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DOI: 10.1212/01.wnl.0000259404.51352.7f 2007;68;S23-S36 Neurology

Pediatric MS Study Group Silvia Tenembaum, Tanuja Chitnis, Jayne Ness, Jin S. Hahn and for the International

Acute disseminated encephalomyelitis

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Acute disseminated encephalomyelitisSilvia Tenembaum, MD; Tanuja Chitnis, MD; Jayne Ness, MD, PhD; and Jin S. Hahn, MD;

for the International Pediatric MS Study Group*

Abstract—Acute disseminated encephalomyelitis (ADEM) is an immune-mediated inflammatory disorder of the CNScharacterized by a widespread demyelination that predominantly involves the white matter of the brain and spinal cord.The condition is usually precipitated by a viral infection or vaccination. The presenting features include an acuteencephalopathy with multifocal neurologic signs and deficits. Children are preferentially affected. In the absence ofspecific biologic markers, the diagnosis of ADEM is still based on the clinical and radiologic features. Although ADEMusually has a monophasic course, recurrent or multiphasic forms have been reported, raising diagnostic difficulties indistinguishing these cases from multiple sclerosis (MS). The International Pediatric MS Study Group proposes uniformdefinitions for ADEM and its variants. We discuss some of the difficulties in the interpretation of available literature dueto the different terms and definitions used. In addition, this review summarizes current knowledge of the main aspects ofADEM, including its clinical and radiologic diagnostic features, epidemiology, pathogenesis, and outcome. An overview ofADEM treatment in children is provided. Finally, the controversies surrounding pediatric MS and ADEM are addressed.

NEUROLOGY 2007;68(Suppl 2):S23–S36

Acute disseminated encephalomyelitis (ADEM) is animmune-mediated inflammatory disorder of theCNS, which is commonly preceded by an infection,and predominantly affects the white matter of thebrain and spinal cord.1-4 Several terms can be foundin the literature to describe patients with ADEM,reflecting the more prominent aspects of the disease:

“Postinfectious or postvaccinial encephalomyelitis,postinfectious multifocal encephalitis,” when the trig-gering events were considered.

“Acute perivascular myelinoclasia, perivenous en-cephalitis, disseminated vasculomyelinopathy,” whenemphasizing the histopathologic features and distri-bution of lesions.

“Acute demyelinating encephalomyelitis, hyperergicencephalomyelitis, postvaccinal perivenous encephali-tis, postencephalitis demyelination,” relating to theprobable immunopathogenetic mechanism.5-16

Based on our current clinicopathologic under-standing of the disease, ADEM is probably the mostappropriate nosologic designation, as the precipitat-ing event may be absent and the pathogenesis of thedisease is unclear.

In the absence of specific biologic markers, thediagnosis of ADEM is based on the clinical and ra-diologic features. Although ADEM usually has amonophasic course, recurrent or multiphasic formshave been reported, raising diagnostic difficulties indistinguishing these cases from multiple sclerosis(MS). This article reviews what we currently knowabout ADEM, including diagnostic features, patho-

genesis, treatment, and outcomes, and includes aproposed definition of this disorder.

Epidemiology. ADEM can occur at any age, but itis more common in pediatric patients than in adults.Rare cases in older adults have been reported,17 al-though careful exclusion of other diseases should beapplied in these cases. The diagnosis is often madein the setting of a defined viral illness or vaccination.Although there appears to be no gender predomi-nance in ADEM,18,19 a male predominance has beendescribed in two pediatric cohorts, with reported fe-male:male ratios of 0.620 and 0.8.21 as opposed to a2:1 female preponderance frequently described forMS. The mean age at presentation in childrenranges from 5 to 8 years.21-23

A seasonal distribution in the winter and springmonths has been found in studies conducted in theUnited States.19,20 A recent study conducted in SanDiego County, CA, estimated the mean incidence ofADEM as 0.4/100,000/year among persons less than20 years of age living in that region.19 Five percent ofthese patients had received a vaccination within 1month prior to the ADEM event, and 93% reportedsigns of infection in the preceding 21 days. There areno clear studies of worldwide distributions of ADEM.Some regional cases are linked to specific vaccines,as in the case of the Semple rabies vaccine, smallpoxvaccine, and older forms of the measles vaccine.

Clinical presentation. ADEM is classically de-scribed as a monophasic disorder which typically be-

*Members of the International Pediatric MS Study Group are listed in the Appendix.From the Department of Pediatric Neurology (S.T.), National Pediatric Hospital, Dr. J.P. Garrahan, Buenos Aires, Argentina; Massachusetts GeneralHospital for Children (T.C.), Brigham & Women’s Hospital, Harvard Medical School, Boston; Department of Pediatrics (J.N.), University of Alabama atBirmingham and Children’s Hospital of Alabama; and Pediatric Neurology Division (J.H.), Stanford University Medical Center, CA.Disclosure: The authors report no conflicts of interest.Address correspondence and reprint requests to Dr. Silvia Tenembaum, Pediatric Neurologist, Pediatric Multiple Sclerosis Clinic, Department of Neurology,National Pediatric Hospital “Dr. J. P. Garrahan,” Buenos Aires, Argentina; e-mail: [email protected], [email protected]

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gins within 2 days to 4 weeks after an antigenicchallenge. Approximately 70 to 77% of patients re-port a clinically evident antecedent infection or vac-cination during the prior few weeks.21,22,24 The typicalsymptoms and signs of ADEM include a rapid onsetencephalopathy associated with a combination of mul-tifocal neurologic deficits. A prodromal phase with fe-ver, malaise, headache, nausea, and vomiting may beobserved shortly before the development of meningealsigns and drowsiness. The clinical course is rapidlyprogressive and usually develops over hours to maxi-mum deficits within days (mean, 4.5 days).21

The initial neurologic features are determined bythe location of the lesions within the CNS. Table 1summarizes the demographic distribution and pre-senting features in recently published case studies ofpatients with ADEM. Frequent neurologic symptomsand signs described in various combinations includeunilateral or bilateral pyramidal signs (60 to 95%),acute hemiplegia (76%), ataxia (18 to 65%), cranialnerve palsies (22 to 45%), visual loss due to opticneuritis (7 to 23%), seizures (13 to 35%), spinal cordinvolvement (24%), impairment of speech (slow,slurred, or aphasia) (5 to 21%), and hemiparesthesia(2 to 3%), with invariable involvement of mental sta-tus, ranging from lethargy to coma.19-23 Although cer-tain signs and symptoms may be observed in bothpediatric and adult cases, such as changes in mental

status, ataxia, motor deficits, and brainstem involve-ment, other features appear to be age related.25

Long-lasting fever22 and headaches19,21-23,26 occurmore frequently in children with ADEM, while sen-sory deficits predominate in adult patients.17 Sei-zures are rarely observed in adult patients withADEM,17 and are mainly seen in children youngerthan 5 years. One study has documented prolongedfocal motor seizures in 70% of the younger patients,with 82% of these patients going on to statusepilepticus.21

Peripheral nervous system (PNS) syndromes suchas acute polyradiculoneuropathy24,27,28 may occur inADEM but are considered rare in childhood ADEMcases. The combination of PNS and CNS featuresmay be more common in adults and was noted in43.6% of one cohort of adult patients.29

There is a wide variation in the severity of theillness. Occasionally, ADEM can present as a subtledisease, with nonspecific irritability, headache, andsomnolence, or may show a rapid progression ofsymptoms and signs to coma and decerebrate rigidi-ty.30 Respiratory failure secondary to brainstem in-volvement or severely impaired consciousness occursin 11% to 16% of cases.21,30

MRI features. Neuroimaging is extremely impor-tant in establishing the diagnosis of ADEM. MRI

Table 1 Demographic characteristics, presenting features, and outcome findings from published ADEM series between 2000 and 2004

Murthyet al.,20

USA,2002,

n � 18

Daleet al.,18

England,2000,

n � 35

Hynsonet al.,22

Australia,2001,

n � 31

Hunget al.,51

Taiwan,2001,

n � 52*

Tenembaumet al.,21

Argentina,2002,

n � 84

Gupteet al.,26

England,2003,

n � 18

Mikaeloffet al.,39

France,2004,

n � 119†

Idrissovaet al.,107

Russia,2003,

n � 90‡

Leakeet al.,19

USA,2004,

n � 42§

Anlaret al.,23

Turkey,2003,

n � 46

Mean age, y (range) 7.5 (2.5–22) 7.4 � 0.65(3–15)

5.9 (2–16) 6.7(0.7–16)

5.3�3.9(0.4–16)

8.6 � 1.2(2.5–16)

7.1 �4.3¶(0.7–16)

9.8 � 0.5(2–16)

6.5 (0.8–18) 8 (1–15)

Male, % 61 54 42 56 64 61 56¶ 54 57 63

Mean follow-up, y (range) 1.8 (0.2–5) 5.8 � 0.8(1–15)

1.5 �1.5 6.6 (1–19) 1.2 � 0.2(0.25–4)

2.9 �3(0.5–14.9)

Mean NR(1–5)

Mean NR(1–5)

Mean NR(1–12)

Preceding illness, % 72 74 71 100 74 50 51¶ 100 93 46

Altered mental status, % 45 69 74 72 69 33 75¶ 44 66 46

Ataxia/cerebellar, % NR 51 65 4 50 50 NR 52 50 28

CN deficits (includes vision), % 23 89 45 13 44 50 55¶ 24 �50 28

Seizures, % 17 17 13 47 35 11 NR 34 19 10

Full recovery, % 72 57 81 71 89 61 92 43–70‡ 86 (2 deaths) 64

Residual focal neurologic deficits, % 16 29 13 8 11 22 NR 4 10 30

Behavior or cognitive problems, % NR 20 6 15 4 11 NR 15 50 10

Recurrent or multiphasic course, % 6 20 13 2 10 11 29† 12 29 (7 MS) 33

* Hung et al. (2001) separated postinfectious encephalomyelitis (n � 38) from ADEM (n � 13) based on the number of MRI lesions, at least three forADEM. No difference in mental status, though 70% in both groups.

† Mikaeloff et al. (2004) initially gave the diagnosis of ADEM to 119 patients (out of 296 with demyelinating event) but reclassified all of them as MS ifany recurrence. As some patients may be considered multiphasic ADEM, we kept the original 119 in analysis. However, in table 1, “¶” provides datafrom only the 85 monophasic cases.

‡ In the series of Idrissova et al., MRI was only performed in the 14 children with more severe clinical course. They reported full recovery only if no fa-tigue was present. However, neurologic disability was identified by telephone contact.

§ Leake et al. (2004) reclassified as MS 7% of the relapsing forms of ADEM.

ADEM � acute disseminated encephalomyelitis; NR � not reported; MS � multiple sclerosis.

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abnormalities are most frequently identified on T2-weighted and fluid-attenuated inversion recovery(FLAIR) sequences as patchy, poorly marginated ar-eas of increased signal intensity. Lesions in ADEMare typically large, multiple, and asymmetric. Theytypically involve the subcortical and central whitematter and cortical gray-white junction of both cere-bral hemispheres, cerebellum, brainstem, and spinalcord.30 The gray matter of the thalami and basalganglia are frequently involved, typically in a sym-metric pattern.21,31 The periventricular white matteris also frequently involved, being described in 30 to60% of cases.20,22,30 Lesions confined to the corpuscallosum are less common. However, large demyeli-nating lesions of the adjacent white matter may ex-tend into the corpus callosum and cross into thecontralateral hemisphere.

Four patterns of cerebral involvement have beenproposed to describe the MRI findings in ADEM21: 1)ADEM with small lesions (less than 5 mm; figure 1);2) ADEM with large, confluent, or tumefactive le-sions, with frequent extensive perilesional edemaand mass effect (figure 2); 3) ADEM with additionalsymmetric bithalamic involvement (figure 3); and 4)acute hemorrhagic encephalomyelitis (AHEM), whensome evidence of hemorrhage can be identified in thelarge demyelinating lesions (figure 4). The MRI pat-tern does not appear to correlate with any particularoutcome or disability, as observed in a large pediat-ric cohort,21 since most lesions tend to resolve onfollow-up imaging studies.21,32 However, this classifi-cation may be useful when considering the differen-tial diagnosis of ADEM and may potentially help toidentify those children for whom the initial ADEM-phenotype is really the first manifestation of MS.

The incidence of gadolinium enhancing lesions onT1-weighted sequences is quite variable in ADEMand may depend on the stage of inflammation.31,33,34

Gadolinium enhancing lesions have been describedin 30 to 100% of patients.21,35,36 The pattern of en-hancement is variable; complete or incomplete ring-

shaped (figure 5), nodular, gyral, or spotty patternshave been described.36-38 Meningeal enhancement ofthe brain or spinal cord is unusual.

Spinal cord involvement in ADEM has been de-scribed in 11 to 28%.18,21-23,39 The typical spinal cordlesion is large and swollen, showing variable en-hancement, and predominantly affects the thoracicregion.

Sequential MRI scanning during the follow-up pe-riod plays an important role in establishing the diag-nosis of ADEM. Monophasic ADEM is not associatedwith the development of new lesions. Completeresolution of MRI abnormalities after treatmenthas been described in 37 to 75% of patients withADEM, and partial resolution in 25 to 53% of

Figure 1. Acute disseminated encepha-lomyelitis with small lesions. (A) AxialT2-weighted MRI showing bilateral,poorly marginated hyperintense lesionsin central, periventricular, and juxta-cortical white matter, (B) also involvingboth thalami and internal capsules, ina 17-month-old boy, 2 weeks after mea-sles vaccination.

Figure 2. Acute disseminated encephalomyelitis with tu-mefactive lesions. Axial T2-weighted image demonstratingextensive, tumefactive, and bihemispheric lesions withperilesional edema, in a 13-year-old boy.

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patients.18,21,24,33,35 Resolution of MRI abnormalitieswithin 6 months has been positively associated witha final diagnosis of ADEM in one study.40 There areno clear criteria documenting how long to continue toimage patients with one ADEM event. However, theauthors suggest reassessing the patient with at leasttwo additional MRI studies after the first normalMRI, over a period of 5 years from the initial episode,as the appropriate way to confirm the absence ofongoing accrual of lesions.

Advanced neuroimaging techniques. Low lev-els of N-acetylaspartate (NAA) and elevated lactatelevels within regions of prolonged T2-MRI signal,without increase in choline, have been observed withquantitative proton MR spectroscopy during theacute stages of ADEM.41,42 These abnormal signalsresolved after normalization of clinical and MRI find-ings. Diffusion and perfusion weighted MRI show adiffusion pattern with reduced, normal, or increaseddiffusion coefficients, or reduced or normal perfusionwithin ADEM lesions.43,44 A global and bilateral de-creased cerebral metabolism has been demonstratedby PET scanning in a case where CT scan had onlyshowed a focal demyelinating lesion.45

SPECT using 99m Tc-HMPAO has consistentlyshown areas of hypoperfusion that are more exten-sive than the MRI lesions.46-48 The time course ofSPECT abnormalities also reflects the clinical coursemore accurately than MRI. In spite of the resolution

of MRI lesions, SPECT with acetazolamide detectspersistent cerebral circulatory impairment that maycontribute to the neurocognitive and language defi-cits observed in some patients with ADEM.49,50

Monophasic and multiphasic ADEM. AlthoughADEM is classically described as a monophasic dis-order, several studies have described ADEM re-lapses, occurring at the following rates: 1/18 (5.5%),20

1/14 (7%),51 8/84 (10%),21 4/31 (13%),22 7/46 (15%),23

7/35 (20%),18 and 9/42 (21%).19 It should be notedthat different diagnostic criteria for relapses wereused in these different studies, which may in partaccount for the variability. In addition, the meanlength of follow-up reported in some of these ADEMseries varied considerably: 18 months,22 22 months,23

5.3 years,18 6.6 years,21 and again may contribute tothe interstudy variability.52

The final outcome of multiphasic ADEM has beendescribed in detail in two pediatric series with long-term follow-up.18,21 In one study, no long-term im-pairment was observed in 86% of multiphasic ADEMpatients.18 Similarly, eight children with multiphasicADEM, who remained relapse-free after a follow-upof 3 to 16 years (mean 8.2 years), had a medianEDSS score of 1 (range 0 to 2.5).21 Serial brain-spinalMRI performed in these patients revealed completeor almost complete resolution of demyelinating le-sions without evidence of new active lesions.

Acute hemorrhagic leukoencephalitis. Acutehemorrhagic leukoencephalitis (AHL), AHEM, andacute necrotizing hemorrhagic leukoencephalitis(ANHLE) of Weston Hurst are variants of an acute,rapidly progressive, and frequently fulminant in-flammatory hemorrhagic demyelination of CNSwhite matter. It is usually triggered by upper respi-ratory tract infections. Death from brain edema iscommon within 1 week of onset of the encephalopa-thy, but increasing evidence of favorable neurologicoutcomes has been published with early and aggres-sive treatment using various combinations of cortico-steroids, immunoglobulin, cyclophosphamide, andplasma exchange.21,53-55

AHL, AHEM, and ANHLE are considered hyper-acute subforms of ADEM and were observed in 2% ofchildren in a large cohort.21 Lesions on MRI tend tobe large, with perilesional edema and mass effect.56,57

Diffusion-weighted imaging disclosing areas of re-stricted diffusion in the affected areas of the brainhas been recently published,57 and this finding mightbe due to acute vasculitis with subsequent vesselocclusion in AHL.

Controversies in diagnosis based on publishedstudies: Rationale for proposed definitions.ADEM should be adequately defined and distin-guished from other diseases affecting the white mat-ter. In particular, a diagnostic challenge lies indistinguishing multiphasic forms of ADEM from MS.This is especially important, not only for prognostic

Figure 3. Acute disseminated encephalomyelitis withbithalamic involvement. Axial T2-weighted MRI showingsymmetric increased signal in both thalami, with addi-tional involvement of the insula and subcortical whitematter, in an 18-month-old boy, 3 weeks after havingmumps.



purposes, but for therapeutic purposes, since a diag-nosis of MS, at least in adult patients, carries therecommendation for early treatment withimmunomodulators.

Historically, different definitions of ADEM havebeen used in published cases of pediatric and adultpatients.17-23,26,39,51 The lack of a uniform definitionand clear clinical and neuroimaging diagnostic crite-ria has led to the classification of other neurologicconditions as ADEM. Due to this lack of uniformity,it is difficult to compare neuroimaging aspects oroutcomes, establish prognostic factors, or comparepercentages of patients with ADEM that evolve intoMS. For example, the proportion of patients initiallydiagnosed with ADEM who go on to be diagnosedwith MS ranges from 9.5%19 to 27%.18 However, twochildren from a cohort of seven diagnosed with “mul-tiphasic ADEM” had monosymptomatic relapses—optic neuritis in one, and a brainstem syndrome inthe other—suggestive of MS.18 Conversely, a recentlypublished study applied the concept that “any second

Figure 4. Acute hemorrhagic encephalo-myelitis. (A) Axial T2-weighted MRIwith prominent bilateral hyperintenselesions, with areas of very low signal,corresponding to breakdown products ofhemoglobin, in a 5-month-old boy, 2weeks after pertussis vaccination. (B)Axial T1-weighted MRI of the samecase, showing spontaneous hyperintensesignal inside the large hypointenselesions.

Figure 5. Sagittal T1-weighted imaging demonstratingtwo lesions with open-ring enhancement in an 8-year-oldgirl, 1 week after an upper respiratory viral infection.



attack after an initial diagnosis of ADEM had to bereclassified as MS,”39 and reported a frequency ofsecond attacks as high as 29%. Thus, the use of auniform definition may help to distinguish ADEMfrom other lifelong demyelinating conditions andprovide a foundation for consistent prospective out-come studies. Nevertheless, the long-term outcomeand evidence of multiple recurrent demyelinatingevents are required conditions to clearly delineateMS from ADEM.

Unusual cases of ADEM have been described inpatients with demyelinating lesions confined to thebrainstem, when the presentation was more indica-tive of a clinical isolated syndrome (CIS) with brain-stem involvement or brainstem encephalitis.58-60 Acase of atypical acute disseminated encephalomyeli-tis is described in a 3-year-old girl, with a longitudi-nal lesion restricted to the spinal cord in the absenceof brain lesions, consistent with longitudinal myeli-tis.61 Unfortunately, the report does not provide im-aging of the brainstem to better explain the child’salteration of consciousness. A neurodegenerative pic-ture with progressive decline in mental and motorskills was reported in an 11-month-old baby follow-ing a meningoencephalitis.62 This infant was misdi-agnosed as having ADEM because the MRI showedsubtle areas of hyperintense signal in the frontal andparieto-occipital white matter that seemed to betransitional areas of myelination or delayed myelina-tion.63 A recent report describes a patient with recur-rent simple and complex partial seizures, who thenprogressed to intractable epilepsia partialis continuaand cognitive decline.64 Although this case repre-sented a classic picture of chronic Rasmussen’s en-cephalitis, because the patient started symptomsafter a viral illness and the initial MRI disclosedhyperintense lesions (although predominantly in-volving cortical and subcortical structures), a diagno-sis of ADEM was suspected. Furthermore, when theseizures recurred after 3 months from onset, the pa-tient was misdiagnosed with multiphasic ADEM.

A variety of terms and definitions have been usedto describe patients with ADEM who relapse. Recur-rent, relapsing, pseudorelapsing, bi- or multiphasicADEM have all been applied using different crite-ria18,21,65-74: time from the first event varies from lessthan 4 to more than 8 weeks; neurologic deficits aredefined as same or different; individuals are eithermonosymptomatic or polysymptomatic; and finallyMRI lesions are described as either in the same ordifferent areas.

ADEM definitions. To avoid misdiagnosis and de-velop a uniform classification, the International Pe-diatric MS Study Group (Study Group) proposes thatthe following three terms be applied to variations ofADEM (see Krupp et al.,74a in this conference report):

ADEM: A first clinical event with a polysymptom-atic encephalopathy, with acute or subacute onset,showing focal or multifocal hyperintense lesions pre-dominantly affecting the CNS white matter; no evi-

dence of previous destructive white matter changesshould be present; and no history of a previous clini-cal episode with features of a demyelinating event. Ifa relapse takes place within 4 weeks of taperingsteroid treatment or within the first 3 months fromthe initial event, this early relapse is consideredtemporally related to the same acute monophasiccondition and would replace the terms “steroid de-pendent ADEM” or “pseudorelapsing ADEM.”

Recurrent ADEM: New demyelinating event ful-filling diagnostic criteria for ADEM, occurring atleast 3 months after the initial ADEM event and atleast 4 weeks after completing steroid therapy, show-ing the same clinical presentation and affecting thesame areas on MRI as the initial ADEM episode.

Multiphasic ADEM: Refers to one or more ADEMrelapses, including encephalopathy and multifocaldeficits, but involving new areas of the CNS on MRIand neurologic examination. Relapses take place atleast 3 months after initial ADEM attack and atleast 4 weeks after completing steroid therapy.

Differential diagnosis. Acute encephalopathyand disseminated demyelination of the CNS in chil-dren represent a diagnostic challenge for pediatricclinicians and neurologists. Many inflammatory andnoninflammatory disorders may have a similar clini-cal and radiologic presentation and should be consid-ered in the diagnostic evaluation.

If an acute encephalopathy is suspected based onhistory and physical examination, the first priorityshould be to rule out an acute bacterial or viral infec-tion of CNS, and to start empiric antibacterial andantiviral treatment. A gadolinium-enhanced MRI ofthe brain and spinal cord (to better define the dis-ease burden) and a lumbar puncture should be per-formed as soon as possible. Evidence of aninflammatory process (CSF pleocytosis, elevatedCSF proteins and immunoglobulin index, gadoliniumenhancement on MRI) should be determined in addi-tion to screening for viral, bacterial, or fungal infec-tious agents (See “Differential diagnosis andevaluation of pediatric MS” in this conference reportfor complete outline of the workup for infectiouscauses of acute encephalopathy). In the absence ofclear evidence of an infectious cause, the neuroimag-ing findings should define the regional distributionof the demyelinating-inflammatory process.

Neuroimaging at the time of the initial event maybe useful in the diagnosis. When the MRI showslarge focal tumor-like lesions, one should considerbrain tumors, Shilder disease, Marburg variant ofMS, and brain abscess.75-77 An MRI pattern withsymmetric bithalamic involvement may be seen inchildren with acute necrotizing encephalopathy,deep cerebral venous thrombosis, hypernatremia,and extrapontine myelinolysis, as well as in childrenwith ADEM after Japanese B encephalitisvaccination.78-84 Basal ganglia involvement may beconsistent with organic aciduria, poststreptococcalADEM, or infantile bilateral striatal necrosis.85,86



The presence of complete ring-enhanced lesions inthe cerebral white matter is unusual in ADEM, andbrain abscess, tuberculomas, neurocysticercosis, tox-oplasmosis, and histoplasmosis should be excluded.36

The diagnosis of MS should be considered in casesof recurrent or multiphasic demyelination, and isdiscussed in detail later in this review.

Treatment and management. There is no stan-dard therapy for ADEM. Most treatment approacheshave employed some form of nonspecific immunosup-pressant therapy similar to that used for MS andother autoimmune diseases, including steroids, IVimmunoglobulin (IVIg), or plasmapheresis. Most ofthe data describing treatment for ADEM are derivedfrom case reports and small series. To date, therehave been no randomized, controlled trials for thetreatment of ADEM in either children or adults.

Steroids. Steroid treatment has been the mostwidely reported therapy for ADEM, typically at highdoses. However, there has been great variety in thespecific steroid formulations employed, routes of ad-ministration, dosing, and tapering regimens. Theearliest report describing steroid treatment forADEM was published in 1953 using ACTH.87 Laterreports in the pre-MRI era described successful useof prednisone, corticotropin, or dexamethasone withmarked improvement of symptoms in both adult andpediatric patients with ADEM.12,88 Several patientsin these reports had recurrence of their symptomswhen the steroid therapy was discontinued and im-proved when steroids were reinstituted.

Most pediatric groups describing their high dosesteroid treatment in detail have used IV methylpred-nisolone (10 to 30 mg/kg/day up to maximum dose of1 g/day) or dexamethasone (1 mg/kg) for 3 to 5days18,21,22,26,89,90 followed by oral steroid taper for 4 to6 weeks with full recovery reported in 50 to 80% ofpatients.18,21,22 In the only comparison of specific cor-ticosteroid regimens, methylprednisolone-treated pa-tients had significantly better outcome with respectto EDSS scores compared to those treated with IVdexamethasone.21 Outcome may also be influencedby the length of steroid taper since an increased riskof relapse has been reported with steroid taper of 3weeks or less.18,23

High-dose steroid treatment is not without risk.Gastric perforation and death due to gastrointestinalbleeding related to methylprednisolone treatment forADEM has been reported.91 Hyperglycemia, hypoka-lemia, high blood pressure, facial flushing, and mooddisorders have also been reported in association withhigh-dose corticosteroid treatment. It is advisable toprovide gastric ulcer prophylaxis while patients areon high dose steroids, in addition to a careful moni-toring of blood pressure, urine glucose, and serumpotassium.

Immunoglobulin. IVIg has been used successfullyin a variety of autoimmune diseases although its

effectiveness in MS is limited. There are multiplecase reports of IVIg being used successfully alone92,93

or in combination61 with corticosteroids in both pedi-atric and adult cases of ADEM, but there have beenno studies which have directly compared IVIg withsteroids, plasmapheresis, or other immunomodula-tory treatments. In some cases, IVIg was adminis-tered after failed IV pulse steroid therapy94-96 or incases of recurrent demyelination.68,70 Reported dos-ing for IVIg has been quite consistent, using a totaldose of 1 to 2 g/kg, administered either as a singledose or over 3 to 5 days. In general, IVIg is welltolerated in the pediatric population. There havebeen isolated case reports of repeated IVIg adminis-tration to treat recurrent episodes of demyelina-tion,97 although it is questionable whether thesecases were definitely MS.

Plasma exchange. The use of plasma exchange inADEM has been reported in only a small number ofcases, typically severe cases when steroid treatmenthas failed. A recent series98 examined the outcomefollowing plasma exchange for 59 patients with avariety of CNS demyelinating conditions, including10 cases of ADEM, and found that 40% of patients(including the ADEM group) had moderate tomarked improvement following plasma exchange. Inthis cohort, a mean number of seven exchanges wasperformed (range 2 to 20) although a breakdown bydemyelinating disease type was not given. In theliterature, there were reports of six pediatric ADEMcases treated with plasma exchange. Four of thesepatients were reported as having a completerecovery,99-101 one had a residual left hemiparesis,102

and the outcome for one patient was not described.103

Plasma exchange may serve to remove the autoan-tibodies that are presumably triggering the demyeli-nation in ADEM, but may also shift the dynamics ofB- and T-cell interaction within the immune system.There is some evidence from case reviews thatplasma exchange may be more effective when givenearly in the disease course.104 However, due to theneed for trained personnel with specialized equip-ment and central venous access for multiple treat-ments over a period of days to weeks, plasmaexchange has often been used as a last resort. Symp-tomatic hypotension, severe anemia, and heparin-associated thrombocytopenia have been described inassociation with plasma exchange.98 The role andtiming of this intensive treatment for ADEM de-serves further investigation; however, for the fore-seeable future plasma exchange will likely continueto be used as a rescue therapy in ADEM when othermodalities fail.

Other therapies. To our knowledge, there havebeen no published reports of interferon-� or glati-ramer acetate used in the acute stage of ADEM al-though there are anecdotal descriptions ofinterferon-� use for episodes of recurrent demyelina-tion consistent with multiphasic ADEM. Some



improvement has been reported with cyclophospha-mide use in adult ADEM patients who respondedpoorly to methylprednisolone,17 but we are unawareof any published reports of cyclophosphamide, aza-thioprine, or other cytostatic drug use in pediatricADEM.

Outcome and prognosis. Untreated ADEM.Limited data exist about the natural history ofADEM in the post-MRI era. In the available casestudies, there is considerable diversity with respectto antecedent infections, clinical presentation, andneuroimaging findings, further complicating out-comes analysis. Classification of recurrence is a ma-jor inconsistency as there is considerabledisagreement about when to classify recurrent demy-elination as multiphasic ADEM vs defining all recur-rent demyelination as MS. Case series from Japan,105

India,106 and Russia107 suggest that the natural his-tory of ADEM in most children is one of gradualimprovement over several weeks, with 50 to 70% ofpatients experiencing full recovery. Improvement inserial MRIs was also shown in seven Japanese pa-tients with untreated postinfectious encephalitis, al-though three patients had residual lesions on MRI.105

Seven of 21 patients with partial recovery in theSouth India group106 had more extensive white mat-ter lesions compared to MRIs of children withcomplete recovery. No other factors, including ante-cedent infections, correlated with outcome.

In contrast, the Moscow group stratified 90 pedi-atric ADEM patients with respect to antecedent in-fections (33% rubella, 29% varicella, 22% withunknown viral antecedent) and recurrence (11%were classified as multiphasic ADEM, most with pre-ceding upper respiratory symptoms). Diagnosis wasbased on clinical symptoms following a prior viralinfection. MRI was routinely obtained only in themultiphasic group. Outcome varied with antecedentinfections with a good outcome reported in 70% ofthe ADEM cases without definite infection vs 54%and 43% normal outcome reported for post-varicellaand post-rubella ADEM, respectively. Specific recov-ery times were described as approximately 3 weeksfor post-rubella ADEM and up to 12 weeks for mul-tiphasic ADEM, with intermediate but more variablerecovery time in the post-varicella and unknownADEM groups.107 Taken together, these reports sug-gest that approximately two-thirds of patients makea complete recovery without specific treatment, butthat recovery may require weeks.

Treated ADEM. Table 1 summarizes the outcomeinformation in recently published case series of 15 ormore patients with ADEM. Over half the patientstreated had a good recovery with minimal or no def-icit. The most common problems seen followingADEM were focal motor deficits ranging from mildclumsiness and ataxia to hemiparesis or blindness.Behavioral and cognitive problems were identified in6 to 50% of children, but are likely underreported in

some series. Less frequent late effects included de-velopment of seizures following ADEM resolution.

Most patients were treated with high-dose ste-roids, although some patients were treated with IVIg(with or without steroids), and plasmapheresis wasused in some severe steroid-resistant cases. Follow-ing initiation of treatment, rapid improvement wassometimes seen within hours although recovery typ-ically evolved over days. More severely affected chil-dren (sometimes obtunded and mechanicallyventilated) often required weeks or months to im-prove and were often treated with multiple immuno-suppressant regimens, making it unclear whetherthe treatment influenced outcome or whether thesepatients improved on their own. Complete recoverywas reported for some of these severe cases, albeitless frequently. The prognosis of ADEM in adult pa-tients has been uniformly reported as favorable.17

Neurocognitive outcome. More attention is be-ing given to subtle neurocognitive deficits followingCNS demyelination in childhood, includingADEM.50,108 Even children thought to have full recov-ery demonstrated subtle neurocognitive deficits inattention, executive function, and behavior50 whenreevaluated more than 3 years after ADEM, al-though these deficits were not as severe as thosereported for pediatric patients with MS.109 One studycompared 19 children with ADEM to a normal age-and sex-matched control group and found that pa-tients younger than 5 years at ADEM diagnosis hadsignificantly lower IQ and educational achievementwhen evaluated at 3.9 years (mean) since illness,while the older-onset patients had slower verbal pro-cessing, having been evaluated at 2.2 years (mean)after presentation.108 Behavioral problems were alsomore prominent in the young-onset ADEM group.Additional studies are required to further character-ize neurocognitive deficits following ADEM. Thesestudies will help to guide assessments in individualpatients and will facilitate appropriate educationalinterventions.

It appears that symptom resolution is more rapidin steroid or IVIg-treated patients. However, due tothe heterogeneity of the patient populations andtreatment regimens, it is difficult to draw any spe-cific conclusions about the impact of treatment rela-tive to long-term outcome. Multicenter prospectivetrials with consistent diagnostic criteria, treatmentprotocols, and uniform data collection are critical toimprove our knowledge regarding management ofchildren and adolescents with cognitive deficits.

ADEM and MS. MS in children can initiallypresent with symptoms and signs that are indistin-guishable from ADEM. However, subsequent neuro-logic events or changes on MRI typical of MS lead tothe diagnosis of MS.18,19,110 The possibility that achild may develop MS is a concern for parents andclinicians, particularly in cases of recurrent or mul-tiphasic ADEM. MS in children can also present



with CIS that more closely resemble typical neuro-logic events seen in adults with MS. CIS differs clin-ically from ADEM, and is defined as either amonofocal or multifocal demyelinating event in theabsence of fever or encephalopathy (except in casesof brainstem syndromes).

Our current consensus definition of pediatric MSstates that a first event of ADEM is not consideredthe first event required for a diagnosis of MS, norcan it be used to determine dissemination in timeand space. In these children, a second demyelinatingevent not meeting criteria for recurrent or multipha-sic ADEM would qualify as an initial event, afterwhich subsequent MRI changes or new demyelinat-ing episodes would lead to a diagnosis of MS. Whilestudies suggest that children with an initial ADEMevent are at higher risk for the eventual develop-ment of MS,18,19,110 the actual risk of MS followingADEM remains unclear. Identifying prognostic indi-cators including biomarkers are needed to furtherclarify the relationship between ADEM and subse-quent risk of an MS diagnosis.

At present, there are no clear prognostic factorsthat determine if a child with a first event of eitherADEM or CIS will eventually develop MS. The riskof developing MS after ADEM has been reported as0%,21 9.5%,19 to 27%18 and 28%39 by different studies.It should be noted that in these studies, varyingcriteria were used to define pediatric MS, and differ-ing lengths of follow-up were used, which may con-tribute to the wide range in incidence. As a generaltrend, ADEM carries a lower risk of developing MSthan CIS events. A study examining patients with afirst demyelinating event, including CIS-like andADEM events, showed that overall, 57% developedMS as defined by two demyelinating events.39 Of pa-tients with an initial diagnosis of ADEM, 28% devel-oped MS. Of those with initial CIS-like events, 86%with optic neuritis and 50% with an initial brain-stem syndrome developed MS. Overall, positive pre-dictive factors for the development of MS were age atonset 10 years or older (hazard ratio [HR], 1.67; 95%CI), MS-suggestive initial MRI (HR 1.54), or opticnerve lesion (HR 2.59). A lower risk of developingMS was found in patients with myelitis (HR 0.23) ormental status change (HR 0.59) at presentation.39

Twenty-nine percent (34 of 119) of children with a priordiagnosis of ADEM developed MS, while 75% (134 of177) of children with a first event consistent with CISdeveloped MS. Although these clinical findings arehelpful and serve as a guide, a definitive diagnosis ofMS cannot be made based on these data. Moreover, useof standardized criteria to define MS in future studieswould greatly enhance interpretation.

Radiologic parameters provide supportive evi-dence for the diagnosis of MS; however, they cannotbe used as predictors for the development of the dis-ease, since many features thought to be unique toMS are also seen in cases of ADEM.20 Lesions in thecorpus callosum, periventricular white matter, anddeep gray matter structures were seen more com-

monly in patients who developed MS.22 However, inother series the same features have been docu-mented in typical cases of ADEM.18,20

Oligoclonal IgG bands in the CSF were found to bepositive in 64 to 92% of pediatric MS cases, and in 0to 29% of ADEM cases,18,21,22,111 but this differencewas not statistically significant18 and so cannot beused as a reliable marker of MS. Thus far, immuno-logic testing has not yielded a reliable marker for thedevelopment of MS from initial demyelinating eventsin children.

To date, there are no clear clinical or radiologicparameters that predict which cases of ADEM or CISwill develop MS.112,113 Early treatment of MS isstrongly advocated in adult patients, and has beenshown to be beneficial in reducing long-term disabil-ity.114,115 Moreover, use of beta-interferon-1a in pedi-atric MS patients has recently been shown to be safeand tolerable.116,117 However, the risk of an inaccu-rate diagnosis of MS, which carries a lifetime burdenand requires ongoing treatment, is generally thoughtto outweigh the risk of delaying diagnosis in order tobe certain of the diagnosis of MS. The proposed defi-nition of pediatric MS may eventually require modi-fication as more information is gathered regardingthe predictability of developing MS after an initialdemyelinating event. Clinical prognostic indicatorsor a biomarker that predicts the development of MSafter an initial demyelinating event in childhood isneeded to facilitate an early and accurate diagnosisof pediatric MS.

Pathogenesis. ADEM is characterized histologi-cally by perivenular infiltrates of T cells and macro-phages, associated with perivenular demyelination.Although ADEM shares common pathologic featureswith MS, distinct pathologic criteria distinguishingthe two diseases have not been defined. There are nosystematic studies comparing the histopathology ofADEM and MS, although such studies would un-doubtedly yield important information on the rela-tionship between these two diseases. A variety ofpathologic features have been described in biopsyand autopsy samples from ADEM and AHEM pa-tients. An autopsy from a 5-year-old boy with fatalADEM grossly described diffuse brain edema, uncaland tonsillar herniation.19 Multifocal perivascularlymphocytic infiltrates associated with fibrin deposi-tion within vascular lumens and adjacent demyelina-tion were observed. There was diffuse anoxic-ischemic neuronal degeneration and intersitialedema. Viral inclusion bodies were not seen in H-Esections. A brain biopsy performed in a 10-year-oldgirl with severe AHEM demonstrated subcorticalWM with perivascular hemorrhagic necrosis withsubacute inflammation consisting of macrophages,neutrophils, and rare lymphocytes. No evidence ofviral, bacterial, fungal, or parasitic infection wasnoted. Although ADEM is typically described as de-myelination with relative preservation of axons, ax-onal damage has been identified in the brains of



some patients.118,119 Lesions largely involve the whitematter, but can also involve the cortex and deep graymatter structures. The CSF is characterized by ele-vated protein and white blood cells. Oligoclonalbands are an acute manifestation in up to 30% ofpatients with ADEM,18 and may be transient. Ele-vated CSF levels of the pro-inflammatory cytokinesIL-6, IL-10, and TNF� have been described.120,121

Acute hemorrhagic and acute necrotizing hemor-rhagic leukoencephalitis (AHEM, AHL, ANHLE) ofWeston Hurst shares some inflammatory histologicfeatures with ADEM; however, demyelination is of-ten more widespread throughout the CNS and is as-sociated with a pronounced neutrophilic infiltrate.ANHLE is characterized by destruction of smallblood vessels associated with acute hemorrhage andfibrin deposition.122 CSF analysis reflects the hemor-rhagic nature of this disease with elevations in pro-tein, RBC, and WBC counts.

ADEM may be classified as either postvaccinial orpostinfectious; however, in many cases no clear ante-cedent history of either is present. Rare cases ofADEM have been described following organtransplantation.123-127 Postinfectious forms of ADEMtypically begin within 2 to 21 days after an infectiousevent; however, longer intervals have also been de-scribed. Viral infections commonly associated withADEM include influenza virus, enterovirus, measles,mumps, rubella, varicella zoster, Epstein Barr virus,cytomegalovirus, herpes simplex virus, hepatitis A,and coxsackievirus. Bacterial triggers include Myco-plasma pneumoniae, Borrelia burgdorferi, Lepto-spira, and beta-hemolytic Streptococcus. Acutehemorrhagic leukoencephalomyelitis (AHLE) typi-cally follows influenza or upper respiratory infection.The only epidemiologically and pathologically provenassociation of ADEM with vaccinations is with theSemple form of the rabies vaccine.3,128-130 Other vacci-nations associated with ADEM include hepatitis B,

pertussis, diphtheria, measles, mumps, rubella,pneumococcus, varicella, influenza, Japanese en-cephalitis, and polio.19,21,131-136 Vaccines produced inCNS tissue including the Semple form of the rabiesvaccine carry a higher risk of ADEM. It is importantto note that in general, vaccination forms withhigh rates of complications are no longer in use.Some reported incidences of encephalomyelitis asso-ciated with various forms of vaccination are listed intable 2.

The pathogenesis of ADEM is unclear; however,given its histologic features and typically monopha-sic course of disease, it has been likened to theanimal model experimental autoimmune encephalo-myelitis (EAE). EAE is an autoimmune demyelinat-ing disease, which can be induced in a variety ofanimal species by immunization with myelin pro-teins or peptides. Moreover, the postvaccinial form ofADEM associated with the Semple rabies vaccine,which contains rabies virus–infected neural tissue,reinforces this analogy to EAE. Viral or bacterialepitopes resembling myelin antigens have the capac-ity to activate myelin-reactive T cell clones throughmolecular mimicry,137 and can thereby elicit a CNS-specific autoimmune response. Thus, it has been sug-gested that microbial infections preceding ADEMelicit a cross-reactive anti-myelin response throughmolecular mimicry. Alternatively, ADEM may becaused by the activation of existing myelin-reactiveT cell clones through a nonspecific inflammatoryprocess.

Theiler murine encephalomyelitis virus–induceddemyelinating disease (TMEV-IDD) model is inducedby direct CNS infection of the neurotropic TMEVpicornavirus, initially resulting in an immune-mediated reaction primarily involving TMEV-specificCD4 and CD8 T cells.138,139 However, during thechronic stages of disease, T cell reactivity to hostmyelin peptides has been observed, indicating

Table 2 Incidence of vaccination-associated ADEM

Vaccination forms Reported incidences of ADEM

Measles

Live measles vaccine 1–2/million131 (compared to 20–30/million incidence of measlesvirus–induced encephalitis)

Rabies

Neural vaccine (Semple) 1/300–1/7,000128

Duck embryo vaccine 1/25,0003

Non-neural human diploid cell �1/75,000

Japanese B encephalitis

Inactivated mouse-brain derived JEV 1993–1999 0.2/100,000 (Japan)132; 0/813,000 (USA)132

Smallpox

New York City Board of Health strain of vaccinia 2002–2004 3/665,000 135 (reporting encephalitis or myelitis)

Diphtheria/pertussis/tetanus 0.9/100,000131

Hepatitis B Eight cases of CNS inflammation within 10 weeks 133Four casesof partial myelitis within 3 months134

ADEM � acute disseminated encephalomyelitis.



epitope spreading has occurred secondary to T cellresponses to myelin breakdown products, resultingin an autoimmune response.140 Both microglia141 anddendritic cells142 from the CNS of TMEV-infectedmice are able to present myelin peptides to naıve Tcells, thereby facilitating epitope spreading to nonvi-ral, host myelin antigens. The TMEV model high-lights the phenomenon of epitope spreadingsecondary to a destructive CNS viral infection result-ing in a secondary autoimmune response and chronicinflammation. Although this model superficiallybears some resemblance to ADEM, it is important tonote that overwhelming evidence has shown thatADEM is not due to direct viral infection of the CNS,but is a secondary immune-mediated phenomenon.Epitope spreading is likely to be an important phe-nomenon in chronic inflammatory diseases such asMS, but involvement in ADEM is unknown.

Sequences in myelin basic protein have beenshown to resemble several viral sequences, and insome cases, cross-reactive T cell responses have beendemonstrated. Examples of cross-reactive T cellswith MBP antigens include HHV-6,143 coronavirus,144

influenza virus hemagglutinin,145 and EBV.146 Prote-olipid protein (PLP) shares common sequences withHaemophilus influenza.147 Semliki forest virus (SFV)peptides mimic myelin oligodendrocyte glycoprotein(MOG).148 Enhanced myelin basic protein (MBP)-reactive T cell responses have been demonstrated inpatients with postinfectious forms of ADEM.149,150 El-evated titers of anti-myelin antibodies in sera frompatients with ADEM have recently been demon-strated as compared to patients with MS or viralencephalitis.151 Previous studies have demonstratedenhanced anti-MBP antibody titers in patients withpostvaccinial ADEM following vaccination with theSemple rabies vaccine.152,153 One of these studiesdemonstrated elevated anti-MBP antibody titers inADEM samples compared with MS samples. Al-though there is controversy surrounding the charac-terization of anti-myelin antibody responses in MS,studies in ADEM have consistently shown detectablelevels, suggesting differences in pathogenesis. Col-lectively, these studies suggest that enhanced T andB cell myelin responses play a role in the pathogene-sis of both postinfectious and postvaccinial ADEM;however, further studies are required to determinecausal relationship.

ADEM was associated with the class II allelesHLA-DRB1*01 and HLA-DRB*03 in a Russianstudy.107 A similar study from Korea showed an asso-ciation of ADEM with HLA-DRB1*1501, as well asHLA-DRB5*0101.154 The same Korean study showedan association of HLA-DRB3*0202 and HLA-DQB1*0502 with acute necrotizing forms of enceph-alopathy. The gene mostly frequently linked withMS is HLA DRB1,155 with DR215,156 being the mostfrequently involved allele. Similar associations havebeen found in the pediatric MS population.157 Thus,class II alleles may play a role in MS as well asADEM; however, the disparity between the alleles

associated with the two diseases suggests differencesin pathogenesis.

Research/future directions. ADEM often posesboth a diagnostic and prognostic dilemma for clini-cians. In the acute stage, there should be a low sus-picion of infection before initiation of corticosteroidor immunosuppressive therapy. Diagnostic tests thatincrease the rapidity of an accurate diagnosis arerecommended. Over the long term, one of the mostpressing questions of a child presenting with ADEM,particularly recurrent or multiphasic forms ofADEM, is the potential risk for conversion to MS.Although ADEM and MS share many similar patho-logic features, prognosis is drastically different.Therefore, identification of a biomarker that can pre-dict the development of MS after an ADEM event iscritical.

Additional studies are required to understand theworldwide epidemiology and distribution of ADEM.These studies may give insight into the pathogenesisof the disease and potential preventative measures.Early identification of triggers for ADEM, such asspecific batches of vaccines, is facilitated by strin-gent monitoring mechanisms.

Current treatments for ADEM generally lead toacceptable outcomes; however, further studies arerequired to investigate the use of additional agents,particularly for refractory or multiphasic cases.There is a paucity of literature on the use of chemo-therapeutic agents for ADEM, although anecdotaluse is prevalent. In addition, use of �-interferons formultiphasic forms of ADEM requires furtherinvestigation.

The use of standardized definitions for ADEM andMS in children and adolescents will help to facilitatefuture studies, regarding the prognosis, pathogene-sis, and treatment of these two diseases.

AppendixThe International Pediatric MS Study Group: Lauren Krupp, MD (chair),Brenda L. Banwell, MD, Anita Belman, MD, Dorothee Chabas, MD, PhD,Tanuja Chitnis, MD, Peter Dunne, MD, Andrew Goodman, MD, Jin S.Hahn, MD, Deborah P. Hertz, MPH, Nancy J. Holland, EdD, RN, MSCN,Douglas Jeffery, MD, PhD, William MacAllister, PhD, Raul Mandler, MD,Maria Milazzo, RN, MS, CPNP, Jayne Ness, MD, PhD, Jorge Oksenberg,PhD, Trena L. Pelham, MD, Daniela Pohl, MD, PhD, Kottil Rammohan,MD, Mary R. Rensel, MD, Christel Renoux, MD, Dessa Sadovnick, PhD,Steven Robert Schwid, MD, Silvia Tenembaum, MD, Cristina Toporas,Emmanuelle Waubant, MD, PhD, Bianca Weinstock-Guttman, MD.

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DOI: 10.1212/01.wnl.0000259404.51352.7f 2007;68;S23-S36 Neurology

Pediatric MS Study Group Silvia Tenembaum, Tanuja Chitnis, Jayne Ness, Jin S. Hahn and for the International

Acute disseminated encephalomyelitis

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