[Subacute sclerosing panencephalitis cases diagnosed by increased CSF/serum measles antibody indices]. / Yüksek BOS/Serum Kizamik Antikor Indeksi ile Tanimlanan Subakut Sklerozan Panensefalit Olgulari

Subacute sclerosing panencephalitis (SSPE) caused by persistent defective measles virus strains, is a progressive neurological disorder of children and adolescents. The aim of this letter was to share the data from SSPE-suspected cases who were definitely diagnosed by the detection of increased antibody index in serum and cerebrospinal fluid (CSF) samples. A total of 11 patients (mean age: 14.3 years) with suspected SSPE between February 2006 to August 2008, were included in the study. Simultaneously obtained serum and CSF samples from patients were analyzed in terms of albumin, total IgG and measles-specific IgG levels (Measles Virus IgG ELISA for CSF Diagnostics, Euroimmun, Germany). The value of CSQrel (relative CSF/serum quotient) ≥ 1.5 was accepted indicative for intrathecal measles antibody synthesis. Seven (63.6%) of the 11 patients' diagnosis were confirmed with the demonstration of elevated CSF/serum indices (CSQrel range: 2.3-36.9; mean: 12.9). Mean age of those seven cases was 12.3 years (age range: 7-21) and four of them were male. The history of patients with high antibody indices indicated that three of four patients who had measles infection had not been vaccinated against measles. These three unvaccinated patients had measles infection at 3rd, 8th and 30th months of age, respectively, and the period of SSPE development were 15, 6 and 4.5 years, respectively. With this letter we would like to emphasize once more that effective measles vaccination is the only way for the prevention of measles and SSPE and the demonstration of increased measles antibody index in simultaneously obtained serum and CSF samples is crucial for the diagnosis of SSPE.

Antibodies to borna disease virus in subacute sclerosing panencephalitis.

Mechanisms causing persistence and reactivation of measles virus in subacute sclerosing panencephalitis (SSPE) are unknown. Borna disease virus (BDV) frequently causes latent or persistent infection in the nervous system. We investigated a possible association of these viruses in SSPE. Although BDV seropositivity was similar in SSPE and control groups, SSPE patients with high antibodies to BDV had earlier and more rapid disease. The findings suggest that BDV might be involved in the course, but not in the etiopathogenesis, of SSPE.

Fulminating adult-onset subacute sclerosing panencephalitis in a 49-year-old man.

CONTEXT: Subacute sclerosing panencephalitis (SSPE) is a rare, slow viral infection caused by a defective measles virus. It is characterized by progressive mental deterioration associated with motor impairment and prominent myoclonus. In about 10% of all cases, the disease can progress rapidly and lead to death within a few months. The oldest previously reported fulminating case was in a 25-year-old man. OBJECTIVE: To emphasize the relationship between retinal involvement and acute SSPE by reporting the case of a 49-year-old man with clinical, laboratory, and pathological evidence of acute SSPE. SETTING: Hôpital de l'Enfant-Jésus, Quebec, Quebec. REPORT OF A CASE: This man was referred to the Department of Neurological Sciences on March 21, 2001, because of recent behavioral changes and progressive cognitive impairment over the past few months. Medical history was unremarkable except for an episode of measles in his childhood. Neurological examination showed bilateral myoclonic jerks. Ophthalmic examination revealed bilateral macular swelling and papilledema. Electroencephalography showed periodic sharp and slow-wave discharges. Magnetic resonance imaging showed bilateral diffuse T2-signal hyperintensities in both periventricular and subcortical white matter. Cerebrospinal fluid antimeasles antibody titers were highly positive. An Omaya reservoir was inserted and therapy using a combination of high-dose intrathecal interferon alfa and oral isoprinosine were administered for 6 weeks. Despite transient subjective improvement in the patient's condition, it continued to deteriorate, he became bedridden, and he died on June 26, 2001. CONCLUSION: To our knowledge, this patient is the oldest case of SSPE reported in the literature. This patient and other patients with acute SSPE associated with bilateral macular swelling described in the literature raised the possibility of measles virus-acquired virulent neurotropism in the retina before invading the central nervous system.

Different transcriptional expression of the matrix gene of the two sibling viruses of the subacute sclerosing panencephalitis virus (Osaka-2 strain) isolated from a biopsy specimen of patient brain.

Two sibling viruses of the subacute sclerosing panencephalitis (SSPE) virus Osaka-2 strain were isolated from a small biopsy specimen of the brain of an SSPE patient just before intraventricular interferon treatment by cocultivation with two different cell lines, Vero cells or B95a cells (Ogura et al, 1997). Both the virus-infected cells were found to be indistinguishable from each other in defective production of cell-free virus and in defective expression of the matrix (M) protein. The sequence analysis of the M genes predicted that they were translatable due to a lack of alteration of the translational start and stop codons for the proteins. A different pattern of the M monocistronic transcripts, however, was observed in a Northern blot analysis of the infected cells. This different pattern was confirmed further by a primer extension analysis. The undetectable expressions of the M proteins in the sibling virus-infected cells are most probably different in their molecular mechanisms. All these results indicate the possibility that the two different, replicable variants existed at Jabbour stage III of the disease's progression in a very small portion of the brain, where no lesion had yet been recognized by a magnetic resonance imaging.

Identification of epitope(s) on the internal virion proteins of rinderpest virus which are absent from peste des petits ruminants virus.

Monoclonal antibodies (MAb) raised against the RBOK vaccine strain of rinderpest virus were characterized by radio-immunoprecipitation (RIPA) and in the indirect ELISA using measles (MV), distemper (CDV), rinderpest (RPV) and peste des petits ruminants viruses (PPRV). Those found to be specific for the matrix (M) protein and the nucleocapsid (N) protein could be classified into different groups on the basis of the anti-morbillivirus MAb classification scheme; a number of these MAb showed a selective recognition of RPV, measles virus and distemper virus, or of different isolates of rinderpest virus, demonstrating that greater inter-isolate variation occurs than was apparent from analyses using polyclonal antisera. One group of anti-F protein MAb (group F1) reacted with all isolates of both RPV and PPRV. A second group of anti-N protein MAb (group N1/A) reacted with all RPV isolates, but not with the PPRV isolates. Furthermore, these group N1/A antibodies reacted strongly with RPV isolates which were upon original isolation of high pathogenicity, but had a weaker reaction against the isolates of this virus which were of low pathogenicity. Thus, MAb against RPV, in particular those against the N protein offered a potential superior to that of molecular analyses for "isolate fingerprinting", the differentiation of RPV from PPRV and the discrimination between rinderpest viruses which had been, upon isolation, of either high or low pathogenicity.

Antigenic modulation of measles subacute sclerosing panencephalitis virus in a persistently infected rat glioma cell line by monoclonal anti-haemagglutinin antibodies.

Rat glioma C6 cells persistently infected with measles subacute sclerosing panencephalitis (SSPE) virus (C6/SSPE) express the viral membrane proteins haemagglutinin (HA) and F on their cell surface as well as the intracellular proteins N, P and M. Previously we have shown that the addition of a polyclonal antibody against the HA antigen to the growth medium of C6/SSPE cells led to a gradual loss of all viral antigens. Here we show that the addition of a monoclonal antibody (MAb K83) leads only to a transient decrease in viral antigens during the first three passages. After the third passage viral antigens start to increase and after five passages they produce more antigens than at the premodulation level. At this point of the MAb treatment, MAb K83 no longer recognized the HA antigen on the surface of the cells and in virus particles produced by these cells in contrast with polyclonal antibodies or other MAbs against the HA antigen. The results suggest that specific variants of the SSPE virus with an altered HA antigen were selected by the MAb treatment.

Ultrastructural and immunohistochemical evidence of measles virus in active otosclerosis.

Because of the similarity between otosclerosis and Paget's disease of bone, and the mounting evidence of a viral cause in Paget's disease, we have investigated a possible viral cause for otosclerosis. Transmission electron microscopy of stapes footplate fragments with active otosclerosis has revealed structures morphologically identical with measles virus nucleocapsid in osteoblasts and preosteoblasts. Immunofluorescence and immunoperoxidase studies have confirmed the presence of measles nucleocapsid antigen in active lesions. Application of sera from patients with subacute sclerosing panencephalitis, a defective measles virus infection of the central nervous system, resulted in positive immunoreaction in areas of active otosclerosis.

[The SSPE model: suggestions for an explication of viral persistence]. / Le modèle de la PESS: suggestions pour une explication de la persistance du virus.

The detection of a latent viral flora intrinsic to the central nervous system (CNS) raises the problem to know if some neuropathogenic strains have the property of initiating persistent infections or if the persistence is the result of the immune response particularities at the CNS level. A review is done of the pathogenic explanations of virus persistence in SSPE, followed by the discussion about two pathogenic alternatives issues from the author's studies: the antigenic "drift" hypothesis and the one of the defective interfering particles preferential synthesis.

[Propionibacterium granulosum KP-45 in the treatment of subacute sclerosing panencephalitis]. / Propionibacterium granulosum KP-45 in der Behandlung der Subakuten Sklerosierenden Panenzephalitis (SSPE).

3 groups of patients, who suffered on SSPE (without treatment, with isoprinosine therapy, combined treatment with propionibacterium granulosum and isoprinosine) are compared. The results show a favourable effect of the combined treatment in a part of the patients. They are discussed in detail.

Identification of a nonproductive, cell-associated form of measles virus by its resistance to inhibition by recombinant human interferon.

Subacute sclerosing panencephalitis (SSPE) is a fatal disease in children and young adults that is caused by persistent infection of the central nervous system (CNS) by a nonproductive, cell-associated form of measles virus. Using an experimental model for SSPE (LEC viral strain in newborn hamsters), we have shown previously that establishment of such CNS infections involves selective elimination from the CNS of productively infected cells by host defensive mechanisms, coupled with the selective sparing of cells carrying nonproductive viral forms. That interferon (IFN) may play a role in this process was suggested by the disappearance of productively infected cells from the CNS tissues prior to the appearance of antiviral antibodies and by the demonstration of cell-associated, IFN-resistant viral variants in the virus stocks that were used. Results of this study support these conclusions by showing that similar IFN-resistant viral variants are present in the HBS strain of SSPE-derived measles virus and that these variants, in the presence of IFN, have properties that are similar to those of naturally occurring cell-associated strains of SSPE viruses, e.g., DR, IP3, and Biken. These IFN-resistant forms of HBS virus were isolated and were shown to maintain their resistance to inhibition by IFN after cloning. However, on removal of IFN, they reverted to productive forms similar to the parental HBS virus. The potential role of such viral forms in the pathogenesis of SSPE is discussed.

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.

Diagnostic and pathogenetic aspects of subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis, usually a rapidly progressive and fatal disease, is a slow virus infection, where measles virus persists in cells of the CNS and in lymphocytes. Four patients, 3 boys and 1 girl, are described, who presented a characteristic disease course, beginning at the age of 12 to 14 years after they had contracted measles infection during infancy or early childhood. The diagnostic criteria including clinical and laboratory CSF findings are summarized, and epidemiologic features related to measles and measles immunization are briefly discussed. In two patients specific measles virus protein antibodies in serum and CSF were analyzed. The results confirm postulated mechanisms for viral persistence in the CNS and suggest in addition a possible role of the viral protein H in the pathogenesis of SSPE.

Protective effect of measles virus inoculation on subacute sclerosing panencephalitis virus-infected mice.

The Biken strain of subacute sclerosing panencephalitis (SSPE) virus caused a fatal neurologic disease in adult mice after intracerebral inoculation. However, the mice were completely protected from the disease when a high dose of measles virus was given intracerebrally after the SSPE virus infection. The measles virus inoculation induced interferon production and immune responses. An experiment with athymic nude mice showed that interferon and anti-measles antibody were able to prolong the incubation period of the disease but not to protect the SSPE virus-infected nude mice from death. For complete protection, T lymphocytes appeared to be essential. The present study suggested that the protective effect of measles virus inoculation is basically due to the induction of immune responses and that SSPE virus infection in mice is susceptible to immune reactions.

Further data on the antigenic drift in subacute sclerosing panencephalitis (SSPE).

Serum and cerebrospinal fluid samples from 43 SSPE patients were investigated by double radial immunodiffusion against a measles virus cell pack antigen. The pattern of immune precipitates suggested that antigenic drift may be involved in the pathogeny of persistent virus infection.

Effect of measles virus antibodies on a measles SSPE virus persistently infected C6 rat glioma cell line.

Maintenance of measles (SSPE-Lec) virus persistently infected C6 rat glioma cells in medium containing polyclonal measles antiserum resulted in the loss of detectable expression of all measles virus proteins. Removal of these cells from antiserum, however, led to a re-expression of virus proteins and the production of infectious virus. Cloning of antibody-modulated non-expressing cells in the presence of antiserum showed that re-expression of virus proteins was not due to an incomplete curing process following the addition of antiserum, as a large number of non-expressing cell clones developed the capacity to express measles virus antigen at different periods after removal of antiserum. Irradiation of persistently infected cells to give a non-growing culture showed that modulation was not mediated by a selection and outgrowth of a small percentage of non-expressing cells originally present in the culture. Antibody directed against C6 membrane proteins did not lead to modulation and it was also shown that only monoclonal antibodies with neutralizing activity could affect intracellular antigen expression. Immunoglobulin Fab fragments with neutralizing activity also had modulating activity. Although all modulated cell clones were more susceptible to homologous virus infection than control C6 cells, it was not possible to rescue any defective measles virus which may have been maintained in the culture.

Localization of measles virus antigens in subacute sclerosing panencephalitis in ferrets.

Young adult male ferrets were inoculated intracerebrally (i.c.) with a cell-associated encephalitogenic subacute sclerosing panencephalitis (SSPE) virus strain to study the pathogenesis of the disease at the ultrastructural level. Most became acutely ill in 8-13 days. Areas of the brain were examined with indirect immunoperoxidase labeling techniques to detect measles antigen. None of these animals showed the characteristic viral nucleocapsids or marked inflammatory response associated with SSPE. However, all had positive immunolabeling of unstructured virus antigen, especially in post-synaptic regions in all areas of the brain that were examined. One ferret, immunized with measles vaccine 40 days prior to challenge with SSPE, became ill 18 days post inoculation (p.i.). Perivascular cuffings of inflammatory cells and large cytoplasmic inclusions of fuzzy nucleocapsids were found in the brain and spinal cord. The study indicates that ferrets which become acutely ill after inoculation with cell-associated SSPE virus do so before there is a marked cellular immune response or formation of virus nucleocapsids.