Acute disseminated encephalomyelitis (ADEM)

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Abstract

ADEM is a disease that is characterized by an inflammatory reaction and demyelination in the central nervous system, with a distinct tendency to a peripheral localization of pathological changes. ADEM happens to occur with a temporal, and probably also with a causative relationship to viral, exanthematous diseases, as well as to preventive vaccinations. However, there are still many unresolved problems with respect to the relationship of ADEM to multiple sclerosis (MS), especially in instances with a multiphasic course of the disease. Many question marks can also be raised in cases, in which the examinations were unable to determine the exact preceding or causative factor. A lot of studies on cytokines and chemokines in blood plasma and CSR from patients with ADEM have enabled investigators to get a better insight into some stages of immunopathological processes, leading to an evolvement of the disease, without a more important impact on the clinical diagnosis.

Introduction

Acute disseminated encephalomyelitis (ADEM) is a disease characterized by an inflammatory reaction and demyelination on the central nervous system (CNS), in the brain and in the spinal cord, with a distinct tendency to a perivenous localization of pathological changes (Menge et al., 2005). ADEM is therefore also known as a perivenous encephalomyelitis. ADEM happens to occur with a temporal and probably also with a causative relationship to a viral, mainly exanthematous disease (post-infection encephalomyelitis), as well as to preventive vaccination (post-vaccination encephalomyelitis), and only very rarely following application of immune sera (Tanembaum et al., 2007, Weng et al., 2006). Nevertheless, there still are many unresolved problems as to the possible relationship of ADEM to MS, especially in instances with a multiphasic course of the disease (DEM). Many question marks can also be raised in cases in which the examinations and medical records were unable to determine the exact preceding or causative factor (Gallas et al., 2006). The acute hemorrhagic encephalomyelitis of Hurst should be considered to represent a variant or else, as only a hyperacute form of the disease. Cases linking the disease to lesions of the central and peripheral nervous system are distinct. These cases can be classified as the variant of Guillain–Barre syndrome (Marchioni et al., 2005).

The term ADEM should not be identified with or extended to cases of encephalitis with lesions resident in the white and grey matter, evoked by a definite virus such as, for instance, the Epstein–Barr or herpes virus, despite of the fact that in some cases a diffuse demyelination may have taken place. Another point is that, in very rare instances, following an infection with the Epstein–Barr virus, there may develop a typical acute hemorrhagic encephalitis of the Hurst type (Hofer et al., 2005). The point of view presented by Tselis and Lisak (2005), that the term ADEM cannot be used for the clinically isolated demyelination syndrome (CIS), retrobulbar optic nerve neuritis, acute transverse myelitis or acute cerebellar ataxia, should also be fully accepted.

Section snippets

Epidemiology

ADEM is an uncommon disease, lacking strict diagnostic criteria. Hence, the annual incidence rate in the population is not precisely known and that is why the figures usually presented refer to the relevant precipitating factor or disease. In a clinical study of childhood ADEM in the Fukuoka Prefecture, Japan, for the period of 1998–2003, Torisu et al. (2010) reported the incidence of ADEM in a population of children aged less than 15 years, which amounted to 0.64 per 100,000 persons per year.

ADEM versus MS

The until now unresolved and an intensely discussed question is whether ADEM and MS are variants of the same disease or they are completely distinct morbid entities. The problem is discussed from both clinical and pathological points of view (Pohl et al., 2007). However, the problem gets even more complicated during vivid discussions concerning the heterogeneity of pathological patterns presented by MS patients, which finally leads to a suggestion that MS is not a uniform disease (Lassmann, 2002

Etiopathogenesis

There are many data pointing to a similarity, although not necessarily an etiological identity, of human ADEM with pathology induced as an experimental disease in animals (EAE). This may be questioned, particularly in post-vaccination instances, especially after application of primitive rubies vaccine (technically unpurified) containing many fragments of myelin with antigenic properties (Huynh et al., 2008). Less explained are the immunological processes leading to ADEM after or in the course

Immunopathology

Immunological studies on active substances (cytokines and chemokines) in blood and cerebrospinal fluid of patients with ADEM provided an insight into individual stages in evolvement of the disease. However, any generalization as to the immunological cascade is only then substantiated, when an analogy is noted with other immunological diseases, such as the most frequent in human multiple sclerosis or those experimentally evoked in animals.

Studies conducted by Ichiyama et al. (2002) revealed

Neuropathology

The focal, perivenous and subependymal changes dominate the pathological pattern. These changes lead to manifestation of disseminated masses or conglomerates. The topography of lesions varies between the cases but with a marked preponderance of the white matter at the cortical–subcortical border. Highly intense infiltrates may also be found in the cerebellum, spinal cord and cerebral trunk. Despite of the markedly greater involvement of the inflammatory reaction in the white matter, the

Clinical pattern

ADEM, the acute inflammatory disease of the central nervous system, develops mostly in a temporal link of one or two weeks following a viral disease or prior vaccinations. Irrespective of the triggering factor, the clinical syndrome begins with fever, headache, vomitus and meningeal signs. Following a few hours or days, a somnolence develops, sometimes leading to comatose condition, seizures and focal, neurological signs, such as limbis pareses, speech disturbances and tremor. The process may

Laboratory tests in ADEM

In the majority of ADEM cases, the cerebrospinal fluid shows only minor and unspecific changes. The cell count is increased, amounting to less than 10 cells/μl, the total protein content is also increased but usually below 100 mg/dl. In many instances, the immunoglobulin level is also elevated but oligoclonal bands are seen only rarely (Stuve et al., 2005, Franciotta et al., 2008). However, the above presented pattern does not allow to distinguish ADEM from MS. The only appreciable difference is

Neuroimaging

Computer tomography (CT), show in many cases hypodense lesions in the cerebral white matter, usually with a gadolinium-positive enhancement. The lesions in the early period are mild and increase in severity with progress of the disease, leading sometimes to immense hypodensic lesions, that may cover a great part of the brain.

Magnetic resonance imaging (MRI) demonstrates many lesions in the white matter in T2 and Flair sequences, which are better recognizable after gadolinium enhancement (

Diagnosis

The diagnosis of acute disseminated encephalomyelitis as well as of the hemorrhagic variant of Hurst constitutes a difficult, and almost never infallibly ascertained task. The main clinical argument involves a temporal relationship to exanthematous viral diseases or to preventive vaccination and probably also to the application of immune sera. These difficulties arise when ADEM follows a not strictly specified infection. They are even more pronounced when the process starts without a trigger

Therapy

Due to the low incidence of ADEM no respective control trials have been performed and, therefore, any evaluation of results is based solely on clinical data. In the acute phase of the disease, a pronounced role is ascribed to the standard treatment performed in an intensive care unit, with procedures reflecting condition of the patient. An intubation of the patient and mechanical respiration are sometimes indispensable. Of great importance is also an accurate management of the electrolyte

Clinical sequelae of ADEM

Very little is known about the late sequelae of ADEM. Donmez et al. (2009) tried to evaluate the prognosis of ADEM with the aid of FLAIR and diffusion-weighted imaging. His opinion was not very enthusiastic: he and other authors only found that the spread of the lesions, particularly the cortical involvement, may have an influence on the prognosis. Bala et al. (2010) have found that in 50% of individuals with a history of ADEM, a marked and definite decline in attention and executive

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