KeywordsADEM, AHEM, demyelination, MRI, imaging, post-streptococcal, multiple sclerosis
Acute disseminated encephalomyelitis (ADEM) is a rare, usually monophasic, immunologically mediated inflammatory disease of the central nervous system (CNS) with characteristic polyfocal involvement of the neuroaxis on imaging. It may occur at any age but is most commonly seen in the pediatric population, with the mean age at presentation between 5 and 8 years. It has a reported incidence of 0.007 to 0.64 per 100,000 persons per year in the pediatric population and shows seasonal variation, with increased incidence during winter and spring. There is slight male predilection (M:F::1.4–2.3:1).
A preceding history of infection, or less likely, vaccination may be elicited in approximately 67% to 93% of patients, with an upper respiratory infection being most commonly associated. Although a number of infectious agents and vaccines have been implicated, ADEM is most frequently associated with measles and rubella infection and immunization with Semple form of rabies vaccine. The duration between the antigenic trigger and initial symptoms of ADEM varies between 4 and 12 days but may be delayed by up to 6 weeks.
The relationship between ADEM and multiple sclerosis (MS) is complex and approximately 6% to 18% of pediatric ADEM patients eventually progress to MS. Risk factors for progression to MS include age greater than 10 years at first presentation, absence of encephalopathy or antecedent infection, presence of oligoclonal bands in cerebrospinal fluid (CSF) or characteristic periventricular lesions on magnetic resonance imaging (MRI), optic neuritis, and positive family history of MS.
Under the revised International Pediatric Multiple Sclerosis Study Group (IPMSSG) criteria, a clinical encephalopathic syndrome must exist for ADEM to be diagnosed. Absence of encephalopathy, or encephalopathy secondary to fever, leads to a diagnosis of clinically isolated syndrome (CIS). Besides encephalopathy, other presenting symptoms include long tract or brainstem dysfunction, ataxia, seizures, optic neuritis, and cranial nerve palsy. Respiratory failure secondary to brainstem involvement may occur in 11% to 16% of cases. Once ADEM develops, any fluctuation in the clinical features or imaging findings within the first 3 months is considered a part of the monophasic illness.
Pathophysiology and Histology
It is generally agreed that ADEM is an autoimmune response to myelin because pathologically similar changes may be induced in a variety of animal models following immunization with myelin proteins or peptides (experimental allergic encephalomyelitis model). This may occur through molecular mimicry wherein the antigen shares a structural similarity to myelin ( Fig. 10.1 ). The ensuing immune response cross-reacts with myelin, inadvertently resulting in an autoimmune CNS injury. Similarity of myelin basic protein (MBP) to several viral sequences and enhanced T-cell response to MBP in patients with ADEM lend support to the theory.
Another potential explanation is activation of preexisting myelin reactive T cells through a nonspecific inflammatory process. Lastly, a less appealing hypothesis is CNS involvement by a neurotropic infectious agent resulting in systemic leakage of autoantigens, thereby triggering an autoimmune response.
Histopathologically, the lesions show perivenous “sleeves” of demyelination dominated by T lymphocytes and macrophages, a finding felt to be characteristic of ADEM ( Fig. 10.2 ).
ADEM lesions predominantly involve the white matter (WM), are large and asymmetric, and have ill-defined margins ( Fig. 10.3 ). Neuroimaging findings may lag behind clinical presentation, rarely by up to 8 weeks. Lesions resolve over a course of few days to weeks, often completely, although partial resolution or residual volume loss may be seen ( Figs. 10.4 and 10.5 ).
Computed tomography (CT) imaging often shows hypodense lesions involving the cerebral WM ( Fig. 10.6 ). Although CT is often abnormal, MRI is generally preferred, given the superior soft tissue detail and improved characterization.
The lesions can virtually occur anywhere along the neuroaxis but show a predilection for the juxtacortical or deep WM. Involvement of the cortical ribbon, basal ganglia, thalami, and brainstem is also well described ( Fig. 10.7 ). When present, optic nerve involvement is commonly bilateral, unlike MS, which is often unilateral ( Fig. 10.8 ). Occasionally, lesions may involve periventricular WM and corpus callosum. Although ADEM by definition is polyfocal, rare cases may show only a solitary lesion or isolated brainstem involvement ( Fig. 10.9 ).
MRI typically shows multiple, asymmetric supratentorial and infratentorial lesions that are iso- to hypointense on T1-weighted imaging (T1WI) and show T2 prolongation. Some authors have described dominant patterns on imaging, which include: (1) ADEM with small lesions (<5 mm) ( Fig. 10.10 ), (2) ADEM with large, confluent, or tumefactive lesions ( Fig. 10.11 ), (3) ADEM with additional bithalamic involvement ( Fig. 10.12 ), and (4) acute hemorrhagic encephalomyelitis (see later).