key: cord-271944-oxtus5vb authors: Joseph, Rudman; Narula, Naureen; Daouk, Aref; Katyal, Nakul; Acharya, Sudeep; Avula, Akshay; Maroun, Rabih title: Seizure And COVID-19: Association and Review of Potential Mechanism date: 2020-10-13 journal: Neurol Psychiatry Brain Res DOI: 10.1016/j.npbr.2020.10.001 sha: doc_id: 271944 cord_uid: oxtus5vb Since the emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) in Wuhan, China, this highly transmissible virus has since spread rapidly around the world. Though respiratory complication is the primarily reported manifestation though rare, yet serious neurological complications are being frequently reported in the literature. In selected coronavirus disease-2019 (COVID-19) cases neurologic complications may manifest as seizures. In this paper, we have reviewed current literature on seizures linked with SARS- COV 2 infection including published or pre-print original articles, review articles, and case reports. We have discussed the electroencephalogram (EEG), imaging, and Cerebrospinal fluid (CSF) findings in COVID-19 patients presenting with seizure. We will be concluding the paper by briefly discussing the three possible seizure development mechanisms in patients infected with SARS- COV 2, which includes - (a) Direct Mechanism (b) Indirect Mechanism and (c) Exacerbation of Seizure in Patients with Epilepsy (PWE). Our aim is to update the physicians working with COVID-19 patients about this potential complication and hope that understanding of these proposed mechanisms can provide an opportunity for the physicians for early diagnosis or even better, help prevent this complication. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV2) is a novel coronavirus that causes Coronavirus Disease of 2019 (COVID- 19) , a disease that can present with a variety of symptoms [1] . COVID-19 was first reported in the Wuhan, Hubei province in China in December 2019 [2] and has since been declared a global pandemic by the World Health Organization [3] . The most common symptoms at the onset of COVID-19 illness are fever, cough, and fatigue; in severe cases, patients may develop severe pneumonia, acute respiratory distress syndrome, and organ failure [4] . Viral encephalitis was the first neurological complication linked to SARS-CoV2 [5] and since then cases have been reported linking COVID-19 to a spectrum of neurological associations. The neurologic symptoms can be seen in up to 36.4% of patients and are reported commonly in patients with a severe respiratory infection [6] . Coronaviruses, a family of large enveloped non-segmented positive-sense RNA viruses, have been associated with neurological manifestations in patients secondary to the neurotropic and neuro-invasive capabilities exhibited. In a study of 70 patients infected with the Middle East respiratory syndrome (MERS)-CoV infection, 8.6% of enrolled patients had seizures (7) (8) . Hung et al reported the first case of status epilepticus associated with COVID19, with the presence of SARS-CoV RNA in both the CSF and serum [9] and since then over the last few months, there has been increased reportage of seizures associated with SARS-COV2. This article presents a review of the current literature on seizures linked with SARS-COV 2 infection and describes possible underlying mechanisms. We searched Medline, Google Scholar, and Pubmed using the keywords; "seizures", SARS COV2'', "COVID-19". Search was limited to the English language manuscript only. The literature search was last done on June 30, 2020. At the time of writing this article, we identified 478 research articles describing neurological complications in SARS-COV-2. 11 of those articles described seizures associated with SARS-COV2. describes the demographic data, time to onset of neurological symptoms, diagnostic criteria, intervention, and outcomes from 11 studies of seizures associated with SARS-COV-2 infection. 11 studies have described a total of 13 cases of seizures (10) (11) (12) (13) (14) (15) (16) (17) (18) (19) (20) . Of the 13 patients, 7 were male and 6 female(10-20). The mean age of these patients was 61.3 years, with standard deviation (SD) 16.73. The mean time for the onset of neurological symptoms from presentation in these 13 patients was 4.69 days, with an SD of 4.51. 5 patients presented with seizures as their only symptom; of these, 3 went on to develop respiratory symptoms while the other 2 only had neurological symptoms [12, 14, 19, 20] . Out of 13 patients, eight patients underwent lumbar puncture. One patient had CSF which was PCR positive for COVID (interestingly, but a negative nasal swab) (15) . Six patients had negative CSF PCRs or were in institutions which could not test the CSF for COVID. Three patients had elevated lymphocytes with otherwise normal findings, one had elevated protein with otherwise normal findings, and the J o u r n a l P r e -p r o o f remaining 3 patients had no findings in their CSF [10, [16] [17] . Lumbar puncture was not performed in 6 patients. Computed tomography (CT) head scan and magnetic resonance imaging (MRI) brain were obtained in all 13 patients. One patient had MRI evidence of ventriculitis and encephalitis, and one patient had multiple, non-enhancing demyelinating lesions [13, 15] . In the remaining eleven patients, imaging studies showed no acute changes. Electroencephalography was obtained in 11 out of 13 patients. Three patients had generalized slowing, and six patients showed focal areas of status epilepticus including the temporal lobe, frontotemporal regions, and the centro-parietal regions [10, 11, 13, [17] [18] [19] [20] . Two patients had negative EEGs. Two patients presented to the hospital already recovered from their seizures and were thus not treated. The other 13 patients were treated with standard anti-seizure medications, including levetiracetam, diazepam, lacosamide, and valproic acid. No reports mentioned if the patients were discharged on anti-seizure medications. Death was reported as an outcome in two out of thirteen patients. Final outcomes were unavailable or not reported for three patients. Poor outcome was reported in three patients with controlled seizures but critically ill due to other reasons. The remaining five patients were discharged with no neurological symptoms As discussed earlier, SARS-COV-2 PCR was reported positive in the CSF in one of the cases with evidence of ventriculitis and encephalitis on the MRI. Another patient had multiple, non-enhancing demyelinating lesions. This demonstrates that SARS-COV-2 is able to directly enter and infect the central nervous system (CNS), causing meningitis and encephalitis, and thereby causing seizures [21] [22] . There are several theorized pathways for SARS-COV-2 to enter the CNS-one of the chief targets of the SARS-COV-2 is the Angiotensin-converting-enzyme-2 (ACE-2) receptor cells [23] . ACE-2 receptors are located on cells throughout the body, including the cardio-respiratory neurons of the brainstem, glial cells, basal ganglia, motor cortex, raphe, and endothelial cells of the brain [24] [25] [26] . Once in the bloodstream, SARS-COV-2 can travel to infect the endothelial cells of the bloodbrain barrier and then accumulate in the various ACE 2 heavy brain regions causing direct infection with neurological sequelae [24, 27] . A second route through which the SARS-COV-2 is theorized to enter the CNS is the olfactory nerve via the nasal cavity [24, 28] . It has been demonstrated that within 7 days of infection, coronavirus (COV) can reach the CSF and brain through the olfactory nerve causing inflammation and demyelinating reactions with potential subsequent seizures, and removal of the olfactory bulb in mice resulted in a restricted invasion of CoV into the CNS [5] . The overloading of ACE-2 receptors by SARS-COV-2 results in the downregulation of ACE-2 expression [23] . This loss of ACE-2 receptors leads to dysfunction of the renin-angiotensin system and elevated production of angiotensin II. The overproduction of angiotensin II results in a cascade of interactions that eventually leads to severe acute lung injury, vasoconstriction, and oxidative processes that promote brain degeneration with the possibility of resulting in seizures [24] . Infection with SARS-COV-2 has been shown to result in a cytokine storm, an immune-mediated life-threatening disease which is caused by impaired natural killer and cytotoxic T-cell function [21, [29] [30] . This impaired function results in excessive secretion of pro-inflammatory cytokines such as tumor necrosis factor α (TNFα), and interleukins (IL) 1, 4, 6, 8, 10, and 18. Experimental studies infecting in vitro cultured glial cells with COV noted enormous production of inflammatory factors such as IL-6, IL-12, IL-15, and TNF-α [5, 7] . IL-6 in particular has been shown to positively correlate with the severity of COVID-2019 symptoms. The overproduction of these factors result in an exaggerated inflammatory response and cause vascular permeability, edema, and widespread inflammation with consequent damage in multiple organs with the ultimate result of progressive systemic organ failure [29] [30] [31] [32] [33] [34] . One potential outcome of cytokine storm is the development of acute encephalopathy with associated seizures. It is well documented that COVID-19 can cause pneumonia and result in devastating hypoxia. Hypoxia can potentiate hypoxic encephalopathy, which can further contribute to the development of seizures. Ischemic brain injury also contributes to cerebral tissue hypoperfusion and may lead to seizures [35] . The effects of COVID-19 on PWE still remain unclear. The importance of maintaining control of epilepsy with AEDs is important as mortality associated with epilepsy is higher in patients with uncontrollable seizures than in those with controllable seizures. Seizures can be provoked by sepsis, fever, sleep deprivation, Electrolyte disturbances-which are seen infrequently with COVID-19. A number of medications are being considered for symptomatic (eg Diphenhydramine) as well as for management of COVID-19 and it is recommended to consider possible interactions between epilepsy medications and these agents [36] [37] [38] Neurologic complications of patients with COVID-19 are common and may manifest as seizures in some patients. However, it still remains unclear as to which potential mechanism is predominantly responsible. More studies are needed to examine these disease pathways in-depth as the world continues to monitor this viral pandemic. Till then, one should try to determine the cause (e.g., hypoxia, fever, sepsis, electrolyte derangements). and manage with the application of general management principals of seizures and status epilepticus. When an antiseizure Medication (ASM )is initiated consideration should be given to the drug factors such as the onset of action, drug interactions, medication associated adverse effects, as well as focus to take into account important patient factors, such as the age of the patient and function of the renal and hepatic. Hereby, I /insert author name/ consciously assure that for the manuscript "Seizure And COVID19: Association and Review of Potential Mechanism" the following is fulfilled: 1) This material is the authors' own original work, which has not been previously published elsewhere. 2) The paper is not currently being considered for publication elsewhere. 3) The paper reflects the authors' own research and analysis in a truthful and complete manner. 4) The paper properly credits the meaningful contributions of co-authors and coresearchers. 5) The results are appropriately placed in the context of prior and existing research. 6) All sources used are properly disclosed (correct citation). 7) All authors have been personally and actively involved in substantial work leading to the paper, and will take public responsibility for its content. I agree with the above statements and declare that this submission follows the policies of Solid State Ionics as outlined in the Guide for Authors and in the Ethical Statement. Date: 08/22/2020 The authors whose names are listed immediately below report the following details of affiliation or involvement in an organization or entity with a financial or non-financial interest in the subject matter or materials discussed in this manuscript. Naming the coronavirus disease (COVID-19) and the virus that causes it China Novel Coronavirus Investigating and Research Team. 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