Definition

Acute disseminated encephalomyelitis (ADEM) is an acute, inflammatory, demyelinating disease of the brain and spinal cord. In most cases, it follows a viral exanthem or virus-like illness, but the disease is not specific to viral infections and has been reported after several bacterial infections, vaccinations, and drug and serum administration.

Terminology is confusing. The disorder is commonly called postinfectious encephalomyelitis, or postmeasles, postvaccinal, or postinfluenzal encephalomyelitis, to describe the clinical setting. Other authors employ terms such as autoimmune or allergic encephalomyelitis, which implies that the mechanism of pathogenesis is known. Perivenular or acute demyelinating encephalomyelitis, as well as ADEM, are descriptive terms for the neuropathological changes. Because the pathology is the defining element for diagnosis, the term acute disseminated encephalomyelitis is most frequently used.

Acute hemorrhagic necrotizing leukoencephalitis is regarded as an exaggerated form of ADEM. This rare disease, however, has distinct clinical and pathological features and is associated with a different spectrum of antecedent infections.⁸

Epidemiology

ADEM occurs worldwide and in all seasons. Immunization policies, however, have dramatically altered the frequency of ADEM and the causal agents. The overall frequency has been reduced by the introduction of vaccines for childhood diseases and by the cessation of vaccination against smallpox. Measles, formerly the commonest cause of ADEM (Table 79-2), has now been eliminated in countries with universal immunization programs. Rubella and mumps virus infections have also been greatly reduced, because many countries use the combined measles-mumps-rubella vaccine. Varicella-zoster virus vaccine has also reduced the cases of ADEM. The second commonest cause of ADEM, vaccination with vaccinia virus, was eliminated after the eradication of smallpox. Before these changes, ADEM was thought to represent one third of all cases of encephalitis; now ADEM represents only about 10% of cases of acute encephalitis. The commonest infections preceding ADEM are nonspecific influenza-like illnesses. ADEM occurs after Epstein-Barr virus, Mycoplasma pneumoniae, and influenza virus infections, but the frequency is uncertain.

Clinical Features

Symptoms and signs of acute encephalitis (fever, nuchal rigidity, depression of consciousness, focal neurological signs, and/or seizures) usually develop 3 days to 3 weeks after the exanthema or respiratory or gastrointestinal illness. Onset of the encephalitis is typically abrupt and reaches maximal intensity within 24 to 48 hours. Signs of the antecedent illness, such as the fading rash of measles or varicella or the persistent lymphadenopathy of Epstein-Barr virus infection, may still be detectable. The spinal fluid usually exhibits lymphocytic pleocytosis and mild elevation of protein content. Increased immunoglobulin G synthesis and oligoclonal bands are usually not found. Myelin basic protein levels may be elevated early in the disease. Virus cultures usually yield negative results. The spinal fluid is entirely normal in some cases.^7,9

In the absence of a characteristic exanthema preceding the disease, differentiation from acute viral encephalitis is difficult. Magnetic resonance imaging (MRI) can be helpful; in ADEM, multiple white matter lesions of similar age or degree of enhancement are found (Fig. 79-1). Also, in the absence of an exanthem or fever, differentiation from the first attack of multiple sclerosis may be difficult; the presence of nonenhancing periventricular lesions on MRI or the presence of oligoclonal bands are consistent with the diagnosis of multiple sclerosis. Childhood onset, fever, severe depression of consciousness or coma, and seizures all are more consistent with a diagnosis of ADEM.¹⁰

Figure 79-1 Acute disseminated encephalomyelitis with Epstein-Barr virus infection. The patient, a female college student, developed Monospot-positive infectious mononucleosis. Two weeks after onset, she abruptly developed multifocal neurological signs, followed by coma. The enhanced magnetic resonance image shows numerous white matter lesions with intense enhancement. The patient subsequently recovered with minimal sequelae.

(Reprinted from Johnson RT, Major EO: Infectious demyelinating diseases. In Lazzarini RA, ed: Myelin Biology and Disorders. San Diego, CA: Elsevier, 2004, pp 953-983.)

Clinical signs vary with some precipitating agents. After chickenpox, one half of the neurological complications are limited to cerebellar ataxia, which may or may not represent a focal form of ADEM. Neurological disease complicates 1% of cases of infectious mononucleosis caused by the Epstein-Barr virus; some are acute demyelinating neuropathies (Guillain-Barré syndrome), some are acute cerebellar ataxia, and others are typical ADEM. Each of these neurological complications characteristically has an onset 1 to 2 weeks after the onset of infectious mononucleosis, which is suggestive of a postinfectious autoimmune process. ADEM and acute demyelinating neuropathy occur as rare complications of HIV infection. These inflammatory, demyelinating complications occur primarily at the time of seroconversion with the initial activation of CD4 cells and are assumed to represent virus-induced autoimmune responses.⁶

Acute transverse myelitis, in some cases, may also be a localized form of ADEM. It may also occur as a result of vascular disease or tumors or as a first attack of multiple sclerosis.¹¹

Pathophysiology

When death occurs during the acute phase, the brain is swollen and congested, and on gross examination, streaks of discoloration are seen along the veins of the white matter. On microscopic examination, mononuclear cells are found along veins and venules, and myelin loss is evident in this area of inflammation; in the spinal cord, this produces a radial pattern (Fig. 79-2). In patients who die later, the flame-shaped demyelinated lesions are more sharply demarcated and contain lipid-laden macrophages.

Figure 79-2 Acute disseminated encephalomyelitis after chickenpox (varicella). The patient, a 12-year-old girl, developed acute paraparesis 2 weeks after the onset of uncomplicated chickenpox. Over the next 3 days, arm weakness, blindness, and seizures developed, and she died. Neuropathological examination showed widespread perivenular demyelination, as shown here in the spinal cord.

(Courtesy of Carlos Pardo.)

In the 1930s, the similarity of this pathology to the perivenular demyelinating disease that complicated postexposure rabies prevention was noted. Postexposure rabies vaccine at that time consisted of inactivated virus grown in sheep or rabbit brain and spinal cord tissue, and it was administrated as a series of daily injections over several weeks. Experimentally monkeys were similarly inoculated repeatedly with rabbit brain homogenates without virus, and this led to a disease resembling ADEM and postrabies vaccine encephalomyelitis—an experimental disease called experimental allergic (or autoimmune) encephalomyelitis.¹² The experimental disease was shown to result from a cell-mediated immune response against myelin proteins. Subsequent investigations of patients with ADEM complicating measles and varicella and of patients receiving rabies vaccines prepared in central nervous system tissue have shown abnormal lymphocyte proliferation responses to purified human myelin basic protein (Table 79-3).^3,7 How a variety of different viral infections leads to an autoimmune response against myelin is unclear. In the case of measles, the virus infects monocytes, which leads to lymphocyte activation and release of several cytokines. The patient cannot respond normally to new antigens and thus is immunocompromised and vulnerable to opportunistic infections. The commonest causes of death secondary to measles are respiratory and gastrointestinal opportunistic infections. Abnormal immune responses also occur, and in about 15% of patients, a lymphocyte proliferative response against myelin can be detected. In a small percentage of these patients, clinical encephalitis develops, even though no virus is found in the brain or spinal cord.⁷

Prevention and Treatment

Introduction of vaccines for childhood viral infections and discontinuation of vaccination against smallpox have had a major effect in reducing the incidence of ADEM. The maintenance of vaccination programs is essential for continued prevention. No treatment has been shown to be effective once the disease occurs. Although many anecdotal reports of the efficacy of corticosteroids are in the literature, the limited randomized or retrospective analyses of steroid treatment are suggestive of no significant benefit. Intensive supportive care is often necessary; lowering of fever, management of seizures, artificial ventilation, reducing intracranial pressure, and prevention of pulmonary, urinary, and skin infections are important, because remarkable recoveries are possible from ADEM even after prolonged coma.

Definition

PML is a subacute demyelinating disease caused by a papovavirus, JC virus, in immunocompromised hosts.

Epidemiology

PML was originally described in 1958 as “a heretofore unrecognized complication of chronic lymphocytic leukemia and Hodgkin’s disease.”¹⁴ It was subsequently reported in patients undergoing aggressive immunosuppression to treat connective tissue diseases and to prevent rejection of transplanted organs. Nevertheless, PML remained a very rare disease. During the first 25 years after its description, only one case was diagnosed at the Johns Hopkins Hospital. With the advent of the acquired immunodeficiency syndrome (AIDS) epidemic in the 1980s, the disease abruptly became common, representing the cause of death in about 4% of patients with AIDS.¹⁵ The disease affects patients with AIDS worldwide.

The JC virus is a papovavirus originally isolated in 1971 from the brain of a young man who had PML complicating Hodgkin’s disease.¹⁶ The virus is ubiquitous but has not been definitely associated with any other illness. The majority of people develop antibody to JC virus between 1 and 14 years of age; by middle age, more than 70% have antibody. No clinical symptoms or signs have been associated with the primary infection.

Clinical Features

PML can develop insidiously at any time during the course of the underlying immunodeficiency disorder. It is the AIDS-defining disease in 1% of HIV-infected patients and is usually not manifested until the CD4 count is low. Paralysis, mental deterioration, visual loss, and sensory abnormalities are the common manifestations; symptoms and signs are often indicative of multifocal disease. Hemiparesis and hemianopsia are common early findings. Signs of cerebellar, brainstem, and spinal cord involvement occur but are less frequent. Affected patients are usually afebrile and free of headache. The presenting deficits progressively worsen; new signs indicating new areas of cerebral involvement evolve, and the course is usually unremitting, leading to death in 3 to 6 months.

The spinal fluid is generally normal with no pleocytosis, normal protein content, and no abnormalities or increase in immunoglobulins. In patients with HIV infections, however, cell and protein level elevations may result from central nervous system infection coexistent with HIV. The electroencephalogram shows nonspecific findings. Serological tests for JC virus antibody are of no help, inasmuch as antibody is present in most adults, its levels are not unusually elevated in PML patients, and it is not found in spinal fluid. Polymerase chain reaction testing for JC virus in spinal fluid is a useful diagnostic method and has a sensitivity rate of 80% to 90%.¹⁷ Computed tomographic imaging or MRI of the brain provides an important clue to the diagnosis of PML. Lucencies on computed tomography or densities on T2-weighted MRI images have a characteristic pattern of multiple nonenhancing lesions of subcortical white matter.

Pathology and Pathogenesis

The neuropathological findings in PML are unique. On gross examination of the brain, discolored lesions in the white matter are evident, ranging from pinpoint size to large confluent areas of leukomalacia. Lesions are most prominent at the cortical white matter junction (Fig. 79-3). Microscopically, foci show a relative sparing of axons and a loss of both oligodendrocytes and myelin. Many oligodendrocytes surrounding the demyelinated foci are greatly enlarged and contain large intranuclear inclusions with a “ground glass” appearance (Fig. 79-4). Within the demyelinated areas, astrocytes are enlarged and have bizarre mitotic forms, multiple nuclei, and multilobular nuclei. In the original description of PML, the authors stated that “astrocytes of this sort are ordinarily met with only in neoplastic processes.”¹⁴ Inflammatory cells are usually absent or in minimal numbers. Immunocytochemical staining for JC virus antigens in glial cells confirms the diagnosis on biopsy or autopsy brain tissue.

Figure 79-3 Progressive multifocal leukoencephalopathy in a middle-aged man with Hodgkin’s disease. Small lesions concentrated along the cortical white matter junction show confluence that will ultimately become large demyelinating lesions undercutting the cortical ribbon.

(Photomicrograph of section from Case 3 of Astrom KE, Mancall EL, Richardson EP: Progressive multifocal leukoencephalopathy. Brain 1958; 81:93-127. Reprinted by permission of Oxford University Press.)

Figure 79-4 Schematic diagram of the selective vulnerability of neural cells in progressive multifocal leukoencephalopathy. Within the demyelinated focus, the oligodendrocytes are depleted; surrounding the focus, they are greatly enlarged and contain large intranuclear inclusion bodies that are packed with virions, often in pseudocrystalline arrays. Within the demyelinated focus, astrocytes are enlarged and many have bizarre forms; some are multinucleated, others contain mitotic figures. The neurons (not shown in the diagram) appear normal, and many intact but demyelinated axons course through the demyelinated focus.

(Modified from Johnson RT: Viral Infections of the Nervous System. Philadelphia: Lippincott-Raven, 1998.)

Speculation that a virus infection might be causative arose from the finding of inclusion bodies and the occurrence of the disease in immunosuppressed patients (Fig. 79-5). In 1965, astonishing electron microscopic findings demonstrating that the inclusion bodies consisted of crystalline arrays of particles corresponding in size to polyomaviruses were published.¹⁸ At that time, no human polyomaviruses were known, but through the use of human fetal brain cultures, JC virus, the first known human polyomavirus, was isolated.¹⁶

Figure 79-5 Schematic diagram of the pathogenesis of systemic infection with JC virus. Primary infection is by unknown route (probably respiratory or gastrointestinal); during asymptomatic infection, virus latency is established in the kidneys and bone marrow; activation has been demonstrated in the kidneys and tonsils, and B cells are infected. Transit of virus into the brain in plasma or B cells is thought to lead to selective infection of glial cells. Asterisk denotes sites of presumed JC virus latency; plus signs denote Active JC replication has been demonstrated.

(Modified from Johnson RT, Major EO: Infectious demyelinating diseases. In Lazzarini RA, ed: Myelin Biology and Disorders. San Diego, CA: Elsevier, 2004, pp 953-983.)

Initial infection with JC virus in childhood is probably through the respiratory route.

Latent virus has been shown in bone marrow and kidneys, and virus has been found in tonsils and urine. B cells have been implicated in the spread of virus, and these cells are thought to carry the virus to the brain after activation in immunosuppressed patients.¹⁹

In the brain, JC virus is unique. Highly productive infection occurs only in oligodendrocytes. Astrocytes in lesions express T antigen, have bizarre forms, and appear to proliferate, which are indications of viral transformation; however, contrary to true transformation, astrocytes contain small numbers of virions. In contrast, except for patches of granular cells in the cerebellum, neurons and other cells appear resistant to infection.²⁰