinum. only cases of cae from egd have been reported in literature prior to this case. received hyperbaric oxygen therapy(hbo). patients had a documented patent foramen ovale (pfo) or some form of arteriovenous (av) shunt. presence of av shunts/ pfo, therapeutic endoscopic procedures providing vascular communication as well as providing pressure gradient are all factors facilitating air embolism associated with egd. hbo therapy has been shown to improve outcomes in cae patients, initiating therapy > hours after insult and early and significant ischemic changes seen on ct/ mri prior to starting therapy were strong predictors of poor outcomes. our patient did not have a documented echocardiogram with a shunt study prior to the egd. cae after egd causing global cerebral bi-hemispheric ischemia as seen in our case is extremely rare. hbo has been shown to improve outcomes. time to treatment > hours and early ct/ mri changes suggest poor outcomes. studies do not recommend benefit of screening for pfo or av shunts prior to every egd.