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Acute disseminated encephalomyelitis

Silvia Tenembaum, Tanuja Chitnis, Jayne Ness, Jin S. Hahn and for the International
Pediatric MS Study Group
Neurology 2007;68;S23-S36
DOI: 10.1212/01.wnl.0000259404.51352.7f

This information is current as of August 1, 2008

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Acute disseminated encephalomyelitis
Silvia 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 CNS

characterized 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 acute
encephalopathy with multifocal neurologic signs and deficits. Children are preferentially affected. In the absence of
specific biologic markers, the diagnosis of ADEM is still based on the clinical and radiologic features. Although ADEM
usually has a monophasic course, recurrent or multiphasic forms have been reported, raising diagnostic difficulties in
distinguishing these cases from multiple sclerosis (MS). The International Pediatric MS Study Group proposes uniform
definitions for ADEM and its variants. We discuss some of the difficulties in the interpretation of available literature due
to the different terms and definitions used. In addition, this review summarizes current knowledge of the main aspects of
ADEM, including its clinical and radiologic diagnostic features, epidemiology, pathogenesis, and outcome. An overview of
ADEM 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 an genesis, treatment, and outcomes, and includes a
immune-mediated inflammatory disorder of the proposed definition of this disorder.
CNS, which is commonly preceded by an infection,
and predominantly affects the white matter of the Epidemiology. ADEM can occur at any age, but it
brain and spinal cord.1-4 Several terms can be found is more common in pediatric patients than in adults.
in the literature to describe patients with ADEM, Rare cases in older adults have been reported,17 al-
reflecting the more prominent aspects of the disease: though careful exclusion of other diseases should be
applied in these cases. The diagnosis is often made
“Postinfectious or postvaccinial encephalomyelitis, in the setting of a defined viral illness or vaccination.
postinfectious multifocal encephalitis,” when the trig-
gering events were considered. Although there appears to be no gender predomi-
nance in ADEM,18,19 a male predominance has been
“Acute perivascular myelinoclasia, perivenous en- described in two pediatric cohorts, with reported fe-
cephalitis, disseminated vasculomyelinopathy,” when
male:male ratios of 0.620 and 0.8.21 as opposed to a
emphasizing the histopathologic features and distri-
bution of lesions. 2:1 female preponderance frequently described for
MS. The mean age at presentation in children
“Acute demyelinating encephalomyelitis, hyperergic ranges from 5 to 8 years.21-23
encephalomyelitis, postvaccinal perivenous encephali-
A seasonal distribution in the winter and spring
tis, postencephalitis demyelination,” relating to the
probable immunopathogenetic mechanism.5-16 months has been found in studies conducted in the
United States.19,20 A recent study conducted in San
Based on our current clinicopathologic under- Diego County, CA, estimated the mean incidence of
standing of the disease, ADEM is probably the most ADEM as 0.4/100,000/year among persons less than
appropriate nosologic designation, as the precipitat- 20 years of age living in that region.19 Five percent of
ing event may be absent and the pathogenesis of the these patients had received a vaccination within 1
disease is unclear. month prior to the ADEM event, and 93% reported
In the absence of specific biologic markers, the signs of infection in the preceding 21 days. There are
diagnosis of ADEM is based on the clinical and ra- no clear studies of worldwide distributions of ADEM.
diologic features. Although ADEM usually has a Some regional cases are linked to specific vaccines,
monophasic course, recurrent or multiphasic forms as in the case of the Semple rabies vaccine, smallpox
have been reported, raising diagnostic difficulties in vaccine, and older forms of the measles vaccine.
distinguishing these cases from multiple sclerosis
(MS). This article reviews what we currently know Clinical presentation. ADEM is classically de-
about ADEM, including diagnostic features, patho- 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 General
Hospital for Children (T.C.), Brigham & Women’s Hospital, Harvard Medical School, Boston; Department of Pediatrics (J.N.), University of Alabama at
Birmingham 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:,

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

Murthy Dale Hynson Hung Tenembaum Gupte Mikaeloff Idrissova Leake Anlar
et al.,20 et al.,18 et al.,22 et al.,51 et al.,21 et al.,26 et al.,39 et al.,107 et al.,19 et al.,23
USA, England, Australia, Taiwan, Argentina, England, France, Russia, USA, Turkey,
2002, 2000, 2001, 2001, 2002, 2003, 2004, 2003, 2004, 2003,
n ⫽ 18 n ⫽ 35 n ⫽ 31 n ⫽ 52* n ⫽ 84 n ⫽ 18 n ⫽ 119† n ⫽ 90‡ n ⫽ 42§ n ⫽ 46

Mean age, y (range) 7.5 (2.5–22) 7.4 ⫾ 0.65 5.9 (2–16) 6.7 5.3⫾3.9 8.6 ⫾ 1.2 7.1 ⫾4.3¶ 9.8 ⫾ 0.5 6.5 (0.8–18) 8 (1–15)
(3–15) (0.7–16) (0.4–16) (2.5–16) (0.7–16) (2–16)

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 1.5 ⬎1.5 6.6 (1–19) 1.2 ⫾ 0.2 2.9 ⫾3 Mean NR Mean NR Mean NR
(1–15) (0.25–4) (0.5–14.9) (1–5) (1–5) (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 for
ADEM. 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 if
any recurrence. As some patients may be considered multiphasic ADEM, we kept the original 119 in analysis. However, in table 1, “¶” provides data
from 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.

gins within 2 days to 4 weeks after an antigenic status, ataxia, motor deficits, and brainstem involve-
challenge. Approximately 70 to 77% of patients re- ment, other features appear to be age related.25
port a clinically evident antecedent infection or vac- Long-lasting fever22 and headaches19,21-23,26 occur
cination during the prior few weeks.21,22,24 The typical more frequently in children with ADEM, while sen-
symptoms and signs of ADEM include a rapid onset sory deficits predominate in adult patients.17 Sei-
encephalopathy associated with a combination of mul- zures are rarely observed in adult patients with
tifocal neurologic deficits. A prodromal phase with fe- ADEM,17 and are mainly seen in children younger
ver, malaise, headache, nausea, and vomiting may be than 5 years. One study has documented prolonged
observed shortly before the development of meningeal focal motor seizures in 70% of the younger patients,
signs and drowsiness. The clinical course is rapidly with 82% of these patients going on to status
progressive and usually develops over hours to maxi- epilepticus.21
mum deficits within days (mean, 4.5 days).21 Peripheral nervous system (PNS) syndromes such
The initial neurologic features are determined by as acute polyradiculoneuropathy24,27,28 may occur in
the location of the lesions within the CNS. Table 1 ADEM but are considered rare in childhood ADEM
summarizes the demographic distribution and pre- cases. The combination of PNS and CNS features
senting features in recently published case studies of may be more common in adults and was noted in
patients with ADEM. Frequent neurologic symptoms 43.6% of one cohort of adult patients.29
and signs described in various combinations include There is a wide variation in the severity of the
unilateral or bilateral pyramidal signs (60 to 95%), illness. Occasionally, ADEM can present as a subtle
acute hemiplegia (76%), ataxia (18 to 65%), cranial disease, with nonspecific irritability, headache, and
nerve palsies (22 to 45%), visual loss due to optic somnolence, or may show a rapid progression of
neuritis (7 to 23%), seizures (13 to 35%), spinal cord symptoms and signs to coma and decerebrate rigidi-
involvement (24%), impairment of speech (slow, ty.30 Respiratory failure secondary to brainstem in-
slurred, or aphasia) (5 to 21%), and hemiparesthesia volvement or severely impaired consciousness occurs
(2 to 3%), with invariable involvement of mental sta- in 11% to 16% of cases.21,30
tus, ranging from lethargy to coma.19-23 Although cer-
tain signs and symptoms may be observed in both MRI features. Neuroimaging is extremely impor-
pediatric and adult cases, such as changes in mental tant in establishing the diagnosis of ADEM. MRI
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Figure 1. Acute disseminated encepha-
lomyelitis with small lesions. (A) Axial
T2-weighted MRI showing bilateral,
poorly marginated hyperintense lesions
in central, periventricular, and juxta-
cortical white matter, (B) also involving
both thalami and internal capsules, in
a 17-month-old boy, 2 weeks after mea-
sles vaccination.

abnormalities are most frequently identified on T2- shaped (figure 5), nodular, gyral, or spotty patterns
weighted and fluid-attenuated inversion recovery have been described.36-38 Meningeal enhancement of
(FLAIR) sequences as patchy, poorly marginated ar- the brain or spinal cord is unusual.
eas of increased signal intensity. Lesions in ADEM Spinal cord involvement in ADEM has been de-
are typically large, multiple, and asymmetric. They scribed in 11 to 28%.18,21-23,39 The typical spinal cord
typically involve the subcortical and central white lesion is large and swollen, showing variable en-
matter and cortical gray-white junction of both cere- hancement, and predominantly affects the thoracic
bral hemispheres, cerebellum, brainstem, and spinal region.
cord.30 The gray matter of the thalami and basal Sequential MRI scanning during the follow-up pe-
ganglia are frequently involved, typically in a sym- riod plays an important role in establishing the diag-
metric pattern.21,31 The periventricular white matter nosis of ADEM. Monophasic ADEM is not associated
is also frequently involved, being described in 30 to with the development of new lesions. Complete
60% of cases.20,22,30 Lesions confined to the corpus resolution of MRI abnormalities after treatment
callosum are less common. However, large demyeli- has been described in 37 to 75% of patients with
nating lesions of the adjacent white matter may ex- ADEM, and partial resolution in 25 to 53% of
tend into the corpus callosum and cross into the
contralateral hemisphere.
Four patterns of cerebral involvement have been
proposed 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 edema
and mass effect (figure 2); 3) ADEM with additional
symmetric bithalamic involvement (figure 3); and 4)
acute hemorrhagic encephalomyelitis (AHEM), when
some evidence of hemorrhage can be identified in the
large demyelinating lesions (figure 4). The MRI pat-
tern does not appear to correlate with any particular
outcome or disability, as observed in a large pediat-
ric cohort,21 since most lesions tend to resolve on
follow-up imaging studies.21,32 However, this classifi-
cation may be useful when considering the differen-
tial diagnosis of ADEM and may potentially help to
identify those children for whom the initial ADEM-
phenotype is really the first manifestation of MS.
The incidence of gadolinium enhancing lesions on
T1-weighted sequences is quite variable in ADEM
and may depend on the stage of inflammation.31,33,34 Figure 2. Acute disseminated encephalomyelitis with tu-
Gadolinium enhancing lesions have been described mefactive lesions. Axial T2-weighted image demonstrating
in 30 to 100% of patients.21,35,36 The pattern of en- extensive, tumefactive, and bihemispheric lesions with
hancement is variable; complete or incomplete ring- perilesional edema, in a 13-year-old boy.
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of MRI lesions, SPECT with acetazolamide detects
persistent cerebral circulatory impairment that may
contribute to the neurocognitive and language defi-
cits observed in some patients with ADEM.49,50

Monophasic and multiphasic ADEM. Although

ADEM 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 noted
that different diagnostic criteria for relapses were
used in these different studies, which may in part
account for the variability. In addition, the mean
length of follow-up reported in some of these ADEM
series varied considerably: 18 months,22 22 months,23
5.3 years,18 6.6 years,21 and again may contribute to
the interstudy variability.52
The final outcome of multiphasic ADEM has been
described 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 ADEM
patients.18 Similarly, eight children with multiphasic
Figure 3. Acute disseminated encephalomyelitis with ADEM, who remained relapse-free after a follow-up
bithalamic involvement. Axial T2-weighted MRI showing of 3 to 16 years (mean 8.2 years), had a median
symmetric increased signal in both thalami, with addi- EDSS score of 1 (range 0 to 2.5).21 Serial brain-spinal
tional involvement of the insula and subcortical white MRI performed in these patients revealed complete
matter, in an 18-month-old boy, 3 weeks after having or almost complete resolution of demyelinating le-
mumps. sions without evidence of new active lesions.

Acute hemorrhagic leukoencephalitis. Acute

patients.18,21,24,33,35 Resolution of MRI abnormalities hemorrhagic leukoencephalitis (AHL), AHEM, and
within 6 months has been positively associated with acute necrotizing hemorrhagic leukoencephalitis
a final diagnosis of ADEM in one study.40 There are (ANHLE) of Weston Hurst are variants of an acute,
no clear criteria documenting how long to continue to rapidly progressive, and frequently fulminant in-
image patients with one ADEM event. However, the flammatory hemorrhagic demyelination of CNS
authors suggest reassessing the patient with at least white matter. It is usually triggered by upper respi-
two additional MRI studies after the first normal ratory tract infections. Death from brain edema is
MRI, over a period of 5 years from the initial episode, common within 1 week of onset of the encephalopa-
as the appropriate way to confirm the absence of thy, but increasing evidence of favorable neurologic
ongoing accrual of lesions. outcomes has been published with early and aggres-
sive treatment using various combinations of cortico-
Advanced neuroimaging techniques. Low lev- steroids, immunoglobulin, cyclophosphamide, and
els of N-acetylaspartate (NAA) and elevated lactate plasma exchange.21,53-55
levels within regions of prolonged T2-MRI signal, AHL, AHEM, and ANHLE are considered hyper-
without increase in choline, have been observed with acute subforms of ADEM and were observed in 2% of
quantitative proton MR spectroscopy during the children in a large cohort.21 Lesions on MRI tend to
acute stages of ADEM.41,42 These abnormal signals be large, with perilesional edema and mass effect.56,57
resolved after normalization of clinical and MRI find- Diffusion-weighted imaging disclosing areas of re-
ings. Diffusion and perfusion weighted MRI show a stricted diffusion in the affected areas of the brain
diffusion pattern with reduced, normal, or increased has been recently published,57 and this finding might
diffusion coefficients, or reduced or normal perfusion be due to acute vasculitis with subsequent vessel
within ADEM lesions.43,44 A global and bilateral de- occlusion in AHL.
creased cerebral metabolism has been demonstrated
by PET scanning in a case where CT scan had only Controversies in diagnosis based on published
showed a focal demyelinating lesion.45 studies: Rationale for proposed definitions.
SPECT using 99m Tc-HMPAO has consistently ADEM should be adequately defined and distin-
shown areas of hypoperfusion that are more exten- guished from other diseases affecting the white mat-
sive than the MRI lesions.46-48 The time course of ter. In particular, a diagnostic challenge lies in
SPECT abnormalities also reflects the clinical course distinguishing multiphasic forms of ADEM from MS.
more accurately than MRI. In spite of the resolution This is especially important, not only for prognostic
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Figure 4. Acute hemorrhagic encephalo-
myelitis. (A) Axial T2-weighted MRI
with prominent bilateral hyperintense
lesions, with areas of very low signal,
corresponding to breakdown products of
hemoglobin, in a 5-month-old boy, 2
weeks after pertussis vaccination. (B)
Axial T1-weighted MRI of the same
case, showing spontaneous hyperintense
signal inside the large hypointense

purposes, but for therapeutic purposes, since a diag-

nosis of MS, at least in adult patients, carries the
recommendation for early treatment with
Historically, different definitions of ADEM have
been used in published cases of pediatric and adult
patients.17-23,26,39,51 The lack of a uniform definition
and clear clinical and neuroimaging diagnostic crite-
ria has led to the classification of other neurologic
conditions as ADEM. Due to this lack of uniformity,
it is difficult to compare neuroimaging aspects or
outcomes, establish prognostic factors, or compare
percentages of patients with ADEM that evolve into
MS. For example, the proportion of patients initially
diagnosed with ADEM who go on to be diagnosed
with MS ranges from 9.5%19 to 27%.18 However, two
children from a cohort of seven diagnosed with “mul-
tiphasic ADEM” had monosymptomatic relapses—
optic neuritis in one, and a brainstem syndrome in Figure 5. Sagittal T1-weighted imaging demonstrating
the other—suggestive of MS.18 Conversely, a recently two lesions with open-ring enhancement in an 8-year-old
published study applied the concept that “any second girl, 1 week after an upper respiratory viral infection.
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attack after an initial diagnosis of ADEM had to be dence of previous destructive white matter changes
reclassified as MS,”39 and reported a frequency of should be present; and no history of a previous clini-
second attacks as high as 29%. Thus, the use of a cal episode with features of a demyelinating event. If
uniform definition may help to distinguish ADEM a relapse takes place within 4 weeks of tapering
from other lifelong demyelinating conditions and steroid treatment or within the first 3 months from
provide a foundation for consistent prospective out- the initial event, this early relapse is considered
come studies. Nevertheless, the long-term outcome temporally related to the same acute monophasic
and evidence of multiple recurrent demyelinating condition and would replace the terms “steroid de-
events are required conditions to clearly delineate pendent ADEM” or “pseudorelapsing ADEM.”
MS from ADEM. Recurrent ADEM: New demyelinating event ful-
Unusual cases of ADEM have been described in filling diagnostic criteria for ADEM, occurring at
patients with demyelinating lesions confined to the least 3 months after the initial ADEM event and at
brainstem, when the presentation was more indica- least 4 weeks after completing steroid therapy, show-
tive of a clinical isolated syndrome (CIS) with brain- ing the same clinical presentation and affecting the
stem involvement or brainstem encephalitis.58-60 A same areas on MRI as the initial ADEM episode.
case of atypical acute disseminated encephalomyeli- Multiphasic ADEM: Refers to one or more ADEM
tis is described in a 3-year-old girl, with a longitudi- relapses, including encephalopathy and multifocal
nal lesion restricted to the spinal cord in the absence deficits, but involving new areas of the CNS on MRI
of brain lesions, consistent with longitudinal myeli- and neurologic examination. Relapses take place at
tis.61 Unfortunately, the report does not provide im- least 3 months after initial ADEM attack and at
aging of the brainstem to better explain the child’s least 4 weeks after completing steroid therapy.
alteration of consciousness. A neurodegenerative pic-
ture with progressive decline in mental and motor Differential diagnosis. Acute encephalopathy
skills was reported in an 11-month-old baby follow- and disseminated demyelination of the CNS in chil-
ing a meningoencephalitis.62 This infant was misdi- dren represent a diagnostic challenge for pediatric
agnosed as having ADEM because the MRI showed clinicians and neurologists. Many inflammatory and
subtle areas of hyperintense signal in the frontal and noninflammatory disorders may have a similar clini-
parieto-occipital white matter that seemed to be cal and radiologic presentation and should be consid-
transitional areas of myelination or delayed myelina- ered in the diagnostic evaluation.
tion.63 A recent report describes a patient with recur- If an acute encephalopathy is suspected based on
rent simple and complex partial seizures, who then history and physical examination, the first priority
progressed to intractable epilepsia partialis continua should be to rule out an acute bacterial or viral infec-
and cognitive decline.64 Although this case repre- tion of CNS, and to start empiric antibacterial and
sented a classic picture of chronic Rasmussen’s en- antiviral treatment. A gadolinium-enhanced MRI of
cephalitis, because the patient started symptoms the brain and spinal cord (to better define the dis-
after a viral illness and the initial MRI disclosed ease burden) and a lumbar puncture should be per-
hyperintense lesions (although predominantly in- formed as soon as possible. Evidence of an
volving cortical and subcortical structures), a diagno- inflammatory process (CSF pleocytosis, elevated
sis of ADEM was suspected. Furthermore, when the CSF proteins and immunoglobulin index, gadolinium
seizures recurred after 3 months from onset, the pa- enhancement on MRI) should be determined in addi-
tient was misdiagnosed with multiphasic ADEM. tion to screening for viral, bacterial, or fungal infec-
A variety of terms and definitions have been used tious agents (See “Differential diagnosis and
to describe patients with ADEM who relapse. Recur- evaluation of pediatric MS” in this conference report
rent, relapsing, pseudorelapsing, bi- or multiphasic for complete outline of the workup for infectious
ADEM have all been applied using different crite- causes of acute encephalopathy). In the absence of
ria18,21,65-74: time from the first event varies from less clear evidence of an infectious cause, the neuroimag-
than 4 to more than 8 weeks; neurologic deficits are ing findings should define the regional distribution
defined as same or different; individuals are either of the demyelinating-inflammatory process.
monosymptomatic or polysymptomatic; and finally Neuroimaging at the time of the initial event may
MRI lesions are described as either in the same or be useful in the diagnosis. When the MRI shows
different areas. large focal tumor-like lesions, one should consider
brain tumors, Shilder disease, Marburg variant of
ADEM definitions. To avoid misdiagnosis and de- MS, and brain abscess.75-77 An MRI pattern with
velop a uniform classification, the International Pe- symmetric bithalamic involvement may be seen in
diatric MS Study Group (Study Group) proposes that children with acute necrotizing encephalopathy,
the following three terms be applied to variations of deep cerebral venous thrombosis, hypernatremia,
ADEM (see Krupp et al.,74a in this conference report): and extrapontine myelinolysis, as well as in children
ADEM: A first clinical event with a polysymptom- with ADEM after Japanese B encephalitis
atic encephalopathy, with acute or subacute onset, vaccination.78-84 Basal ganglia involvement may be
showing focal or multifocal hyperintense lesions pre- consistent with organic aciduria, poststreptococcal
dominantly affecting the CNS white matter; no evi- ADEM, or infantile bilateral striatal necrosis.85,86
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The presence of complete ring-enhanced lesions in effectiveness in MS is limited. There are multiple
the cerebral white matter is unusual in ADEM, and case reports of IVIg being used successfully alone92,93
brain abscess, tuberculomas, neurocysticercosis, tox- or in combination61 with corticosteroids in both pedi-
oplasmosis, and histoplasmosis should be excluded.36 atric and adult cases of ADEM, but there have been
The diagnosis of MS should be considered in cases no studies which have directly compared IVIg with
of recurrent or multiphasic demyelination, and is steroids, plasmapheresis, or other immunomodula-
discussed in detail later in this review. tory treatments. In some cases, IVIg was adminis-
tered after failed IV pulse steroid therapy94-96 or in
Treatment and management. There is no stan- cases of recurrent demyelination.68,70 Reported dos-
dard therapy for ADEM. Most treatment approaches ing for IVIg has been quite consistent, using a total
have employed some form of nonspecific immunosup- dose of 1 to 2 g/kg, administered either as a single
pressant therapy similar to that used for MS and dose or over 3 to 5 days. In general, IVIg is well
other autoimmune diseases, including steroids, IV tolerated in the pediatric population. There have
immunoglobulin (IVIg), or plasmapheresis. Most of been isolated case reports of repeated IVIg adminis-
the data describing treatment for ADEM are derived tration to treat recurrent episodes of demyelina-
from case reports and small series. To date, there tion,97 although it is questionable whether these
have been no randomized, controlled trials for the cases were definitely MS.
treatment of ADEM in either children or adults.
Plasma exchange. The use of plasma exchange in
Steroids. Steroid treatment has been the most ADEM has been reported in only a small number of
widely reported therapy for ADEM, typically at high cases, typically severe cases when steroid treatment
doses. However, there has been great variety in the has failed. A recent series98 examined the outcome
specific steroid formulations employed, routes of ad- following plasma exchange for 59 patients with a
ministration, dosing, and tapering regimens. The variety of CNS demyelinating conditions, including
earliest report describing steroid treatment for 10 cases of ADEM, and found that 40% of patients
ADEM was published in 1953 using ACTH.87 Later (including the ADEM group) had moderate to
reports in the pre-MRI era described successful use marked improvement following plasma exchange. In
of prednisone, corticotropin, or dexamethasone with this cohort, a mean number of seven exchanges was
marked improvement of symptoms in both adult and performed (range 2 to 20) although a breakdown by
pediatric patients with ADEM.12,88 Several patients demyelinating disease type was not given. In the
in these reports had recurrence of their symptoms literature, there were reports of six pediatric ADEM
when the steroid therapy was discontinued and im- cases treated with plasma exchange. Four of these
proved when steroids were reinstituted. patients were reported as having a complete
Most pediatric groups describing their high dose recovery,99-101 one had a residual left hemiparesis,102
steroid treatment in detail have used IV methylpred- and the outcome for one patient was not described.103
nisolone (10 to 30 mg/kg/day up to maximum dose of Plasma exchange may serve to remove the autoan-
1 g/day) or dexamethasone (1 mg/kg) for 3 to 5 tibodies that are presumably triggering the demyeli-
days18,21,22,26,89,90 followed by oral steroid taper for 4 to nation in ADEM, but may also shift the dynamics of
6 weeks with full recovery reported in 50 to 80% of B- and T-cell interaction within the immune system.
patients.18,21,22 In the only comparison of specific cor- There is some evidence from case reviews that
ticosteroid regimens, methylprednisolone-treated pa- plasma exchange may be more effective when given
tients had significantly better outcome with respect early in the disease course.104 However, due to the
to EDSS scores compared to those treated with IV need for trained personnel with specialized equip-
dexamethasone.21 Outcome may also be influenced ment and central venous access for multiple treat-
by the length of steroid taper since an increased risk ments over a period of days to weeks, plasma
of relapse has been reported with steroid taper of 3 exchange has often been used as a last resort. Symp-
weeks or less.18,23 tomatic hypotension, severe anemia, and heparin-
High-dose steroid treatment is not without risk. associated thrombocytopenia have been described in
Gastric perforation and death due to gastrointestinal association with plasma exchange.98 The role and
bleeding related to methylprednisolone treatment for timing of this intensive treatment for ADEM de-
ADEM has been reported.91 Hyperglycemia, hypoka- serves further investigation; however, for the fore-
lemia, high blood pressure, facial flushing, and mood seeable future plasma exchange will likely continue
disorders have also been reported in association with to be used as a rescue therapy in ADEM when other
high-dose corticosteroid treatment. It is advisable to modalities fail.
provide gastric ulcer prophylaxis while patients are
on high dose steroids, in addition to a careful moni- Other therapies. To our knowledge, there have
toring of blood pressure, urine glucose, and serum been no published reports of interferon-␤ or glati-
potassium. ramer acetate used in the acute stage of ADEM al-
though there are anecdotal descriptions of
Immunoglobulin. IVIg has been used successfully interferon-␤ use for episodes of recurrent demyelina-
in a variety of autoimmune diseases although its tion consistent with multiphasic ADEM. Some
April 17, 2007 NEUROLOGY 68(Suppl 2) S29
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improvement has been reported with cyclophospha- some series. Less frequent late effects included de-
mide use in adult ADEM patients who responded velopment of seizures following ADEM resolution.
poorly to methylprednisolone,17 but we are unaware Most patients were treated with high-dose ste-
of any published reports of cyclophosphamide, aza- roids, although some patients were treated with IVIg
thioprine, or other cytostatic drug use in pediatric (with or without steroids), and plasmapheresis was
ADEM. used in some severe steroid-resistant cases. Follow-
ing initiation of treatment, rapid improvement was
Outcome and prognosis. Untreated ADEM. sometimes seen within hours although recovery typ-
Limited data exist about the natural history of ically evolved over days. More severely affected chil-
ADEM in the post-MRI era. In the available case dren (sometimes obtunded and mechanically
studies, there is considerable diversity with respect ventilated) often required weeks or months to im-
to antecedent infections, clinical presentation, and prove and were often treated with multiple immuno-
neuroimaging findings, further complicating out- suppressant regimens, making it unclear whether
comes analysis. Classification of recurrence is a ma- the treatment influenced outcome or whether these
jor inconsistency as there is considerable patients improved on their own. Complete recovery
disagreement about when to classify recurrent demy- was reported for some of these severe cases, albeit
elination as multiphasic ADEM vs defining all recur- less frequently. The prognosis of ADEM in adult pa-
rent demyelination as MS. Case series from Japan,105 tients has been uniformly reported as favorable.17
India,106 and Russia107 suggest that the natural his-
tory of ADEM in most children is one of gradual Neurocognitive outcome. More attention is be-
improvement over several weeks, with 50 to 70% of ing given to subtle neurocognitive deficits following
patients experiencing full recovery. Improvement in CNS demyelination in childhood, including
serial MRIs was also shown in seven Japanese pa- ADEM.50,108 Even children thought to have full recov-
tients with untreated postinfectious encephalitis, al- ery demonstrated subtle neurocognitive deficits in
though three patients had residual lesions on MRI.105 attention, executive function, and behavior50 when
Seven of 21 patients with partial recovery in the reevaluated more than 3 years after ADEM, al-
South India group106 had more extensive white mat- though these deficits were not as severe as those
ter lesions compared to MRIs of children with reported for pediatric patients with MS.109 One study
complete recovery. No other factors, including ante- compared 19 children with ADEM to a normal age-
cedent infections, correlated with outcome. and sex-matched control group and found that pa-
In contrast, the Moscow group stratified 90 pedi- tients younger than 5 years at ADEM diagnosis had
atric ADEM patients with respect to antecedent in- significantly lower IQ and educational achievement
fections (33% rubella, 29% varicella, 22% with when evaluated at 3.9 years (mean) since illness,
unknown viral antecedent) and recurrence (11% while the older-onset patients had slower verbal pro-
were classified as multiphasic ADEM, most with pre- cessing, having been evaluated at 2.2 years (mean)
ceding upper respiratory symptoms). Diagnosis was after presentation.108 Behavioral problems were also
based on clinical symptoms following a prior viral more prominent in the young-onset ADEM group.
infection. MRI was routinely obtained only in the Additional studies are required to further character-
multiphasic group. Outcome varied with antecedent ize neurocognitive deficits following ADEM. These
infections with a good outcome reported in 70% of studies will help to guide assessments in individual
the ADEM cases without definite infection vs 54% patients and will facilitate appropriate educational
and 43% normal outcome reported for post-varicella interventions.
and post-rubella ADEM, respectively. Specific recov- It appears that symptom resolution is more rapid
ery times were described as approximately 3 weeks in steroid or IVIg-treated patients. However, due to
for post-rubella ADEM and up to 12 weeks for mul- the heterogeneity of the patient populations and
tiphasic ADEM, with intermediate but more variable treatment regimens, it is difficult to draw any spe-
recovery time in the post-varicella and unknown cific conclusions about the impact of treatment rela-
ADEM groups.107 Taken together, these reports sug- tive to long-term outcome. Multicenter prospective
gest that approximately two-thirds of patients make trials with consistent diagnostic criteria, treatment
a complete recovery without specific treatment, but protocols, and uniform data collection are critical to
that recovery may require weeks. improve our knowledge regarding management of
children and adolescents with cognitive deficits.
Treated ADEM. Table 1 summarizes the outcome
information in recently published case series of 15 or ADEM and MS. MS in children can initially
more patients with ADEM. Over half the patients present with symptoms and signs that are indistin-
treated had a good recovery with minimal or no def- guishable from ADEM. However, subsequent neuro-
icit. The most common problems seen following logic events or changes on MRI typical of MS lead to
ADEM were focal motor deficits ranging from mild the diagnosis of MS.18,19,110 The possibility that a
clumsiness and ataxia to hemiparesis or blindness. child may develop MS is a concern for parents and
Behavioral and cognitive problems were identified in clinicians, particularly in cases of recurrent or mul-
6 to 50% of children, but are likely underreported in tiphasic ADEM. MS in children can also present
S30 NEUROLOGY 68(Suppl 2) April 17, 2007
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with CIS that more closely resemble typical neuro- monly in patients who developed MS.22 However, in
logic events seen in adults with MS. CIS differs clin- other series the same features have been docu-
ically from ADEM, and is defined as either a mented in typical cases of ADEM.18,20
monofocal or multifocal demyelinating event in the Oligoclonal IgG bands in the CSF were found to be
absence of fever or encephalopathy (except in cases positive in 64 to 92% of pediatric MS cases, and in 0
of brainstem syndromes). to 29% of ADEM cases,18,21,22,111 but this difference
Our current consensus definition of pediatric MS was not statistically significant18 and so cannot be
states that a first event of ADEM is not considered used as a reliable marker of MS. Thus far, immuno-
the first event required for a diagnosis of MS, nor logic testing has not yielded a reliable marker for the
can it be used to determine dissemination in time development of MS from initial demyelinating events
and space. In these children, a second demyelinating in children.
event not meeting criteria for recurrent or multipha- To date, there are no clear clinical or radiologic
sic ADEM would qualify as an initial event, after parameters that predict which cases of ADEM or CIS
which subsequent MRI changes or new demyelinat- will develop MS.112,113 Early treatment of MS is
ing episodes would lead to a diagnosis of MS. While strongly advocated in adult patients, and has been
studies suggest that children with an initial ADEM shown to be beneficial in reducing long-term disabil-
event are at higher risk for the eventual develop- ity.114,115 Moreover, use of beta-interferon-1a in pedi-
ment of MS,18,19,110 the actual risk of MS following atric MS patients has recently been shown to be safe
ADEM remains unclear. Identifying prognostic indi- and tolerable.116,117 However, the risk of an inaccu-
cators including biomarkers are needed to further rate diagnosis of MS, which carries a lifetime burden
clarify the relationship between ADEM and subse- and requires ongoing treatment, is generally thought
quent risk of an MS diagnosis. to outweigh the risk of delaying diagnosis in order to
At present, there are no clear prognostic factors be certain of the diagnosis of MS. The proposed defi-
that determine if a child with a first event of either nition of pediatric MS may eventually require modi-
ADEM or CIS will eventually develop MS. The risk fication as more information is gathered regarding
of developing MS after ADEM has been reported as the predictability of developing MS after an initial
0%,21 9.5%,19 to 27%18 and 28%39 by different studies. demyelinating event. Clinical prognostic indicators
It should be noted that in these studies, varying or a biomarker that predicts the development of MS
criteria were used to define pediatric MS, and differ- after an initial demyelinating event in childhood is
ing lengths of follow-up were used, which may con- needed to facilitate an early and accurate diagnosis
tribute to the wide range in incidence. As a general of pediatric MS.
trend, ADEM carries a lower risk of developing MS
than CIS events. A study examining patients with a Pathogenesis. ADEM is characterized histologi-
first demyelinating event, including CIS-like and cally by perivenular infiltrates of T cells and macro-
ADEM events, showed that overall, 57% developed phages, associated with perivenular demyelination.
MS as defined by two demyelinating events.39 Of pa- Although ADEM shares common pathologic features
tients with an initial diagnosis of ADEM, 28% devel- with MS, distinct pathologic criteria distinguishing
oped MS. Of those with initial CIS-like events, 86% the two diseases have not been defined. There are no
with optic neuritis and 50% with an initial brain- systematic studies comparing the histopathology of
stem syndrome developed MS. Overall, positive pre- ADEM and MS, although such studies would un-
dictive factors for the development of MS were age at doubtedly yield important information on the rela-
onset 10 years or older (hazard ratio [HR], 1.67; 95% tionship between these two diseases. A variety of
CI), MS-suggestive initial MRI (HR 1.54), or optic pathologic features have been described in biopsy
nerve lesion (HR 2.59). A lower risk of developing and autopsy samples from ADEM and AHEM pa-
MS was found in patients with myelitis (HR 0.23) or tients. An autopsy from a 5-year-old boy with fatal
mental status change (HR 0.59) at presentation.39 ADEM grossly described diffuse brain edema, uncal
Twenty-nine percent (34 of 119) of children with a prior and tonsillar herniation.19 Multifocal perivascular
diagnosis of ADEM developed MS, while 75% (134 of lymphocytic infiltrates associated with fibrin deposi-
177) of children with a first event consistent with CIS tion within vascular lumens and adjacent demyelina-
developed MS. Although these clinical findings are tion were observed. There was diffuse anoxic-
helpful and serve as a guide, a definitive diagnosis of ischemic neuronal degeneration and intersitial
MS cannot be made based on these data. Moreover, use edema. Viral inclusion bodies were not seen in H-E
of standardized criteria to define MS in future studies sections. A brain biopsy performed in a 10-year-old
would greatly enhance interpretation. girl with severe AHEM demonstrated subcortical
Radiologic parameters provide supportive evi- WM with perivascular hemorrhagic necrosis with
dence for the diagnosis of MS; however, they cannot subacute inflammation consisting of macrophages,
be used as predictors for the development of the dis- neutrophils, and rare lymphocytes. No evidence of
ease, since many features thought to be unique to viral, bacterial, fungal, or parasitic infection was
MS are also seen in cases of ADEM.20 Lesions in the noted. Although ADEM is typically described as de-
corpus callosum, periventricular white matter, and myelination with relative preservation of axons, ax-
deep gray matter structures were seen more com- onal damage has been identified in the brains of
April 17, 2007 NEUROLOGY 68(Suppl 2) S31
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Table 2 Incidence of vaccination-associated ADEM

Vaccination forms Reported incidences of ADEM

Live measles vaccine 1–2/million131 (compared to 20–30/million incidence of measles
virus–induced encephalitis)
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
New York City Board of Health strain of vaccinia 2002–2004 3/665,000 (reporting encephalitis or myelitis)
Diphtheria/pertussis/tetanus 0.9/100,000
Hepatitis B Eight cases of CNS inflammation within 10 weeks Four cases
of partial myelitis within 3 months134

ADEM ⫽ acute disseminated encephalomyelitis.

some patients.118,119 Lesions largely involve the white pertussis, diphtheria, measles, mumps, rubella,
matter, but can also involve the cortex and deep gray pneumococcus, varicella, influenza, Japanese en-
matter structures. The CSF is characterized by ele- cephalitis, and polio.19,21,131-136 Vaccines produced in
vated protein and white blood cells. Oligoclonal CNS tissue including the Semple form of the rabies
bands are an acute manifestation in up to 30% of vaccine carry a higher risk of ADEM. It is important
patients with ADEM,18 and may be transient. Ele- to note that in general, vaccination forms with
vated CSF levels of the pro-inflammatory cytokines high rates of complications are no longer in use.
IL-6, IL-10, and TNF␣ have been described.120,121 Some reported incidences of encephalomyelitis asso-
Acute hemorrhagic and acute necrotizing hemor- ciated with various forms of vaccination are listed in
rhagic leukoencephalitis (AHEM, AHL, ANHLE) of table 2.
Weston Hurst shares some inflammatory histologic The pathogenesis of ADEM is unclear; however,
features with ADEM; however, demyelination is of- given its histologic features and typically monopha-
ten more widespread throughout the CNS and is as- sic course of disease, it has been likened to the
sociated with a pronounced neutrophilic infiltrate. animal model experimental autoimmune encephalo-
ANHLE is characterized by destruction of small myelitis (EAE). EAE is an autoimmune demyelinat-
blood vessels associated with acute hemorrhage and ing disease, which can be induced in a variety of
fibrin deposition.122 CSF analysis reflects the hemor- animal species by immunization with myelin pro-
rhagic nature of this disease with elevations in pro- teins or peptides. Moreover, the postvaccinial form of
tein, RBC, and WBC counts. ADEM associated with the Semple rabies vaccine,
ADEM may be classified as either postvaccinial or which contains rabies virus–infected neural tissue,
postinfectious; however, in many cases no clear ante- reinforces this analogy to EAE. Viral or bacterial
cedent history of either is present. Rare cases of epitopes resembling myelin antigens have the capac-
ADEM have been described following organ ity to activate myelin-reactive T cell clones through
transplantation.123-127 Postinfectious forms of ADEM molecular mimicry,137 and can thereby elicit a CNS-
typically begin within 2 to 21 days after an infectious specific autoimmune response. Thus, it has been sug-
event; however, longer intervals have also been de- gested that microbial infections preceding ADEM
scribed. Viral infections commonly associated with elicit a cross-reactive anti-myelin response through
ADEM include influenza virus, enterovirus, measles, molecular mimicry. Alternatively, ADEM may be
mumps, rubella, varicella zoster, Epstein Barr virus, caused by the activation of existing myelin-reactive
cytomegalovirus, herpes simplex virus, hepatitis A, T cell clones through a nonspecific inflammatory
and coxsackievirus. Bacterial triggers include Myco- process.
plasma pneumoniae, Borrelia burgdorferi, Lepto- Theiler murine encephalomyelitis virus–induced
spira, and beta-hemolytic Streptococcus. Acute demyelinating disease (TMEV-IDD) model is induced
hemorrhagic leukoencephalomyelitis (AHLE) typi- by direct CNS infection of the neurotropic TMEV
cally follows influenza or upper respiratory infection. picornavirus, initially resulting in an immune-
The only epidemiologically and pathologically proven mediated reaction primarily involving TMEV-specific
association of ADEM with vaccinations is with the CD4 and CD8 T cells.138,139 However, during the
Semple form of the rabies vaccine.3,128-130 Other vacci- chronic stages of disease, T cell reactivity to host
nations associated with ADEM include hepatitis B, myelin peptides has been observed, indicating
S32 NEUROLOGY 68(Suppl 2) April 17, 2007
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epitope spreading has occurred secondary to T cell associated with the two diseases suggests differences
responses to myelin breakdown products, resulting in pathogenesis.
in an autoimmune response.140 Both microglia141 and
dendritic cells142 from the CNS of TMEV-infected Research/future directions. ADEM often poses
mice are able to present myelin peptides to naı̈ve T both a diagnostic and prognostic dilemma for clini-
cells, thereby facilitating epitope spreading to nonvi- cians. In the acute stage, there should be a low sus-
ral, host myelin antigens. The TMEV model high- picion of infection before initiation of corticosteroid
lights the phenomenon of epitope spreading or immunosuppressive therapy. Diagnostic tests that
secondary to a destructive CNS viral infection result- increase the rapidity of an accurate diagnosis are
ing in a secondary autoimmune response and chronic recommended. Over the long term, one of the most
inflammation. Although this model superficially pressing questions of a child presenting with ADEM,
bears some resemblance to ADEM, it is important to particularly recurrent or multiphasic forms of
note that overwhelming evidence has shown that ADEM, is the potential risk for conversion to MS.
ADEM is not due to direct viral infection of the CNS, Although ADEM and MS share many similar patho-
but is a secondary immune-mediated phenomenon. logic features, prognosis is drastically different.
Epitope spreading is likely to be an important phe- Therefore, identification of a biomarker that can pre-
nomenon in chronic inflammatory diseases such as dict the development of MS after an ADEM event is
MS, but involvement in ADEM is unknown. critical.
Sequences in myelin basic protein have been Additional studies are required to understand the
shown to resemble several viral sequences, and in worldwide epidemiology and distribution of ADEM.
some cases, cross-reactive T cell responses have been These studies may give insight into the pathogenesis
demonstrated. Examples of cross-reactive T cells of the disease and potential preventative measures.
with MBP antigens include HHV-6,143 coronavirus,144 Early identification of triggers for ADEM, such as
influenza virus hemagglutinin,145 and EBV.146 Prote- specific batches of vaccines, is facilitated by strin-
olipid protein (PLP) shares common sequences with gent monitoring mechanisms.
Haemophilus influenza.147 Semliki forest virus (SFV) Current treatments for ADEM generally lead to
peptides mimic myelin oligodendrocyte glycoprotein acceptable outcomes; however, further studies are
(MOG).148 Enhanced myelin basic protein (MBP)- required to investigate the use of additional agents,
reactive T cell responses have been demonstrated in particularly for refractory or multiphasic cases.
patients with postinfectious forms of ADEM.149,150 El- There is a paucity of literature on the use of chemo-
evated titers of anti-myelin antibodies in sera from therapeutic agents for ADEM, although anecdotal
patients with ADEM have recently been demon- use is prevalent. In addition, use of ␤-interferons for
strated as compared to patients with MS or viral multiphasic forms of ADEM requires further
encephalitis.151 Previous studies have demonstrated investigation.
enhanced anti-MBP antibody titers in patients with The use of standardized definitions for ADEM and
postvaccinial ADEM following vaccination with the MS in children and adolescents will help to facilitate
Semple rabies vaccine.152,153 One of these studies future studies, regarding the prognosis, pathogene-
demonstrated elevated anti-MBP antibody titers in sis, and treatment of these two diseases.
ADEM samples compared with MS samples. Al-
though there is controversy surrounding the charac-
terization of anti-myelin antibody responses in MS,
The International Pediatric MS Study Group: Lauren Krupp, MD (chair),
studies in ADEM have consistently shown detectable Brenda L. Banwell, MD, Anita Belman, MD, Dorothee Chabas, MD, PhD,
levels, suggesting differences in pathogenesis. Col- Tanuja Chitnis, MD, Peter Dunne, MD, Andrew Goodman, MD, Jin S.
Hahn, MD, Deborah P. Hertz, MPH, Nancy J. Holland, EdD, RN, MSCN,
lectively, these studies suggest that enhanced T and Douglas Jeffery, MD, PhD, William MacAllister, PhD, Raul Mandler, MD,
B cell myelin responses play a role in the pathogene- Maria Milazzo, RN, MS, CPNP, Jayne Ness, MD, PhD, Jorge Oksenberg,
sis of both postinfectious and postvaccinial ADEM; PhD, Trena L. Pelham, MD, Daniela Pohl, MD, PhD, Kottil Rammohan,
MD, Mary R. Rensel, MD, Christel Renoux, MD, Dessa Sadovnick, PhD,
however, further studies are required to determine Steven Robert Schwid, MD, Silvia Tenembaum, MD, Cristina Toporas,
causal relationship. Emmanuelle Waubant, MD, PhD, Bianca Weinstock-Guttman, MD.
ADEM was associated with the class II alleles
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Acute disseminated encephalomyelitis
Silvia Tenembaum, Tanuja Chitnis, Jayne Ness, Jin S. Hahn and for the International
Pediatric MS Study Group
Neurology 2007;68;S23-S36
DOI: 10.1212/01.wnl.0000259404.51352.7f
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