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Background: In Japan, the incidence of subacute sclerosing panencephalitis (SSPE) has reduced; however, the medical conditions and factors associated with disease progression remain unclear., Methods: A nationwide survey of SSPE was conducted using a questionnaire in 2022. We conducted a descriptive analysis of the patients with SSPE in 2022 and Cox proportional hazards analyses for disease progression. We compared the patients with SSPE with those in a 2007 survey., Results: A total of 37 surviving patients with SSPE were enrolled [median age: 32 years (range: 16-52 years)]. No new cases have been identified since 2017 in the survey. Jabbour stage IV was the most common stage (66.7%). The hazard ratios (95% confidence intervals) of male sex and age at the time of measles infection (years) were 2.56 (1.13-5.76) and 0.57 (0.34-0.93), respectively. Compared with those in 2007, the proportion of patients in hospitals decreased from 13.7% to 2.7%, whereas that of patients in nursing facilities increased from 17.6% to 29.7%. The proportions of patients prescribed inosine pranobex, interferon and ribavirin at the time of the survey decreased from 96.1% to 79.4%, 74.8% to 14.3% and 25.3% to 0%, respectively. The proportions of patients with gastrostomy, tracheostomy and ventilator use increased from 5.9% to 69.7%, 23.3% to 60.0% and 10.8% to 32.4%, respectively., Conclusions: Decreased measles cases in Japan reduced new SSPE cases. However, surviving patients in 2022 had advanced disease stages and needed medical care. Male sex and early measles infection were significantly associated with disease progression., Competing Interests: The authors have no conflicts of interest to disclose., (Copyright © 2023 Wolters Kluwer Health, Inc. All rights reserved.)

High measles-specific antibody titers in the cerebrospinal fluid (CSF) have important diagnostic significance for subacute sclerosing panencephalitis (SSPE), a progressive neurological disorder caused by measles virus variants. However, the diagnostic reference value of antibody levels and the usefulness of the CSF/serum ratio measured using enzyme immunoassays (EIAs) for SSPE diagnosis remain unclear. To facilitate SSPE diagnosis using EIAs, measles immunoglobulin G (IgG) titers in the CSF and serum of patients with and without SSPE were measured and their CSF/serum antibody ratios evaluated. Serum and CSF antibody levels were compared among three patients with SSPE (59 paired samples), 37 non-SSPE patients, and 2618 patients of unknown backgrounds. Of the 59 paired samples from three patients with SSPE, 56 paired samples (94.9%) showed CSF measles IgG levels ≥0.5 IU/mL and a CSF/serum ratio ≥0.05, whereas non-SSPE cases showed CSF measles IgG levels <0.1 IU/mL and a CSF/serum ratio <0.03. Of the 2618 CSF samples with unknown backgrounds, 951 showed measurable IgG levels with EIA, with a CSF/serum ratio peak of 0.005-0.02, with a 90th percentile of 0.05. Assuming the SSPE criteria as CSF measles IgG ≥0.5 IU/mL and a CSF/serum ratio ≥0.05, only 20 samples (0.8%) with unknown backgrounds were categorized as having SSPE. Conversely, assuming the non-SSPE criteria as CSF measles IgG <0.1 IU/mL and a CSF/serum ratio <0.03, 2403 samples (92%) with unknown backgrounds were categorized as not having SSPE. In conclusion, high CSF/serum ratios (≥0.05) and high measles CSF IgG levels (≥0.5 IU/mL) may be useful for diagnosing SSPE., (© 2022 The Societies and John Wiley & Sons Australia, Ltd.)

Subacute sclerosing panencephalitis (SSPE) is a late-onset, intractable, and fatal viral disease caused by persistent infection of the central nervous system with a measles virus mutant (SSPE virus). In Japan, interferon-α and ribavirin are administered intracerebroventricularly to patients with SSPE. However, as the therapeutic effect is insufficient, more effective drugs are needed. Favipiravir, which is clinically used as an anti-influenza drug, demonstrates anti-viral effects against RNA viruses. In this study, the antiviral effect of favipiravir against measles virus (Edmonston strain) and SSPE virus (Yamagata-1 strain) was examined in vitro. The 50% effective concentration (EC 50 ) of favipiravir (inhibiting viral plaque formation by 50%) against Edmonston and Yamagata-1 strains were 108.7 ± 2.0 μM (17.1 ± 0.3 μg/mL) and 38.6 ± 6.0 μM (6.1 ± 0.9 μg/mL), respectively, which were similar to those of ribavirin. The antiviral activity of favipiravir against the SSPE virus was demonstrated for the first time in this study.

Subacute sclerosing panencephalitis (SSPE) is a late-onset, intractable, and fatal viral disease caused by persistent infection of the central nervous system by a mutant strain of the measles virus. Ribavirin intracerebroventricular therapy has already been administered to several SSPE patients in Japan based on fundamental and clinical research findings from our group, with positive therapeutic effects reported in some patients. However, the efficacy of this treatment approach has not been unequivocally established. Hence, development of more effective therapeutic methods using new antiviral agents is urgently needed. This review describes the current status of SSPE treatment and research, highlighting promising approaches to the development of more effective therapeutic methods.

Background: Subacute sclerosing panencephalitis (SSPE) is a progressive neurologic disorder caused by the measles virus (MV) and is identified by positive MV-specific antibody titers, detected mainly by hemagglutination inhibition (HI) tests in the cerebrospinal fluid (CSF). However, an alternative method, the enzyme immunoassay (EIA), has increasingly become a preferred method for detecting MV antibodies. To establish the index for SSPE diagnosis using EIA, we investigated the correlation between HI and EIA titers of MV antibodies in SSPE patients., Methods: Data on MV antibody titers and measurement methods at the time of diagnosis in 89 Japanese SSPE cases diagnosed between 1979 and 2006 were obtained by a survey. We also assessed the serum and CSF MV antibody titers in three patients with SSPE and serum MV antibody titers in 38 healthy adults using immunoglobulin G (IgG)-EIA and HI., Results: In all cases diagnosed as SSPE, IgG-EIA titers in the CSF were ≥0.49 IU/mL. There was a positive correlation between serum antibody values in the controls measured by IgG-EIA and HI. In patients with SSPE, both serum and CSF antibody values, measured by IgG-EIA, and HI, were positively correlated, and a positive correlation was found between the serum and CSF MV antibody titers as measured by IgG-EIA. The serum/CSF MV antibody titer ratios determined by IgG-EIA were <20 in most SSPE patients., Conclusions: Immunoglobulin G-EIA may be a suitable alternative method for SSPE diagnosis; however, its potential utility and the cut-off point of ≥0.49 IU/mL should be tested with additional patient cohorts., (© 2020 Japan Pediatric Society.)

Background: Subacute sclerosing panencephalitis (SSPE) is a slow virus infectious disease resulting from persistent infection with mutant measles virus. At present, there is no effective treatment for SSPE. Interferon-α and inosine pranobex have both been used for the treatment of SSPE, and partial success has been reported for the antiviral drug, ribavirin (RBV). The standardization of dosage method is necessary to carry out treatment with RBV more safely and effectively. In this study, RBV concentrations in cerebrospinal fluid (CSF) were monitored during the intraventricular administration using a subcutaneous continuous infusion pump., Methods: Three patients with new-onset SSPE were treated with RBV using a subcutaneous continuous infusion pump. On days 3-10 after the start of RBV infusion, CSFs were obtained by lumbar tap, and the concentration of RBV in the CSF was measured using high-performance liquid chromatography., Results: RBV concentration increased in a dose-dependent manner in all 3 patients, and the target concentration could be generally maintained without any severe side effects. We observed that the clinical symptoms were temporarily relieved in each case. In the 2 cases for whom treatment is continuing, the patients remain in stage III, while the patient who discontinued the therapy progressed to stage IV., Conclusion: The target RBV concentration in the CSF could be maintained continuously by intraventricular administration using a subcutaneous continuous infusion pump. The accumulation of further cases is necessary to confirm the safety and efficacy of this medical treatment.

Measles virus (MV) isolates from patients with subacute sclerosing panencephalitis (SSPE) differ from wild-type MV virologically. However, few animal models have reported viruses with characteristics of the SSPE virus. The MV Edmonston strain was inoculated into the subarachnoid space of nude mice. All nude mice displayed weight loss and required euthanasia, with a mean survival duration of 73.2 days. The viral load in the brain was 4- to 400-fold higher than the inoculated load, and brain infection was confirmed by immunostaining. Gene sequencing of the viruses revealed that amino acid mutations occurred more frequently in matrix proteins. The most common mutation was a uridine-to-cytosine transition. The virus exhibited lower free virus particle formation ability than the Edmonston strain. When nude mice were challenged with 2 × 10(2) PFU of the brain-derived virus, the mean survival duration was 34.7 days, which was significantly shorter than that of the mice challenged with 4 × 10(4) PFU of the Edmonston strain (P < 0.01). This study indicated that MV in a nude mouse model of persistent infection exhibited characteristics of the SSPE virus. This model may prove useful in elucidating the pathogenic mechanism of SSPE and developing potential therapeutics.

Investigators conducted a retrospective epidemiological study of subacute sclerosing panencephalitis, a fatal disease caused by measles infection, over the past few years in Japan. Data on 118 cases obtained from a questionnaire sent to attending physicians were analyzed. The annual incidence of subacute sclerosing panencephalitis was approximately 0.03 cases per million from 2001 to 2005. Children infected with measles at a young age (<12 months) showed a high incidence of subacute sclerosing panencephalitis, and those infected before 6 months of age showed earlier onset. Because a positive correlation was found between the prevalence of measles and the onset of subacute sclerosing panencephalitis, particularly among children infected at an early age, it is vital to eradicate measles infection by vaccination.

Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal central nervous system disorder that results from a persistent SSPE virus infection. Compound which inhibits the replication of SSPE virus might be a candidate for the specific drug for SSPE. Out of several compounds which had been tried for the treatment of SSPE, two drugs, i.e., inosiplex and interferon-alpha, were reported to be effective. Those drugs, however, could not cure the disease. Recently, ribavirin therapy has been proposed as novel antiviral chemotherapy for SSPE. By intraventricular administration, ribavirin level in CSF reaches a concentration at which ribavirin could completely inhibit the replication of SSPE virus. Thus, intraventricular ribavirin therapy might eradicate SSPE virus from the CNS and stop the progression of SSPE syndrome. The therapeutic efficacy should be evaluated in the patients who are treated with the therapy at an early stage of SSPE.

Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal central nervous system disorder that results from a persistent SSPE virus infection. The efficacy of inosine pranobex, an antiviral/immunomodulator agent, remains controversial. Intraventricular interferon-alpha combined with oral inosine pranobex slows the progressive course of SSPE, but does not cure the disease. We examined a wide variety of antiviral compounds for their inhibitory effects on SSPE virus strains in vitro and in vivo, and found that ribavirin had potent inhibitory activity against SSPE. We tried to treat SSPE patients first with high-dose intravenous ribavirin therapy, and then with intraventricular ribavirin therapy. Ribavirin therapy seemed to have a certain effect on clinical courses of patients with SSPE. To reach the conclusion that ribavirin therapy is clinically effective, clinical trials on many cases will be required.

Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal central nervous system disorder that results from a persistent SSPE virus infection. Compound which inhibits the replication of SSPE virus might be a candidate for the specific drug for SSPE. Out of several compounds which had been tried for the treatment of SSPE, two drugs, i.e., inosiplex and interferon-a were reported to be effective. Those drugs, however, could not cure the disease. Recently, ribavirin therapy has been proposed as novel antiviral chemotherapy for SSPE. By intraventricular administration, ribavirin level in CSF reaches a concentration at which ribavirin could completely inhibit the replication of SSPE virus. Thus, intraventricular ribavirin therapy might eradicate SSPE virus from the CNS and stop the progression of SSPE syndrome. The therapeutic efficacy should be evaluated in the patients who are treated with the therapy at an early stage of SSPE.

Ribavirin is a broad-spectrum antiviral drug with inhibitory activity against many RNA viruses, including measles virus. Five patients with subacute sclerosing panencephalitis (SSPE) were treated with ribavirin by intraventricular administration. Although there were transient side effects attributed to ribavirin, such as drowsiness, headache, lip and gingival swelling, and conjunctival hyperemia, intraventricular ribavirin therapy was generally safe and well tolerated. The cerebrospinal fluid (CSF) ribavirin concentration decreased, as described by a monoexponential function, after a single intraventricular dose. There was considerable interindividual variability, however, in the peak level and half-life. We aimed to adjust the individual dose and frequency of intraventricular administration based on the peak level and half-life of ribavirin in the CSF in order to maintain the CSF ribavirin concentration at the target level. Clinical effectiveness (significant neurologic improvement and/or a significant decrease in titers of hemagglutination inhibition antibodies against measles virus in CSF) was observed for four of five patients. For these four patients, CSF ribavirin concentrations were maintained at a level at which SSPE virus replication was almost completely inhibited in vitro and in vivo, whereas the concentration was lower in the patient without clinical improvement. These results suggest that intraventricular administration of ribavirin is effective against SSPE if the CSF ribavirin concentration is maintained at a high level. Intraventricular ribavirin therapy should be pursued further for its potential use for patients with SSPE and might be applied in the treatment of patients with encephalitis caused by other RNA viruses.

Ten patients with SSPE were surveyed during the last 4 years from the viewpoint of clinical safety for use of ribavirin therapy. Although effectiveness varied among cases, they were all treated safely with intraventricular ribavirin. This study suggests that treatment is safe and well-tolerated.

Subacute sclerosing panencephalitis (SSPE) is a degenerative disease of the central nervous system that leads to death within a few years. Recently, it has been reported that combination therapy with intraparenchymal interferon-alpha (INF-alpha) and intraventricular ribavirin is effective. An 11-year-old SSPE patient whose clinical symptoms progressed rapidly, was treated first with intraventricular INF-alpha and then with combined intraventricular INF-alpha and ribavirin therapy. To monitor viral load over the course of the therapy, measles virus RNA was quantified using a real-time polymerase chain reaction assay. Measles virus RNA decreased rapidly after the INF-alpha therapy was started, paralleling the decrease in the measles antibody titer in the cerebrospinal fluid and the improvement in the neurological disability. After intraventricular ribavirin was combined with INF-alpha therapy, no further improvement was observed. The neurological disability gradually progressed, although the amount of virus RNA remained low.

A survey was made on 10 patients with subacute sclerosing panencephalitis (SSPE) during the last four years from the viewpoint of clinical safety of ribavirin therapy in Japan. Although the age of onset, latent period, and effectiveness were variable among the cases, they were treated safely with intraventricular ribavirin combined with high doses of interferon (IFN). Their clinical stages on admission ranged from the first to fourth of Jabbour's classification, and those on the beginning of ribavirin therapy also ranged from the first to fourth. Seven of them were first treated with intraventricular IFN-alpha monotherapy, however, the combination of intraventricular IFN-alpha and ribavirin was started after clinical worsening. Although 5 patients showed slow progression, seven responded to the therapy with clinical improvement or decreased measles antibody titers in the CSF. Especially, one patient showed improvement to Jabbour's first stage and no further progression during the following 3 years. Ribavirin therapy caused no severe effects. Lip swelling (50%), sleepiness (40%), and headache (30%) were noted. Although we were unable to perform a double-blinded clinical study for ethical reasons, our results suggest that treatment with intraventricular ribavirin and high doses of IFN may be effective for SSPE. Early administration of intraventricular ribavirin and IFN might be considered especially to IFN in non-responders. To establish this combination therapy as a safe and effective treatment of SSPE, further studies are necessary on the role of ribavirin in the pathogenesis as well as its effects in the central nervous system.

Two patients with subacute sclerosing panencephalitis (SSPE) were treated safely and effectively with high doses of intravenous ribavirin combined with intraventricular alpha interferon. The ribavirin concentrations maintained in the serum and cerebrospinal fluid were higher than those which inhibit SSPE virus replication in vitro and in vivo.

Two patients with subacute sclerosing panencephalitis (SSPE) are described. They were diagnosed on admission to the hospital with SSPE, as judged on cerebrospinal fluid examination involving reverse transcription followed by polymerase chain reaction, at the second stage of Jabbour's classification. They first were treated with intraventricular interferon-alpha monotherapy; however, the combination of interferon-alpha and IV ribavirin was started at 8 and 5 months after beginning the interferon-alpha monotherapy, respectively. Although slow progressive brain atrophy was observed in Patient 1 on brain magnetic resonance imaging before the ribavirin therapy, no further progression was noted 11 months after starting combination therapy with ribavirin. The event-related potential study results and audiography of the right ear improved in Patient 1 after the combination therapy was initiated. In Patient 2 the hypertonicity, neurobladder incontinence, and dysphagia improved 3 months after starting the combination treatment. Although this group of patients is small, these results suggest treatment with intrathecal high-dose interferon-alpha and IV ribavirin is effective in the treatment of SSPE. Early administration of intrathecal high-dose interferon-alpha and IV ribavirin should be considered as a possible therapy for SSPE patients, especially interferon-nonresponding ones.

We studied the effects of two antiviral agents, human interferon-alpha (IFN-alpha) and ribavirin, on subacute sclerosing panencephalitis (SSPE) virus infections in hamsters. By intracranial administration, IFN-alpha alone improved the survival of infected hamsters by 20% at a dose of 6 x 10(4) IU/kg every other day for 10 days. When the dose of IFN-alpha was increased incrementally to 6 x 10(6) IU/kg, the survival rate increased by 70% in a dose-dependent manner. The combination of IFN-alpha and ribavirin had a synergic inhibitory effect on the replication of SSPE virus in cell culture. Combination of IFN-alpha (at a dose of 6 x 10(5) IU/kg) with ribavirin (at a dose of 1 mg/kg) completely prevented mortality. This was significantly better than either IFN-alpha or ribavirin monotherapy (p < 0.05). Under the conditions used, IFN-alpha did not enhance the toxicity of ribavirin in hamsters. Intraventricular administration of high dose IFN-alpha and ribavirin may have potential usefulness in the treatment of patients with SSPE.

The ribavirin concentration in hamster brains was measured by a high-performance liquid chromatography (HPLC) system and a bioassay system. When ribavirin was administered intracranially at a dosage of 10 mg/kg of body weight per day for 10 days, a dosage which results in 100% survival of hamsters infected with subacute sclerosing panencephalitis (SSPE) virus and which inhibits the replication of SSPE virus in hamster brains, the ribavirin concentration in the brains estimated by HPLC and bioassay was kept higher than 50 micrograms/g for 10 days. The effective concentration in vivo corresponds to the concentration at which ribavirin completely inhibits the replication of SSPE virus in vitro. The maximal tolerable ribavirin concentration for hamsters was calculated to be 150 micrograms/g. Although ribavirin shows toxicity to the animals at a relatively low concentration (250 to 400 micrograms/g), intrathecal or intraventricular administration of ribavirin should be explored for potential use in the treatment of patients with SSPE, while the ribavirin concentration in cerebrospinal fluid or brain tissue should be monitored.

The antiviral activity of ribavirin was studied in hamsters infected with subacute sclerosing panencephalitis (SSPE) virus. Ribavirn did not improve the survival of infected hamsters when administered intraperitoneally at the maximal nonlethal dose of 50 mg/kg/day for 10 days. However, when administered intracranially, ribavirin improved the survival of infected hamsters in a dose-dependent manner. The 50% effective dose was calculated to be 1.4 mg/kg/day, and the selectivity index, based on the ratio of the 50% lethally toxic dose (31 mg/kg/day) to the 50% effective dose, was 22. When begun 12 h, but not 36 h, postinfection, ribavirin at a dose of 10 mg/kg/day completely prevented mortality and inhibited the replication of SSPE virus in brains of infected hamsters. Intrathecal or intraventricular administration of ribavirin should be explored for potential use in the treatment of patients with SSPE.