Development Of Subacute Sclerosing Panencephalitis Research Articles

Atypical early presentation of subacute sclerosing panencephalitis in children: A case series

Subacute sclerosing panencephalitis (SSPE) is a progressive neurodegenerative disease of children and young adults that may occur as an uncommon complication 7–10 years after a measles infection. In measles – endemic countries like India, the incidence of this fatal disease is high and more number of new cases are detected in recent times. In this case series, we have presented three cases of SSPE between the 4 and 5 years age group, presented with abnormal movement and neuroregression and diagnosed by characteristic clinical features, raised anti-measles antibody titer in CSF, and typical Electroencephalography findings. All of them had a history of measles infection before the vaccination and very short latency period between measles infection and the development of SSPE. They were discharged in stable condition after the treatment with oral Isoprinosine and intrathecal Interferon alfa 2b. Early age of presentation, short latency period, and apparently good response to treatment for the time being prompted us to present these cases.

Association of Interleukin 18, Interleukin 2, and Tumor Necrosis Factor Polymorphisms with Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a progressive inflammatory and degenerative disorder of the central nervous system. The measles virus (MV) and host and environmental factors are involved in the development of SSPE, but the precise mechanism by which the MV causes SSPE is still unknown. Studies have indicated that in SSPE patients, specific polymorphisms of certain genes are most likely involved in impairing the host's ability to eradicate the MV. The purpose of our study was to elucidate the role of polymorphisms in the genes encoding interleukin (IL)-2, IL-18, and tumor necrosis factor alpha (TNF-α) in the development of SSPE. Using the polymerase chain reaction with sequence-specific primers, the single-nucleotide polymorphisms (SNPs) of the promoter regions of IL-2 (-330), TNF-α (-308), and IL-18 (-137 and -607) were studied in 54 patients with SSPE and 72 healthy controls. The frequency of SSPE patients with the AA genotype of IL-18 at position -607 was significantly higher than the frequency of those with the CC genotype (p<0.001, odds ratio [OR]: 5.76), and a significantly higher proportion of patients had the C allele at -137 compared with the controls (p=0.002, OR: 2.72). In a haplotype analysis of two SNPs in the IL-18 gene, the frequency of the CA haplotype was significantly higher in SSPE patients (p<0.001, OR: 3.99) than in the controls. The IL-2 (-330) and TNF-α (-308) polymorphisms revealed no significant differences. In conclusion, these data suggest that the IL-18 gene polymorphisms at position -607 and -137 might be genetic risk factors for the SSPE disease.

Are SCN1A gene mutations responsible for genetic susceptibility to subacute sclerosing panencephalitis?

Dravet syndrome, characterized predominantly by myoclonus, has a striking clinical resemblance to subacute sclerosing panencephalitis (SSPE). Patients with Dravet syndrome develop significant mental decline with advancing age of affected child like in SSPE. It is well established that SCN1A gene mutations are associated with Dravet syndrome. Even periodic EEG complexes have been described in Dravet syndrome. In addition to Dravet syndrome, several other types of acute and subacute encephalopathic syndromes having clinical and electroencephalographic resemblance to SSPE are associated with SCN1A gene mutations. SSPE is a devastating progressive inflammatory disorder of the central nervous system. It is caused by persistent infection of the brain by an aberrant measles virus. Only a few of a vast number of measles infected pediatric population develop SSPE. There are several reports describing presence of SSPE is close relatives and it has been described previously in sibling and twin pairs. A genetic susceptibility for development of SSPE is likely. In fact, a variety of genetic abnormalities have already been described in patients with SSPE. It can also be argued that because of striking clinical resemblance between Dravet and various epileptic and encephalopathic syndromes associated with SCN1A gene mutations and SSPE, SCN1A gene abnormalities may also be responsible for susceptibility to SSPE in measles infected children.

Drug-Indiced Aseptic Meningitis: Development of Subacute Sclerosing Panencephalitis Following Repeated Intraventricular Infusion Therapy with Interferon Alpha/Beta

Interferon (IFN)-α was reported to be effective in longterm intrathecal treatment of subacute sclerosing panencephalitis (SSPE). However, the side effects related with longterm use of IFN-α/β are unclear. We evaluated the therapeutic effects of IFN-α/β in a 13-years-old patient with SSPE. The cerebrospinal fluid (CSF) measles antibody titer was 64 × NT/128×HI, IgG-index was 4.5, and the SSPE diagnosis was based on electroencephalography (Jabbour-stage II on admission). With Inosiplex (INP) given orally, IFN-α (3 × 10(6) units) was infused intraventricularly twice-a-week for 1-year. Resultantly, CSF cell count was elevated (2502/3), total protein and glucose levels were normal; however, DIAM occurred repeatedly. Consequently, reduced IFN-α (5 × 10(5) units) with hydrocorton was administered at 2-months interval for 19 months, during which, DIAM occurred four times. Therefore, IFN-β (3 × 10(6) units; twice-a-week) therapy was started and continued for 3 years. Although the symptoms were improved considerably, DIAM recurred after 15-months therapy and CSF cell counts were also elevated (2121/3). Since SSPE progressed to Jabbour-stage IV, indicated by irreversible consciousness disorder, IFN therapy was discontinued and INP monotherapy was followed for another 3 years. We, therefore, concluded that the longterm intraventricular IFN-α/β infusion therapy of SSPE involved the potential risk of DIAM with serious irreversible neurological sequelae and should be monitored carefully.

感染症の宿主遺伝要因－抗酸菌感染症と亜急性硬化性全脳炎に対する免疫遺伝学的アプローチ－

Genetic susceptibility to infectious diseases can be explained by nucleotide alteration (mutation, polymorphism, etc.) of genes encoding molecules involved in the entry of or the immune response to microorganisms. We have conducted studies on host genetic factors for the development of mycobacterial infections and subacute sclerosing panencephalitis (SSPE) in the past decade. First, we identified autosomal dominant IFN-gamma receptor deficiency as a predominant genetic basis of patients with bacille Calmette-Guérin osteomyelitis in Japan. Second, by gene-based association analysis of 21 candidate genes, it was suggested that genetic variants of IL-12 receptor beta1 gene (IL12RB1) confer genetic susceptibility to tuberculosis, and are associated with the progression of the disease in Japanese. Third, we demonstrated that variants of several genes encoding molecules associated with innate immunity (MxA and TLR3 genes) and acquired immunity (IL4 and programmed cell death 1 [PD1] genes) were associated with the development of SSPE. Immunogenetical approaches to infectious diseases would help us to evaluate the risk for disease development and progression, individualize prevention and treatment strategies, and create new therapies.

Subacute Sclerosing Panencephalitis: More Cases of This Fatal Disease Are Prevented by Measles Immunization than Was Previously Recognized

The most severe sequela of measles virus infection is subacute sclerosing panencephalitis (SSPE), a fatal disease of the central nervous system that generally develops 7-10 years after infection. From 1989 through 1991, a resurgence of measles occurred in the United States, with 55,622 cases of measles reported. The purpose of the present study was to identify cases of SSPE that were associated with the resurgence of measles and to calculate the risk of developing SSPE. Brain tissue samples obtained from 11 patients with a presumptive diagnosis of SSPE were tested for the presence of measles virus RNA. Measles virus genotypes were determined by reverse-transcription polymerase chain reaction (RT-PCR) and by analysis of the sequences of the PCR products. A search of the literature was conducted to identify reports of cases of SSPE in persons residing in the United States who had measles during 1989-1991. The measles virus sequences derived from brain tissue samples obtained from 11 patients with SSPE confirmed the diagnosis of SSPE. For 5 of the 11 patients with SSPE who had samples tested by RT-PCR and for 7 patients with SSPE who were identified in published case reports, it was determined that the development of SSPE was associated with the measles resurgence that occurred in the United States during 1989-1991. The estimated risk of developing SSPE was 10-fold higher than the previous estimate reported for the United States in 1982. Vaccination against measles prevents more cases of SSPE than was originally estimated.

A continuing high incidence of subacute sclerosing panencephalitis (SSPE) in the Eastern Highlands of Papua New Guinea.

The aims of this descriptive study were to confirm the high incidence of subacute sclerosing panencephalitis (SSPE) previously reported from Papua New Guinea (PNG) and to relate SSPE to previous measles vaccination and measles illness. From February 1997 to April 1999 we diagnosed a total of 55 patients with SSPE at Goroka Base General Hospital in Eastern Highlands Province (EHP) of PNG. The diagnosis was based on high cerebrospinal fluid and serum measles virus antibody titres with progressive neurological disorder and myoclonic jerks. Of these 55 patients 42 were from EHP, including 32 whose onset was in the 2-year period 1997-1998. The annual incidence of SSPE in EHP in these 2 years was 98 per million population under 20 years of age, the highest ever reported. This incidence was more than ten times higher than the highest incidence in the prevaccine era reported from elsewhere. The mean age of onset of SSPE was 7.7 years (range 2.8-14.8 years) and the interval between measles and the onset of SSPE, where known, had a mean of 5.9 years and a range of 2.5-11.1 years. Among the SSPE patients 19 had a documented history of measles vaccination. Eight of these 19 also had documentation of previous measles illness; of these, seven were vaccinated after the development of measles and one was vaccinated 20 days before measles illness. Two non-SSPE children received vaccination twice which was documented and subsequently developed measles which was also substantiated by documentation. Two patients with SSPE yielded amplified nucleotide sequences of measles virus that were different from any of the vaccine strains. We found no evidence to implicate measles vaccination in the development of SSPE.

Contribution of the interleukin 4 gene to susceptibility to subacute sclerosing panencephalitis.

Although the exact pathogenesis of subacute sclerosing panencephalitis (SSPE) remains to be determined, both viral and host factors seem to be involved. To identify host genetic factors involved in the development of SSPE. We investigated the association of polymorphisms in the T helper (Th)1 and Th2 cytokine, and related genes (interferon [IFN]-gamma, IFN-gamma receptor 1 [IFN-gamma R1], IFN-gammaR2 [IRF-1], interleukin 12 receptor beta 1 [IL-12Rbeta1], IL-4, IL-4R, and IL-10 genes) with SSPE in Japanese subjects. A significant association (P =.03) was observed between SSPE and the T allele of the biallelic polymorphism at position -589 in the promoter region of the IL-4 gene. The IRF-1 allele 1 tended to interact with the IL-4 promoter -589 T genotype in the development of SSPE (P =.06), as judged on logistic regression analysis. The frequency of the genotype combination of IL-4 promoter -589 T and IRF-1 allele 1 (at least 1 allele) in patients with SSPE was much higher than that in the controls (47.7% vs 22.0%; P =.003, chi2 analysis). However, there was no association between other polymorphisms and SSPE. To our knowledge, this study is the first to demonstrate the possibility that the IL-4 promoter gene -589 T gene polymorphism with increased IL-4 synthesis in combination with IRF-1 allele 1 confers host genetic susceptibility to SSPE in Japanese subjects.

Analysis of measles virus binding sites of the CD46 gene in patients with subacute sclerosing panencephalitis.

Measles virus (MV) binding sites of the CD46 gene were sequenced in patients with subacute sclerosing panencephalitis (SSPE) and in controls. There were 3 novel polymorphisms, including C/T at nucleotide position 38 (C/T38), G/A at position 176 (G/A176), and C/T at position 453 (C/T453), at allele frequencies of.97:.03, .99:.01, and.97:.03, respectively. The G/A176 polymorphism causes an Arg/Gln amino acid change within the essential binding sites of MV, whereas the C/A38 polymorphism causes a Ser/Phe change outside the MV binding sites. The C/T453 polymorphism does not produce an amino acid change. Two of the 40 SSPE patients and 2 of the 32 controls had both C/T38 and C/T453 polymorphisms in heterozygous patterns. One control subject, but no SSPE patients, had the G/A176 polymorphism in a heterozygous pattern. Thus, it is not likely that CD46 gene alteration has a role as a host susceptibility factor in the development of SSPE.

Subacute sclerosing panencephalitis is typically characterized by alterations in the fusion protein cytoplasmic domain of the persisting measles virus

Our recent extensive analysis of three cases of subacute sclerosing panencephalitis (SSPE) revealed intriguing genetic defects in the persisting measles virus (MV): the fusion (F) genes encoded truncated cytoplasmic F protein domains (Cattaneo et al., Virology 173, 415–425, 1989). Now this MV genomic region has been investigated in eight additional SSPE cases by PCR amplification, replacement cloning into a vector containing the F gene of a lytic MV, in vitro expression, and sequencing. In all cases at least part of the clones showed mutations leading to F protein truncations, elongation, or nonconservative amino acid replacements. It is proposed that alteration of the F protein cytoplasmic domain may play a critical role in the development of SSPE.

Subacute Sclerosing Panencephalitis: Are Antigenic Changes Involved in Measles Virus Persistence?

Subacute sclerosing panencephalitis (SSPE) is a rare, fatal complication of measles virus infection arising years after acute measles. During this chronic disease process, characteristic measles virus inclusions are present in the cells of the central nervous system (CNS). During SSPE, infectious virus is not present either in the CNS or other tissues, but it has proved possible, in some cases, to rescue a measles-like virus by cocultivation techniques. These viruses may differ from measles virus, and from each other, but no single, stable property differentiates them. Differences between various strains of measles virus are of a similar magnitude to those observed between SSPE and measles viruses. This chapter discusses experiments to differentiate these agents using monoclonal antibodies raised against purified measles virus Edmonston. In no case is an isolate of measles virus available from the acute phase of infection preceding the develoment of SSPE by the same patient. This event is modeled in vitro by using a tissue culture of Vero cells persistently infected with an SSPE virus “Lec,” and this system is compared to other carrier cultures. These in vitro persistent infections differ from any in vivo persistence, because they are maintained in the absence of an immune response and may provide an insight into the importance of that phenomenon in the development of SSPE.

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.