REVIEW

Neurology and the COVID-19 PandemicGatheringData for an InformedResponse

Brigit High Alison M Hixon PhD Kenneth L Tyler MD Amanda L Piquet MD and Victoria S Pelak MD

Neurology Clinical Practice April 2021 vol 11 no 2 e48-e63 doi101212CPJ0000000000000908

Correspondence

Dr Pelak

victoriapelakcuanschutzedu

AbstractPurpose of ReviewThe current coronavirus disease 2019 (COVID-19) pandemic causedby the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)is one of the greatest medical crises faced by our current generation ofhealth care providers Although much remains to be learned about thepathophysiology of SARS-CoV-2 there is both historical precedent fromother coronaviruses and a growing number of case reports and series thatpoint to neurologic consequences of COVID-19

Recent FindingsOlfactorytaste disturbances and increased risk of strokes andencephalopathies have emerged as potential consequences ofCOVID-19 infection Evidence regarding whether these sequelae resultindirectly from systemic infection or directly from neuroinvasion bySARS-CoV-2 is emerging

SummaryThis review summarizes the current understanding of SARS-CoV-2 placed in context with ourknowledge of other human coronaviruses Evidence and data regarding neurologic sequelae ofCOVID-19 and the neuroinvasive potential of human coronaviruses are provided along with asummary of patient registries of interest to the Neurology community

Coronaviruses (CoVs) are ubiquitous pathogens and have been isolated from many animalspecies ranging from turkeys to bats to beluga whales1 CoVs belong within the taxonomicfamily Coronaviridae which is further divided into 4 generamdashα- β- γ- and δ-CoVs2 Thereare 7 known species of human CoVs (HCoVs) and all are in the α- and β-CoV genera34

HCoVs consist of 2 α-CoVs HCoV-NL63 and HCoV-229E and 5 β-CoVs HCoV-OC43HCoV-HKU1 severe acute respiratory syndrome (SARS)-CoV-1 Middle East respiratorysyndrome (MERS)-CoV and now the recently identified SARS-CoV-2 which is responsiblefor the coronavirus disease 2019 (COVID-19) pandemic1ndash4

Of the 7 HCoVs the -NL63 -229E -OC43 and -HKU1 species are endemic worldwide andare primarily associated with mild upper respiratory disease (the common cold)1ndash4 In the past30 years the 3 other HCoV species have now emerged to infect humans and are most wellknown for causing severe respiratory disease SARS-CoV-1 MERS-CoV and SARS-CoV-2The modern outbreaks of these HCoVs are thought to represent bat-to-human zoonotictransmissions with the involvement of an intermediate host Although the SARS-CoV-2

These authors contributed equally to the manuscript

Medical Scientist Training Program (BH AMH) Rocky Mountain Taste and Smell Center (BH) Department of Neurology (KLT ALP VSP) and Department of Ophthalmology (VSP)University of Colorado School of Medicine Aurora

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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outbreak was first associated with workers at a live animalmarket in Wuhan China the exact origin and evolution ofthis virus remains to be fully delineated56

Basic VirologyCoV virions are 125 μm in diameter and are composed of ahost-derived lipid envelope surrounding a helical nucleocapsidwith a single strand of positive-sense RNA (+ssRNA) as the viralgenome47 (figure 1) CoV genome sizes range from 26 to 32 kband are the largest known +ssRNA viral genome8 These ge-nomes encode viral proteins that assist in different steps of theviral life cycle and thus are potential vaccine targets CoVs arenamed for their distinctive crown-like appearance under electronmicroscopy resulting from a radiating array of spike (S) proteinsprojecting from the viral envelope17 The S protein is critical forCoV binding to cell receptors In addition the viral genomeencodes other structural proteins including the membrane (M)protein which helps to shape the viral envelope and disrupt hostinterferons and envelope (E) protein which participates in var-ious stages of the viral life cycle and contributes to host cell death(figure 1)1910 The nucleocapsid (N) protein which surroundsthe RNA genome acts as an RNA chaperone (figure 1)179

The significance of the genomic differences betweenSARS-CoV-2 and the other modern HCoVs and the implications for diseasephenotype and tropism remains to be fully characterized Fol-lowing identification of the first case cluster inWuhan China inlate December 2019 the pathogen was isolated by January 72020 and the whole-genome sequence was shared with theWorld Health Organization only 5 days later on January 12202011 The available sequencing data indicate that the genomesize is 298 kb with 14 open reading frames encoding 27 pro-teins8 SARS-CoV-2 appears more closely related to SARS-CoV-1 (79 homology) and more distantly related to MERS-CoV(50 homology)6812 Like SARS-CoV-1 SARS-CoV-2 usesthe angiotensin-converting enzyme 2 (ACE-2) receptor andappears to have a 4- to 20-fold higher ACE-2 binding affinity

than SARS-CoV-113ndash15 SARS-CoV-2 also appears to have theability to use a host protease furin to cleave the viral Sprotein This furin cleavage site is not found in SARS-CoV-1and its exact function in the SARS-CoV-2 life cycle has yet to bedetermined15 Acquisition of mutations allowing for furincleavage has been seen in other viruses such as influenza andMERS-CoV and has been implicated in causing increasedvirulence and promoting cross-species transmission1617 Itmay function in enhancing viral fusion following receptorbinding or assist in viral exit from an infected cell

Clinical Spectrum and Transmissionof COVID-19As of May 30 2020 there have been over 59 million confirmedcases of COVID-19 worldwide with over 365000 deaths18 Theglobal case fatality rate is estimated to range from 2 to 5although testing variability between countriesmdashincluding a lackof testing formild and asymptomatic casesmdashlikely overestimatesthis range19 In most instances COVID-19 is less lethal than thedisease caused by SARS-CoV-1 which had a case fatality rate of11However the higher rate of human-to-human transmissionof SARS-CoV-2 has created a global pandemic with dire impli-cations for health care capacity SARS-CoV-2 is thought to betransmitted primarily through respiratory droplets when aninfected person coughs or sneezes (figure 2A)20 The virus canremain viable on various surfaces thus allowing potential fomitetransmission20 Finally asymptomatic carriers who tend to beyounger and healthier than those with moderate or severecourses of disease are increasingly being recognized as drivers ofdisease propagation However the exact prevalence of this groupis unclear due to gaps in testing2122

The incubation time to symptom onset following exposure canrange from2 to14 days (mean 5 days)2324 Typical COVID-19presenting symptoms include fever cough and shortness ofbreath25 Chest CT abnormalities are observed in nearly allhospitalized patients with COVID-19 and consist of ground-

Figure 1 Schematic of a SARS-CoV-2 Virion

The image depicts the severe acute respiratory syndrome coro-navirus 2 (SARS-CoV-2) virion with lipid bilayer membrane andshows the structural spike (S) membrane (M) envelope (E) andnucleocapsid (N) proteins The virion contains a single-strandpositive-sense RNA (+ssRNA) genome surrounded by its N proteinchaperone The S M E and N proteins are possible targets forvaccine development

NeurologyorgCP Neurology Clinical Practice | Volume 11 Number 2 | April 2021 e49

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Figure 2 Proposed Pathways of SARS-CoV-2 Systemic Infection and Neuroinvasion

(A) Initial infection by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) with viral entry into the nasopharynx oropharynx larynx andlungs (B) Magnified cross-section of a lung alveolus and capillary SARS-CoV-2 is known to infect type II pneumocytes as well as endothelial cells whichexpress the angiotensin-converting enzyme 2 (ACE-2) From the lungs the virus could enter the vasculature and circulate to other organs resulting inmultiorgan infection and sepsis Inflammation of cells such as neutrophils monocytes and lymphocytes could contribute to viral access to thevasculature due capillary leakage and direct tissue damage Thismay also be an initial site for viral infection of immune cells such asmacrophages andlymphocytes which have been shown to become infected by other coronaviruses such as SARS-CoV-1 and express the ACE-2 receptor (C) Sagittalcross-section of the brain at the level of the third and fourth ventricles with surrounding structures Hematogenous spread could lead to direct viralinfection of the CNS or infection of the CNS via the circumventricular organs (CVOs) including the subfornical organs the vascular organ of the laminaterminalis (OVLT) the median eminence and the area postrema which do lack a blood-brain barrier and have been shown to express ACE-2 SARS-CoV-2 may also access the CNS via the choroid plexus depicted on the roof of the third ventricle and in the fourth ventricle Virus could infect thevasculature of these regions which expresses ACE-2 or traffic into the CNS via infected lymphocytes (D) Sagittal cross-section of the upper re-spiratory tract SARS-CoV-2 infection has been associated with hyposmia and hypogeusia in a significant number of patients ACE-2 has been found inthe non-neuronal cells of the olfactory system suggesting dysfunction damage to non-neuronal cells as a cause of anosmia Hypogeusia could becaused by viral infection of gustatory neurons of cranial nerves VII (chorda tympani of the facial nerve) CN IX and CN X all of which project to thenucleus of the solitary tract in the brainstem and are known to express ACE-2 Gustatory pathways could contribute to viral CNS access to thebrainstem that ultimately contributes to respiratory dysfunction Infection of the brainstem could worsen respiratory distress in patients with severeCOVID-19 For all panels SARS-CoV-2 virions are depicted as green dots Black or white arrows show possible directions of viral spread in each organor tissue

e50 Neurology Clinical Practice | Volume 11 Number 2 | April 2021 NeurologyorgCP

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glass opacities with bilateral multiple lobular and subsegmentalareas of consolidation2526 Most symptomatic individualshave a mild course that resolves without the need for hos-pitalization but infection can rapidly progress to severedisease with multiorgan failure and death2427 Severe com-plications of COVID-19 include acute respiratory distresssyndrome acute kidney injury acute cardiac disease anddisseminated intravascular coagulopathy and laboratory find-ings can include leukopenia lymphopenia or lymphocytosisabnormal liver enzymes elevated D-dimer and elevatedinflammatory markers (eg interleukin [IL]-6 ferritin andC-reactive protein)1924

The risk of developing severe COVID-19 increases pro-gressively with age Individuals gt65 years in age are more likelyto experience hospitalization intensive care unit admissionmechanical ventilation and death compared with youngerpeople252829 These epidemiologic patterns of COVID-19 aresimilar to those seen with SARS-CoV-1 and MERS-CoV3031

Although children tend to experience milder symptoms and abetter prognosis compared with adults there have beenemerging reports from Europe and North America of multi-system inflammatory conditions like that of Kawasaki diseaseand hyperinflammatory shock syndrome in children andadolescents3233 The association between SARS-CoV-2 andsevere pediatric disease is likely a reflection the size of the globaloutbreak in diverse populations rather than increased virulenceof the SARS-CoV-2 compared with other modern HCoVs

For the 3 modern HCoVsmdashSARS-CoV-1 MERS and SARS-CoV-2mdasha key feature of severe disease is a dysregulated im-mune response that damages the lungs and organs above andbeyond the direct viral damage1034 The exact mechanismsdriving this hyperinflammatory immunopathology are not wellunderstood and may be multifactorial10 Overall individualswith severe disease appear to have rapid viral replication in thelungs with increases in alveolar macrophages and proin-flammatory cytokines including tumor necrosis factor-α IL-1IL-6 and ferritin34 Seemingly paradoxically as many as 80 ofpatients with COVID-19 develop lymphopenia35 The exactcause of lymphopenia is unknown but could be due to tissueredistribution to areas of infection (lungs) direct viral infectionof lymphocytes followed by cell death or cytokine-inducedlymphotoxicity103436 Together these factors promotemassiveinflammation and cytokine storm

Health-related comorbidities also contribute to the de-velopment of severe disease with 94 of deaths occurring inpatientswith at least 1 comorbidity37 Conditions increasing therisk of severe disease include diabetes hypertension Class IIIobesity (body mass index gt40 kgm2) severe or chronic car-diac disease chronic lung disease including moderate to severeasthma and being male37 Members of racial minorities in theUnited States are at a higher risk of poor outcomes that aremost likely due to inequalities in medical care and the higherprevalence of comorbidities in this population driven by healthdisparities38 The relationship between these comorbidities and

development of cytokine storm could be driven by changes inreceptor expression and dysregulation of innate immunity andinflammation that can occur in these disease states amongother hypotheses

Neurologic Sequelae of SARS-CoV-2and COVID-19Although COVID-19 is primarily a disease of the re-spiratory tract neurologic symptoms are increasingly beingrecognized39ndash50 With a rapid rise in severely ill patients ner-vous system manifestations can be overlooked masked by se-dation during ventilation or be of lower priority when severerespiratory and cardiac compromise occur The neurologicsequelae that have been described to date are discussed withattention to available evidence for indirect direct or post-infectious mechanisms

Olfactory and Taste DisturbancesThe CDC recently expanded the COVID-19 symptom listfrom the typical fever cough and shortness of breath triad toinclude sudden onset of taste andor smell loss37 Table 1summarizes studies focusing on tastesmell dysfunction withCOVID-19 The prevalence of these symptoms among pa-tients with COVID-19 is estimated around 5273 (95confidence interval [CI] 2964ndash7523) for olfactorydysfunction and 4393 (95 CI 2046ndash6895) for gus-tatory dysfunction in a meta-analysis of published reportsbefore April 19 202051 The timing of onset of the olfactorytaste disorders presents particular interest because they mayoccur earlier than other hallmark features of COVID-19(fever or cough) which opens the possibility of using themas initial screening measures52 In a cohort of hospitalizedpatients in Milan Italy 20 experienced smell and tastedisturbance before admission whereas the remainderreported these disturbances during their hospital stay39

Taste alterations were noted to be more prevalent beforehospitalization (91) whereas taste and smell changes wereequally prevalent during hospitalization39 In other anotherreport symptoms of loss of taste smell or both have beennoted to persist for up to several weeks41 Although olfactorydisturbances are common in other upper respiratory illnessesof viral origin due to sinonasal symptoms (rhinorrhea andcongestion) these are less commonly observed in patientswith COVID-1951 The lack of sinonasal symptoms suggestsviral-mediated dysfunction of gustatory and olfactory organsrather than inflammatory damage however the exact mecha-nisms remain to be determined

Cerebrovascular DiseaseA small but growing number of reports suggest an increasedrisk of stroke as a potential complication of COVID-19 in-fection (table 2)4253ndash56 Predisposition to stroke may berelated to an infection-induced coagulopathy as indicated byelevated D-dimer elevated fibrinogen and thrombocytope-nia common in patients with severe COVID-19 disease54

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Table 1 Summary of Current Reports on Acute Taste and Smell Sequelae of COVID-19

Study type Location Patient characteristics Neurologic symptoms Evaluation Reference

Multicenter questionnaire Belgium FranceSpain and Italy

417 patients mean age 369 y(range 19ndash77 y) female 263(631) male 154 (369) allwith mild COVID-19

Anosmia or hyposmia856 dysgeusia 880

Online questionnaire of OlfactoryDisordersmdashNegative Statements

Lechien et al 202041

Case report Aarhus Denmark Female patient in early 30swithmild COVID-19

Anosmia and hypogeusia Anosmia verified with Sniffin Sticks extendedtest (848) hypogeusia verified with tastespray screening (24) taste drop test (2440)and taste strips (1216)

Haldrup et al 202040

Single-center cross-sectional survey Milan Italy 59 patients median age 60 y(range 50ndash74 y) female 29(322) male 30 (678) allwere hospitalized with COVID-19 but capable of completingthe survey

Sudden onset olfactory ortaste disorder in 20patients (339)

Self-reported Giacomelli et al 202039

Case series Padua Italy 6 patients no furtherdescriptions given

Sudden-onset hyposmiaand hypogeusia as only ormain COVID-19 symptom

Suprathreshold Odor Rating Test using sixodors to confirm hyposmia

Marchese-Ragona et al202044 (note nonndashpeer-reviewed report)

Case control Tehran Iran 60 hospitalized patients withCOVID-19 median age 4655 plusmn1217 y female 40 (67) male20 (33) COVID-19 diseasemild (42) moderate (48)and severe (10)

Mild microsmia (13)moderate microsmia(27) severe microsmia(33) and anosmia (25)

University of Pennsylvania SmellIdentification Test of 40 odorants

Moein et al 202045

Retrospective observational Mulhouse France 54 (47) of 114 examined andor hospitalized patients withCOVID-19 with reportedanosmia mean age 47 plusmn 16 yfemale 36 (67)male 18 (33)

Anosmia mean duration89 plusmn 63 d anosmiadeveloped 44 plusmn 19 d afterinfection onset dysgeusiain 85

Self-reported Klopfenstein et al 2020102

Retrospective review Tehran Iran 8 patients with sudden-onsetanosmia 5 COVID-19+ agerange 22ndash44 y female 6 (75)male 2 (25)

Anosmia in 88 patientsonset between 2 and 4d after fever ageusia in 28 patients

Self-reported Gilani et al 2020103

Case report Madrid Spain 40-y-old Venezuelan femaleradiologist caring for multiplesymptomatic patients withCOVID-19

Anosmia 3 d aftersymptom onset anosmiaresolved after 14 d

Self-reported Ollarves-Carrero et al2020104

Case series Washington DC 177 pediatric and young adultpatients (25hospitalized 20critically ill) male 92 (52)female 85 (48)

Loss of taste and smell in15 (9) patients

Methods not described DeBaisi et al 2020105

Abbreviation COVID-19 = coronavirus disease 2019

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Table 2 Summary of Current Reports on Acute Neurologic Sequelae of COVID-19

Study type Location Patient characteristics Neurologic symptoms Imaging Laboratory findings Reference

3 centersretrospective

Wuhan Hubei China 214 patients mean age527 plusmn 155 y female 127(593) male 87 (407)severe COVID-19 88(411)

Any neurologic signs orsymptoms 78 (364) CNSsigns or symptoms(dizziness headacheimpaired consciousnessacute cerebrovasculardisease ataxia and seizure)53 (248) PNS signs orsymptoms (tasteimpairment smellimpairment visionimpairment and nervepain) 19 (89)

None described Patients with severesymptoms uarr CRP D-dimer darrlymphocytes uarr BUNCr

Mao et al 202043

Single-centerretrospective

Wuhan Hubei China 221 patients mean age533 plusmn 159 y female 90(40middot7)male 131 (59middot3)severe COVID-19 94(42middot5)

AIS 11 (5) CVST 1 (0middot5)CH 1 (0middot5)

Representative brain CTsshowing new-onset AISCVST and left basalganglia CH

Blood from patients with AISCVSTCH showed uarr WBCsneutrophils CRP D-dimer darrlymphocytes

Li et al 202042

Case report Shimokato ChuoYamanashi Japan

24-y-old man withheadache fatigue andfever

Altered mental statusseizures meningitisencephalitis

Brain MRI DWI showinghyperintensities along theright lateral ventricleFLAIR showinghyperintense signals inthe mesial temporal lobeand hippocampus T2WIshowing pan-paranasalsinusitis

CSF uarr opening pressure uarrWBCs SARS-CoV-2+ by RT-PCR blood uarr WBCs uarr CRP

Moriguchi et al 202046

Case report Beijing Hebei China 56-y-old patient ofunknown sex

Viral encephalitis None CSF SARS-CoV-2+ by RT-PCR Zhou et al 202050

(note nonndashpeer-reviewedreport)

Case report Detroit MI Female patient age in late50s with 3 d of cough andfever with COVID-19 innasal swab

Altered mental status andnecrotizing hemorrhagicencephalopathy

Head CT with symmetrichypoattenuation withinbilateral medial thalamiwith normal CT angiogramand venogram brain MRIwith hemorrhagic rim-enhancing lesions withinbilateral thalami medialtemporal lobes andsubinsular regions

CSF traumatic punctureunable to test for SARS-CoV-2via RT-PCR

Poyiadji et al 202047

Retrospectivecase study

Leiden and Rotterdamthe Netherlands

Analysis of 184 COVID-19+admitted to the ICUs of 3hospitals for 1 mo 3184(16) had strokes patientcharacteristics notdescribed

COVID-19 pneumoniarequiring ICU admissionfollowed by development ofcoagulopathy and stroke

Ischemia strokediagnosed with CT

None described Klok et al 202053

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Table 2 Summary of Current Reports on Acute Neurologic Sequelae of COVID-19 (continued)

Study type Location Patient characteristics Neurologic symptoms Imaging Laboratory findings Reference

Case series New York NY 5 adult patients aged33ndash49 y 1 female 4 maleswith mild COVID-19

2 patients wereasymptomatic with COVID-19 3 had fever cough orfatigue all developedsymptoms of severe strokewith reducedconsciousness gaze palsydysarthria andorhemiplegia

CT CTA CTP andor MRIshowed large vesselocclusions in all patients

Blood uarr fibrinogen (60) uarr D-dimer (60)

Oxley et al 202055

Case report Barcelona CataloniaSpain

50-y-old man with severeCOVID-19

While in ICU with bilateralpneumonia developedacute-onset right facialparalysis and left limbweakness

Head CT perfusion mapshowed hypoperfusion inthe left paramedianthalamic artery head MRIshowed left medialthalamic infarct

None described Rudilosso et al 202056

Case series Wuhan Hubei China 69-y-old male 70-y-oldmale and 65-y-old femalepatients with severeCOVID-19

Presentedwith fever coughdyspnea and headache andlater developed evidencecerebral infarcts 1 patientalso had distal limbischemia

Head CT showed diffuseacute cerebral infarctionsin cerebral hemispheresin all patients 2 patientsalso had cerebellarinfarctions

Blood darr lymphocytes darrplatelets uarr D-dimer uarrfibrinogen all had positiveanticardiolipin IgA andantindashβ2-glycoprotein I IgAand IgG

Zhang et al 202058

Case report Boca Raton FL 74-y-old male patient withsevere COVID-19

Fever cough headache andaltered mental status

Head CT showed evidenceof distant posteriorcerebral artery strokeEEG described asconsistent withencephalopathy lefttemporal lobedysfunction and possibleepileptogenicity

CSF no evidence of infection Filatov et al 202059

Rome Italy 78-y-old female patientwith mild COVID-19

Focal status epilepticusfollowed by fever 12 h later

Head MRI showed noevidence of new cerebrallesions ictal EEG showedseizure activity localizedover left-fronto-centro-temporal regions

Blood darr lymphocytes darrplatelets uarr CRP

Vollono et al 202061

Case report Jingzhou China 66-y-old female patientwith moderate COVID-19

Progressive arm and legweakness with decreaseddistal sensationmdashtreatedwith IVIg

Nerve conduction studiessupporting demyelinatingneuropathy

SARS-CoV-2 in oropharyngealswab by RT-PCRlymphocytopeniathrombocytopenia normalCSF

Zhao et al 202049

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Table 2 Summary of Current Reports on Acute Neurologic Sequelae of COVID-19 (continued)

Study type Location Patient characteristics Neurologic symptoms Imaging Laboratory findings Reference

Case series Pavia Italy 5 patients aged 23ndash77 yfemale 1 (20) male 5(80) all had mild COVID-19

Flaccid tetraparesis (60)flaccid paraplegia (20)flaccid tetraplegia (20)facial diplegia (20) facialweakness (40)paresthesias (100)respiratory failure(60)mdashtreated with IVIg

MRI brain performed in 4patients with one showingfacial nerve enhancementin patient with facialdiplegia MRI spineperformed in all patientswith caudal nerve rootenhancement found in 1patient

CSF in 4 patients tested uarrprotein SARS-CoV-2 negativeby RT-PCR negativeantiganglioside antibodies in4 patients tested

Toscano et al 202048

Case report Saint-Etienne France 64-y-old male patient withfever and cough for 2 dadmitted to hospital afterrotator cuff injury foundto be SARS-CoV-2 positiveon nasal swab

Bilateral upper and lowerextremity flaccid severeparesthesia developedbeginning 11 d after initialsymptom onset swallowingdisturbancemdashtreated withIVIg

None reported SARS-CoV-2 in oropharyngealswab by RT-PCRdemyelinating pattern onEMG

Camdessanche et al202063

Case report 54-y-old Caucasian femalepatient with no precedingfever or respiratorysymptoms but withtemporary loss of tasteand smell

Progressive proximallypronounced paraparesisareflexia and sensory losswith tingling of allextremities consistent withan acute demyelinatinginflammatorypolyneuropathy beginning10 d beforeadmissionmdashtreated withIVIg

None reported SARS-CoV-2 in oropharyngealswab by RT-PCR CSF withalbuminocytologicdissociation demyelinatingpattern on EMG

Scheidl et al 202062

Abbreviations AIS = acute ischemic stroke BUN=blood urea nitrogen CH = cerebral hemorrhage COVID-19 = coronavirus disease 2019 Cr = creatinine CRP =C-reactive protein CVST = central venous sinus thrombosis DWI =diffusion-weighted imaging FLAIR = fluid-attenuated inversion recovery Ig = immunoglobulin PNS = peripheral nervous system RT-PCR = reverse transcription PCR SARS-CoV-2 = severe acute respiratory syndromecoronavirus 2 T2WI = T2-weighted imaging WBC = white blood cell

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Large vessel strokes have also been reported in relativelyhealthy individuals aged 30ndash50 years with only minorCOVID-19 symptoms55 As discussed in the next sectionsinfection of endothelial vasculature by SARS-CoV-2 couldlead to endothelial dysfunction and this dysfunction com-bined with hypercoagulability could predispose to eitherthrombotic or hemorrhagic stroke Another possiblemechanism explaining stroke-associated COVID-19 couldbe the development of prothrombotic immunoglobulinssuch as antiphospholipid antibodies and lupus anticoagu-lant that have now been reported in some patients withCOVID-19 both with and without signs of stroke (table2)545758 Procoagulant antibodies however may be tran-siently expressed in many disease states and more work isneeded to understand their prevalence and significance inCOVID-19ndashassociated stroke

Encephalitis and EncephalopathyThere have been 2 cases of viral encephalitis or meningitisencephalitis with SARS-CoV-2 RNA found in the CSF(table 2)4650 Detection of SARS-CoV-2 in the CSF the goldstandard for causal diagnosis of CNS infection suggests aneuroinvasive potential for this virus Encephalopathy may bean indirect (ie non-CNS invasion) presenting feature of severeCOVID-19 particularly in the elderly and COVID-19 shouldbe included in the differential for those presenting with signs ofillness and altered mental status (AMS)59 Acute necrotizingencephalopathy which is likely an inflammatory disorder re-lated to a viral-induced cytokine storm was described in anairline worker in her late fifties with SARS-CoV-2 infection whoexperienced AMS that rapidly progressed to coma (table 2)47

This case highlights the potential for more than 1 viral-inducedindirect (ie noninvasive) mechanism to cause encephalopathy

SeizureA retrospective study of 304 patients with no history of ep-ilepsy or seizure showed no increase in risk for developingnew-onset seizures following COVID-19 infection60 How-ever viral illnesses can lower seizure thresholds in those withepilepsy due to alterations in medication metabolism duringillness as illustrated by a case report of a patient withCOVID-19 and a history of well-controlled seizures due toremote history of herpes encephalitis who presented withfocal status epilepticus despite an absence of respiratorysymptoms (table 2)61 This case highlights the need tomonitor for changes in those with epilepsy and SARS-CoV-2exposure

Guillain-Barre SyndromeSeveral single case reports detail the emergence of Guillain-Barre syndrome (GBS) as a postinfectious complicationSARS-COV-2 (table 2)48496263 In addition 5 patients inNorthern Italy were reported to develop flaccid limb weak-ness and tingling consistent with GBS following SARS-CoV-2 infection48 Outcomes for the Italian patients were poorwith 2 patients requiring continued ventilation and 4 withsignificant weakness at 4-week follow-up despite treatment

with IV immunoglobulin4849 With time the full extent andprognosis of GBS associated with COVID-19 will be betterunderstood

Impact on Preexisting Inflammatory Disordersof the Nervous SystemThe CDC reports that immunocompromised individuals are ata higher risk of severe illness from SARS-CoV-2 infection but aspecific evidence of such and outcomes are lacking37 Beforeadvising patients to alter ongoing therapies that target theimmune system the risk of neurologic disease progressionmust be weighed against the current unknowns relatedto COVID-19 There exists a balance between suppressingthe inflammatory response and creating an environment thatpromotes viral proliferation Broadly acting agents glucocor-ticoids which suppress both innate and adaptive arms of theimmune system have been used during the severe respiratoryphase of COVID-19 although recommendations against glu-cocorticoids in COVID-19 exist64 Other agents such asalemtuzumab (targets CD52 present on T and B lymphocytes)and cladribine (depletes B and T lymphocytes) can causeprofound lymphopenia and may exacerbate the lymphopeniaand immune dysregulation already seen in severe COVID-19More narrow targeting of proinflammatory cytokines may ac-tually be beneficial in COVID-19 including drugs such asbaricitinib (inhibits Janus kinase inflammatory pathway) toci-lizumab (antindashIL-6 receptor) and siltuximab (antindashIL-6) Useof these drugs in COVID-19 has some shown some promise insmall trials but data from randomized controlled trials arepending6566 Many of the immunomodulatory or immuno-suppressive agents commonly used for inflammatory neuro-logic disorders such as rituximab ocrelizumab fingolimodnatalizumab and azathioprine have unknown impact on therisk of infection with SARS-CoV-2 and on the severity ofcomplications from COVID-19 The decision to continue onthese agents with careful monitoring for COVID-19 symptomsto prevent exacerbation of devastating neurologic disordersshould be made on a case-by-case basis until further data areavailable67

Neurologic Sequelae of Other HCoVsIt is noteworthy that neuroinvasion has been demonstrated inalmost all the other β-CoVs368ndash80 Table 3 details all studiesdescribed in this section A series of postmortem studies onindividuals who died as a result of SARS-CoV-1 in 2003 somewith neurologic symptoms before death revealed that SARS-CoV-1 can become widely disseminated during infection andcan be found within the CNS7072747980 SARS-CoV-1 viruswas identified by several different methods including by RT-PCR in CSF and brain tissue and by immunohistochemistryin cortical and hypothalamic neurons71727479 Rare casesstudies have also implicated HCoV-OC43 and -229E ascauses of encephalomyelitis encephalitis and acute flaccidparalysis in children757778 Histopathology is not availablefor any cases of MERS-CoV Neurologic symptoms of

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Table 3 Summary of Studies on the Neurologic Sequelae of Human Coronaviruses Before SARS-CoV-2

HCoV Study typePatientcharacteristics Neurologic symptoms CNS imaging Specimen examined Cellstissue CoV Reference

SARS-CoV-1 Case series Postmortem samplesfrom 4 patients withconfirmed SARS 3males aged 25ndash57 y 1female aged 62 y

1 patient had headacheno other neurologicsymptoms described

None described Cerebrum cerebellumpituitary lung lymphnode spleen heart liverkidney adrenal glandparathyroid gland bonemarrow skin esophagusgastric fundus smallintestine pancreasthyroid aorta testisovary uterus and striatedmuscle by IHC and ISH

SARS in neurons of thecerebrum by IHC and ISHpituitary lung stomachsmall intestine kidneyadrenal skin parathyroidand liver by IHC and ISH

Ding et al 200371Ding et al 200470

SARS-CoV-1 Case series Postmortem samplesfrom 8 patients withconfirmed SARS nofurther clinicaldescriptions provided

None described None described Brain by light microscopyEM RT-PCR lungstrachea esophagus smallintestines largeintestines kidneysstomach liver spleenpancreas testes heartadrenals thyroid andskeletal muscle by ISH andEM

Virus in neurons ofhypothalamus and cortexlight microscopy EM anddetectable in brain tissueby RT-PCR lungs tracheaesophagus smallintestines largeintestines and kidneys byISH and EM

Gu et al 200572

SARS-CoV-1 Case report 59-y-old woman hx ofIgA nephropathy withfevers chills coughand diarrhea

Vomiting confusionseizures and statusepilepticus

CT showed noabnormalities

Tracheal aspirate serumCSF by RT-PCR

Tracheal aspirate serumCSF by RT-PCR

Hung et al 200379

SARS-CoV-1 Case report 32-y-old woman 26-wkpregnant with feverschills myalgias andcough

Seizures MRI showed noabnormalities

CSF by RT-PCR CSF by RT-PCR Lau et al 200474

SARS-CoV-1 Case report 39-y-old man withfever and progressivepneumonia

Dysphoria vomitingdelirium and coma

CT showed broadischemia necrosis andedema

Brain tissue with IHC RT-PCR viral culture EM

Virus in glia and neuronsby IHC detectable frombrain tissue by RT-PCRviral culture EM

Xu et al 200580

HCoV-OC43 Case report 11-mo-old male withsevere combinedimmunodeficiency noprodrome noted

Irritability sleepinessfeeding problems andabnormal posturing

MRI showed volume lossand abnormal graymattersignal by T2WI

Brain biopsy by RT-PCRand IHC

Brain tissue by RT-PCRHCoV antigen in neuronsand neuropil by IHC

Morfopoulou et al 200675

HCoV-OC43and 229E

Case report 3-y-old female withURI prodrome

Acute flaccid paralysisfollowing viral URI

None Nasal swabs CSF by RT-PCR

Nasal swabs by RT-PCR Turgay et al 201577

HCoV-OC43 Case report 15-y-old male with URIprodrome

Acute disseminatedencephalomyelitis

MRI showed diffuse whitematter lesions brain andspinal cord on T2WI

Nasal swabs CSF by RT-PCR

Nasal swabs CSF by RT-PCR

Yeh et al 200478

Continued

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Table 3 Summary of Studies on the Neurologic Sequelae of Human Coronaviruses Before SARS-CoV-2 (continued)

HCoV Study typePatientcharacteristics Neurologic symptoms CNS imaging Specimen examined Cellstissue CoV Reference

MERS-CoV Case series 70 patients withlaboratory-confirmedMERS 657 male343 female medianage 62 y (range 1ndash90 y)

Headache (129) andconfusion (297)

None Respiratory swabs by RT-PCR

Respiratory swabs by RT-PCR

Saad et al 201476

MERS-CoV Case series 3 adult patients aged45ndash72 y all withsymptoms ofrespiratory disease orfever

1 patient had ataxiavomiting and confusion 1patient had stroke withhemiparesis followed bycoma 1 patient had comaand encephalitis

MRI with widespreadwhite matter andsubcortical lesions onT2WI in all 3 patients

Tracheal aspirate in 3patients CSF in 2 patientsby RT-PCR

Tracheal aspirate in 3patients by RT-PCR

Arabi et al 201569

MERS-CoV Case series 2 patients 34-y-oldwoman with fever and28-y-old man withfevermyalgias coughand dizziness

A 34-y-old womandeveloped headachenausea vomiting andcoma 2 wk followingMERS a 28-y-old mandeveloped lower limbparaplegia withnumbness in stockingdistribution

34-y-old woman CTshowed frontal lobehemorrhage and edemaa 28-y-old man hadabnormal nerveconduction studies andnormal MRI

Both had respiratoryswabs by RT-PCR a 28-y-old man had CSF studies

Respiratory swabs by RT-PCR

Algahtani et al 201668

MERS-CoV Case series 2 male 2 female adultpatients aged 38ndash55 ywith symptoms ofrespiratory disease

1 patient hadhypersomnolence andweakness in all 4 limbs 1patient had tingling inhands and legs with legweakness 1 patient hadtingling in both hands andfeet 1 patient had tinglingin both hands

None described Nasal swabs in 3 patients1 patient with confirmedexposure

Nasal swabs Kim et al 201773

Abbreviations CoV = coronavirus EM = electron microscopy HCoV = human coronavirus IHC = immunohistochemistry ISH = in situ hybridization MERS = Middle East respiratory syndrome RT-PCR = reverse transcriptionPCR SARS = severe acute respiratory syndrome T2WI = T2-weighted imaging URI = upper respiratory infection

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headache and confusion were reported in 10ndash25 of pa-tients with MERS-CoV during acute infection76 There are 2reports of MERS-CoVndashassociated hemorrhagic stroke6869

MERS-CoV has been more commonly associated withpostinfectious complications such as GBS68697376 One caseseries documented diffuse subcortical gray and white matterdamage in 3 patients following severe MERS-CoV infectionpossibly due to hypoxic-ischemic injury although 1 patientmay have had acute disseminated encephalomyelitis a de-myelinating disease that attacks white matter in the brain andspinal cord69 There have also been 5 cases of patients whodeveloped GBS-like flaccid paralysis and paresthesia followingMERS-CoV infection6873

Possible Mechanisms ofHCoV NeuroinvasionGiven our knowledge of other HCoVs we describe 2 po-tential methods by which SARS-CoV-2 could invade thenervous system hematogenous and transsynaptic spread(figure 2 BndashD)

Potential for Hematogenous Spread to the CNSFor many viruses initial infection of the lungs has beendemonstrated to lead to access to the circulatory system withthe presence of virus in the blood (eg viremia) ACE-2 isexpressed on vascular endothelium of arteries and veins inhumans and could serve as a gateway to multiorgan HCoVdisease81 In addition infected monocytes and lymphocytescould carry HCoV to multiple sites throughout the body aprior study demonstrated SARS-CoV-1 infection of mono-cytes and lymphocytes in 6 out of 22 blood samples frominfected patients72 Monocytes and lymphocytes couldtherefore act as Trojan Horses for viral CNS access as hasbeen shown in coxsackie B3 virus and cytomegalovirus in-fections82 Taken together it is possible that viremia andhematogenous trafficking via infected white blood cells mayallow for SARS-CoV-2 access to the CNS via CNS capillarieswhich are particularly extensive and highly permeable withincircumventricular organs (CVOs) that localize to periven-tricular regions of the brain and lack a blood-brain barrier(BBB) (figure 2 B and C)8183 ACE-2 expression in severalCVOs are responsible for detecting compositional changesin the peripheral circulation and transmitting this in-formation to autonomic control centers in the hypothalamusand brainstem84 A study investigating ACE-2 expression inwild type mice found that ACE-2 is expressed in the sub-fornical organs the vascular organ of the lamina terminalisthe median eminence and the area postrema85 (figure 2C)The latter has projections to other ACE-2ndashexpressing re-gions of the brainstem notably the dorsal motor nucleus ofthe vagus nerve (CN X) and the nucleus of the solitary tractwhich is involved in taste processing Furthermore ACE-2 ishighly expressed in the choroid plexus of humans In-flammation produced by pathologic conditions such ashypoxic-ischemic injury that occurs with severe COVID-19

can lead to the release of proinflammatory cytokines bymicroglia and brain endothelial cells which along with ox-idative stress and increased nitric oxide productiondegrading the BBB86 and increasing susceptibility for viralentry via hematogenous spread In this pathologic state virusand leukocytes could enter the CSF via the choroid plexusand lead to infiltration of brain tissue86 (figure 2C)

Consideration of Transsynaptic Spread tothe CNSAnother potential route to the CNS is transsynaptic spreadthrough tissues innervated by nerves for taste and smell(figure 2D) particularly in light of the numerous case re-ports and emerging studies describing disturbances in tasteandor smell without rhinorrhea in patients with confirmedCOVID-19 (see table 2 for details)39ndash414445 When con-sidering transsynaptic spread via gustatory system compo-nents it is important to note that ACE-2 is crucial to sodiumhomeostasis which influences salt appetite and perceptionof salty taste ACE-2 is highly expressed in the lingual tastebuds and in the tongue epithelium of mice along with otherrenin-angiotensin aldosterone system components that areinnervated by gustatory afferents87 although the expressionof ACE-2 in human gustatory afferents has not been char-acterized Recent work describes significant expression ofACE-2 in human oral tissues in the epithelial cells includingthe tongue and palate where taste budsmdashwhich are com-prised of specialized epithelial cells innervated by gustatoryafferentsmdashreside ACE-2 receptors are also widely expressedin the human CNS and particularly widely throughout thebrainstem Renin-angiotensin system components (ACEand AngIIR) have also been detected specifically throughoutthe human nucleus of the solitary tractmdashwhere gustatoryafferents terminatemdashas well as in the dorsal motor nucleusof the vagus nerve and both the rostral and caudal ventro-lateral reticular nucleus of the human brainstem88 In addi-tion to receiving gustatory information the nucleus of thesolitary tract receives general visceral afferents from thecardiovascular pulmonary and gastrointestinal systems IfSARS-CoV-2 were capable of invasion via chemosensoryandor chemoreceptive neurons this could account for thevariety of symptoms observed in patients with COVID-19including taste disturbances hypoxia cardiac complicationsand even gastrointestinal complaints

A significant effort is being made to understand the role of theolfactory system in COVID-19 symptomatology AlthoughACE-2 is known to be expressed in the olfactory system and inthe olfactory bulbs ofmice87 the anosmia of COVID-19 is morelikely mediated through non-neuronal cell types of the olfactoryepithelium Human olfactory sensory neurons have little ex-pression or coexpression of ACE-2 whereas non-neuronal celltypes of the olfactory epithelium had high levels of expressionand coexpression of these SARS-CoV-2 entry genes89ndash91 Thesefindings suggest that disruption or loss of smell is more likely aresult of damage to or dysfunction of non-neuronal cell typesrather than infection of neuronal cells (figure 2D)

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Table 4 A Sampling of COVID-19 Reporting Databases for Neurologic Conditions and Registries Outside of Neurology

Database Location Purpose Partnersinstitutions

COVID-19 reporting databases for neurologic conditions

COVID-19 infections in MS amp Related Conditions North America Define the impact of COVID-19 on patients with MS andhow factors such as age comorbidities and MStreatments affect COVID outcomes

National MS Society Consortium of MS Centers

COVID-19 Cardiovascular Disease Registry (includes stroke) United States Aggregate data and aid research on the diseasetreatment protocols and risk factors tied to adversecardiovascular outcomes

American Heart Society

Acute Encephalopathy in Critically Ill Patients with COVID-19 France Reporting the prevalence of acute encephalopathy atinitial management in criticalintensive care orneurocritical care to report its morbidity and mortalityand to identify prognostic factors

COVID-19 registries outside of neurology

ASH RC COVID-19 Registry for Hematologic Malignancy United States Collect and disseminate surveillance data on the naturalhistory of patients with COVID-19 and hematologicmalignancies

ASH Research Collaborative

COVID-19 Dermatology Registry International Understand dermatologic manifestations of the COVID-19 virus

American Academy of Dermatology

COVID-19 in Pregnancy and Newborns United States Understand course of COVID-19 in pregnant women University of California San Francisco

ASCO Survey on COVID-19 in Oncology Registry United States Collect both baseline and follow-up data onhow the virusaffects cancer care and cancer patient outcomes duringthe COVID-19 pandemic and into 2021

The COVID-19 Global Rheumatology Alliance Registry International Create a secure deidentified international casereporting registry for cases of COVID-19 in rheumatologypatients and then curate and disseminate the outputsfrom that registry

The COVIDndash19 Global Rheumatology AllianceSteering Committee

COVID-19 Pediatric Observatory France Describe the clinical phenotypes of hospitalized pediatricpatients with COVID-19 in France according to agegroups

Centre Hospitalier Intercommunal Creteil

COVID-19 in patients with HIV United States Characterize the clinical presentation and disease courseof COVID-19 in patients with HIV

University of MissourindashColumbia

Abbreviations ASCO = American Society of Clinical Oncology ASH RC = American Society of Hematology Research Collaborative COVID-19 = coronavirus disease 2019

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Additional gaps remain in our understanding of CNSinvasion First although it is certainly plausible that ACE-2mdashtheknown SARS-CoV-2 receptormdashplays a role in CNS infectionother receptors that remain to be discovered might better ex-plain COVID-19 CNS manifestations Second other host fac-tors may be necessary to explain pathogenesis in specific tissuesThis is most evident in tissues that have high expression ofACE-2 receptors yet appear to not be significantly affected byinfection For example ACE-2 is strongly expressed in the di-gestive system according to the Human Protein Altas92 and yetgastrointestinal symptoms are reported in a minority of patientswith COVID-1925

Long-term Neurologic Sequelae ofCoV InfectionAn important consideration for HCoVs is the evidence forpotential long-term persistence in CNS tissue Infection ofimmortalized neuronal and oligodendrocyte cells lines withHCoV-OC43 and -229E respectively revealed viral antigenand infectious particles in a small proportion of the cell pop-ulations through dozens of cell passages9394 T lymphocytesfrom patients with multiple sclerosis contain antigens thatcross-react with antigens of HCoV-229E previously suggestinga link between HCoV infection and CNS immune-relateddisease95 and mice infected intracerebrally with HCoV-OC43developed long-term behavioral deficits with chronic loss ofhippocampal neurons and viral RNA detected by RT-PCR forup to 1 year postinfection96

There has been significant interest in the link between chronicneurologic disease and infectious events and some viral infec-tions are known to cause persistent neurologic disease For ex-ample measles persistence in the CNS can cause subacutesclerosing panencephalitis to begin 1 month to 27 years afterinitial infection97 There is also growing evidence that viral in-fections could be among the many environmental factors pre-disposing individuals to development of neurodegenerativediseases West Nile virus infection in the CNS results in upre-gulation of α-synuclein which appears to have an innate immunefunction suggesting a mechanistic link between viral infectionand the development of Parkinson disease98 Varicella zostervirus (VZV) which infects gt90 of the world population canreactivate in sensory ganglia to cause shingles and other sequelaecerebrovascular infection and stroke99 VZV can increase theproduction of amylin and amyloid β and has a theoretical po-tential to be associated with the risk of Alzheimer disease99

Monitoring the long-term association of viruses with neurologicdisease has a historic precedent Between 1916 and 1927 theworld was swept with a phenomenon known as encephalitislethargica (EL)100101 This syndrome resulted in symptoms ofextreme fatigue abnormal eye movements and parkinsonian-like motor symptoms Estimates suggest that EL afflicted over 1million people to cause up to 500000 deaths100101 The mostlikely culprit for this widespread phenomenon has been thought

to be a viral infection such as the 1918 H1N1 influenza buthistorical epidemiologic and histologic examinations have beeninconclusive100 Neurologists should be prepared tomonitor forchanges and future neurologic sequelae related to the COVID-19 pandemic

Clinical Recommendationsand ResourcesTo effectively understand the neurologic consequences ofCOVID-19 and the potential for neurologic disorders andtheir therapies to be risk factors for COVID-19 complica-tions standardized and large-scale collaborative data col-lection is necessary Multiple medical specialty groups suchas the American Society of Clinical Oncology and the GlobalRheumatology Alliance have developed registries for theirrespective patient populations Recently the Consortium ofMultiple Sclerosis Centers and the National Multiple Scle-rosis Society created COViMS to capture data on clinicaloutcomendashrelated COVID-19 in patients with prior di-agnosis of MS and related disorders and to learn aboutrelative risks associated with disease-modifying treatmentsin the setting of COVID-19 As the list of registries continueto grow (table 4) we must keep in mind that the trueprevalence of disease will remain uncertain without large-scale testing in asymptomatic people and serology for an-tibodies to SARS-CoV-2 Reports of increased incidence ofdeath at home in major cities point to the lack of accuratedata and future registry data will be a biased sample withoutmore widespread testing

ConclusionsHCoVs have the capacity to be neuropathogenic There isincreasing evidence that SARS-CoV-2 can cause both directand indirect neurologic disease but much remains tobe learned For now caution must be taken in regard toattributing neurologic disease to direct neuronal infectionby SARs-CoV-2 until protocols can be developed that allowfor postmortem tissue investigations and in the absence ofthat it is prudent to view neurologic outcomes signs andsymptoms associated with COVID-19 through the lens ofprior discoveries related to other HCoVs The impact ofCOVID-19 on preexisting neurologic disorders and the impactof immunosuppressive and immunomodulatory therapies onthe course of COVID-19 are currently unknown Patient reg-istries and improved testing for acute infection and exposure toSARS-CoV-2 will improve clinical decision-making in themanagement of neurologic disorders during the COVID-19pandemic

AcknowledgmentThe authors thank Dr Thomas E Finger for his guidance andthoughts on this manuscript especially on the topics of tasteand smell

NeurologyorgCP Neurology Clinical Practice | Volume 11 Number 2 | April 2021 e61

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

Study FundingBH is supported by funding from the NIH (NIDCDDC014728-04S1 to Dr Finger) AMH is supported by afellowship from the NIAID (F30 AI136403-01A1) KLT issupported by funding from the NIH (R01 NS101208) and isthe recipient of a VA Merit Award

DisclosureThe authors report no disclosures relevant to themanuscriptFull disclosure form information provided by the authors isavailable with the full text of this article at Neurologyorgcp

Publication HistoryReceived byNeurology Clinical Practice April 30 2020 Accepted in finalform June 18 2020

References1 Perlman S Netland J Coronaviruses post-SARS update on replication and

pathogenesis Nat Rev Microbiol 20097439ndash450

2 Coronaviridae Study Group of the International Committee on Taxonomy of VirusesThe species Severe acute respiratory syndrome-related coronavirus classifying 2019-nCoV and naming it SARS-CoV-2 Nat Microbiol 20205536ndash544

3 Desforges M Le Coupanec A Dubeau P et al Human coronaviruses and otherrespiratory viruses underestimated opportunistic pathogens of the central nervoussystem Viruses 20191214

4 Li F Receptor recognition mechanisms of coronaviruses a decade of structuralstudies J Virol 2015891954ndash1964

5 Tang X Wu C Li X et al On the origin and continuing evolution of SARS-CoV-2Natl Sci Rev 202071012ndash1023

6 Wu F Zhao S Yu B et al A new coronavirus associated with human respiratorydisease in China Nature 2020579265ndash269

7 Graham RL Baric RS Recombination reservoirs and the modular spike mech-anisms of coronavirus cross-species transmission J Virol 2010843134ndash3146

8 Wu A Peng Y Huang B et al Genome composition and divergence of the novelcoronavirus (2019-nCoV) originating in China Cell Host Microbe 202027325ndash328

9 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

10 Channappanavar R Perlman S Pathogenic human coronavirus infections causesand consequences of cytokine storm and immunopathology Semin Immunopathol201739529ndash539

11 Wang C Horby PW Hayden FG Gao GF A novel coronavirus outbreak of globalhealth concern Lancet 2020395470ndash473

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

13 Hoffmann M Kleine-Weber H Schroeder S et al SARS-CoV-2 cell entry dependson ACE2 and TMPRSS2 and is blocked by a clinically proven protease inhibitorCell 2020181271ndash280e8

14 Wrapp D Wang N Corbett KS et al Cryo-EM structure of the 2019-nCoV spike inthe prefusion conformation Science 20203671260ndash1263

15 Walls AC Park YJ Tortorici MA Wall A McGuire AT Veesler D Structurefunction and antigenicity of the SARS-CoV-2 spike glycoprotein Cell 2020181281ndash292e6

16 Menachery VD Dinnon KH III Yount BL Jr et al Trypsin treatment unlocksbarrier for zoonotic bat coronavirus infection J Virol 202094e01774ndash19

17 Nao N Yamagishi J Miyamoto H et al Genetic predisposition to acquire a poly-basic cleavage site for highly pathogenic avian influenza virus hemagglutinin mBio20178e02298ndash16

18 Dong E Du H Gardner L An interactive web-based dashboard to track COVID-19in real time Lancet Infect Dis 202020533ndash534

19 Phua J Weng L Ling L et al Intensive care management of coronavirus disease2019 (COVID-19) challenges and recommendations Lancet Respir Med 20208506ndash517

20 van Doremalen N Bushmaker T Morris DH et al Aerosol and surface stability ofSARS-CoV-2 as compared with SARS-CoV-1 N Engl J Med 20203821564ndash1567

21 Bai Y Yao L Wei T et al Presumed asymptomatic carrier transmission of COVID-19 JAMA 20203231406ndash1407

22 Ye F Xu S Rong Z et al Delivery of infection from asymptomatic carriers ofCOVID-19 in a familial cluster Int J Infect Dis 202094133ndash138

23 Li Q Guan X Wu P et al Early transmission dynamics in Wuhan China of novelcoronavirus-infected pneumonia N Engl J Med 20203821199ndash1207

24 Auwaerter PG Coronavirus COVID-19 (SARS-CoV-2) [online] Available athopkinsguidescomhopkinsviewJohns_Hopkins_ABX_Guide540747allCoronavirus_COVID_19__SARS_CoV_2_ Accessed April 21 2020

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

26 Shi H Han X Jiang N et al Radiological findings from 81 patients with COVID-19pneumonia in Wuhan China a descriptive study Lancet Infect Dis 202020425ndash434

27 World Health Organization Report of the WHO-China Joint Mission on Coro-navirus Disease 2019 (COVID-19) Geneva Switzerland WHO 2020

28 Liu K Chen Y Lin R Han K Clinical features of COVID-19 in elderly patients acomparison with young and middle-aged patients J Infect 202080e14ndashe18

29 CDC COVID-19 Response Team Severe outcomes among patients with corona-virus disease 2019 (COVID-19)mdashUnited States February 12ndashMarch 16 2020MMWR Morb Mortal Wkly Rep 202069343ndash346

30 Alghamdi IG Hussain II Almalki SS Alghamdi MS Alghamdi MM El-SheemyMAThe pattern of Middle East respiratory syndrome coronavirus in Saudi Arabia adescriptive epidemiological analysis of data from the Saudi Ministry of Health Int JGen Med 20147417ndash423

31 Chan-Yeung M Xu RH SARS epidemiology Respirology 20038(suppl 1)S9ndashS14

32 Ludvigsson JF Systematic review of COVID-19 in children shows milder cases and abetter prognosis than adults Acta Paediatr 20201091088ndash1095

33 Viner RM Whittaker E Kawasaki-like disease emerging complication during theCOVID-19 pandemic Lancet 20203951741ndash1743

34 Mehta P McAuley DF Brown M Sanchez E Tattersall RS Manson JJ COVID-19consider cytokine storm syndromes and immunosuppression Lancet 20203951033ndash1034

35 Huang G Kovalic AJ Graber CJ Prognostic value of leukocytosis and lymphopeniafor coronavirus disease severity Emerg Infect Dis 202026

36 Li G Fan Y Lai Y et al Coronavirus infections and immune responses J Med Virol202092424ndash432

37 CDC Coronavirus Disease 2019 (COVID-19) [online] Atlanta GA CDC38 Yancy CW COVID-19 and African Americans JAMA Epub 2020 Apr 1539 Giacomelli A Pezzati L Conti F et al Self-reported olfactory and taste disorders in

SARS-CoV-2 patients a cross-sectional study Clin Infect Dis Epub 2020 Mar 2640 HaldrupM JohansenMI Fjaelstad AW Lugte- og smagstab som primaeligre symptom

pa COVID-19 [online] Ugeskr Laeligger 2020182V04200205

TAKE-HOME POINTS

Human coronaviruses have been shown to beneuropathogenic

Potential mechanisms of neuropathogenesis ofSARS-CoV-2 include hematogenous and transsy-naptic spread based on viral receptor expression

Neurologic sequelae of COVID-19 involve indirectdirect and postinfectious diseasemechanisms withconsequences that include stroke encephalitisencephalopathy and Guillain-Barre syndrome

Patient registries will be useful to identify and trackneurologic sequelae of SARS-CoV-2 infection andwill improve our understanding of the impact ofCOVID-19 on the nervous system

Appendix Authors

Name Location Contribution

Brigit High University ofColorado Aurora

Wrote themanuscript andmadethe tables

AlisonM HixonPhD

University ofColorado Aurora

Wrote themanuscript made thetables and made the figures

Kenneth LTyler MD

University ofColorado Aurora

Edited the manuscript

Amanda LPiquet MD

University ofColorado Aurora

Wrote themanuscript andmadethe tables

Victoria SPelak MD

University ofColorado Aurora

Wrote themanuscript andmadethe tables

e62 Neurology Clinical Practice | Volume 11 Number 2 | April 2021 NeurologyorgCP

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

41 Lechien JR Chiesa-Estomba CM De Siati DR et al Olfactory and gustatory dys-functions as a clinical presentation of mild-to-moderate forms of the coronavirusdisease (COVID-19) a multicenter European study Eur Arch Otorhinolaryngol20202772251ndash2261

42 Li Y Wang M Zhou Y et al Acute Cerebrovascular Disease Following COVID-19A Single Center Retrospective Observational Study SSRN Scholarly PaperRochester NY Social Science Research Network 2020 Report No ID 3550025

43 Mao L Jin HWangM et al Neurologic manifestations of hospitalized patients withcoronavirus disease 2019 in Wuhan China JAMA Neurol 2020771ndash9

44 Marchese-Ragona R Ottaviano G Nicolai P Vianello A Carecchio M Suddenhyposmia as a prevalent symptom of COVID-19 infection Otolaryngology 2020Preprint 2020-04-07

45 Moein ST Hashemian SMR Mansourafshar B Khorram-Tousi A Tabarsi P DotyRL Smell dysfunction a biomarker for COVID-19 Int Forum Allergy Rhinol Epub2020 Apr 17

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

47 Poyiadji N Shahin G Noujaim D Stone M Patel S Griffith B COVID-19-associated acute hemorrhagic necrotizing encephalopathy CT and MRI featuresRadiology 2020296E119ndashE120

48 Toscano G Palmerini F Ravaglia S et al Guillain-Barre syndrome associated withSARS-CoV-2 N Engl J Med 20203822574ndash2576

49 Zhao H Shen D Zhou H Liu J Chen S Guillain-Barre syndrome associated withSARS-CoV-2 infection causality or coincidence Lancet Neurol 202019383ndash384

50 Zhou L Zhang M Wang J Gao J Sars-Cov-2 underestimated damage to nervoussystem Travel Med Infect Dis 2020 Epub 2020 Mar 24

51 Tong JY Wong A Zhu D Fastenberg JH Tham T The prevalence of olfactory andgustatory dysfunction in COVID-19 patients a systematic review and meta-analysisOtolaryngol Head Neck Surg 20201633ndash11

52 Kaye R Chang CWD Kazahaya K Brereton J Denneny JC COVID-19 anosmiareporting tool initial findings Otolaryngol Head Neck Surg 2020163132ndash134

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

55 Oxley TJ Mocco J Majidi S et al Large-vessel stroke as a presenting feature ofCovid-19 in the young N Engl J Med 2020382e60

56 Rudilosso S Esteller D Urra X Chamorro A Thalamic perforating artery stroke oncomputed tomography perfusion in a patient with coronavirus disease 2019 J StrokeCerebrovasc Dis 202029104974

57 Harzallah I Debliquis A Drenou B Lupus anticoagulant is frequent in patients withCovid-19 J Thromb Haemost Epub 2020 Apr 23

58 Zhang Y Xiao M Zhang S et al Coagulopathy and antiphospholipid antibodies inpatients with Covid-19 N Engl J Med 2020382e38

59 Filatov A Sharma P Hindi F Espinosa PS Neurological complications of corona-virus disease (COVID-19) encephalopathy Cureus 202012e7352

60 Lu L XiongW Liu D et al New-onset acute symptomatic seizure and risk factors incorona virus disease 2019 a retrospective multicenter study Epilepsia 202061e49ndashe53

61 Vollono C Rollo E Romozzi M et al Focal status epilepticus as unique clinicalfeature of COVID-19 a case report Seizure 202078109ndash112

62 Scheidl E Canseco DD Hadji-Naumov A Bereznai B Guillain-Barre syndromeduring SARS-CoV-2 pandemic a case report and review of recent literatureJ Peripher Nerv Syst 202025204ndash207

63 Camdessanche JP Morel J Pozzetto B Paul S Tholance Y Botelho-Nevers ECOVID-19 may induce Guillain-Barre syndrome Rev Neurol (Paris) 2020176516ndash518

64 Zhang W Zhao Y Zhang F et al The use of anti-inflammatory drugs in thetreatment of people with severe coronavirus disease 2019 (COVID-19) the per-spectives of clinical immunologists from China Clin Immunol 2020214108393

65 Luo P Liu Y Qiu L Liu X Liu D Li J Tocilizumab treatment in COVID-19 a singlecenter experience J Med Virol 202092814ndash818

66 McKee S Positive early data from siltuximab COVID-19 trial [online] Available atpharmatimescomnewspositive_early_data_from_siltuximab_covid-19_trial_1334145 Accessed April 20 2020

67 Brownlee W Bourdette D Broadley S Killestein J Ciccarelli O Treating multiplesclerosis and neuromyelitis optica spectrum disorder during the COVID-19 pan-demic Neurology 202094949ndash952

68 Algahtani H Subahi A Shirah B Neurological complications of Middle East re-spiratory syndrome coronavirus a report of two cases and review of the literatureCase Rep Neurol Med 201620163502683

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

70 Ding Y He L Zhang Q et al Organ distribution of severe acute respiratory syn-drome (SARS) associated coronavirus (SARS-CoV) in SARS patients implicationsfor pathogenesis and virus transmission pathways J Pathol 2004203622ndash630

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

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

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

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

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

76 Saad M Omrani AS Baig K et al Clinical aspects and outcomes of 70 patients withMiddle East respiratory syndrome coronavirus infection a single-center experiencein Saudi Arabia Int J Infect Dis 201429301ndash306

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