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

Discussion

This is the first study to report epidemiologic, clinical, laboratory and radiographic features of ADEM in a defined, sizeable population during a decade and to compare CSF cytokines in patients with ADEM, viral meningoencephalitis and controls without evidence of CNS inflammation. We found that ADEM risk for San Diego Country children was similar regardless of gender, ethnicity or (considering population density) geographic area. Risk factors such as immunizations, animal or arthropod exposures or travel to a specific place were identified only infrequently and did not point to a common underlying etiology. Most children had only mild CSF or peripheral blood abnormalities. Children likely to have single episodes of demyelination were difficult to distinguish from those likely to have recurrent ADEM or MS on initial presentation.

The lack of pathognomonic epidemiologic, clinical and laboratory features in ADEM and the insensitivity of CT imaging supports use of MR to distinguish ADEM from other causes of acute childhood encephalopathy. Abnormalities were best seen on T2 and FLAIR sequences which demonstrated areas of increased signal in the white matter of the cerebrum, cerebellum, brain stem, basal ganglia and, occasionally, in deep gray matter. This distribution is consistent with previous observations.[59,60,61,62] Lesions were nonhemorrhagic, usually non-contrast-enhancing and asymmetric and correlated unreliably with neurologic signs (data not shown). ADEM is likely to be diagnosed with greater frequency as more MR evaluation of children with encephalomyelitis is performed. This may result in earlier diagnosis of MS in a subset of patients.

We found both type 1 and 2 helper T cell cytokines (IFN-γ and IL-10) to be significantly lower in patients with ADEM than in patients with EV meningoencephalitis at the time of acute presentation. IFN-γ is critical for orchestration of type 1 helper T cell responses and for clearance of some neurotropic viruses.[63,64] This diminishes to some degree the likelihood that acute CNS viral infection(s) directly cause ADEM, though further studies are warranted.

Two of 3 patients initially diagnosed with ADEM but subsequently diagnosed with MS in our study had >10-fold higher CSF IFN-γ concentrations compared with ADEM patients at the time of first clinical onset; the third MS patient had similar IFN-γ values. Reproducible CSF markers are needed for early identification of patients initially diagnosed with ADEM but likely to have MS. This is especially important now that early diagnosis and treatment have been reported to delay or even prevent MS recurrence.[65,66]

The principal rationale for using corticosteroids and IVIG to accelerate convalescence in ADEM has been down-regulation of CNS immune activation, eg, autoreactive T or B cells. However, the impact of corticosteroids on clinical outcomes in ADEM has not been prospectively evaluated. The number of patients not receiving corticosteroids in this study was small (n = 9), and nonrandomized treatment practices did not allow us to draw conclusions about corticosteroid efficacy. Besides corticosteroids and IVIG, other treatments reported to improve demyelinating diseases include plasmapheresis (ADEM), hypothermia (ADEM) and bone marrow transplantation (EAE), although no therapy was evaluated prospectively or in large numbers of subjects.[67,68,69,70,71,72,73] In some animals, permucosal or parenteral vaccination with myelin-associated antigens decreases or prevents pathologic lesions in EAE, suggesting that the context in which antigens are presented to the immune system is important for determining tolerance or autoimmunity.[74,75]

This study has several limitations. We are likely to have underestimated true ADEM incidence because less severe cases may not have been hospitalized or had MR imaging (required for our case definition to maximize specificity for demyelination). Case detection probably improved during the study period as a result of increased use of MR during recent years. The risk of ADEM in San Diego (33° N latitude) may not represent risk in other geographic areas. Although unknown in ADEM, a positive correlation exists between MS incidence and early childhood upbringing in regions of high northern or southern latitude. A systematic search was not performed for all infectious pathogens possibly associated with ADEM; variability in performance and methods of microbiologic testing, and the retrospective nature of part of this study, may have diminished the ability to identify infectious antecedents. Inflammation in brain parenchyma may not have been reflected in CSF cytokine measurements, and cytokines other than those we measured may play an important role in ADEM pathogenesis and recovery. Serial CSF measurements were not available to compare cytokine levels during acute illness and convalescence. Future studies of CSF cytokines and other immune parameters at various disease time points, as well as standardized risk factor assessment and laboratory evaluation for antecedent infection, will be important to extend these preliminary observations.

The clinician caring for patients with ADEM faces many questions regarding the possible infectious antecedents, immune response and pathogenesis, duration of neurologic symptoms, probability of recurrence or progression to MS, value of corticosteroid or other therapy and prospects for prevention.[76,77,78,79,80,81] The epidemiologic and immunologic determinants of ADEM susceptibility and the impact of corticosteroids or other therapies must be defined further.

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