CHAPTER 79 ACUTE DISSEMINATED ENCEPHALOMYELITIS AND PROGRESSIVE MULTIFOCAL LEUKOENCEPHALOPATHY
Viral infections lead to a variety of demyelinating diseases of the central and peripheral nervous systems in animals and humans. These diseases may be acute or chronic with progressive or relapsing-remitting courses. The pathology and pathogenesis are varied; inflammation may or may not be prominent; the oligodendrocytes or Schwann cells that maintain the myelin may or may not be altered.1
In natural and experimental animal infections, a number of mechanisms have been studied (Table 79-1). Some involve infections of oligodendrocytes, and such infections can expose myelin membranes of the cell to systemic immune responses or can cause direct lysis of the oligodendrocytes; the latter is the apparent mechanism of demyelination in progressive multifocal leukoencephalopathy (PML) in humans. In lentivirus infections of sheep and goats, the microglia and macrophages in the central nervous system are infected, and the astrocytes and oligodendrocytes are not. Cytokines or viral proteins released by the infected cells appear to lead to myelin disruption.2
TABLE 79-1 Mechanisms of Virus-Induced CNS Demyelination
CNS, central nervous system.
From Johnson RT, Major EO: Infectious demyelinating diseases. In Lazzarini R, ed: Myelin Biology and Disorders. San Diego, CA: Academic Press, 2004.
Demyelination can also result from immune responses against myelin in the absence of nervous system infection. When myelin proteins are injected in vaccines made from nerve tissues, an acute, autoimmune, demyelinating encephalomyelitis can be evoked.3 Sequence similarity between infectious agents and encephalitogenic neural proteins may lead to an autoimmune response, a phenomenon called molecular mimicry.4,5 Finally, infection can activate T cells, leading to hindered cell-mediated immune responses and inappropriate cell-mediated immune responses at the same time. This disruption of immune responses in combination with autoimmune responses is seen in human immunodeficiency virus (HIV) infections6 and appears to be the cause of acute postmeasles encephalomyelitis.7
ACUTE DISSEMINATED ENCEPHALOMYELITIS
Definition
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
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.
