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Cerebrospinal fluid findings in patients with seizure in the setting of COVID-19: A review of the literature

Open ArchivePublished:May 17, 2021DOI:https://doi.org/10.1016/j.seizure.2021.05.003

      Highlights

      • We identified 69 patients with COVID-19 who had a seizure and CSF obtained.
      • CSF SARS-CoV-2 was positive for 6/45 (13%) patients.
      • Of 11 patients who had CSF autoimmune antibody panels, 2 (18%) were positive.
      • Based on CSF, it is unlikely seizures in these patients are a result of viral neuroinvasion.

      Abstract

      We reviewed the literature on cerebrospinal fluid (CSF) studies in patients who had a seizure in the setting of COVID-19 infection to evaluate for evidence of viral neuroinvasion. We performed a systematic review of Medline and Embase to identify publications that reported one or more patients with COVID-19 who had a seizure and had CSF testing preformed. The search ranged from December 1st 2019 to November 18th 2020. We identified 56 publications which described 69 unique patients who met our inclusion criteria. Of the 54 patients whose past medical history was provided, 2 (4%) had epilepsy and 1 (2%) had a prior seizure in the setting of hyperglycemia, but the remaining 51 (94%) had no history of seizures. Seizure was the initial symptom of COVID-19 for 15 (22%) patients. There were 26 (40%) patients who developed status epilepticus. SARS-CoV-2 PCR testing was performed in the CSF for 45 patients; 6 (13%) had a positive CSF SARS-CoV-2 PCR, only 1 (17%) of whom had status epilepticus. The cycle thresholds were not reported. Evaluation for CSF SARS-CoV-2 antibodies (directly or indirectly, via testing for CSF oligoclonal bands or immunoglobulins) was performed in 26 patients, only 2 (8%) of whom had evidence of intrathecal antibody synthesis. Of the 11 patients who had CSF autoimmune antibody panels tested, 1 had NMDA antibodies and 1 had Caspr-2 antibodies. Detection of SARS-CoV-2 in the CSF of patients with seizures who have COVID-19 is uncommon. Our review suggests that seizures in this patient population are not likely due to direct viral invasion of the brain.

      Keywords

      1. Introduction

      Since the onset of the pandemic, there have been innumerable reports of neurologic manifestations of COVID-19, the most common of which are anosmia, ageusia, dizziness, encephalopathy, and headache [
      • Frontera JA
      • Sabadia S
      • Lalchan R
      • et al.
      A prospective study of neurologic disorders in hospitalized COVID-19 patients in New York City.
      ,
      • Mao L
      • Jin H
      • Wang M
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ,
      • Lu L
      • Xiong W
      • Liu D
      • et al.
      New onset acute symptomatic seizure and risk factors in coronavirus disease 2019: a retrospective multicenter study.
      ]. Seizures have also been described in patients with COVID-19, but studies of patients with COVID-19 who had neurological events found that only 0.51.6% of patients had seizures [
      • Frontera JA
      • Sabadia S
      • Lalchan R
      • et al.
      A prospective study of neurologic disorders in hospitalized COVID-19 patients in New York City.
      ,
      • Mao L
      • Jin H
      • Wang M
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ]. However, given the magnitude of the pandemic and the number of people infected worldwide, this relatively rare neurologic manifestation has been reported a myriad of times.
      There have been several mechanisms proposed to explain the occurrence of seizures in COVID-19 patients. While some suggest seizures in this population may be related to hypoxia or proinflammatory cytokines, it has also been hypothesized that seizures may be the result of viral neuroinvasion [
      • Desforges M
      • Le Coupanec A
      • Brison E
      • Meessen-Pinard M
      • Talbot PJ
      Neuroinvasive and neurotropic human respiratory coronaviruses: potential neurovirulent agents in humans.
      ,
      • Desforges M
      • Le Coupanec A
      • Dubeau P
      • et al.
      Human coronaviruses and other respiratory viruses: underestimated opportunistic pathogens of the central nervous system?.
      ,
      • Koralnik IJ
      • Tyler KL.
      COVID-19: a global threat to the nervous system.
      ].
      Review of cerebrospinal fluid (CSF) is one way to evaluate for viral neuroinvasion. There have been multiple reports of electroencephalography (EEG) findings in patients with COVID-19 [
      • Carroll E
      • Neumann H
      • Aguero-Rosenfeld ME
      • et al.
      Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus.
      ]; however, the CSF findings in COVID-19 patients with seizures have not been systematically examined. Herein, we systematically review the CSF results in published case reports and case series of patients with COVID-19 who had seizures to evaluate for evidence of viral neuroinvasion.

      2. Methods

      As part of a larger review of published reports of patients with COVID-19 who had neurological symptoms prompting CSF testing, we identified 1,182 unique publications from December 1, 2019 and November 18, 2020 by searching Medline and Embase using the population search terms “COVID-19” or “SARS-CoV-2” and the intervention search terms “cerebrospinal fluid” or “csf” or “spinal puncture” or “spinal tap” or “lumbar puncture” or “meningitis” or “encephalitis” or “encephalomyelitis” or “seizure” or “encephalopathy” or “myelitis” or “Guillain Barre” or “polyradiculitis” or “Miller Fisher” [
      • Lewis A
      • Frontera JA
      • Placantonakis D
      • Galetta S
      • Balcer L
      • Melmed K.
      Cerebrospinal fluid in COVID-19: a systematic review of the literature.
      ]. Two neurologists (AL and KM) independently screened these references using Covidence Systematic Review Software and performed full-text review to identify documents that were written in English and provided details on at least one unique patient with COVID-19 diagnosed based on positive SARS-CoV-2 PCR or serologic testing who had a neurological symptom and CSF testing [

      Covidence systematic review software. In. Vol Veritas Health Innovation. Melbourne, Australia.

      ]. We excluded publications that described patients who had an acute neurological diagnosis that could potentially impact CSF results (such as subarachnoid hemorrhage or another intracranial infection) and added additional relevant publications based on review of references and other sources. This resulted in identification of 242 publications.
      Two neurologists (EC and AL) reviewed all 242 publications to identify publications that described a patient with COVID-19 who had CSF obtained and had a seizure. This resulted in identification of 56 publications. Cases were reviewed and organized based on CSF findings. If a patient had more than one lumbar puncture, we included the results from the CSF that was acquired closest to the time of the first reported seizure. CSF results were converted to a common unit to facilitate comparison. This search was performed in accordance with PRISMA guidelines (Fig. 1).

      3. Results

      Our systematic review identified 69 unique patients who had a seizure in the setting of COVID-19 and had CSF studies available for review (Supplemental Table 1) [
      • Abdi S
      • Ghorbani A
      • Fatehi F.
      The association of SARS-CoV-2 infection and acute disseminated encephalomyelitis without prominent clinical pulmonary symptoms.
      ,
      • Benameur K
      • Agarwal A
      • Auld SC
      • et al.
      Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Atlanta, Georgia, USA, 2020.
      ,
      • Carroll E
      • Neumann H
      • Aguero-Rosenfeld ME
      • et al.
      Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus.
      ,
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,
      • Djellaoui A
      • Seddik L
      • Cleret De Langavant L
      • Cattan S
      • Bachoud-Lévi AC
      • Hosseini H
      Posterior reversible encephalopathy syndrome associated with SARS-CoV-2 infection.
      ,
      • Dono F
      • Carrarini C
      • Russo M
      • et al.
      New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.
      ,
      • Edén A
      • Kanberg N
      • Gostner J
      • et al.
      CSF biomarkers in patients with COVID-19 and neurological symptoms: a case series.
      ,

      Elkady A, Rabinstein AA. Acute necrotizing encephalopathy and myocarditis in a young patient with COVID-19. 2020;7(5):e801.

      ,
      • Ghosh R
      • Dubey S
      • Finsterer J
      • Chatterjee S
      • Ray BK.
      SARS-CoV-2-associated acute hemorrhagic, necrotizing encephalitis (AHNE) presenting with cognitive impairment in a 44-year-old woman without comorbidities: a case Report.
      ,
      • Guilmot A
      • Maldonado Slootjes S
      • Sellimi A
      • et al.
      Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
      ,
      • Hosseini AA
      • Shetty AK
      • Sprigg N
      • Auer DP
      • Constantinescu CS.
      Delirium as a presenting feature in COVID-19: Neuroinvasive infection or autoimmune encephalopathy?.
      ,
      • Keller E
      • Brandi G
      • Winklhofer S
      • et al.
      Large and small cerebral vessel involvement in severe COVID-19: detailed clinical workup of a case series.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Pilotto A
      • Masciocchi S
      • Volonghi I
      • et al.
      Clinical presentation and outcomes of SARS-CoV-2 related encephalitis: the ENCOVID multicentre study.
      ,
      • Sattar SBA
      • Haider MA
      • Zia Z
      • Niazi M
      • Iqbal QZ.
      Clinical, radiological, and molecular findings of acute encephalitis in a COVID-19 patient: a rare case report.
      ,

      Song E, Chow RD, Jiang R, et al. Immunologically distinct responses occur in the CNS of COVID-19 patients. bioRxiv : the preprint server for biology.2020.

      ,
      • Zambreanu L
      • Lightbody S
      • Bhandari M
      • et al.
      A case of limbic encephalitis associated with asymptomatic COVID-19 infection.
      ,
      • Abdulsalam MA
      • Abdulsalam AJ
      • Shehab D.
      Generalized status epilepticus as a possible manifestation of COVID-19.
      ,
      • Afshar H
      • Yassin Z
      • Kalantari S
      • et al.
      Evolution and resolution of brain involvement associated with SARS- CoV2 infection: A close Clinical - Paraclinical follow up study of a case.
      ,
      • Anand P
      • Al-Faraj A
      • Sader E
      • et al.
      Seizure as the presenting symptom of COVID-19: a retrospective case series.
      ,
      • Anand P
      • Lau KHV
      • Chung DY
      • et al.
      Posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019: two cases and a review of the literature.
      ,
      • Ayatollahi P
      • Tarazi A
      • Wennberg R.
      Possible autoimmune encephalitis with claustrum sign in case of Acute SARS-CoV-2 Infection.
      ,
      • Balloy G
      • Leclair-Visonneau L
      • Péréon Y
      • et al.
      Non-lesional status epilepticus in a patient with coronavirus disease 2019.
      ,
      • Bellon M
      • Schweblin C
      • Lambeng N
      • et al.
      Cerebrospinal fluid features in SARS-CoV-2 RT-PCR positive patients.
      ,
      • Bernard-Valnet R
      • Pizzarotti B
      • Anichini A
      • et al.
      Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection.
      ,
      • Canham LJW
      • Staniaszek LE
      • Mortimer AM
      • Nouri LF
      • Kane NM.
      Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: a case series.
      ,
      • Casez O
      • Willaume G
      • Grand S
      • et al.
      SARS-CoV-2 related encephalitis: MRI pattern of the olfactory tract involvement.
      ,
      • Conte G
      • Avignone S
      • Carbonara M
      • et al.
      COVID-19-associated PRES-like encephalopathy with perivascular gadolinium enhancement.
      ,
      • Dharsandiya M
      • Shah K
      • Patel K
      • Patel T
      • Patel A
      • Patel A.
      SARS-CoV-2 viral sepsis with meningoencephalitis.
      ,
      • Dixon L
      • Varley J
      • Gontsarova A
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ,
      • Doo FX
      • Kassim G
      • Lefton DR
      • Patterson S
      • Pham H
      • Belani P.
      Rare presentations of COVID-19: PRES-like leukoencephalopathy and carotid thrombosis.
      ,
      • Dugue R
      • Cay-Martínez KC
      • Thakur KT
      • et al.
      Neurologic manifestations in an infant with COVID-19.
      ,
      • Duong L
      • Xu P
      • Liu A.
      Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020.
      ,
      • Elgamasy S
      • Kamel MG
      • Ghozy S
      • Khalil A
      • Morra ME
      • Islam SMS.
      First case of focal epilepsy associated with SARS-coronavirus-2.
      ,
      • Emami A
      • Fadakar N
      • Akbari A
      • et al.
      Seizure in patients with COVID-19.
      ,
      • Farhadian S
      • Glick LR
      • Vogels CBF
      • et al.
      Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.
      ,
      • García-Howard M
      • Herranz-Aguirre M
      • Moreno-Galarraga L
      • et al.
      Case report: benign infantile seizures temporally associated with COVID-19.
      ,
      • Haddad S
      • Tayyar R
      • Risch L
      • et al.
      Encephalopathy and seizure activity in a COVID-19 well controlled HIV patient.
      ,
      • Hafizi F
      • Kherani S
      • Shams M.
      Meningoencephalitis from SARS-CoV-2 infection.
      ,
      • Haider A
      • Siddiqa A
      • Ali N
      • Dhallu M.
      COVID-19 and the brain: acute encephalitis as a clinical manifestation.
      ,
      • Huang YH
      • Jiang D
      • Huang JT.
      SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis.
      ,
      • Karimi N SRA
      • Rouhani N
      Frequent convulsive seizures in an adult patient with COVID-19: a case report.
      ,
      • Kihira S
      • Delman BN
      • Belani P
      • et al.
      Imaging features of acute encephalopathy in patients with COVID-19: a case series.
      ,
      • Lyons S
      • O'Kelly B
      • Woods S
      • et al.
      Seizure with CSF lymphocytosis as a presenting feature of COVID-19 in an otherwise healthy young man.
      ,
      • McAbee GN
      • Brosgol Y
      • Pavlakis S
      • Agha R
      • Gaffoor M.
      Encephalitis associated with COVID-19 infection in an 11-year-old child.
      ,
      • Mirzaee SMM
      • Gonçalves FG
      • Mohammadifard M
      • Tavakoli SM
      • Vossough A.
      Focal cerebral arteriopathy in a pediatric patient with COVID-19.
      ,
      • Moriguchi T
      • Harii N
      • Goto J
      • et al.
      A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.
      ,
      • Paterson RW
      • Brown RL
      • Benjamin L
      • et al.
      The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.
      ,
      • Rebeiz T
      • Lim-Hing K
      • Khazanehdari S
      • Rebeiz K.
      Behavioral changes without respiratory symptoms as a presenting Sign of COVID-19 encephalitis.
      ,
      • Rifino N
      • Censori B
      • Agazzi E
      • et al.
      Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy.
      ,
      • Santos De Lima F
      • Issa N
      • Seibert K
      • et al.
      Epileptiform activity and seizures in patients with COVID-19.
      ,
      • Shahbaznejad L
      • Navaeifar MR
      • Abbaskhanian A
      • Hosseinzadeh F
      • Rahimzadeh G
      • Rezai MS.
      Clinical characteristics of 10 children with a pediatric inflammatory multisystem syndrome associated with COVID-19 in Iran.
      ,
      • Sripadma P
      • Rai A
      • Wadhwa C.
      Postpartum atypical posterior reversible encephalopathy syndrome in a COVID-19 patient - an obstetric emergency.
      ,
      • Westhoff TH
      • Seibert FS
      • Bauer F
      • et al.
      Allograft infiltration and meningoencephalitis by SARS-CoV-2 in a pancreas-kidney transplant recipient.
      ,
      • Zanin L
      • Saraceno G
      • Panciani PP
      • et al.
      SARS-CoV-2 can induce brain and spine demyelinating lesions.
      ]. Patients ranged in age from 6-weeks to 96-years-old. The majority of patients had no history of seizures, and had moderate or severe COVID-19 symptoms (based on WHO guidelines [

      HQ TWHO. Clinical Management of COVID-19: Interim Guidance. https://www.who.int/publications/i/item/clinical-management-of-covid-19. Published 2020. Updated 27 May 2020. Accessed.

      ]). Seizures were the initial symptom of COVID-19 in 15/69 (22%) patients. The majority of patients (42/69, 61%) had generalized seizures, and 26/69 (40%) patients had status epilepticus (clinical or subclinical). The time between seizure onset and lumbar puncture was specified for 15/69 (22%) patients (median of 1 day with interquartile range of -3- 4). Although the outcome for 13/69 (19%) patients remained unknown at the time of their respective article publication, the majority of patients recovered and were discharged from the hospital (43/56, 77%), but 13 (23%) died (Table 1).
      Table 1Patient characteristics.
      Patient age range6-weeks to 96-years-old
      History of seizure, n= 54
      Reported history of epilepsy2 (4%)
      Prior seizure not related to underlying epilepsy1 (2%)
      No prior seizure history51 (94%)
      COVID severity of disease, n = 44
      Mild COVID symptoms8 (18%)
      Moderate COVID symptoms18 (45%)
      Severe COVID symptoms18 (45%)
      Number of days between onset of COVID-19 symptoms and seizure n = 580–52 days [median 4 days, interquartile range (IQR) 0–10 days]
      Seizure as the presenting symptom, n = 6915 (22%)
      Seizure semiology, n = 69
      Generalized seizure42 (61%)
      Focal seizure8 (12%)
      Generalized and focal seizures2 (3%)
      Unspecified semiology17 (26%)
      EEG findings, n = 41
      Normal5 (12%)
      Abnormal, but without seizure or epileptiform discharges16 (39%)
      Abnormal with epileptiform discharges or other patterns at high risk for seizure, but without seizure9 (22%)
      Seizure11 (27%)
      Status epilepticus (clinical or subclinical), n = 6926 (40%)
      Neuroimaging results, n = 65
      Normal24 (37%)
      Abnormal, but with no discrete lesion9 (14%)
      Abnormal, with a discrete lesion32 (49%)
      Outcome, n = 69
      Recovered43 (62%)
      Dead13 (19%)
      Unknown13 (19%)

      3.1 CSF pleocytosis

      Though the CSF red blood cell count (RBC) was reported for only 19/69 (28%) patients [
      • Benameur K
      • Agarwal A
      • Auld SC
      • et al.
      Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Atlanta, Georgia, USA, 2020.
      ,
      • Carroll E
      • Neumann H
      • Aguero-Rosenfeld ME
      • et al.
      Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus.
      ,
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ,
      • Sattar SBA
      • Haider MA
      • Zia Z
      • Niazi M
      • Iqbal QZ.
      Clinical, radiological, and molecular findings of acute encephalitis in a COVID-19 patient: a rare case report.
      ,
      • Zambreanu L
      • Lightbody S
      • Bhandari M
      • et al.
      A case of limbic encephalitis associated with asymptomatic COVID-19 infection.
      ,
      • Anand P
      • Al-Faraj A
      • Sader E
      • et al.
      Seizure as the presenting symptom of COVID-19: a retrospective case series.
      ,
      • Ayatollahi P
      • Tarazi A
      • Wennberg R.
      Possible autoimmune encephalitis with claustrum sign in case of Acute SARS-CoV-2 Infection.
      ,
      • Canham LJW
      • Staniaszek LE
      • Mortimer AM
      • Nouri LF
      • Kane NM.
      Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: a case series.
      ,
      • Dugue R
      • Cay-Martínez KC
      • Thakur KT
      • et al.
      Neurologic manifestations in an infant with COVID-19.
      ,
      • Duong L
      • Xu P
      • Liu A.
      Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020.
      ,
      • Farhadian S
      • Glick LR
      • Vogels CBF
      • et al.
      Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.
      ,
      • Haddad S
      • Tayyar R
      • Risch L
      • et al.
      Encephalopathy and seizure activity in a COVID-19 well controlled HIV patient.
      ,
      • Hafizi F
      • Kherani S
      • Shams M.
      Meningoencephalitis from SARS-CoV-2 infection.
      ,
      • Haider A
      • Siddiqa A
      • Ali N
      • Dhallu M.
      COVID-19 and the brain: acute encephalitis as a clinical manifestation.
      ,
      • Lyons S
      • O'Kelly B
      • Woods S
      • et al.
      Seizure with CSF lymphocytosis as a presenting feature of COVID-19 in an otherwise healthy young man.
      ,
      • McAbee GN
      • Brosgol Y
      • Pavlakis S
      • Agha R
      • Gaffoor M.
      Encephalitis associated with COVID-19 infection in an 11-year-old child.
      ,
      • Mirzaee SMM
      • Gonçalves FG
      • Mohammadifard M
      • Tavakoli SM
      • Vossough A.
      Focal cerebral arteriopathy in a pediatric patient with COVID-19.
      ,

      Cai Y, Kim DJ, Takahashi T, et al. Kynurenic acid underlies sex-specific immune responses to COVID-19. medRxiv : the preprint server for health sciences. 2020.

      ], the CSF white blood cell (WBC) count was reported for 67/69 patients (97%). The CSF WBC count ranged from 0 to 350 cells/µL; one-third of patients (22/67 patients, 33%) had pleocytosis (CSF WBC count of >5 cells/µL) [
      • Dono F
      • Carrarini C
      • Russo M
      • et al.
      New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.
      ,

      Elkady A, Rabinstein AA. Acute necrotizing encephalopathy and myocarditis in a young patient with COVID-19. 2020;7(5):e801.

      ,
      • Ghosh R
      • Dubey S
      • Finsterer J
      • Chatterjee S
      • Ray BK.
      SARS-CoV-2-associated acute hemorrhagic, necrotizing encephalitis (AHNE) presenting with cognitive impairment in a 44-year-old woman without comorbidities: a case Report.
      ,
      • Guilmot A
      • Maldonado Slootjes S
      • Sellimi A
      • et al.
      Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Pilotto A
      • Masciocchi S
      • Volonghi I
      • et al.
      Clinical presentation and outcomes of SARS-CoV-2 related encephalitis: the ENCOVID multicentre study.
      ,
      • Sattar SBA
      • Haider MA
      • Zia Z
      • Niazi M
      • Iqbal QZ.
      Clinical, radiological, and molecular findings of acute encephalitis in a COVID-19 patient: a rare case report.
      ,
      • Anand P
      • Lau KHV
      • Chung DY
      • et al.
      Posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019: two cases and a review of the literature.
      ,
      • Ayatollahi P
      • Tarazi A
      • Wennberg R.
      Possible autoimmune encephalitis with claustrum sign in case of Acute SARS-CoV-2 Infection.
      ,
      • Bernard-Valnet R
      • Pizzarotti B
      • Anichini A
      • et al.
      Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection.
      ,
      • Canham LJW
      • Staniaszek LE
      • Mortimer AM
      • Nouri LF
      • Kane NM.
      Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: a case series.
      ,
      • Casez O
      • Willaume G
      • Grand S
      • et al.
      SARS-CoV-2 related encephalitis: MRI pattern of the olfactory tract involvement.
      ,
      • Dharsandiya M
      • Shah K
      • Patel K
      • Patel T
      • Patel A
      • Patel A.
      SARS-CoV-2 viral sepsis with meningoencephalitis.
      ,
      • Duong L
      • Xu P
      • Liu A.
      Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020.
      ,
      • Emami A
      • Fadakar N
      • Akbari A
      • et al.
      Seizure in patients with COVID-19.
      ,
      • Hafizi F
      • Kherani S
      • Shams M.
      Meningoencephalitis from SARS-CoV-2 infection.
      ,
      • Huang YH
      • Jiang D
      • Huang JT.
      SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis.
      ,
      • Lyons S
      • O'Kelly B
      • Woods S
      • et al.
      Seizure with CSF lymphocytosis as a presenting feature of COVID-19 in an otherwise healthy young man.
      ,
      • McAbee GN
      • Brosgol Y
      • Pavlakis S
      • Agha R
      • Gaffoor M.
      Encephalitis associated with COVID-19 infection in an 11-year-old child.
      ,
      • Moriguchi T
      • Harii N
      • Goto J
      • et al.
      A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.
      ,
      • Rebeiz T
      • Lim-Hing K
      • Khazanehdari S
      • Rebeiz K.
      Behavioral changes without respiratory symptoms as a presenting Sign of COVID-19 encephalitis.
      ], but the remainder of patients had a normal CSF WBC count. Only 8/22 (36%) patients with pleocytosis also had a CSF RBC count reported, all of whom had a CSF WBC:RBC ratio >1:500 [
      • Sattar SBA
      • Haider MA
      • Zia Z
      • Niazi M
      • Iqbal QZ.
      Clinical, radiological, and molecular findings of acute encephalitis in a COVID-19 patient: a rare case report.
      ,
      • Anand P
      • Lau KHV
      • Chung DY
      • et al.
      Posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019: two cases and a review of the literature.
      ,
      • Ayatollahi P
      • Tarazi A
      • Wennberg R.
      Possible autoimmune encephalitis with claustrum sign in case of Acute SARS-CoV-2 Infection.
      ,
      • Canham LJW
      • Staniaszek LE
      • Mortimer AM
      • Nouri LF
      • Kane NM.
      Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: a case series.
      ,
      • Duong L
      • Xu P
      • Liu A.
      Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020.
      ,
      • Hafizi F
      • Kherani S
      • Shams M.
      Meningoencephalitis from SARS-CoV-2 infection.
      ,
      • Huang YH
      • Jiang D
      • Huang JT.
      SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis.
      ,
      • Lyons S
      • O'Kelly B
      • Woods S
      • et al.
      Seizure with CSF lymphocytosis as a presenting feature of COVID-19 in an otherwise healthy young man.
      ,
      • McAbee GN
      • Brosgol Y
      • Pavlakis S
      • Agha R
      • Gaffoor M.
      Encephalitis associated with COVID-19 infection in an 11-year-old child.
      ]. Of the 24 patients who were in status epilepticus at some point during their clinical course whose CSF WBC count was reported, 10 (42%) had pleocytosis; the CSF WBC count ranged from 0 to 76 cells/µL (Fig. 2) [
      • Dono F
      • Carrarini C
      • Russo M
      • et al.
      New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.
      ,

      Elkady A, Rabinstein AA. Acute necrotizing encephalopathy and myocarditis in a young patient with COVID-19. 2020;7(5):e801.

      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Pilotto A
      • Masciocchi S
      • Volonghi I
      • et al.
      Clinical presentation and outcomes of SARS-CoV-2 related encephalitis: the ENCOVID multicentre study.
      ,
      • Bernard-Valnet R
      • Pizzarotti B
      • Anichini A
      • et al.
      Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection.
      ,
      • Canham LJW
      • Staniaszek LE
      • Mortimer AM
      • Nouri LF
      • Kane NM.
      Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: a case series.
      ,
      • Emami A
      • Fadakar N
      • Akbari A
      • et al.
      Seizure in patients with COVID-19.
      ,
      • McAbee GN
      • Brosgol Y
      • Pavlakis S
      • Agha R
      • Gaffoor M.
      Encephalitis associated with COVID-19 infection in an 11-year-old child.
      ,
      • Moriguchi T
      • Harii N
      • Goto J
      • et al.
      A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.
      ].
      The patient with the highest CSF WBC count (350 cells/µL) was reported by Rebeiz et al; the CSF RBC count was not provided, but the CSF protein was 297 mg/dL [
      • Rebeiz T
      • Lim-Hing K
      • Khazanehdari S
      • Rebeiz K.
      Behavioral changes without respiratory symptoms as a presenting Sign of COVID-19 encephalitis.
      ]. The patient was a man in his 30s who presented with fever and encephalopathy, then developed seizures a few weeks later and was found to have diffuse cortical, basal ganglia, and corpus callosum diffusion weighted imaging (DWI) changes on his MRI, felt to be consistent with encephalitis, and ultimately progressed to brain death.

      3.2 CSF Protein

      The CSF protein was reported for 64/69 (93%) patients [
      • Abdi S
      • Ghorbani A
      • Fatehi F.
      The association of SARS-CoV-2 infection and acute disseminated encephalomyelitis without prominent clinical pulmonary symptoms.
      ,
      • Benameur K
      • Agarwal A
      • Auld SC
      • et al.
      Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Atlanta, Georgia, USA, 2020.
      ,
      • Carroll E
      • Neumann H
      • Aguero-Rosenfeld ME
      • et al.
      Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus.
      ,
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,
      • Djellaoui A
      • Seddik L
      • Cleret De Langavant L
      • Cattan S
      • Bachoud-Lévi AC
      • Hosseini H
      Posterior reversible encephalopathy syndrome associated with SARS-CoV-2 infection.
      ,
      • Dono F
      • Carrarini C
      • Russo M
      • et al.
      New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.
      ,

      Elkady A, Rabinstein AA. Acute necrotizing encephalopathy and myocarditis in a young patient with COVID-19. 2020;7(5):e801.

      ,
      • Ghosh R
      • Dubey S
      • Finsterer J
      • Chatterjee S
      • Ray BK.
      SARS-CoV-2-associated acute hemorrhagic, necrotizing encephalitis (AHNE) presenting with cognitive impairment in a 44-year-old woman without comorbidities: a case Report.
      ,
      • Guilmot A
      • Maldonado Slootjes S
      • Sellimi A
      • et al.
      Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
      ,
      • Hosseini AA
      • Shetty AK
      • Sprigg N
      • Auer DP
      • Constantinescu CS.
      Delirium as a presenting feature in COVID-19: Neuroinvasive infection or autoimmune encephalopathy?.
      ,
      • Keller E
      • Brandi G
      • Winklhofer S
      • et al.
      Large and small cerebral vessel involvement in severe COVID-19: detailed clinical workup of a case series.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Pilotto A
      • Masciocchi S
      • Volonghi I
      • et al.
      Clinical presentation and outcomes of SARS-CoV-2 related encephalitis: the ENCOVID multicentre study.
      ,
      • Sattar SBA
      • Haider MA
      • Zia Z
      • Niazi M
      • Iqbal QZ.
      Clinical, radiological, and molecular findings of acute encephalitis in a COVID-19 patient: a rare case report.
      ,

      Song E, Chow RD, Jiang R, et al. Immunologically distinct responses occur in the CNS of COVID-19 patients. bioRxiv : the preprint server for biology.2020.

      ,
      • Zambreanu L
      • Lightbody S
      • Bhandari M
      • et al.
      A case of limbic encephalitis associated with asymptomatic COVID-19 infection.
      ,
      • Abdulsalam MA
      • Abdulsalam AJ
      • Shehab D.
      Generalized status epilepticus as a possible manifestation of COVID-19.
      ,
      • Afshar H
      • Yassin Z
      • Kalantari S
      • et al.
      Evolution and resolution of brain involvement associated with SARS- CoV2 infection: A close Clinical - Paraclinical follow up study of a case.
      ,
      • Anand P
      • Al-Faraj A
      • Sader E
      • et al.
      Seizure as the presenting symptom of COVID-19: a retrospective case series.
      ,
      • Anand P
      • Lau KHV
      • Chung DY
      • et al.
      Posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019: two cases and a review of the literature.
      ,
      • Ayatollahi P
      • Tarazi A
      • Wennberg R.
      Possible autoimmune encephalitis with claustrum sign in case of Acute SARS-CoV-2 Infection.
      ,
      • Balloy G
      • Leclair-Visonneau L
      • Péréon Y
      • et al.
      Non-lesional status epilepticus in a patient with coronavirus disease 2019.
      ,
      • Bellon M
      • Schweblin C
      • Lambeng N
      • et al.
      Cerebrospinal fluid features in SARS-CoV-2 RT-PCR positive patients.
      ,
      • Bernard-Valnet R
      • Pizzarotti B
      • Anichini A
      • et al.
      Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection.
      ,
      • Canham LJW
      • Staniaszek LE
      • Mortimer AM
      • Nouri LF
      • Kane NM.
      Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: a case series.
      ,
      • Conte G
      • Avignone S
      • Carbonara M
      • et al.
      COVID-19-associated PRES-like encephalopathy with perivascular gadolinium enhancement.
      ,
      • Dharsandiya M
      • Shah K
      • Patel K
      • Patel T
      • Patel A
      • Patel A.
      SARS-CoV-2 viral sepsis with meningoencephalitis.
      ,
      • Dixon L
      • Varley J
      • Gontsarova A
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ,
      • Doo FX
      • Kassim G
      • Lefton DR
      • Patterson S
      • Pham H
      • Belani P.
      Rare presentations of COVID-19: PRES-like leukoencephalopathy and carotid thrombosis.
      ,
      • Dugue R
      • Cay-Martínez KC
      • Thakur KT
      • et al.
      Neurologic manifestations in an infant with COVID-19.
      ,
      • Duong L
      • Xu P
      • Liu A.
      Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020.
      ,
      • Emami A
      • Fadakar N
      • Akbari A
      • et al.
      Seizure in patients with COVID-19.
      ,
      • Farhadian S
      • Glick LR
      • Vogels CBF
      • et al.
      Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.
      ,
      • García-Howard M
      • Herranz-Aguirre M
      • Moreno-Galarraga L
      • et al.
      Case report: benign infantile seizures temporally associated with COVID-19.
      ,
      • Haddad S
      • Tayyar R
      • Risch L
      • et al.
      Encephalopathy and seizure activity in a COVID-19 well controlled HIV patient.
      ,
      • Hafizi F
      • Kherani S
      • Shams M.
      Meningoencephalitis from SARS-CoV-2 infection.
      ,
      • Haider A
      • Siddiqa A
      • Ali N
      • Dhallu M.
      COVID-19 and the brain: acute encephalitis as a clinical manifestation.
      ,
      • Huang YH
      • Jiang D
      • Huang JT.
      SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis.
      ,
      • Karimi N SRA
      • Rouhani N
      Frequent convulsive seizures in an adult patient with COVID-19: a case report.
      ,
      • Kihira S
      • Delman BN
      • Belani P
      • et al.
      Imaging features of acute encephalopathy in patients with COVID-19: a case series.
      ,
      • Lyons S
      • O'Kelly B
      • Woods S
      • et al.
      Seizure with CSF lymphocytosis as a presenting feature of COVID-19 in an otherwise healthy young man.
      ,
      • McAbee GN
      • Brosgol Y
      • Pavlakis S
      • Agha R
      • Gaffoor M.
      Encephalitis associated with COVID-19 infection in an 11-year-old child.
      ,
      • Mirzaee SMM
      • Gonçalves FG
      • Mohammadifard M
      • Tavakoli SM
      • Vossough A.
      Focal cerebral arteriopathy in a pediatric patient with COVID-19.
      ,
      • Paterson RW
      • Brown RL
      • Benjamin L
      • et al.
      The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.
      ,
      • Rebeiz T
      • Lim-Hing K
      • Khazanehdari S
      • Rebeiz K.
      Behavioral changes without respiratory symptoms as a presenting Sign of COVID-19 encephalitis.
      ,
      • Rifino N
      • Censori B
      • Agazzi E
      • et al.
      Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy.
      ,
      • Shahbaznejad L
      • Navaeifar MR
      • Abbaskhanian A
      • Hosseinzadeh F
      • Rahimzadeh G
      • Rezai MS.
      Clinical characteristics of 10 children with a pediatric inflammatory multisystem syndrome associated with COVID-19 in Iran.
      ,
      • Sripadma P
      • Rai A
      • Wadhwa C.
      Postpartum atypical posterior reversible encephalopathy syndrome in a COVID-19 patient - an obstetric emergency.
      ,
      • Westhoff TH
      • Seibert FS
      • Bauer F
      • et al.
      Allograft infiltration and meningoencephalitis by SARS-CoV-2 in a pancreas-kidney transplant recipient.
      ,
      • Zanin L
      • Saraceno G
      • Panciani PP
      • et al.
      SARS-CoV-2 can induce brain and spine demyelinating lesions.
      ,
      • Bigaut K
      • Mallaret M
      • Baloglu S
      • et al.
      Guillain-Barre syndrome related to SARS-CoV-2 infection.
      ] and ranged from 15 to 541 mg/dL. There were 27 patients (39%) with CSF protein >60 mg/dL [
      • Carroll E
      • Neumann H
      • Aguero-Rosenfeld ME
      • et al.
      Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus.
      ,
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,
      • Ghosh R
      • Dubey S
      • Finsterer J
      • Chatterjee S
      • Ray BK.
      SARS-CoV-2-associated acute hemorrhagic, necrotizing encephalitis (AHNE) presenting with cognitive impairment in a 44-year-old woman without comorbidities: a case Report.
      ,
      • Hosseini AA
      • Shetty AK
      • Sprigg N
      • Auer DP
      • Constantinescu CS.
      Delirium as a presenting feature in COVID-19: Neuroinvasive infection or autoimmune encephalopathy?.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Pilotto A
      • Masciocchi S
      • Volonghi I
      • et al.
      Clinical presentation and outcomes of SARS-CoV-2 related encephalitis: the ENCOVID multicentre study.
      ,

      Song E, Chow RD, Jiang R, et al. Immunologically distinct responses occur in the CNS of COVID-19 patients. bioRxiv : the preprint server for biology.2020.

      ,
      • Zambreanu L
      • Lightbody S
      • Bhandari M
      • et al.
      A case of limbic encephalitis associated with asymptomatic COVID-19 infection.
      ,
      • Abdulsalam MA
      • Abdulsalam AJ
      • Shehab D.
      Generalized status epilepticus as a possible manifestation of COVID-19.
      ,
      • Anand P
      • Lau KHV
      • Chung DY
      • et al.
      Posterior reversible encephalopathy syndrome in patients with coronavirus disease 2019: two cases and a review of the literature.
      ,
      • Bernard-Valnet R
      • Pizzarotti B
      • Anichini A
      • et al.
      Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection.
      ,
      • Canham LJW
      • Staniaszek LE
      • Mortimer AM
      • Nouri LF
      • Kane NM.
      Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: a case series.
      ,
      • Conte G
      • Avignone S
      • Carbonara M
      • et al.
      COVID-19-associated PRES-like encephalopathy with perivascular gadolinium enhancement.
      ,
      • Dixon L
      • Varley J
      • Gontsarova A
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ,
      • Doo FX
      • Kassim G
      • Lefton DR
      • Patterson S
      • Pham H
      • Belani P.
      Rare presentations of COVID-19: PRES-like leukoencephalopathy and carotid thrombosis.
      ,
      • Duong L
      • Xu P
      • Liu A.
      Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020.
      ,
      • Elgamasy S
      • Kamel MG
      • Ghozy S
      • Khalil A
      • Morra ME
      • Islam SMS.
      First case of focal epilepsy associated with SARS-coronavirus-2.
      ,
      • Haddad S
      • Tayyar R
      • Risch L
      • et al.
      Encephalopathy and seizure activity in a COVID-19 well controlled HIV patient.
      ,
      • Hafizi F
      • Kherani S
      • Shams M.
      Meningoencephalitis from SARS-CoV-2 infection.
      ,
      • Haider A
      • Siddiqa A
      • Ali N
      • Dhallu M.
      COVID-19 and the brain: acute encephalitis as a clinical manifestation.
      ,
      • Huang YH
      • Jiang D
      • Huang JT.
      SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis.
      ,
      • McAbee GN
      • Brosgol Y
      • Pavlakis S
      • Agha R
      • Gaffoor M.
      Encephalitis associated with COVID-19 infection in an 11-year-old child.
      ,
      • Paterson RW
      • Brown RL
      • Benjamin L
      • et al.
      The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.
      ,
      • Rebeiz T
      • Lim-Hing K
      • Khazanehdari S
      • Rebeiz K.
      Behavioral changes without respiratory symptoms as a presenting Sign of COVID-19 encephalitis.
      ,
      • Westhoff TH
      • Seibert FS
      • Bauer F
      • et al.
      Allograft infiltration and meningoencephalitis by SARS-CoV-2 in a pancreas-kidney transplant recipient.
      ]. Half of the patients (13/26, 48%) who were in status epilepticus at some point during their clinical course had a CSF protein >60 mg/dL (Fig. 3) [
      • Carroll E
      • Neumann H
      • Aguero-Rosenfeld ME
      • et al.
      Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus.
      ,
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,

      Elkady A, Rabinstein AA. Acute necrotizing encephalopathy and myocarditis in a young patient with COVID-19. 2020;7(5):e801.

      ,
      • Hosseini AA
      • Shetty AK
      • Sprigg N
      • Auer DP
      • Constantinescu CS.
      Delirium as a presenting feature in COVID-19: Neuroinvasive infection or autoimmune encephalopathy?.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Pilotto A
      • Masciocchi S
      • Volonghi I
      • et al.
      Clinical presentation and outcomes of SARS-CoV-2 related encephalitis: the ENCOVID multicentre study.
      ,
      • Abdulsalam MA
      • Abdulsalam AJ
      • Shehab D.
      Generalized status epilepticus as a possible manifestation of COVID-19.
      ,
      • Bernard-Valnet R
      • Pizzarotti B
      • Anichini A
      • et al.
      Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection.
      ,
      • Canham LJW
      • Staniaszek LE
      • Mortimer AM
      • Nouri LF
      • Kane NM.
      Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: a case series.
      ,
      • Conte G
      • Avignone S
      • Carbonara M
      • et al.
      COVID-19-associated PRES-like encephalopathy with perivascular gadolinium enhancement.
      ,
      • Doo FX
      • Kassim G
      • Lefton DR
      • Patterson S
      • Pham H
      • Belani P.
      Rare presentations of COVID-19: PRES-like leukoencephalopathy and carotid thrombosis.
      ,
      • Emami A
      • Fadakar N
      • Akbari A
      • et al.
      Seizure in patients with COVID-19.
      ,
      • McAbee GN
      • Brosgol Y
      • Pavlakis S
      • Agha R
      • Gaffoor M.
      Encephalitis associated with COVID-19 infection in an 11-year-old child.
      ,
      • Paterson RW
      • Brown RL
      • Benjamin L
      • et al.
      The emerging spectrum of COVID-19 neurology: clinical, radiological and laboratory findings.
      ].
      The patient with the highest CSF protein (541 mg/dL) was a 33-year-old woman with generalized status epilepticus reported by Elkady et al [

      Elkady A, Rabinstein AA. Acute necrotizing encephalopathy and myocarditis in a young patient with COVID-19. 2020;7(5):e801.

      ]. Her CSF was also notable for a WBC count of 26 cells/µL and neuroimaging showed diffuse brain swelling with bilateral hemorrhagic thalamic and cerebellar lesions, which were attributed to acute necrotizing encephalopathy. Despite treatment with high-dose steroids, she had a cardiac arrest five days after admission and died.

      3.3 CSF SARS-CoV 2 PCR

      SARS-CoV-2 PCR testing was performed in the CSF for 45/69 (65%) patients [
      • Carroll E
      • Neumann H
      • Aguero-Rosenfeld ME
      • et al.
      Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus.
      ,
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,
      • Djellaoui A
      • Seddik L
      • Cleret De Langavant L
      • Cattan S
      • Bachoud-Lévi AC
      • Hosseini H
      Posterior reversible encephalopathy syndrome associated with SARS-CoV-2 infection.
      ,
      • Dono F
      • Carrarini C
      • Russo M
      • et al.
      New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.
      ,
      • Edén A
      • Kanberg N
      • Gostner J
      • et al.
      CSF biomarkers in patients with COVID-19 and neurological symptoms: a case series.
      ,
      • Guilmot A
      • Maldonado Slootjes S
      • Sellimi A
      • et al.
      Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
      ,
      • Hosseini AA
      • Shetty AK
      • Sprigg N
      • Auer DP
      • Constantinescu CS.
      Delirium as a presenting feature in COVID-19: Neuroinvasive infection or autoimmune encephalopathy?.
      ,
      • Keller E
      • Brandi G
      • Winklhofer S
      • et al.
      Large and small cerebral vessel involvement in severe COVID-19: detailed clinical workup of a case series.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Pilotto A
      • Masciocchi S
      • Volonghi I
      • et al.
      Clinical presentation and outcomes of SARS-CoV-2 related encephalitis: the ENCOVID multicentre study.
      ,
      • Sattar SBA
      • Haider MA
      • Zia Z
      • Niazi M
      • Iqbal QZ.
      Clinical, radiological, and molecular findings of acute encephalitis in a COVID-19 patient: a rare case report.
      ,
      • Zambreanu L
      • Lightbody S
      • Bhandari M
      • et al.
      A case of limbic encephalitis associated with asymptomatic COVID-19 infection.
      ,
      • Afshar H
      • Yassin Z
      • Kalantari S
      • et al.
      Evolution and resolution of brain involvement associated with SARS- CoV2 infection: A close Clinical - Paraclinical follow up study of a case.
      ,
      • Ayatollahi P
      • Tarazi A
      • Wennberg R.
      Possible autoimmune encephalitis with claustrum sign in case of Acute SARS-CoV-2 Infection.
      ,
      • Balloy G
      • Leclair-Visonneau L
      • Péréon Y
      • et al.
      Non-lesional status epilepticus in a patient with coronavirus disease 2019.
      ,
      • Bellon M
      • Schweblin C
      • Lambeng N
      • et al.
      Cerebrospinal fluid features in SARS-CoV-2 RT-PCR positive patients.
      ,
      • Bernard-Valnet R
      • Pizzarotti B
      • Anichini A
      • et al.
      Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection.
      ,
      • Canham LJW
      • Staniaszek LE
      • Mortimer AM
      • Nouri LF
      • Kane NM.
      Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: a case series.
      ,
      • Casez O
      • Willaume G
      • Grand S
      • et al.
      SARS-CoV-2 related encephalitis: MRI pattern of the olfactory tract involvement.
      ,
      • Conte G
      • Avignone S
      • Carbonara M
      • et al.
      COVID-19-associated PRES-like encephalopathy with perivascular gadolinium enhancement.
      ,
      • Dixon L
      • Varley J
      • Gontsarova A
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ,
      • Dugue R
      • Cay-Martínez KC
      • Thakur KT
      • et al.
      Neurologic manifestations in an infant with COVID-19.
      ,
      • Duong L
      • Xu P
      • Liu A.
      Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020.
      ,
      • Farhadian S
      • Glick LR
      • Vogels CBF
      • et al.
      Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.
      ,
      • Huang YH
      • Jiang D
      • Huang JT.
      SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis.
      ,
      • Karimi N SRA
      • Rouhani N
      Frequent convulsive seizures in an adult patient with COVID-19: a case report.
      ,
      • Kihira S
      • Delman BN
      • Belani P
      • et al.
      Imaging features of acute encephalopathy in patients with COVID-19: a case series.
      ,
      • Lyons S
      • O'Kelly B
      • Woods S
      • et al.
      Seizure with CSF lymphocytosis as a presenting feature of COVID-19 in an otherwise healthy young man.
      ,
      • Mirzaee SMM
      • Gonçalves FG
      • Mohammadifard M
      • Tavakoli SM
      • Vossough A.
      Focal cerebral arteriopathy in a pediatric patient with COVID-19.
      ,
      • Moriguchi T
      • Harii N
      • Goto J
      • et al.
      A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.
      ,
      • Rifino N
      • Censori B
      • Agazzi E
      • et al.
      Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy.
      ,
      • Santos De Lima F
      • Issa N
      • Seibert K
      • et al.
      Epileptiform activity and seizures in patients with COVID-19.
      ,
      • Westhoff TH
      • Seibert FS
      • Bauer F
      • et al.
      Allograft infiltration and meningoencephalitis by SARS-CoV-2 in a pancreas-kidney transplant recipient.
      ,
      • Zanin L
      • Saraceno G
      • Panciani PP
      • et al.
      SARS-CoV-2 can induce brain and spine demyelinating lesions.
      ]. Of these, 6/45 (13%) had a positive CSF SARS-CoV-2 PCR, 1 (17%) of whom was in status epilepticus at some point during their clinical course [
      • Sattar SBA
      • Haider MA
      • Zia Z
      • Niazi M
      • Iqbal QZ.
      Clinical, radiological, and molecular findings of acute encephalitis in a COVID-19 patient: a rare case report.
      ,
      • Duong L
      • Xu P
      • Liu A.
      Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020.
      ,
      • Huang YH
      • Jiang D
      • Huang JT.
      SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis.
      ,
      • Mirzaee SMM
      • Gonçalves FG
      • Mohammadifard M
      • Tavakoli SM
      • Vossough A.
      Focal cerebral arteriopathy in a pediatric patient with COVID-19.
      ,
      • Moriguchi T
      • Harii N
      • Goto J
      • et al.
      A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.
      ,
      • Rifino N
      • Censori B
      • Agazzi E
      • et al.
      Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy.
      ,
      • Westhoff TH
      • Seibert FS
      • Bauer F
      • et al.
      Allograft infiltration and meningoencephalitis by SARS-CoV-2 in a pancreas-kidney transplant recipient.
      ]. The cycle threshold (the number of amplification cycles required for the target gene to exceed the threshold, which is inversely related to viral load) was not reported for any of these patients. Of the four patients with a positive CSF SARS-CoV-2 PCR whose severity of COVID-19 was noted, 2 (50%) had moderate COVID-19. EEG results were only provided for two patients with a positive CSF SARS-CoV-2 PCR; one had a normal EEG and the other had an abnormal EEG, but no epileptiform activity. The majority (4/6, 66%) of patients with a positive CSF SARS-CoV-2 PCR had abnormal neuroimaging (Table 2).
      Table 2Patients with Positive SARS-CoV-2 CSF PCR.
      AuthorAge/SexHistory of epilepsySeverity of COVID-19Number of days between onset of illness and seizureStatus epilepticusEEG findingsCSF RBC count (cells/µL)CSF WBC count (cells/µL)CSF protein (mg/dL)SARS-CoV-2 CSF PCRCSF SARS-CoV-2 AbCSF Oligoclonal BandsCSF autoimmune antibody panelImaging findingsOutcome
      Duong et al.
      • Afshar H
      • Yassin Z
      • Kalantari S
      • et al.
      Evolution and resolution of brain involvement associated with SARS- CoV2 infection: A close Clinical - Paraclinical follow up study of a case.
      and Huang et al
      • Duong L
      • Xu P
      • Liu A.
      Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020.
      41FNMildNRNAbnormal, but w/o epileptiform activity6570100+NRNRNRNormal CTRecovered
      Mirzaee et al
      • Mirzaee SMM
      • Gonçalves FG
      • Mohammadifard M
      • Tavakoli SM
      • Vossough A.
      Focal cerebral arteriopathy in a pediatric patient with COVID-19.
      12MNNR0NNR100021+NRNRNRAcute strokes in the left middle cerebral artery territory with associated microhemorrhagesRecovered
      Moriguchi et al
      • Moriguchi T
      • Harii N
      • Goto J
      • et al.
      A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.
      24MNModerate9YNRNR12NR+NRNRNRHyperintense signal along the wall of the lateral ventricle and in the temporal lobe, hippocampal atrophy, pan-paranasal sinusitisUnknown
      Rifino et al
      • Rifino N
      • Censori B
      • Agazzi E
      • et al.
      Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy.
      60MNNR0NNormalNRNormalNormal+NRNRNRNormal CTRecovered
      Sattar et al
      • Sattar SBA
      • Haider MA
      • Zia Z
      • Niazi M
      • Iqbal QZ.
      Clinical, radiological, and molecular findings of acute encephalitis in a COVID-19 patient: a rare case report.
      44MNSevere27NNR16851139+NR--Bifrontal hyperintensitiesRecovered
      Westhoff et al
      • Westhoff TH
      • Seibert FS
      • Bauer F
      • et al.
      Allograft infiltration and meningoencephalitis by SARS-CoV-2 in a pancreas-kidney transplant recipient.
      69MNModerate10NNRNR1110+NRNRNRMeningeal enhancement and white matter edema without mass effectRecovered

      3.4 CSF SARS-CoV-2 antibody testing

      SARS-CoV-2 antibody testing was reported in the CSF for 2/69 (3%) patients [
      • Benameur K
      • Agarwal A
      • Auld SC
      • et al.
      Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Atlanta, Georgia, USA, 2020.
      ,

      Song E, Chow RD, Jiang R, et al. Immunologically distinct responses occur in the CNS of COVID-19 patients. bioRxiv : the preprint server for biology.2020.

      ]; both were positive.
      Song et al. evaluated CSF and serum SARS-CoV-2 antibodies in a 60-year-old man who had a seizure [

      Song E, Chow RD, Jiang R, et al. Immunologically distinct responses occur in the CNS of COVID-19 patients. bioRxiv : the preprint server for biology.2020.

      ]. Though details of his clinical course were not available for review, his CSF analysis revealed a WBC count of 2 cells/µL, protein of 66 mg/dL, and positive SARS-CoV-2 antibodies. A SARS-CoV-2 epitope Luminex panel was used to compared CSF and serum SARS-CoV-2 antibodies. This demonstrated there were unique antibodies specific to different regions of the spike protein in both compartments. Though his individual CSF biomarkers were not provided, they were included in a cumulative analysis of six patients with COVID-19 who had CSF testing, and when compared to controls, the patients with COVID-19 had elevated CSF Interleukin-8 (IL-8), Interleukin-1β (IL-1β), Interleukin-12 (IL-12) and Fibroblast Growth Factor-2 (FGF-2). These biomarkers were all normal in plasma, prompting the authors to conclude patients with COVID-19 have an immunologically distinct response in the central nervous system. Clinical outcome was not reported.
      Benameur et al reported a 34-year-old man with hypertension who presented with fever, shortness of breath, and cough [
      • Benameur K
      • Agarwal A
      • Auld SC
      • et al.
      Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Atlanta, Georgia, USA, 2020.
      ]. Nasopharyngeal SARS-CoV-2 PCR was positive. His respiratory status declined and he required intubation, after which he developed encephalopathy with myoclonus on hospital day nine. EEG suggested that the myoclonus was “seizure-related.” MRI on hospital day 15 showed a non-enhancing hyperintense lesion within the splenium of the corpus callosum. CSF analysis revealed an elevated opening pressure of 48 cm H2O, no pleocytosis, and mildly increased protein. CSF SARS-CoV-2 PCR was negative, but CSF SARS-CoV-2 antibody testing was positive. No further testing was performed to distinguish intrathecal antibody synthesis from transudation of antibodies, or antibody-secreting cells, into the CSF via a damaged blood-brain barrier. Several CSF biomarkers were sent; while Interleukin-10 (IL-10) was normal, Interleukin-6 (IL-6), IL-8, Interferon Gamma Induced Protein-10 (IP-10), Tumor Necrosis Factor-α (TNF-α), and IL-1β were all elevated compared to healthy controls. Serum inflammatory markers were not sent. Clinical outcome was not reported.

      3.5 Oligoclonal bands

      CSF oligoclonal bands were tested in 22/69 (31%) patients [
      • Abdi S
      • Ghorbani A
      • Fatehi F.
      The association of SARS-CoV-2 infection and acute disseminated encephalomyelitis without prominent clinical pulmonary symptoms.
      ,
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,
      • Djellaoui A
      • Seddik L
      • Cleret De Langavant L
      • Cattan S
      • Bachoud-Lévi AC
      • Hosseini H
      Posterior reversible encephalopathy syndrome associated with SARS-CoV-2 infection.
      ,
      • Dono F
      • Carrarini C
      • Russo M
      • et al.
      New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.
      ,

      Elkady A, Rabinstein AA. Acute necrotizing encephalopathy and myocarditis in a young patient with COVID-19. 2020;7(5):e801.

      ,
      • Ghosh R
      • Dubey S
      • Finsterer J
      • Chatterjee S
      • Ray BK.
      SARS-CoV-2-associated acute hemorrhagic, necrotizing encephalitis (AHNE) presenting with cognitive impairment in a 44-year-old woman without comorbidities: a case Report.
      ,
      • Guilmot A
      • Maldonado Slootjes S
      • Sellimi A
      • et al.
      Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
      ,
      • Hosseini AA
      • Shetty AK
      • Sprigg N
      • Auer DP
      • Constantinescu CS.
      Delirium as a presenting feature in COVID-19: Neuroinvasive infection or autoimmune encephalopathy?.
      ,
      • Keller E
      • Brandi G
      • Winklhofer S
      • et al.
      Large and small cerebral vessel involvement in severe COVID-19: detailed clinical workup of a case series.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Pilotto A
      • Masciocchi S
      • Volonghi I
      • et al.
      Clinical presentation and outcomes of SARS-CoV-2 related encephalitis: the ENCOVID multicentre study.
      ,
      • Sattar SBA
      • Haider MA
      • Zia Z
      • Niazi M
      • Iqbal QZ.
      Clinical, radiological, and molecular findings of acute encephalitis in a COVID-19 patient: a rare case report.
      ,
      • Zambreanu L
      • Lightbody S
      • Bhandari M
      • et al.
      A case of limbic encephalitis associated with asymptomatic COVID-19 infection.
      ,
      • Afshar H
      • Yassin Z
      • Kalantari S
      • et al.
      Evolution and resolution of brain involvement associated with SARS- CoV2 infection: A close Clinical - Paraclinical follow up study of a case.
      ]. One patient had oligoclonal bands specific to the CSF [
      • Guilmot A
      • Maldonado Slootjes S
      • Sellimi A
      • et al.
      Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
      ], and one patient had positive oligoclonal bands in the CSF, but it was not delineated if these were matched or unmatched in the serum [
      • Dono F
      • Carrarini C
      • Russo M
      • et al.
      New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.
      ].
      Guilmot et al reported an 80-year-old patient who presented with two weeks of asthenia and weight loss, followed by paroxysmal episodes of dysarthria, a generalized tonic-clonic seizure, and neuropsychiatric symptoms [
      • Guilmot A
      • Maldonado Slootjes S
      • Sellimi A
      • et al.
      Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
      ]. He had no respiratory symptoms. MRI was unremarkable, and EEG demonstrated generalized slowing. CSF analysis was notable for a WBC count of 9 cells/µL, protein of 46 mg/dL, CSF-specific IgG oligoclonal bands, and positive anti-contactin-associated-protein 2 (Caspr2) IgG antibodies, which were also present in the serum. The authors did not mention whether an oncological workup was performed. The patient was treated with levetiracetam, methylprednisolone, and plasmapheresis, and had no additional seizures.
      Dono et al reported an 81-year-old man with hypertension who presented with fever, dyspnea, and cough for seven days [
      • Dono F
      • Carrarini C
      • Russo M
      • et al.
      New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.
      ]. On day 14, he became mildly confused. EEG at that time showed no epileptiform discharges, but on day 16, his mental status worsened, and he developed myoclonic jerking; EEG was consistent with status epilepticus, and he required aggressive escalation of anti-seizure medications including a midazolam infusion. On day 23, MRI showed multiple non-enhancing hyperintense areas in the bilateral parietal cortex, left temporal cortex, and right cingulate cortex. CSF examination showed a WBC count of 26 cells/µL, normal glucose, protein of 47 mg/dL, and positive oligoclonal bands. However, it was not noted whether these bands were matched in the serum. He had a cardiac arrest and died 45 days after admission.

      3.6 CSF Immunoglobulins

      Of the 60 patients who had seizures in the setting of COVID-19 and did not have a positive CSF SARS-CoV-2 PCR, CSF SARS-CoV-2 antibodies or CSF-specific oligoclonal bands, 6 had CSF immunoglobulins measured, only 1 of which was elevated [
      • Benameur K
      • Agarwal A
      • Auld SC
      • et al.
      Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Atlanta, Georgia, USA, 2020.
      ,
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,
      • Edén A
      • Kanberg N
      • Gostner J
      • et al.
      CSF biomarkers in patients with COVID-19 and neurological symptoms: a case series.
      ,
      • Keller E
      • Brandi G
      • Winklhofer S
      • et al.
      Large and small cerebral vessel involvement in severe COVID-19: detailed clinical workup of a case series.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Farhadian S
      • Glick LR
      • Vogels CBF
      • et al.
      Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.
      ,
      • Rebeiz T
      • Lim-Hing K
      • Khazanehdari S
      • Rebeiz K.
      Behavioral changes without respiratory symptoms as a presenting Sign of COVID-19 encephalitis.
      ]. Ghosh et al reported a 44-year-old woman who developed fever, myalgias, cough, and hypogeusia 10 days prior to hospital admission [
      • Ghosh R
      • Dubey S
      • Finsterer J
      • Chatterjee S
      • Ray BK.
      SARS-CoV-2-associated acute hemorrhagic, necrotizing encephalitis (AHNE) presenting with cognitive impairment in a 44-year-old woman without comorbidities: a case Report.
      ]. She became encephalopathic 7 days after symptom onset, then presented to the hospital 3 days later after she had a generalized tonic-clonic seizure. MRI brain revealed a frontoparietal hyperintense lesion with surrounding edema and a focus of hemorrhage. Her CSF analysis was notable for pleocytosis with WBC count of 20 cells/µL, normal protein, and an elevated IgG index (no value provided), with no evidence of oligoclonal bands. The authors did not conclude these findings were consistent with intrathecal antibody synthesis.

      3.7 Autoimmune antibodies

      In addition to the aforementioned patient reported by Guilmot et al who had Caspr2 IgG antibodies in the CSF, there were 10 other patients (11/69; 16%) whose CSF results included an autoimmune antibody panel [
      • Carroll E
      • Neumann H
      • Aguero-Rosenfeld ME
      • et al.
      Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus.
      ,
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,
      • Dono F
      • Carrarini C
      • Russo M
      • et al.
      New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.
      ,
      • Guilmot A
      • Maldonado Slootjes S
      • Sellimi A
      • et al.
      Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
      ,
      • Hosseini AA
      • Shetty AK
      • Sprigg N
      • Auer DP
      • Constantinescu CS.
      Delirium as a presenting feature in COVID-19: Neuroinvasive infection or autoimmune encephalopathy?.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Pilotto A
      • Masciocchi S
      • Volonghi I
      • et al.
      Clinical presentation and outcomes of SARS-CoV-2 related encephalitis: the ENCOVID multicentre study.
      ,
      • Sattar SBA
      • Haider MA
      • Zia Z
      • Niazi M
      • Iqbal QZ.
      Clinical, radiological, and molecular findings of acute encephalitis in a COVID-19 patient: a rare case report.
      ,
      • Zambreanu L
      • Lightbody S
      • Bhandari M
      • et al.
      A case of limbic encephalitis associated with asymptomatic COVID-19 infection.
      ,
      • Bernard-Valnet R
      • Pizzarotti B
      • Anichini A
      • et al.
      Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection.
      ]. Though the majority (9/11, 82%) of these were negative, a patient described by Monti et al had N-Methyl-D-aspartate (NMDA) antibodies in the CSF [
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ].
      The patient was a 50-year-old man who had new psychiatric symptoms for four days then began having focal motor seizures with impaired awareness. He went on to develop refractory status epilepticus which lasted for 47 days. Initial CSF analysis was notable for WBC count of 76 cells/µL and slightly elevated protein. Repeat lumbar puncture one week later showed CSF WBC count of 25 cells/µL and normal protein. Oligoclonal bands were present, but matched in serum, and IgG index was normal. NMDA antibodies were present in the CSF, but not serum. CSF and serum IL-6 were elevated (4.58 pg/mL with normal not reported and 52 pg/mL with reported normal <10 pg/mL, respectively). CSF IL-8 was also elevated (40.1 pg/mL; normal not reported), but TNF-α and IL-1β were normal. One month later, the CSF WBC count was 16 cells/µL and the protein was 105 mg/dL, oligoclonal bands were no longer present, the IgG index was elevated (1.45 with reported normal <0.7) and NMDA antibodies were still present in the CSF, but not the serum. CSF and serum IL-6 increased further to 5.75 pg/mL and 206 pg/mL, respectively, as did CSF IL-8 (744 pg/mL). Oncologic workup was unrevealing. After a four-month hospital course, during which he was treated with plasma-exchange and two rounds of intravenous immunoglobulin, he was discharged in good condition.

      3.8 Other CSF biomarkers

      In addition to the aforementioned patients described by Song et al, Benameur et al, and Monti et al, CSF biomarkers were tested in the CSF of 3 or 4 other patients (Keller at al described 5 patients with COVID-19 who had neurological symptoms, only 1 of whom had seizures, and reported 4/5 had elevated CSF IL-6, but it is not clear if the patient with seizures was amongst those with elevated CSF IL-6) [
      • Benameur K
      • Agarwal A
      • Auld SC
      • et al.
      Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Atlanta, Georgia, USA, 2020.
      ,
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,
      • Edén A
      • Kanberg N
      • Gostner J
      • et al.
      CSF biomarkers in patients with COVID-19 and neurological symptoms: a case series.
      ,
      • Keller E
      • Brandi G
      • Winklhofer S
      • et al.
      Large and small cerebral vessel involvement in severe COVID-19: detailed clinical workup of a case series.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Farhadian S
      • Glick LR
      • Vogels CBF
      • et al.
      Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.
      ].
      Le Guennec et al and Delorme et al described a 69-year-old man who developed status epilepticus following five days of cough, fever, and anosmia [
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ]. CSF analysis was notable for a WBC count of 1 cell/µL, protein of 66 mg/dL, and normal glucose. IL-6 was elevated in both the CSF and serum (16 pg/mL in CSF with reported normal <2.5 pg/mL and 28.8 pg/mL in serum with reported normal <6.5 pg/mL). Tau was also markedly elevated (>2,000 pg/mL, normal range 150–450 pg/ml); the authors suggested that this could be secondary to a pre-existing neurodegenerative process but may also reflect neuronal damage in the setting of encephalitis/status epilepticus. Several additional CSF biomarkers were sent, including IL-10, which was normal; β-amyloid, which was low (570 pg/ml, normal range 650–2000 pg/ml); and Interferon-α (INF-α), which was negative. The patient improved following treatment with intravenous immunoglobulin and was successfully extubated one week after admission.
      Farhadian et al reported a 78-year-old kidney transplant recipient on tacrolimus and mycophenolate mofetil who presented with 3 days of moderate COVID-19 symptoms and confusion, then had a generalized tonic-clonic seizure on the day of admission [
      • Farhadian S
      • Glick LR
      • Vogels CBF
      • et al.
      Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.
      ]. CSF analysis revealed RBC count of 350 cells/µL, WBC count of 1 cells/µL, and normal protein. IL-6, IL-8, Interleukin-17A (IL-17A), and IP-10 were elevated in both the serum and CSF when compared to control patients. IL-10 was normal in both the serum and CSF. Monocyte Chemoattractant Protein-1 (MCP-1) was uniquely elevated in the CSF. MRI brain revealed generalized atrophy and patchy subcortical white matter disease. She was treated with tocilizumab and hydroxychloroquine and was discharged after one month.
      Eden et al reported a 60-year-old man with cardiac disease, diabetes mellitus, hypertension, and obesity, who developed severe COVID-19 requiring intubation [
      • Edén A
      • Kanberg N
      • Gostner J
      • et al.
      CSF biomarkers in patients with COVID-19 and neurological symptoms: a case series.
      ]. He later had multiple seizures, but the semiology was not noted, and it was not mentioned if he met criteria for status epilepticus. NCHCT was normal, and EEG was remarkable only for generalized background slowing. CSF analysis revealed a normal WBC count (<3cells/µL), negative SARS-CoV-2 PCR, and normal IgG index, but elevated Neopterin (>40 nmol/L; reported normal 5.8 nmol/L) and β2-microglobulin (>2.5 mg/L; reported normal 1.8 mg/L). Serum Neopterin and β2-microglobulin were also elevated. The authors attributed these findings to indirect effects of systemic infection and immune activation on the central nervous system. Outcome was not noted.

      4. Discussion

      There are a number of reasons why patients with COVID-19 may develop seizures including, but not limited to: hypoxia, electrolyte derangements, systemic infections, hypo- or hyperglycemia, acute kidney injury, cytokine storming, shock, medications, or stroke [
      • Lu L
      • Xiong W
      • Liu D
      • et al.
      New onset acute symptomatic seizure and risk factors in coronavirus disease 2019: a retrospective multicenter study.
      ,
      • Vohora D
      • Jain S
      • Tripathi M
      • Potschka H.
      COVID-19 and seizures: Is there a link?.
      ]. However, it has also been hypothesized that seizures in this patient population could be the result of viral neuroinvasion [
      • Mao L
      • Jin H
      • Wang M
      • et al.
      Neurologic manifestations of hospitalized patients with coronavirus disease 2019 in Wuhan, China.
      ,
      • Vohora D
      • Jain S
      • Tripathi M
      • Potschka H.
      COVID-19 and seizures: Is there a link?.
      ,
      • Zubair AS
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      ]. Though neuropathological studies are the most definitive way to evaluate for viral neuroinvasion, CSF results can also demonstrate evidence of viral neuroinvasion. Thus, in this systematic review, we reviewed the CSF results for patients with COVID-19 who had a seizure.
      After identifying 69 patients who had a seizure in the setting of COVID-19 and had CSF studies available for review [
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      ,
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      CSF biomarkers in patients with COVID-19 and neurological symptoms: a case series.
      ,

      Elkady A, Rabinstein AA. Acute necrotizing encephalopathy and myocarditis in a young patient with COVID-19. 2020;7(5):e801.

      ,
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      ,
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      ], we found that 6/45 (13%) had a positive CSF SARS-CoV-2 PCR (though cycle threshold was not reported for any of them) [
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      ,
      • Delorme C
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      ,
      • Djellaoui A
      • Seddik L
      • Cleret De Langavant L
      • Cattan S
      • Bachoud-Lévi AC
      • Hosseini H
      Posterior reversible encephalopathy syndrome associated with SARS-CoV-2 infection.
      ,
      • Dono F
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      New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.
      ,
      • Edén A
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      • et al.
      CSF biomarkers in patients with COVID-19 and neurological symptoms: a case series.
      ,
      • Guilmot A
      • Maldonado Slootjes S
      • Sellimi A
      • et al.
      Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
      ,
      • Hosseini AA
      • Shetty AK
      • Sprigg N
      • Auer DP
      • Constantinescu CS.
      Delirium as a presenting feature in COVID-19: Neuroinvasive infection or autoimmune encephalopathy?.
      ,
      • Keller E
      • Brandi G
      • Winklhofer S
      • et al.
      Large and small cerebral vessel involvement in severe COVID-19: detailed clinical workup of a case series.
      ,
      • Le Guennec L
      • Devianne J
      • Jalin L
      • et al.
      Orbitofrontal involvement in a neuroCOVID-19 patient.
      ,
      • Monti G
      • Giovannini G
      • Marudi A
      • et al.
      Anti-NMDA receptor encephalitis presenting as new onset refractory status epilepticus in COVID-19.
      ,
      • Pilotto A
      • Masciocchi S
      • Volonghi I
      • et al.
      Clinical presentation and outcomes of SARS-CoV-2 related encephalitis: the ENCOVID multicentre study.
      ,
      • Sattar SBA
      • Haider MA
      • Zia Z
      • Niazi M
      • Iqbal QZ.
      Clinical, radiological, and molecular findings of acute encephalitis in a COVID-19 patient: a rare case report.
      ,
      • Zambreanu L
      • Lightbody S
      • Bhandari M
      • et al.
      A case of limbic encephalitis associated with asymptomatic COVID-19 infection.
      ,
      • Afshar H
      • Yassin Z
      • Kalantari S
      • et al.
      Evolution and resolution of brain involvement associated with SARS- CoV2 infection: A close Clinical - Paraclinical follow up study of a case.
      ,
      • Ayatollahi P
      • Tarazi A
      • Wennberg R.
      Possible autoimmune encephalitis with claustrum sign in case of Acute SARS-CoV-2 Infection.
      ,
      • Balloy G
      • Leclair-Visonneau L
      • Péréon Y
      • et al.
      Non-lesional status epilepticus in a patient with coronavirus disease 2019.
      ,
      • Bellon M
      • Schweblin C
      • Lambeng N
      • et al.
      Cerebrospinal fluid features in SARS-CoV-2 RT-PCR positive patients.
      ,
      • Bernard-Valnet R
      • Pizzarotti B
      • Anichini A
      • et al.
      Two patients with acute meningoencephalitis concomitant with SARS-CoV-2 infection.
      ,
      • Canham LJW
      • Staniaszek LE
      • Mortimer AM
      • Nouri LF
      • Kane NM.
      Electroencephalographic (EEG) features of encephalopathy in the setting of Covid-19: a case series.
      ,
      • Casez O
      • Willaume G
      • Grand S
      • et al.
      SARS-CoV-2 related encephalitis: MRI pattern of the olfactory tract involvement.
      ,
      • Conte G
      • Avignone S
      • Carbonara M
      • et al.
      COVID-19-associated PRES-like encephalopathy with perivascular gadolinium enhancement.
      ,
      • Dixon L
      • Varley J
      • Gontsarova A
      • et al.
      COVID-19-related acute necrotizing encephalopathy with brain stem involvement in a patient with aplastic anemia.
      ,
      • Dugue R
      • Cay-Martínez KC
      • Thakur KT
      • et al.
      Neurologic manifestations in an infant with COVID-19.
      ,
      • Duong L
      • Xu P
      • Liu A.
      Meningoencephalitis without respiratory failure in a young female patient with COVID-19 infection in Downtown Los Angeles, early April 2020.
      ,
      • Farhadian S
      • Glick LR
      • Vogels CBF
      • et al.
      Acute encephalopathy with elevated CSF inflammatory markers as the initial presentation of COVID-19.
      ,
      • Huang YH
      • Jiang D
      • Huang JT.
      SARS-CoV-2 detected in cerebrospinal fluid by PCR in a case of COVID-19 encephalitis.
      ,
      • Karimi N SRA
      • Rouhani N
      Frequent convulsive seizures in an adult patient with COVID-19: a case report.
      ,
      • Kihira S
      • Delman BN
      • Belani P
      • et al.
      Imaging features of acute encephalopathy in patients with COVID-19: a case series.
      ,
      • Lyons S
      • O'Kelly B
      • Woods S
      • et al.
      Seizure with CSF lymphocytosis as a presenting feature of COVID-19 in an otherwise healthy young man.
      ,
      • Mirzaee SMM
      • Gonçalves FG
      • Mohammadifard M
      • Tavakoli SM
      • Vossough A.
      Focal cerebral arteriopathy in a pediatric patient with COVID-19.
      ,
      • Moriguchi T
      • Harii N
      • Goto J
      • et al.
      A first case of meningitis/encephalitis associated with SARS-Coronavirus-2.
      ,
      • Rifino N
      • Censori B
      • Agazzi E
      • et al.
      Neurologic manifestations in 1760 COVID-19 patients admitted to Papa Giovanni XXIII Hospital, Bergamo, Italy.
      ,
      • Santos De Lima F
      • Issa N
      • Seibert K
      • et al.
      Epileptiform activity and seizures in patients with COVID-19.
      ,
      • Westhoff TH
      • Seibert FS
      • Bauer F
      • et al.
      Allograft infiltration and meningoencephalitis by SARS-CoV-2 in a pancreas-kidney transplant recipient.
      ,
      • Zanin L
      • Saraceno G
      • Panciani PP
      • et al.
      SARS-CoV-2 can induce brain and spine demyelinating lesions.
      ]; 2/26 (8%) demonstrated evidence of intrathecal antibody synthesis (though one had Caspr2 IgG in the CSF in addition to CSF-specific oligoclonal bands, so their bands may have been demonstrative of those antibodies rather than SARS-CoV-2 antibodies) [
      • Abdi S
      • Ghorbani A
      • Fatehi F.
      The association of SARS-CoV-2 infection and acute disseminated encephalomyelitis without prominent clinical pulmonary symptoms.
      ,
      • Benameur K
      • Agarwal A
      • Auld SC
      • et al.
      Encephalopathy and encephalitis associated with cerebrospinal fluid cytokine alterations and coronavirus disease, Atlanta, Georgia, USA, 2020.
      ,
      • Carroll E
      • Neumann H
      • Aguero-Rosenfeld ME
      • et al.
      Post-COVID-19 inflammatory syndrome manifesting as refractory status epilepticus.
      ,
      • Delorme C
      • Paccoud O
      • Kas A
      • et al.
      Covid-19-related encephalopathy: a case series with brain FDG-PET/CT findings.
      ,
      • Djellaoui A
      • Seddik L
      • Cleret De Langavant L
      • Cattan S
      • Bachoud-Lévi AC
      • Hosseini H
      Posterior reversible encephalopathy syndrome associated with SARS-CoV-2 infection.
      ,
      • Dono F
      • Carrarini C
      • Russo M
      • et al.
      New-onset refractory status epilepticus (NORSE) in post SARS-CoV-2 autoimmune encephalitis: a case report.
      ,
      • Edén A
      • Kanberg N
      • Gostner J
      • et al.
      CSF biomarkers in patients with COVID-19 and neurological symptoms: a case series.
      ,

      Elkady A, Rabinstein AA. Acute necrotizing encephalopathy and myocarditis in a young patient with COVID-19. 2020;7(5):e801.

      ,
      • Ghosh R
      • Dubey S
      • Finsterer J
      • Chatterjee S
      • Ray BK.
      SARS-CoV-2-associated acute hemorrhagic, necrotizing encephalitis (AHNE) presenting with cognitive impairment in a 44-year-old woman without comorbidities: a case Report.
      ,
      • Guilmot A
      • Maldonado Slootjes S
      • Sellimi A
      • et al.
      Immune-mediated neurological syndromes in SARS-CoV-2-infected patients.
      ,
      • Hosseini AA
      • Shetty AK
      • Sprigg N
      • Auer DP
      • Constantinescu CS.
      Delirium as a presenting feature in COVID-19: Neuroinvasive infection or autoimmune encephalopathy?.