Keywords

Introduction

Acute disseminated encephalomyelitis (ADEM), also called postinfectious encephalitis/encephalomyelitis, is an immune-mediated inflammatory and demyelinating syndrome of the central nervous system (CNS). It is typically multifocal but monophasic [1]. In most subjects ADEM follows within a few days to weeks of a triggering event, typically infection or more rarely vaccination (Table 11.1). The vaccine relationship has been questioned, and some studies report no association [2, 3]. A minority of patients have no identifiable prior event. A critical concept is that ADEM does not represent an ongoing CNS infection.

Table 11.1 Triggering events for postinfectious encephalitis/encephalomyelitis
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ADEM is predominantly a pediatric disorder. The average age at onset is 5–8 years [4,5,6]. ADEM is much less common in adults, where it can occur at any age but particularly affects young adults. It is rare in the very young (ages 2–3 years) and in the elderly. The incidence in children is reported to range from 0.1 to 0.64 cases per 100,000 population per year [4, 7,8,9,10]. Most series show a slight male predominance. ADEM is said to account for at least 8%, and perhaps as high as 20%, of acute encephalitis cases [11].

Pathology

The pathologic hallmark of ADEM is widespread white and gray matter perivenous inflammation with demyelination [12]. The inflammatory infiltrate is made up of predominantly lymphocytes and monocytes/macrophages. Inflammation results in subsequent “sleeve-like” demyelination, with axons relatively spared [13]. In a recent pathology study, perivenous demyelination was associated with a distinct pattern of cortical microglial activation without myelin loss [12]. Perivenous lesions can coalesce to form larger demyelinated lesions. This neuropathology is quite distinct from multiple sclerosis (MS) or acute viral encephalitis. MS involves confluent demyelination [12]. Gross pathology can involve brain congestion and swelling, with engorged blood vessels within the white matter. Microscopically this is associated with hyperemia, endothelial swelling, vessel wall infiltration by inflammatory cells, and perivascular edema [14].

Acute hemorrhagic leukoencephalitis (AHLE), a hyperacute variant of ADEM discussed below, shows a somewhat different pathology, with prominent neutrophil infiltration, punctate petechial and ringlike hemorrhages, necrotizing vasculitis, and early perivascular astrocyte damage [4, 15].

Clinical Features

At least 70% of patients report an antecedent prodromal event, with neurologic symptoms beginning 2–30 days later [11]. Most often this is infection, with less than 5% following vaccination [16]. Rabies vaccine, when it contained neural tissue components, was a clear risk [4]. Viral infection is the commonest trigger, but nonviral pathogens and rare noninfectious exposures are also reported [17, 18]. Classically exanthematous infections such as measles (0.1%) were a particular risk. The prototypic clinical picture of ADEM involves multifocal neurologic deficits superimposed on a diffuse encephalopathy (Table 11.2) [19]. There may be seizures. Altered consciousness is a key feature. Drowsiness, lethargy, stupor, or coma is much more suggestive for ADEM than is simple irritability or mood disturbance. Cognitive deficits are seen [20], and multifocal deficits can involve motor, sensory, visual, coordination, and gait disturbances. Ataxia and language disturbance may be more common in children than adults [19, 21]. Lower urinary tract dysfunction can be seen in 33% and may persist [22]. It is also common to have neurologic abnormalities outside the brain itself. The spinal cord is involved in up to 67% of cases, particularly in adults [11, 13]. Peripheral nervous system (PNS) involvement (polyradiculoneuropathy) occurs in 5–44% [11, 23], perhaps reflecting that ADEM is part of a much broader immune-mediated neurologic spectrum that includes Guillain-Barre syndrome. The clinical course is rapid, with maximal deficits within 2–5 days [4]. Unusual clinical manifestations include acute psychosis, cerebellar mutism, various movement disorders, and Klüver-Bucy syndrome [24,25,26,27,28]. ADEM can certainly present with a picture that suggests mass lesion with increased intracranial pressure. It has also developed following aseptic meningitis [29]. Sustained high fever and hyponatremia were noted in these meningitis patients.

Table 11.2 Clinical features of postinfectious encephalitis/encephalomyelitis
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Based on the most current diagnostic criteria (see below), clinical features may fluctuate. New features may appear over a 3-month period and are still considered one episode. A small minority of ADEM patients (2–4%) will have a second attack [30]. In 80%, this second attack occurs within 2 years [30]. An early follow-up brain MRI (within 6 months), if it has new or persistent lesions, predicts multiphasic ADEM [31]. Brain MRI follow-up up to 2 years did not find silent MRI lesions in the monophasic group. Some pediatric ADEM patients will go on to develop MS, neuromyelitis optica spectrum disorder (NMOSD), or ADEM followed by optic neuritis (ADEM-ON) [4].

Diagnosis

Diagnosis of ADEM depends on a consistent clinical and laboratory picture, with other possibilities ruled out. It is a diagnosis of exclusion [4]. Core laboratory tests involve blood work, neuroimaging, and cerebrospinal fluid (CSF) evaluation. The International Pediatric MS Study Group revised their formal consensus definition criteria for pediatric ADEM in 2012 (Table 11.3). They recognize the monophasic and multiphasic (second attack) variants. More than two attacks are now felt to reflect a chronic relapsing disorder, such as MS or NMOSD [30]. The revised diagnostic criteria propose that after pediatric ADEM, MS criteria would be met if a second clinical event occurred ≥3 months later, was nonencephalopathic, and was associated with new MRI lesions meeting dissemination in space criteria. The ADEM diagnostic criteria require polysymptomatic onset with encephalopathy. Many earlier studies did not use formal diagnostic standards, and entered patients with CNS inflammatory syndromes of unknown etiology, with or without encephalopathy. In such series up to 58% of what was considered ADEM did not have encephalopathy [32].

Table 11.3 Revised pediatric postinfectious encephalitis/encephalomyelitis ADEM diagnostic criteria [30]
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The diagnosis in adults is more problematic, since it is fairly easy to include multifocal clinically isolated syndrome (CIS) (representing the first attack of relapsing MS) in ADEM series, unless encephalopathy is required. Encephalopathy is virtually never seen in MS relapses. In one series of 60 patients over age 15, who presented with an acute demyelinating syndrome, ADEM was differentiated from MS by meeting at least two of three critical criteria: atypical clinical symptoms for MS, absent CSF oligoclonal bands, or gray matter involvement [33]. In another study of 40 adult ADEM cases, 35% were said to have developed MS [34]. However, encephalopathy was not required for the original ADEM diagnosis. A recent series reported on five elderly subjects (ages 57–85 years) with pathologically confirmed ADEM [35]. Their initial differential diagnosis was broad.

ADEM should be considered in anyone who presents with a suggestive neurologic syndrome. Recent illness or vaccination increases likelihood of this diagnosis, but is not required. The rare postvaccinal cases typically follow a primary rather than revaccination [13].

Neuroimaging is central for the diagnosis of ADEM. Although brain CT may show patchy areas of low attenuation in white matter, with focal or diffuse cortical enhancement, it is normal in about 70% of patients and is much less sensitive than magnetic resonance imaging (MRI) [36]. Brain MRI with and without contrast should be carried out in all patients, unless contraindicated. Normal brain MRI probably excludes a diagnosis of classic ADEM, although imaged lesions may be delayed for several weeks [37]. MRI typically shows multiple T2/FLAIR hyperintense lesions involving white matter but also gray matter. ADEM lesions may (but do not have to) lack sharp borders. The classical imaging features for ADEM are symmetric bilateral lesions, relative periventricular sparing, and deep gray matter involvement. Deep gray matter (basal ganglia, thalamus) involvement is reported in 15–60% of adult cases [38]. Bilateral thalamic involvement is reported in 12% of pediatric cases [39]. In a recent study, MRI criteria were evaluated to differentiate ADEM from MS; the so-called Callen MS-ADEM criteria had the best sensitivity (75%) and specificity (91%) [40]. They involved meeting at least two of the following three criteria: absence of a diffuse bilateral lesion pattern, presence of black holes, and two or more periventricular lesions. Lesions affect subcortical white matter predominantly, although middle cerebellar peduncle and periventricular involvement can be seen [41]. Diffuse extensive supratentorial white matter involvement has also been seen [38]. Sometimes there can be a single tumefactive lesion, which can even be confined to the brainstem [10].

Contrast enhancement is not that helpful. Although very suggestive when it involves all lesions, there may be enhancement of only a subset of lesions, or none may enhance. There can be rare presentations with multiple ring enhancing lesions [42]. In pediatric ADEM, contrast enhancement of one or more lesions is noted in 14–30% [30].

Follow-up brain MRI 6 months after presentation should show partial or complete resolution of lesions, with no new lesions [13]. Spinal cord MRI may be abnormal as well. Cord lesions in ADEM are more likely to involve the thoracic region and may be diffuse and longitudinally extensive [43, 44].

There are limited reports using nonconventional MRI techniques. It would be helpful if a unique diagnostic imaging signature could be developed. Using diffusion MRI, apparent diffusion coefficient (ADC) was reported as decreased in early ADEM lesions and increased in later stages [41]. In another small series, diffusion tensor imaging signal was reported as abnormal in ADEM vs. MS basal ganglia [45]. A recent series showed ADC values increased in 70% of 17 pediatric ADEM cases, consistent with vasogenic edema [46]. Using MR spectroscopy, acute and chronic phases of ADEM showed distinct patterns. Reduced N-acetylaspartate to creatine ratios were noted in supratentorial normal-appearing white matter, while choline to creatine ratios were increased acutely, but decreased back toward normal later. Myoinositol to creatine ratios were decreased acutely, but increased in the chronic phase, consistent with gliosis. Elevated lipids and lactate were noted in the acute phase for all subjects, but later normalized [47]. Elevated glutamine/glutamate was present in 67% acutely and then dropped. The authors suggested that the decrease in myoinositol during the acute phase might distinguish ADEM from MS [47]. Unlike MS, normal-appearing brain tissue did not show abnormal magnetization transfer imaging or diffusion tensor imaging values [48].

CSF is routinely examined as part of the diagnostic workup. It helps to exclude direct infection. CSF can be normal in up to 33% of cases [11]. Most often there is a low-grade mononuclear pleocytosis, with mildly elevated protein and normal glucose. Rarely neutrophils may predominate. All cultures and stains, and any PCR or antigen tests, should be negative. CSF pressure may be elevated. Positive oligoclonal bands or elevated intrathecal IgG production is reported in a minority of cases. ADEM can be associated with oligoclonal bands in both CSF and serum [11]. If positive, they are transient and not persistently abnormal. Myelin basic protein (MBP) is often elevated in CSF, as a nonspecific acute injury marker.

With regard to other laboratory testing, about 50% of patients show peripheral leukocytosis or elevated acute-phase reactants [21]. Myelin oligodendrocyte glycoprotein (MOG) IgG antibody should be obtained if possible (see below). Electroencephalogram (EEG) generally shows diffuse background slowing [19]. Brain biopsy is rarely necessary but may be indicated in confusing cases (particularly with continued deterioration).

Differential Diagnosis

The differential diagnosis of ADEM involves principally other causes of encephalitis or encephalomyelitis, stupor, or brain MRI white matter lesions (Table 11.4) [1, 49,50,51,52,53,54]. The differential is influenced somewhat by age, since conditions such as mitochondrial disorders are more likely in the young, while toxic abuse is more likely in adults.

Table 11.4 Differential diagnosis of postinfectious encephalitis/encephalomyelitis
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Management

Symptomatic management involves general supportive measures, such as assuring airway and venous access, controlling fever, and treating electrolyte imbalance. Seriously ill patients or those who decompensate should be managed in an intensive care unit (ICU) setting, since increased intracranial pressure is a major concern in severe cases. Appropriate measures are taken to prevent venous thrombosis, and any seizures are treated.

There are no randomized controlled trials for treatment of ADEM. Corticosteroids are standard therapy based on class III evidence [55]. The most typical dose is 1 g intravenous (IV) methylprednisolone for 3–7 days. Occasionally higher doses (up to 2 g) are used. Plasma exchange (typically seven exchanges) can be considered in steroid-unresponsive patients. The expected response rate is at least 44% [56]. Males, those with preserved reflexes, and those who receive early (within 21 days) plasma exchange appear to do better. In one study early treatment, and improvement at discharge, predicted good response 6 months post exchange [57]. Treatment with intravenous immune globulin (IVIG) can also be considered in steroid-resistant patients, typically 1–2 g/kg over 2–5 days [36, 58]. IVIG is preferred to plasma exchange for postvaccinal ADEM [13, 59]. PNS involvement, milder onset disability, and lower CSF albumin have predicted IVIG treatment response [11]. IV cyclophosphamide has also been used for patients who continue to deteriorate. Rarely aggressive surgical decompression or hypothermia may be needed to control brain swelling [60,61,62].

Prognosis

With the exception of the AHLE hyperacute variant, ADEM overall has a good prognosis. Mortality rate is less than 5% in pediatric series, but has been reported as high as 8–25% in adults requiring ICU admission [38, 63]. Most patients make a good recovery from ADEM, though there may be permanent deficits in 10–30% including cognitive and psychosocial deficits [27, 28, 32, 34, 64]. In a pediatric series, initially severe course was associated with cognitive and visual spatial deficits years later [65]. In recent studies pediatric ADEM patients showed significantly reduced age-expected brain volume growth, and white matter development, compared to controls [66, 67]. Adults are reported to have a worse disease course and outcome than children [21]. In one small series of eight patients, brainstem involvement was associated with poorer outcome [68]. Peripheral nervous system involvement may also be associated with poorer recovery and higher risk of relapse [69]. Seizures and coma are also suggested to indicate worse prognosis [19, 27]. Other features associated with poorer outcome were older age onset, female gender, increased CSF protein, and spinal cord involvement [23]. In another very small series (two patients), decreased ADC in the internal capsule, consistent with cytotoxic edema, predicted poor motor outcome [70]. Patients with a relapsing attack are reported to have a good outcome in long-term (9–13 years) follow-up [71].

ADEM Spectrum Overlap Disorders

ADEM can be considered part of a spectrum of CNS disorders (Table 11.5). As discussed previously, ADEM is typically monophasic but can involve a repeat episode in 2–4% of cases. A repeat episode must occur beyond 3 months. By convention, this is considered multiphasic ADEM.

Table 11.5 Postinfectious encephalitis/encephalomyelitis CNS spectrum overlap disorders
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MOG IgG antibody is reported in a subset of demyelinating CNS disorders. It is more common in pediatric cases and with optic neuritis (especially bilateral). It requires a cell-based assay for reliable detection of conformationally sensitive IgG. ELISA and immunoblot, used previously, provided unreliable results [72]. Anti-MOG IgG is rarely if ever detected in MS. However, it accounts for about 10% of seronegative NMOSD (negative for aquaporin 4 IgG antibodies). It is reported in subjects with optic neuritis, encephalitis with brain demyelinating lesions, and myelitis. Some have suggested the eponym MOG-IgG-associated optic neuritis, encephalitis, and myelitis (MONEM) for this cohort [73]. The highest titers have been reported in ADEM but are generally transient and clear with recovery [72]. However persistent antibodies are also found in an unusual subset of ADEM that is followed by one or more attacks of optic neuritis (ADEM-ON ).

In a Dutch study, this variant accounted for only 1.2% of pediatric acquired demyelinating disease [74]. Anti-MOG antibodies are said to predict a non-MS disease course [75]. ADEM-ON is typically anti-MOG IgG positive in blood. In an analysis of 17 pediatric patients, relapses involved a unilateral or bilateral optic neuritis (94.4%) or ADEM (5.6%) [76]. During a median follow-up of 5.3 years, half of relapses occurred at the time corticosteroids were being tapered (to <10 mg) or within 4 weeks of discontinuation. Residual deficits were found in 71%. Interattack intervals could exceed 5 years. There is a case report of good response to rituximab [77]; others report corticosteroid responsiveness [76]. The acute attack in MOG-related syndromes is treated with corticosteroids, plasma exchange, IVIG, or cyclophosphamide [73]. The optimal long-term therapeutic approach to MOG-related syndromes is unclear, but currently includes prolonged corticosteroids over months, pulse IVIG, anti-CD20 monoclonal antibody, or immunosuppression [73]. It is important to follow titers, since loss of antibodies may allow withdrawal of therapy.

AHLE (Hurst syndrome) is a very rare disorder. It is the hyperacute and most severe form of ADEM [78, 79]. AHLE typically follows nonspecific respiratory tract infection. Clinical onset involves fever, confusion proceeding to stupor and coma, seizures, and focal neurologic deficits that mimic a rapidly expanding mass lesion within the brain. Mortality approaches 70% and occurs within days, with severe morbidity in survivors. MRI shows large hemispheric white matter lesions, with relative sparing of gray matter (although basal ganglia and thalamus may be involved, as can brainstem/cerebellum and spinal cord) [15]. There may be limited MRI enhancement despite evidence of edema and hemorrhage. On diffusion MRI, both acute and subacute lesions showed increased ADC values [15]. CSF shows pleocytosis with RBCs. Neuropathology involves polymorphonuclear cell infiltration with fibrinoid necrosis of small blood vessels, perivascular exudates, microhemorrhages, and cerebral edema. Myelin loss occurs in the setting of relative preservation of axons. There are no formal guidelines on treatment , but one can formulate a reasonable approach based on small case series (Table 11.6). Therapy requires aggressive treatment of increased intracranial pressure and other complications [36]. Corticosteroids with plasma exchange, IVIG, and/or immunosuppressants (cyclophosphamide) may be tried , and surgical intervention and hypothermia may be needed for severe cases [60,61,62, 80,81,82]. Clinical improvement has been noted within 2 days of starting plasma exchange.

Table 11.6 Management of acute hemorrhagic leukoencephalitis
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Acute necrotizing encephalopathy , formally characterized in 1995, is a rare disease which follows influenza, parainfluenza, human herpesvirus-6, measles, or mycoplasma infections [83, 84]. Young children under the age of 5 years, particularly from an Asian background (Japan and Taiwan), seem to be preferentially vulnerable [85]. The clinical syndrome is fulminant, with fever and altered mental status within 1–4 days of the viral febrile illness, progressing to coma within 24–72 h. Seizures (often refractory to treatment) are common, and mortality is 30–70%, typically due to cardiorespiratory issues [86]. Brain MRI shows multiple symmetric lesions involving the thalami, brainstem tegmentum, cerebellum, periventricular white matter, and putamen [85]. The differential diagnosis includes Reye syndrome, Leigh’s disease (subacute necrotizing encephalomyelopathy), Wernicke encephalopathy, Sandhoff disease, cerebrovascular event, or tumor [87]. CSF shows increased protein without pleocytosis and has been PCR positive for virus in only a minority of cases. Serum aminotransferases but not blood ammonia may be elevated. Postmortem studies show tissue necrosis, vascular changes with petechial hemorrhages, local vessel congestion, microthrombi, and vasogenic edema [86]. Some patients show high circulating levels of interleukin-6 and tumor necrosis factor [83]. Corticosteroids administered within 24 h of onset may be associated with better outcome, at least when brainstem is not involved [87]. An autosomal dominant disorder, involving recurrent bouts of acute necrotizing encephalopathy, has been associated with missense mutations in the Ran-binding protein 2 (RANBP2) gene on chromosome 2. This gene codes for a nuclear pore component [85, 88]. Acute necrotizing encephalopathy shows many similarities to AHLE. A recent case of AHLE in a 6-year-old girl with sickle cell disease was associated with a novel RANBP2 variant [89]. It is interesting to speculate whether acute necrotizing encephalopathy is an expression of AHLE in the very young.

Bickerstaff brainstem encephalitis is characterized by ophthalmoparesis, ataxia, and other CNS features including impaired consciousness. It appears to be part of a very broad neuroimmune spectrum which includes Guillain-Barré syndrome, especially the Miller Fisher variant [90, 91]. Reflexes in these brainstem encephalitis patients may be increased, normal, or even absent. Patients can show central motor and sensory abnormalities, and up to 66% have anti-GQ1b antibodies [92]. CSF shows cytoalbuminologic dissociation most often, but 32% do have a pleocytosis. Brain MRI is abnormal in up to 30%, with T2-hyperintense lesions most often within the brainstem [93]. Bickerstaff brainstem encephalitis is treated with either IVIG or plasma exchange [94]. Outcome is generally good with spontaneous recovery, but several deaths have occurred [95].

MS is the major acquired CNS inflammatory demyelinating disease. It is certainly in the differential diagnosis for ADEM but can also be considered part of this immune-mediated spectrum. This is especially true for pediatric MS but also for adult-onset MS. Pediatric MS is discussed in a separate chapter. Compared to ADEM, pediatric MS is not monophasic. It has onset typically over age 10 years, shows female predominance, and has no triggering event. It is more likely to have a monosymptomatic vs. polysymptomatic onset and is much less likely to involve any encephalopathic features, bilateral optic neuritis, fever, headache, meningismus, or seizures [32, 96]. Family history of MS also favors MS over ADEM [32]. However up to 20% of pediatric MS patients experience ADEM as their initial event and then go on to clear-cut MS [97, 98]. These children tend to be under 10 years of age. Laboratory distinctions are helpful. In MS the CSF is more likely to show oligoclonal bands which persist, without increased protein or pleocytosis. Brain MRI is much more likely to show periventricular perpendicular and corpus callosum ovoid lesions with well-defined margins, without gray matter or brainstem/cerebellar macroscopic lesions [32, 96]. MS MRI lesions increase over time and do not resolve the way ADEM lesions do. MS spinal cord MRI lesions are virtually never longitudinally extensive (extending three or more vertebral segments) except in rare pediatric cases. MRI diffusion-weighted imaging shows MS vs. ADEM differences. ADC values within the corpus callosum were consistently elevated in MS compared to ADEM or neurosarcoidosis patients, consistent with nonrestricted water diffusion due to demyelination.

For adult-onset MS, multifocal CIS can be confused with ADEM, but a key feature is the lack of encephalopathy as a component of the CIS presentation.

Etiology

ADEM is considered an immune-mediated CNS syndrome. It is believed that myelin components are generally the autoimmune targets. Several hypotheses have been proposed. The first is based on molecular mimicry. In this scenario an environmental pathogen or external vaccination contains antigenic epitopes that cross-react with myelin components and results in a misdirected systemic immune attack against the CNS. This would be akin to the major animal model for MS, experimental allergic/autoimmune encephalomyelitis, because it involves a systemic immune pathogenesis. This hypothesis is partially supported by early reports that rabies vaccines developed in CNS tissues had an excessive high rate of postinfectious sequelae.

A second hypothesis involves a transient infection of the CNS that results in blood-brain barrier damage, with release of sequestered myelin antigens to the systemic immune system. This is temporally linked to a secondary organ-specific immune attack against the CNS.

A third hypothesis requires a critically timed two-hit infection, with the second infection reactivating previously primed autoreactive lymphocytes.

In a limited number of cases, there is one final interesting observation: a mutation in the SCNIA sodium channel that has been associated with postvaccination ADEM [13, 99, 100].

T cells sensitized to MBP have been reported in ADEM. In an immunologic study of ADEM, most patients showed lymphocyte proliferation to MBP [101]. Some patients show antibodies to glycolipids such as galactocerebroside, as well as myelin proteins. IgG antibodies to MOG (but not to proteolipid protein or aquaporin 4) are present in most ADEM patients but are typically transient [102]. IgM antibodies to MOG were only found in 3 of 19 ADEM cases. In another series involving 19 children with ADEM vs. 25 with CIS, 28 other neurologic disease patients, and 30 healthy controls, IgM to EBV early antigen was present in 16% of ADEM cases only. Serum IgG to EBV was no different between ADEM and controls, but titers were higher in CIS patients. High IgG titers to native MOG were found only in the ADEM and CIS cohorts and were unrelated to the EBV antibody response [103]. There has been a particular interest in anti-MOG antibodies because they demyelinate in vitro MOG. MOG is expressed on the outer lamella of the myelin sheath. Persistent MOG antibodies in ADEM mark a group at risk for subsequent optic neuritis (ADEM-ON).

Cytokines are implicated as well [104] , and lesion formation is said to involve cytokines such as interleukin-2 (IL-2), interferon-γ, and tumor necrosis factor [105]. In a study of chemokines and cytokines in ADEM, MS, and healthy control subjects, ADEM showed elevated CSF levels of chemokines involved in neutrophil and T helper 2 cell attraction [106]. There was no difference in serum cytokine/chemokine levels.

Human leukocyte antigen alleles have been studied a little bit in ADEM and in various populations have been similar (but not identical) to those associated with MS [107]. A recent child with biopsy-documented ADEM showed two heterozygous mutations of the polymerase gamma gene, consistent with mitochondrial disease [108]. The significance of this association in a single case is unclear.

Summary

ADEM is an important neuroimmune syndrome that is part of a spectrum of CNS inflammatory demyelinating diseases. It is distinct from MS and carries overall a good prognosis with the exception of the hyperacute AHLE variant. The immunopathogenesis is not well understood, which limits development of preventive strategies and definitive therapies. A recent focus on IgG to MOG is helping to define useful ADEM subsets.

Diagnostic paradigms continue to be refined. Management involves appropriate supportive care and early institution of immunomodulatory therapies such as corticosteroids, plasma exchange, and IVIG. Aggressive management is always justified to control increased intracranial pressure, since such patients can ultimately do very well once this monophasic syndrome has ended.