Functional properties of measles virus proteins derived from a subacute sclerosing panencephalitis patient who received repeated remdesivir treatments.

Subacute sclerosing panencephalitis (SSPE) is a rare but fatal late neurological complication of measles, caused by persistent measles virus (MeV) infection of the central nervous system. There are no drugs approved for the treatment of SSPE. Here, we followed the clinical progression of a 5-year-old SSPE patient after treatment with the nucleoside analog remdesivir, conducted a post-mortem evaluation of the patient's brain, and characterized the MeV detected in the brain. The quality of life of the patient transiently improved after the first two courses of remdesivir, but a third course had no further clinical effect, and the patient eventually succumbed to his condition. Post-mortem evaluation of the brain displayed histopathological changes including loss of neurons and demyelination paired with abundant presence of MeV RNA-positive cells throughout the brain. Next-generation sequencing of RNA isolated from the brain revealed a complete MeV genome with mutations that are typically detected in SSPE, characterized by a hypermutated M gene. Additional mutations were detected in the polymerase (L) gene, which were not associated with resistance to remdesivir. Functional characterization showed that mutations in the F gene led to a hyperfusogenic phenotype predominantly mediated by N465I. Additionally, recombinant wild-type-based MeV with the SSPE-F gene or the F gene with the N465I mutation was no longer lymphotropic but instead efficiently disseminated in neural cultures. Altogether, this case encourages further investigation of remdesivir as a potential treatment of SSPE and highlights the necessity to functionally understand SSPE-causing MeV.IMPORTANCEMeasles virus (MeV) causes acute, systemic disease and remains an important cause of morbidity and mortality in humans. Despite the lack of known entry receptors in the brain, MeV can persistently infect the brain causing the rare but fatal neurological disorder subacute sclerosing panencephalitis (SSPE). SSPE-causing MeVs are characterized by a hypermutated genome and a hyperfusogenic F protein that facilitates the rapid spread of MeV throughout the brain. No treatment against SSPE is available, but the nucleoside analog remdesivir was recently demonstrated to be effective against MeV in vitro. We show that treatment of an SSPE patient with remdesivir led to transient clinical improvement and did not induce viral escape mutants, encouraging the future use of remdesivir in SSPE patients. Functional characterization of the viral proteins sheds light on the shared properties of SSPE-causing MeVs and further contributes to understanding how those viruses cause disease.

Place of magistral preparations to continue the treatment if the drug is commercially stopped worldwide? A case report of a 10-year-old child with subacute sclerosing panencephalitis (SSPE) requiring inosiplex.

Subacute sclerosing panencephalitis (SSPE) is a late-onset and fatal viral disease caused by persistent infection of the central nervous system by measles virus (MeV). We present the case of a 10-year-old child from South Asia affected by SSPE, stabilized with a combination of intrathecal interferon-α2b (INF-α2b) injections and oral inosiplex and how we continued the treatment when inosiplex was commercially stopped worldwide.

A 12-YEAR-OLD ASIAN INDIAN BOY WITH BILATERAL RAPIDLY PROGRESSIVE NECROTIZING MACULAR RETINITIS.

PURPOSE: To describe clinical and imaging findings in a young boy presenting with bilateral rapidly progressive necrotizing macular retinitis. METHODS: A 12-year-old Asian Indian boy developed bilateral progressive macular retinitis. He had generalized tonic-clonic seizures for the past 3 months and gave a history of poor scholastic performance with dementia of recent onset. Multimodal imaging comprising and detailed systemic and laboratory work-up was performed. RESULTS: Both eyes showed rapidly progressive full-thickness retinitis lesions observed as disruption of retinal architecture in both eyes. Left eye optical coherence tomography shows full-thickness retinal involvement with sparing of the internal limiting membrane. Electroencephalogram and magnetic resonance imaging (brain) were suggestive of subacute sclerosing panencephalitis and the diagnosis was confirmed by elevated cerebrospinal fluid and serum IgG measles. The patient did not survive despite treatment with systemic interferon therapy. CONCLUSION: It is important to look for the measles virus as a probable cause of necrotizing retinitis and neurologic symptoms in immunocompetent unvaccinated young patients. Early referral to a neurologist may assist in the early diagnosis of subacute sclerosing panencephalitis and targeted therapy.

A multicentre observational study of the prevalence, management, and outcomes of subsegmental pulmonary embolism.

BACKGROUND: The incidence of subsegmental pulmonary embolism (SSPE) has increased with improvements in imaging technology. There is clinical equipoise for SSPE treatment, with conflicting evidence of improved mortality or reduced venous thromboembolism recurrence with anticoagulation. SSPE studies have significant heterogeneity and often lack adequately matched disease comparator groups. OBJECTIVES: To determine the prevalence, management, and outcomes of SSPE and compare them to patients with main, lobar, segmental, and no pulmonary embolism (PE). PATIENTS/METHODS: All adult patients undergoing CT pulmonary angiography (CTPA) between 2013 and 2019, at 3 UK hospitals were included in the study. CTPA reports were text mined for language relating to PE, and then further manually screened for the presence and anatomical location of PE. Patient groups were propensity matched by age, sex, and year of CTPA prior to analysis. 3-month outcomes of major bleeding, VTE recurrence, and death were recorded. RESULTS: 79 (3.8%) SSPEs were identified from 2,055 diagnoses of PE, and 14,300 CTPA reports. 44 (56%) of SSPEs were single artery emboli, 25 (32%) were multiple unilateral emboli, and 10 (13%) were multiple bilateral emboli. Mortality, VTE recurrence and major bleeding were similar at 3 months across all groups. 87.3% of SSPE imaging reports had an additional radiological diagnosis, with pleural effusion (30%), consolidation (19%), and cardiomegaly (19%) being the most common. CONCLUSION: The prevalence of SSPE was 3.8% of all PEs and there were a substantial number of additional radiological findings in the SSPE group that may have accounted for their symptoms.

Favorable outcomes of interferon-α and ribavirin treatment for a male with subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a slow virus infection associated with mutant measles virus (MeV). The long-term outcome of antiviral treatments remains to be determined. We herein present a Japanese boy who was diagnosed with SSPE at 10 years of age. Intraventricular infusions of interferon-α effectively prevented the progress of symptoms during 14 years of follow-up period. Flow-cytometric analysis demonstrated higher proportion of T helper 17 cells (Th17, 18.2%) than healthy controls (4.8-14.5%) despite the normal subpopulation of peripheral lymphocytes. These data suggest that a group of patients with SSPE may show favorable responses to intraventricular infusions of interferon-α.

Advances in Antiviral Therapy for Subacute Sclerosing Panencephalitis.

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.

Antiviral Effect of Favipiravir (T-705) against Measles and Subacute Sclerosing Panencephalitis Viruses.

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 (EC50) 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.

Aprepitant in the Treatment of Subacute Sclerosing Panencephalitis: A Randomized, Double-Blind, Placebo-Controlled Study.

BACKGROUND: Aprepitant is a neurokinin-1 receptor antagonist approved for the treatment of chemotherapy-induced nausea. We aimed to investigate the safety and efficacy of aprepitant in patients with subacute sclerosing panencephalitis. METHODS: A randomized, double-blind, placebo-controlled study was conducted in patients with subacute sclerosing panencephalitis assigned to receive two courses of aprepitant 250 mg/day orally or placebo for 15 days with an interval of two months between courses. Primary end points were safety and tolerability, and secondary end point was clinical improvement or stabilization assessed by subacute sclerosing panencephalitis scoring system. Electroencephalography (EEG), brain magnetic resonance imaging, and cerebrospinal fluid measles-specific immunoglobulin G index were evaluated before and after treatment. RESULTS: Sixty-two patients with subacute sclerosing panencephalitis were allocated to aprepitant (n = 31, median age 18 years) or placebo (n = 31, median age 22 years) group. Fifteen patients left the study within the first six months and 12 patients left between six and 12 months. Aprepitant was well tolerated and treatment-associated adverse events were similar to those described in the treatment of nausea. Clinical status at six and 12 months' follow-up did not differ between aprepitant and placebo groups. Post-treatment EEG scores at 12 months were better in the aprepitant group (P = 0.015). Cerebral atrophy on magnetic resonance imaging increased in both groups, whereas measles-specific immunoglobulin G index decreased in the placebo group. CONCLUSIONS: In this first clinical trial of aprepitant treatment in patients with subacute sclerosing panencephalitis, the drug was safe and well tolerated. No clinical effect was observed. A modest improvement in EEG findings might justify trials for longer periods because EEG changes can precede clinical findings in subacute sclerosing panencephalitis.

Clinical conundrum: status epilepticus culminating into acute dystonia myoclonus.

A 7-year-old child who suffered from symptomatic focal epilepsy as a sequel to perinatal hypoxia used to have frequent seizures. This time she developed prolonged status epilepticus lasting for over 5 hours. She received a treatment in the form of intravenous midazolam and reinitiation of sodium valproate and clobazam that were discontinued previously. Seizures were controlled over a couple of hours, but she remained unresponsive. Later, she developed acute onset dystonia (day 3 post-status epilepticus) and also myoclonic jerks. She presented to us after 3 weeks of onset of these complaints and we considered hypoxic encephalopathy resulting from prolonged status epilepticus or acute encephalitis or non-convulsive status epilepticus. However, acute onset dystonia and periodicity of myoclonic jerks were pointers against it, and on evaluation, she was diagnosed with atypical fulminant subacute sclerosing panencephalitis (SSPE). Knowing the atypical presentations of SSPE is important in planning management and prognostication.

Case Report: Subacute Sclerosing Panencephalitis in Pregnancy Mimicking Posterior Reversible Encephalopathy Syndrome.

In posterior reversible encephalopathy syndrome, brain magnetic resonance imaging (MRI) reveals bilateral occipital, parietal, and subcortical white matter hyperintensities on T2/fluid-attenuated inversion recovery (FLAIR) sequences. After treatment, imaging abnormalities are usually reversible. Eclampsia is the most frequent cause of posterior reversible encephalopathy syndrome in pregnancy. We report a 24-year-old woman, who presented to our clinic 4 weeks after normal vaginal delivery with bilateral vision loss. Loss of vision was first noticed in the 20th week of pregnancy. Even after delivery, her vision did not improve. In the postpartum period, she started having periodic myoclonic jerks. Electroencephalography demonstrated periodic generalized discharges. A brain MRI performed in the 20th week of the antepartum period showed bilateral parieto-occipital cortical white matter T2/FLAIR hyperintensities. A follow-up brain MRI, 5 months later, revealed marked reversal of white matter signal changes. Cerebrospinal fluid examination revealed raised anti-measles antibody titer, confirming the diagnosis of subacute sclerosing panencephalitis. In conclusion, in a patient with subacute sclerosing panencephalitis (SSPE) during the postpartum period, cortical vision loss and parieto-occipital white matter T2/FLAIR hyperintensities can simulate eclampsia. Inadvertent treatment with magnesium sulfate is likely if the diagnosis is missed.

Role of the Th1 and Th17 Pathway in Subacute Sclerosing Panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a progressive and fatal disease caused by reactivation of a mutated measles virus in brain tissue. The process of reactivation is yet to be elucidated. In this study, the possible roles of the Th1 (interleukin [IL]-12, interferon [IFN]-γ) and the Th17 axis (IL-23, IL-17, IL-22), particularly of IL-17, in the pathogenesis of SSPE were investigated. Briefly, mononuclear cells from SSPE patients were stimulated using measles virus peptide, and the release of IL-12, IL-23, IL-22, IFN-γ, and IL-17 cytokines was measured using enzyme-linked immunosorbent assay and/or enzyme-linked immunosorbent spot assay (ELISpot). We found that in comparison to the mononuclear cells obtained from healthy donors, cells from SSPE patients exhibited increased levels of IL-12, IL-23, IL-17, IL-22, and IFN-γ cytokines in response to measles virus stimulation. However, the same result was not obtained with cytomegalovirus and phytohemagglutinin. Using flow cytometry, mononuclear cells obtained from SSPE patients and healthy controls were also analyzed for the presence of intracellular IL-17 in response to measles virus stimulation. On stimulation, the number of IL-17-positive cells were found to be higher among mononuclear cells obtained from the patients. In addition, the numbers of IL-17- and IFN-γ-positive cells were significantly increased in SSPE patients. In conclusion, this study demonstrates that both the IL-12/IFN-γ and the IL-23/IL-17/IL-22 pathways are functionally abnormal in SSPE pathogenesis. Targeting these pathways and their specific pro-inflammatory mediator production may provide a new strategy to suppress SSPE development.

Adult-Onset Subacute Sclerosing Panencephalitis Presented with Neuropsychiatric Symptoms.

Subacute sclerosing panencephalitis (SSPE) is a progressive neurodegenerative disease caused by persistent infection of the brain with the measles virus. The most clinical presentations are behavioural changes and deterioration of mental status. The diagnosis is made with the characteristic clinical picture along with the consistent laboratory findings such as increased anti-measles antibody levels in cerebrospinal fluid accompanied by typical electroencephalographic and cranial imaging findings. SSPE usually affects children. Adult-onset SSPE is very rare and often presents with atypical features. We report here the case of a 62-year female presented with neuropsychiatric symptoms in whom SSPE was diagnosed based on cerebrospinal fluid, electroencephalographic and cranial imaging findings.

Maintaining Concentration of Ribavirin in Cerebrospinal Fluid by a New Dosage Method; 3 Cases of Subacute Sclerosing Panencephalitis Treated Using a Subcutaneous Continuous Infusion Pump.

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.

New Insights into Measles Virus Brain Infections.

Measles virus (MeV) may persist in the brain, causing fatal neurodegenerative diseases, subacute sclerosing panencephalitis, and measles inclusion-body encephalitis. However, the mechanism of MeV propagation in the brain remains unexplained because human neurons affected by the diseases do not express the known receptors for MeV. Recent studies have revealed that certain changes in the ectodomain of the MeV fusion (F) protein play a key role in MeV spread in the brain. These changes destabilize the prefusion form of the F protein and render it hyperfusogenic, which in turn allows the virus to propagate in neurons. Based on crystal structures of the F protein, effective fusion inhibitors could be developed to treat these diseases.

Subacute sclerosing panencephalitis should be eliminated by measles vaccination.

1 patient with SSPE at 4 y. He had had measles and measles encephalitis at 7.5 months. In China, the first and the second measles immunizations are recommended at 8 months and at 18-24 months, respectively. We recommend above immunizations should be given separately at 6 months and at 12-15 months.

HIV-associated sub-acute sclerosing panencephalitis - an emerging threat?

Earlier age of measles virus infection predisposes to development of sub-acute sclerosing panencephalitis (SSPE) and this risk is heightened in HIV-infected children. We describe a HIV-infected young adult on antiretroviral therapy, presenting with a non-classical, fulminant form of SSPE to highlight the unpredictable nature of measles presentation. The recent spate of measles outbreaks due to virus introduction in populations with sub-optimal vaccine coverage or waning immunity and co-existing paediatric HIV cohorts is a cause for concern.