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1/12. Mononucleosis-associated subacute sclerosing panencephalitis.

    A thirteen-year-old girl died of subacute sclerosing panencephalitis (SSPE) which occurred as part of a complex encephalitic illness related to acute infectious mononucleosis. The cerebrospinal fluid (CSF) Epstein-Barr virus (EBV) fluorescent antibody (FA) titer was 1:64. Electron microscopic examination revealed 17 nanometer (nm) diameter paramyxovirus-like nucleocapsids in brain sections and 90 nm diameter herpes virus-like enveloped particles in negatively stained brain tissue extracts. Indirect FA staining of cerebral cortex sections demonstrated both measles and EBV antigenic material. EBV antigenic material has not previously been demonstrated in brain tissue. The proportion of B lymphocytes among the patient's peripheral blood lymphocytes was significantly increased as compared to normal controls, while the T lymphocyte percentage was normal. It is suggested that defects in cellular immunity associated with infectious mononucleosis may have been responsible for activation of latent measles-like virus. This is the tenth reported case in which two viruses have been associated with SSPE. This is the third instance in the authors' experience in which acute EBV infection has occurred coincident with the development of SSPE.
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2/12. Reconstitution of T cell function in patients with subacute sclerosing panencephalitis treated with thymus humoral factor.

    Two patients with subacute sclerosing panencephalitis (SSPE) showed impairment of cell-mediated immunity, as indicated by a low T cell number, decreased intracellular cyclic amp levels of peripheral blood lymphocytes, negative graft-vs.-host reaction in vivo, negative skin reactions to common antigens and, in one of the patients, abnormal reactions in migration inhibition factor tests. Since some of the impaired T cell functions in one of the patients were reconstituted in vitro by the administration of thymus humoral factor (THF), a thymic hormone shown in an earlier study to regulate maturation of T lymphocytes in in vitro and in vivo animal models, a course of THF administration was given to both patients in this study. in vitro and in vivo assays, which reflect T cell competence, were performed before and after a daily schedule of THF administration that lasted for 10 days in one patient and 21 days in the other. The results of this preliminary trial suggested that THF was capable of reconstituting the impaired T cell functions in both patients after a short term of treatment. These preliminary results should encourage additional long-term therapeutic trials with THF in SSPE patients with impaired cell-mediated immunity.
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3/12. Cell-mediated immunity to measles virus in subacute sclerosing panencephalitis.

    Four patients with subacute sclerosing panencephalitis were investigated for their specific cellular and humoral immunities against measles virus. Lymphocytotoxicity mediated by peripheral blood lymphocytes was evaluated with the colony inhibition test of target cells having measles antigen. The lymphocytes from two patients of subacute sclerosing panencephalitis (SSPE) specifically destroyed the carrier cells; however, no significant lymphocytotoxicity was observed in the other two patients. The result suggests the heterogeneity in cellular immune states in SSPE patients.
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4/12. Visualization of defective measles virus particles in cerebrospinal fluid in subacute sclerosing panencephalitis.

    measles virus particles were visualized in the CSF of two patients with verified subacute sclerosing panencephalitis (SSPE) by using scanning electron microscopy. Immunologic identification of the accumulated particles was performed with monoclonal antibodies, directly conjugated to carboxylated microspheres, specific for different measles virus antigens. The beads were amassed on the filter surface after a 1-hr incubation in the CSF. Spherical particles with a diameter ranging between 150 and 500 nm were detected. Such particles bound specifically to latex beads covered by monoclonal antibodies to measles virus hemagglutinin but not to beads conjugated with monoclonal antibodies specific for nucleoprotein. Adding the two monoclonal antibodies to measles virus hemagglutinin to the CSF agglutinated the virus particles in a dose-dependent way. Further, no particles in the CSF bound to microspheres conjugated with monoclonal antibodies to non-related antigens of sendai virus, cytomegalovirus, or human immunodeficiency virus. Similarly sized particles were also identified by transmission electron microscopy after concentrating the CSF.
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5/12. subacute sclerosing panencephalitis and multiple sclerosis: in vitro measles immunity and sensitization to myelin basic protein.

    Three children with subacute sclerosing panencephalitis (SSPE), 12 patients with multiple sclerosis (MS) and 12 healthy persons were studied by the macrophage migration inhibition factor (MIF) assay with measles and rubella antigens and with myelin basic protein. For the SSPE patients the mean migration indexes /- standard deviation were 44.1 /- 10.9 for measles antigen, 38.7 /- 12.3 for rubella antigen and 49.8 /- 25.7 for myelin basic protein; for the MS patients the indexes were 103.0 /- 10.6, 93.8 /- 15.0 and 89.3 /- 19.9; and for the healthy subjects the indexes were 68.8 /- 22.6, 77.7 /- 31.3 and 100.1 /- 6.5. The results of this study showed increased cellular immunity to measles and rubella in SSPE patients as compared with healthy persons, and absence of immunity to measles in MS patients. patients with MS showed hypersensitivity to myelin basic protein during clinical exacerbations that was not associated with changes in immunity to measles, whereas all SSPE patients showed a significant response regardless to stage of illness.
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6/12. adult-onset subacute sclerosing panencephalitis: immunocytochemical and electron microscopic demonstration of the viral antigen.

    We report a case of subacute sclerosing panencephalitis (SSPE) in a 52 year-old man, who developed rapidly progressive mental deterioration, myoclonic seizures, quadriplegia, and remained incapacitated until his death 4 years after the onset of symptoms. Immunocytochemical and electron microscopic studies are reported. Titers of measles virus antibodies were consistently high in both serum and cerebrospinal fluid, and periodic synchronous discharges were recorded on EEG. Suppressed cellular immunity was noted in skin test with phytohemagglutinin. The brain was extensively destroyed by inflammatory processes. There were either laminar or widespread areas of cortical necrosis associated with neuronophagia, neuronal loss, glial proliferation, and perivascular lymphocytic cuffing. Numerous intranuclear inclusions, in the neurons and glial cells, stained with immunoperoxidase using antiserum to sspe virus; ultrastructurally, these inclusions were made of tubular nucleocapsids of paramyxovirus. Neurofibrillary changes were occasionally encountered in the pigmented neurons. The white matter showed extensive loss of myelinated fibers and increased numbers of astrocytes with bizarre nuclei. This well-documented case of SSPE in an adult might be related to a condition of impaired cellular immunity.
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7/12. subacute sclerosing panencephalitis: an immune complex disease?

    Vascular osmiophilic deposits of entangled tubular profiles were demonstrated by electronmicroscopy in the cerebral tissue of a patient with subacute sclerosing panencephalitis. Measles viral antigen, IgG, IgM, and C3 were found in the same distribution, indicating that the deposits represent immune complexes. To our knowledge, this is the first demonstration of immune complexes in the vessels of the central nervous system.
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8/12. Distribution of measles antigen and immunoglobulin-containing cells in the CNS in subacute sclerosing panencephalitis (SSPE) and atypical measles encephalitis.

    The immunoperoxidase technique has been used to study the distribution of measles virus antigen and immunoglobulin (Ig)-containing cells within the CNS, in 5 cases of subacute sclerosing panencephalitis (SSPE) and 1 case of atypical measles encephalitis. measles virus antigen was demonstrated within the brain in all cases, and in the spinal cord in 1 case of SSPE. Ig-containing cells were also demonstrated in all cases, the proportions of the different light and heavy chain types varying somewhat from case to case. In SSPE IgG constituted the major and IgA the principal minor heavy chain demonstrated. In all cases of SSPE there was significant excess of light-chain-containing over heavy-chain-containing cells. In the case of atypical measles encephalitis there was a paucity of Ig-containing cells and a relatively high proportion (39%) of these contained IgM. The case of atypical measles encephalitis differed from those of SSPE also in the presence of multinucleate giant cells, some of which contained measles virus antigen.
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9/12. subacute sclerosing panencephalitis after passive immunization and natural measles infection: role of antibody in persistence of measles virus.

    subacute sclerosing panencephalitis (SSPE) developed in a patient in whom natural measles infection was anteceded by immunization with measles immune serum globulin (ISG). This observation prompted experimental studies of the role of antibody in viral persistence. When Balb/c mice were infected with the hamster neurotropic measles virus, acute encephalopathy was fatal in 80% of the animals. When measles antibody was administered 3 days after virus inoculation, the acute disease was abolished and subacute encephalitis had a 30% mortality. The subacute disease was characterized by the presence of neuronal viral antigen, meningitis, and encephalitis. Induction of viral persistence was therefore a consequence of antibody transfer during viral infection. Caution is advised in human prophylaxis with immune globulin.
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10/12. Immunologic and virologic studies of measles inclusion body encephalitis in an immunosuppressed host: the relationship to subacute sclerosing panencephalitis.

    An immunosuppressed child with acute lymphoblastic leukemia in clinical remission developed measles inclusion body encephalitis (MIBE). Although measles antigen and nonbudding measles virus nucleocapsids were detected in brain tissue, no virus was isolated. Immune precipitation of measles virus proteins with the patient's serum showed no detectable antibody to virus M protein, a finding that has been reported in subacute sclerosing panencephalitis (SSPE). The virologic and immune precipitation studies suggest a similar virus mutation in MIBE and SSPE. The pathogenesis of the two diseases may also be similar.
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