REVIEW

Potential Neurologic Manifestationsof COVID-19Anna S Nordvig MD Kathryn T Fong MD Joshua Z Willey MD MS Kiran T Thakur MD

Amelia K Boehme PhD MSPH Wendy S Vargas MD Craig J Smith MBChB MD MRCP

and Mitchell SV Elkind MD MS

Neurology Clinical Practice April 2021 vol 11 no 2 e135-e146 doi101212CPJ0000000000000897

Correspondence

Dr Nordvig

as3703cumccolumbiaedu

AbstractPurpose of ReviewNeurologic complications are increasingly recognized in the corona-virus disease 2019 (COVID-19) pandemic COVID-19 is caused bythe novel severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) This coronavirus is related to severe acute respiratory syn-drome coronavirus (SARS-CoV) and other human coronavirus-relatedillnesses that are associated with neurologic symptoms These symp-toms raise the question of a neuroinvasive potential of SARS-CoV-2

Recent FindingsPotential neurologic symptoms and syndromes of SARS-CoV-2include headache fatigue dizziness anosmia ageusia anorexiamyalgias meningoencephalitis hemorrhage altered conscious-ness Guillain-Barre syndrome syncope seizure and stroke Inaddition we discuss neurologic effects of other coronavirusesspecial considerations for management of neurologic patientsand possible long-term neurologic and public health sequelae

SummaryAs SARS-CoV-2 is projected to infect a large part of the worldrsquos population understanding thepotential neurologic implications of COVID-19 will help neurologists and others recognize andintervene in neurologic morbidity during and after the pandemic of 2020

Coronavirus disease 2019 (COVID-19) is the first coronavirus to cause a global pandemic1

and neurologic problems are increasingly recognized among its complications The UnitedStates now has the highest number of cases worldwide2 Spread of the virus is projected tocontinue for months3 COVID-19 is caused by the novel severe acute respiratory syndromecoronavirus 2 (SARS-CoV-2) a single-stranded RNA virus that belongs to the sarbecovirusfamily of betacoronaviruses together with SARS-CoV Middle East respiratory syndromecoronavirus (MERS-CoV) belongs to a related family of betacoronaviruses4

Neurologic involvement is documented in SARS-CoV MERS-CoV and other coronavirus-related illnesses5ndash8 Now as SARS-CoV-2 is projected to infect a large part of the worldrsquospopulation within a short period3 neurologists should be aware of the neurotropic mechanismsand clinical presentations known in other coronaviruses the potential short-term neurologic

Department of Neurology (ASN KTF JZW KTT AKB WSV MSVE) Vagelos College of Physicians and Surgeons Columbia University and the New York Presbyterian HospitalDepartment of Epidemiology (AKB MSVE) Mailman School of Public Health Columbia University New York NY Division of Cardiovascular Sciences (CJS) Lydia Becker Institute ofImmunology and Inflammation University of Manchester and Manchester Centre for Clinical Neurosciences (CJS) Salford Royal NHS Foundation Trust Manchester AcademicHealth Science Centre Salford United Kingdom

Funding information and disclosures are provided at the end of the article Full disclosure form information provided by the authors is available with the full text of this article atNeurologyorgcp

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effects of COVID-19 the special considerations for manage-ment of neurologic patients during the 2020 crisis and thepossible long-term medical and public health sequelae

MethodsA literature review was conducted on PubMed and Lit-COVID Search terms included all combinations ofldquoCOVID-19rdquo ldquoSARS-CoV-2rdquo and ldquocoronavirusrdquo withldquoneurologyrdquo ldquoneurologicrdquo and ldquonervous systemrdquo Therewere 233 articles published before May 8 2020 that wereidentified and reviewed for pertinence and validity Thefirst author reviewed all articles Other authors providedcritical feedback A formal systematic review includingreview of each article by multiple authors was not pursuedgiven the exigencies of the pandemic

Phylogenetic Review of SARS-CoV-2 andRelated CoronavirusesCoronaviruses are divided into genera by serologic cross-reactivity and then further delineated into lineages SARS-CoV-2 is a member of the betacoronavirus (group 2 genus)and sarbecovirus lineage (lineage 2) The only other hu-man coronavirus in this lineage is SARS-CoV which shares79 genetic sequence identity with SARS-CoV-29 Fea-tures of other betacoronaviruses are listed in table 1 Be-cause the genomic sequence identity in conservedreplicase domains (ORF 1ab) is less than 90 be-tween SARS-CoV-2 and all other members of the

betacoronavirus family SARS-CoV-2 has been denoted asa novel betacoronavirus9

Neurologic Involvement inOther CoronavirusesAlthough acute and chronic neurologic diseases in animalshave been described in relation to nonhuman strains ofcoronavirus10 reports of neurologic manifestations fromhuman coronaviruses are infrequent (table 2)11ndash18 There arenumerous proposed mechanisms for neurologic in-volvement by coronaviruses in animals and humans19

Among the 7 strains of human coronavirus known to bepathogenic 3 strains have been detected in the CNS 2strains responsible for up to 30 of common colds HCoV-229E and HCoV-OC43620 as well as SARS-CoV21

The clinical respiratory illness in COVID-19 is similar toSARS and involvement of other organs may also be similarbetween the 2 diseases22 The angiotensin-converting en-zyme 2 (ACE2) is the portal of entry for both SARS-CoVand SARS-CoV-222 ACE2 on neurons was implicated as theentry point of CNS infection by SARS-CoV23

In a 2008 mouse study using a selective antibody ACE2 wasfound to be widespread on the cardiorespiratory neurons ofthe brainstem (raphe nuclei nucleus of the tractus solitariusand rostral ventrolateral medulla) hypothalamus (para-ventricular nucleus) and the subfornical organ as well as themotor cortex24ndash26 Human studies using quantitative in vitro

Table 1 Neurologically Notable Coronaviruses in Humans and Animalse-68

Coronavirus HostHostentry Reservoir

Site ofdiscovery

Major geographicdistribution Systemic features

Associated neurologicfeatures

SARS-CoV Human ACE2 Bats andcivets

China China TaiwanSingapore and Vietnam

Mild to severerespiratory illness

Encephalopathy seizurestroke polyneuropathyand myopathy

MERS-CoVe-69 Human DPP4 Bats andcamels

SaudiArabia

Egypt Oman Qatarand Saudi Arabia

Moderate to severerespiratory illness

Encephalopathy ischemicstroke and intracerebralhemorrhage

HCoV-OC43 Human Unknown Bats androdents

Global Mild respiratory illness ADEM (case report) andacute encephalitis(possible)

HCoV-229E Human APN Bats andcamelids

Global Mild respiratory illness Encephalitis (possible)

HCoV-NL63e-70 Human ACE2 Global Mild respiratory illness None reported

Mouse hepatitis virus Mouse Severe pneumonitisand SARS

Acute encephalitis orchronic demyelinatingdiseasee-7

Sialodacryoadenitiscoronavirus

Rat Neurologic infectione-71

Hemagglutinatingencephalomyocarditisvirus

Pig Neurologic infectione-71

Abbreviations ACE2 = angiotensin-converting enzyme 2 ADEM = acute disseminated encephalomyelitis APN = aminopeptidase N DPP4 = dipeptidylpeptidase 4MERS-CoV (50 identity with SARS-CoV-2)

e136 Neurology Clinical Practice | Volume 11 Number 2 | April 2021 NeurologyorgCP

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Table 2 Neurologic Findings in Case Reports of SARS-CoV MERS-CoV and HCoV-OC43

DemographicClinicalpresentation Neurologic presentation CSF findings Neurologic clinical studies

Autopsyfindings

SARS-CoV

32-y-old woman 26 wkpregnant38

Fever myalgias dry coughprogressed to respiratory and renalfailure extubated day 27

Generalized tonic-clonicconvulsions on day 22

+ SARS-CoV RNA otherwisenoninflammatory with 20 RBCsper mm3

Normal MRI day 46Normal EEG day 39

Survived

59-y-old woman IgAnephropathy on peritonealdialysis14

Fever chills cough diarrhea andrespiratory distress

Vomiting and appendiculartwitching on hospital day 5

+ SARS-CoV RNA 6884 copiesmLa

otherwise noninflammatoryNormal HCTNo MRI or EEG available

Outcome not provided

39-y-old man18 Fever chills headaches dizzinessmyalgias treated with ribavirinsteroids for 1 mo bacterialpneumonia and ARDS

Obscured monocular visiondysphoria delirium and vomitingafter 1 mo

NA CT showed abnormalitiesconsistent with ischemia or brainedema on day 33 and brainherniation day 35

Viral N protein in glial cells andneurons Enveloped viral particlescompatible with coronavirus insuspended tissueb

51-y-old woman36 Fever dyspnea cough anddiarrhea progressed to multipleorgan failure and intubation

Distal-predominant 4-limbweakness and leg numbness onday 21

NA EMG polyradiculoneuropathy Survived

48-y-old woman36 Fever dyspnea and myalgiaprogressed to multiple organfailure and intubation

Distal-predominant 4-limbweakness and bilateral fingernumbness on day 24

Protein 46 mgdL negative SARS-CoV

EMG axonopathic sensorimotorpolyneuropathy recovery by day92

Survived

42-y-old woman36 Fever and dyspnea progressed tomultiple organ failure andintubation

Distal-predominant 4-limbweakness and left foot numbnesson day 25

Protein 15 mgdL 0 cells negativeSARS-CoV

CPK 9050 EMG myopathy withasymmetric sensorimotorpolyneuropathy (axonopathic)recovery day 87

Survived

31-y-old man36 Fever cough and soft stool Proximal leg weakness on day 22 NA EMG myopathy complete recoveryby day 94

Survived

MERS-CoV

74-y-old man with HTN DMand dyslipidemiae-72

Unclear initial presentation feverlater had lymphopenia withcritically low absolute CD4 and CD8counts

Confusion ataxia and vomiting Noninflammatory with negativeMERS-CoV RT-PCR

MRI multifocal nonenhancing T1hypo- T2 hyperintensitiesrestriction subcortical gray andwhite matter

No autopsy

57-y-old man with HTN andDMe-73

Flu-like illness myocardialischemia pulmonary edema andgangrenous toe

Bilateral multifocal anteriorcirculation stroke

NA CTA near occlusion at origin of bothinternal carotid arteries middlecerebral artery narrowing and novasculitis

No autopsy

45-y-old man with HTNchronic kidney disease andischemic heart diseasee-73

Fever respiratory symptomsdiarrhea pneumonia and kidneyinjury

After tracheostomy on hospital day24 impaired consciousness

Elevated protein negative MERS-CoV RT-PCR

MRI confluent T2 hyperintensitiesin bilateral white matter andcorticospinal tracts noenhancement or restriction

Survived discharged home day 107

Continued

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Table 2 Neurologic Findings in Case Reports of SARS-CoV MERS-CoV and HCoV-OC43 (continued)

DemographicClinicalpresentation Neurologic presentation CSF findings Neurologic clinical studies

Autopsyfindings

42-y-old woman with obesityand DMe-74

ARDS lymphopenia leukopeniaand treated with steroids andantivirals

Diabetes insipidus then massiveintraparenchymal hemorrhagewith SAH

Unable due to tonsillar herniation No aneurysm visualized on CTA No autopsy

34-y-old woman with DMe-73 ARDS lymphopenia inflammationand DIC

Intracranial hemorrhage on day 14 NA Head CT with ICH massive edemaand midline shift

No autopsy

28-y-old mane-73 Fever ARDS and bacterialpneumonia

Myalgias then paraparesisparesthesia (critical illness)

NA EMG length-dependent axonalpolyneuropathyNormal spine MRI

Survived

HCoV-OC43

9mo old with acute leukemiae-

75Fever and upper airway symptoms Altered consciousness and

myoclonic seizuresNegative CSF Normal head CT and abnormal

brain MRIBrain tissue positive for HCoV-OC43

11 mo old with combinedimmunodeficiency8

Respiratory infection Encephalitis NA Brain tissue positive for HCoV-OC43

15-y-old mane-76 Upper respiratory symptoms Ascending numbness and gaitdifficulty 5 d before hospitalization

+ HCoV-OC43 RNA MRI of the brain and spine acutedisseminated encephalomyelitis

Survived

Abbreviations ARDS = acute respiratory distress syndrome CTA = computed tomography angiogram DIC = disseminated intravascular coagulation DM = diabetes mellitus type 2 HTN = hypertension ICH = intracerebralhemorrhage NA = not available SAH = subarachnoid hemorrhagea SARS-CoV RNA was isolated in both CSF and serum at 6884 and 6750 copiesmL respectivelyb Full autopsy revealed aspergillus pneumonia neuronal denaturation and necrosis broad glial cell hyperplasia with gliosome formation and edema Immunohistochemistry staining of glial cells and neurons revealed thepresence of viral N protein which was absent in a control specimen An inflammatory infiltrate of CD68+ monocytesmacrophages and CD3+ T lymphocytes were also seen by immunohistochemistry There was no report ofelectron microscopic examination or the identification of viral particles in brain tissue A suspension of brain tissue was prepared and inoculated into cell culture which produced enveloped viral particles compatible withcoronavirus when examined by transmission electron microscopy

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autoradiography have shown ACE2 on neurons and glia inthe hypothalamus midbrain pons cerebellum medullaoblongata and basal ganglia27 although the enzymersquos dis-tribution in the human CNS is not as well characterized as inmice28

ACE2 is also found on endothelial cells29 Endothelial in-volvement in the brain could theoretically also lead to blood-brain barrier (BBB) disruption such as that found in hy-pertension30 and a proinflammatory state31

In mouse models there is immunohistochemical evidence ofSARS-CoV and MERS-CoV CNS invasion especially in thebrainstem32ndash34 In an underpowered human autopsy studyin situ hybridization confirmed the presence of viral RNA ofHCoV-229E and HCoV-OC43 strains in brain bank samplesof 14 of 39 (36) patients with multiple sclerosis (MS) andin 7 of 51 (14) controls (25 normal controls and 26 pa-tients with other neurologic diseases)6

In the pediatric population HCoVs have been associated withclinical neurologic disease In a single-center Chinese studyIgM antibodies to HCoV were found in the CSF of 12 ofhospitalized childrenwith encephalitis over a 1-month period17

Rare case reports suggest a link to fatal encephalitis and acutedisseminated encephalomyelitis (table 2)

The SARS-CoV epidemic in 2003 tallied over 8000 infectionsand 700 deaths Case reports of neurologic illness in SARS-CoV(table 2) include central and peripheral nervous systemmanifestationsmdashdelirium reduced level of consciousness1418

seizures1218 stroke myopathy1135 neuropathy36 and striatedmuscle vasculitis37

MERS-CoV has not been isolated from CSF or postmortembrain specimens among approximately 2500 laboratory-confirmed cases but there are 6 patients described withneurologic illness following an intensive care unit (ICU)course (table 2)

Another autopsy study from 8 confirmed SARS cases foundevidence of SARS-CoV genetic material in the brain by in situhybridization electronmicroscopy andRT-PCR38 The signalswere confined to the cytoplasm of numerous neurons in thehypothalamus and cortex Edema and scattered red de-generation of the neurons were present in the brains of 6 of the8 confirmed cases of SARS SARS viral sequences and patho-logic changes were not present in the brains of unconfirmedcases or 6 age-matched head trauma control cases The reportdoes not specify if any of the 8 SARS cases manifested neu-rologic symptoms during their acute illness Importantlyedema and acidophilic neuronal degeneration are nonspecificmarkers of acute neuronal injury39mdashthere was no reportedevidence of direct pathologic effects of SARS-CoV This studytherefore does not confirm whether the genomic sequencesdetected are indicative of direct viral invasion virus-relatedbrain injury or an incidental secondary phenomenon

Weaknesses of these studies include limited or inconsistentinformation about autopsy inconsistent neuroimaging evi-dence of cerebral injury comorbid conditions and morbid-ities of intensive care treatment that are known to causeneurologic events Many questions arise about the role ofimmunosuppression in these cases did steroids alone or incombination with SARS-associated lymphopenia facilitateneuroinvasion Was the patient with autoimmune historyreceiving immunosuppressive treatment In addition end-stage renal disease requiring dialysis may have contributed toan underlying immunosuppressed state

Mechanisms of CNS Injury by Coronavirusesand Other Infections and Implicationsfor SARS-CoV-2HCoVs have proven capable of using at least 3 pathways fordirect viral entry into the CNS15mdashsome of these may berelevant to SARS-CoV-2 (table 3)

First direct inoculation of the olfactory bulb through thecribriform plate may be one mechanism for the introductionof the virus into the CNS32e-8 Direct intranasal inoculationof SARS-CoV in mice induced widespread SARS-CoV neu-ronal infection in areas with first- or second-order connec-tions with the olfactory bulb within 7 days After inoculationtransneuronal spread was the likely mechanism for furtherviral infection32 In a 1990 study ablation of the olfactorybulb prevented the spread of the mouse hepatitis virus type 3coronavirus (MHV) on nasal inoculation40 Moreover lowdoses of MERS-CoV introduced intranasally in mice resultedonly in CNS infection and spared other organs in miceproviding indirect evidence for neurotropism34

In COVID-19 small studies are showing high rates of self-reported anosmia and also ageusia (perhaps due to in-volvement of gustatory receptors) often without rhinorrheaor nasal congestione-1ndashe-3 Olfactory and gustatory dysfunc-tion may be independent and persistent symptoms even asthey are highly correlated in incidence (table 4) Whether thepresence of these symptoms indicates transnasal spread andportends a mechanism that causes greater neurologic diseaserequires further study

Second in pigs and birds after infection of peripheral nerveterminals through oronasal inoculation CNS invasion mayalso occur by retrograde synaptic transmission through sen-sory nerves and ganglia Trans-synaptic transfer has beendocumented in other coronavirus animal models such asswine hemagglutinating encephalomyelitis virus (whereeventual brainstem infection was first detected in the tri-geminal and vagal sensory nuclei) and avian bronchitisviruse-4

In a 2015 study of MHV in mice BBB invasion by corona-viruses correlated with virus-induced disruption of tightjunctions on brainmicrovascular endothelial cells This led toBBB dysfunction and enhanced permeabilitye-5 When MHV

NeurologyorgCP Neurology Clinical Practice | Volume 11 Number 2 | April 2021 e139

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is directly inoculated into the CNS proinflammatory cyto-kines and chemokines surge Neutrophils natural killer cellsand monocytemacrophages rapidly migrate to the CNSsecreting matrix metalloproteinases to permeate the BBBVirus-specific T cells infiltrate the CNS oligodendroglia areprimary targets of infection Importantly the virus becomesundetectable in the CSF 2 weeks postinfection but persistsmainly in white matter tracts As a result of this largelyimmune-mediated response animals develop demyelinatinglesions within the brain and spinal cord that are associatedwith clinical manifestations including awkward gait andhindlimb paralysise-6ndashe-8 Although SARS-CoV-2 has not yetbeen identified in CNS endothelium viral particles werefound on electron microscopy in renal endothelial cells of 1patient with a remote history of renal transplant the 2 othersin the series had systemic endotheliitis but no viral par-ticlese-9

Acute infections may be a trigger for stroke due to increasedinflammation and consequent thrombosise-10ndashe-12 In analy-ses from the Cardiovascular Health Study (CHS) and theAtherosclerosis Risk in Communities study recent hospi-talization for infection was associated with an increased riskof strokee-13 In CHS among 669 participants who experi-enced a stroke the risk of stroke increased following hos-pitalization for infection within the previous 30 days (oddsratio 73 95 confidence interval 19ndash409) A population-based cohort study from Denmark showed that 80 ofcardiovascular events after exposure to bacteremia occurred

during the index hospitalization with the risk of strokehighest in the first 3ndash15 days postinfectione-14 Even in-fluenza and minor respiratory and urinary tract infections areassociated with increased stroke risk and vaccinations mayhelp prevent strokee-12e-15 A Cochrane review of 8 ran-domized controlled trials (12029 participants) providesevidence that influenza vaccination decreased cardiovascularoutcomes and a case series study found that the risk of strokewas increased after respiratory tract infection and was re-duced after vaccination against influenza pneumococcal in-fection and tetanuse-16 Research with administrative datahas also identified sepsis as a stroke trigger although theabsolute risk is lowe-12

Some critically ill patients with COVID-19 experience asystemic inflammatory response syndrome (cytokine storm)that may lead to endothelial dysfunctione-17mdasha known riskfactor for thromboembolic eventse-18 Many systemicmarkers of proinflammatory activation are elevated in-cluding multiple cytokines For example peripheral tumornecrosis factor-α a key upstream mediator of the systemicinflammatory response and interleukin-6 (IL-6) a key driverof the acute-phase response are higher in more severeCOVID-1922e-19

IL-6 is critically involved in thromboinflammatory activa-tion and elevated concentrations may therefore drive aprothrombotic state Perturbations to the thrombosis-coagulation pathways have also been reported Disruptionto both anticoagulant (eg reduced antithrombin and ele-vated lupus anticoagulant) and procoagulantthrombotic(increased fibrinogen D-dimer and increased prothrombintime) pathways is reminiscent of disseminated in-travascular coagulation (table 4) e-20 In a case series of 5COVID-19 skin and lung biopsies thrombotic microvas-cular injury was associated with extensive complementactivatione-21

There have been several reports of acute myopericarditis andother cardiac complications with SARS-CoV-2e-22 and SARS-CoVe-23 which combined with hypercoagulability couldalso lead to stroke as a consequence of cardiac arrhythmiaand dysfunction causing cardiac embolism

In summary neurologic effects of coronaviruses includingSARS-CoV-2 may be triggered by direct cytopathic effects ofthe virus secondary effects of severe pulmonary infection thesystemic inflammatory response (cytokine storm) or acombination of these

Clinical Neurologic Findings in COVID-19Reports of early and mild neurologic symptoms of COVID-19 differ in both symptom classification and incidence despitemost of them being reported from hospitalized cohorts themost commonly reported symptoms are headache mildconfusion dizziness myalgias fatigue anorexia anosmiaand ageusia (table 4) Many of these reported symptoms are

Table 3 Potential Mechanisms for Neurologic Injury inCOVID-19

Routes of direct CNS viral invasion32e-77

Peripheral nerve infection (eg direct intranasal inoculationmechanoreceptors andchemoreceptors in the lung and lower respiratory airwaysperhaps oropharyngeal)

Olfactory receptor neuron infection through direct inoculation

Retrograde trans-synaptic transmission after infection of theperipheral nerve

Direct CNS neuronal entry

BBB disruption and infection of microvascular endothelial cellsfollowing viremia

Infection of circulating leukocytes38 that traffic the virus across theBBB (Trojan horse entry)

Indirect mechanisms for neuronal injury

Systemic inflammation (includes hypercoagulable state andcytokine storm)

Endothelial invasion injury and thrombosis

Hypoxic-anoxic brain injury after cardiorespiratory failure

CNS demyelination

Abbreviation BBB = blood-brain barrier

e140 Neurology Clinical Practice | Volume 11 Number 2 | April 2021 NeurologyorgCP

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

Table 4 Neurologic Findings in Case Reports and Case Series of Systemic SARS-CoV-2 Infection (COVID-19)

Possible neurologic symptom N of cohort Comment Region

Early and mild neurologic symptoms

Hyposmiaanosmia 357 856 Mild-to-moderate patients questionnaire response10 d postonset

Western Europee-2

44 611 25 hospitalized 75 outpatients Italye-78

11 51 Hospitalized patients Chinae-27

1 40-y-old woman with anosmia cough headache and without ageusia MRIinflammation of olfactory clefts

Francee-79

12 56 Hospitalized patients Chinae-27

Hypogeusiaageusia 342 888 Mild-to-moderate patients questionnaire response Western Europee-2

39 542 25 hospitalized 75 outpatients Italye-78

Fatiguemalaiseasthenia 418 380 Hospitalized patients Chinae-80

69 263 Hospitalized mainly mildly ill patients Chinae-81

48 667 25 hospitalized 75 outpatients 19 d postonset Italye-78

18 346 Critically ill hospitalized patients Chinae-82

Headache 150 136 Hospitalized patients Chinae-80

30 417 25 hospitalized 75 outpatients 19 d postonset Italye-78

28 131 Hospitalized patients Chinae-27

17 65 Hospitalized mainly mildly ill patients Chinae-81

9 65 Hospitalized patients Chinae-83

3 79 Hospitalized patients China22

3 58 Critically ill hospitalized patients Chinae-82

Anorexia 55 399 Hospitalized patients Chinae-83a

Dizziness 36 168 Hospitalized patients Chinae-27

13 94 Hospitalized patients Chinae-83

Myalgia + fatigue + arthralgia 48 348 Hospitalized patients Chinae-83

6 115 Critically ill hospitalized patients Chinae-82

18 439 Hospitalized patients China22

164 149 Hospitalized patients Chinae-80

Nerve pain 5 23 Hospitalized patients Chinae-27

More severe neurologic symptoms (partial table see appendix e-1)

Post-ARDS encephalopathy 26 650 MRI 1113 bifrontotemporal perfusion abnormalities 813 leptomeningeal enhancement CSF 27 OCBs 17elevated immunoglobulins and protein no SARS-CoV-2EEG only 18 diffuse bifrontal slowing

Francee-84

Impaired consciousness 16 75 Hospitalized patients Chinae-27

Muscle injury 23 107 Hospitalized patients Chinae-27

Stroke 13 59 3 small vessel occlusions 5 large vessel stenosis and 3cardioembolic 1 cerebral venous thrombosis 1hemorrhage (onset 10 d)

Chinae-28

6 28 Hospitalized patients (57 in severe infections vs 08in nonsevere infections)

Chinae-27

3 37 Arterial ischemic strokes (cumulative incidence) The Netherlandse-47

Continued

NeurologyorgCP Neurology Clinical Practice | Volume 11 Number 2 | April 2021 e141

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nonspecific found in many viral illnesses and may or maynot indicate CNS involvement

For example although robust evidence for anosmia and ageusiais lacking theAmericanAcademyofOtolaryngologyndashHead andNeck Surgery has established a COVID-19 Anosmia ReportingTool for Clinicianse-24 as data emergee-25e-26 In contrast tolow rates of anosmia and ageusia in hospitalized or critically illpatients 2 retrospective studies of only patients with mild-to-moderate COVID-19 report high rates of olfactory and gus-tatory impairment of over 68ndash80e-1e-2 Although there maybe substantial selection bias in the questionnaire responsethese symptoms may be more prominent or more acknowl-edged in milder disease

SARS-CoV-2 is associated with more serious neurologiccomplications including ischemic stroke intracerebral hem-orrhage encephalopathy Guillain-Barre syndrome menin-goencephalitis syncope seizures possible demyelinationand recrudescence of prior strokes seizure syndromes orMS pseudorelapse (table 4)

In a series of 214 from Wuhan China40 of patients hadat least 1 comorbidity that increased the risk of stroke such

as hypertension cardiovascular disease diabetes or cancerPatients with stroke had higher D-dimer levels comparedwith both those with severe non-CNS symptoms and thosewith nonsevere CNS symptoms Although milder neurologicsymptoms occurred within 1ndash2 days of symptom onset themean onset of stroke and impaired consciousness was 8ndash10days into the illnesse-27 Other case series have reportedstroke onset within 0ndash4 days (table 4)

Among 13 patients with stroke in a Wuhan series therewere 3 small vessel 5 large vessel and 3 cardioembolicstrokes as well as 1 cerebral venous thrombosis and 1hemorrhagee-28 This suggests that the mechanism ofstroke is likely not specific to a particular pathophysiologicfeature of the SARS-CoV-2 virus but rather the result ofnonspecific effects of inflammation and endothelial andcoagulation dysfunction likely superimposed on preexist-ing risk factors

Although systemic inflammation from infectious disease is arecognized stroke risk factor as discussed above largestudies on other viruses such as influenza A show only a 1incidence of stroke over a period of 45 dayse-12 In acuterespiratory distress syndrome (ARDS) intensive care

Table 4 Neurologic Findings in Case Reports and Case Series of Systemic SARS-CoV-2 Infection (COVID-19) (continued)

Possible neurologic symptom N of cohort Comment Region

6 53ndash85 y old 66 large vessel occlusions (3 multiterritory infarcts 2 concurrentvenous thromboses 2 ischemic strokes despite therapeutic anticoagulation) D-

dimer levels ge1000 μgL (onset 0ndash24 d)

United Kingdome-85

5 33ndash49 y old 55 large vessel occlusions 35 with elevated fibrinogen D-dimer andferritin (onset 0 y)

New Yorke-86

4 73ndash88 y old 1 embolic 2 large vessel stenosis 1 internal carotid occlusion (onset0ndash2 d)

New Yorke-87

4 45ndash77 y old 2 suspected large vessel stenosis and 2 small vessel occlusions onMRI 34 elevated D-dimer 24 elevated CRP 14 elevated ferritin none critically ill

(onset 1ndash4 d)

Turkeye-88

3 65ndash70 y old multiple bilateral cerebral infarcts and ARDS (onset 10ndash33 d)b Chinae-89

Guillain-Barre syndrome (partial listcontinued in appendix e-1)

5 23ndash77 y old EMG 35 axonal 25 demyelinating 25 antiganglioside Ab CSF 35albuminocytologic dissociation no SARS-CoV-2 MRI 2 caudal and 1 facial nerve

enhancement (onset 5ndash10 d)

Italye-90

1 61-y-old woman EMG demyelinating neuropathy CSF protein 124 mgdL 5cellsμL (presenting symptom 4 d after visiting endemic region)

Chinae-91

1 65-y-old man EMG motor-sensory axonal neuropathy MRI negative (onset2+wk)

Irane-92

1 71-y-old man EMG acute polyradiculoneuritis with prominent demyelinationCSF protein 54 mgdL 9 cellsμL no SARS-CoV-2 (onset day 8)

Italye-93

Abbreviations ARDS = acute respiratory distress syndrome CRP = C-reactive protein ICU = intensive care unit Ig = immunoglobulin OCB = oligoclonal bandThe remainder of the more severe neurologic symptoms (Miller-Fisher syndrome polyneuritis cranialis syncope recrudescence seizure ataxiameningoencephalitis hemorrhage and possible demyelination) are listed in appendix e-1 (linkslwwcomCPJA183)e-References related to this article can be accessed at linkslwwcomCPJA184a Anorexia was reported in 55 (399) of which 667 required ICU care vs 304 non-ICU care Nineteen patients with nausea and vomiting (137) withoutthe skew in distribution of those requiring ICU care vs non-ICU careb All had elevated prothrombin time fibrinogen concentrations D-dimer IgA anticardiolipin antibody and IgAG antindashβ-glycoprotein I antibodies but notlupus anticoagulant The authors concluded that the multiple cerebral infarcts were related to secondary antiphospholipid syndrome although all patientswere older and had conventional vascular risk factors and other potential explanations (eg findings of atrial fibrillation or cerebral vasculitis) were notreported

e142 Neurology Clinical Practice | Volume 11 Number 2 | April 2021 NeurologyorgCP

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patients patients treated with standard-of-care mechanicalventilation (with referral to venovenous extracorporealmembrane oxygenation [ECMO] for refractory cases)developed only 5 ischemic stroke and 2ndash4 hemor-rhagic stroke eventse-29

The causes of common neurologic symptoms in critical ill-ness may include drug-induced paralysis hypotensionECMO concomitant superinfections profound changes insystemic thromboinflammationimmune cellular functionand extended immobility Profound multiorgan involvementof COVID-19maymultiply intensive care issues contributingto deliriume-30 Of 113 deceased patients with COVID-19 in1 series 23 (20) had hypoxic encephalopathye-31 Chinesebrain autopsies show endovasculitis endothelial damagecerebral edema hyperemia and neurodegeneration withSARS-CoV-2e-32mdashmany of these findings could also be at-tributed to critical illness as discussed earlier To understandthe neurologic role of SARS-CoV-2 in critically ill patientswith COVID-19 further data are needed on the frequency ofneurologic complications of critical illness such as throm-bosis critical illness myoneuropathy and cerebral hypo-perfusion For example the American Heart AssociationrsquosGet With The Guidelines COVID-19 registry will add anurgent module designed to capture nation-wide data on thecardiovascular and neurologic effects of COVID-19e-33

At-risk Neurologic PatientsAs suggested by coronavirus mechanisms of neurologic injurythere is potential for some neurologic patients to be at increasedrisk for further morbidity (table 5) Patients with preexistingBBB compromise may be at higher risk Stroke-induced sup-pression of the innate and adaptive immune systems mediatedby dysregulation of the autonomic nervous system is welldescribede-34 andmay increase susceptibility to and severity ofSARS-CoV-2 infection in the acute phase of stroke andtherefore worsen clinical outcomes Another potential risk ofinfection is the dementia-related behaviors that may make itdifficult for patients to comply with key infection preventionmeasures (eg remembering to wash hands)e-35

Given the susceptibility of patients with respiratory comor-bidities to COVID-19 some neurologic patients may be moresusceptible to COVID-19ndashrelated morbidity due to underly-ing respiratory compromise in preexisting neuromusculardiseasee-36 major strokee-18 and advanced neurodegenerationFor example in hemispheric stroke cough expiratory musclefunction and functional residual capacity are impairede-37e-38

Other neurologic patients with frequent cardiac comorbiditiessuch as patients with Parkinson disease may also be at higherrisk although there is no evidence that Parkinson disease orother movement disorders decrease chance of survival whencompared with otherwise similar patientse-39 As seen withother infections patients with chronic deficits having COVID-19 may have recrudescence or worsening of their neurologicsymptoms including seizure MS pseudorelapse or residuafrom strokee-40

Immunosuppressed patients have been specifically cautionedabout COVID-19e-41 although clear data regarding their riskare not yet available Clinicians and patients are alreadyweighing these advisories when deciding on standard-of-caretreatmentse-42 the data remain controversiale-43ndashe-46

Thromboembolic disease is common in COVID-19 Deepvenous thrombosis was confirmed in 27 of 184 COVID-19ICU patients (of which pulmonary embolism was 81)despite prophylaxise-47 Traditional contraindications to an-ticoagulant therapy such as a prolonged activated partialthromboplastin time (aPTT) may not be as helpful in pa-tients with COVID-19 in whom prolonged aPTT and lupusanticoagulant may be seene-48 Neurologists and intensivistswill need to carefully weigh the benefits of antithrombotictherapies against the risks of intracerebral hemorrhage

Although staging models of clinical COVID-19 disease pro-gression warrant consideration of neurologic involvemente-49

the realities of sterilization and staffing of head imaging studiesduring a pandemic are restrictive and may limit neurologicinvestigations in patients with COVID-19 who have severecardiopulmonary complications

Finally widespread social isolation policies may be restrictingneurologic patient access to specialist care with widespreadclosures of outpatient neurology offices As the case fatalityrate of COVID-19 for elderly patients with dementia is 3-11xthat of patients in their 50se-50 patients with dementia may

Table 5 COVID-19 Considerations for Specific NeurologicPatients

Preexisting neurologic conditionPossible considerations to beaddressed

Structural lesions Decreased seizure thresholdrecrudescence

Neuromuscular respiratorycompromise diaphragmaticweakness

Worse outcome with COVID-19respiratory symptoms

Myasthenia gravis Respiratory compromise withcontraindicated medications(hydroxychloroquineazithromycin)

Neuroinflammatory andautoimmune disorders

Discussions with patients aboutimmunomodulatory medications

Acute stroke Hospital shortages limiting staffingutilization of advancedinterventional mechanisms

Reluctance to present urgently tohospital during pandemic

Recognizing prothrombotic state ofCOVID-19

Dementia Possible increased risk of infection(eg difficulty following strict handhygiene)

Susceptibility to postinfectiousdelirium

NeurologyorgCP Neurology Clinical Practice | Volume 11 Number 2 | April 2021 e143

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

be disproportionately affected by stringent restrictionsaimed at protecting the highest COVID-19 risk group

Longer-term Neurologic Implicationsof COVID-19It remains unknown whether SARS-CoV-2 will causelonger-term neurologic morbidity It is important to con-sider whether widespread recovered COVID-19 in ourpopulation will be a risk factor for other neurologicsequelae

Psychiatric disease and fatigue may occur in severe COVID-19survivors as was reported after SARS For example 63 ofSARS survivors from a Hong Kong hospital responded to asurvey a mean 41 months after recovery over 40 had activepsychiatric illness 40 complained of chronic fatigue and 27met the 1994 diagnostic criteria for Chronic Fatigue SyndromeIn another small study of 22 SARS survivorswhowere unable toreturn to workmainly as health care workers symptoms closelyoverlapped with chronic fibromyalgia (chronic fatigue painweakness depression and sleep disturbance)13

Longer-term stroke risk factors may also be elevated aftersevere coronavirus infectione-22 For example in a 12-yearfollow-up study of 25 patients infected with SARS-CoV andtreated with methylprednisolone vs 25 healthy controls(average age 47 years body mass index 24 kgm2) 68 vs40 reported hyperlipidemia 60 vs 16 reported glucosemetabolism disorder and 44 vs 0 reported cardiovascularsystem abnormalitiese-51 Mechanisms for these increasedprevalences are uncertain

Infection is a risk factor for decreased cognitive functionboth acutely and over time In addition a dose response withseverity of infection has been associated with acceleratedcognitive declinee-52 Common infections such as upper re-spiratory tract infections pneumonia periodontalinfectionsinflammation and general infections particularlyconcurrent infections are also associated with an increasedrisk of Alzheimer disease and related dementiase-53ndashe-61

Sepsis survivors showed not only cognitive deficits in verballearning and memory but had reduction of left hippocampalvolume compared with healthy controlse-62 Seventy percentto 100 of ARDS survivors had cognitive impairment atdischargemdash46ndash80 1 year latermdashand worse impairmentcorrelated with ARDS severitye-63 Cognitive and behavioralimpairment after COVID-19 may warrant study

Finally ongoing and planned critical trials of neurodegen-erative and nonndashlife-threatening chronic neurologic disor-ders are being paused to keep elderly and vulnerable patientsaway from hospitals which could have implications for thosetrials as well as advances in neurodegeneration research

Implications for Pediatric NeurologyImplications for pediatric neurology remain very uncertainjust 2 case reports suggest COVID-19ndashassociated paroxysmal

events in infants (table 4)e-64 Coronavirus HCoV-OC43was detected in the CSF of a child presenting with acutedemyelinating encephalomyelitis16 Although other pediat-ric viral infections were associated with a higher incidence ofdiseases such as MS there is insufficient evidence to makethe same assertion about coronaviruses717e-65 Rare neuro-logic complications of medium-vessel vasculitis have alsooccurred in the paste-66 and now a case of Kawasaki diseaseafter COVID-19 has been reportede-67 Because the out-comes of COVID-19 seem to be more favorable in manychildren it will be difficult to estimate the potential role ofcoronavirus infection in long-term pediatric neurologichealth

SARS-CoV-2 is associated with several neurologic symptomsand syndromes including headache fatigue anosmia ageusiaanorexia myalgias asthenia meningitis Guillain-Barre syn-drome altered consciousness syncope and stroke Un-derstanding the potential neurologic implications ofCOVID-19 and lessons from previous experience withcoronaviruses will help neurologists and others recognizeand intervene in neurologic morbidity during and after thepandemic of 2020 It is difficult to fully separate the directneurologic effects of COVID-19 from the secondary neu-rologic complications of critical systemic illness but bothissues need to be considered given the overwhelming spreadof COVID-19

AcknowledgmentThe authors thank Dr Richard Mayeux for his helpful reviewof a draft of this manuscript

Study FundingAnna S Nordvig is supported by NINDS 5T32 NS007153(PI Elkind) and the Charles and Ann Lee Brown FellowshipKiran T Thakur is supported by NIH 1K23NS105935-01Amelia K Boehme is supported by NINDS NIH R03NS101417 and NINDS NIMHD R21 MD012451 Craig JSmith is supported by the University of Manchester andSalford Royal NHS Foundation Trust and has receivedfunding from the NIHR MRC and the Leducq FoundationMitchell Elkind is supported by the National Institute ofNeurological Disorders and Stroke and the Leducq Foun-dation The content is solely the responsibility of the authorsand does not necessarily represent the official views of thesponsoring institutions

DisclosureThe authors report no disclosures relevant to the manu-script Full disclosure form information provided by theauthors is available with the full text of this article atNeurologyorgcp

Publication HistoryReceived byNeurology Clinical Practice April 16 2020 Accepted in finalform June 12 2020

e144 Neurology Clinical Practice | Volume 11 Number 2 | April 2021 NeurologyorgCP

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

References1 World Health Organization WHO Director-Generalrsquos opening remarks at the media

briefing on COVID-19mdashMarch 11 20202 Johns Hopkins University amp Medicine Coronavirus Resource Center [online]

Available at httpscoronavirusjhuedumaphtml Accessed July 16 20203 Ferguson N Laydon D Nedjati Gilani G et al Report 9 Impact of non-

pharmaceutical interventions (NPIs) to reduce COVID19 mortality and healthcaredemand 2020

4 Zhu N Zhang DWangW et al A novel coronavirus from patients with pneumonia inChina 2019 N Engl J Med 2020382727ndash733

5 Desforges M Le Coupanec A Dubeau P et al Human coronaviruses and otherrespiratory viruses underestimated opportunistic pathogens of the central nervoussystem Viruses 20201214

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

7 Principi N Bosis S Esposito S Effects of coronavirus infections in children EmergInfect Dis 201016183

8 Morfopoulou S Brown JR Davies EG et al Human coronavirus OC43 associatedwith fatal encephalitis N Engl J Med 2016375497ndash498

9 Lu R Zhao X Li J et al Genomic characterisation and epidemiology of 2019 novelcoronavirus implications for virus origins and receptor binding Lancet 2020395565ndash574

10 Elliott R Li F Dragomir I Chua MMW Gregory BD Weiss SR Analysis of the hosttranscriptome from demyelinating spinal cord of murine coronavirus-infected micePLoS One 20138e75346

11 Tsai L Hsieh S Chang Y Neurological manifestations in severe acute respiratorysyndrome Acta Neurol Taiwan 200514113

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

13 Moldofsky H Patcai J Chronic widespread musculoskeletal pain fatigue depressionand disordered sleep in chronic post-SARS syndrome a case-controlled study BMCNeurol 20111137

14 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

15 Bohmwald K Galvez N Rıos M Kalergis AM Neurologic alterations due to re-spiratory virus infections Front Cell Neurosci 201812386

16 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 2004113e73ndashe76

17 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

18 Xu J Zhong S Liu J et al Detection of severe acute respiratory syndrome coronavirusin the brain potential role of the chemokine mig in pathogenesis Clin Infect Dis2005411089ndash1096

19 Steardo L Zorec R Verkhratsky A Neuroinfection may potentially contribute topathophysiology and clinical manifestations of COVID-19 Acta Physiol (Oxf) 2020229e13473

20 Le Coupanec A Desforges M Meessen-Pinard M et al Cleavage of a neuroinvasivehuman respiratory virus spike glycoprotein by proprotein convertases modulatesneurovirulence and virus spread within the central nervous system PLoS Pathog201511e1005261

21 Desforges M Le Coupanec A Brison E Meessen-Pinard M Talbot PJ Neuroinvasiveand neurotropic human respiratory coronaviruses potential neurovirulent agents inhumans In Adhikari R Thapa S eds Infectious Diseases and Nanomedicine I IndiaSpringer 201475ndash96

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

23 Netland J Meyerholz DK Moore S Cassell M Perlman S Severe acute respiratorysyndrome coronavirus infection causes neuronal death in the absence of encephalitisin mice transgenic for human ACE2 J Virol 2008827264ndash7275

24 Doobay MF Talman LS Obr TD Tian X Davisson RL Lazartigues E Differentialexpression of neuronal ACE2 in transgenic mice with overexpression of the brain renin-angiotensin system Am J Physiol Regul Integr Comp Physiol 2007292R373ndashR381

TAKE-HOME POINTS

Diverse neurologic manifestations and long-termneuropsychiatric sequelae have been reported ininfections with numerous previously knowncoronaviruses

Potential neurologic complications of COVID-19include headache fatigue dizziness anosmiaageusia anorexia myalgias meningoencephalitishemorrhage altered consciousness Guillain-Barresyndrome syncope seizure and stroke

Mechanisms of neurologic diseasemay be similar toother coronaviruses especially to SARS-CoV whichis phylogenetically most similar and enters cellsthrough the same protein angiotensin-convertingenzyme 2

Postulatedmechanisms of neurologic damage fromother coronaviruses suggest the possibility ofsystemic disease sequelae (including inflammationthrombosis and hypoxia) direct neuroinvasiveness(although neurotropism has never been definitivelyshown) peripheral nervous system and muscleinvolvement and possible immune-mediated para-and postinfectious effects

In neurologic patients special consideration isneeded for compliance with hygiene and socialdistancing COVID-19 symptom identificationstroke management and comorbidity manage-ment

Appendix Authors

Name Location Contribution

Anna S NordvigMD

Columbia University TheNew York PresbyterianHospital

Designed andconceptualized thearticle interpreted thedata and drafted themanuscript forintellectual content

Kathryn T FongMD

Columbia University TheNew York PresbyterianHospital

Interpreted the data andsignificant role in revisingthe manuscript forintellectual content

Joshua Z WilleyMD MS

Columbia University TheNew York PresbyterianHospital

Interpreted the data andrevised the manuscriptfor intellectual content

Kiran T ThakurMD

Columbia University TheNew York PresbyterianHospital

Interpreted the data andrevised the manuscriptfor intellectual content

Amelia K BoehmePhD MSPH

Columbia University TheNew York PresbyterianHospital

Interpreted the data andrevised the manuscriptfor intellectual content

Appendix (continued)

Name Location Contribution

Wendy S VargasMD

Columbia University TheNew York PresbyterianHospital

Interpreted the data andrevised the manuscriptfor intellectual content

Craig J SmithMBChB MD MRCP

University of ManchesterUnited Kingdom

Interpreted the data andrevised the manuscriptfor intellectual content

Mitchell SVElkind MD MS

Columbia University TheNew York PresbyterianHospital

Provided supervision andfunding interpreted thedata and major role inrevising the manuscriptfor intellectual content

NeurologyorgCP Neurology Clinical Practice | Volume 11 Number 2 | April 2021 e145

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

25 Gowrisankar YV Clark MA Angiotensin II regulation of angiotensin-convertingenzymes in spontaneously hypertensive rat primary astrocyte cultures J Neurochem201613874ndash85

26 Xia H Lazartigues E Angiotensin-converting enzyme 2 central regulator for car-diovascular function Curr Hypertens Rep 201012170ndash175

27 MacGregor DPMuroneC SongK Allen AM PaxinosGMendelsohn FA AngiotensinII receptor subtypes in the human central nervous system Brain Res 1995675231ndash240

28 Xia H Lazartigues E Angiotensin-converting enzyme 2 in the brain properties andfuture directions J Neurochem 20081071482ndash1494

29 Lovren F Pan Y Quan A et al Angiotensin converting enzyme-2 confers endothelialprotection and attenuates atherosclerosis Am J Physiol Heart Circ Physiol 2008295H1377ndashH1384

30 Biancardi VC Stern JE Compromised blood-brain barrier permeability J Physiol20165941591ndash1600

31 Varatharaj A Galea I The blood-brain barrier in systemic inflammation Brain Be-havior Immun 2017601ndash12

32 Li YC Bai WZ Hashikawa T The neuroinvasive potential of SARS-CoV2 may be atleast partially responsible for the respiratory failure of COVID-19 patients J MedVirol 202092552ndash555

33 McCray PB Pewe L Wohlford-Lenane C et al Lethal infection of K18-hACE2 miceinfected with severe acute respiratory syndrome coronavirus J Virol 200781813ndash821

34 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

35 Tsai LK Hsieh ST Chao CC et al Neuromuscular disorders in severe acute re-spiratory syndrome Arch Neurol 2004611669ndash1673

36 Chao CC Tsai LK Chiou YH et al Peripheral nerve disease in SARS report of a caseNeurolgy 2003611820ndash1821

37 Ding Y Wang H Shen H et al The clinical pathology of severe acute respiratorysyndrome (SARS) a report from China J Pathol 2003200282ndash289

38 Gu J Gong E Zhang B et al Multiple organ infection and the pathogenesis of SARSJ Exp Med 2005202415ndash424

39 Rahaman P Del Bigio MR Histology of brain trauma and hypoxia-ischemia AcadForensic Pathol 20188539ndash554

40 Perlman S Evans G Afifi A Effect of olfactory bulb ablation on spread of a neuro-tropic coronavirus into the mouse brain J Exp Med 19901721127

(References e-1 to e-108 available at linkslwwcomCPJA184)

e146 Neurology Clinical Practice | Volume 11 Number 2 | April 2021 NeurologyorgCP

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

DOI 101212CPJ0000000000000897202111e135-e146 Published Online before print June 30 2020Neurol Clin Pract

Anna S Nordvig Kathryn T Fong Joshua Z Willey et al Potential Neurologic Manifestations of COVID-19

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