Subacute sclerosing panencephalitis (SSPE): isolation of a defective variant of measles virus from brain obtained at autopsy.

A cytopathic agent causing formation of syncytial giant cells was isolated by co-cultivation of human embryonic lung cells with brain cells obtained at autopsy from a patient with subacute sclerosing panencephalitis. Measles specific intracellular immunofluorescence was detected in syncytial giant cells developed by the agent. Paramyxovirus-like nucleocapsids were observed by electron microscopy in nuclei of the syncytial giant cells. Measles specific immunofluorescence was also detected on the surface of unfixed syncytial giant cells. However, the synycytial giant cells did not produce either virions or hemogglutinin, and did not show hemadsorption of African green monkey red cells. Hence, the newly isolated agent seems to be a defective variant of measles virus, and was designated as the SSPE-"BIKEN" strain.     

Subacute sclerosing panencephalitis in papua new guinean children: the cost of continuing inadequate measles vaccine coverage

Introduction

Subacute sclerosing panencephalitis (SSPE) is a late, rare and usually fatal complication of measles infection. Although a very high incidence of SSPE in Papua New Guinea (PNG) was first recognized 20 years ago, estimated measles vaccine coverage has remained at ≤70% since and a large measles epidemic occurred in 2002. We report a series of 22 SSPE cases presenting between November 2007 and July 2009 in Madang Province, PNG, including localized clusters with the highest ever reported annual incidence.

Methodology/Principal Findings

As part of a prospective observational study of severe childhood illness at Modilon Hospital, the provincial referral center, children presenting with evidence of meningo-encephalitis were assessed in detail including lumbar puncture in most cases. A diagnosis of SSPE was based on clinical features and presence of measles-specific IgG in cerebrospinal fluid and/or plasma. The estimated annual SSPE incidence in Madang province was 54/million population aged <20 years, but four sub-districts had an incidence >100/million/year. The distribution of year of birth of the 22 children with SSPE closely matched the reported annual measles incidence in PNG, including a peak in 2002.

Conclusions/Significance

SSPE follows measles infections in very young PNG children. Because PNG children have known low seroconversion rates to the first measles vaccine given at 6 months of age, efforts such as supplementary measles immunisation programs should continue in order to reduce the pool of non-immune people surrounding the youngest and most vulnerable members of PNG communities.     

Subacute sclerosing panencephalitis: detection of measles virus RNA in appendix lymphoid tissue before clinical signs.

An appendix removed 15 days before onset of symptoms of subacute sclerosing panencephalitis was examined retrospectively for measles virus ribonucleic acid (RNA). Tissue sections hybridised in situ to a cloned measles virus probe of deoxyribonucleic acid specific for nucleocapsid protein showed that many cells of the lymphoid tissue contained measles virus RNA. In contrast, only a few infected lymphoid cells were detected in three out of six seropositive controls and none in three seronegative infants. A widespread chronic viral infection of the immune system, established after measles, may promote or even initiate nerve cell infection in subacute sclerosing panencephalitis.     

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.     

Partial C4 deficiency in subacute sclerosing panencephalitis

In an immunogenetic study, 23 subacute sclerosing panencephalitis (SSPE) patients and their families were studied for the HLA region markers HLA-A, B, C, DR, BF, C2, C4A, C4B, GLO I, and PGM3. In addition, C3, C4, and factor B serum levels were determined. A highly significant association of C4A^*QO with SSPE was found. Furthermore, two rare haplotypes, C4A*QOB*9QO, two C4ACh+ allotypes, and four Ch partial inhibitors were detected, which possibly impair the function of the C4 molecules. HLA-DR5 was increased. In addition, a number of rare HLA-A, C, B, DR haplotypes were observed. It is postulated that rare C4 molecular deficiency might be a predisposing factor in the pathogenesis of SSPE.     

Subacute sclerosing panencephalitis virus dominantly interferes with replication of wild-type measles virus in a mixed infection: implication for viral persistence.

Interaction between the Edmonston or Nagahata strain of acute measles virus (MV) and the defective Biken strain of MV isolated from a patient with subacute sclerosing panencephalitis (SSPE) was examined by a cell fusion protocol. Biken-CV-1 cells nonproductively infected with Biken strain SSPE virus were fused with neomycin-resistant CV-1 cells. All the fused cells selected with the neomycin analog G418 expressed Biken viral proteins, as determined by an immunofluorescence assay. This procedure enabled the transfer of Biken viral genomes into cells previously infected with MV. In the fused cells coinfected by Biken strain SSPE virus and Edmonston or Nagahata strain MV, early MV gene expression was suppressed, as determined by immunoprecipitation with strain-specific antibodies. Maturation of Edmonston strain MV was also suppressed. When the coinfected fused cells were selected with G418, Biken viral proteins remained at a constant level for up to 7 weeks. Wild-type MV proteins gradually decreased to a barely detectable level after 4 weeks and became undetectable after 7 weeks. Immunofluorescence studies showed a steady decline in cells expressing wild-type MV proteins in the coinfected cultures. These results suggest that Biken strain SSPE virus dominantly interferes with the replication of wild-type MV. The possible mechanisms of dominant interference and the implication for evolution of a persistent MV infection are discussed.     

Elevated interleukin-12 and CXCL10 in subacute sclerosing panencephalitis

Immunosuppression associated with measles virus (MV) can be demonstrated by cytokine production failure in subacute sclerosing panencephalitis (SSPE) and may have implications on the pathogenesis of the disease. Cytokines (IL-12, IL-10, IL-4, IL-17, IL-18, IFN-alpha, IFN-gamma) and chemokines (CXCL8, CXCL10, CCL2 and CCL5) were measured in the cerebrospinal fluid (CSF) and serum samples from 60 patients with SSPE, 36 patients with infectious and/or inflammatory (IN) and 28 with other non-inflammatory (NIN) neurological diseases by ELISA. IL-12 p70+p40 was elevated in CSF and sera of SSPE when compared to the NIN group. However, the CSF levels of IL-12 p70 alone were not increased, indicating an increase of p40. The CSF of SSPE patients also showed relatively higher levels of IL-10 than that of the NIN group. CXCL10 levels in CSF were significantly higher in SSPE, whereas CXCL8 was increased in sera compared to NIN. No difference was detected in IFN-gamma, IFN-alpha, IL-17, IL-18, IL-4 or CCL2 and CCL5 levels. These results demonstrate that immune response against MV in SSPE may be impaired, although some T cell/Th1 inducing stimulations are present.