Acute disseminated encephalomyelitis: an acute

Acute disseminated encephalomyelitis: an acute hit against the brain Til Mengea, Bernd C. Kieseiera, Stefan Nesslera, Bernhard Hemmera, Hans-Peter Hartunga and Olaf Stu¨vea,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 paraor 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. ß 2007 Lippincott Williams & Wilkins. a

Department of Neurology, Heinrich-Heine-University of Du¨sseldorf, Germany and Department of Neurology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, USA b

Correspondence to Til Menge, MD, Department of Neurology, Heinrich-Heine-University, Moorenstrasse 5, D-40225 Du¨sseldorf, Germany Fax: +49 211 811 8485; e-mail: [email protected] Current Opinion in Neurology 2007, 20:247–254

Abbreviations ADEM CNS CSF EAE IFN IL MOG MS TME

acute disseminated encephalomyelitis central nervous system cerebrospinal fluid experimental autoimmune encephalomyelitis interferon interleukin myelin oligodendrocyte glycoprotein multiple sclerosis Theiler’s murine encephalomyelitis

ß 2007 Lippincott Williams & Wilkins 1350-7540

Introduction Acute disseminated encephalomyelitis (ADEM) is a disease 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 disease of the CNS. Up to three-quarters of cases may be regarded as postinfectious or postimmunization encephalomyelitis. 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 concepts A 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 incidence 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 247

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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 vaccinated 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 encephalomyelitis (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 recognized 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 antigenspecific 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 reactivation 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 7–14day 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 ADEMcompatible 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 de´ja` vu [14] discussed below.

The re-infectious etiology

CNS demyelination may be induced by direct neurotoxicity 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 emergence of a self-reactive and encephalitogenic T cell response. Possibly secondary to the secretion of proinflammatory 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 mechanisms of CNS demyelination [15,16]. Other models, including the above mentioned LCMV model or genetically engineered murine vaccinia virus, complement the pathogenic studies of ADEM [17]. The latter, in particular, combines the concepts of molecular mimicry with that of an inflammatory cascade: Following an antecedent, 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 demyelination [17].

Pathological considerations There are certain distinctions between the histopathological 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 periventricular areas. Lesions are infiltrated by lymphocytes, macrophages and to a lesser extent neutrophils. In addition, there is perivascular edema, endothelial swelling and vascular endothelial infiltrations (not resembling vasculitis). Demyelination may not be present in hyperacute or acute lesions, but may develop later in the lesion’s evolution in a rather pathognomonic ‘sleeve-like’


Acute disseminated encephalomyelitis Menge et al. 249

fashion; that is, confined to the hypercellular areas. In general, there is only slight damage to axons.

antibodies, providing a possible link to humoral molecular mimicry [32].

While pathogenic involvement of cytokines and chemokines has been unequivocally established in MS [20], studies conducted in ADEM so far have yielded conflicting data:

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 macrophages/monocytes secreting chemokines and cytokines appears likely. Their role in the initiation or perpetuation of ADEM, however, has to be further clarified. CNSspecific autoantibodies may play a pathogenic role in a subset of patients. These findings corroborate the autoimmune nature of the disease and potentially provide avenues for therapeutic strategies. They also, however, underscore the pathogenic heterogeneity of ADEM, despite clinical similarities.

(1) The 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) In 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) Production of interferon (IFN)-g, a proinflammatory signature T helper type 1 (Th1) cytokine, causally related to autoimmunity but not IL-4 by CD3þ peripheral blood T cells, was found to be elevated in four ADEM cases compared with controls [23]. (4) Predominant IL-4, but not IFN-g secretion, was detected in myelin-reactive peripheral T cells from ADEM patients compared with controls [24]. (5) In the CSF, one study reported a predominant Th1 cytokine profile, with decreased IL-17 levels, a cytokine recently associated with the pathogenesis of MS, in 14 ADEM patients compared with controls [25]. (6) Two 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 disease etiology and prognosis have been a major focus of research efforts recently (reviewed in [27,28]). Recently, assays involving native myelin oligodendrocyte glycoprotein (MOG), a putative target autoantigen in MS, yielded 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 infection, were found to be positive for antibasal ganglia

Clinical presentation and diagnosis Our current knowledge of the clinical presentation, diagnosis 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 published 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 hospitalization 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


250 Demyelinating diseases 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)

Age of onset Clinical presentation

Cerebrospinal fluid MRI

Follow-up MRI

Typical for monophasic ADEM

More likely in relapsing CNS demyelination of children

Childhood (median 6.5a) Preceding infection/vaccination Headaches, fever, lethargy Encephalopathy, e.g. altered mental stateb or behaviour, in combination with polysymptomatic presentation ataxia brainstem symptoms pyramidal signs Oligoclonal banding in 12.5%c Often transient [36,51,52] Extensive lesion loadd Confluent and ill-defined lesionsd Bilateral deep gray matter lesions (thalamus, basal ganglia)d Perifocal odema and mass effect Absence of previous demyelinating activity (‘T1 black holes’) Status quo or lesion resolution; new lesions are not compatible with ADEM

Adolescence (median 14.25) Monosymptomatic presentation pyramidal signs mononuclear optic neuritis brainstem symptoms transverse myelitis

Intrathecal immunoglobulin synthesis Permanent oligoclonal banding in the majority of cases Sole presence of well defined lesionse Corpus callosum long-axis perpendicular lesions (‘Dawson’s fingers’)e Periventricular lesions Hypointense ‘black holes’ on T1-weighted images

Dissemination in time and space; evolution of clinically silent lesions possible

a

Median age calculated from [2]. 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. b

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 disseminated encephalomyelitis (ADEM) and childhood multiple sclerosis (MS)

Median frequencies of clinical features derived from clinical studies of ADEM (left bars, light grey) [1,4–6,35,37,39–41,43,44] and childhood MS (right bars, dark grey) [40,42,43,45–49]. Bars represent range. Encephalopathy denotes altered mental or behavioral state. Note that not all studies contributed equally to all feature entries. Three studies compared ADEM and childhood MS side by side [40,42,43]; additionally two studies compared clinical features of ADEM versus multifocal ADEM [39,44].

overlap with MS. Lumbar puncture performed to rule out any acute infectious meningoencephalitis [50] may reveal a mild lympho-monocytic pleocytosis and elevation of albumin. The occurrence of CSF-specific oligoclonal 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 pathological 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



evidence of dissemination in time of CNS demyelination;. 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 detection 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

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 acute disseminated encephalomyelitis versus multiple sclerosis As discussed above, neither pathognomonic nor diseasespecific 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 diagnosis 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 onethird 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) If 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

Table 2 Differential diagnoses of acute disseminated encephalomyelitis (ADEM) Pathogenic event

Possible differential diagnosis

Infectious

Viral, bacterial or parasitic meningoencephalitis HIV-associated encephalopathies: subacute HIV encephalitis progressive multifocal leukoencephalopathy Multiple sclerosis Neurosarcoidosis Behc¸et’s disease Antiphospholipid antibody syndrome Primary isolated CNS angiitis Vasculitis secondary to rheumatic autoimmune diseases, including systemic lupus erythematodes CNS neoplasia CNS metastasis of a systemic malignancy Mitochondrial encephalopathies: MELAS (mitochondrial encephalopathy with lactic acidosis and stroke like episodes) Adrenoleukodystrophy

CNS inflammation due to autoimmunity CNS vascular disease (plus inflammation) Mass lesion Inherited myelopathies and encephalopathies

Specific features, overlap to ADEM and relevant diagnostic tools to establish or exclude these differential diagnoses have been reviewed previously [2]. CNS, central nervous system.


252 Demyelinating diseases

process. Depending on the treatment regime adopted, such flare-ups are confined to within 3 months of the initial diagnosis. (2) In 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 treatment 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 incomplete 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 structures, the disease should be regarded as multifocal ADEM. (3) The 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 childhood 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 enhancing lesions – the initial diagnosis of ADEM should be revised to MS. (4) If, 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 MRIcentered diagnostic criteria [57]. The authors propose this follow-up procedure that, compared 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 individually.

Treatment and prognosis Once 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

general, treatment should be initiated as early as possible and as aggressively as necessary [59]. Due to the lack of controlled clinical trials, intravenous high-dose corticosteroids are widely accepted as first-line treatment, based on empiric and observational 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]. Additionally, various other antiinflammatory and immunosuppressant therapies may also be beneficial, as reported in several case studies: plasmapheresis [35,61], highdose intravenous immunoglobulin (IVIG) [36,60,62], mitoxantrone, or cyclophosphamide [62,63]. These should be considered as alternative therapies if corticosteroid 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].

Conclusion The 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 mechanisms 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



developed and explored further, as they appear to most faithfully mimic ADEM.

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