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Acute Disseminated Encephalomyelitis

Gray, Matthew Philip MD, MS; Gorelick, Marc H. MD, MSCE

doi: 10.1097/PEC.0000000000000825
CME Review Article

Acute disseminated encephalomyelitis is a primarily pediatric, immune-mediated disease characterized by demyelination and polyfocal neurologic symptoms that typically occur after a preceding viral infection or recent immunization. This article presents the pathophysiology, diagnostic criteria, and magnetic resonance imaging characteristics of acute disseminated encephalomyelitis. We also present evaluation and management strategies.

Assistant Professor of Pediatrics (Gray) and Professor of Pediatrics (Gorelick), Section of Emergency Medicine, Department of Pediatrics, Medical College of Wisconsin, Milwaukee, WI.

The authors and staff in a position to control the content of this CME activity and their spouses/life partners (if any) have disclosed that they have no financial relationships with, or financial interest in, any commercial organizations pertaining to this educational activity.

Reprints: Matthew Philip Gray, MD, MS, Department of Pediatrics, Medical College of Wisconsin, 999 N 92nd St, Suite CCC 550, Milwaukee, WI 53226 (e-mail: mgray@mcw.edu).

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TARGET AUDIENCE

This CME activity is intended for clinicians who care for children. Pediatricians, pediatric emergency physicians, emergency physicians, family medicine physicians, as well as nurse practitioners and physician assistants working in ambulatory and acute care settings will find this article helpful.

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LEARNING OBJECTIVES

After completion of this article, the reader should be able to:

  1. Identify common presenting symptoms and describe the typical clinical course of acute disseminated encephalomyelitis (ADEM).
  2. Identify appropriate diagnostic studies needed to diagnose acute ADEM.
  3. Summarize appropriate treatment options for ADEM.
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CASE

A previously healthy 6-year-old boy is brought to the emergency department for concern of changes in behavior and difficulty swallowing. For the past week, he has been having periods of inattention and difficulty completing assignments in school, as well as being more tearful and having inappropriate outbursts of crying. He was initially seen by his primary physician who considered these symptoms behavioral because of some family stresses. The parents are now concerned because for 2 days, he has had some drooling and difficulty swallowing, as well as a nasal voice. Three weeks earlier, he had fever and sore throat; strep testing was negative, but he was treated empirically with penicillin. His physical examination results are normal, except for the neurologic examination results. He is oriented and alert but occasionally cries during the examination. His voice is hyponasal, and when given a drink of water, he swallows slowly. Cranial nerves are otherwise intact, strength and deep tendon reflexes are normal, and sensation is grossly intact. His gait is wide based and ataxic. He has normal finger-to-nose testing on the right, but on the left, he repeatedly uses his thumb or pinky instead of his index finger.

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Background

Acute disseminated encephalomyelitis (ADEM) is an immune-mediated disease characterized by demyelination and polyfocal neurologic symptoms. It typically occurs after a preceding viral infection or recent immunization. Preceding infection can be identified in 64% to 93% of cases,1–5 and onset of symptoms is typically within 2 to 4weeks of infection.1,5–7 Acute disseminated encephalomyelitis is primarily a pediatric disease with an average age at onset of 5 to 8years.3–5,8–12 Leake etal3 estimated the incidence of ADEM at 0.4 per 100,000 per year among persons younger than 20years in San Diego County, California, although a more recent study from Canada has estimated the incidence at 0.2 per 100,000 children younger than 18years.10 There is no clear sex difference although a few cohort studies and 1 systematic review of 750 patients with ADEM have suggested a slight male predominance, with estimated female to male ratios ranging from 0.6 to 0.8 to 1.4,5,12 Studies from North America have demonstrated seasonal increases in incidence during the winter and spring.13

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Clinical Features

Acute disseminated encephalomyelitis is a heterogeneous clinical entity that is best viewed as a syndrome.14 Acute disseminated encephalomyelitis typically follows a rapidly progressive monophasic course, followed by favorable long-term outcomes. Prodromal symptoms can include fever, malaise, headache, nausea, and vomiting progressing to encephalopathy and coma.1,3,4,7,12,13,15 The mean time to maximum symptoms has been estimated at 4.5days.5 Fever, headache, and seizures are more common in children.5,9,16 Multifocal neurologic abnormalities at presentation are common and are dependent on the location of the central nervous system (CNS) lesions. These neurologic findings can include but are not limited to encephalopathy, ataxia, hemiplegia or hemiparasthesias, cranial nerve palsies, visual changes, seizures, and speech impairment.2–5,8,15 Respiratory failure has been seen in up to 11% to 16%.5,11

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Pathophysiology

The pathologic hallmark of ADEM includes inflammatory reaction surrounding blood vessels with perivenular demyelination. This pattern has been shown to be associated with an encephalopathic presentation and a monophasic disease course.17 The demyelination is the result of a transient autoimmune response toward myelin or other self-antigens. It is largely thought that the autoimmune response is the result of either molecular mimicry or direct infection of the central nervous system. In the case of molecular mimicry, it is hypothesized that structural similarities between causative pathogen and host cells result in T-cell activation, but these similarities are not sufficient enough to induce tolerance.18,19 Alternatively, it has been hypothesized that direct CNS infection with a neurotropic pathogen results in disruption of the blood-brain barrier allowing CNS autoantigens to leak into the systemic circulation and induce T-cell activation.20,21

Antibodies against myelin oligodendrocyte glycoprotein have been identified in several demyelinating diseases in children including up to 40% of children with ADEM.22,23 High levels of antibodies have been detected during the acute disease and have been shown to diminish with recovery.24–28 The clinical relevance of these and other antibodies, however, is unclear. Interestingly, patients with anti–myelin oligodendrocyte glycoprotein antibodies and those without have similar clinical courses, suggesting that there are multiple disease mechanisms in play. Van Haren etal29 have identified IgG and IgM autoantibody profiles for both ADEM and multiple sclerosis (MS), another demyelinating condition; differences in these profiles may help differentiate the 2 diseases at initial presentation.

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Diagnostic Criteria

In 2007, the International Pediatric Multiple Sclerosis Study Group published provisional definitions for pediatric-acquired demyelinating conditions including ADEM.30 These definitions were updated in 2013.14Table 1 outlines the diagnostic criteria for pediatric ADEM. Within the revised criteria, encephalopathy was defined by consensus as “an alteration of consciousness or behavioral change unexplained by fever, systemic illness, or postictal symptoms.”

TABLE 1

TABLE 1

Patients presenting without encephalopathy but with a first clinically isolated, monophasic event presumed to be from an inflammatory demyelinating cause are now categorized as clinically isolated syndrome. Clinically isolated syndrome has been distinctly defined on the basis of evidence demonstrating that absence of encephalopathy increases the risk of developing MS.8,31

“Recurrent ADEM” has been eliminated under the new guidelines, and a revised definition of multiphasic ADEM has been proposed. Multiphasic ADEM is defined by 2 episodes consistent with ADEM separated by 3months but not followed by any further events. Further relapse is felt to be indicative of chronic disease and typically leads to the diagnosis of MS or neuromyelitis optica. For those patients whose conditions are later diagnosed with MS, onset is considered to be the time of initial ADEM diagnosis.

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Evaluation

Encephalopathy has very broad differential diagnosis and is commonly caused by the infectious encephalitides. As such, when encephalopathy is present, it is imperative to assess for and rule out life-threatening causes including bacterial, viral, and arthropod-borne CNS infections. Evaluation should be based on symptoms as well as epidemiology and should include CSF testing for herpes simplex virus.32 Approximately two thirds of patients with ADEM will have a mild pleocytosis with lymphocyte predominance.11,12,15 Empiric antibiotic and antiviral treatment should be strongly considered, whereas further evaluation and imaging are pending.32 Other possible laboratory abnormalities include modest elevation of inflammatory markers such as erythrocyte sedimentation rate or C-reactive protein, but these are of questionable diagnostic significance.

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Magnetic Resonance Imaging Characteristics

Magnetic resonance imaging (MRI) is the mainstay of defining and diagnosing ADEM. Five characteristic patterns of CNS involvement seen on MRI have been proposed (Table 2).5,33 Lesions are typically ill-defined, are most notable on T2-weighted and Fluid-attenuated inversion recovery (FLAIR) imaging, and have bilateral cerebral involvement (Fig. 1).34,35 Thalamic and basal ganglia lesions are common and more indicative of ADEM, whereas presence or persistence of hypointense lesions in white matter is more predictive of MS. In addition, the presence of periventricular lesions is more indicative of MS.5,36,37

TABLE 2

TABLE 2

FIGURE 1

FIGURE 1

Despite the advances in MRI capabilities, making a definitive diagnosis of ADEM at the time of initial presentation remains a challenge. Several MRI-based criteria have been developed to aid in the differentiation of ADEM from MS.38–42 The KIDMUS41 criteria have been shown to be very specific for MS; however, the criteria have a poor sensitivity in distinguishing MS from ADEM. More recently, Callen etal39 retrospectively validated MRI criteria with a 95% specificity and 81% sensitivity for classifying MS from ADEM at initial presentation. The Callen MS-ADEM criteria include any 2 of the following: (1) 2 or more periventricular lesions, (2) presence of black holes, or (3) absence of a diffuse bilateral lesion distribution pattern. These criteria were tested in a cohort of 48 children in Canada. Ketelslegers etal43 tested the sensitivity and specificity of the Callen MS-ADEM criteria as well as 3 other MRI criteria in a cohort of 49 children in the Netherlands. The MS-ADEM criteria had the best combined test characteristics with a sensitivity of 75% and specificity of 95%. Further advances in MRI and immunologic testing will continue to improve our ability to prognosticate at the time of initial diagnosis.

Repeat MRI in the follow-up phase of care is important in establishing the diagnosis of ADEM. The International Pediatric Multiple Sclerosis Study Group suggests obtaining at least 2 additional scans for a 5-year period after the first negative scan.13

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Treatment

Currently, there are no randomized control trials in children or adults to determine optimum treatment for ADEM. Systemic corticosteroids, by consensus, are largely considered a first-line therapy. Typical dosing regimens include methylprednisolone 20–30mg/kg per day (max, 1g) intravenously for 3 to 5days, followed by oral prednisone at a dose of 1 to 2mg/kg per day for 1 to 2weeks with a subsequent 2 to 6week taper.44–46 A single retrospective trial demonstrated better outcomes when using methylprednisolone compared with dexamethasone.5 In addition, there is limited evidence to suggest an increased risk of relapse with oral steroid tapers less than 3weeks in duration.9,11

Minimal evidence exists for the use of second-line therapies. Therapies used in steroid refractory cases typically consist of intravenous immunoglobulin (IVIG) and plasmapharesis. When used, IVIG is typically given at a total dose of 2g/kg for 2 to 5days.44,45 In 2011, the American Academy of Neurology published an evidence-based guideline for the use of plasmapharesis in CNS demyelinating disease, and their recommendation is that plasma exchange may be considered in cases of ADEM refractory to high-dose steroid therapy.54 There are limited case reports that include pediatric patients in which plasmapharesis has been used for patients failing first-line treatment.47–49 Currently, no evidence exists supporting the use of other immunomodulatory therapies in children with ADEM.

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Long-term Outcomes

Acute disseminated encephalomyelitis generally has a very favorable outcome. Complete recovery has been reported in 57% to 94% of patients in several cohorts.3–5,11–13,50 Among patients with residual deficits, clumsiness, ataxia, hemiparesis, and blindness are more commonly seen.5 More attention has recently been paid to long-term behavioral and cognitive impairments. Parrish etal51 found an increase in parental and patient self-reporting of fatigue and an increase in parental reporting of depression. There was no difference in self-reporting of depression between patients with ADEM and healthy controls. Suppiej etal52 completed IQ, neuropsychological, and quality of life testing in 22 patients with monophasic ADEM. Mean group scores were within the normal range; however, there were differences in individual neuropsychological functions with attention being the most commonly affected. They found no correlation to radiologic recovery on MRI. Hahn etal53 also demonstrated a variety of mild cognitive deficits and also found no correlation to radiologic recovery on MRI.

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Case Denouement

Because of the encephalopathy, the child had broad laboratory testing that was remarkable only for an erythrocyte sedimentation rate of 33mm/h and c-reactive protein of 0.9mg/L. A lumbar puncture revealed 62 white blood cells per high power field (66% lymphocytes). Magnetic resonance imaging showed extensive subcortical and deep white matter edema and demyelination. A presumptive diagnosis of ADEM was made, and the child was admitted to the hospital and begun on intravenous methylprednisolone. His symptoms stabilized, and he was discharged home after 4 days. Subsequent test results included an elevated titer of antibodies to myelin basic protein in the CSF. At follow-up evaluation 3 months later, his symptoms had resolved.

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Keywords:

disseminated encephalomyelitis; ADEM

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