Anda di halaman 1dari 16

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

The online version of this article, along with updated information and services, is
located on the World Wide Web at:
http://www.neurology.org/cgi/content/full/68/16_suppl_2/S23

Neurology® is the official journal of the American Academy of Neurology. Published continuously
since 1951, it is now a weekly with 48 issues per year. Copyright © 2007 by AAN Enterprises, Inc.
All rights reserved. Print ISSN: 0028-3878. Online ISSN: 1526-632X.

Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008


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: silviatenembaum@hotmail.com, solier@ciudad.com.ar

Copyright © 2007 by AAN Enterprises, Inc. S23


Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
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
S24 NEUROLOGY 68(Suppl 2) April 17, 2007
Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
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.
April 17, 2007 NEUROLOGY 68(Suppl 2) S25
Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
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
S26 NEUROLOGY 68(Suppl 2) April 17, 2007
Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
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
lesions.

purposes, but for therapeutic purposes, since a diag-


nosis of MS, at least in adult patients, carries the
recommendation for early treatment with
immunomodulators.
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.
April 17, 2007 NEUROLOGY 68(Suppl 2) S27
Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
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
S28 NEUROLOGY 68(Suppl 2) April 17, 2007
Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
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
Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
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
Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
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
Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
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 measles
virus–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
135
New York City Board of Health strain of vaccinia 2002–2004 3/665,000 (reporting encephalitis or myelitis)
131
Diphtheria/pertussis/tetanus 0.9/100,000
133
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
Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
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-
Appendix
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
HLA-DRB1*01 and HLA-DRB*03 in a Russian References
study.107 A similar study from Korea showed an asso- 1. Rust RS. Multiple sclerosis, acute disseminated encephalomyelitis,
ciation of ADEM with HLA-DRB1*1501, as well as and related conditions. Semin Pediatr Neurol 2000;7:66–90.
2. Dale RC. Acute disseminated encephalomyelitis. Semin Pediatr Infect
HLA-DRB5*0101.154 The same Korean study showed Dis 2003;14:90–95.
an association of HLA-DRB3*0202 and HLA- 3. Garg RK. Acute disseminated encephalomyelitis. Postgrad Med J
DQB1*0502 with acute necrotizing forms of enceph- 2003;79:11–17.
4. Jones CT. Childhood autoimmune neurologic diseases of the central
alopathy. The gene mostly frequently linked with nervous system. Neurol Clin 2003;21:745–764.
MS is HLA DRB1,155 with DR215,156 being the most 5. Marsden JP, Hurst EW. Acute perivascular myelinoclasis (“acute dis-
seminated encephalomyelitis”) in smallpox. Brain 1932;55:181–193.
frequently involved allele. Similar associations have 6. Davison C, Brock S. Acute demyelinating encephalomyelitis following
been found in the pediatric MS population.157 Thus, respiratory disease. Bull Neurol Inst NY 1937;6:504–514.
7. Van Bogaert L. Post-infectious encephalomyelitis and multiple sclero-
class II alleles may play a role in MS as well as sis; the significance of perivenous encephalomyelitis. J Neuropathol
ADEM; however, the disparity between the alleles Exp Neurol 1950;9:219–249.

April 17, 2007 NEUROLOGY 68(Suppl 2) S33


Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
8. Ferraro A, Roizin L. Hyperergic encephalomyelitides following exan- 40. Richer LR, Sinclair DB, Bhargava R. Neuroimaging features of acute
thematic diseases, infectious diseases and vaccination. J Neuropathol disseminated encephalomyelitis in childhood. Pediatr Neurol 2005;32:
Exp Neurol 1957;16:423–445. 30–36.
9. DeVries. Postvaccinal perivenous encephalitis. Amsterdam: Elsevier, 41. Bizzi A, Ulug AM, Crawford TO, et al. Quantitative proton MR spec-
1960. troscopic imaging in acute disseminated encephalomyelitis. AJNR
10. Carpenter S, Lampert PW. Postinfectious perivenous encephalitis and Am J Neuroradiol 2001;22:1125–1130.
acute hemorrhagic leukoencephalitis. In: Minckler J, ed. Pathology of 42. Mader I, Wolff M, Nagele T, Niemann G, Grodd W, Kuker W. MRI and
the nervous system. New York: McGraw-Hill, 1968:2260–2269. proton MR spectroscopy in acute disseminated encephalomyelitis.
11. Poser ChM. Disseminated vasculomyelinopathy. A review of the clini- Childs Nerv Syst 2005;21:566–572.
cal and pathologic reactions of the nervous system in hyperergic dis- 43. Harada M, Hisaoka S, Mori K, Yoneda K, Noda S, Nishitani H. Differ-
eases. Acta Neurol Scand 1969:37 suppl:33–44. ences in water diffusion and lactate production in two different types
12. Pasternak JF, De Vivo DC, Prensky AL. Steroid responsive encephalo- of postinfectious encephalopathy. J Magn Reson Imaging 2000;11:559–
myelitis in childhood. Neurology 1980;30:481–486. 563.
13. Lukes SA, Norman D. Computed tomography in acute disseminated 44. Bernarding J, Braun J, Koennecke HC. Diffusion- and perfusion-
encephalomyelitis. Ann Neurol 1983;13:567–572. weighted MR imaging in a patient with acute disseminated encephalo-
14. Dunn V, Bale JF, Zimmerman RA, Perdue Z, Bell WE. MRI in children myelitis (ADEM). J Magn Reson Imaging 2002;15:96–100.
with postinfectious disseminated encephalomyelitis. Magn Reson Im- 45. Tabata K, Shishido F, Uemura K, et al. Positron emission tomography
aging 1986;4:25–32. in acute disseminated encephalomyelitis: a case report. Kaku Igaku
15. Boulloche J, Parain D, Mallet E, Tron P. Postinfectious encephalitis 1990;27:261–265.
with multifocal white matter lesions. Neuropediatrics 1989;20:173– 46. Broich K, Horwich D, Alavi A. HMPAO-SPECT and MRI in acute
175. disseminated encephalomyelitis. J Nucl Med 1991;32:1897–1900.
16. Brinar VV. Non-MS recurrent demyelinating diseases. Clin Neurol 47. San Pedro EC, Mountz JM, Liu HG, Deutsch G. Postinfectious cereb-
Neurosurg 2004;106:197–210. ellitis: clinical significance of Tc-99m HMPAO brain SPECT compared
17. Schwarz S, Mohr A, Knauth M, Wildemann B, Storch-Agenlocher B. with MRI. Clin Nucl Med 1998;23:212–216.
Acute disseminated encephalomyelitis: a follow-up study of 40 adult 48. Itti E, Huff K, Cornford ME, Itti L, Poruri K, Mishkin FS. Postinfec-
patients. Neurology 2001;56:1313–1318. tious encephalitis. A coregistered SPECT and magnetic resonance im-
18. Dale RC, de Sousa C, Chong WK, Cox TC, Harding B, Neville BG. aging study. Clin Nucl Med 2002;27:129–130.
Acute disseminated encephalomyelitis, multiphasic disseminated en- 49. Okamoto M, Ashida KI, Imaizumi M. Hypoperfusion following enceph-
cephalomyelitis and multiple sclerosis in children. Brain 2000;123: alitis: SPECT with acetazolamide. Eur J Neurol 2001;8:471–474.
2407–2422. 50. Hahn CD, Miles BS, MacGregor DL, Blaser SI, Banwell BL, Hether-
19. Leake JAD, Albani S, Kao AS, et al. Acute disseminated encephalomy- ington CR. Neurocognitive outcome after acute disseminated encepha-
elitis in childhood: epidemiologic, clinical and laboratory features. Pe- lomyelitis. Pediatr Neurol 2003;29:117–123.
diatr Infect Dis J 2004;23:756–764. 51. Hung K-L, Liao H-T, Tsai M-L. The spectrum of postinfectious enceph-
20. Murthy KSN, Faden HS, Cohen ME, Bakshi R. Acute disseminated alomyelitis. Brain Dev 2001;23:42–45.
encephalomyelitis in children. Pediatrics 2002;110:21–28. 52. Tardieu M, Mikaeloff Y. What is acute disseminated encephalomyelitis
21. Tenembaum S, Chamoles N, Fejerman N. Acute disseminated enceph- (ADEM)? Eur J Paediatr Neurol 2004;8:239–242.
alomyelitis: a long-term follow-up study of 84 pediatric patients. Neu- 53. Seales D, Greer M. Acute hemorrhagic leukoencephalitis: a successful
rology 2002;59:1224–1231. recovery. Arch Neurol 1991;48:1086–1088.
22. Hynson JL, Kornberg AJ, Coleman LT, Shield L, Harvey AS, Kean 54. Rosman PN, Gottlieb SM, Bernstein CA. Acute hemorrhagic leukoen-
MJ. Clinical and neuroradiologic features of acute disseminated en- cephalitis: recovery and reversal of magnetic resonance imaging find-
cephalomyelitis in children. Neurology 2001;56:1308–1312. ings in a child. J Child Neurol 1997;12:448–454.
23. Anlar B, Basaran C, Kose G, et al. Acute disseminated encephalomy- 55. Klein C, Wijdicks EFM, Earnest IVF. Full recovery after acute hemor-
elitis in children: outcome and prognosis. Neuropediatrics 2003;34: rhagic leukoencephalitis (Hurst’s disease). J Neurol 2000;247:977–979.
194–199. 56. Kuperan S, Ostrow P, Landi MK, Bakshi R. Acute hemorrhagic leu-
24. Amit R, Shapira Y, Blank A, Aker M. Acute, severe, central and koencephalitis vs. ADEM: FLAIR MRI and neuropathology findings.
peripheral nervous system combined demyelination. Pediatr Neurol Neurology 2003;60:721–722.
1986;2:47–50. 57. Mader I, Wolff M, Niemann G, Küker W. Acute haemorrhagic enceph-
25. Menge T, Hemmer B, Nessler S, et al. Acute disseminated encephalo- alomyelitis (AHEM): MRI findings. Neuropediatrics 2004;35:143–146.
myelitis. An update. Arch Neurol 2005;62:1673–1680. 58. Miller DH, Scaravilli F, Thomas DCT, Harvey P, Hirsch NP. Acute
26. Gupte G, Stonehouse M, Wassmer E, Coad NA, Whitehouse WP. Acute disseminated encephalomyelitis presenting as a solitary brainstem
disseminated encephalomyelitis: a review of 18 cases in childhood. J mass. J Neurol Neurosurg Psychiatry 1993;56:920–922.
Paediatr Child Health 2003;39:336–342. 59. Tateishi K, Takeda K, Mannen T. Acute disseminated encephalomyeli-
27. Amit R, Glick B, Itzchak Y, Dgani Y, Meyeir S. Acute severe combined tis confined to brainstem. J Neuroimaging 2002;12:67–68.
demyelination. Child’s Nerv Syst 1992;8:354–356. 60. Firat AK, Karakas HM, Yakinci C, Altinok T, Alkan A, Biçak U. An
28. Nadkarni N, Lisak R. Guillain-Barré syndrome (GBS) with bilateral unusual case of acute disseminated encephalomyelitis confined to
optic neuritis and central white matter disease. Neurology 1993;43: brainstem. Magn Reson Imaging 2004;22:1329–1332.
842–843. 61. Straussberg R, Schonfeld T, Weitz R, Karmazyn B, Harel L. Improve-
29. Marchioni E, Ravaglia S, Piccolo G, et al. Postinfectious inflammatory ment of atypical acute disseminated encephalomyelitis with steroids
disorders: subgroups based on prospective follow-up. Neurology 2005; and intravenous immunoglobulins. Pediatr Neurol 2001;24:139–143.
65:1057–1065. 62. Garg BP, Kleiman MB. Acute disseminated encephalomyelitis present-
30. Wingerchuk DM. Postinfectious encephalomyelitis. Curr Neurol Neu- ing as a neurodegenerative disease in infancy. Pediatr Neurol 1994;11:
rosci Rep 2003;3:256–264. 57–58.
31. Baum PA, Barkovich AJ, Koch TK, Berg BO. Deep grey matter in- 63. van der Knaap MS, Valk J. Myelination and retarded myelination. In:
volvement in children with acute disseminating encephalomyelitis. van der Knaap MS, Valk J, eds. Magnetic resonance of myelin, myeli-
AJNR Am J Neuroradiol 1994;15:1275–1283. nation, and myelin disorders. 2nd ed. Berlin-Heidelberg: Springer-
32. Kimura S, Unayama T, Mori T. The natural history of acute dissemi- Verlag, 1995:31–52.
nated leukoencephalitis. A serial magnetic resonance imaging study. 64. Ramaswamy V, Sinclair DB, Wheatley BM, Richer L, Snyder T. Epi-
Neuropediatrics 1992;23:192–195. lepsia partialis continua: acute disseminated encephalomyelitis or
33. Kesselring J, Miller DH, Robb SA, et al. Acute disseminated encepha- Rasmussen’s encephalitis? Pediatr Neurol 2005;32:341–345.
lomyelitis and MRI findings and the distinction from multiple sclero- 65. Shoji H, Kusuhara T, Honda Y, et al. Relapsing acute disseminated
sis. Brain 1990;113:291–302. encephalomyelitis associated with chronic Epstein-Barr virus infec-
34. Singh S, Alexander M, Korah IP. Acute disseminated encephalomyeli- tion: MRI findings. Neuroradiology 1992;34:340–342.
tis: MR imaging features. AJR Am J Roentgenol 1999;173:1101–1107. 66. Khan S, Yaqub BA, Poser CMAL, Deeb SM, Bohlega S. Multiphasic
35. Khong PL, Ho HK, Cheng PW, Wong VC, Goh W, Chan FL. Childhood disseminated encephalomyelitis presenting as alternating hemiplegia.
acute disseminated encephalomyelitis: the role of brain and spinal J Neurol Neurosurg Psychiatry 1995;58:467–470.
cord MRI. Pediatr Radiol 2002;32:59–66. 67. Tsai M-L, Hung K-L. Multiphasic disseminated encephalomyelitis
36. Lim KE, Hsu YY, Hsu WC, Chan CY. Multiple complete ring-shaped mimicking multiple sclerosis. Brain Dev 1996;18:412–414.
enhanced MRI lesions in disseminated encephalomyelitis. Clin Imag- 68. Hahn JS, Siegler DJ, Enzmann D. Intravenous gammaglobulin ther-
ing 2003;27:281–284. apy in recurrent acute disseminated encephalomyelitis. Neurology
37. Caldemeyer KS, Smith RR, Harris TM, Edwards MK. MRI in acute 1996;46:1173–1174.
disseminated encephalomyelitis. Neuroradiology 1994;36:216–220. 69. Apak RA, Anlar B, Saatci I. A case of relapsing acute disseminated
38. Van Meyden CH, de-Villers JFK, Middlecote BD, Terbalanche J. Gad- encephalomyelitis with high dose corticosteroid treatment. Brain Dev
olinium ring enhancement and mass effect in acute disseminating 1999;21:279–282.
encephalomyelitis. Neuroradiol 1994;36:221–223. 70. Revel-Vilk S, Hurvitz H, Klar A, Virozov Y, Korn-Lubetzki I. Recur-
39. Mikaeloff Y, Suissa S, Vallée L, et al. First episode of acute CNS rent acute disseminated encephalomyelitis associated with acute cyto-
inflammatory demyelination in childhood: prognostic factors for multi- megalovirus and Epstein-Barr virus infection. J Child Neurol 2000;15:
ple sclerosis and disability. J Pediatr 2004;144:246–252. 421–424.

S34 NEUROLOGY 68(Suppl 2) April 17, 2007


Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
71. Cohen O, Steiner-Birmanns B, Biran I, Abramsky O, Honigman S, 99. Stricker RB, Miller RG, Kiprov DD. Role of plasmapheresis in acute
Steiner I. Recurrence of acute disseminated encephalomyelitis at the disseminated (postinfectious) encephalomyelitis. J Clin Apheresis
previously affected brain site. Arch Neurol 2001;58:797–801. 1992;7:173–179.
72. Härtel C, Schilling S, Gottschalk S, Sperner J. Multiphasic dissemi- 100. Ramachandrannair R, Rafeequ M, Girija AS. Plasmapheresis in child-
nated encephalomyelitis associated with streptococcal infection. Eur J hood acute disseminated encephalomyelitis. Ind Pediatr 2005;42:479–
Paediatr Neurol 2002;6:327–329. 482.
73. Mariotti P, Batocchi AP, Colosimo C, et al. Multiphasic demyelinating 101. Miyazawa R, Hikima A, Takano Y, Arakawa H, Tomomasa T,
disease involving central and peripheral nervous system in a child. Morikawa A. Plasmapheresis in fulminant acute disseminated enceph-
Neurology 2003;60:348–349. alomyelitis. Brain Dev 2001;23:424–426.
74. Alper G, Schor NF. Toward the definition of acute disseminated en- 102. Balestri P, Grosso S, Acquaviva A, Bernini M. Plasmapheresis in a
cephalitis of childhood. Curr Opin Pediatr 2004;16:637–640. child affected by acute disseminated encephalomyelitis. Brain Dev
74a. Krupp LB, Banwell B, Tenembaum S, for the International Pediatric 2000;22:123–126.
MS Study Group. Consensus definitions proposed for pediatric multi- 103. Newton R. Plasma exchange in acute post-infectious demyelination.
ple sclerosis and related childhood disorders. Neurology 2007; Dev Med Child Neurol 1981;23:538–543.
68(suppl 2):S7–S12. 104. Lin CH, Jeng JS, Yip PK. Plasmapheresis in acute disseminated en-
75. Poser CM, Goutières F, Carpentier MA, Aicardi J. Shilder’s myelino- cephalomyelitis. J Clin Apheresis 2004;19:154–159.
clastic diffuse sclerosis. Pediatrics 1986;77:107–112. 105. Kimura S, Nezu A, Ohtsuki N, Kobayashi T, Osaka H, Uehara S.
76. Kepes JJ. Large focal tumor-like demyelinating lesions of the brain: Serial magnetic resonance imaging in children with postinfectious
intermediate entity between MS and acute disseminated encephalo- encephalitis. Brain Dev 1996;18:461–465.
myelitis? A study of 31 patients. Ann Neurol 1993;33:18–27. 106. Murthy JM, Yangala R, Meena AK, Jaganmohan RJ. Acute dissemi-
77. Tenembaum S, Galicchio S, Grañana N, et al. Demyelinating enceph- nated encephalomyelitis: clinical and MRI study from South India.
alopathies with large focal lesions: diagnostic clues. Brain Dev 1998; J Neurol Sci 1999;165:133–138.
20:434. Abstract. 107. Idrissova Z, Boldyreva MN, Dekonenko EP, et al. Acute disseminated
78. Mizuguchi M, Abe J, Mikkaichi K, et al. Acute necrotizing encephalop- encephalomyelitis in children: clinical features and HLA-DR linkage.
athy of childhood: a new syndrome presenting with multifocal, sym- Eur J Neurol 2003;10:537–546.
metric brain lesions. J Neurol Neurosurg Psychiatry 1995;58:555–561. 108. Jacobs RK, Anderson VA, Neale JL, Shield LK, Kornberg AJ. Neuro-
79. Mizuguchi M. Acute necrotizing encephalopathy of childhood: a novel psychological outcome after acute disseminated encephalomyelitis: im-
form of acute encephalopathy prevalent in Japan and Taiwan. Brain pact of age at illness onset. Pediatr Neurol 2004;31:191–197.
Dev 1997;19:81–92. 109. Banwell BL, Anderson PE. The cognitive burden of multiple sclerosis
80. Suwa K, Yamagata T, Momoi MT, et al. Acute relapsing encephalopa- in children. Neurology 2005;64:891–894.
thy mimicking acute necrotizing encephalopathy in a 4-year-old boy. 110. Morimatsu M. Recurrent ADEM or MS? Intern Med 2004;43:647–648.
Brain Dev 1999;21:554–558. 111. Pohl D, Rostasy K, Reiber H, Hanefeld F. CSF characteristics in early-
81. Ruggieri M, Polizzi A, Pavone L, Musumeci S. Thalamic syndrome in onset multiple sclerosis. Neurology 2004;63:1966–1967.
children with measles infection and selective, reversible thalamic in- 112. Mikaeloff Y, Adamsbaum C, Husson B, et al. MRI prognostic factors
volvement. Pediatrics 1998;101:112–119. for relapse after acute CNS inflammatory demyelination in childhood.
82. Hartfield D, Loewy J, Yager J. Transient thalamic changes on MRI in Brain 2004;127:1942–1947.
a child with hypernatremia. Pediatr Neurol 1999;20:60–62. 113. Tardieu M, Mikaeloff Y. Multiple sclerosis in children. Int MS J 2004;
83. Ohtaki E, Murakami Y, Komori H, et al. Acute disseminated encepha- 11:36–42.
lomyelitis after Japanese B encephalitis vaccination. Pediatr Neurol 114. Rudick RA, Goodman A, Herndon RM, Panitch HS. Selecting relaps-
ing remitting multiple sclerosis patients for treatment: the case for
1992;8:137–139.
early treatment. J Neuroimmunol 1999;98:22–28.
84. Cusmai R, Bertini E, Di Capua M, et al. Bilateral, reversible, selective
115. Coyle PK, Hartung HP. Use of interferon beta in multiple sclerosis:
thalamic involvement demonstrated by brain MR and acute severe
rationale for early treatment and evidence for dose- and frequency-
neurological dysfunction with favorable outcome. Neuropediatrics
dependent effects on clinical response. Mult Scler 2002;8:2–9.
1994;25:44–47.
116. Pohl D, Rostasy K, Gärtner J, Hanefeld F. Treatment of early onset
85. Goutières F, Aicardi J. Acute neurological dysfunction associated with
multiple sclerosis with subcutaneous interferon beta-1a. Neurology
destructive lesions of the basal ganglia in children. Ann Neurol 1982;
2005;64:888–890.
12:328–332.
117. Tenembaum SN, Segura MJ. Interferon beta-1a treatment in child-
86. Dale RC, Church AJ, Cardoso F, et al. Post streptococcal acute dissem-
hood and juvenile-onset multiple sclerosis. Neurology 2006;67:511–
inated encephalomyelitis with basal ganglia Involvement and auto-
513.
reactive antibasal ganglia antibodies. Ann Neurol 2001;50:588–595.
118. Ghosh N, DeLuca GC, Esiri MM. Evidence of axonal damage in hu-
87. Miller HG, Gibbons JL. Acute disseminated encephalomyelitis and man acute demyelinating diseases. J Neurol Sci 2004;222:29–34.
acute disseminated sclerosis; results of treatment with A.C.T.H. BMJ 119. DeLuca GC, Ebers GC, Esiri MM. Axonal loss in multiple sclerosis: a
1953;4850:1345–1348. pathological survey of the corticospinal and sensory tracts. Brain
88. Ziegler DK. Acute disseminated encephalomyelitis. Arch Neurol 1966; 2004;127:1009–1018.
14:476–488. 120. Ichiyama T, Shoji H, Kato M, et al. Cerebrospinal fluid levels of
89. Shahar E, Andraus J, Savitzki D, Pilar G, Zelnik N. Outcome of severe cytokines and soluble tumour necrosis factor receptor in acute dissem-
encephalomyelitis in children: effect of high-dose methylprednisolone inated encephalomyelitis. Eur J Pediatr 2002;161:133–137.
and immunoglobulins. J Child Neurol 2002;17:810–814. 121. Dale RC, Morovat A. Interleukin-6 and oligoclonal IgG synthesis in
90. Kotlus BS, Slavin ML, Guthrie DS, Kodsi SR. Ophthalmologic mani- children with acute disseminated encephalomyelitis. Neuropediatrics
festations in pediatric patients with acute disseminated encephalomy- 2003;34:141–145.
elitis. J AAPOS 2005;9:179–183. 122. Kumar V, Cotran RS, Robbins SL. Robbins basic pathology, updated
91. Thomas GS, Hussain IH. Acute disseminated encephalomyelitis: a edition. 7th ed. Saunders; 2004.
report of six cases. Med J Malaysia 2004;59:342–351. 123. Horowitz MB, Comey C, Hirsch W, Marion D, Griffith B, Martinez J.
92. Nishikawa M, Ichiyama T, Hayashi T, Ouchi K, Furukawa S. Intrave- Acute disseminated encephalomyelitis (ADEM) or ADEM-like inflam-
nous immunoglobulin therapy in acute disseminated encephalomyeli- matory changes in a heart-lung transplant recipient: a case report.
tis. Pediatr Neurol 1999;21:583–586. Neuroradiology 1995;37:434–437.
93. Kleiman M, Brunquell P. Acute disseminated encephalomyelitis: re- 124. Re A, Giachetti R. Acute disseminated encephalomyelitis (ADEM) af-
sponse to intravenous immunoglobulin. J Child Neurol 1995;10:481– ter autologous peripheral blood stem cell transplant for non-Hodgkin’s
483. lymphoma. Bone Marrow Transplant 1999;24:1351–1354.
94. Sahlas DJ, Miller SP, Guerin M, Veilleux M, Francis G. Treatment of 125. Iwanaga T, Ooboshi H, Imamura T, et al. A case of acute disseminated
acute disseminated encephalomyelitis with intravenous immunoglobu- encephalomyelitis after renal transplantation. Rinsho Shinkeigaku
lin. Neurology 2000;54:1370–1372. 2001;41:792–796.
95. Pradhan S, Gupta RP, Shashank S, Pandey N. Intravenous immuno- 126. Au WY, Lie AK, Cheung RT, et al. Acute disseminated encephalomy-
globulin therapy in acute disseminated encephalomyelitis. J Neurol elitis after para-influenza infection post bone marrow transplantation.
Sci 1999;165:56–61. Leuk Lymphoma 2002;43:455–457.
96. Marchioni E, Marinou-Aktipi K, Uggetti C, et al. Effectiveness of in- 127. Tomonari A, Tojo A, Adachi D, et al. Acute disseminated encephalomy-
travenous immunoglobulin treatment in adult patients with steroid- elitis (ADEM) after allogeneic bone marrow transplantation for acute
resistant monophasic or recurrent acute disseminated myeloid leukemia. Ann Hematol 2003;82:37–40.
encephalomyelitis. J Neurol 2002;249:100–104. 128. Hemachudha T, Griffin DE, Giffels JJ, Johnson RT, Moser AB, Pha-
97. Pittock SJ, Keir G, Alexander M, Brennan P, Hardiman O. Rapid nuphak P. Myelin basic protein as an encephalitogen in encephalomy-
clinical and CSF response to intravenous gamma globulin in acute elitis and polyneuritis following rabies vaccination. N Engl J Med
disseminated encephalomyelitis. Eur J Neurol 2001;8:725. 1987;316:369–374.
98. Keegan M, Pineda AA, McClelland RL, Darby CH, Rodriguez M, Wein- 129. Hemachudha T, Griffin DE, Johnson RT, Giffels JJ. Immunologic
shenker BG. Plasma exchange for severe attacks of CNS demyelina- studies of patients with chronic encephalitis induced by post-exposure
tion: predictors of response. Neurology 2002;58:143–146. Semple rabies vaccine. Neurology 1988;38:42–44.

April 17, 2007 NEUROLOGY 68(Suppl 2) S35


Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
130. Murthy JM. Acute disseminated encephalomyelitis. Neurol India 145. Markovic-Plese S, Hemmer B, Zhao Y, Simon R, Pinilla C, Martin R.
2002;50: 238–243. High level of cross-reactivity in influenza virus hemagglutinin-specific
131. Fenichel GM. Neurological complications of immunization. Ann Neu- CD4⫹ T-cell response: implications for the initiation of autoimmune
rol 1982;12:119–128. response in multiple sclerosis. J Neuroimmunol 2005;169:31–38.
132. Takahashi H, Pool V, Tsai TF, Chen RT. Adverse events after Japa- 146. Lang HL, Jacobsen H, Ikemizu S, et al. A functional and structural
nese encephalitis vaccination: review of post-marketing surveillance basis for TCR cross-reactivity in multiple sclerosis. Nat Immunol
data from Japan and the United States. The VAERS Working Group. 2002;3:940–943.
Vaccine 2000;18:2963–2969. 147. Olson JK, Croxford JL, Miller SD. Virus-induced autoimmunity: po-
133. Tourbah A, Gout O, Liblau R, et al. Encephalitis after hepatitis B tential role of viruses in initiation, perpetuation, and progression of
vaccination: recurrent disseminated encephalitis or MS? Neurology T-cell-mediated autoimmune disease. Viral Immunol 2001;14:227–
1999;53:396–401. 250.
134. Karaali-Savrun F, Altintas A, Saip S, Siva A. Hepatitis B vaccine 148. Mokhtarian F, Zhang Z, Shi Y, Gonzales E, Sobel RA. Molecular mim-
related-myelitis? Eur J Neurol 2001;8:711–715. icry between a viral peptide and a myelin oligodendrocyte glycoprotein
135. Sejvar JJ, Labutta RJ, Chapman LE, Grabenstein JD, Iskander J, peptide induces autoimmune demyelinating disease in mice. J Neuro-
Lane JM. Neurologic adverse events associated with smallpox vaccina- immunol 1999;95:43–54.
tion in the United States, 2002-2004. JAMA 2005;294:2744–2750. 149. Pohl-Koppe A, Burchett SK, Thiele EA, Hafler DA. Myelin basic pro-
136. Ozawa H, Noma S, Yoshida Y, Sekine H, Hashimoto T. Acute dissem- tein reactive Th2 T cells are found in acute disseminated encephalo-
inated encephalomyelitis associated with poliomyelitis vaccine. Pedi- myelitis. J Neuroimmunol 1998;91:19–27.
atr Neurol 2000;23:177–179. 150. Jorens PG, VanderBorght A, Ceulemans B, et al. Encephalomyelitis-
137. Wucherpfennig KW, Strominger JL. Molecular mimicry in T cell- associated antimyelin autoreactivity induced by streptococcal exotox-
mediated autoimmunity: viral peptides activate human T cell clones ins. Neurology 2000;54:1433–1441.
specific for myelin basic protein. Cell 1995;80:695–705. 151. O’Connor KC, Robinson WH, De-Jager PL, et al. High-throughput analy-
138. Clatch RJ, Lipton HL, Miller SD. Characterization of Theiler’s murine sis of autoantibodies recognizing myelin antigens in acute disseminated
encephalomyelitis virus (TMEV)-specific delayed-type hypersensitivity encephalomyelitis. Neurology 2005;64(suppl 1):A417. Abstract.
responses in TMEV-induced demyelinating disease: correlation with 152. Ubol S, Hemachudha T, Whitaker JN, Griffin DE. Antibody to pep-
clinical signs. J Immunol 1986;136:920–927. tides of human myelin basic protein in post-rabies vaccine encephalo-
139. Rodriguez M, Pavelko KD, Njenga MK, Logan WC, Wettstein PJ. The myelitis sera. J Neuroimmunol 1990;26:107–111.
balance between persistent virus infection and immune cells deter- 153. O’Connor KC, Chitnis T, Griffin DE, et al. Myelin basic protein-
mines demyelination. J Immunol 1996;157:5699–5709. reactive autoantibodies in the serum and cerebrospinal fluid of multi-
140. Miller SD, Vanderlugt CL, Begolka WS, et al. Persistent infection with ple sclerosis patients are characterized by low-affinity interactions.
Theiler’s virus leads to CNS autoimmunity via epitope spreading. Nat J Neuroimmunol 2003;136:140–148.
Med 1997;3:1133–1136. 154. Oh HH, Kwon SH, Kim CW, et al. Molecular analysis of HLA class
141. Katz-Levy Y, Neville KL, Girvin AM, et al. Endogenous presentation II-associated susceptibility to neuroinflammatory diseases in Korean
of self myelin epitopes by CNS-resident APCs in Theiler’s virus- children. J Korean Med Sci 2004;19:426–430.
infected mice. J Clin Invest 1999;104:599–610. 155. Stewart GJ, McLeod JG, Basten A, Bashir HV. HLA family studies
142. McMahon EJ, Bailey SL, Castenada CV, Waldner H, Miller SD. and multiple sclerosis: a common gene, dominantly expressed. Hum
Epitope spreading initiates in the CNS in two mouse models of multi- Immunol 1981;3:13–29.
ple sclerosis. Nat Med 2005;11:335–339. 156. Haines JL, Ter-Minassian M, Bazyk A, et al. A complete genomic
143. Tejada-Simon MV, Zang YC, Hong J, Rivera VM, Zhang JZ. Cross- screen for multiple sclerosis underscores a role for the major histocom-
reactivity with myelin basic protein and human herpesvirus-6 in mul- patability complex. The Multiple Sclerosis Genetics Group. Nat Genet
tiple sclerosis. Ann Neurol 2003;53:189–197. 1996;13:469–471.
144. Talbot PJ, Paquette JS, Ciurli C, Antel JP, Ouellet F. Myelin basic 157. Boiko AN, Gusev EI, Sudomoina HA, et al. Association and linkage of
protein and human coronavirus 229E cross-reactive T cells in multiple juvenile MS with HLA-DR2(15) in Russians. Neurology 2002;58:658–
sclerosis. Ann Neurol 1996;39:233–240. 660.

S36 NEUROLOGY 68(Suppl 2) April 17, 2007


Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008
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

Updated Information including high-resolution figures, can be found at:


& Services http://www.neurology.org/cgi/content/full/68/16_suppl_2/S23
Permissions & Licensing Information about reproducing this article in parts (figures, tables)
or in its entirety can be found online at:
http://www.neurology.org/misc/Permissions.shtml
Reprints Information about ordering reprints can be found online:
http://www.neurology.org/misc/reprints.shtml

Downloaded from www.neurology.org by BRANDON ZIELINSKI on August 1, 2008