key: cord-0912984-pocccocr
authors: Werner, Cassidy; Scullen, Tyler; Mathkour, Mansour; Zeoli, Tyler; Beighley, Adam; Kilgore, Mitchell D.; Carr, Christopher; Zweifler, Richard M.; Aysenne, Aimee; Maulucci, Christopher M.; Dumont, Aaron S.; Bui, Cuong J.; Keen, Joseph R.
title: Neurological Impact of Coronavirus Disease (COVID-19): Practical Considerations for the Neuroscience Community
date: 2020-05-06
journal: World Neurosurg
DOI: 10.1016/j.wneu.2020.04.222
sha: 821ac6fe434122ec2c5d6c85449b5bf32e97e44f
doc_id: 912984
cord_uid: pocccocr

Abstract Background The coronavirus disease of 2019 (COVID-19) that is caused by infection with the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has recently been designated a pandemic by the World Health Organization, affecting 2.7 million individuals globally as of April 25, 2020 with over 187,000 deaths. A growing body of evidence supports central nervous system (CNS) involvement. Methods We conducted a review of the literature for articles concerning COVID-19 pathophysiology, neurological manifestations, and neuroscience provider recommendations and guidelines. Results CNS manifestations range from vague non-focal complaints to severe neurologic impairment associated with encephalitis. It is unclear whether neurological dysfunction is due to direct viral injury or systemic disease. The virus may affect brainstem pathways that lead to indirect respiratory dysfunction in addition to direct pulmonary injury. Necessary adaptations in patient management, triage, and diagnosis are evolving in light of ongoing scientific and clinical findings. Conclusions This review consolidates the current body of literature regarding the neurological impact of coronaviruses, discusses the reported neurologic manifestations of COVID-19, and highlights recommendations for patient management. Specific recommendations pertaining to clinical practice for neurologists and neurosurgeons are provided.

The coronavirus disease of 2019 (COVID- 19) has recently been designated as a pandemic by the World Health Organization (WHO). 1 The disease is caused by the novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2, previously known as 2019-nCoV), 1 a member of the pathogenic coronaviridae family, which includes enveloped positive sense single stranded ribonucleic acid (+ssRNA) viruses typically responsible for a spectrum of respiratory and gastrointestinal diseases. 1 Confirmed disease has afflicted 2.7 million patients globally as of April 25, 2020 with an associated mortality of 187,700 (7.0%). 2 SARS-CoV-2 is most closely related to SARS-CoV-1, with a genetic homology of 76.9%. 3 Though coronaviruses predominantly cause enteric and respiratory illness, members of coronaviridae have a demonstrated ability to produce neuromuscular and neurological symptoms. [4] [5] [6] [7] [8] [9] Experimental and clinical studies suggest brainstem involvement and the potential for trans-neuronal virus transmission in addition to misdirected host immune responses. [10] [11] [12] [13] The exact mechanisms, however, for clinical neurological disease secondary to coronavirus infection remain unclear. Recent reports indicate that SARS-CoV-2 is similarly capable of causing severe neurological disease, [14] [15] [16] including meningoencephalitis, various viral associated necrotizing encephalitides that are similar to influenza associated encephalopathy (IAE), and secondary cytokine induced acute necrotizing syndromes seen with hemagglutinin 1 neuraminidase 1 influenza virus (H1N1). [14] [15] [16] These findings highlight the dramatic impact on daily healthcare delivery during this pandemic, [17] [18] [19] [20] making COVID-19 an additional challenge in clinical neuroscience. This review consolidates the current body of knowledge on the coronaviruses with a focus on the nervous system, discusses the reported neurologic manifestations of COVID-19, and highlights recommendations for patient management. Specific recommendations pertaining to clinical practice for neurologists and neurosurgeons are provided.

The authors performed a literature review using PubMed and Google Scholar to identify relevant English-language articles published through April 25, 2020. General terms included "coronavirus", "severe acute respiratory syndrome coronavirus", "SARS-CoV-2", "SARS-CoV", "MERS", and "COVID-19". These terms were used in combination with the terms "neurology", "neurological", and "neurosurgery" to identify case reports, retrospective studies, and articles on nervous system pathophysiology. Additional searches with the terms "management", "guidelines", "spine", "stroke", "trauma", "brain tumors", "transnasal", and "pediatrics" were used to identify articles with guidelines or recommendations for providers. The authors screened for relevant articles based on title and abstract. Additional relevant articles were identified from the review of citations referenced. The included number of articles by subject was as follows: 27 that described pathophysiology, 18 that discussed guidelines for providers, 18 that presented or analyzed retrospective studies, 5 that included 6 case reports of neurological manifestations of COVID-19, and 4 that provided general information concerning disease history or epidemiology.

Early prospective evidence from the presumptive origin of SARS-CoV-2 infection in Wuhan, the capital of the Hubei province in the People's Republic of China, reported that the first 41 hospitalized patients with confirmed COVID-19 had pre-existing diabetes mellitus type 2 (DM2) (20%), hypertension (15%), and cardiovascular disease (15%). 21 Expansion of this cohort to include an additional 162 confirmed cases in a subsequent, retrospective, multicenter study demonstrated the unique finding that increased age was significantly associated with greater odds of mortality for every additional year of patient age. 22 This finding is supported by trends reported in other populations that suggest COVID-19 disproportionately affects the elderly and is not consistent with bimodal patterns of age distribution typical of moderate to severe viral disease. 23, 24 A systematic review and meta-analysis performed by Wang et al. that evaluated 1,558 COVID-19 positive patients across six studies 21,25-29 further identified chronic obstructive pulmonary disease (COPD) and cerebrovascular disease as significantly associated comorbidities. 30 Further studies identified obesity and kidney disease as potential risk factors for SARS-CoV-2 infection and predictors of COVID-19 severity. [31] [32] [33] [34] Since many of these comorbidities are seen in patients undergoing treatment for neurological conditions, particularly obese patients with ischemic occlusive and hemorrhagic cerebrovascular disease, neurological and neurosurgical patients at increased risk. [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] It is intuitive that severe pulmonary dysfunction via acute respiratory distress syndrome (ARDS) would exacerbate preexisting systemic disease via increased intrapulmonary shunting, decreased alveolar recruitment, increased pulmonary resistance, and hypoxemia. [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] Furthermore, a pre-existing history of ischemic or hemorrhagic stroke has been demonstrated to be a significant risk factor for the development of ARDS in a neurointensive setting [22] [23] [24] [25] [26] [27] [28] [29] [30] [31] and therefore it becomes critical to differentiate direct viral injury from systemic pathophysiology.

The majority of available knowledge on SARS-CoV-2 pathophysiology has been derived from literature regarding SARS-CoV-1. 32 Both viruses have been shown to enter lower respiratory epithelium via a spike protein (encoded by the viral S gene) attachment to the Angiotensin Converting Enzyme 2 receptor (ACE2R). [32] [33] [34] Although there is less than 75% similarity between the S gene in the two viruses and the receptor-binding domain is well conserved, SARS-CoV-2 S still provides a significant increase in receptor affinity. 3, [32] [33] [34] Early reports recommended avoidance of ACE inhibitors and angiotensin receptor blockers (ARBs) due to a presumed increase in available binding sites as a result of decreased functional competitive inhibition. 35 However, these agents have not been shown to increase ACE2R density and preliminary studies have shown that ACE inhibitors and ARBs may actually confer benefit. [35] [36] [37] [38] [39] While ACE2R is found primarily in lung alveolar epithelium, 40 it is present on the surface of central nervous system (CNS) neurons, which suggests potential neurotropism. 41 SARS-CoV-2 may enter the CNS either directly from contiguous spread from nasopharyngeal mucosa through the cribriform plate or hematogenously secondary to viremia, 42 as both upper airway epithelium and vascular endothelium express ACE2R. 40 An axodendritic trans-synaptic route has been reported as a potential mechanism for CNS dissemination. 10, 43 Rodent models infected with intranasal SARS-CoV-1 have demonstrated particular tropism for the cerebrum, thalamus, and rhombencephalon derivatives typical of viral encephalitis. 44 While coronaviridae CNS entry is well documented, the role in neurological disease remains under investigation. 45, 46 Reports implicate potential central involvement of respiratory failure compounding primary pulmonary injury via direct infection of the pontine and medullary respiratory centers by COVID-19. 10 With a median symptom onset of 8 days for the development of ARDS, SARS-CoV-2 CNS involvement is possible by the time of intensive care (ICU) admission, strengthening the consideration of a mixed central and peripheral etiology of pulmonary compromise. 25 Additionally, SARS-CoV-2 may incite non-inflammatory encephalopathy, which has been previously implicated in SARS-CoV-1 infection. 47 Neurological manifestations of SARS-CoV-1 include seizure, generalized polyneuropathy, mixed axonal neuropathy, and primary myopathy. 7, 48, 49 Tsai et al. noted that while the neuromuscular disorders were considered secondary to critical illness, there remained evidence for direct viral injury of motor units. 49 Similarly, in MERS, viral associated encephalopathy has been reported with confusion, coma, ataxia, and focal motor deficits. 9 An early retrospective series from clusters in Wuhan reported associated clinical CNS involvement in 36.4% of COVID-19 cases throughout disease course increasing to 45.5% in severe disease. 50 Mild CNS involvement entailed dizziness (16.8%), headache (13.1%), ataxia (0.5%), hypogeusia (5.6%), and hyposmia (5.1%), and peripheral symptoms such as neuralgia (2.3%). 50 Severe neuromuscular and CNS manifestations included skeletal muscle injury (10.7%), acute cerebrovascular disease (2.8%), and epilepsy (0.5%). 50 An additional observational series by Helms et al. showed that 84% of their patients had neurologic signs: confusion (65%), agitation (69%), corticospinal tract signs (67%), and dysexecutive syndrome (36%). 51 Eight of 13 (62%) patients that underwent brain MRI showed leptomeningeal enhancement. 51 It is difficult to differentiate symptoms due to primary viral injury from secondary systemic involvement characteristic in an ICU setting. 50.51 As with all critically ill patients, it is vital that intensivists and primary care physicians monitor for neurological manifestations of COVID-19, as they may indicate and potentially precede progression to severe disease. [44] [45] [46] [47] [48] [49] [50] 

To the best of our knowledge, six individual cases of neurological manifestations have been reported (Table 1 ). Symptoms ranged from generalized encephalopathy to those consistent with viral encephalitis/meningitis as well as peripheral neuropathies. [14] [15] [16] 52, 53 Encephalitides were heterogenous with one patient resembling the necrotizing form typical of orthomyxoviruses and another with focal mesial involvement characteristic of herpes viruses.

Transcriptase-Polymerase Chain Reaction (RT-PCR) confirmed COVID-19 who presented with three days of cough, fever, and altered mental status (AMS). 15 Non-contrast computed tomography (CT) demonstrated symmetric hypoattenuation within bilateral medial thalami. 15, 44 Vascular imaging was normal whereas magnetic resonance imaging (MRI) demonstrated hemorrhagic rim enhancing lesions within bilateral thalami, medial temporal lobes, and subinsular region reminiscent of the acute necrotizing encephalopathy associated with IAE. [14] [15] [16] Cerebrospinal fluid (CSF) analysis was sterile at 3 days and negative for herpes simplex virus (HSV)-1 and 2, varicella zoster virus (VZV), West Nile virus (WNE), and fungal antigens. 15 CSF chemistry was non-diagnostic. 15 A presumptive diagnosis of viral associated acute hemorrhagic necrotizing encephalopathy was given, and the patient was managed with intravenous immunoglobulin (IVIG). 15 The patient's outcome was not reported 15 but presumably poor considering the high mortality associated with this condition.

The second case involved a 74-year-old male with history of atrial fibrillation, acute ischemic stroke (AIS), Parkinson's disease (PD), and COPD who presented with fever and cough. 14 Chemistries and chest x-ray (CXR) were normal and after being discharged and treated for COPD exacerbation, 14 the patient was readmitted within 24-hours with worsening respiratory symptoms, headache, and delirium. 14 Repeat CXR confirmed a small right pleural effusion and bilateral ground glass opacities and SARS-CoV-2 PCR returned positive. 14 The patient deteriorated neurologically into a non-verbal, unresponsive state and localized to stimulation. 14 Head CT was unrevealing however electroencephalography (EEG) showed bilateral diffuse slowing typical of encephalopathy along with focal slowing in the left temporal region with sharply contoured waves suspicious for epileptiform activity. 14 Antiepileptic drugs (AED) were given for non-convulsive seizures. 14 Brain MRI was not conducted.

The patient developed ARDS requiring intubation and was started on antiinflammatories, viral protease inhibitors (hydroxychloroquine, lopinavir, and ritonavir), and broad-spectrum antibiotics. 14 CSF analysis was normal except for slightly slightly elevated protein (68mg/dL). 14 PCR for HSV-1 and 2, cytomegalovirus (CMV), and respiratory syncytial virus (RSV) were negative. 14 The source of encephalopathy was indeterminate due to incomplete workup.

presented with nine days of worsening headache, fatigue, fever, and sore throat. 16 The patient was found and developed a generalized tonic clonic (GTC) seizure during transport to the hospital. 16 A Glasgow Coma Score (GCS) of 6 necessitated intubation and he progressed to status epilepticus. 16 Head CT was negative but chest CT demonstrated small ground glass hyperdensities in the right superior and bilateral inferior lobes. 16 CSF was normal and opening pressure was 32 cmH 2 O. Antibodies against HSV1 and VZV were negative, 16 however, COVID-19 infection was confirmed by CSF SARS-CoV-2 Real-Time RT-PCR despite having a negative nasopharyngeal swab. 16 The patient was treated with IV ceftriaxone, vancomycin, acyclovir, corticosteroids and levetiracetam. 16 The viral protease inhibitor favipiravir was started on the second day of admission. 16 Brain MRI showed diffusion restriction along the wall of the right temporal horn and fluid attenuated inversion recovery (FLAIR) sequences revealed hyperintensity of the right mesial structures common in herpes encephalitis. 16 The patient remained in the ICU with poor prognosis.

Case 4 involved a 64-year-old male who initially had two days of fever, cough, insomnia, and muscle soreness. 52 His fever and cough resolved with symptomatic treatment, however ten days later he was found lethargic and unresponsive. Head CT showed no abnormalities. A throat swab RT-PCR assay performed the following day was positive for SARS-CoV-2. Neurologic exam showed neck stiffness, AMS, bilateral ankle clonus, and positive Brudzinski, left Babinski, and right Chaddock signs. The patient was treated with oxygen, arbidol, ribavirin, traditional Chinese medicine, and supportive care. Five days later, CSF was normal and opening pressure was 20 cmH 2 O. CSF was negative for SARS-CoV-2. Nine days later, his neurologic exam normalized and he was discharged on day eleven after two consecutive negative throat swabs.

Cases 5 was of a 50-year-old man who presented with a 2-day history of diplopia, perioral paresthesia, anosmia, ageusia, and gait instability in addition to a 5-day history of fever, cough, headache, and low back pain. 53 His exam findings were consistent with right internuclear opthalmoparesis and right fascicular oculomotor palsy. His serum was positive to the GD1b-IgG antibody and oropharyngeal swab was positive for SARS-CoV-2 using Real-Time RT-PCR, however CSF was negative. He was treated with IVIG 0.4g/kg for 5 days and he had a resolution of his neurological symptoms (except for anosmia and ageusia) within two weeks. Case 6, reported by the same authors, was of a 39-year-old man who presented with diplopia, diarrhea and a low-grade fever for three days. 53 Although his mentation was normal, he had bilateral abduction deficits and fixation nystagmus. Deep tendon reflexes were absent. Oropharyngeal swab was positive for SARS-CoV-2 on Real-Time RT-PCR, however CSF was negative. The patient was treated symptomatically and completely recovered by two-week follow-up.

These cases illustrate the different manifestations and rapid progression of CNS involvement. In the first four cases, each patient presented with cough and fever, and rapidly developed AMS. [14] [15] [16] 52 In cases 5 and 6, mental status remained normal, but patients presented with cranial and peripheral nerve deficits. 53 In all cases, CSF analysis was unrevealing except for Case 3 that confirmed presence of SARS-CoV-2 despite a negative nasopharyngeal swab. 16 This raises a significant concern for provider safety performing intrathecal procedures as it is unclear if virus can be transmitted from CSF to mucus membranes, which has been demonstrated in Human Immunodeficiency Virus (HIV) 1 and 2). 54 This also underscores that a negative nasopharyngeal swab cannot definitively rule out active COVID-19 infection and may indicate the need for CSF PCR testing in neurologically affected patients.

While severe COVID-19 associated CNS disease is rare, 14-22 mild neurological symptoms are common. 14,50 These symptoms include loss of smell and taste, headache, nausea, vomiting, paresthesia, and mild seizures. 16, 55, 56 A study by Beltran-Corbellini et al. showed that new-onset anosmia and ageusia were significantly more frequent among COVID-19 patients than influenza patients, and can suggest infection. 56 While mild involvement is difficult to attribute to primary viral injury, 55 it is critical to also recognize CNS signs such as AMS and seizures as potential presenting symptoms of SARS-CoV-2 infection. 16 Management strategies have highlighted the need for urgent screening and detection of SARS-CoV-2 in these patients but it should be noted that a negative nasal swab Real-Time RT-PCR does not necessarily rule out disease. 16 There have been reports of patients with vague complaints of fever and headache who were admitted to a neurology service after being ruled negative for COVID-19 but later tested positive with Real-Time RT-PCR as symptoms progressed. 50 Early CSF analysis should be considered when early CNS involvement is detected so that anti-inflammatory interventions and escalation of care can be implemented. 19, 55 Waldman et al. established guidelines for patients with neurological symptoms that minimize healthcare exposure by limiting the number of providers in patient rooms, bundling laboratory orders, adjusting medication administration, and altering frequency of neurological checks to a minimum necessary to provide effective care. 19 

As the current pandemic evolves, diagnostic and treatment strategies will be updated. 55 Case 3 underscores the need for increased vigilance in patients with neurological manifestations who initially test negative using the nasopharyngeal swab and suggests the utility of CSF PCR for diagnosis. 16 Cranial imaging should be used judiciously to minimize the risk of transmission to healthcare workers. Patients with CNS involvement have shown significantly lower lymphocyte levels, platelet counts, and higher blood urea nitrogen (BUN) than patients without CNS involvement, which may aid in evaluating and stratifying disease severity. 50 

Treatment with IVIG and corticosteroids has been variable. 15 IVIG may mitigate severe cytokine storming and alleviate secondary vasogenic edema. 15, 55 Seizures should be managed with AEDs 14 and, given anecdotal evidence, anti-inflammatories/anti-parasitics, hydroxychloroquine, and viral protease inhibitors such lopinavir and ritonavir may be considered. 14, 57 The increased prevalence of acute cerebrovascular disease in patients with severe infection is thought to be related to elevated D-dimer levels, which have been previously shown to correlate with unfavorable outcomes in stroke patients. 50,58 COVID-19 patients appear to be hypercoagulable with a propensity for thromboemboli and should be started on venous thromboembolism prophylaxis when indicated. Furthermore, cerebrovascular disease is a known predisposing factor for the development of ARDS, 50, 58 and although no specific guidelines exist regarding pre-existing stroke or elevated D-dimer, these patients require increased vigilance.

A summary of published guidelines and recommendations is provided Table 2 .

Waldman et al. advocated for training all neurology team members on nasopharyngeal sampling techniques, PPE conservation and utilization, and protocols for handling suspected infected patients 19 with special care during lumbar punctures and ventriculostomies. 16, 19 Providers at Columbia and New York Presbyterian Hospital emphasized a transition to "curbside" consultations for non-urgent patients and telemedicine, especially for strokes, 19 which has had wide-spread success in the management of acute cerebrovascular disease in accredited comprehensive stroke centers. 54 Other changes include cessation of all clinical trials that require patent contact in facilities lacking protective equipment. 19 To protect operating staff, Forrester et al. advocated for treating all patients as presumptive positive unless definitely shown otherwise. 59 For urgent surgery that could be delayed 24 hours, SARS-CoV-2 Real-Time RT-PCR was conducted prior to procedure. 59 For confirmed positive or presumptive positive patients in the absence of testing, N-95 respirator masks and droplet attire were required for every person in the OR, including the cleaning staff. 59 Providers not directly involved in intubation were advised to leave the room due to high-risk of virus transmission. 59 Zou et al. described additional safety measures such as utilizing minimally invasive approaches, prone positioning, and caution when suctioning. 60 Burke et al. published a checklist that can be distributed to anesthesia, nursing and OR staff to provide objective data about which neurosurgical cases will be scheduled and the resources that will be required. 61 The adequacy of protection provided by N95 respirators in both aerosolizing and nonaerosolizing procedures is uncertain and controversial with some advocating they are excessive in non-aerosolizing interventions and not cost-effective, while others argue the opposite. 62, 63 Until transmission risk is better understood, the safest option is to utilize respirators in all procedures involving positive and presumptive positive patients.

To decrease exposure while maintaining consultative services, many neurosurgical and neurology departments have shifted to a telemedicine approach for both clinic and postoperative care. 19, 55, 61, 64, 65 Secure videoconferencing and proper documentation of telehealth visits are reimbursable, and while they decrease the number of clinic visits overall, persistent numbers of patient interactions have been reported. 64 Ochsner Health Neurosciences in New Orleans, LA has converted to an almost exclusive telemedicine platform utilizing audio and video virtual clinic visits, except in the event of neurological deficits or in situations requiring wound management.

Patients can be screened virtually and, if found to have a neurological deficit, a traditional clinic visit can be arranged. In regard to specific conditions such as migraine management, providers have called for insurance companies to relax regulations and broaden access to anti-CGRP drugs to decrease botulinum injections in the clinic. 65 However, Waldman et al. proposed continuing injections in an effort to decrease emergency department utilization and exposure. 19 

Burke et al. described a neurosurgical treatment algorithm that provides scheduling recommendations for elective and urgent cases based on disease burden in the community. 61 Moreover, they recommended limiting the number of cases instead of types of cases in order to allow surgeons to triage their own schedule. 61 Eichberg et al. described developing a multidisciplinary review committee for all urgent cases, including malignant brain tumors and progressive cervical spondylotic myelopathy. 64 Emergent cases such as cauda equina syndrome, AIS, and ruptured intracranial aneurysms or arteriovenous malformations (AVMs) that require emergent or urgent surgery are to be continued without need for the review committee. 64 Patients should be screened for COVID-19 in the preoperative window and, if possible, a two-week delay implemented for cases with a positive result. 64 Post-surgical management of uncomplicated craniotomies and endoscopic skull-based procedures may even defer ICU placement, with a higher emphasis placed upon step-down units in an effort to conserve ICU beds. 64 Lombardy, Italy implemented a comprehensive, large-scale neurosurgical approach. 66 The regional neurosurgical infrastructure was restructured, in which 4 of 21 hospitals were deemed "hubs" for accepting all urgent and emergent neurosurgical cases. 66 These included cerebral hemorrhages (subarachnoid and intraparenchymal), acute hydrocephalus, and spinal cord compression. 66 

As emergent mechanical thrombectomy (MT) is the gold standard in the treatment of large vessel occlusion, there is little room to alter the assessment process. 67 Khosravani et al. advocated for continued telemedicine and when direct clinical evaluation is necessary, maximum PPE be used from initial paramedic evaluation and hospital codes to the intraoperative intervention. 20 Additionally, the Society of NeuroInterventional Surgery recommends that providers continue the normal inclusion and exclusion therapy for MT. 68 Prophylactic intubation should be considered in patients with severe deficits due to the high contamination risk of intraprocedural intubation. 68 All patients presenting with stroke symptoms should undergo infection screening. 20 Stroke protocol at Columbia and New York Presbyterian Hospital was updated to include COVID-19 screening, including temperature and oxygen saturation levels, prior to performing the National Institute of Health stroke scale. 19 Barcchini et al. maintained a safe stroke unit in Veneto, Italy by utilizing a mobile CT for COVID-positive or COVID-suspected patients. 69 Fraser et al. recommended that if multiple angiography suites are available, one should be designed a "COVID room" and stocked with enhanced PPE. 68 If possible, all AIS post-thrombectomy patients should undergo COVID-19 testing to help preserve resources during their postoperative care. 68 

Patients with ruptured aneurysms should be treated according to the emergent nature of the disease 64 and admitted to the neurocritical care unit or a COVID-19 equipped respiratory critical care unit with appropriate neurocritical care services to maintain subarachnoid hemorrhage management protocols. While there are no specific guidelines pertaining to aneurysms and AVMs, conservative treatment should be employed until elective cases can resume, if possible. Both symptomatic and non-symptomatic giant unruptured aneurysms need to be considered on an individual basis; the risks and benefits of treatment timelines should be discussed with interdisciplinary care teams and family members. Patients with ruptured AVMs should be admitted to an appropriate critical care unit with recommended management protocols to stabilize the intracranial hemorrhage, monitor for hydrocephalus and intracranial hypertension, and screen for high risk associated aneurysms that may require urgent intervention. The majority of patients with ruptured AVMs may be able to be discharged once the primary bleed has been stabilized and plans for delayed, elective treatment have been made. When cases are emergent or cannot be delayed, patients should undergo rapid COVID-19 testing, if available, and should be treated as presumed positive with maximum PPE.

Slowly progressive tumors without significant associated vasogenic edema such as lowgrade gliomas and extra-axial masses can be delayed and monitored with surveillance imaging. 70 Regarding high-grade gliomas, Mohile et al. have published specific guidelines and advocate for continuing standard of care for younger patients but possibly refusing surgical intervention in older patients with frailty or comorbidities. 70 The European Organization for Research and Treatment of Care (EORTC) glioblastoma calculator (https://www.eortc.be/tools/gbmcalculator/)

can be used to help make objective decisions based on health status. Regardless of age, the benefit of standard therapy for high-grade gliomas likely outweighs the risk of complications or death from COVID-19. 70 Conservative measures and denial of life-extending therapy need to be carefully considered and addressed with the patient and family.

Clinic visits for neurooncology patients should be reserved for those absolutely requiring in-person examination or radiation therapy. 70 Telemedicine should be utilized and patients requiring chemotherapy should practice strict social distancing. Conservative doses of chemotherapy should be considered to avoid immunosuppression in susceptible patients. 70 If a patient develops COVID-19 symptoms during treatment, chemotherapy should be stopped immediately and the patient should be tested regardless of previous test results. 70 If positive, chemotherapy should be held until recovery. 70 For patients requiring radiation therapy and frequent visits, Mohile et al. suggested continuing therapy for younger COVID-positive patients with mild symptoms. 70 For older patients with comorbidities, possible exposure during radiation treatment may outweigh the risks of COVID-19, therefore shorter courses or withholding treatment should be considered.

Anecdotal evidence from a cohort of international otolaryngologists and neurosurgeons reported a high incidence of surgeons and surgical staff contracting COVID-19 after being involved in transnasal surgeries, several of whom developed severe sequelae of the disease including death. 71 They warned of the increased risks associated with transnasal surgeries due to high viral shedding from the nasal and oropharyngeal cavity.

It was recommended that all operating room staff wear the same protective equipment. 71 Surgeries were limited to urgent and emergent cases, such as pituitary apoplexy, and preoperative testing was implemented. Normal PPE was acceptable for asymptomatic patients who tested negative, whereas full powered air-purifying respirator (PAPR) was recommended for emergent cases when patients tested positive. For those who test positive and are not emergent, surgery was postponed until their infection cleared and a repeat test was negative.

The United Kingdom's National Health Service (NHS) released guidelines regarding the management of spine surgery illustrating the need to expedite emergency cases of spinal infections and metastatic spinal cord compression in order to decrease exposure risk and length of stay. 72 the NHS recommended higher scrutiny of urgent elective cases that could have imminent neurological decompensation, while continuing day procedures such as discectomies and injections for severe radicular pain. 72 Conservative treatment should be given priority unless operative management is unavoidabe. 72 These strategies are similar to those proposed by U.S. hospitals, with an aim at decreasing exposure burdens and streamlining discharge for in-patient neurosurgical patients. 60, 73 In relation to neurotrauma, the NHS recommends that specialized major trauma centers prioritize patients with easily reversible conditions such as extradural and subdural hematoma with mass effect, as opposed to accepting patients with diffuse injuries that require advanced monitoring and critical care resources in which the benefit is relatively limited. 72 Some strategies suggest a more conservative approach to managing cranial and spine injuries through telemedicine with local non-specialists. 19 In accordance with measures to preserve resources and combat critical care staffing issues, traumatic brain injury management should focus on treatment futility at an earlier stage compared to non-pandemic conditions.

Regarding pediatric neurosurgery cases, Wellons et al. recommended limiting patient interactions for staff and visitors at Children's hospitals and proposed greater reliance on phone triaging for patients with chronic neurosurgical issues. 74 As these patients may require regular clinic visits, it is important to screen for urgency. In regard to equipment, pediatric neurosurgeons should be prepared to loan out pediatric ventilators or convert ICU units for adult patients. 74 

The cessation of elective cases has substantially decreased neurosurgical patient volume. 64 With smaller caseloads, fewer physicians are needed. 64 Similarly to the strategy recommended by Burke et al., 61 our institution halved the number of neurosurgery residents on inpatient service in an effort to limit exposure and prevent spread among the residents. Residents were split into two teams that alternate inpatient duties every 2 weeks, resulting in fewer residents in the hospital for non-emergent consultation. The rationale is a decreased exposure to potential COVID-19 carriers and decreased turnover of PPE materials with an alternating two

week 'off period' that serves as a functional self-quarantine. Residents and attendings from the neuroscience specialties have been redeployed to cover the respiratory ICU for critical COVID-19 patients. With a decrease in clinical workload, greater emphasis has been focused on academics and research.

Although the majority of patients with COVID-19 will either not have or have only mild neurological manifestations, it is clear that SARS-CoV-2 affects the central nervous system. As the pandemic grows, so too will the collective understanding of how to manage this novel virus.

Because some of the neurological sequela of this disease can be devastating, the neuroscience community must be aware of the neurological impact of COVID-19 and how to approach it. 

• Have all personnel trained on proper PPE wear, nasopharyngeal sampling techniques, and handling of COVID-19 patients. 19 • Use telemedicine for consults when appropriate. 19 • Wear proper PPE when performing LPs and placing EVDs.

• Telemedicine when appropriate. 64 

• Elective: Halt all elective cases. 64 • Urgent: Consult multidisciplinary review committee. 64 • Emergent: Continue as indicated, with heightened attention to PPE. 64 • OR Safety: Act as if every patient is infected with SARS-CoV-2 and wear PPE (N-95 mask and droplet attire) accordingly. 59

• Wear proper PPE when in contact with the patient. 20, 68 • Require COVID-19 screening before stroke scale assessment. 19 • Consider mobile CT units and designated areas for COVID-positive or COVID-suspected patients, where available. 69 • Consider prophylactic intubation prior to angiography/MT for patients at high risk of respiratory failure. 68 Neuro-Oncology Transnasal Surgery

• Implement pre-operative COVID-19 testing. 71 • Postpone non-emergent cases with patients who test positive until their infection is cleared and a repeat test is negative. 71 • PAPR for emergent cases with patients who test positive. 71 Spine Surgery

• Determine if pathology requires emergent intervention and consider conservative management when appropriate, especially in COVID-19 patients. 60, 72, 73 • Use minimally invasive procedures, prone positioning, special care with suction devices, and gentle procedures when possible. 60 

• Limit patient interactions for staff and visitors. 74 

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High prevalence of obesity in severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) requiring invasive mechanical ventilation

Obesity in patients younger than 60 years is a risk factor for Covid-19 hospital admission

Kidney disease is associated with in-hospital death of patients with COVID-19

Chronic kidney disease is associated with severe coronavirus disease 2019 (COVID-19) infection

ACE2 receptor expression and severe acute respiratory syndrome coronavirus infection depend on differentiation of human airway epithelia

Cryo-EM structure of the 2019-nCoV spike in the prefusion conformation

Potential harmful effects of discontinuing ACE-inhibitors and ARBs in COVID-19 patients

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension

Renin-Angiotensin System Blockers and the COVID-19 Pandemic: At Present There Is No Evidence to Abandon Renin-Angiotensin System Blockers

Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis

Angiotensin-converting enzyme 2 in the brain: properties and future directions

Evidence of the COVID-19 Virus Targeting the CNS: Tissue Distribution, Host-Virus Interaction, and Proposed Neurotropic Mechanisms

Axonal Transport Enables Neuron-to-Neuron Propagation of Human Coronavirus OC43

Lethal infection of K18-hACE2 mice infected with severe acute respiratory syndrome coronavirus

Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans

Coronavirus Infections in the Central Nervous System and Respiratory Tract Show Distinct Features in Hospitalized Children

Severe Acute Respiratory Syndrome Coronavirus Infection Causes Neuronal Death in the Absence of Encephalitis in Mice Transgenic for Human ACE2

Possible Central Nervous System Infection by SARS Coronavirus

Neurological manifestations in severe acute respiratory syndrome

Neurologic Manifestations of Hospitalized Patients With Coronavirus Disease

Neurologic Features in Severe SARS-CoV-2 Infection

Concomitant neurological symptoms observed in a patient diagnosed with coronavirus disease 2019

Miller Fisher Syndrome and polyneuritis cranialis in COVID-19

Biosafety Guidelines. StatPearls [Internet]. Treasure Island (FL)

Nervous system involvement after infection with COVID-19 and other coronaviruses

Acute-onset smell and taste disorders in the context of Covid-19: a pilot multicenter PCR-based case-control study

Should chloroquine and hydroxychloroquine be used to treat COVID-19? A rapid review. BJGP Open

Prognostic Value of Serum D-Dimer in Noncardioembolic Ischemic Stroke

Precautions for Operating Room Team Members during the COVID-19 Pandemic

Advice on Standardized Diagnosis and Treatment for Spinal Diseases during the Coronavirus Disease 2019 Pandemic

Letter: The Coronavirus Disease 2019 Global Pandemic: A Neurosurgical Treatment Algorithm

Medical Masks vs N95 Respirators for Preventing COVID-19 in Health Care Workers A Systematic Review and Meta-Analysis of Randomized Trials. Influenza Other Respir Viruses

Effectiveness of N95 respirators versus surgical masks against influenza: A systematic review and meta-analysis

Academic Neurosurgery Department Response to COVID-19 Pandemic: The University of Miami/Jackson Memorial Hospital Model

Migraine Care in the Era of COVID-19: Clinical Pearls and Plea to Insurers

Neurosurgery during the COVID-19 pandemic: update from Lombardy, northern Italy

Temporary Emergency Guidance to US Stroke Centers During the COVID-19 Pandemic

Society of NeuroInterventional Surgery recommendations for the care of emergent neurointerventional patients in the setting of covid-19

Acute stroke management pathway during Coronavirus-19 pandemic

Urgent Considerations for the Neurooncologic Treatment of Patients with Gliomas During the COVID-19 Pandemic

Precautions for endoscopic transnasal skull base surgery during the COVID-19 pandemic

Clinical guide for the management of patients requiring spinal surgery during the Coronavirus pandemic

COVID-19 and spinal surgery

Early lessons in the management of COVID-19 for the pediatric neurosurgical community from the leadership of the American Society of Pediatric Neurosurgeons

Highlights:• Nervous system manifestations of COVID-19 have been reported.• Neurological symptoms in COVID-19 patients affect diagnosis and treatment strategies.