ARTICLE

Neurologic and neuroimagingfindings in patientswith COVID-19A retrospective multicenter study

Stephane Kremer MD PhD Franccedilois Lersy MD Mathieu Anheim MD PhD Hamid Merdji MD

Maleka Schenck MD Helene Oesterle MD Federico Bolognini MD Julien Messie MD Antoine Khalil MD

Augustin Gaudemer MD Sophie Carre MD Manel Alleg MD Claire Lecocq MD Emmanuelle Schmitt MD

Rene Anxionnat MD PhD Franccedilois Zhu MD Lavinia Jager MD Patrick Nesser MD Yannick Talla Mba MD

Ghazi Hmeydia MD Joseph Benzakoun MD Catherine Oppenheim MD PhD

Jean-Christophe Ferre MD PhD Adel Maamar MD Beatrice Carsin-Nicol MD Pierre-Olivier Comby MD

Frederic Ricolfi MD PhD Pierre Thouant MD Claire Boutet MD PhD Xavier Fabre MD

Geraud Forestier MD Isaure de Beaurepaire MD Gregoire Bornet MD Hubert Desal MD PhD

Gregoire Boulouis MD Jerome Berge MD Apolline Kazemi MD Nadya Pyatigorskaya MD PhD

Augustin Lecler MD PhD Suzana Saleme MD Myriam Edjlali-Goujon MD PhD Basile Kerleroux MD

Jean-Marc Constans MD PhD Pierre-Emmanuel Zorn PhD Muriel Mathieu PhD Seyyid Baloglu MD

Franccedilois-Daniel ArdellierMD ThibaultWillaumeMD Jean-ChristopheBrisset PhD Sophie CaillardMD PhD

Olivier Collange MD PhD Paul Michel Mertes MD PhD Francis Schneider MD PhD

Samira Fafi-Kremer PharmD PhD Mickael Ohana MD PhD Ferhat Meziani MD PhD

Nicolas Meyer MD PhD Julie Helms MD PhD and Franccedilois Cotton MD PhD

Neurologyreg 202095e1868-e1882 doi101212WNL0000000000010112

Correspondence

Dr Kremer

stephanekremer

chru-strasbourgfr

AbstractObjectiveTo describe neuroimaging findings and to report the epidemiologic and clinical charac-teristics of patients with coronavirus disease 2019 (COVID-19) with neurologicmanifestations

MethodsIn this retrospective multicenter study (11 hospitals) we included 64 patients with confirmedCOVID-19 with neurologic manifestations who underwent a brain MRI

ResultsThe cohort included 43 men (67) and 21 women (33) their median age was 66 (range20ndash92) years Thirty-six (56) brain MRIs were considered abnormal possibly relatedto severe acute respiratory syndrome coronavirus Ischemic strokes (27) leptomeningeal

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These authors contributed equally to this work

From the Hopitaux Universitaires de Strasbourg (SK FL SB F-DA TW) Service drsquoimagerie 2 Hopital de Hautepierre Engineering Science Computer Science and ImagingLaboratory (SK NM) UMR 7357 University of StrasbourgndashCNRS Service de Neurologie (M Anheim) Hopitaux Universitaires de Strasbourg Institut de Genetique et de BiologieMoleculaire et Cellulaire (M Anheim) INSERM-U964CNRS-UMR7104Universite de Strasbourg Illkirch Federation de Medecine Translationnelle de Strasbourg (M Anheim) Uni-versite de Strasbourg Hopitaux universitaires de Strasbourg (HM FM JH) Service de Medecine Intensive Reanimation Nouvel Hopital Civil INSERM (French National Institute ofHealth and Medical Research) (HM FM) UMR 1260 Regenerative Nanomedicine Federation de Medecine Translationnelle de Strasbourg Medecine Intensive-Reanimation (MSFS) Hopital de Hautepierre Hopitaux Universitaires de Strasbourg Service deNeuroradiologie (HO FB JM) Hopitaux Civils de Colmar Service drsquoImagerie (A Khalil AG) Unite deNeuroradiologie Assistance Publique-Hopitaux de Paris Hopital Bichat Claude Bernard Universite Paris Diderot (A Khalil) Paris Service de Neurologie (S Carre CL) CentreHospitalier de Haguenau Service de Radiologie (M Alleg) Centre Hospitalier de Haguenau Service de Neuroradiologie (ES RA FZ) Hopital Central CHU de Nancy CHIC Unisante(LJ PN YTM) Hopital Marie Madeleine Forbach Neuroimaging Department (GH J Benzakoun CO G Boulouis ME-G BK) GHU Paris Psychiatrie et Neurosciences HopitalSainte-Anne Universite de Paris INSERMU1266 F-75014 CHU Rennes (J-CF BC-N) Department of Neuroradiology CHU Rennes (AM) Medical Intensive Care Unit Department ofNeuroradiology (P-OC FR PT) University Hospital of Dijon Hopital Franccedilois Mitterrand Service de Radiologie (CB) CHU de Saint-Etienne Service de Reanimation (XF) CH deRoanne Service de Neuroradiologie (GF SS) CHU de Limoges Radiology Department (IdB G Bornet) Hopital Prive drsquoAntony Department of Diagnostic and InterventionalNeuroradiology (HD) University Hospital Nantes Neuroradiology Department (J Berge) CHUdeBordeaux Service deNeuroradiologie (A Kazemi) CHUde Lille Assistance PubliqueHopitaux de Paris (NP) Service de Neuroradiologie Hopital Pitie-Salpetriere Sorbonne Universite (NP) Univ Paris 06 UMR S 1127 CNRS UMR 7225 ICM F-75013 Service deNeuroradiologie Diagnostique (AL) Foundation A Rothschild Hospital Paris EA CHIMERE 7516 (J-MC) Universite de Picardie Jules Verne Service de NeuroRadiologie pole ImagerieMedicale Centre Hospitalo-Universitaire drsquoAmiens Hopitaux Universitaires de Strasbourg (P-EZ MM) UCIEC Pole drsquoImagerie Strasbourg Observatoire Franccedilais de la Sclerose enPlaques (J-CB) Lyon Nephrology and Transplantation Department (S Caillard) Hopitaux Universitaires de Strasbourg Inserm UMR S1109 (S Caillard) LabEx TransplantexFederation de Medecine Translationnelle de Strasbourg Universite de Strasbourg Hopitaux Universitaires de Strasbourg (OC PMM) Service drsquoAnesthesie-Reanimation NouvelHopital Civil HopitauxUniversitaires de Strasbourg (SF-K) Laboratoire de VirologieMedicale Radiology Department (MO) Nouvel Hopital Civil StrasbourgUniversity Hospital CHUde Strasbourg (NM) Service de Sante Publique GMRC F-67091 Strasbourg Immuno-Rhumatologie Moleculaire (SF-K JH) INSERM UMR_S1109 LabEx TRANSPLANTEX Centre deRecherche drsquoImmunologie et drsquoHematologie Faculte de Medecine Federation Hospitalo-Universitaire OMICARE Federation de Medecine Translationnelle de Strasbourg Universitede Strasbourg MRI Center (FC) Centre Hospitalier Lyon Sud Hospices Civils de Lyon and Universite Lyon 1 (FC) CREATIS-LRMN CNRSUMR5220-INSERM U630 VilleurbanneFrance

Go to NeurologyorgN for full disclosures Funding information and disclosures deemed relevant by the authors if any are provided at the end of the article

e1868 Copyright copy 2020 American Academy of Neurology

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited

enhancement (17) and encephalitis (13) were the most frequent neuroimaging findings Confusion (53) was the mostcommon neurologic manifestation followed by impaired consciousness (39) presence of clinical signs of corticospinal tractinvolvement (31) agitation (31) and headache (16) The profile of patients experiencing ischemic stroke was differentfrom that of other patients with abnormal brain imaging the former less frequently had acute respiratory distress syndrome(p = 0006) and more frequently had corticospinal tract signs (p = 002) Patients with encephalitis were younger (p = 0007)whereas agitation was more frequent for patients with leptomeningeal enhancement (p = 0009)

ConclusionsPatients with COVID-19 may develop a wide range of neurologic symptoms which can be associated with severe and fatalcomplications such as ischemic stroke or encephalitis In terms of meningoencephalitis involvement even if a direct effect of thevirus cannot be excluded the pathophysiology seems to involve an immune or inflammatory process given the presence of signsof inflammation in both CSF and neuroimaging but the lack of virus in CSF

ClinicalTrialsgov identifierNCT04368390

In December 2019 many unexplained pneumonia cases oc-curred in China12 In January 2020 the causative agent wasidentified as a novel coronavirus which has been called severeacute respiratory syndrome coronavirus 2 (SARS-CoV-2) givingthe disease the name coronavirus disease 2019 (COVID-19)Coronaviruses have neuroinvasive capacities because they areisolated in both brains and CSF of infected animals andhumans3ndash8 However few neurologic complications with humancoronaviruses (hCoVs) were documented in the past 2 decades

Concerning COVID-19 5 recent publications have presentedneuroimaging presentations of patients with neurologiccomplications9ndash13

The first studies that focused on clinical features of patientswith COVID-191211 showed neurologic manifestations such asheadache dizziness confusion hypogeusia hyposmia and moresevere neurologic disorders especially for patients hospitalized inintensive care units (ICUs) In a recent cohort of 214 patients11

248 of them presented CNS manifestations and 6 cases ofstrokes were diagnosed The neurologic symptoms were morecommon in cases of severe respiratory infection11 It has recentlybeen reported12 that patients referred to ICU frequently experi-enced encephalopathywith agitation confusion and corticospinaltract signs Brain MRI revealed in some patients leptomeningealenhancement (LME) and cerebral blood flow abnormalities

Despite these findings the potential brain injuries related toCOVID-19 have not been well described with neuroimagingin a large cohort Thus our aims were to describe the neu-roimaging findings in a population of COVID-19 with neu-rologic manifestations who underwent brain MRI to assessthe frequency of these abnormalities and to correlate thesefindings with clinical features

MethodsThis retrospective national multicenter study was initiated bythe French Neuroradiology Society

Patient cohortPatients with COVID-19 from 11 French centers including 6university hospitals and 5 general hospitals were includedfromMarch 16 2020 until April 9 2020 The number of casesincluded from each center was as follows 29 in Strasbourg 11in Colmar 7 in Paris (Bichat) 5 in Haguenau 4 in Nancy 4again in Paris (Sainte-Anne) 3 in Rennes 2 in Dijon 1 inSaint-Etienne 1 in Forbach and 1 in Antony

The diagnosis of COVID-19 was based on the following cri-teria possible exposure history symptoms clinically com-patible with COVID-19 and detection of SARS-CoV-2 byreverse transcriptase-PCR (RT-PCR) assays on the naso-pharyngeal throat or lower respiratory tract swabs Inclusioncriteria were diagnosis of COVID-19 with neurologic mani-festation and a brain MRI assessment Exclusion criteria weremissing data or noncontributory (lack of sequences numer-ous artifacts) data regarding brain MRI

The diagnosis of acute respiratory distress syndrome (ARDS)was based on Berlin criteria14

Clinical and laboratory data were extracted from the patientsrsquoelectronic medical records in the hospital information system

Virologic assessmentQuantitative real-time RT-PCR tests for SARS-CoV-2 nucleicacid were performed on upper or lower respiratory tract swabsand CSF Primer and probe sequences were targeting 2regions on the RdRp gene which are specific to SARS-CoV-2Assay sensitivity was asymp10 copies per reaction

Brain MRI protocolsImaging studies were conducted on 15T or 3T MRI Themulticenter nature of the study and the various clinical pre-sentations did not allow standardization of sequences

The most frequently sequences performed were 3DT1-weighted spin-echo with and without contrast-enhancedimaging diffusion-weighted imaging gradient echo T2 or

NeurologyorgN Neurology | Volume 95 Number 13 | September 29 2020 e1869

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited

susceptibility-weighted imaging 2D or 3D fluid-attenuatedinversion recovery (FLAIR) postcontrast and 3D time-of-flight magnetic resonance angiography of the circle of Willis

Brain MRI readingAfter anonymization images were presented to readers withour GE Picture Archiving and Communication System(General Electric Milwaukee WI) Two neuroradiologists(SK and FL with 20 and 9 years of experience in neuro-radiology respectively) who were blinded to all patient dataindependently reviewed all brain MRIs The final diagnosiswas determined by consensus and if consensus could not bereached a third neuroradiologist (SB with 9 years of expe-rience in neuroradiology) was questioned

Neuroimaging abnormalities were divided into 3 groupsischemic stroke encephalitis and LME Ischemic strokeswere classified into large artery infarctions watershed cere-bral infarctions lacunar infarctions and hypoxic-ischemicinjuries Encephalitis was ranked as limbic encephalitis cy-totoxic lesion of the corpus callosum (CLOCC) radiologicacute disseminated encephalomyelitis (ADEM) radiologicacute hemorrhagic necrotizing encephalopathy and mis-cellaneous encephalitis

Encephalitis was defined as brain parenchymal abnormalFLAIR hyperintensity involving gray matter (GM) whitematter or basal ganglia with variable enhancement localizedmainly in medial temporal and inferior frontal lobes in case oflimbic encephalitis The term CLOCC has been proposed re-cently to describe a clinicoradiologic syndrome characterizedby a transient mild encephalopathy and a reversible lesion ofthe corpus callosum localized mainly to the central part of thesplenium onMRI CLOCCs are the consequence of numerousetiologies the 2 most frequent being antiepileptic drug with-drawal and infections They are related to a cytokine increaseinducing glutamate elevation in the extracellular space leadingto a dysfunction of callosal neurons and microglia with in-tracellular water influx resulting in cytotoxic edema15

ADEM is an autoimmune-mediated disease occurring afterviral infections and vaccinations Multifocal demyelinatinglesions involving white matter but also GM (basal ganglia) areseen with variable enhancement Acute hemorrhagic necro-tizing encephalopathy is a fulminant inflammatory de-myelinating disease which is considered the most severe formof ADEM associated with hemorrhagic lesions

A brain MRI without acute significative abnormalities orshowing lesions unrelated to SARS-CoV-2 was considerednormal

Statistical analysisData were described with frequency and proportion (numberpercent) for categorical variables and mean median andrange for quantitative data Categorical data were comparedwith the Fisher exact test Quantitative data were compared

with analysis of variance Multiple correspondence analysis(MCA) was used to give a simultaneous multivariate de-scription of clinical and radiologic characteristics of all di-agnostic groups MCA plots display results either for thesubjects or for their characteristics Those plots are to beinterpreted on the basis of the proximity of the data points 2subjects who are close on a plot share a common pattern ofsymptoms and 2 clinical symptoms that are close on a plotdescribe similar types of subjects Ellipses are drawn aroundthe mean position of each characteristic such that non-overlapping ellipses can be considered to show a contrastbetween the subjects who share 1 or the other characteristic

Computations were made with 353 through R-Studio withthe readxl and FactoMineR packages (R Foundation forStatistical Computing Vienna Austria) A value of p lt 005was considered significant

Standard protocol approvals registrationsand patient consentsThe study was approved by the ethics standards committeeon human experimentation of Strasbourg University Hos-pital (CE-2020-37) and was in accordance with the 1964Declaration of Helsinki and its later amendments Due to theemergency in the context of COVID-19 pandemic responsiblefor acute respiratory and neurologic manifestations pandemicthe requirement for patientsrsquo written informed consent waswaived

The study has been registered in ClinicalTrialsgov(NCT04368390)

Data availabilityWe state that the data published are available and anonymizedand will be shared on request by email to the correspondingauthor from any qualified investigator for purposes of repli-cating procedures and results

ResultsA total of 68 patients with COVID-19 were included in thismulticenter study Among them 4 were excluded becausetheir brain MRIs were considered noncontributory

Clinical characteristicsThe demographic and clinical characteristics of the 64patients and their neurologic manifestations are summarizedin tables 1 through 3 The most frequent neurologic mani-festations were confusionagitationalteration of conscious-ness corticospinal tract signs and headache

Complementary data concerning patients with COVID-19with acute ischemic stroke are given in table 2 including riskfactors clinical presentation echocardiography and ECGresults neuroimaging description and D-dimer serum levelFurther information related to patients with COVID-19 withmeningoencephalitis is given in table 3

e1870 Neurology | Volume 95 Number 13 | September 29 2020 NeurologyorgN

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Neuroimaging findingsAmong the 64MRIs included 41 (64) were performed withgadolinium-based contrast agent administration Thirty-onehad a postcontrast FLAIR and 18 had a delayed postcontrastFLAIR The latter was achieved asymp10 minutes after the in-jection after the realization of conventional postcontrastFLAIR and enhanced T1-weighted imaging Thirty-six (56)brain MRIs were considered abnormal possibly related toSARS-CoV-2

Ischemic strokes (27) (figure e-1 available from Dryaddoiorg105061dryadw9ghx3fm7) LME (17) (figure 1)and encephalitis (13) (figures 2 and 3 and figure e-2 availablefrom Dryad) were the most frequent neuroimaging findingsLME was seen on both postcontrast T1-weighted and FLAIRsequences and was even better visualized when delayed post-contrast FLAIR was performed These signal abnormalitieswere not present on precontrast T1 or FLAIR images

Among the 8 encephalitis 2 cases of limbic encephalitis2 cases of radiologic acute hemorrhagic necrotizing encepha-lopathy 2 cases of miscellaneous encephalitis 1 case of radio-logic ADEM and 1 case of CLOCC were described

CSF analysisTwenty-five (39) patients underwent a lumbar puncture 7in the encephalitis group 8 in the LME group 2 in the is-chemic stroke group and 8 in the normal brain MRI group

CSF glucose was normal in all cases

In the encephalitis group (table 3) 6 patients showedmarkersof inflammation 4 had pleocytosis 5 had high levels of pro-tein 2 had elevated immunoglobulin G and another hadoligoclonal bands that were identical in CSF and serum In theLME group (table 3) 6 patients showed markers of in-flammation 2 had pleocytosis 3 had high levels of protein 2

Table 1 History neurologic manifestations and clinical characteristics of the cohort

All patients(n = 64)

Ischemic stroke(n = 17)

Encephalitis(n = 8)

LME(n = 11) p Value

Sex n () 028

Men 43 (67) 11 (65) 7 (88) 5 (46)

Women 21 (33) 6 (35) 1 (12) 6 (54)

Age y 0007

Mean 65 75 61 66

Median 66 75 59 64

Range 20ndash92 59ndash92 55ndash71 51ndash81

History of stroke n () 7 (11) 4 (24) 0 1 (9) 036

History of seizures n () 3 (5) 1 (6) 0 0 1

Another neurologic history n () 9 (14) 2 (12) 0 0 017

History of autoimmune diseases n () 7 (11) 3 (18) 0 1 (9) 083

History of hematologic malignancies n () 4 (6) 1 (6) 0 1 (9) 1

Headaches n () 10 (16) 3 (18) 2 (25) 1 (9) 085

Seizures n () 1 (2) 0 0 0 1

Anosmia n () 2 (3) 1 (6) 0 1 (9) 031

Ageusia n () 4 (6) 0 1 (13) 1 (9) 045

Clinical signs of corticospinal tract involvement n () 20 (31) 10 (59) 1 (13) 4 (36) 002

Disturbance of consciousness n () 25 (39) 3 (18) 4 (50) 6 (55) 015

Confusion n () 34 (53) 7 (41) 3 (38) 6 (55) 034

Agitation n () 20 (31) 1 (6) 3 (38) 7 (64) 0009

Oxygen therapy n () 53 (83) 13 (76) 8 (100) 10 (91) 052

ARDS n () 33 (52) 3 (18) 6 (75) 8 (73) 0006

Death n () 7 (11) 2 (12) 2 (25) 0 038

Abbreviations ARDS = acute respiratory distress syndrome LME = leptomeningeal enhancement

NeurologyorgN Neurology | Volume 95 Number 13 | September 29 2020 e1871

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Table 2 Characteristics of patients with COVID-19 with acute ischemic stroke

Sex Age y Risk factors Clinical presentation

Days from COVID-19respiratory symptomonset to ischemicstroke symptom onset

Treatment up tothis time point

Arrhythmias (ECGor echocardiography)

BrainMRI

Large vesselocclusion

D-dimers(reference range lt400) μgL

M 86 HypertensionDyslipidemia

Left hemiplegiaimpairedconsciousness

1 Supportive No LAI Distal M1 occlusionwith thrombus

NR

M 71 HypertensionDiabetesmellitus

Left hemiplegia 16 Antibiotics Yes (previouslyunknown)

LAI Distal M1 occlusionwith thrombus

2860

F 74 mdash Bilateral pyramidal tract signs 8 AntibioticsHydroxychloroquine

No WCI mdash gt20000

M 63 Smoking Left-sided weaknessleft-sidedsensory inattention

14 Antibiotics Yes (previouslyunknown)

LAI mdash 1000

M 65 HypertensionDiabetesmellitusDyslipidemiaHOS

Impaired consciousness 22 Antibiotics No WCI mdash 1570

F 78 Hypertension Dysarthria 3 Supportive No WCI mdash 720

F 75 HypertensionDyslipidemiaAtrial Fibrillation

Aphasiaright hemiplegiaimpaired consciousnessagitation

6 Supportive NR LAI ICA occlusion NR

M 79 HypertensionDyslipidemiaHOS

Headachesimpairedconsciousnessconfusion

5 Supportive No WCI mdash NR

F 71 HypertensionSmokingAtrial fibrillation

Left hemiplegia 3 Supportive Yes LAI Proximal M2occlusion

gt20000

M 59 HypertensionSmoking

Left hemiplegialeft facial droop 1 Supportive No LAI Proximal M1occlusion withthrombus

2868

M 66 HypertensionDyslipidemiaDiabetesmellitus

Left pyramidal tract signsleftfacial droopaphasia

4 Supportive No LAI ICA dissection 5227

M 72 DyslipidemiaAtrial fibrillation

Impaired consciousness 15 Antibiotics Yes LAI mdash 993

M 78 Hypertension Dysarthriaright-sidedweaknessright facial droop

16 Supportive No LAI mdash NR

Continued

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had elevated immunoglobulin G and 4 had oligoclonal bandsthat were identical in CSF and serum In the ischemic strokegroup 1 patient had a high level of protein

The RT-PCR SARS-CoV-2 analysis was negative in the 20patients who were investigated The analysis was not realizedfor 5 patients 1 with a normal brain MRI 2 with an ischemicstroke 1 with encephalitis and 1 with LME Cultures for otherviruses or bacteria were always negative when performed

Correlation analysisThere were statistically significant differences between thevarious groups concerning age (p = 0007) the presence ofpyramidal tract signs (p = 002) agitation (p = 0009) andrespiratory status (ARDS) (p = 0006) (table 1)

The MCA showed that the ischemic stroke group could bedistinguished from the 3 others which largely overlap (figure 4)Most patients with ischemic stroke (numbers and dots in redon the plot) are located on the same lower-right half of thegraph indicating a commonality of symptoms Those patientscan be overall described as older with no ARDS no oxygenrequirement no confusion no disturbances of consciousnessand a lower death rate The converse is true for the 3 otherdiagnoses that cannot be distinguished Considering eachclinical manifestation separately (figure e-3 available fromDryad doiorg105061dryadw9ghx3fm7) subjects can bedistinguishedmainly on the basis of a global pattern dependingon their oxygen requirement seizure sex headaches history ofautoimmune disease history of seizure age anosmia confu-sion and disturbances of consciousness

DiscussionThis is the first large nationwide cohort of MRIs performed inpatients with COVID-19 with neurologic manifestations

The majority of patients had MRI abnormalities with seriousand various findings beyond the severe respiratory disease(half of the patients had ARDS and 11 died) cerebrovas-cular disease (especially ischemic stroke large artery infarc-tions more frequently than watershed cerebral infarctions)encephalitis (including limbic encephalitis radiologic ADEMCLOCC and radiologic acute hemorrhagic necrotizing en-cephalopathy) and focal or even diffuse LME The hetero-geneity of the imaging abnormalities was underpinned byheterogeneous clinical manifestations ranging from anosmiaageusia or headache to more severe findings such as confu-sion with agitation loss of consciousness and corticospinaltract signs Some correlations were found between clinical andimaging findings allowing the identification of clinicoradio-logic profiles of patients with COVID-19 displaying neuro-logic manifestations

Ischemic stroke was 1 kind of clinicoradiologic phenotype itwas an acute event arising in older patients who more fre-quently had corticospinal tract signs but was less frequentlyTa

ble

2Charac

teristicsofpatients

withCOVID-19withac

ute

isch

emicstroke

(con

tinue

d)

Sex

Age

yRiskfactors

Clinicalpre

senta

tion

Days

from

COVID

-19

resp

irato

rysy

mpto

monse

tto

isch

emic

stro

kesy

mpto

monse

tTr

eatm

entupto

this

timepoint

Arrhythmias(ECG

orech

oca

rdiogr

aphy)

Bra

inMRI

Larg

eve

ssel

occ

lusion

D-dim

ers

(refere

nce

range

lt400

)μgL

M76

mdashConfusion

24Su

pportive

No

WCI

mdash397

7

F92

mdashConfusion

10Su

pportive

No

WCI

mdash98

7

F77

Hyp

ertension

HOS

Lefthem

iplegialeft

homonym

oushem

ianopia

hea

dac

hes

minus2(stroke

prece

ded

resp

iratory

symptoms

by2d)

mdashYe

s(previously

unkn

own)

LAI

P2occlusion

NR

M88

Hyp

ertension

Dyslip

idem

iaDiabetes

mellitus

Atrialfibrilla

tion

HOS

Righthem

iplegiaim

paired

consciousn

ess

minus2(stroke

prece

ded

resp

iratory

symptoms

by2d)

mdashYe

sLA

IProximal

M2

occlusion

NR

Abbreviations

COVID-19=co

ronav

irusdisea

se20

19H

OS=history

ofstroke

IC=intern

alca

rotidarteryL

AI=

largeartery

infarctionN

R=Notrealized

WCI=

watersh

edce

rebralinfarction

NeurologyorgN Neurology | Volume 95 Number 13 | September 29 2020 e1873

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited

Table 3 Characteristics of patients with COVID-19 with meningoencephalitis

Sex Age y Clinical symptoms

Days from COVID-19respiratory symptomonset to brain MRI Treatment up to this time point CSF analysis Imaging findings

F 71 Confusionimpairedconsciousnessagitation

22 Oxygen therapyAntibioticsLopinavir-ritonavir

0 celluarr Total protein 057 gL

Miscellaneous encephalitisdiffusionand T2FLAIR hyperintensitiesinvolving supratentorial WM

M 64 Confusionimpairedconsciousnessagitation

17 Oxygen therapyAntibioticsLopinavir-ritonavir

40 cellsmm3

uarr Total protein 11 gLuarr Immunoglobulin G 56 mgL

Miscellaneous encephalitisFLAIRhyperintensity involving both middlecerebellar peduncles

M 56 Impaired consciousnesspathologic wakefulness whensedation was stopped

23 Admitted to ICUMechanical ventilationAntibiotics

1 cellmm3

uarr Total protein 2 gLuarr Immunoglobulin G 169 mgLOligoclonal bands identical in CSF and serum

Radiologic acute hemorrhagicnecrotizing encephalopathy

M 66 Impaired consciousnesspathologic wakefulness whensedation was stopped

34 Admitted to ICUMechanical ventilationAntibioticsLopinavir-ritonavir

NR Radiologic acute hemorrhagicnecrotizing encephalopathy

M 55 Headachesdizzinessimpairedconsciousness

3 mdash 7 cellsmm3

uarr Total protein 056 gLCLOCC

M 56 Headaches 20 Admitted to ICUMechanical ventilationAntibiotics

3 cellsmm3

Total protein 024 gLLeft limbic encephalitis

M 58 Ataxia 21 Admitted to ICUMechanical ventilationAntibioticsHydroxychloroquine

4 cellsmm3

uarr Total protein 077 gLLeft limbic encephalitis

M 60 Confusionimpairedconsciousnessagitation

13 Admitted to ICUMechanical ventilationAntibioticsHydroxychloroquine

0 cellTotal protein 03 gL

Radiologic ADEM

F 51 Movement disordersagitation 16 mdash 5 cellsuarr Total protein 066 gL

Focal LME

F 59 Headachesdizziness 18 Admitted to ICUMechanical ventilationAntibioticsLopinavir-ritonavir

NR Focal LME

M 62 Confusionimpairedconsciousnessagitation

19 Admitted to ICUMechanical ventilationAntibioticsLopinavir-ritonavir

0 cellTotal protein 023 gLImmunoglobulin G 33 mgLOligoclonal bands identical in CSF and serum

Diffuse LME

Continued

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Table 3 Characteristics of patients with COVID-19 with meningoencephalitis (continued)

Sex Age y Clinical symptoms

Days from COVID-19respiratory symptomonset to brain MRI Treatment up to this time point CSF analysis Imaging findings

M 78 Agitation 15 Admitted to ICUMechanical ventilationAntibioticsLopinavir-ritonavir

NR Focal LME

M 72 Impaired consciousnessbilateralpyramidal tract signs

20 Oxygen therapyAntibioticsLopinavir-ritonavirHydroxychloroquine

0 cellTotal protein 023 gLImmunoglobulin G 17 mgLOligoclonal bands identical in CSF and serum

Focal LME

M 61 Impaired consciousnessbilateralpyramidal tract signsconfusionagitation

14 Oxygen therapyAntibioticsHydroxychloroquine

1 cellmm3

Total protein 023 gLImmunoglobulin G 17 mgL

Focal LME

M 66 Confusionimpairedconsciousnessagitation

22 Admitted to ICUMechanical ventilationAntibiotics

NR Focal LME

F 53 Confusionimpairedconsciousness

29 Admitted to ICUMechanical ventilationAntibioticsLopinavir-ritonavir

0 cellTotal protein 029 gLImmunoglobulin G 21 mgL

Focal LME

F 64 Bilateral pyramidal tract signs 11 Admitted to ICUMechanical ventilationAntibiotics

2 cellsmm3

Total protein 030 gLImmunoglobulin G 15 mgLOligoclonal bands identical in CSF and serum

Focal LME

F 77 Bilateral pyramidal syndromeconfusionagitation

30 Admitted to ICUMechanical ventilationAntibioticsLopinavir-ritonavirHydroxychloroquine

1 cellmm3

uarr Total protein 080 gLuarr Immunoglobulin G 58 mgL

Diffuse LME

F 81 Confusionimpairedconsciousnessagitation

20 Admitted to ICUMechanical ventilationAntibioticsHydroxychloroquine

80 cellsmm3

uarr Total protein 062 gLuarr Immunoglobulin G 38 mgLOligoclonal bands identical in CSF and serum

Focal LME

Abbreviations ADEM = Acute disseminated encephalomyelitis CLOCC = cytotoxic lesion of the corpus callosum COVID-19 = coronavirus disease 2019 FLAIR = fluid-attenuated inversion recovery ICU = intensive care unitLME = leptomeningeal enhancement NR = not realized WM = white matter

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isprohibited

requiring oxygen or presenting an ARDS This profile couldbe distinguished from the 2 others LME and encephalitisThe encephalitis profile affected younger patients and seemedto be particularly severe because it was associated with theneed for oxygen ARDS and death

Stroke patients less frequently had ARDS and this result is inagreement with the 6 patients with stroke previously reportedin that only 2 patients were admitted to ICUs16 One mayhypothesize that strokes in patients with COVID-19 could bedue to procoagulant events leading to thrombosis17 ratherthan to the systemic inflammatory process that accompaniesARDS which is also directed against the CNS However thisneeds to be assessed by further studies dedicated to stroke andthrombosis in patients with COVID-19

In our study 17 (27) patients had an acute ischemic strokeas was previously reported with SARS-CoV18 Middle Eastrespiratory syndrome coronavirus (MERS-CoV)19 andSARS-CoV-2111617 and among them 11 had large arteryinfarctions (including 6 proximal artery occlusions 2 cases ofinternal carotid artery dissection or occlusion) and 6 hadwatershed cerebral infarctions For 15 of 17 patients with anischemic stroke the respiratory symptoms related to COVID-19 had begun before this acute event while stroke precededrespiratory symptoms by 2 days for 2 patients

Several mechanisms are likely to be associated It is nowknown that SARS-CoV-2 could directly lead to myocardialinjury promoting cardiac arrhythmias associated with em-bolic events20 Six of our patients had arrhythmias which werepreviously unknown for 3 of them In the same way a severeacute myocardial injury may be associated with a decrease inbrain perfusion and therefore with watershed cerebralinfarctions As previously mentioned it is acknowledged thatviruses particularly SARS-CoV-221 are associated with anincrease of prothrombotic events such as ischemic stroke2223

Thereby viral infections may elevate procoagulant markersleading to thrombosis disseminated intravascular coagulationand hemorrhagic events23 As Beyrouti et al16 recently men-tioned all our patients tested showed elevated D-dimersmarkedly elevated (gt1000 μgL) for 10 of the 11 patientstested

Varicella zoster virus is also associated with direct vascularinvolvement and eventually arteritis promoting ischemicstroke events22 Furthermore the more severe critically illpatients hospitalized in ICUs have probably had hypoxemiaand hypotension leading to brain injuries18

Of the 36 abnormal MRIs 8 diagnoses of encephalitis weremade and LME was described especially on postcontrast T1-weighted and FLAIR in 11 patients either focal (single focus

Figure 1 Leptomeningeal enhancement

Axial T1 (A) before and (B) 5 minutes after contrast axial FLAIR (C) before and (D) immediately after contrast and (E and F) delayed (10 minutes) postcontrastaxial fluid-attenuated inversion recovery (FLAIR) weighted MRIs Woman 77 years of age diffuse leptomeningeal linear FLAIR and T1 contrast enhancement(arrows) not visible on precontrast T1 and FLAIR (arrows) but seen better on delayed postcontrast FLAIR weighted MRIs (E and F)

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vs multiple foci) or diffuse and preferentially located in theposterior supratentorial regions of the brain

Two main pathophysiologic hypotheses can be advanced toexplain the neuroimaging findings in the inflammatory profilegroup First SARS-CoV-2 may have a neuroinvasive potentialsimilar to other hCoVs because this family of viruses is relatedto each other genetically It is not clear if the virus can infiltratethe CNS with active replication and direct damage to braincells (viral encephalitis) as observed with other viruses suchas herpes simplex virus Likewise viral meningitis due to di-rect infiltration of the virus into the CSF may also be con-sidered because it was previously reported with SARS-CoV-1Indeed SARS-CoV-1 RNA was detected in the CSF of 2patients with seizures2425 A recent case report10 has de-scribed for the first time a case of seizures with the detection ofSARS-CoV-2 RNA in the CSF Similarly leptomeningealinflammation may be present adjacent to subpial corticallesions in the case of viral meningoencephalitis In the case ofviral encephalitis CSF analysis usually demonstrates lym-phocytic pleocytosis26 In addition the CSF protein level istypically elevated in viral encephalitis CSF viral RT-PCR isusually positive but can be negative if done too early This wasnot the case in our series and our results are in accordance

with recently published data that demonstrated an absence ofCSF pleocytosis and negative SARS-CoV-2 RT-PCR (5 of 5patients) but elevated protein level (4 of 5 patients) inpatients presenting cerebral MRI cortical abnormalities13

MRI pictures of viral encephalitis vary with causal pathogenNevertheless viral encephalitis usually involves cerebral GMwith diffusion restriction and can be associated with intrale-sional and diffuse leptomeningeal contrast enhancement Thiswas not the case in our series and did not argue for the directeffect of the virus It is all the more likely that the directdetection of SARS-CoV-2 RNA by RT-PCR was alwaysnegative in all our CSF samples

An alternative hypothesis appears more relevant the neuro-virulence of hCoVs especially MERS-CoV seems to bea consequence of immune-mediated processes1927ndash29 IndeedADEM and Bickerstaff brainstem encephalitis which weredescribed with MERS-CoV18ndash27 are 2 examples of autoim-mune demyelinating diseases resulting from a postinfectious orparainfectious process A recent case report9 has describeda case of acute hemorrhagic necrotizing encephalopathy (whichis the most severe form of ADEM) associated with COVID-19which strengthens the hypothesis of a predominant immuno-logic mechanism In our cohort we also described 2 cases of

Figure 2 Encephalitis

(A B D) Axial fluid-attenuated inversion recovery (FLAIR) and(C) diffusion-weighted MRIs (A) Man 56 years of age lefthippocampus and amygdala FLAIR hyperintensity (B)Woman 71 years of age periventricular and subcorticalwhite matter FLAIR confluent hyperintensities (C) Man 55years of age corpus callosum splenium diffusion hyper-intensity (D) Man 64 years of age FLAIR middle cerebellarpeduncle hyperintensity

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limbic encephalitis and 1 case of CLOCC Concerning thelatter no treatment had been started or stopped in previousweeks Thus 75 of encephalitis cases in our cohort (limbicencephalitis CLOCC radiologic ADEM radiologic acutehemorrhagic necrotizing encephalopathy) are possibly con-sidered immune-mediated diseases Therefore SARS-CoV-2ndashmediated disease is driven largely by immunologic processesand the same mechanisms could explain LME Indeed thearachnoid and pial membranes form the leptomeninges anda significant amount of antigen-presenting cells are present inthe subarachnoid space30 Thus initial immune activationoccurs in the subarachnoid space which is a site for antigenpresentation lymphocyte accumulation and proliferation andantibody production30 All lead to an important local in-flammatory infiltrate with a blood-CSF barrier disruptionwhich can also explain LME Thus LME can be linked toinflammatory or immunologic responses as previously de-scribed in animal models of autoimmune encephalomyelitis31

with some neurotropic viruses such as human T-cell leukemiavirus and HIV31 and in several immune-mediated neurologicdiseases31 Moreover a very similar intracranial pattern hasbeen described in an animal study in piglets affected by gas-troenteritis coronavirus32 Indeed histology demonstrateddiffuse pia matter gliosis with mild congestion of the meningeal

and parenchymal vessels with neuronal degeneration locatedmostly in posterior parietooccipital lobes24 PostcontrastFLAIR is the best sequence to highlight LME but a potentialpitfall is inhalation of increased levels of oxygen by patients whoare intubated which may increase subarachnoid space signalintensity noted on FLAIR images within the basal cisterns andsulcus along the cerebral convexities33 That is why we havechosen in this situation to acquire systematically precontrastand postcontrast FLAIR sequences to avoid misinterpretationof FLAIR hyperintensity within the subarachnoid spaces andnot to misdescribe a meningeal enhancement For our 11patients with LME no precontrast FLAIR signal abnormalitieswere visible in the subarachnoid spaces

Our study has several limitations mainly due to its multicenterand retrospective design First brain MRI protocols were dic-tated by clinical need and the patterns of working could bedifferent among the 11 centers even if neuroradiologists areused to work together Thus 36 of the MRIs were performedwithout administration of gadolinium-based contrast agentsnotably preventing the detection of LME therefore probablyunderestimating it Moreover LMEs are very subtle neuro-imaging findings which need the realization of delayed post-contrast FLAIR sequences which were not done in the vast

Figure 3 Radiologic acute disseminated encephalomyelitis

(A E I) Axial fluid-attenuated inversion recovery (FLAIR) (B F J) axial diffusion (B F J) apparent diffusion coefficient (ADC) map and (D H L) postcontrast T1-weighted MRIs Man 60 years of age subcortical periventricular corpus callosum and posterior fossa white matter FLAIR hyperintensities without contrastenhancement (arrows) Some lesions appear hyperintense on diffusion-weightedMRIs with decreased ADC corresponding to cytotoxic edema (stars) Otherlesions present an ADC increase corresponding to vasogenic edema (cross)

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majority of the centers Second we did not realize a follow-upMRI and some abnormalities could have appeared duringfollow-up Third outcomes were not available for all patients atthe time of writing Thus the mortality rate is probablyunderestimated in our cohort Fourth although patients withCOVID-19may develop a wide range of neurologic symptomswhich can be associated with ischemic stroke or encephalitis itis difficult to state without a controlled general neurologicpopulation that such events are more frequent in patients withCOVID-19 However it now seems well established thatthrombotic events are particularly frequent in patients withCOVID-1921 Moreover encephalitis which is a rare disorderin the general population34 was surprisingly frequent in ourpopulation

In this large multicentric national cohort most patients withCOVID-19 (56) with neurologic manifestations had brainMRI abnormalities such as ischemic stroke LME and enceph-alitis Because the detection of LME suggests the abnormality ofbrain MRI it would be interesting to realize systematicallypostcontrast FLAIR acquisition in patients with COVID-19

Concerning the cases of encephalitis and LME even if a directviral origin cannot be eliminated the pathophysiology of braindamage related to SARS-COV-2 seems rather to involve aninflammatory or autoimmune response The knowledge ofthe various clinicoradiologic manifestations of COVID-19could be helpful for the best care of the patients and ourunderstanding of the disease In addition to SARS cytokine

Figure 4 Multiple correspondence analysis

The ischemic stroke group (red) can be distinguished from the 3 others which largely overlapMost patients with ischemic stroke (numbers and dots in red onthe plot) are located on the same lower-right half of the graph indicating a commonality of symptoms Diag 1 (black) = normal brain MRI Diag 2 (red) =ischemic stroke Diag 3 (green) = encephalitis Diag 4 (blue) = leptomeningeal enhancement

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storm syndrome and heart failure brain injuries may con-tribute to increased mortality This highlights the importanceof neurologic evaluation especially for patients hospitalized inICU with clinical deterioration or worsening of their symp-toms which can be associated with an acute neurologic event

AcknowledgmentThe authors thank Marie Cecile Henry Feugeas for her workin data acquisition for this study

Study fundingNo targeted funding reported

DisclosureThe authors report no disclosures relevant to the manuscriptGo to NeurologyorgN for full disclosures

Publication historyReceived by Neurology April 28 2020 Accepted in final formJune 9 2020

Appendix Authors

Name Location Contribution

StephaneKremer MDPhD

University Hospital ofStrasbourg France

Designed and conceptualizedthe study acquisition of datainterpreted the data draftedthe manuscript forintellectual content

Franccedilois LersyMD

University Hospital ofStrasbourg France

Designed and conceptualizedthe study acquisition of datainterpreted the data draftedthe manuscript forintellectual content

MathieuAnheim MDPhD

University Hospital ofStrasbourg France

Designed and conceptualizedthe study interpreted thedata revised the manuscriptfor intellectual content

Hamid MerdjiMD

University Hospital ofStrasbourg France

Acquisition of data revisedthe manuscript forintellectual content

MalekaSchenck MD

University Hospital ofStrasbourg France

Acquisition of data revisedthe manuscript forintellectual content

HeleneOesterle MD

Hospital of ColmarFrance

Acquisition of data revisedthe manuscript forintellectual content

FedericoBolognini MD

Hospital of ColmarFrance

Acquisition of data revisedthe manuscript forintellectual content

Julien MessieMD

Hospital of ColmarFrance

Acquisition of data revisedthe manuscript forintellectual content

Antoine KhalilMD PhD

Bichat Hospital ParisFrance

Acquisition of data revisedthe manuscript forintellectual content

AugustinGaudemer MD

Bichat Hospital ParisFrance

Acquisition of data revisedthe manuscript forintellectual content

Appendix (continued)

Name Location Contribution

Sophie CarreMD

Hospital ofHaguenau France

Acquisition of data revisedthe manuscript forintellectual content

Manel AllegMD

Hospital ofHaguenau France

Acquisition of data revisedthe manuscript forintellectual content

Claire LecocqMD

Hospital ofHaguenau France

Acquisition of data revisedthe manuscript forintellectual content

EmmanuelleSchmitt MD

University Hospital ofNancy France

Acquisition of data revisedthe manuscript forintellectual content

ReneAnxionnatMD PhD

University Hospital ofNancy France

Acquisition of data revisedthe manuscript forintellectual content

Franccedilois ZhuMD

University Hospital ofNancy France

Acquisition of data revisedthe manuscript forintellectual content

Lavinia JagerMD

Hospital of ForbachFrance

Acquisition of data revisedthe manuscript forintellectual content

Patrick NesserMD

Hospital of ForbachFrance

Acquisition of data revisedthe manuscript forintellectual content

Yannick TallaMba MD

Hospital of ForbachFrance

Acquisition of data revisedthe manuscript forintellectual content

GhaziHmeydia MD

Saint-Anne hospitalParis France

Acquisition of data revisedthe manuscript forintellectual content

JosephBenzakounMD

Saint-Anne hospitalParis France

Acquisition of data revisedthe manuscript forintellectual content

CatherineOppenheimMD PhD

Saint-Anne HospitalParis France

Acquisition of data revisedthe manuscript forintellectual content

Jean-ChristopheFerre MD PhD

University Hospital ofRennes France

Acquisition of data revisedthe manuscript forintellectual content

Adel MaamarMD

University Hospital ofRennes France

Acquisition of data revisedthe manuscript forintellectual content

BeatriceCarsin-NicolMD

University Hospital ofRennes France

Acquisition of data revisedthe manuscript forintellectual content

Pierre-OlivierComby MD

University hospitalsof Dijon France

Acquisition of data revisedthe manuscript forintellectual content

FredericRicolfi MDPhD

University hospitalsof Dijon France

Acquisition of data revisedthe manuscript forintellectual content

PierreThouant MD

University hospitalsof Dijon France

Acquisition of data revisedthe manuscript forintellectual content

Claire BoutetMD PhD

University hospital ofSaint-Etienne France

Acquisition of data revisedthe manuscript forintellectual content

e1880 Neurology | Volume 95 Number 13 | September 29 2020 NeurologyorgN

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited

References1 Chen N Zhou M Dong X et al Epidemiological and clinical characteristics of 99

cases of 2019 novel coronavirus pneumonia in Wuhan China a descriptive studyLancet 2020395507ndash513

2 Huang C Wang Y Li X et al Clinical features of patients infected with 2019 novelcoronavirus in Wuhan China Lancet 2020395497ndash506

3 Glass WG Subbarao K Murphy B Murphy PM Mechanisms of host defense fol-lowing severe acute respiratory syndrome‐coronavirus (SARS‐CoV) pulmonary in-fection of mice J Immunol 20041734030ndash4039

4 Li K Wohlford‐Lenane C Perlman S et al Middle East respiratory syndromecoronavirus causes multiple organ damage and lethal disease in mice transgenic forhuman dipeptidyl peptidase 4 J Infect Dis 2016213712ndash722

5 Arbour N Day R Newcombe J Talbot PJ Neuroinvasion by human respiratorycoronaviruses J Virol 2000748913ndash8921

6 Desforges M Le Coupanec A Stodola JK Meessen-Pinard M Talbot PJ Humancoronaviruses viral and cellular factors involved in neuroinvasiveness and neuro-pathogenesis Virus Res 2014194145ndash158

7 Desforges M Le Coupanec A Dubeau P et al Human coronaviruses and otherrespiratory viruses underestimated opportunistic pathogens of the central nervoussystem Viruses 201912E14

8 Bohmwald K Galvez NMS Rıos M Kalergis AM Neurologic alterations due torespiratory virus infections Front Cell Neurosci 201812386

9 Poyiadji N Shahin G Noujaim D Stone M Patel S Griffith B COVID-19-associatedacute hemorrhagic necrotizing encephalopathy CT and MRI features Radiology2020201187

10 Moriguchi T Harii N Goto J et al A first case of meningitisencephalitis associatedwith SARS-coronavirus-2 Int J Infect Dis 20209455ndash58

11 Mao L Jin H Wang M et al Neurologic manifestations of hospitalized patients withcoronavirus disease 2019 in Wuhan China JAMA Neurol 2020771ndash9

Appendix (continued)

Name Location Contribution

Xavier FabreMD

Hospital of RoanneFrance

Acquisition of data revisedthe manuscript forintellectual content

GeraudForestier MD

Hospital of AntonyFrance

Acquisition of data revisedthe manuscript forintellectual content

Isaure deBeaurepaireMD

Hospital of AntonyFrance

Acquisition of data revisedthe manuscript forintellectual content

GregoireBornet MD

Hospital of AntonyFrance

Acquisition of data revisedthe manuscript forintellectual content

Hubert DesalMD PhD

University Hospital ofNantes France

Acquisition of data revisedthe manuscript forintellectual content

GregoireBoulouis MD

Saint-Anne HospitalParis France

Acquisition of data revisedthe manuscript forintellectual content

Jerome BergeMD

University Hospital ofBordeaux France

Acquisition of data revisedthe manuscript forintellectual content

ApollineKazemi MD

University Hospital ofLille France

Acquisition of data revisedthe manuscript forintellectual content

NadyaPyatigorskayaMD

Pitie-SalpetriereHospital ParisFrance

Acquisition of data revisedthe manuscript forintellectual content

AugustinLecler MD

Foundation ARothschild Paris

Acquisition of data revisedthe manuscript forintellectual content

SuzanaSaleme MD

University Hospital ofLimoges France

Acquisition of data revisedthe manuscript forintellectual content

Myriam Edjlali-Goujon MD

Saint-Anne HospitalParis France

Acquisition of data revisedthe manuscript forintellectual content

BasileKerleroux MD

University Hospital ofTours France

Acquisition of data revisedthe manuscript forintellectual content

Jean-MarcConstans MDPhD

University Hospital ofAmiens France

Acquisition of data revisedthe manuscript forintellectual content

Pierre-EmmanuelZorn PhD

University Hospitalsof Strasbourg France

Major role in the acquisitionof data

MurielMatthieu PhD

University Hospitalsof Strasbourg France

Major role in the acquisitionof data

Seyyid BalogluMD

University Hospitalsof Strasbourg France

Acquisition of datarevised the manuscriptfor intellectualcontent

Franccedilois-DanielArdellier MD

University Hospitalsof Strasbourg France

Acquisition of data revisedthe manuscript forintellectual content

ThibaultWillaume MD

University Hospitalsof Strasbourg France

Acquisition of datarevised the manuscriptfor intellectualcontent

Appendix (continued)

Name Location Contribution

Jean-ChristopheBrisset PhD

French Observatoryof Multiple SclerosisLyon France

Interpretation of the datarevised the manuscript forintellectual content

SophieCaillard MDPhD

University Hospitalsof Strasbourg France

Acquisition of data revisedthe manuscript forintellectual content

OlivierCollange MDPhD

University Hospitalsof Strasbourg France

Acquisition of data revisedthe manuscript forintellectual content

Paul MichelMertes MDPhD

University Hospitalsof Strasbourg France

Acquisition of data revisedthe manuscript forintellectual content

FrancisSchneider MDPhD

University Hospitalsof Strasbourg France

Acquisition of data revisedthe manuscript forintellectual content

Samira Fafi-KremerPharmD

University Hospitalsof Strasbourg France

Acquisition of data revisedthe manuscript forintellectual content

MickaelOhana MDPhD

University Hospitalsof Strasbourg France

Acquisition of data revisedthe manuscript forintellectual content

FerhatMeziani MDPhD

University Hospitalsof Strasbourg France

Acquisition of data revisedthe manuscript forintellectual content

Nicolas MeyerMD PhD

University Hospitalsof Strasbourg France

Major role in the analysis andinterpretation of the data

Julie HelmsMD PhD

University Hospitalsof Strasbourg France

Designed and conceptualizedthe study interpreted thedata revised the manuscriptfor intellectual content

FranccediloisCotton MDPhD

University Hospitalsof Strasbourg France

Designed and conceptualizedthe study interpreted thedata revised the manuscriptfor intellectual content

NeurologyorgN Neurology | Volume 95 Number 13 | September 29 2020 e1881

Copyright copy 2020 American Academy of Neurology Unauthorized reproduction of this article is prohibited

12 Helms J Kremer S Merdji H et al Neurologic features in severe SARS-CoV-2infection N Engl J Med 20203822268ndash2270

13 Kandemirli SG Dogan L Sarikaya ZT et al Brain MRI findings in patients in theintensive care unit with COVID-19 infection Radiology Epub 2020 May 8

14 Ferguson ND Fan E Camporota L et al The Berlin definition of ARDS an expandedrationale justification and supplementary material Intensive Care Med 2012381573ndash1582

15 Starkey J Kobayashi N Numaguchi Y Moritani T Cytotoxic lesions of the corpuscallosum that show restricted diffusion mechanisms causes and manifestationsRadiographics 201737562ndash576

16 Beyrouti R Adams ME Benjamin L et al Characteristics of ischaemic stroke asso-ciated with COVID-19 J Neurol Neurosurg Psychiatry Epub 2020 Apr 30

17 Hess DC Eldahshan W Rutkowski E COVID-19-related stroke Transl Stroke Res202011322ndash325

18 Umapathi T Kor AC Venketasubramanian N et al Large artery ischaemic stroke insevere acute respiratory syndrome (SARS) J Neurol 20042511227ndash1231

19 Arabi YM Harthi A Hussein J et al Severe neurologic syndrome associated withMiddle East respiratory syndrome corona virus (MERS-CoV) Infection 201543495ndash501

20 Guo T Fan Y ChenM et al Cardiovascular implications of fatal outcomes of patientswith coronavirus disease 2019 (COVID-19) JAMA Cardiol Epub 2020 Mar 27

21 Helms J Tacquard C Severac F et al High risk of thrombosis in patients in severeSARS-CoV-2 infection a multicenter prospective cohort study Intensive Care Med2020461089ndash1098

22 NagelMAMahalingamRCohrs RJ GildenD Virus vasculopathy and stroke an under-recognized cause and treatment target Infect Disord Drug Targets 201010105ndash111

23 Subramaniam S Scharrer I Procoagulant activity during viral infections Front Biosci(Landmark Ed) 2018231060ndash1081

24 Hung EC Chim SS Chan PK et al Detection of SARS coronavirus RNA in thecerebrospinal fluid of a patient with severe acute respiratory syndrome Clin Chem2003492108ndash2109

25 Lau KK Yu WC Chu CM Lau ST Sheng B Yuen KY Possible central nervoussystem infection by SARS coronavirus Emerg Infect Dis 200410342ndash344

26 Toledano M Davies NWS Infectious encephalitis mimics and chameleons PractNeurol 201919225ndash237

27 Kim JE Heo JH Kim HO et al Neurological complications during treatment ofMiddle East respiratory syndrome J Clin Neurol 201713227ndash233

28 Li Y Li H Fan R et al Coronavirus infections in the central nervous system andrespiratory tract show distinct features in hospitalized children Intervirology 201659163ndash169

29 Yeh EA Collins A Cohen ME Duffner PK Faden H Detection of coronavirus in thecentral nervous system of a child with acute disseminated encephalomyelitis Pedi-atrics 2004113(pt 1)e73ndashe76

30 Kivisakk P Imitola J Rasmussen S et al Localizing central nervous system immunesurveillance meningeal antigen-presenting cells activate T cells during experimentalautoimmune encephalomyelitis Ann Neurol 200965457ndash469

31 Absinta M Cortese IC Vuolo L et al Leptomeningeal gadolinium enhancementacross the spectrum of chronic neuroinflammatory diseases Neurology 2017881439ndash1444

32 Papatsiros VG Stylianaki I Papakonstantinou G Papaioannou N Christodoulo-poulos G Case report of transmissible gastroenteritis coronavirus infection associatedwith small intestine and brain lesions in piglets Viral Immunol 20193263ndash67

33 Stuckey SL Goh TD Heffernan T Rowan D Hyperintensity in the subarachnoidspace on FLAIR MRI AJR Am J Roentgenol 2007189913ndash921

34 Parpia AS Li Y Chen C Dhar B Crowcroft NS Encephalitis Ontario Canada 2002-2013 Emerg Infect Dis 201622426ndash432

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DOI 101212WNL0000000000010112202095e1868-e1882 Published Online before print July 17 2020Neurology

Steacutephane Kremer Franccedilois Lersy Mathieu Anheim et al multicenter study

Neurologic and neuroimaging findings in patients with COVID-19 A retrospective

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