Acute Disseminated Encephalomyelitis and Acute Hemorrhagic

ARTICLE OPEN ACCESS

Acute Disseminated Encephalomyelitis andAcute Hemorrhagic Leukoencephalitis FollowingCOVID-19Systematic Review and Meta-synthesis

Giovanna S Manzano MD Caleb R S McEntire MD Maria Martinez-Lage MD Farrah J Mateen MD PhD

and Spencer K Hutto MD

Neurol Neuroimmunol Neuroinflamm 20218e1080 doi101212NXI0000000000001080

Correspondence

Dr Hutto

shuttoemoryedu

AbstractBackground and ObjectivesSince the onset of the COVID-19 pandemic a growing number of reports have described casesof acute disseminated encephalomyelitis (ADEM) and acute hemorrhagic leukoencephalitis(AHLE) following infection with COVID-19 Given their relatively rare occurrence the pri-mary objective of this systematic review was to synthesize their clinical features response totreatments and clinical outcomes to better understand the nature of this neurologic conse-quence of COVID-19 infection

MethodsPatients with a history of COVID-19 infection were included if their reports provided adequatedetail to confirm a diagnosis of ADEM or AHLE by virtue of clinical features radiographicabnormalities and histopathologic findings Cases purported to be secondary to vaccinationagainst COVID-19 or occurring in the context of a preexisting relapsing CNS demyelinatingdisease were excluded Case reports and series were identified via PubMed on May 17 2021and 4 additional cases from the authorsrsquo hospital files supplemented the systematic review of theliterature Summary statistics were used to describe variables using a complete case analysisapproach

ResultsForty-six patients (28 men median age 495 years 13 gt50 years old) were analyzed derivedfrom 26 case reports or series originating from 8 countries alongside 4 patient cases from theauthorsrsquo hospital files COVID-19 infection was laboratory confirmed in 91 of cases andinfection severity necessitated intensive care in 67 ADEM occurred in 31 cases whereasAHLE occurred in 15 with a median presenting nadir modified Rankin Scale score of 5(bedridden) Anti-MOG seropositivity was rare (115 patients tested) Noninflammatory CSFwas present in 30 Hemorrhage on brain MRI was identified in 42 Seventy percent receivedimmunomodulatory treatments most commonly steroids IV immunoglobulins or plasma-pheresis The final mRS score was ge4 in 64 of patients with adequate follow-up informationincluding 32 who died

DiscussionIn contrast to ADEM cases from the prepandemic era reported postndashCOVID-19 ADEM andAHLE cases were often advanced in age at onset experienced severe antecedent infectiondisplayed an unusually high rate of hemorrhage on neuroimaging and routinely had poor

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From the Division of Neuroimmunology and Neuroinfectious Diseases (GSM CRSM FJM SKH) Department of Neurology Massachusetts General Hospital Boston MA andDepartment of Pathology (MM-L) Massachusetts General Hospital Boston MA

Go to NeurologyorgNN for full disclosures Funding information is provided at the end of the article

The Article Processing Charge was funded by the authors

This is an open access article distributed under the terms of the Creative Commons Attribution-NonCommercial-NoDerivatives License 40 (CC BY-NC-ND) which permits downloadingand sharing the work provided it is properly cited The work cannot be changed in any way or used commercially without permission from the journal

Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the American Academy of Neurology 1

neurologic outcomes including a high mortality rate Findings are limited by nonstandardized reporting of cases truncatedfollow-up information and presumed publication bias

Acute disseminated encephalomyelitis (ADEM) is an in-flammatory demyelinating disease of the CNS characterizedby fulminant multifocal neurologic injury and distinct neu-ropathologic findings1 ADEM is classically thought to bepreceded by vaccination or a systemic infection of whichupper respiratory tract infections are most commonly repor-ted2 Given that ADEM is more common in children con-sensus criteria for clinically diagnosing ADEM exist forchildren only1 In the absence of a biomarker the diagnosis ofADEM is largely reliant on the clinical presentation supportedby typical MRI findings and the exclusion of competing di-agnoses through ancillary testing Most ADEM cases areclinically monophasic but a small number are recurrent orsubsequently realized to be the initial presentation of a re-lapsing CNS demyelinating disease such as MS myelin oli-godendrocyte glycoprotein antibody disease or neuromyelitisoptica spectrum disorder2

Since the onset of the coronavirus (COVID-19) pandemic inNovember 2019 neurologic complications of SARS-CoV-2infection are increasingly recognized Parainfectious neuro-logic injury is well described and ageusia and anosmia arecomponents of the primary constellation of symptoms andcan be early signs of infection34 Headache delirium anddizziness are also common clinical accompaniments56 Theneuroinflammatory events following COVID-19 particularlyADEM and its severe variant acute hemorrhagic leukoence-phalitis (AHLE and Weston-Hurst disease) occur rarely andhave yet to be synthesized in the literature Most publishedreports are single cases or small case series However theglobal clinical experience on ADEM and AHLE in the settingof COVID-19 appears to be growing

In this case series and systematic literature review we reportthe collective experience of ADEM and AHLE followingCOVID-19 We characterize the disease course diagnostictest findings patient outcomes and treatment approaches ofboth COVID-19 and the subsequent presentations of ADEMand AHLE Given the novelty of this virus and the ongoingnature of the global pandemic we address the available datafor the phenotypic presentations of ADEM and AHLE therelationship to COVID-19 disease factors and highlight issuesfor future research data gathering and clinical care Finallywe consider whether COVID-associated ADEM and AHLEcases differ from their counterparts that predated the pandemic

MethodsOverviewWe performed a systematic review for cases of postndashCOVID-19 ADEM and AHLE in the medical literature adding casesevaluated at our institution The Massachusetts GeneralBrigham (MGB) Institutional Review Board approved thestudy

Information SourcesCases were principally obtained by systematically searchingPubMed Four cases originating from the MGB health caresystem were included in the final synthesis of individual cases

Search Strategy and Screening ProcessWe searched pubmedgov on May 17 2021 for cases ofCOVID-19 followed by ADEM or AHLE The followingsearch strategy was used [coronavirus disease OR coronavi-rus OR COVID OR COVID-19 OR SARS-CoV OR SARS-CoV-2] AND [acute disseminated encephalomyelitis ORADEMOR acute hemorrhagic leukoencephalitis OR AHLE]A time filter of reports published between December 1 2019and May 17 2021 was applied no further restrictions wereplaced on the search results Article titles and abstracts in-dicating a possible central neuroinflammatory relationship toCOVID-19 were included for a more detailed review of thefull-text article One neurologist author with neuro-immunology subspecialty expertise (SKH) screened theinitial search results without the assistance of automation Ofthe 435 results 46 articles were further reviewed by at least 2authors with neurology training (GSM CRM andSKH) with a third neuroimmunologist reviewer available toadjudicate disagreements (FJM) A total of 26 articles wereretained

Criteria for Case Selection

Inclusion CriteriaPatients of any age with a history of COVID-19 infection wereincluded in the study if their case descriptions provided suf-ficient details to confirm a clinical diagnosis of ADEM orAHLE ADEM was defined as a first multifocal event of ful-minant CNS demyelination supported either histopatholog-ically or radiographically by white matter lesions consistentwith demyelination Encephalopathy was not required forinclusion in line with multiple studies suggesting its lower

GlossaryADEM = acute disseminated encephalomyelitis AHLE = acute hemorrhagic leukoencephalitis IPMSSG = InternationalPediatric Multiple Sclerosis Study Group IVIG = IV immunoglobulin MGB = Massachusetts General Brigham mRS =modified Rankin Scale OCB = oligoclonal band

2 Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 NeurologyorgNN

prevalence in adult populations278 AHLE diagnoses requiredthe additional criteria of hyperacute onset and evidence ofhemorrhage (micro- or macro-) on neuroimaging or brainpathology910

We defined COVID-19 infection in a manner consistent withguidance from the United States Centers for Disease Controland Prevention and the Infectious Diseases Society ofAmerica (1) clinical symptoms consistent with COVID-19without laboratory confirmation in the absence of an alter-native explanation (2) nasopharyngeal swab positive forCOVID-19 PCR with or without symptoms or (3) positiveCOVID-19 serologies with or without symptoms11-14 Thepresence of clinical symptoms without laboratory confirma-tion of infection was included as a criterion on account of poortesting capacity in many countries early in the pandemicAsymptomatic infections are known to constitute a significantpercentage of patients with COVID-19 and therefore weelected to include patients with only laboratory evidence ofinfection to capture the full spectrum of COVID-19-associated ADEM and AHLE1516

Exclusion CriteriaTo avoid the possibility of coincidental COVID-19 acquisi-tion during hospitalization with ADEM or AHLE cases withwell-established neurologic injury or a preexisting history of arelapsing CNS demyelinating disease before COVID-19symptom onset were excluded To ensure strict fidelity tothe immunologic reaction to actual viral infection cases oc-curring in the context of vaccination for COVID-19 wereexcluded Additional exclusion criteria included articles notpresenting original data (topical reviews and systematic re-views) and those cases with insufficient information to de-termine the accuracy of an ADEM or AHLE diagnosis and itsrelationship to COVID-19 infection

Data Acquisition and AnalysisThe collected cases from the literature review and medicalrecords were each reviewed by at least 2 authors whoextracted prespecified variables of interest into a central da-tabase using a standardized template Demographic clinicalserum and CSF laboratory tests neuroimaging treatmentcourse and patient outcomes were collected No assumptionswere made regarding missing data Absence of informationwas noted as not reported or not available

The geographical origin of a case was based on the location ofthe original authorsrsquo primary practice affiliation The timedelay from onset of COVID-19 infection to neurologicsymptoms could not be determined in many cases often dueto discovery of neurologic disease in the setting of persistentencephalopathy following sedation weaning in cases intu-bated originally for COVID infection Quantitative reportingof CSF oligoclonal bands (OCBs) was rare in the literaturereview so their presence was reported qualitatively to reflectthat limitation Modified Rankin Scale (mRS) scores wereretrospectively extrapolated from published case descriptions

In circumstances where a limited follow-up or clinical exam-ination was provided the mRS score was not calculated anddocumented as insufficient data

Summary statistics were used to describe the data fromreported cases as a single group Medians means and rangeswere reported using a complete case analysis approach Caseswith missing data were not included in the synthesis of theparticular variable for which the data point was missing Allanalyses were performed using Microsoft Excel

Mass General Brigham CasesThe Mass General Brigham Research Patient Data Registrywas searched for patients with diagnoses of COVID-19 orpersonal history of COVID-19 and the additional diagnosis ofADEM on March 29 2021 The Research Patient DataRegistry queries the electronic medical records of all hospitalsand clinics within the Mass General Brigham system Fourcases meeting the above inclusion and exclusion criteria of theliterature review were identified and 11 were excluded

Data AvailabilityAnonymized data will be made available to qualified investi-gators subject to ethics board approvals Pertinent data pointsfor the literature review are provided in eTables S2 and S3linkslwwcomNXIA584 and the eReferences for in-corporated cases reports are included in S4 linkslwwcomNXIA584

ResultsA PRISMA flow diagram illustrating the case selection processis presented in Figure 1 Twenty-six articles (8 case series and18 case reports) were identified in the literature reviewyielding 42 patient cases Three new cases were identifiedthrough query of the MGB electronic medical records alongwith 1 additional case under review for publication by one ofthe authors (SKH) A total of 46 patient cases were analyzed(Tables 1ndash3) Cases originated from the United States (15)United Kingdom (13) Singapore (6) Brazil (5) Iran (3)India (2) Italy (2) and Greece (1) A slight male pre-dominance was noted in cases overall (61 male to 37female) however there was a female predominance inreported pediatric cases (lt18 years old 80 female to 20male)

Features of Antecedent COVID-19 Infectionandor ExposureOf 46 total patients included 39 had a symptomatic re-spiratory illness before the onset of subsequent neurologicsymptoms The etiology of the preceding respiratory illnesswas objectively confirmed to be COVID-19 in 42 patients themajority by nasopharyngeal COVID-19 PCR testing(Table 1) Of those confirmed to have had precedingCOVID-19 via serologic testing for SARS-CoV-2 antibodies(14 of 42 confirmed cases) qualitative results were

NeurologyorgNN Neurology Neuroimmunology amp Neuroinflammation | Volume 8 Number 6 | November 2021 3

reported Inpatient hospitalization was warranted for 83 ofthe patients with majority necessitating intensive care unitlevel of care requiring sedation and ventilation (Table 1) Ofthe 39 patients with symptomatic COVID-19 infection only14 patients received COVID-19 directed therapy Thesetherapies included remdesivir monotherapy (3 patients)convalescent plasma monotherapy (4 patients) remdesivirand convalescent plasma (1 patient) hydroxychloroquinemonotherapy (1 patient) hydroxychloroquine and conva-lescent plasma (1 patient) stress-dose steroids (1 patient)and a combination of multiple therapies inclusive of azi-thromycin hydroxychloroquine lopinavir ritonavir andanakinra (1 patient) or a combination of interferon beta-1blopinavir and ritonavir (2 patients)

Included in our literature review are 4 patients from theUnited Kingdom with presumed COVID-19 precedingADEM and AHLE (cases 4 5 7 and 8) Presumption of priorCOVID-19 infection was accepted in these patients due to thedevelopment of severe respiratory illness during the earlyphase of the pandemic when COVID-19 was endemic in theUnited Kingdom (spring 2020) and routine testing waslimited

Clinical Characteristics of PostndashCOVID-19ADEMAs noted in Table 2 the duration from COVID-19 symptomonset to development of ADEM and AHLE varied with aslight majority occurring within 15ndash30 days The acuity ofprogression of neurologic disease ranged from acute (lt24hours) to subacute (between 24 hours to 10 days) to chronic(gt10 days) with 22 of patients demonstrating subacuteprogression of disease Notably the rate of neurologic diseaseprogression could not be determined in 30 patients (65)due to insufficient reporting andor patient-specific factorsmost commonly being a period of prolonged sedation beforeneurologic disease discovery Neurologic signs and symptomsvaried with the majority demonstrating encephalopathy(78) that encompassed confusion lethargy and difficultywaking from sedation Focal motor deficits were the secondmost common clinical manifestation of disease (43) Atclinical nadir of ADEM and AHLE the retrospective mRSscore ranged from 1 to 6 (mRS score mean 46 median 5)AHLE was diagnosed in 15 cases by the primary authors andaffirmed on review Neuroimaging evidence further con-firmed this diagnosis in 14 of these 15 cases Imaging mo-dalities revealing hemorrhage were brain MRI for 10 cases(5 cases via susceptibility-weighted imaging 1 case via

Figure 1 PRISMA Flow Diagram Demonstrating Case Selection Methodology

PRISMA flowdiagram illustrating source information used the screening process used and its effects on excluded articles and final articles and cases selectedfor study inclusion


susceptibility-weighted angiography and 4 cases without se-quence specification) an MRI cervical spine in 1 case (se-quence not specified) and noncontrast head CT in 3 cases Inone case author reporting was the only source of validation ofAHLE as no supporting imaging or pathology was madeavailable

Diagnostic Studies and Radiographic FeaturesLumbar puncture was performed in 37 of 46 patients with anormal profile (cell count protein IgG and OCBs) in 11 of37 patients (30) At least 1 marker of inflammation in the

Table 1 Patient Demographics and Features ofAntecedent COVID-19 Infection

Patient demographic characteristics

Age at diagnosis of ADEM years n ()

0ndash10 5 (11)

11ndash20 1 (2)

21ndash30 5 (11)

31ndash40 5 (11)

41ndash50 7 (15)

51ndash60 15 (33)

gt60 6 (13)

Unspecified 2 (4)

Sex

Female 17 (37)

Male 28 (61)

Unspecified 1 (2)

Features of antecedent COVID-19

COVID-19 diagnostics n ()

Nasopharyngeal SARS-CoV-2 swab 34 (74)

Serologic SARS-CoV-2 antibody 6 (13)

Method not specified 2 (4)

Presumed positive cases 4 (9)

COVID-19 level of care

ICU ventilatedsedated 29 (63)

ICU not ventilated 2 (4)

Hospital floor admission 3 (7)

Inpatient level of care not specified 4 (9)

Outpatient care 8 (17)

Receipt of COVID-19 therapies 14 (30)

Abbreviations ADEM = acute disseminated encephalomyelitis ICU = in-tensive care unit

Table 2 Clinical Features of PostndashCOVID-19 ADEM

Clinical features of postndashCOVID-19 ADEM

Phenotype n ()

ADEM 31 (67)

AHLE 15 (33)

Duration since COVID-19 symptom onset days

0ndash7 5 (11)

8ndash14 7 (15)

15ndash30 9 (20)

31ndash60 3 (7)

Indeterminable 22 (48)

ADEMAHLE onset acuity

Acute (lt24 hours) 5 (11)

Subacute (24 hoursndash10 days) 10 (22)

Chronic (gt10 days) 1 (2)


ADEMAHLE presenting symptomssigns

Encephalopathy 36 (78)

Seizure 5 (11)

Aphasia 2 (4)

Focal motor deficits 20 (43)

Focal sensory deficits 9 (20)

Cranial nerve deficits 11 (24)

Cerebellar deficits 5 (11)

Urinary retention 2 (4)

Autonomic instability 2 (4)

Brainstem 4 (9)

None reporteda 1 (2)

Nadir mRS score at ADEMAHLE presentation

1 2 (4)

2 1 (2)

3 4 (9)

4 5 (11)

5 29 (63)

6 4 (9)


Abbreviations ADEM= acute disseminated encephalomyelitis AHLE = acutehemorrhagic leukoencephalitis mRS = Modified Rankin ScaleVariables for which there was insufficient information available in the casereports tomake an accurate determination are classified as indeterminablea This case was an autopsy-confirmed diagnosis of ADEM


CSF (pleocytosis elevated protein elevated IgG index orpresence of OCBs) was found in 26 of 37 patients (70)Serum anti-myelin oligodendrocyte glycoprotein (anti-MOG) antibodies and anti-aquaporin-4 (anti-AQP4) anti-bodies were each tested in 15 patients with 1 patient found tohave anti-MOG antibody positivity titer not specified(Table 3)

A brain MRI was obtained for 43 cases Imaging abnor-malities are summarized in Table 3 and representativeimages from the MGB case series are presented in Figure 2In the 3 cases without brain MRI performed diagnosis wasmade via postmortem autopsy An example of pathologyobtained from diagnostic biopsy in 1 living patient is shownin Figure 3 Only 24 patients additionally underwent MRIof the spine of which 54 had abnormal findings SpineMRI displayed longitudinal extensive myelitis in 4 patientsshort segment lesions in 7 patients and both long and shortsegment lesions in 1 patient (details in eTable 2 linkslwwcomNXIA584) Insufficient detail precluded de-termination of spinal lesion length in 1 patient

Only 17 cases had repeat imaging at the time of follow-up Ofthese patients the majority demonstrated radiographic im-provement (71 Table 4) Two patients (cases 32 and 344 of total cases) had normal MRIs initially on days 2 and 6after neurologic symptom onset and were found to have re-markably abnormal imaging on interval scans obtained ondays 4 and 50 respectively We chose to include these patientsbecause this phenomenon of delayed neuroimaging conver-sion has been previously noted in 7 of patients in a largeADEM case series with long-term follow-up17

Neurologic-Directed Treatment andPatient OutcomesAs shown in Table 4 acute neurologic-directed treatmentswere received by the majority of patients (70) Treatmentregimens varied from corticosteroid or IV immunoglobulin(IVIG) monotherapy to corticosteroids with IVIG andorplasmapheresis to initiation of long-term immunosuppres-sants Two patients required neurosurgical interventions(cases 4 and 7 detailed in eTable 3 linkslwwcomNXIA584) due to edema and resultant midline shift associatedwith disease burden

Duration between ADEMAHLE diagnosis and follow-upwidely varied and was reported for 17 cases (range 14ndash240days median 50 days) Duration between ADEMAHLEdiagnosis and date of death was not reliably reported In-sufficient reporting precluded the ability to assess post-intervention clinical outcome in 39 of patients Of the 28cases with sufficient data to determine a final retrospectivemRS score most remained severely affected by their diseaseAnmRS score of 4 or greater was noted in 1828 (64) and 9patients died (32 of those with follow-up 20 of the entirecohort)

Table 3 PostndashCOVID-19 ADEM Diagnostics

Serology and CSF findings

Anti-MOG seropositivity ntotal known ()

Positive 1 patient 115 (7)

Absent 14 patients 1415 (93)

Anti-AQP4 seropositivity

Positive 015 (0)

Absent 1515 (100)

CSF pleocytosis

Present 1237 (32)

Absent 2437 (65)

Not reported 137 (3)

CSF protein

Elevated 1937 (51)

Normal 1737 (46)


CSF IgG index

Elevated 25 (40)

Normal 35 (60)

CSF OCB

Present 525 (20)

Absent 2025 (80)

Neuroimaging lesion localization

T2FLAIR Hyperintensities ntotal known ()

Supratentorial 4143 (95)

Infratentorial 2243 (51)

Spinal cord 1324 (54)

Enhancement

Intracranial 1542 (36)


Hemorrhage


Spinal cord 024 (0)

Abbreviations ADEM = acute disseminated encephalomyelitis AQP4 =aquaporin-4 FLAIR = fluid-attenuated inversion recovery IgG = immuno-globulin G MOG = myelin oligodendrocyte glycoprotein OCB = oligoclonalband T2 = T2-weighted MRI sequenceThe denominator refers to the total number of cases for which the variableis known or could be accurately discerned (which may be less than the totalcohort of 46 patients) CertainMRI sequencesmaynot have been performedor reported throughout all locations of the central neuraxis in all cases Onecase with a brain and spine MRI was described as having not receivedcontrast on account of renal failure Three patients identified on autopsy didnot have MRIs performed Hemorrhage refers to either micro- or macro-hemorrhage Intracranial refers to both supratentorial and infratentoriallocations Spinal refers to lesion localization at any point in the spinal cordparenchyma


International Pediatric Multiple SclerosisStudy Group Criteria for ADEMThe International Pediatric Multiple Sclerosis Study Group(IPMSSG) criteria are the only set of consensus-foundeddiagnostic criteria for ADEM and created primarily for pe-diatric patients Because of a lack of adult-specific diagnosticcriteria IPMSSG criteria are often extrapolated to the adultpopulation These criteria rely on specified clinical and ra-diographic features and exclusion of alternative etiologies1

The size of radiographic lesions was not reliably reported forall reviewed cases Therefore we presume that patients whowere identified as having ADEM or AHLE by the reportingauthors did demonstrate characteristic lesion size and fea-tures as per the IPMSSG criterion Accounting for thispresumption 3846 (83) total cases met the IPMSSGcriterion for ADEM inclusive of pathologically confirmedcases

DiscussionSince the onset of the pandemic a growing number of casereports noting the development of ADEM and AHLE fol-lowing COVID-19 infection have been published In thissystematic review of available cases to date we synthesize theevidence that ADEM and AHLE occur postndashCOVID-19highlighting this temporal association We clarify the clinicalfeatures ancillary testing results and outcomes of postndashCOVID-19 ADEM and AHLE Although postndashCOVID-19ADEM and AHLE cases were similar to those of the pre-pandemic era in some aspects such as the clinical features ofADEM and AHLE and the time between systemic infectionand demyelination onset we also found differences in thereported postndashCOVID-19 ADEM and AHLE cases as awhole (1) the vast majority of reported cases are adults ratherthan children (2) the preceding systemic infection was often

Figure 2 Neuroimaging Examples From the MGB Case Series

Axial brain MRI sequences of patients with post-COVID ADEM from the MGB case series (AndashC)Axial brain MRI sequences from case 1 displayFLAIR hyperintensities in the bilateral frontallobes anterior temporal lobes and cerebellum(D and E) Axial brain MRI sequences from case 2show bilateral FLAIR hyperintensities with aprominent right parietal lesion that enhancesas well as nodular enhancement of the rightcorona radiata and occipital horn of the rightlateral ventricle (F) Sagittal postcontrast T1 se-quence of the cervical spine MRI from case 2displays a focus of intramedullary enhancementat C4-5 (red box) (GndashI) Axial brain MRI se-quences from case 3 show diffuse multifocal T2FLAIR lesions (G and I) and a predominant open-ring contrast enhancement pattern of severallesions in the T1 postcontrast sequence (H)ADEM = acute disseminated encephalomyelitisMGB = Massachusetts General Brigham


severe as opposed to trivial (3) hemorrhage within lesionswas common on neuroimaging (4) MOG antibody sero-positivity was rare (5) morbidity with ADEM was high de-spite the use of standard ADEM treatments and (6) mortalitywas common even with relatively short follow-up281819

Our findings lend plausibility to COVID-19 acting as a viraltrigger for ADEM and AHLE as has been postulated withother pathogens in the past including coronaviruses (MERSand OC43)18-22 With the exception of a few early cases oc-curring before widespread COVID-19 testing availability al-most all (91) included patients had laboratory-confirmedinfection usually in close temporal association with COVID-19 diagnoses These findings are biologically supported bymounting evidence that SARS-CoV-2 shares epitopes withneuronal proteins which may incite subsequent autoimmu-nity involving the CNS via molecular mimicry2324

In contrast to childhood being the traditional vulnerabilityperiod of prepandemic ADEM most postndashCOVID-19ADEM and AHLE cases reported to date occurred inadults usually of advanced age (nearly half gt50 years old)218

We speculate that this finding is likely multifactorial (1) allhumans were immunologically naive to the virus therebymassively extending the candidate pool for primary viral in-fection (2) COVID-19 on average tends to cause moresevere infections in adults which lends itself to the potentialfor a more severe inflammatory response and (3) severeinfections will require more intensive prospective medicalmonitoring which may lead to a higher detection rate of

ADEM diagnosis and enhanced recall bias for subsequentneurologic complications1625 It is possible that the ex-traordinary nature of these cases in adults led to publicationbias of more unusual cases but the very high number ofreports in adults compared with children makes the hy-pothesis that ADEM and AHLE postndashCOVID-19 exist andare more likely in adults

The sustained and varying location of now gt40 reportsdemonstrates that ADEM and AHLE are recognized albeitrare potential consequences of severe COVID-19 infectionNearly two-thirds of patients required intensive care for theantecedent infection Failure to awaken and resume in-dependent ventilation were the most common clinical sce-narios suggesting the presence of coexisting neurologic injuryCOVID-19 infections did span the spectrum of disease se-verity however with a smaller fraction of patients managed inless intensive settings It should be noted that asymptomaticor mildly symptomatic COVID-19 infections commonly oc-cur and the link between them and CNS demyelination maygo undetected if serologic testing for COVID-19 is notpursued1516

Pediatric ADEM has an association with antibodies againstMOG in 35ndash65 of cases which carries prognostic value bysuggesting a higher likelihood of recurrent demyelinatingevents in the future26-29 Although testing was incompleteonly a single MOG-seropositive case was identified in ourcohort which was a 13-month-old female (13 children withreported testing were positive all 12 adults negative)

Figure 3 Neuropathology Examples of PostndashCOVID-19 ADEM

Brain pathology from case 2 of the MGB series (case details provided in the supplementary files linkslwwcomNXIA584) Low-power images (AndashD)demonstrate markedly cellular brain parenchyma with prominent perivascular inflammation and reduced myelinated fibers (A LuxolndashHampE stain) withrelative preservation of axons (B neurofilament immunohistochemistry) The cellular population is composed largely of macrophages (C CD68 immuno-histochemistry) whereas the perivascular infiltrates are predominantly T cells (D CD3 immunohistochemistry) Higher-power views (EndashH) characterize theperivascular infiltrates as composed of small mature lymphocytes and focally prominent plasma cells (E HampE open arrows) whereas the surrounding tissueis composed of numerous foamy macrophages (solid arrows) and reactive astrocytes Immunohistochemistry demonstrates scattered perivascular andparenchymal plasma cells (F CD138) numerous parenchymal foamy macrophages (G CD68) and marked perivascular T cells (H CD3) ADEM = acutedisseminated encephalomyelitis MGB = Massachusetts General Brigham


There was a relatively high rate of noninflammatory CSF inpostndashCOVID-19 ADEMAHLE with 30 (1137) failing todemonstrate at least 1 marker of inflammation similar toprepandemic ADEM reports where 70ndash81 had some evi-dence of inflammation in the CSF23031 Our finding of CSF-restricted oligoclonal bands in 20 (525) of patients isconsistent with prepandemic ADEM descriptions in childrenand adults where the frequency is usually less than 30232

Forty-two percent of patients had evidence for hemorrhage onbrain MRI significantly higher than that seen for classicADEM Prior studies have shown much lower frequencies ofhemorrhage approximating 2 of cases33 The cause behindthis remains uncertain but it is conceivable that the pre-dilection of COVID-19 to involve the microcirculation may becontributory and therefore could be a unique feature to thisviral trigger either as a result of direct infection or perhapsalso secondary to molecular mimicry34-36 It may also be abyproduct of proinflammatory cytokines promoting endothe-lial dysfunction in more severe cases of COVID-19 infection36

The prospect for a favorable outcome (mRS score of le2) incases with reported follow-up was low (20) and that ofmortality quite high (32) If all patients lost to follow-up aregiven a favorable mRS score of 0ndash2 rates for unfavorableoutcomes are 41 This remains quite high in comparison tohistorical cohorts where typically less than 30 have similarlydefined unfavorable outcomes737 In addition to the possi-bility that postndashCOVID-19 ADEM and AHLEmay inherentlyportend worse outcomes additional possible explanationsinclude the direct effects of COVID-19 infection on survivalhesitancy to apply immunotherapy for ADEM or AHLE onaccount of concurrent COVID-19 infection and publicationbias toward AHLE The baseline health and comorbidities ofthese patients may be worse than prior ADEM cohorts inkeeping with their high rate of more severe COVID-19 in-fections Extending follow-up over time will be an importanttool in clarifying outcomes in this specific patient population

Included cases mostly originated from countries with highnumbers of infections early in the pandemic (United StatesUnited Kingdom Italy and Iran) and high numbers of in-fections overall (United States Brazil and India)3839 Singa-pore was disproportionately represented in our cohort

Table 4 Interventions and Outcomes of PostndashCOVID-19ADEM

ADEM treatment

Treatment n ()

Not reported 5 (11)

Supportive care only 9 (20)

Received neurologic treatment 32 (70)

IVMP without oral taper 17

IVMP followed by oral taper 7

Oral steroids only 10

IVIG monotherapy 2

IVIG + IVMP plusmn PLEX 11

Plasmapheresis 4

Rituximab 1

Ocrelizumab 1

Cyclophosphamide 1

Neurosurgical intervention 2

Mannitol 1

Posthospitalization follow-up

Follow-up duration days n ()

1ndash30 7 (15)

31ndash60 5 (11)

gt60 5 (11)

Deceased 9 (20)

Not recorded 20 (43)

Final mRS score

0 3 (7)

1 2 (4)

2 4 (9)

3 1 (2)

4 6 (13)

5 3 (7)

6 (deceased) 9 (20)

Unclear or no follow-up recorded 18 (39)

Final radiographic outcome

Radiographic improvement 1217 (71)

Radiographic stability 217 (12)

Radiographic worsening 317 (18)

Abbreviations ADEM = acute disseminated encephalomyelitis IVIG = IVimmunoglobulin IVMP = IV methylprednisolone mRS = modified RankinScale PLEX = plasmapheresisThe denominator is assumed to be 46 unless otherwise denoted Neuro-logic-directed treatment received was not mutually exclusive as patientsmay have receivedmore thanone of the therapies listed Follow-up durationrefers to the time from ADEM onset to the last reported follow-up The finalmRS score was retrospectively calculated in patients with sufficient in-formation to determine the score at last reported follow-up and final ra-diographic outcome was determined on the basis of the last noninitial MRIsreported


(6 cases included) despite having only 61331 cases in total asof May 9 202139 This unexpectedly high contribution mostlikely reflects the impact of Singaporersquos prospective surveil-lance for neurologic complications in all laboratory-confirmedinfections since the onset of the pandemic until August202040 As countries continue progressing through the pan-demic in their own unique ways others will likely be able toapply the lessons learned here as they gain their own experi-ence with postndashCOVID-19 ADEM and AHLE

ADEM and AHLE remain rare occurrences followingCOVID-19 infection but the observations cited here em-phasize another reason for the need for primary prevention ofinfection Additional recommendations include monitoringfor neurologic complications in sedated patients carefullyprobing for preceding COVID-19 infection (historically andvia laboratory means) in those presenting with ADEM orAHLE and evaluating for MOG seropositivity especially inchildren Alongside the administration of COVID-19ndashdirected therapies earlier and more aggressive interventionsfor ADEM and AHLEmay be necessary to avoid a severe finaloutcome Coexisting neurologic injury of this type (ADEMAHLE) could be considered a relatively poor prognosticmarker Although ADEM itself is considered a fixed entity interms of its clinical features it may manifest more severely inits course in response to this particular infectious trigger Aninternational registry of such cases is urgently needed to fullyexamine the scope of postndashCOVID-19 ADEM and AHLE andwould offer an opportunity to collect and report cases in astandardized manner across all ranges of severity and in allpatient settings

Our findings are limited by the lack of standardized reportingof individual cases and the resultant variability in the quality ofsuch reporting which contributed to incomplete data forsome variables of interest Given the novelty of COVID-19and its neurologic associations many of the reports fromearlier in the pandemic were likely prioritized for rapid pub-lication resulting in truncated follow-up information and ofcourse experience with COVID-19 remains in its youth at lessthan 15 years since the first recognized case in humans

Study FundingNo targeted funding reported

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

Publication HistoryReceived by Neurology Neuroimmunology amp NeuroinflammationMay 28 2021 Accepted in final form July 6 2021

References1 Krupp LB Tardieu M Amato MP et al International Pediatric Multiple Sclerosis

Study Group criteria for pediatric multiple sclerosis and immune-mediated centralnervous system demyelinating disorders revisions to the 2007 definitionsMult Scler201319(10)1261-1267

2 Koelman DLH Chahin S Mar SS et al Acute disseminated encephalomyelitis in228 patients a retrospective multicenter US study Neurology 201686(22)2085-2093

3 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 Otorhinolaryngol Suppl2020277(8)2251-2261

4 Lee Y Min P Lee S Kim S Prevalence and duration of acute loss of smell or taste inCOVID-19 patients J Korean Med Sci 202035(18)e174

5 Collantes MEV Espiritu AI Sy MCC Anlacan VMM Jamora RDG Neurologicalmanifestations in COVID-19 infection a systematic review and meta-analysis Can JNeurol Sci 202148(1)66-76

6 Chen X Laurent S Onur OA et al A systematic review of neurological symptoms andcomplications of COVID-19 J Neurol 2021268(2)392-402

7 Ketelslegers IA Visser IER Neuteboom RF Boon M Catsman-Berrevoets CEHintzen RQ Disease course and outcome of acute disseminated encephalomyelitis ismore severe in adults than in children Mult Scler 201117(4)441-448

8 Schwarz S Mohr A Knauth M Wildemann B Storch-Hagenlocher B Acute dis-seminated encephalomyelitis a follow-up study of 40 adult patients Neurology 200156(10)1313-1318

9 Kuperan S Ostrow P Landi MK Bakshi R Acute hemorrhagic leukoencephalitis vsADEM FLAIR MRI and neuropathology findings Neurology 200360(4)721-722

10 Grzonka P Scholz M De Marchis GM et al Acute hemorrhagic leukoencephalitis acase and systematic review of the literature Front Neurol 202011899

11 The Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19Molecular Diagnostic Testing Infectious Diseases Society of America Accessed May17 2021 idsocietyorgpractice-guidelinecovid-19-guideline-diagnostics

12 Infectious Diseases Society of America Guidelines on the Diagnosis of COVID-19Serologic Testing Infectious Diseases Society of America Accessed May 17 2021idsocietyorgCOVID19guidelinesserology

13 Stokes EK Zambrano LD Anderson KN et al Coronavirus disease 2019 casesurveillancemdashUnited States January 22ndashMay 30 2020 Morbidity Mortality WeeklyRep 202069(24)759-765

Appendix Authors

Name Location Contribution

Giovanna SManzanoMD

MassachusettsGeneral HospitalBoston

Designed and conceptualized thestudy major role in the acquisition ofdata analyzed the data drafted themanuscript for intellectual contentand creation of tables and figures

Caleb R SMcEntireMD


Interpreted the data revised themanuscript for intellectual contentand major role in the acquisition ofdata

MariaMartinez-Lage MD


Creation of figures and revised themanuscript for intellectual content

Farrah JMateen MDPhD


Designed and conceptualized thestudy interpreted the dataadjudicated interraterdisagreements revised themanuscript for intellectual contentand study supervision

Spencer KHutto MD


Designed and conceptualized thestudy major role in the acquisition ofdata analyzed the data drafted themanuscript for intellectual contentstudy supervision and creation oftables


14 Coronavirus Disease 2019 (COVID-19) 2020 Interim Case Definition Centers forDisease Control and Prevention wwwncdcgovnndssconditionscoronavirus-dis-ease-2019-covid-19case-definition2020 (accessed 18 May 2021)

15 Oran DP Topol EJ The proportion of SARS-CoV-2 infections that are asymptom-atic a systematic review Ann Intern Med 2021174(5)655-662

16 He J Guo YMao R Zhang J Proportion of asymptomatic coronavirus disease 2019 asystematic review and meta-analysis J Med Virol 202193(2)820-830

17 Wong YYM van Pelt ED Ketelslegers IA Catsman-Berrevoets CE Hintzen RQNeuteboom RF Evolution of MRI abnormalities in paediatric acute disseminatedencephalomyelitis Eur J Paediatr Neurol 201721(2)300-304

18 Pavone P Pettoello-Mantovano M Le Pira A et al Acute disseminated encephalo-myelitis a long-term prospective study and meta-analysis Neuropediatrics 201041(6)246-255

19 Iype M Kunju PAM Saradakutty G Anish TS Sreedharan M Ahamed SM Shortterm outcome of ADEM results from a retrospective cohort study from South IndiaMult Scler Relat Disord 201718128-134

20 Yamaguchi Y Torisu H Kira R et al A nationwide survey of pediatric acquireddemyelinating syndromes in Japan Neurology 201687(19)2006-2015

21 Arabi YMHarthi A Hussein J et al Severe neurologic syndrome associated withMiddleEast respiratory syndrome corona virus (MERS-CoV) Infection 201543(4)495-501

22 Ann YE Collins A Cohen M Duffner PK Faden H Detection of coronavirus in thecentral nervous system of a child with acute disseminated encephalomyelitis Pedi-atrics 2004133(1 pt 1)e73-e76

23 Yapici-Eser H Koroglu YE Oztop-Cakmak O Keskin O Gursoy A Gursoy-OzdemirY Neuropsychiatric symptoms of COVID-19 explained by SARS-CoV-2 proteinsrsquomimicry of human protein interactions Front Hum Neurosci 202115656313

24 Gammazza AM Legare S Bosco GL et al Molecular mimicry in the post-COVID-19signs and symptoms of neurovegetative disorders Lancet Microbe 20212(3)e94

25 Ludvigsson JF Systematic review of COVID-19 in children shows milder cases and abetter prognosis than adults Acta Paediatr 2020109(6)1088-1095

26 Hennes EM Baumann M Schanda K et al Prognostic relevance of MOG antibodiesin children with an acquired demyelinating syndrome Neurology 201789(9)900-908

27 Probstel AK Dornmair K Bittner R et al Antibodies to MOG are transient inchildhood acute disseminated encephalomyelitis Neurology 201177(6)580-588

28 Duignan S Wright S Rossor T et al Myelin oligodendrocyte glycoprotein andaquaporin-4 antibodies are highly specific in children with acquired demyelinatingsyndromes Dev Med Child Neurol 201860(9)958-962

29 Baumann M Sahin K Lechner C et al Clinical and neuroradiological differences ofpaediatric acute disseminating encephalomyelitis with and without antibodies to themyelin oligodendrocyte glycoprotein J Neurol Neurosurg Psychiatry 201586(3)265-272

30 Krishna Murthy SN Faden HS Cohen ME Bakshi R Acute disseminated enceph-alomyelitis in children Pediatrics 2002110(2)e1-e7

31 Hynson JL Kornberg AJ Coleman LT Shield L Harvey AS Kean MJ Clinical andneuroradiologic features of acute disseminated encephalomyelitis in children Neu-rology 200156(10)1308-1312

32 Dale RC de Sousa C Chong WK Cox TCS Harding B Neville BGR Acute dis-seminated encephalomyelitis multiphasic disseminated encephalomyelitis and mul-tiple sclerosis in children Brain 2000123(pt 12)2407-2422

33 Tenembaum S Chamoles N Fejerman N Acute disseminated encephalomyelitis along-term follow-up study of 84 pediatric patients Neurology 200259(8)1224-1231

34 Varga Z Flammer AJ Steiger P et al Endothelial cell infection and endotheliitis inCOVID-19 Lancet 2020395(10234)1417-1418

35 Monteil V Kwon H Prado P et al Inhibition of SARS-CoV-2 infections in engi-neered human tissues using clinical-grade soluble human ACE2 Cell 2020181(4)905-913e7

36 Pons S Fodil S Azoulay E Zafrani L The vascular endothelium the cornerstone oforgan dysfunction in severe SARS-CoV-2 infection Crit Care 202024(1)353

37 Lin CH Jeng JS Hsieh ST Yip PK Wu RM Acute disseminated encephalomyelitis afollow-up study in Taiwan J Neurol Neurosurg Psychiatry 200778(2)162-167

38 Coronavirus Disease (COVID-19) Situation Report 132 World Health Organizationwhointemergenciesdiseasesnovel-coronavirus-2019situation-reports (accessed18 May 2021)

39 COVID-19 Weekly Epidemiological Update World Health Organization whointpublicationsmitemweekly-epidemiological-update-on-covid-19mdash11-may-2021(accessed 18 May 2021)

40 Koh JS de Silva DA Quek AML et al Neurology of COVID-19 in Singapore J NeurolSci 2020418117118


DOI 101212NXI000000000000108020218 Neurol Neuroimmunol Neuroinflamm

Giovanna S Manzano Caleb R S McEntire Maria Martinez-Lage et al Following COVID-19 Systematic Review and Meta-synthesis

Acute Disseminated Encephalomyelitis and Acute Hemorrhagic Leukoencephalitis

This information is current as of August 27 2021

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Academy of Neurology All rights reserved Online ISSN 2332-7812Copyright copy 2021 The Author(s) Published by Wolters Kluwer Health Inc on behalf of the AmericanPublished since April 2014 it is an open-access online-only continuous publication journal Copyright

is an official journal of the American Academy of NeurologyNeurol Neuroimmunol Neuroinflamm

neurologic outcomes including a high mortality rate Findings are limited by nonstandardized reporting of cases truncatedfollow-up information and presumed publication bias

Acute disseminated encephalomyelitis (ADEM) is an in-flammatory demyelinating disease of the CNS characterizedby fulminant multifocal neurologic injury and distinct neu-ropathologic findings1 ADEM is classically thought to bepreceded by vaccination or a systemic infection of whichupper respiratory tract infections are most commonly repor-ted2 Given that ADEM is more common in children con-sensus criteria for clinically diagnosing ADEM exist forchildren only1 In the absence of a biomarker the diagnosis ofADEM is largely reliant on the clinical presentation supportedby typical MRI findings and the exclusion of competing di-agnoses through ancillary testing Most ADEM cases areclinically monophasic but a small number are recurrent orsubsequently realized to be the initial presentation of a re-lapsing CNS demyelinating disease such as MS myelin oli-godendrocyte glycoprotein antibody disease or neuromyelitisoptica spectrum disorder2

Since the onset of the coronavirus (COVID-19) pandemic inNovember 2019 neurologic complications of SARS-CoV-2infection are increasingly recognized Parainfectious neuro-logic injury is well described and ageusia and anosmia arecomponents of the primary constellation of symptoms andcan be early signs of infection34 Headache delirium anddizziness are also common clinical accompaniments56 Theneuroinflammatory events following COVID-19 particularlyADEM and its severe variant acute hemorrhagic leukoence-phalitis (AHLE and Weston-Hurst disease) occur rarely andhave yet to be synthesized in the literature Most publishedreports are single cases or small case series However theglobal clinical experience on ADEM and AHLE in the settingof COVID-19 appears to be growing

In this case series and systematic literature review we reportthe collective experience of ADEM and AHLE followingCOVID-19 We characterize the disease course diagnostictest findings patient outcomes and treatment approaches ofboth COVID-19 and the subsequent presentations of ADEMand AHLE Given the novelty of this virus and the ongoingnature of the global pandemic we address the available datafor the phenotypic presentations of ADEM and AHLE therelationship to COVID-19 disease factors and highlight issuesfor future research data gathering and clinical care Finallywe consider whether COVID-associated ADEM and AHLEcases differ from their counterparts that predated the pandemic

MethodsOverviewWe performed a systematic review for cases of postndashCOVID-19 ADEM and AHLE in the medical literature adding casesevaluated at our institution The Massachusetts GeneralBrigham (MGB) Institutional Review Board approved thestudy

Information SourcesCases were principally obtained by systematically searchingPubMed Four cases originating from the MGB health caresystem were included in the final synthesis of individual cases

Search Strategy and Screening ProcessWe searched pubmedgov on May 17 2021 for cases ofCOVID-19 followed by ADEM or AHLE The followingsearch strategy was used [coronavirus disease OR coronavi-rus OR COVID OR COVID-19 OR SARS-CoV OR SARS-CoV-2] AND [acute disseminated encephalomyelitis ORADEMOR acute hemorrhagic leukoencephalitis OR AHLE]A time filter of reports published between December 1 2019and May 17 2021 was applied no further restrictions wereplaced on the search results Article titles and abstracts in-dicating a possible central neuroinflammatory relationship toCOVID-19 were included for a more detailed review of thefull-text article One neurologist author with neuro-immunology subspecialty expertise (SKH) screened theinitial search results without the assistance of automation Ofthe 435 results 46 articles were further reviewed by at least 2authors with neurology training (GSM CRM andSKH) with a third neuroimmunologist reviewer available toadjudicate disagreements (FJM) A total of 26 articles wereretained

Criteria for Case Selection

Inclusion CriteriaPatients of any age with a history of COVID-19 infection wereincluded in the study if their case descriptions provided suf-ficient details to confirm a clinical diagnosis of ADEM orAHLE ADEM was defined as a first multifocal event of ful-minant CNS demyelination supported either histopatholog-ically or radiographically by white matter lesions consistentwith demyelination Encephalopathy was not required forinclusion in line with multiple studies suggesting its lower

GlossaryADEM = acute disseminated encephalomyelitis AHLE = acute hemorrhagic leukoencephalitis IPMSSG = InternationalPediatric Multiple Sclerosis Study Group IVIG = IV immunoglobulin MGB = Massachusetts General Brigham mRS =modified Rankin Scale OCB = oligoclonal band

























0ndash10 5 (11)

11ndash20 1 (2)

21ndash30 5 (11)

31ndash40 5 (11)

41ndash50 7 (15)

51ndash60 15 (33)

gt60 6 (13)

Unspecified 2 (4)

Sex

Female 17 (37)

Male 28 (61)

Unspecified 1 (2)

















Phenotype n ()

ADEM 31 (67)

AHLE 15 (33)


0ndash7 5 (11)

8ndash14 7 (15)

15ndash30 9 (20)

31ndash60 3 (7)









Seizure 5 (11)

Aphasia 2 (4)







Brainstem 4 (9)



1 2 (4)

2 1 (2)

3 4 (9)

4 5 (11)

5 29 (63)

6 4 (9)















Positive 015 (0)

Absent 1515 (100)

CSF pleocytosis

Present 1237 (32)

Absent 2437 (65)


CSF protein

Elevated 1937 (51)

Normal 1737 (46)


CSF IgG index

Elevated 25 (40)

Normal 35 (60)

CSF OCB

Present 525 (20)

Absent 2025 (80)






Enhancement



Hemorrhage


Spinal cord 024 (0)
























ADEM treatment

Treatment n ()

Not reported 5 (11)






IVIG monotherapy 2


Plasmapheresis 4

Rituximab 1

Ocrelizumab 1

Cyclophosphamide 1


Mannitol 1



1ndash30 7 (15)

31ndash60 5 (11)

gt60 5 (11)

Deceased 9 (20)


Final mRS score

0 3 (7)

1 2 (4)

2 4 (9)

3 1 (2)

4 6 (13)

5 3 (7)

6 (deceased) 9 (20)




























Appendix Authors


Giovanna SManzanoMD



Caleb R SMcEntireMD









Spencer KHutto MD












































Reprints



























0ndash10 5 (11)

11ndash20 1 (2)

21ndash30 5 (11)

31ndash40 5 (11)

41ndash50 7 (15)

51ndash60 15 (33)

gt60 6 (13)

Unspecified 2 (4)

Sex

Female 17 (37)

Male 28 (61)

Unspecified 1 (2)

















Phenotype n ()

ADEM 31 (67)

AHLE 15 (33)


0ndash7 5 (11)

8ndash14 7 (15)

15ndash30 9 (20)

31ndash60 3 (7)









Seizure 5 (11)

Aphasia 2 (4)







Brainstem 4 (9)



1 2 (4)

2 1 (2)

3 4 (9)

4 5 (11)

5 29 (63)

6 4 (9)















Positive 015 (0)

Absent 1515 (100)

CSF pleocytosis

Present 1237 (32)

Absent 2437 (65)


CSF protein

Elevated 1937 (51)

Normal 1737 (46)


CSF IgG index

Elevated 25 (40)

Normal 35 (60)

CSF OCB

Present 525 (20)

Absent 2025 (80)






Enhancement



Hemorrhage


Spinal cord 024 (0)
























ADEM treatment

Treatment n ()

Not reported 5 (11)






IVIG monotherapy 2


Plasmapheresis 4

Rituximab 1

Ocrelizumab 1

Cyclophosphamide 1


Mannitol 1



1ndash30 7 (15)

31ndash60 5 (11)

gt60 5 (11)

Deceased 9 (20)


Final mRS score

0 3 (7)

1 2 (4)

2 4 (9)

3 1 (2)

4 6 (13)

5 3 (7)

6 (deceased) 9 (20)




























Appendix Authors


Giovanna SManzanoMD



Caleb R SMcEntireMD









Spencer KHutto MD












































Reprints















0ndash10 5 (11)

11ndash20 1 (2)

21ndash30 5 (11)

31ndash40 5 (11)

41ndash50 7 (15)

51ndash60 15 (33)

gt60 6 (13)

Unspecified 2 (4)

Sex

Female 17 (37)

Male 28 (61)

Unspecified 1 (2)

















Phenotype n ()

ADEM 31 (67)

AHLE 15 (33)


0ndash7 5 (11)

8ndash14 7 (15)

15ndash30 9 (20)

31ndash60 3 (7)









Seizure 5 (11)

Aphasia 2 (4)







Brainstem 4 (9)



1 2 (4)

2 1 (2)

3 4 (9)

4 5 (11)

5 29 (63)

6 4 (9)















Positive 015 (0)

Absent 1515 (100)

CSF pleocytosis

Present 1237 (32)

Absent 2437 (65)


CSF protein

Elevated 1937 (51)

Normal 1737 (46)


CSF IgG index

Elevated 25 (40)

Normal 35 (60)

CSF OCB

Present 525 (20)

Absent 2025 (80)






Enhancement



Hemorrhage


Spinal cord 024 (0)
























ADEM treatment

Treatment n ()

Not reported 5 (11)






IVIG monotherapy 2


Plasmapheresis 4

Rituximab 1

Ocrelizumab 1

Cyclophosphamide 1


Mannitol 1



1ndash30 7 (15)

31ndash60 5 (11)

gt60 5 (11)

Deceased 9 (20)


Final mRS score

0 3 (7)

1 2 (4)

2 4 (9)

3 1 (2)

4 6 (13)

5 3 (7)

6 (deceased) 9 (20)




























Appendix Authors


Giovanna SManzanoMD



Caleb R SMcEntireMD









Spencer KHutto MD












































Reprints









0ndash10 5 (11)

11ndash20 1 (2)

21ndash30 5 (11)

31ndash40 5 (11)

41ndash50 7 (15)

51ndash60 15 (33)

gt60 6 (13)

Unspecified 2 (4)

Sex

Female 17 (37)

Male 28 (61)

Unspecified 1 (2)

















Phenotype n ()

ADEM 31 (67)

AHLE 15 (33)


0ndash7 5 (11)

8ndash14 7 (15)

15ndash30 9 (20)

31ndash60 3 (7)









Seizure 5 (11)

Aphasia 2 (4)







Brainstem 4 (9)



1 2 (4)

2 1 (2)

3 4 (9)

4 5 (11)

5 29 (63)

6 4 (9)















Positive 015 (0)

Absent 1515 (100)

CSF pleocytosis

Present 1237 (32)

Absent 2437 (65)


CSF protein

Elevated 1937 (51)

Normal 1737 (46)


CSF IgG index

Elevated 25 (40)

Normal 35 (60)

CSF OCB

Present 525 (20)

Absent 2025 (80)






Enhancement



Hemorrhage


Spinal cord 024 (0)
























ADEM treatment

Treatment n ()

Not reported 5 (11)






IVIG monotherapy 2


Plasmapheresis 4

Rituximab 1

Ocrelizumab 1

Cyclophosphamide 1


Mannitol 1



1ndash30 7 (15)

31ndash60 5 (11)

gt60 5 (11)

Deceased 9 (20)


Final mRS score

0 3 (7)

1 2 (4)

2 4 (9)

3 1 (2)

4 6 (13)

5 3 (7)

6 (deceased) 9 (20)




























Appendix Authors


Giovanna SManzanoMD



Caleb R SMcEntireMD









Spencer KHutto MD












































Reprints















Positive 015 (0)

Absent 1515 (100)

CSF pleocytosis

Present 1237 (32)

Absent 2437 (65)


CSF protein

Elevated 1937 (51)

Normal 1737 (46)


CSF IgG index

Elevated 25 (40)

Normal 35 (60)

CSF OCB

Present 525 (20)

Absent 2025 (80)






Enhancement



Hemorrhage


Spinal cord 024 (0)
























ADEM treatment

Treatment n ()

Not reported 5 (11)






IVIG monotherapy 2


Plasmapheresis 4

Rituximab 1

Ocrelizumab 1

Cyclophosphamide 1


Mannitol 1



1ndash30 7 (15)

31ndash60 5 (11)

gt60 5 (11)

Deceased 9 (20)


Final mRS score

0 3 (7)

1 2 (4)

2 4 (9)

3 1 (2)

4 6 (13)

5 3 (7)

6 (deceased) 9 (20)




























Appendix Authors


Giovanna SManzanoMD



Caleb R SMcEntireMD









Spencer KHutto MD












































Reprints

























ADEM treatment

Treatment n ()

Not reported 5 (11)






IVIG monotherapy 2


Plasmapheresis 4

Rituximab 1

Ocrelizumab 1

Cyclophosphamide 1


Mannitol 1



1ndash30 7 (15)

31ndash60 5 (11)

gt60 5 (11)

Deceased 9 (20)


Final mRS score

0 3 (7)

1 2 (4)

2 4 (9)

3 1 (2)

4 6 (13)

5 3 (7)

6 (deceased) 9 (20)




























Appendix Authors


Giovanna SManzanoMD



Caleb R SMcEntireMD









Spencer KHutto MD












































Reprints



















ADEM treatment

Treatment n ()

Not reported 5 (11)






IVIG monotherapy 2


Plasmapheresis 4

Rituximab 1

Ocrelizumab 1

Cyclophosphamide 1


Mannitol 1



1ndash30 7 (15)

31ndash60 5 (11)

gt60 5 (11)

Deceased 9 (20)


Final mRS score

0 3 (7)

1 2 (4)

2 4 (9)

3 1 (2)

4 6 (13)

5 3 (7)

6 (deceased) 9 (20)




























Appendix Authors


Giovanna SManzanoMD



Caleb R SMcEntireMD









Spencer KHutto MD












































Reprints









ADEM treatment

Treatment n ()

Not reported 5 (11)






IVIG monotherapy 2


Plasmapheresis 4

Rituximab 1

Ocrelizumab 1

Cyclophosphamide 1


Mannitol 1



1ndash30 7 (15)

31ndash60 5 (11)

gt60 5 (11)

Deceased 9 (20)


Final mRS score

0 3 (7)

1 2 (4)

2 4 (9)

3 1 (2)

4 6 (13)

5 3 (7)

6 (deceased) 9 (20)




























Appendix Authors


Giovanna SManzanoMD



Caleb R SMcEntireMD









Spencer KHutto MD












































Reprints
























Appendix Authors


Giovanna SManzanoMD



Caleb R SMcEntireMD









Spencer KHutto MD












































Reprints












































Reprints
















Reprints




Documents

Acute Disseminated Encephalomyelitis and Acute Hemorrhagic