Acute disseminated encephalomyelitis (ADEM) is an immune-mediated central nervous system (CNS) disorder. Patients with ADEM have multifocal inflammatory (but noninfectious) lesions within the brain or spinal cord. There is usually a history of a preceding upper respiratory infection or immunization within a few weeks of onset of the neurological manifestations. The pathophysiology likely involves an excessive immunological response that attacks myelin. The histological features include infiltration of monocytoid cells and perivenous demyelination. Patients with ADEM usually experience a sudden onset of multifocal neurological signs and symptoms. The CNS lesions may completely subside within a few weeks, or progress to glial scars. Important considerations in the diagnosis of ADEM include the clinical presentation, cerebrospinal fluid (CSF) analysis, neuroimaging studies, and the absence of another definable cause of the symptoms. The clinical differential diagnosis includes multiple sclerosis, leukodystrophy, and mitochondrial encephalomyopathy. ADEM is a monophasic disorder. Multiphasic disseminated encephalomyelitis refers to a relapsing form.^1–4

In temperate climates, ADEM most often occurs in the winter and spring. Because the precipitating infection has usually resolved by the time neurological symptoms occur, microbiological examinations are often negative. ADEM can follow infections with various organisms, such as Epstein-Barr virus, Mycoplasma pneumoniae, influenza, measles, pertussis, cytomegalovirus, and varicella-zoster virus. CSF evaluation often demonstrates mild pleocytosis and elevation of protein. The most common neurological features of ADEM are motor deficits such as ataxia, paraparesis, hemiparesis, or monoparesis. Altered consciousness is also common. Patients with spinal cord involvement may have paraparesis, sensory deficits, and/or urinary retention. Complete clinical recovery occurs in most patients with ADEM. The most commonly employed treatment is intravenous corticosteroids. Intravenous immune globulin is an alternative therapy.

MRI of patients with ADEM demonstrates multifocal hyperintense lesions on T2-weighted and fluid-attenuated inversion recovery (FLAIR) images (Figure 17-1). These hyperintense foci predominantly represent inflammatory edema. Because there is usually little or no myelin breakdown, proton MR spectroscopy (MRS) demonstrates normal choline levels in ADEM lesions. This is in contradistinction to some of the important considerations in the differential diagnosis that are associated with demyelination and have elevated choline levels, such as acute-phase multiple sclerosis and various leukodystrophies. Lactate levels are also usually normal in ADEM; lactate is often elevated in mitochondrial encephalopathies and in some acute plaques of multiple sclerosis. N-Acetylaspartate (NAA) is sometimes decreased in the active phase of ADEM, with subsequent complete or partial normalization. The lesions of ADEM usually have increased water motion on diffusion-weighted images, that is, high signal intensity on apparent diffusion coefficient (ADC) images. The presence of extensive areas of restricted diffusion in a patient with ADEM indicates a high likelihood for progression to encephalomalacia and gliosis. There is usually restricted diffusion in acute multiple sclerosis plaques and in brain lesions due to vasculitis.^1,5,6

Tenembaum et al recognized 4 general neuroimaging patterns of ADEM.⁷ (1) Most patients have disseminated, often asymmetrical, lesions. The cortical gray matter and subcortical white matter are common sites. (2) About one-fourth of patients have large cerebral white matter lesions, as well as lesions in the central gray matter structures. (3) The third group (approximately 10%) includes patients with bilateral thalamic lesions in conjunction with white matter involvement. (4) Approximately 2% of patients have a clinically severe variant, with confluent areas of edema and hemorrhagic necrosis; this is termed acute hemorrhagic encephalomyelitis (Figure 17-2). With all forms of ADEM, there can be involvement of the brain stem or spinal cord, either in isolation or in conjunction with cerebral and cerebellar disease. Cranial nerve involvement (e.g., the optic nerves) can also be present (Figure 17-3). The brain lesions of ADEM are sometimes fleeting, with new or growing lesions appearing on sequential images studies as other foci fade. In some patients, new lesions develop despite an improving clinical course. Contrast enhancement on MR images occurs in about one-third of patients with ADEM. Enhancement can be homogeneous, heterogeneous, or ringlike (Figures 17-4 and 17-5). Spinal cord involvement usually appears on MR as extensive lesions that are hyperintense on T2-weighted images. The spinal lesions are sometimes multifocal.^7,8

Multiple sclerosis is the most common demyelinating disease in adults but is infrequent in children. Approximately 5% of adults with multiple sclerosis had a clinical onset prior to the age of 18 years, most often as adolescents. Multiple sclerosis is a cell-mediated and antibody-mediated autoimmune white matter disease. Myelin and oligodendrocytes are the target tissues of the immune response. Foci of scarring or inflammation can occur throughout the CNS. Individuals with the histocompatibility complex type HLA-DR2 are particularly susceptible to this disorder; this is most common in people of northern European descent. Environmental factors such as viral infections, bacterial infections, and antigens may expose macrophages and microglial cells to myelin antigens. Activation and proliferation of T lymphocytes lead to antibody production.^9–12

Most patients with multiple sclerosis have the relapsing-remitting subtype that is characterized by an abrupt episodic onset of symptoms. Symptoms frequently develop over hours or days, peak within several days, and then improve gradually over the next several weeks. Recurrence is common, although medical therapy reduces the risk for, and the severity of, relapses. Approximately 20% of untreated patients with the relapsing-remitting subtype of multiple sclerosis are clinically stable for many years but eventually develop a secondary progressive phase of the disease. An additional subtype of multiple sclerosis that is uncommon in the pediatric age group is the primary progressive form, which has lower levels of inflammatory markers, fewer lesions on MR, and is unresponsive to immunomodulatory agents.^13,14

An accurate diagnosis of multiple sclerosis is problematic for many patients. Many of the symptoms are nonspecific. Pediatric multiple sclerosis patients often fail to meet the established clinical and imaging criteria for the diagnosis of adult-onset disease. During the initial presentation, CSF studies are normal in 30% to 40% of patients and evoked potentials are normal in 40% to 50%. When positive, CSF analysis shows elevated immunoglobulin G levels and oligoclonal bands, due to the humoral immune response to myelin antigens. In a patient with compatible clinical features and at least 2 typical lesions on MR, the likelihood of an eventual firm diagnosis of multiple sclerosis is 90%. MR is the most sensitive technique for the detection of demyelinating plaques in patients with multiple sclerosis. However, there is relatively poor correlation between the MR findings and the clinical manifestations of the disease.^15–18

The histopathological manifestations of multiple sclerosis in the cerebrum include varying degrees of perivascular inflammation, proliferation of astrocytes, loss of myelin, and destruction of axons. MRI typically demonstrates multiple ovoid and confluent areas that are hyperintense on T2-weighted images (Figures 17-6 and 17-7). Individual lesions often have well-defined margins. There is sometimes a central area of very high T2 signal intensity, surrounded by a region of moderate hyperintensity. Acute plaques typically have restricted diffusion. Hypointensity of plaques on T1-weighted images correlates with the histological findings of matrix destruction and axon loss. Lesions in the periventricular white matter are often ovoid and oriented perpendicular to the adjacent ventricle (“Dawson fingers” sign) (Figure 17-8). Contrast enhancement is typical with new lesions but usually disappears within a few to several weeks. Concomitant spinal cord lesions are often present; the cervical cord is the most common site (Figure 17-9).^19,20

MRS typically demonstrates elevation of choline during the acute phase of demyelination in patients with multiple sclerosis, due to increased levels of the myelin breakdown products glycerophosphocholine and phosphocholine. Inflammation within an acute plaque may lead to elevation of lactate. A relatively normal NAA peak in the acute phase suggests limited cell loss. A chronic plaque usually has subnormal choline and NAA peaks. Diffusion tensor imaging demonstrates reduced anisotropy in affected white matter. Diffusion tensor imaging and MRS sometimes indicate involvement of otherwise normal-appearing cerebral white matter adjacent to plaques.^21–23