Subacute Sclerosing Panencephalitis
Subacute sclerosing panencephalitis (Dawson encephalitis) is a chronic encephalitis caused by persistent measles virus infection of the central nervous system. Dawson was the first to describe it clearly and to postulate a viral cause. Subsequently, measles virus was isolated from the brains of patients with subacute sclerosing panencephalitis (SSPE).
SSPE is a rare disease that occurs worldwide. The disease has been diagnosed in patients 6 mo to older than 30 yr of age, but it affects primarily children and young adolescents. In more than 85% of cases, onset occurs from 5 to 15 yr of age. Infection with measles at younger than 18 mo of age seems to increase the risk of SSPE substantially. The risk among boys is more than twice that among girls, and it is higher among rural children than city children, children with more than two siblings, and children of lower socioeconomic status. SSPE was once especially common in the southeastern United States, the Ohio River valley, and some New England states. Recently, cases have been more common in the western United States and in New York City, especially among Hispanic immigrant children. Exposure to birds and other animals has been reported with abnormal frequency in the histories of patients with SSPE; the reason is not clear.
The annual incidence of SSPE in the United States fell markedly from 0.61 cases per 1 million persons younger than 20 yr of age in 1960 to 0.06 cases per 1 million in 1980. Since 1982, fewer than five new cases in the entire country have been registered with the U.S. National SSPE Registry each year. The decrease roughly parallels the progressive decline in the annual number of measles cases diagnosed since the introduction of live attenuated measles vaccine in the United States in 1963. The risk of SSPE has been estimated at 8.5 SSPE cases per 1 million cases of measles for a 6-yr period, during which the estimated risk after measles vaccination was only 0.7 cases per 1 million doses of vaccine. The overwhelming advantage of measles vaccination in preventing SSPE is clear.
In a recent case control study, the lack of vaccination was a highly significant risk factor for SSPE, and in a survey in England and Wales the relative risk of SSPE after measles infection was 29 times that of the risk of SSPE after measles vaccination. In cases occurring in vaccinated children, it has not been determined whether SSPE resulted from persistent infection with the attenuated measles virus of the vaccine, from undiagnosed wild-type measles infection preceding vaccination, or from vaccine failure and subsequent undiagnosed measles. SSPE continues to occur in areas of the world where measles remains unchecked and may be anticipated to increase wherever compliance with vaccination protocols diminishes.
Children with SSPE generally have a history of typical measles, which may have been either mild or severe, with full recovery several years before the onset of neurologic disease. Some patients with SSPE have had measles pneumonia, but none have had a history of typical measles encephalitis. The mean interval between measles and onset of SSPE was formerly about 7 yr, but recently it has increased to 12 yr. In vaccinated patients without a history of measles, the mean interval between vaccination and onset of SSPE was 5 yr before 1980 and 7.7 yr between 1980 and 1986.
The histopathology of SSPE consists of inflammation, necrosis, and repair. Brain biopsy performed in the early stages of SSPE shows mild inflammation of the meninges and a panencephalitis involving cortical and subcortical gray matter as well as white matter, with cuffs of plasma cells and lymphocytes around blood vessels ( Fig. 225–3 ) and increased numbers of glia throughout. Neuronal loss may not be marked until later in the course of the illness, when loss of myelin secondary to neuronal degeneration may be apparent. Intranuclear inclusion bodies surrounded by clear halos (Cowdry type A) may be seen within the nuclei of neurons, astrocytes, and oligodendrocytes. On electron microscopy, the inclusions are seen to contain tubular structures typical of the nucleocapsids of paramyxoviruses. Measles viral antigens can be demonstrated by labeled antibody techniques within the inclusions as well as in cells without inclusions. Lesions may be unevenly distributed throughout the brain, and biopsy is not always diagnostic.
The same findings of inclusion-body panencephalitis are generally present at autopsy; however, late in the disease it may be difficult to find typical areas of inflammation, and the main histopathologic changes are necrosis and gliosis. The disease is believed to begin in the cortical gray matter, progressing then to the subcortical white and gray matter (myoclonus probably results from extrapyramidal involvement) and finally to the lower structures. Although persistent infection of lymphoid tissues with measles virus has been reported, these show no pathologic changes.
It has been proposed that viral mutation may render the measles virus more likely to establish persistent central nervous system (CNS) infection, and multiple mutations have been found in isolates from patients with SSPE. However, no consistent genomic abnormalities have been identified in those isolates, and clusters of SSPE cases suggestive of strains of special virulence have been described only rarely. It has also been theorized that patients with SSPE have subtle predisposing immune deficiency; the markedly increased risk of SSPE after measles in infancy suggests that either immunologic immaturity or persistence of maternal antibodies to measles virus is involved in the later occurrence of the disease.
Complete measles virus particles are not found in the brains of patients with SSPE, and the matrix (M) protein required for the final assembly and budding of virus from the host cells is missing not only from the brain tissue of patients but also from cells cultured from their brains; however, the full complement of genetic material needed to code for all proteins, including the M protein, is present and functional. Several studies have suggested that M proteins are encoded but that because of a variety of mutations they cannot bind to nucleocapsid, resulting in
Figure 225.1-3 A cuff of inflammatory cells surrounds a blood vessel in the cerebral cortex of a child with subacute sclerosing panencephalitis. (Courtesy of Janice Stevens, MD, National Institute of Mental Health, and Peggy Swoveland, MD, University of Maryland School of Medicine.)
accumulation of incomplete measles virus that cannot be cleared either by antibodies or by cell-mediated immunity.
The clinical picture of SSPE tends to be quite stereotypical; almost 70% of cases have an acute, subacute, or chronic progressive course; fewer than 10% have remissions. The onset is usually insidious and is marked by subtle changes in behavior and deterioration of schoolwork; this is followed by more overtly bizarre behavior and finally by frank dementia.
There is no fever, photophobia, or other findings of acute encephalitis except for occasional complaints of headache. Diffuse neurologic disease becomes progressively more severe. The appearance of massive, repetitive myoclonic jerks, generally symmetric, involving especially the axial musculature and occurring at 5–10-sec intervals, marks the onset of the second clinical stage of SSPE. The myoclonic jerks appear to be abnormal movements rather than epileptic seizures, but true convulsions can also occur at any stage of the illness. In addition to myoclonic jerks, which tend to disappear as the disease progresses, a variety of other abnormal movements and dystonias have been observed. Cerebellar ataxia may occur. Retinopathy and optic atrophy may appear, sometimes even before the behavioral changes. Dementia progresses to stupor and coma, sometimes with autonomic insufficiency. Patients may be rigid or spastic with decorticate postures, or they may be flaccid.
The speed of progression is highly variable, but in at least 60% of patients the course is inexorable and relatively rapid. The total duration of illness may be as short as a few months, but most patients survive for 1–3 yr after diagnosis, with a mean of about 18 mo. Occasional patients show some spontaneous improvement and live for more than 10 yr. In recent years, the few patients diagnosed with SSPE in the United States have tended to have a relatively long survival, perhaps because of improvements in chronic care.
Blood tests are normal except for elevated titers of antibodies to measles virus; IgG and IgM antibodies are directed against all the component proteins of measles virus except the M protein. Cell content of the cerebrospinal fluid (CSF) is generally normal, although stained sediments may show plasma cells. Total protein content of the CSF is normal or only slightly elevated; however, the gamma globulin fraction is greatly elevated (usually comprising at least 20% of total protein), resulting in a paretic type of colloidal gold curve. When the CSF is examined by electrophoresis or isoelectric focusing, oligoclonal bands of Ig are often observed. IgG and IgM antibodies to measles virus, not normally found in unconcentrated CSF, make up most of the Ig, and these can often be detected in dilutions of 1:8 or more. The complement fixation test has been especially useful for demonstrating antibodies in CSF, but hemagglutination inhibition, immunofluorescence, and other serologic tests, including enzyme-labeled immunosorbent assays (ELISA), are also satisfactory. The usual ratio of antibody in serum to CSF is reduced (<1:200) for measles antibodies, whereas the serum-to-CSF ratio is normal for other viral antibodies and for albumin, indicating that the increased amounts of measles antibodies in the CSF of patients with SSPE result from synthesis within the nervous system and that the blood-brain barrier is normal.
Early in the course of disease, the electroencephalogram (EEG) may be normal or show only moderate nonspecific slowing. In the myoclonic stage, most patients with SSPE have “suppression-burst episodes” in which high-amplitude slow and sharp waves recur at intervals of 3–5?sec on a slow background; however, this pattern is not unique to SSPE. Later in the illness, the EEG becomes increasingly disorganized and shows high-amplitude, random dysrhythmic slowing; in terminal disease, the amplitude may fall.
CT or MRI scans of patients with SSPE may show variable cortical atrophy and ventricular enlargement, and there may be focal or multifocal low-density lesions in the white matter. However, these studies may be normal, especially early in the disease.
Brain biopsy is no longer needed to diagnose SSPE. When performed, it often shows the typical histopathologic findings described earlier. Examination of frozen sections by immunofluorescence techniques may demonstrate the presence of measles viral antigens. Persistence of measles virus infection in cultures may be demonstrated by labeled antibody techniques before the complete virus appears. Many specimens fail to yield complete virus. Modifications of the polymerase chain reaction can detect various regions of the measles virus RNA in frozen and even paraffin-embedded brain tissue specimens of patients with SSPE. Nucleic acid hybridization techniques have also been used to demonstrate the measles viral genome.
It is most important to rule out potentially treatable illnesses such as bacterial infections and tumors. The diverse cerebral storage diseases and nonstorage poliodystrophies, leukodystrophies, and demyelinating diseases of childhood can also produce progressive dementia with seizures and paralysis resembling SSPE. Early in the course of illness, SSPE must be distinguished from atypical acute viral encephalitides. Other slow viral infections, such as Creutzfeldt-Jakob disease (CJD) and progressive rubella panencephalitis, must be considered in appropriate age groups. The presence of a typical EEG pattern suggests SSPE, as do unusually high levels of measles antibodies in serum. The diagnosis is practically confirmed if measles antibodies are detected in CSF.
The persistent measles infection seen in SSPE does not result in complete virus particles. Patients with SSPE, therefore, pose no hazard of infection to others, and no special precautions need ordinarily be taken. Blood precautions might be justified under special circumstances.
Administration of inosiplex (100?mg/kg/24?hr) may prolong survival and may produce some clinical improvement in the degree of disability. Other treatments have been ineffective. The use of anticonvulsants, maintenance of nutritional status, prompt treatment of secondary bacterial infections, physical therapy, and other supportive care may also prolong survival and improve the quality of life for the patient and family. Information on current therapeutic trials can be obtained from the U.S. National SSPE Registry (Dr. Paul R. Dyken, Institute for Research in Childhood Neurodegenerative Diseases, Mobile, Alabama; Telephone 334-478-6424).
Patients with SSPE have the usual secondary complications associated with incapacitating neurologic diseases, such as recurrent pneumonias and decubitus ulcers.
Few patients live for longer than 3 yr after the diagnosis of SSPE, and those who do survive longer are usually disabled.
Measles vaccination is the most important measure to prevent SSPE.