Acute disseminated encephalomyelitis: an acute hit against the brain

C

Acute disseminated encephalom
yelitis: an acute hit against
the brainTil Mengea, Bernd C. Kieseiera, Stefan Nesslera, Bernhard Hemmera,Hans-Peter Hartunga and Olaf Stuvea,b

Purpose of review

In this review, the possible etiology, clinical characteristics,

diagnosis, and treatment of acute disseminated

encephalomyelitis (ADEM) are discussed. ADEM is a para-

or postinfectious autoimmune demyelinating disease of the

central nervous system and has been considered a

monophasic disease. The highest incidence of ADEM is

observed during childhood.

Recent findings

Over the last decade, many cases of multiphasic ADEM

have been reported. The occurrence of relapses potentially

poses a diagnostic dilemma for the treating physician, as it

may be difficult to distinguish multiphasic ADEM from

multiple sclerosis (MS). Many retrospective patient studies

have thus focused on the clinical and paraclinical features of

ADEM and have attempted to define specific diagnostic

criteria. Additionally, several experimental models have

provided insight with respect to the pathogenic relation of

an infectious event and subsequent demyelinating

autoimmunity.

Summary

Capitalizing on experience based on a large body of well

characterized patient data collected both cross-sectionally

and longitudinally, pharmacotherapy has been improved

and mortality and comorbidities due to ADEM have been

reduced. Unfortunately, the pathogenic events that trigger

the initial clinical attack, and possibly pave the way for

ongoing relapsing disease, remain unknown. Clinically

applicable diagnostic criteria are still lacking.

Keywords

acute disseminated encephalomyelitis, central nervous

system, experimental autoimmune encephalomyelitis,

multiple sclerosis, Theiler’s murine encephalomyelitis,

vaccination

Curr Opin Neurol 20:247–254. � 2007 Lippincott Williams & Wilkins.

aDepartment of Neurology, Heinrich-Heine-University of Dusseldorf, Germany andbDepartment of Neurology, University of Texas Southwestern Medical Center atDallas, Dallas, Texas, USA

Correspondence to Til Menge, MD, Department of Neurology,Heinrich-Heine-University, Moorenstrasse 5, D-40225 Dusseldorf, GermanyFax: +49 211 811 8485; e-mail: [email protected]

Current Opinion in Neurology 2007, 20:247–254

opyright © Lippincott Williams & Wilkins. Unauth

Abbreviations

ADEM a

orize

cute disseminated encephalomyelitis
CNS c entral nervous system CSF c erebrospinal fluid EAE e xperimental autoimmune encephalomyelitis IFN in terferon IL in terleukin MOG m yelin oligodendrocyte glycoprotein MS m ultiple sclerosis TME T heiler’s murine encephalomyelitis
� 2007 Lippincott Williams & Wilkins1350-7540

IntroductionAcute disseminated encephalomyelitis (ADEM) is a dis-

ease of the young; most commonly it affects children with

an estimated incidence of 0.8/100 000/year [1]. The

median age of onset is 6.5 years [2]. ADEM has also been

reported in young and elderly adults, but the incidence is

low [3]. In adults, it can be challenging to interpret an

initial demyelinating event of the central nervous system

(CNS) as ADEM or the first clinical event of multiple

sclerosis (MS).

ADEM is considered a monophasic demyelinating dis-

ease of the CNS. Up to three-quarters of cases may be

regarded as postinfectious or postimmunization encepha-

lomyelitis. In this scenario, there appears to be a temporal

association between a febrile event and the onset of

neurological disease [1,4–6]. Typically, the latency

between a febrile illness and the onset of neurological

symptoms is 7–14 days.

Immunopathogenetic conceptsA growing number of pathogens associated with ADEM

have been reported in the scientific literature, mostly as

single patient case reports (reviewed in [2]). For most

vaccines incidence rates are as low as 0.1–0.2 per 100 000

vaccinated individuals [2]. Noteworthy, the incidence

of measles vaccination-associated ADEM is about

0.1/100 000, and thus considerably lower than the inci-

dence of ADEM after a wild-type measles encephalitis

(up to 100/100 000), which is also complicated by a higher

mortality [7]. Interestingly, for two vaccines, against

Japanese B encephalitis (JBE) and rabies, respectively,

certain strains were associated with ADEM incidence

rates as high as one in 600 [8]. These viral strains were

identified to be contaminated with host animal CNS

d reproduction of this article is prohibited.

247

mailto:[email protected]

C

248 Demyelinating diseases

tissue in which they were propagated. Specifically, the

rabies Semple strain had been cultured in rabbit or goat

brain tissue, whereas the JBE strain had been grown in

murine brain. Indeed, high-affinity antibodies directed

against myelin-basic protein (MBP), a major component

of myelin, could be identified in ADEM patients vacci-

nated with Semple strain rabies, but not MS patients,

similar to observations made in MBP-immunized rabbits

[9]. The recognition that the parenteral inoculation of

CNS autoantigens can lead to autoimmune disease was

one of the seminal observations in immunology [10], and

established experimental autoimmune encephalomyeli-

tis (EAE) as an animal model of MS. The development of

vaccines that are based on recombinant proteins has

significantly lowered the incidence of ADEM in the

developed world.

Based on experimental and clinical data that have been

accumulated by many investigators over decades, the

following pathogenic concepts of ADEM have been

proposed:

Molecular mimicry

Due to certain delicate structural or partial amino-acid

sequence homologies, antigenic epitopes are shared

between an inoculated pathogen or vaccine and a host

CNS protein, The pathogen is hence not readily recog-

nized as ‘foreign’ in order to be eliminated, nor as ‘self’,

which would result in immune tolerance [11]. Initially the

pathogen is processed at the site of inoculation, leading to

T cell activation, which in turn cross-activates antigen-

specific B cells. Such activated autoreactive T cells and

B cells are capable of entering the CNS during the course

of routine immune surveillance [12]. By chance, they may

encounter the homologous myelin protein – even long

after clearance of the pathogen. Following local reactiva-

tion by antigen presenting cells, an inflammatory immune

reaction against the presumed foreign antigen is elicited,

and the initially physiological immune response engenders

detrimental autoimmunity distant from the original site of

inoculation. This cascade of events was demonstrated

experimentally by transgenic insertion of a lymphocytic

choriomeningitis virus (LCMV) antigen in murine

oligodendrocytes. Once these animals were inoculated

intraperitoneally with the respective LCMV strain, the

infection was cleared at the entry site. Following a 7–14-

day interval, CNS inflammation occurred, leading to

myelin pathology and functional clinical deficits [13].

The kinetics of this experimental model are strikingly

similar to those observed between the preceding infection

or vaccination, and the subsequent onset of ADEM-

compatible symptoms in human patients. Interestingly,

secondary infection with an unrelated, yet cross-reactive

virus prompts clinical and histopathological enhancement

of the disease [13]. This notion provides a link to the

concept of viral deja vu [14��] discussed below.

opyright © Lippincott Williams & Wilkins. Unautho

The re-infectious etiology

CNS demyelination may be induced by direct neurotoxi-

city of neurotropic virus (such as measles). In contrast,

vaccination with an attenuated virus strain may only be

harmful if during a preceding infection previously primed

virus-specific cytotoxic T cells are reactivated. This was

only recently elegantly modeled in murine LCMV CNS

disease [14��].

The postinfectious etiology

After a direct CNS infection with a neurotropic pathogen,

CNS tissue may be damaged and the blood–brain barrier

(BBB) disrupted. This may result in systemic leakage of

CNS-confined autoantigens into the systemic circulation,

where they are processed in systemic lymphatic organs,

causing breakdown of tolerance with subsequent emer-

gence of a self-reactive and encephalitogenic T cell

response. Possibly secondary to the secretion of proin-

flammatory cytokines, chemoattractants or other soluble

factors in situ, this CNS inflammation perpetuates itself

even further.

Theiler’s murine encephalomyelitis (TME), established

in the 1930s, is another commonly utilized animal model

of ADEM that has allowed investigators to specifically

study infectious and parainfectious pathogenic mechan-

isms of CNS demyelination [15,16]. Other models,

including the above mentioned LCMV model or geneti-

cally engineered murine vaccinia virus, complement the

pathogenic studies of ADEM [17�]. The latter, in particu-

lar, combines the concepts of molecular mimicry with

that of an inflammatory cascade: Following an antece-

dent, clinically uneventful infection with a virus that

expresses determinants which allow molecular mimicry

to occur (‘first hit’), a second infection with an unrelated

virus (‘second hit’) results in sufficient reactivation of the

primed autoreactive T cells to eventuate CNS demyeli-

nation [17�].

Pathological considerationsThere are certain distinctions between the histopatho-

logical findings in ADEM and MS. MS lesions are

heterogeneous in terms of lesion age and composition

of the cellular components. At least four lesion patterns

have been described [18]. In contrast, ADEM lesions are

almost always of similar age, and consist of mostly one

distinct pattern [19]: perivenous inflammation around

small vessels in both CNS white and grey matter. The

areas of disease are not necessarily confined to the peri-

ventricular areas. Lesions are infiltrated by lymphocytes,

macrophages and to a lesser extent neutrophils. In

addition, there is perivascular edema, endothelial swel-

ling and vascular endothelial infiltrations (not resembling

vasculitis). Demyelination may not be present in hyper-

acute or acute lesions, but may develop later in the

lesion’s evolution in a rather pathognomonic ‘sleeve-like’

rized reproduction of this article is prohibited.

C

Acute disseminated encephalomyelitis Menge et al. 249

fashion; that is, confined to the hypercellular areas. In

general, there is only slight damage to axons.

While pathogenic involvement of cytokines and chemo-

kines has been unequivocally established in MS [20],

studies conducted in ADEM so far have yielded conflict-

ing data:

(1) T

op

he proinflammatory cytokines tumor necrosis factor

(TNF)-a and interleukin (IL)-1b, but not IL-6 are

expressed in situ in lesions of one adult ADEM

patient [21].

(2) I
n contrast, IL–6 and TNF-a, but not IL-1b levels
were found elevated in the cerebrospinal fluid (CSF)

of 18 ADEM patients [22].

(3) P
roduction of interferon (IFN)-g, a proinflammatory
signature T helper type 1 (Th1) cytokine, causally

related to autoimmunity but not IL-4 by CD3þperipheral blood T cells, was found to be elevated

in four ADEM cases compared with controls [23].

(4) P
redominant IL-4, but not IFN-g secretion, was
detected in myelin-reactive peripheral T cells from

ADEM patients compared with controls [24].

(5) I
n the CSF, one study reported a predominant Th1
cytokine profile, with decreased IL-17 levels, a cyto-

kine recently associated with the pathogenesis of MS,

in 14 ADEM patients compared with controls [25�].

(6) T
wo other groups could not detect either Th1 or Th2
cytokine profiles in the CSF of 17 ADEM cases [26�]

or elevated levels for IFN-g, IL-10 or IL-12 [1].

In MS, the roles of pathogenic autoantibodies and in

particular of antimyelin antibodies as biomarkers of dis-

ease etiology and prognosis have been a major focus of

research efforts recently (reviewed in [27,28]). Recently,

assays involving native myelin oligodendrocyte glyco-

protein (MOG), a putative target autoantigen in MS, y-

ielded promising results discriminating MS from other

diseases [29,30]. ADEM cases have not yet been included

in any of the studies, possibly due to the much lower

incidence of this disease. A recent study, however,

undertook the effort to compare anti-MOG antibody

reactivities of 56 pediatric ADEM cases by a number

of commonly employed assays, such as enzyme-linked

immunosorbent assay (ELISA), radioimmunoassay,

cytometry against native MOG, and a new genetically

engineered tetrameric MOG molecule [31��]; only by the

latter (tetramer) assay, performed under solution-phase

conditions and hence detecting conformation-dependent

antibodies of higher affinity, anti-MOG antibodies could

be detected in 18% of ADEM cases, but in less than 1% of

MS cases [31��]. Additionally, a subgroup of ADEM

cases, those with a novel clinical phenotype of dystonic

extrapyramidal movement disorders and a behavioral

syndrome after group A b-hemolytic streptococcal infec-

tion, were found to be positive for antibasal ganglia

yright © Lippincott Williams & Wilkins. Unauth

antibodies, providing a possible link to humoral molecu-

lar mimicry [32].

Despite the discrepancies described, which may be due

to low patient numbers and different assay and study

designs, a pathogenic involvement of T cells and macro-

phages/monocytes secreting chemokines and cytokines

appears likely. Their role in the initiation or perpetuation

of ADEM, however, has to be further clarified. CNS-

specific autoantibodies may play a pathogenic role in a

subset of patients. These findings corroborate the auto-

immune nature of the disease and potentially provide

avenues for therapeutic strategies. They also, however,

underscore the pathogenic heterogeneity of ADEM,

despite clinical similarities.

Clinical presentation and diagnosisOur current knowledge of the clinical presentation, diag-

nosis and prognosis of ADEM has been gathered from a

number of observational studies that in aggregate

included more than 600 patients. The follow-up periods

of many studies provided important information on the

clinical course of this disease. The majority of studies

focused on pediatric patients. Studies that were pub-

lished up to 2004 have been reviewed and summarized

by us and others [2,33�]. Since then, five additional

retrospective studies were published in 2005 and 2006

[34–37,38�]; one was a follow-up of an existing cohort

[38�], one reported exclusively on 60 adult ADEM

patients [36] and one on both children and adults [34].

In these recently reported series, neurological signs and

symptoms of patients afflicted with ADEM developed

subacutely over a period of days, and led to hospitaliz-

ation within a week [39]. The disease [3,4,6] occasionally

progressed after diagnosis and treatment initiation [35].

Importantly, the initial symptoms were nonspecific,

including headaches, fever, lethargy, with distinct

functional neurological or cognitive defects developing

gradually.

Since MS is the most important differential diagnosis

(discussed below in detail), many studies have attempted

to identify neurological symptoms specific for ADEM.

As of yet, no pathognomonic clinical features have

been discerned. A number of symptoms, however, are

encountered more frequently in ‘true’ ADEM cases;

they have been compiled and summarized from the

studies mentioned and from our own clinical experience

(Table 1). In general, the clinical presentation of ADEM

may be very heterogeneous. The most prevalent

clinical symptoms and findings are shown in Fig. 1

[4–6,35,37,39–42,43�,44–49]. A combination of altered

consciousness or behavior and multifocal neurological

deficits, especially in close relation to an infection, should

raise the clinician’s suspicion to consider ADEM in the

orized reproduction of this article is prohibited.

C


Table 1 Clinically relevant predictors for monophasic acute disseminated encephalomyelitis (ADEM) versus relapsing central

nervous system (CNS) demyelinating disease, such as childhood multiple sclerosis (MS)

Typical for monophasic ADEM More likely in relapsing CNS demyelination of children

Age of onset Childhood (median 6.5a) Adolescence (median 14.25)Clinical presentation Preceding infection/vaccination Monosymptomatic presentation

Headaches, fever, lethargy pyramidal signsEncephalopathy, e.g. altered mental stateb

or behaviour, in combination withpolysymptomatic presentationataxia

mononuclear optic neuritisbrainstem symptomstransverse myelitis

brainstem symptomspyramidal signs

Cerebrospinal fluid Oligoclonal banding in 12.5%c Intrathecal immunoglobulin synthesisOften transient [36,51,52] Permanent oligoclonal banding in the majority of cases

MRI Extensive lesion loadd Sole presence of well defined lesionse

Confluent and ill-defined lesionsd Corpus callosum long-axis perpendicular lesions (‘Dawson’s fingers’)e

Bilateral deep gray matter lesions(thalamus, basal ganglia)d

Periventricular lesionsHypointense ‘black holes’ on T1-weighted images

Perifocal odema and mass effectAbsence of previous demyelinating activity

(‘T1 black holes’)Follow-up MRI Status quo or lesion resolution; new lesions

are not compatible with ADEMDissemination in time and space; evolution of clinically silent

lesions possible

a Median age calculated from [2].b Highly suggestive for ADEM in children under the age of 10 years [54]; considered mandatory for the diagnosis of ADEM [38�].c Median frequency of oligoclonal banding derived from [4–6,39,40,52,55].d Indicative of ADEM, but neither specific, nor predictive.e Specific predictors for relapses in children with MRI evidence of CNS demyelination [41].Refer to Fig. 1 for a comparison of typical clinical features.

differential. Several paraclinical tools provide further

information and aid in establishing the diagnosis (or rule

out differential diagnoses); again, however, none of the

tests is specific for ADEM, and results have a substantial


Figure 1 Frequencies of typical clinical features of acute dis-

seminated encephalomyelitis (ADEM) and childhood multiple

sclerosis (MS)

Median frequencies of clinical features derived from clinical studies ofADEM (left bars, light grey) [1,4–6,35,37,39–41,43�,44] and childhoodMS (right bars, dark grey) [40,42,43�,45–49]. Bars represent range.Encephalopathy denotes altered mental or behavioral state. Note thatnot all studies contributed equally to all feature entries. Three studiescompared ADEM and childhood MS side by side [40,42,43�]; addition-ally two studies compared clinical features of ADEM versus multifocalADEM [39,44].

overlap with MS. Lumbar puncture performed to rule

out any acute infectious meningoencephalitis [50�] may

reveal a mild lympho-monocytic pleocytosis and eleva-

tion of albumin. The occurrence of CSF-specific oligo-

clonal bands (OCBs), a hallmark of MS, varies between 0

and 58% with a median of 12.5% over all studies that have

reported OCBs (Table 1). OCBs may be present only

transiently [36,51,52], which is in sharp contrast to MS,

and which may indicate that a disease-causing antigen is

only transiently expressed within or outside the CNS.

Specialty laboratory tests, such as infectious pathogen

serology, CSF culture or PCR detection from blood or

CSF are further required to exclude an acute infectious

condition; that is, CNS inflammation due to parenchymal

microbial invasion [50�].

MRI of the brain, and optionally the spinal cord, is the

most widely applied diagnostic tool. More and more

studies have exclusively included patients with patho-

logical MRI readings compatible with disseminated CNS

demyelination [1,3–6,34,35,44]. One recent study [35]

focused specifically on the MRI findings, and noted that

the initial MRI, performed 2–3 days after symptoms

onset, may not show evidence of disease. Interestingly,

patients with a normal MRI on admission displayed

progressive clinical disease, and eventually (up until

day 25) developed disseminated CNS demyelination

on MRI. Thus, in the context of substantial clinical

suspicion and progressive disease, a follow-up MRI is

highly warranted. With regard to a differential diagnosis

of MS, the initial MRI should be reviewed for radiological


C


evidence of dissemination in time of CNS demye-

lination;. that is, simultaneous presence of older lesions

(in particular ‘T1 black holes’) and lesions with and

without gadolinium enhancement that would reflect prior

subclinical inflammatory and demyelinating activity.

Such dissemination in time is a strong indicator for MS

[53], although not yet well studied and defined in

children [41].

Similar to the clinical and CSF features, and likely due to

the low incidence of the disease [34,54], there are no

specific and hence diagnostic MRI criteria for ADEM.

Lesion patterns more frequently encountered in ADEM

are summarized in Table 1. These include the detec-

tion of widespread, multifocal, or extensive (lesion load

> 50% of total white matter volume) white matter

lesions and lesions in the deep gray matter (thalamus,

basal ganglia) [4,34,41]. In addition, two specific MRI

patterns – corpus callosum long-axis perpendicular

lesions (‘Dawson’s fingers’) and periventricular lesions

– are clearly seen more commonly in MS [3,39] and

appear to be associated with a higher risk of experiencing

MS-defining relapses [41].

Follow-up MRI scans after a minimum interval of

6 months afford to establish or confirm a diagnosis of

ADEM [4,39,40,51,55]. While in ADEM lesions should

resolve or remain at least unchanged, the appearance of

new lesions is strongly suggestive of MS (‘dissemination

in time’, see above) [36,51,52].

Before the MRI era, brain biopsies were not uncommonly

performed due to detection of large lesions on CAT scans

with possible mass effect. Since the advent of MRI,

however, biopsies are only rarely undertaken, mostly

when a solitary lesion with a mass effect is apparent,

the medical history is inconclusive (for instance, with

the absence of prior infection, but prolonged general

malaise and weight loss), or to rule out primary CNS


Table 2 Differential diagnoses of acute disseminated encephalomy

Pathogenic event Possible differential diagno

Infectious Viral, bacterial or parasiticHIV-associated encephalo

subacute HIV encephaliprogressive multifocal le

CNS inflammation due to autoimmunity Multiple sclerosisNeurosarcoidosisBehcet’s disease

CNS vascular disease (plus inflammation) Antiphospholipid antibodyPrimary isolated CNS angVasculitis secondary to rhe

Mass lesion CNS neoplasiaCNS metastasis of a syste

Inherited myelopathies and encephalopathies Mitochondrial encephalopaMELAS (mitochondrial e

Adrenoleukodystrophy

Specific features, overlap to ADEM and relevant diagnostic tools to establish oCNS, central nervous system.

malignancies or brain metastasis. In the absence of

detailed histopathological classification guidelines that

would enable the pathologist to unequivocally establish

the diagnosis of ADEM, routine diagnostic biopsies are

widely discouraged, as it may also delay timely initiation

of treatment.

In conclusion, the diagnosis of ADEM is made on clinical

grounds with the guidance of MRI after exclusion of an

acute infectious condition by lumbar puncture and

further microbiological laboratory tests.

Differential diagnosis, recurrent acutedisseminated encephalomyelitis versusmultiple sclerosisAs discussed above, neither pathognomonic nor disease-

specific clinical presentations can be defined nor are

paraclinical tests available to unequivocally diagnose

ADEM. If in doubt, the diagnosis has to be made by

exclusion from a number of likely differential diagnoses,

the most relevant of which are summarized in Table 2.

The most important and most common differential diag-

nosis with regard to therapeutic options and prognosis,

however, is MS and will be discussed in detail below. As

mentioned earlier, ADEM is considered a monophasic

disease. It is now recognized, however, that up to one-

third of ADEM patients will have relapses in the future

[2,33�,38�,41]. It is currently impossible to predict which

patients will follow such a multiphasic disease course. In

this respect, several distinct clinical settings need to be

discerned, which in the past have led to confusion in the

scientific literature:

(1) I

ori

eliti

sis

menipathitisukoe

syndiitisuma

micthiesncep

r exc

f the relapse occurs in close temporal relation to

antiinflammatory treatment – typically during the

dose-tapering interval or shortly after discontinuation

of treatment (see below) – it should be regarded as a

flare-up of the initially monophasic disorder, and may

not be associated with reactivation of the disease

zed reproduction of this article is prohibited.

s (ADEM)

ngoencephalitises:

ncephalopathy

rome

tic autoimmune diseases, including systemic lupus erythematodes

malignancy:halopathy with lactic acidosis and stroke like episodes)

lude these differential diagnoses have been reviewed previously [2].

Copy


process. Depending on the treatment regime

adopted, such flare-ups are confined to within

3 months of the initial diagnosis.

(2) I
n contrast, if a relapse occurs after an interval of at
least 3 months, this should be regarded as reactivation

of the disease. Noteworthy, the interval of 3 months is

arbitrarily defined with respect to the common treat-

ment regimes. In any case, it has to be ascertained

that the initial clinical event is truly terminated; that

is, complete remission or a stable plateau of incom-

plete remission has been achieved. If the relapse

involves similar neuro-anatomical areas as the initial

event, the diagnosis should be refined to recurrent

ADEM. If the relapse affects new anatomical struc-

tures, the disease should be regarded as multifocal

ADEM.

(3) T
he authors strongly recommend performing a
follow-up MRI in the event of a multifocal ADEM;

this is done in order to detect new or newly enhancing

lesions, which would equate to ‘dissemination in

time’ [53], supporting a diagnosis of MS. Since these

MRI criteria may not be directly applicable to child-

hood MS [41,56], however, we propose performing

an additional MRI scan 3–6 months later. If this

reveals ongoing subclinical disease activity – that

is, lesion evolution or consistent presence of enhan-

cing lesions – the initial diagnosis of ADEM should

be revised to MS.

(4) I
f, however, two relapses occur within this 6-month
period, the initial diagnosis of ADEM has to be

rejected and a diagnosis of MS can be made entirely

on clinical grounds according to the older, less MRI-

centered diagnostic criteria [57].

The authors propose this follow-up procedure that, com-

pared with current MS diagnostic criteria [53,57], is less

stringent at least in pediatric patients. Our proposal is

based on the following rationale. Numerous follow-up

studies reported only one relapse event in most patients

despite considerable follow-up intervals [1,4–6,38�,44]. If

a diagnosis of MS is established prematurely in these

children, they are stigmatized with a chronic disease,

anxiously awaiting the next relapses and disability,

which may never ensue, and possibly treated indefinitely.

Since early immunomodulatory treatment is not formally

approved for childhood MS [58], it appears justifiable to

extend the follow-up interval before finally diagnosing

MS. A diagnosis may be made more readily in relapsing

adult ADEM patients, but should be considered indivi-

dually.

Treatment and prognosisOnce ADEM is diagnosed – and an acute infectious CNS

inflammatory disorder ruled out – the therapeutic aim is

to abbreviate the CNS inflammatory reaction as quickly

as possible, and to speed up clinical recovery. Hence, in

right © Lippincott Williams & Wilkins. Unautho

general, treatment should be initiated as early as possible

and as aggressively as necessary [59].

Due to the lack of controlled clinical trials, intrave-

nous high-dose corticosteroids are widely accepted

as first-line treatment, based on empiric and obser-

vational evidence [60]. The initial treatment regime

consists of high-dose intravenous methylprednisolone

with a cumulative dose of 3–5 g, followed by a prolonged

oral prednisolone taper of 3–6 weeks [4–6]. Addition-

ally, various other antiinflammatory and immunosup-

pressant therapies may also be beneficial, as reported

in several case studies: plasmapheresis [35,61], high-

dose intravenous immunoglobulin (IVIG) [36,60,62],

mitoxantrone, or cyclophosphamide [62,63]. These

should be considered as alternative therapies if corticos-

teroid treatment shows no clinical effect or if relative

and absolute contraindications for corticosteroids exist

[34–36,62,63].

With the advent of widespread and immediate use of

high-dose steroids and the dramatic decrease of wild-type

measles infections, the long-term prognosis of ADEM

with regards to functional and cognitive recovery is

favorable. In many studies, full recovery occurred in

about 50–75% [35,36,39,44,52,55], and it ranged between

70 and 90% if minor residual disability was considered

[39,44,52]. It should be stressed, however, that the

mortality of postinfectious ADEM may still be as high

as 5%. The average time period to recovery was reported

to range between 1 and 6 months [4,39]. Some studies

have associated an unfavorable prognosis to a sudden

onset, an unusually high severity of the neurological

symptoms, and unresponsiveness to steroid treatment

[34,40].

ConclusionThe etiopathogenesis of ADEM remains enigmatic.

Recent case series, however, have shed light on the

natural history, therapeutic options and prognosis of

the disease. Yet, a number of questions remain puzzling

and unresolved. What is the inciting event of ADEM?

Specifically, is there a genetic background that promotes

susceptibility to CNS autoimmune disease after exposure

to particular infectious pathogens? What are the mech-

anisms that render most cases of ADEM self-limiting?

What are the biological markers associated with ADEM,

particularly with its prognosis?

Translational research is hampered by the low incidence

of ADEM. Prospective studies are much needed in order

to identify and apply predictive diagnostic criteria. It may

well be feasible to implement a multicenter database

with systematic patient entries in order to increase

statistical power and to identify predictors of relapses.

Experimentally, second hit animal models should be


C


developed and explored further, as they appear to most

faithfully mimic ADEM.

References and recommended readingPapers of particular interest, published within the annual period of review, havebeen highlighted as:� of special interest�� of outstanding interest

Additional references related to this topic can also be found in the CurrentWorld Literature section in this issue (p. 358).

1 Leake JA, Albani S, Kao AS, et al. Acute disseminated encephalomyelitis inchildhood: epidemiologic, clinical and laboratory features. Pediatr Infect Dis J2004; 23:756–764.

2 Menge T, Hemmer B, Nessler S, et al. Acute disseminated encephalomyelitis:an update. Arch Neurol 2005; 62:1673–1680.

3 Schwarz S, Mohr A, Knauth M, et al. Acute disseminated encephalomyelitis:a follow-up study of 40 adult patients. Neurology 2001; 56:1313–1318.

4 Hynson JL, Kornberg AJ, Coleman LT, et al. Clinical and neuroradiologicfeatures of acute disseminated encephalomyelitis in children. Neurology2001; 56:1308–1312.

5 Murthy SN, Faden HS, Cohen ME, Bakshi R. Acute disseminated encepha-lomyelitis in children. Pediatrics 2002; 110:e21.

6 Tenembaum S, Chamoles N, Fejerman N. Acute disseminated encephalo-myelitis: a long-term follow-up study of 84 pediatric patients. Neurology 2002;59:1224–1231.

7 Fenichel GM. Neurological complications of immunization. Ann Neurol 1982;12:119–128.

8 Hemachudha T, Griffin DE, Giffels JJ, et al. Myelin basic protein as anencephalitogen in encephalomyelitis and polyneuritis following rabies vacci-nation. N Engl J Med 1987; 316:369–374.

9 O’Connor KC, Chitnis T, Griffin DE, et al. Myelin basic protein-reactiveautoantibodies in the serum and cerebrospinal fluid of multiple sclerosispatients are characterized by low-affinity interactions. J Neuroimmunol 2003;136:140–148.

10 Rivers TM, Sprunt DH, Berry GP. Observations on the attempts to produceacute disseminated allergic encephalomyelitis in primates. J Exp Med 1933;58:39–53.

11 Fujinami RS, Oldstone MB. Amino acid homology between the encephalito-genic site of myelin basic protein and virus: mechanism for autoimmunity.Science 1985; 230:1043–1045.

12 Hickey WF. Basic principles of immunological surveillance of the normalcentral nervous system. Glia 2001; 36:118–124.

13 Evans CF, Horwitz MS, Hobbs MV, Oldstone MB. Viral infection of trans-genic mice expressing a viral protein in oligodendrocytes leads to chroniccentral nervous system autoimmune disease. J Exp Med 1996; 184:2371–2384.

14

��Merkler D, Horvath E, Bruck W, et al. ‘Viral deja vu’ elicits organ-specificimmune disease independent of reactivity to self. J Clin Invest 2006; 116:1254–1263.

The investigators demonstrate the concept of ‘viral deja vu’: two related butindependently encountered viral infections can cause organ-specific immunedisease without molecular mimicry of self and without breaking self tolerance.

15 Lipton HL. Theiler’s virus infection in mice: an unusual biphasic diseaseprocess leading to demyelination. Infect Immun 1975; 11:1147–1155.

16 Miller SD, McRae BL, Vanderlugt CL, et al. Evolution of the T-cell repertoireduring the course of experimental immune-mediated demyelinating diseases.Immunol Rev 1995; 144:225–244.

17

�McCoy L, Tsunoda I, Fujinami RS. Multiple sclerosis and virus inducedimmune responses: autoimmunity can be primed by molecular mimicry andaugmented by bystander activation. Autoimmunity 2006; 39:9–19.

The authors use this review to introduce a novel mouse model in which CNSautoimmunity is initiated by two subsequent infectious events, first with a molecularmimicry pathogen and second with an unrelated neurotropic virus.

18 Lucchinetti C, Bruck W, Parisi J, et al. Heterogeneity of multiple sclerosislesions: implications for the pathogenesis of demyelination. Ann Neurol 2000;47:707–717.

19 Prineas J, McDonald WI, Franklin R. Demyelinating diseases. In: Graham D,Lantos P, editors. Greenfield’s neuropathology, 7th ed. London: Arnold;2002. pp. 471–550.

20 Frohman EM, Racke MK, Raine CS. Multiple sclerosis: the plaque and itspathogenesis. N Engl J Med 2006; 354:942–955.


21 Kadhim H, De Prez C, Gazagnes MD, Sebire G. In situ cytokine immuneresponses in acute disseminated encephalomyelitis: insights into pathophy-siologic mechanisms. Hum Pathol 2003; 34:293–297.

22 Ichiyama T, Shoji H, Kato M, et al. Cerebrospinal fluid levels of cytokines andsoluble tumour necrosis factor receptor in acute disseminated encephalo-myelitis. Eur J Pediatr 2002; 161:133–137.

23 Yoshitomi T, Matsubara T, Nishikawa M, et al. Increased peripheral bloodinterferon gamma-producing T cells in acute disseminated encephalomyelitis.J Neuroimmunol 2000; 111:224–228.

24 Pohl-Koppe A, Burchett SK, Thiele EA, Hafler DA. Myelin basic proteinreactive Th2 T cells are found in acute disseminated encephalomyelitis.J Neuroimmunol 1998; 91:19–27.

25

�Ishizu T, Minohara M, Ichiyama T, et al. CSF cytokine and chemokine profilesin acute disseminated encephalomyelitis. J Neuroimmunol 2006; 175:52–58.

In this study, the authors simultaneously measured 16 cytokines/chemokines incerebrospinal fluid (CSF) from 14 patients with ADEM and 20 controls. The resultssuggest that various cytokines implicated in the activation of macrophages/microglias and Th1 and Th2 cells are upregulated in CSF in patient withADEM.

26

�Franciotta D, Zardini E, Ravaglia S, et al. Cytokines and chemokines incerebrospinal fluid and serum of adult patients with acute disseminatedencephalomyelitis. J Neurol Sci 2006; 247:202–207.

In this article, the authors measured numerous Th1/Th2 cytokines and 18 che-mokines in the CSF and serum of 17 ADEM patients, 14 patients with MS, andseven healthy controls. Their data suggest that the upregulation of chemokinesactive on neutrophils and Th2 cells differentiates ADEM from MS inflammation, andthat both Th1 and Th2 chemokines may be produced in ADEM.

27 Archelos JJ, Storch MK, Hartung HP. The role of B cells and autoantibodies inmultiple sclerosis. Ann Neurol 2000; 47:694–706.

28 Reindl M, Khalil M, Berger T. Antibodies as biological markers for pathophy-siological processes in MS. J Neuroimmunol 2006; 180:50–62.

29 Lalive PH, Menge T, Delarasse C, et al. Antibodies to native myelin oligoden-drocyte glycoprotein are serologic markers of early inflammation in multiplesclerosis. Proc Natl Acad Sci U S A 2006; 103:2280–2285.

30 Zhou D, Srivastava R, Nessler S, et al. Identification of a pathogenic antibodyresponse to native myelin oligodendrocyte glycoprotein in multiple sclerosis.Proc Natl Acad Sci U S A 2006; 103:19057–19062.

31

��O’Connor KC, McLaughlin KA, De Jager PL, et al. Self-antigen tetramersdiscriminate between myelin autoantibodies to native or denatured protein.Nat Med 2007; 13:211–217.

This paper reports on a novel genetically engineered MOG tetramer that has beenused to assess antibody reactivities in a solution-phase based assay. The authorshave not only tested reactivity in 56 pediatric ADEM cases, but have analysedsamples also by commonly applied anti-MOG assays, such as ELISA and radio-immunoassay. The show that samples active in the MOG tetramer assay arespecific for a conformational epitope. These findings were specific for ADEM andcould not be found in MS.

32 Dale RC, Church AJ, Cardoso F, et al. Poststreptococcal acute disseminatedencephalomyelitis with basal ganglia involvement and auto-reactive antibasalganglia antibodies. Ann Neurol 2001; 50:588–595.

33

�Wingerchuk DM. The clinical course of acute disseminated encephalomye-litis. Neurol Res 2006; 28:341–347.

This review provides an excellent summary of the current retrospective studiesrelating to the clinical presentation and the disease course.

34 Lin CH, Jeng JS, Hsieh ST, et al. Acute disseminated encephalomyelitis:a follow-up study in Taiwan. J Neurol Neurosurg Psychiatry 2007; 78:162–167.

35 Khurana DS, Melvin JJ, Kothare SV, et al. Acute disseminated encephalo-myelitis in children: discordant neurologic and neuroimaging abnormalitiesand response to plasmapheresis. Pediatrics 2005; 116:431–436.

36 Marchioni E, Ravaglia S, Piccolo G, et al. Postinfectious inflammatory dis-orders: subgroups based on prospective follow-up. Neurology 2005; 65:1057–1065.

37 Weng WC, Peng SS, Lee WT, et al. Acute disseminated encephalomyelitisin children: one medical center experience. Acta Paediatr Taiwan 2006; 47:67–71.

38

�Mikaeloff Y, Caridade G, Husson B, et al. Acute disseminated encephalo-myelitis cohort study: prognostic factors for relapse. Eur J Paediatr Neurol2006; 20 December [Epub ahead of print].

This study comprises 2-year follow-up data of a previously reported ADEM/childhood MS cohort [40,41]. Here the authors identify risk factors associatedwith relapses within the follow-up period in 132 children with a first demyelinatingevent compatible with ADEM. The authors applied very stringent diagnosticcriteria, yet relapses occurred in 18% of cases.

orized reproduction of this article is prohibited.

C


39 Dale RC, de Sousa C, Chong WK, et al. Acute disseminated encephalo-myelitis, multiphasic disseminated encephalomyelitis and multiple sclerosis inchildren. Brain 2000; 123 (Pt 12):2407–2422.

40 Mikaeloff Y, Suissa S, Vallee L, et al. First episode of acute CNS inflammatorydemyelination in childhood: prognostic factors for multiple sclerosis anddisability. J Pediatr 2004; 144:246–252.

41 Mikaeloff Y, Adamsbaum C, Husson B, et al. MRI prognostic factors forrelapse after acute CNS inflammatory demyelination in childhood. Brain2004; 127:1942–1947.

42 Brass SD, Caramanos Z, Santos C, et al. Multiple sclerosis vs acutedisseminated encephalomyelitis in childhood. Pediatr Neurol 2003; 29:227–231.

43

�Pohl D, Hennemuth I, von Kries R, Hanefeld F. Paediatric multiple sclerosisand acute disseminated encephalomyelitis in Germany: results of a nation-wide survey. Eur J Pediatr 2007; 12 January [Epub ahead of print].

This study has reviewed by chart analysis and questionnaire the clinical andparaclinical features of ADEM and childhood MS cases in Germany. It providesepidemiological survey data of these diagnoses in regards to the pediatricpopulation.

44 Anlar B, Basaran C, Kose G, et al. Acute disseminated encephalomyelitis inchildren: outcome and prognosis. Neuropediatrics 2003; 34:194–199.

45 Weng WC, Yang CC, Yu TW, et al. Multiple sclerosis with childhood onset:report of 21 cases in Taiwan. Pediatr Neurol 2006; 35:327–334.

46 Simone IL, Carrara D, Tortorella C, et al. Course and prognosis in early-onsetMS: comparison with adult-onset forms. Neurology 2002; 59:1922–1928.

47 Shiraishi K, Higuchi Y, Ozawa K, et al. Clinical course and prognosis of 27patients with childhood onset multiple sclerosis in Japan. Brain Dev 2005;27:224–227.

48 Ozakbas S, Idiman E, Baklan B, Yulug B. Childhood and juvenile onsetmultiple sclerosis: clinical and paraclinical features. Brain Dev 2003; 25:233–236.

49 Boiko A, Vorobeychik G, Paty D, et al. Early onset multiple sclerosis: alongitudinal study. Neurology 2002; 59:1006–1010.

50

�Davies NW, Sharief MK, Howard RS. Infection-associated encephalopathies:their investigation, diagnosis, and treatment. J Neurol 2006; 253:833–845.

This reviews provides a broad overview on the differential diagnoses of acuteencephalopathy beyond ADEM.


51 Kesselring J, Miller DH, Robb SA, et al. Acute disseminated encephalomye-litis: MRI findings and the distinction from multiple sclerosis. Brain 1990; 113(Pt 2):291–302.

52 O’Riordan JI, Gomez-Anson B, Moseley IF, Miller DH. Long term MRI follow-up of patients with post infectious encephalomyelitis: evidence for a mono-phasic disease. J Neurol Sci 1999; 167:132–136.

53 Polman CH, Reingold SC, Edan G, et al. Diagnostic criteria for multiplesclerosis: 2005 revisions to the ‘McDonald criteria’. Ann Neurol 2005;58:840–846.

54 Tardieu M, Mikaeloff Y. What is acute disseminated encephalomyelitis(ADEM)? Eur J Paediatr Neurol 2004; 8:239–242.

55 Gupte G, Stonehouse M, Wassmer E, et al. Acute disseminated encepha-lomyelitis: a review of 18 cases in childhood. J Paediatr Child Health 2003;39:336–342.

56 Hahn CD, Shroff MM, Blaser SI, Banwell BL. MRI criteria for multiplesclerosis: evaluation in a pediatric cohort. Neurology 2004; 62:806–808.

57 Poser CM, Paty DW, Scheinberg L, et al. New diagnostic criteria for multiplesclerosis: guidelines for research protocols. Ann Neurol 1983; 13:227–231.

58 Chabas D, Green AJ, Waubant E. Pediatric multiple sclerosis. NeuroRx 2006;3:264–275.

59 Kaji M, Kusuhara T, Ayabe M, et al. Survey of herpes simplex virus infections ofthe central nervous system, including acute disseminated encephalomyelitis,in the Kyushu and Okinawa regions of Japan. Mult Scler 1996; 2:83–87.

60 Shahar E, Andraus J, Savitzki D, et al. Outcome of severe encephalomyelitisin children: effect of high-dose methylprednisolone and immunoglobulins.J Child Neurol 2002; 17:810–814.

61 Keegan M, Pineda AA, McClelland RL, et al. Plasma exchange for severeattacks of CNS demyelination: predictors of response. Neurology 2002;58:143–146.

62 Marchioni E, Marinou-Aktipi K, Uggetti C, et al. Effectiveness of intravenousimmunoglobulin treatment in adult patients with steroid-resistant monophasicor recurrent acute disseminated encephalomyelitis. J Neurol 2002; 249:100–104.

63 Apak RA, Anlar B, Saatci I. A case of relapsing acute disseminated ence-phalomyelitis with high dose corticosteroid treatment. Brain Dev 1999;21:279–282.


Documents

Acute disseminated encephalomyelitis: an acute hit against the brain