SSPE is an infrequent but almost always fatal progressive panencephalitis. The clinical and histopathologic descriptions of this disease can be found in the medical literature dating from early in this century; however, not until 1950 was the term subacute sclerosing panencephalitis used to describe a progressive encephalitis with characteristic histologic findings of perivascular infiltrates of CD4⁺ lymphocytes and plasma cells in both the gray and white matter and CD8⁺ lymphocytes in the brain parenchyma. In the 1960s, measles virus was identified as the causative agent of SSPE, a finding that has been validated by the dramatic drop in the number of cases of SSPE after the institution of universal measles immunization in the United States and northern Europe. Several pathogenic mechanisms for the development of SSPE have been proposed, but most experimental data have been consistent with persistence of the measles virus in the CNS. The persistence of measles virus is associated with unique mutational events of the measles matrix protein and possibly positive immune selection of those genes encoding the viral fusion and hemagglutinin proteins. The mechanisms leading to persistence of measles virus in the CNS in the face of host immune responses likely is secondary to extended viral tropism resulting from an immunologic selection of variants and evasion of protective host responses. Alternatively, persistence could be a direct result of extended viral tropism without a requirement of immune selection.

Natural history studies have demonstrated that the incidence of disease is approximately one in 10 million in the developed world, whereas in some Asian countries, such as Pakistan, the incidence may be 100-fold higher. A recent report from New Guinea documented an incidence of nearly 10 cases per 100,000 population, nearly 1,000-fold higher than that observed in North America and northern Europe. In the United States, SSPE previously has been reported to occur more frequently in white children from rural areas and, in particular, those in the southeastern United States. Risk factors for the development of SSPE within a population include a high incidence of wild-type measles virus infection and the acquisition of measles before the second year of life. Interestingly, both these risk factors have been modified by measles vaccination. Studies from the Netherlands demonstrated a tenfold drop in the incidence of SSPE after the incorporation of measles virus into routine immunization schedules. No genetic markers have been associated with the development of SSPE, although the disease occurs approximately two to three times more commonly in men than in women. Cases of SSPE have been reported after measles vaccination, with an estimated incidence of 1.0 to 2.5 cases per 1 million doses of vaccine. However, these studies failed to determine whether subclinical, wild-type measles virus infection occurred in these cases before administration of vaccine. In fact, no direct evidence exists that the vaccine strains of measles virus can cause SSPE, and vaccine strains of measles virus have not been isolated from the brains of patients with SSPE.

The clinical signs and symptoms of SSPE present in patients between the ages of 6 and 10 years (range, ages 2 to 49 years). Two cases of SSPE have been reported in infants younger than 2 years of age and have been thought to be associated with the congenital or perinatal acquisition of measles virus. In most cases, the onset of SSPE occurs 4 and 8 years after having wild-type measles virus infection. The clinical course of SSPE has been described by various staging systems, the most widely used being that suggested by Jabbour. Usually, clinical presentation or stage I includes such progressive psychointellectual disturbances as mood changes, poor school performance, depression, or hyperactivity. Often, this stage lasts for less than 6 months. Physical findings in stage I are nonspecific, although a pigmented retinopathy has been reported in a small percentage of patients. Stage II can include a variety of motor disorders, including seizures, myoclonic jerks, and akinetic drop attacks. Intellectual function continues to deteriorate during this stage. In contrast to the relatively brief duration of stage I, patients may exhibit findings consistent with stage II for 6 months to more than 1 year. Progression to stage III is heralded by the increased frequency of myoclonic jerks, spasticity, rigidity, and decorticate posturing. Often, hypothalamic dysfunction is manifest by hyperpyrexia, pallor, and flushing. Similar to stage I, stage III often is brief, lasting less than 6 months. Stage IV often is associated with a vegetative state. Although most patients follow a clinical course consistent with this staging system, approximately 5% to 10% of patients may survive for several years, remaining static in stage II or stage III. Alternatively, a similar number of patients may have a fulminant and progressive course lasting less than 3 months.

Laboratory findings consistent with the diagnosis of SSPE include a characteristic electroencephalogram (EEG), the presence of oligoclonal IgG in the cerebrospinal fluid (CSF), and
an elevated titer of antimeasles antibody in the CSF. Both computed tomography (CT) and magnetic resonance imaging (MRI) have been used to demonstrate focal lesions in the brain. The imaging findings usually begin in the cortical-subcortical white matter and progress to periventricular white matter; however, these findings do not reflect the clinical stages of the disease. The EEG finding of periodic, synchronous bilateral discharges on a background of suppressed electrical activity (burst-suppression pattern) has been suggested to be characteristic of SSPE. However, the EEG is not diagnostic, and the absence of this finding does not exclude the diagnosis of SSPE. A more consistent finding is CSF pleocytosis consisting of lymphocytes and elevated protein, presumably secondary to the presence of increased levels of IgG. The increased CSF IgG results from oligoclonal antimeasles IgG, which can represent as many as 20% to 40% of the total CSF IgG. The finding of measles-specific oligoclonal IgG in the CSF, together with a compatible clinical course, is diagnostic of SSPE.

The treatment of SSPE has been unsuccessful. Early trials with the antiviral compound isoprinosine suggested a possible clinical benefit; however, subsequent trials and questions surrounding the study design of the original trial have led to the conclusion that this compound does not alter the natural history of SSPE in most patients. Other compounds used to treat SSPE include interferon-alpha, ribavirin, and immune-response modifiers. To date, significant efficacy has not been reported for any of these agents. Therefore, the most effective therapeutic strategy appears to be aggressive implementation of universal measles vaccine programs.

PML is a demyelinating, degenerative CNS disease that is caused by persistent infection with the human polyoma virus, JC virus. Initially, the disease was described in patients with underlying immunodeficiencies associated with lymphoproliferative disorders and congenital immunodeficiencies. Subsequently, it was associated with immunosuppressive therapy in allograft recipients. Although the number of organ allotransplantations increased dramatically during the early 1980s, PML remained a very rare disease, with fewer than 200 cases reported in the literature. When the incidence of human immunodeficiency virus 1 (HIV-1) infection increased exponentially during the 1980s, acquired immunodeficiency syndrome (AIDS) rapidly became the most common underlying disease associated with the development of PML. Between 1981 and 1990, 971 documented cases of PML were reported to the Centers for Disease Control and Prevention (CDC). Estimates have suggested that as many as 5% of patients with untreated AIDS will develop PML. PML is a disease primarily of adults; however, well-documented cases have been described in pediatric patients with congenital immunodeficiencies, those undergoing immunosuppressive therapy after receiving allografts, and children with AIDS.