Acute Disseminated Encephalomyelitis in Childhood: Epidemiologic, Clinical and Laboratory Feature

John A. D. Leake, MD, MPH; Salvatore Albani, MD, PhD; Annie S. Kao, MS, MPH; Melvin O. Senac, MD; Glenn F. Billman, MD; Mark P. Nespeca, MD; Amy D. Paulino, BS; Eileen R. Quintela, BS; Mark H. Sawyer, MD; John S. Bradley, MD

Disclosures

Pediatr Infect Dis J. 2004;23(8) 

In This Article

Abstract and Introduction

Background: Acute disseminated encephalomyelitis (ADEM) is a central nervous system demyelinating disease that usually follows an apparently benign infection in otherwise healthy young persons. The epidemiology, infectious antecedents and pathogenesis of ADEM are poorly characterized, and some ADEM patients are subsequently diagnosed with multiple sclerosis (MS).
Methods: We retrospectively (1991-1998) and prospectively (1998-2000) studied all persons aged < 20 years diagnosed with ADEM from the 3 principal pediatric hospitals in San Diego County, CA, during 1991-2000. Acute neurologic abnormalities and imaging evidence of demyelination were required for study inclusion. Epidemiologic variables, risk factors, clinical course, laboratory and radiographic findings, neuropathology and treatment data were analyzed. Interleukin (IL)-12, interferon-γ(IFN-γ) and IL-10 were assayed in blinded manner on cerebrospinal fluid (CSF) obtained prospectively from a subset of ADEM cases and compared with CSF from patients with enteroviral (EV) meningoencephalitis confirmed by polymerase chain reaction (PCR) and controls without pleocytosis.
Results: Data were analyzed on 42 children and adolescents diagnosed with ADEM during 1991-2000, and CSF IL-12, IFN-γ and IL-10 levels were compared among ADEM (n = 14), EV meningoencephalitis (n = 14) and controls without pleocytosis (n = 28). Overall incidence of ADEM was 0.4/100,000/year; incidence quadrupled during 1998-2000 compared with earlier years. No gender, age stratum, ethnic group or geographic area was disproportionately affected. A total of 4 (9.5%) patients initially diagnosed with ADEM were subsequently diagnosed with MS after multiple episodes of demyelination. Although most children eventually recovered, 2 died, including 1 of the 3 ultimately diagnosed with MS. Magnetic resonance imaging was required for diagnosis among 74% of patients; computerized tomography findings were usually normal. Patients with EV had significantly higher mean CSF IFN-γ (P = 0.005) and IL-10 (P = 0.05) than patients with ADEM and controls without CSF pleocytosis. CSF from ADEM patients had CSF cytokine values statistically similar to those of 3 patients subsequently diagnosed with MS.
Conclusions: ADEM is a potentially severe demyelinating disorder likely to be increasingly diagnosed as more magnetic resonance imaging studies are performed on patients with acute encephalopathy. Further characterization of the central nervous system inflammatory response will be needed to understand ADEM pathogenesis, to improve diagnostic and treatment strategies and to distinguish ADEM from MS.

Acute disseminated encephalomyelitis (ADEM), also known as postinfectious encephalomyelitis, is a demyelinating central nervous system (CNS) disorder that usually follows infection or more rarely vaccination.[1,2,3] The epidemiology and pathogenesis of ADEM are incompletely understood. Although ADEM most often occurs in childhood and has been estimated to account for 10-15% of acute encephalitis cases in the United States,[4] few descriptions of childhood ADEM have been published.[5,6,7,8,9,10,11,12] Many infectious causes of meningoencephalitis are indistinguishable from ADEM with the use of routinely available clinical or laboratory criteria, and pediatric infectious disease specialists are often asked to evaluate patients with ADEM. Diagnosis is presumptively made by exclusion of other diagnoses and CNS imaging and is only rarely confirmed by neuropathology.

Clinical, radiographic and pathologic features of ADEM also resemble multiple sclerosis (MS) and, in animal models, experimental autoimmune encephalomyelitis (EAE). Although ADEM is generally a monophasic illness lasting weeks to months, a small subset of children and a moderate proportion of adults who have recurrent demyelinating episodes are ultimately diagnosed with MS.[13,14,15] It is possible that ADEM, recurrent ADEM and MS represent different pathologic entities, but they are usually indistinguishable on initial clinical and radiographic evaluation.

It has not been definitively established whether ADEM or MS is caused by ongoing infection with undiagnosed pathogens or by postinfectious immune phenomena.[16] Respiratory or gastrointestinal tract symptoms and/or signs commonly precede ADEM and MS, and many viral and bacterial infections have been associated with ADEM onset.[1,17,18,19,20,21,22,23,24,25] However, microbiologic and serologic testing often fails to reveal evidence of a recent or ongoing infection, and infectious disease diagnostic evaluation is far from uniform. Additionally ADEM has been observed after vaccination with animal brain-derived rabies vaccines and, rarely, after administration of other vaccines.[3,26,27,28,29,30]

The lack of evidence for ongoing infection or vaccination in most cases and the usual time lapse of a few weeks between infectious symptoms or signs and ADEM onset have promoted the view that ADEM is a postinfectious immune disease. Molecular mimicry, eg, similarities between viral epitopes and host myelin antigens such as myelin basic protein, myelin oligodendrocyte glycoprotein and proteolipid protein, has been proposed as an explanation for autoreactive immune responses to CNS white matter after an infectious trigger.[31,32,33,34,35,36,37] Susceptibility to demyelination, at least for MS and EAE, is likely to have genetic determinants.[38,39,40,41,42] Many human and animal studies have suggested that proinflammatory cytokines play a role in MS and EAE pathogenesis.[43,44,45,46,47,48,49] However, limited immunologic data have been reported in ADEM.[50,51,52,53]

To define epidemiology, identify antecedent infections or vaccinations and describe clinical, laboratory, neuropathologic and radiographic features of ADEM, we studied retrospectively all children diagnosed with ADEM at the 3 principal pediatric inpatient facilities in San Diego County, CA, during 1991-1998 and prospectively evaluated patients during 1998-2000. We compared CSF cytokines from children with ADEM to 2 groups of CSF specimens, 1 with enteroviral (EV) meningoencephalitis and 1 without CSF pathogens or pleocytosis.

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