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.

Obstetric outcomes in pregnant women with subacute sclerosing panencephalitis (SSPE): a systematic review of case reports and case series.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a devastating brain disease caused by persistent infection by the measles virus. Several cases of SSPE in pregnant ladies have been described. This systematic review is focused on maternal and foetal outcomes among pregnant women with SSPE. METHODS: We searched four databases (PubMed, Embase, Scopus, and Google Scholar). We reviewed all relevant cases, published until 14 August 2022. The review was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. The protocol was registered with PROSPERO (CRD42022348630). The search items that we used were "((Pregnancy) OR (delivery)) AND (Subacute sclerosing panencephalitis (SSPE))". Dyken's criteria were used for the diagnosis of SSPE in pregnant women. The extracted data was recorded in an Excel sheet. The Joanna Briggs Institute Critical Appraisal tool for case reports was used to assess the quality of published cases. RESULTS: We came across 19 reports describing details of 21 cases. The age of SSPE-affected women varied from 14 to 34 years (mean 23 years). In the majority (n=14), clinical manifestations were started in the antepartum period. Nine pregnant SSPE women presented with vision loss. After delivery, 13 SSPE-affected women died. On the contrary, 15 foetuses, though the majority were preterm, were alive. Five foetuses either died soon after birth or were still-born. CONCLUSION: In conclusion, SSPE in pregnancy is often missed, as it mimics eclampsia. SSPE in pregnancy usually has a devastating course. Universal early childhood measles vaccination is the only way to fight this menace.

[Measles subacute sclerosing panencephalitis (SSPE): A still present and still mysterious fatal disease. History, Diagnosis and Assumptions]. / La panencéphalite sclérosante subaiguë de la rougeole - Une maladie mortelle encore présente et toujours mystérieuse.

Subacute sclerosing panencephalitis, a late complication of measles, is still present during epidemics of this disease due to insufficient vaccination. After a historical review, the importance of the diagnostic criteria and the pathophysiology of SSEP are discussed. Numerous studies on the parameters of innate immunity and interferon responses tend to show a decrease in the activity of cellular immunity. Several hypotheses are formulated based on the publications of the different forms of the disease: Congenital, perinatal, forms with short incubation similar to acute inclusion encephalitis (AIE), rapidly evolving forms, forms of the immunocompromised, or even adults. Familial forms have been identified, suggesting a genetic cause. Based on the duration of the latency period, two groups have been individualized, prompting a retrospective and prospective analysis of the exomes of these patients. The knowledge of the genes involved should be useful for the understanding of the pathophysiology of SSPE and other late neurological RNA virus infections.

Title: La panencéphalite sclérosante subaiguë de la rougeole - Une maladie mortelle encore présente et toujours mystérieuse. Abstract: La panencéphalite sclérosante subaiguë (PESS), une complication tardive de la rougeole, est encore présente lors d'épidémies de cette maladie dues aux insuffisances de la vaccination. Après un rappel historique, nous aborderons la physiopathologie de la PESS et l'importance des critères diagnostiques. De nombreux travaux portant sur les paramètres de l'immunité innée et sur ceux des réponses interféron tendent à montrer une baisse de l'activité de l'immunité cellulaire au cours de cette maladie. Nous formulons ici plusieurs hypothèses s'appuyant sur des publications concernant différentes formes de la maladie : congénitales, périnatales, formes à incubation courte, semblables à l'encéphalite aiguë à inclusions (EAI), formes d'évolution rapide, formes retrouvées chez les immunodéprimés ou chez l'adulte. Des formes familiales ont également été identifiées, suggérant une origine génétique. Selon la durée de la période de latence entre rougeole et la PESS, deux groupes de patients ont été individualisés, incitant à des analyses rétrospective et prospective des exomes de ces malades. La connaissance des gènes participant à la maladie devrait être utile pour la compréhension de la physiopathologie de la PESS mais aussi d'autres infections neurologiques tardives dues à des virus à ARN.

Subacute Sclerosing Panencephalitis in Children: The Archetype of Non-Vaccination.

Subacute sclerosing panencephalitis (SSPE) is a late complication of measles virus infection that occurs in previously healthy children. This disease has no specific cure and is associated with a high degree of disability and mortality. In recent years, there has been an increase in its incidence in relation to a reduction in vaccination adherence, accentuated by the COVID-19 pandemic. In this article, we take stock of the current evidence on SSPE and report our personal clinical experience. We emphasise that, to date, the only effective protection strategy against this disease is vaccination against the measles virus.

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.

Subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a slowly progressive brain disorder caused by mutant measles virus. SSPE affects younger age groups. SSPE incidence is proportional to that of measles. High-income countries have seen substantial decline in SSPE incidence following universal vaccination against measles. SSPE virus differs from wild measles virus. Measles virus genome recovered from the autopsied brain tissues demonstrates clustered mutations in virus genome particularly in the M gene. These mutations destroy the structure and functioning of the encoded proteins. Complete infectious virus particle has rarely been recovered from the brain. Human neurons lack required receptor for entry of measles virus inside the neurons. Recent in vitro studies suggest that mutations in F protein confer hyperfusogenic properties to measles virus facilitating transneuronal viral spread. The inflammatory response in the brain leads to extensive tissue damage. Clinically, SSPE is characterized by florid panencephalitis. Clinically, SSPE is characterized by cognitive decline, periodic myoclonus, gait abnormalities, vision loss, and ultimately to a vegetative state. Chorioretinitis is a common ocular abnormality. Electroencephalography (EEG) shows characteristic periodic discharges. Neuroimaging demonstrates periventricular white matter signal abnormalities. In advanced stages, there is marked cerebral atrophy. Definitive diagnosis requires demonstration of elevated measles antibody titers in cerebrospinal fluid (CSF). Many drugs have been used to stabilize the course of the disease but without evidence from randomized clinical trials. Six percent of patients may experience prolonged spontaneous remission. Fusion inhibitor peptide may, in the future, be exploited to treat SSPE. A universal vaccination against measles is the only proven way to tackle this menace currently.

Subacute Sclerosing Panencephalitis: The Devastating Measles Complication That Might Be More Common Than Previously Estimated.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a fatal complication of measles. We reviewed California cases from 1998-2015 to understand risk factors for SPPE and estimate incidence. METHODS: SSPE cases had clinically compatible symptoms and measles antibody detection in cerebrospinal fluid (CSF) or medical record documentation of SSPE. Cases were identified though a state death certificate search, Centers for Disease Control and Prevention reports, or investigations for undiagnosed neurologic disease. Measles detection in CSF was performed by serology at the California Department of Public Health or at clinical laboratories. RESULTS: Seventeen SSPE cases were identified. Males outnumbered females 2.4:1. Twelve (71%) cases had a history of measles-like illness; all 12 had illness prior to 15 months of age. Eight (67%) children were exposed to measles in California. SSPE was diagnosed at a median age of 12 years (3-35 years), with a latency period of 9.5 years (2.5-34 years). Among measles cases reported to CDPH during 1988-1991, the incidence of SSPE was 1:1367 for children <5 years, and 1:609 for children <12 months at time of measles disease. CONCLUSIONS: SSPE cases in California occurred at a high rate among unvaccinated children, particularly those infected during infancy. Protection of unvaccinated infants requires avoidance of travel to endemic areas, or early vaccination prior to travel at age 6-11 months. Clinicians should be aware of SSPE in patients with compatible symptoms, even in older patients with no specific history of measles infection. SSPE demonstrates the high human cost of "natural" measles immunity.

SLAM- and nectin-4-independent noncytolytic spread of canine distemper virus in astrocytes.

UNLABELLED: Measles and canine distemper viruses (MeV and CDV, respectively) first replicate in lymphatic and epithelial tissues by using SLAM and nectin-4 as entry receptors, respectively. The viruses may also invade the brain to establish persistent infections, triggering fatal complications, such as subacute sclerosis pan-encephalitis (SSPE) in MeV infection or chronic, multiple sclerosis-like, multifocal demyelinating lesions in the case of CDV infection. In both diseases, persistence is mediated by viral nucleocapsids that do not require packaging into particles for infectivity but are directly transmitted from cell to cell (neurons in SSPE or astrocytes in distemper encephalitis), presumably by relying on restricted microfusion events. Indeed, although morphological evidence of fusion remained undetectable, viral fusion machineries and, thus, a putative cellular receptor, were shown to contribute to persistent infections. Here, we first showed that nectin-4-dependent cell-cell fusion in Vero cells, triggered by a demyelinating CDV strain, remained extremely limited, thereby supporting a potential role of nectin-4 in mediating persistent infections in astrocytes. However, nectin-4 could not be detected in either primary cultured astrocytes or the white matter of tissue sections. In addition, a bioengineered "nectin-4-blind" recombinant CDV retained full cell-to-cell transmission efficacy in primary astrocytes. Combined with our previous report demonstrating the absence of SLAM expression in astrocytes, these findings are suggestive for the existence of a hitherto unrecognized third CDV receptor expressed by glial cells that contributes to the induction of noncytolytic cell-to-cell viral transmission in astrocytes. IMPORTANCE: While persistent measles virus (MeV) infection induces SSPE in humans, persistent canine distemper virus (CDV) infection causes chronic progressive or relapsing demyelination in carnivores. Common to both central nervous system (CNS) infections is that persistence is based on noncytolytic cell-to-cell spread, which, in the case of CDV, was demonstrated to rely on functional membrane fusion machinery complexes. This inferred a mechanism where nucleocapsids are transmitted through macroscopically invisible microfusion events between infected and target cells. Here, we provide evidence that CDV induces such microfusions in a SLAM- and nectin-4-independent manner, thereby strongly suggesting the existence of a third receptor expressed in glial cells (referred to as GliaR). We propose that GliaR governs intercellular transfer of nucleocapsids and hence contributes to viral persistence in the brain and ensuing demyelinating lesions.

[Measles in France]. / La rougeole en France.

From January 2008 to May 2012, over 22,000 cases of measles were reported in France. The highest incidence rate was observed in children below one year of age. Over 50% of cases were reported in young adults. Almost 5,000 patients were hospitalised including 1,023 with severe pneumonia, 27 with encephalitis and/or myelitis : 10 died. This situation is linked to insufficient and heterogeneous vaccination coverage with pockets of susceptible people allowing virus circulation. Although the vaccine coverage in children has now improved for both doses, the issue of convincing young susceptible adults to catch up for measles vaccination remains critical, if the elimination target is to be met, and in order to protect the most vulnerable population unable to benefit from this vaccination (children below 1 year, immunodeficient people, pregnant women).

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.

A 22-year-old Australian woman with atypical subacute sclerosing panencephalitis diagnosed at postmortem.

Measles remains a significant global health problem. Despite the decline in measles prevalence in Australia following the implementation of a national vaccination program, challenges surrounding this disease remain. This report describes a 22-year-old woman who presented with coordination loss, tremor, choreiform movements and marked visual blurring, and her condition rapidly deteriorated to coma and death. Antemortem investigations did not yield a unifying diagnosis. Postmortem examination provided a diagnosis of subacute sclerosing panencephalitis. This patient had a rare neurological complication of measles infection, and her condition is remarkable for the atypical clinical presentation.

Measles: not just a childhood rash.

In recent years, the number of US measles cases has increased, and outbreaks in adults continue to be reported in communities with a high number of unvaccinated people. These trends underscore the need for high overall measles vaccination coverage, and for physicians to entertain the diagnosis of measles in adult patients with a febrile illness and rash.

PD1 as a common candidate susceptibility gene of subacute sclerosing panencephalitis.

Although the exact pathogenesis of subacute sclerosing panencephalitis (SSPE) remains to be determined, our previous data suggested a genetic contribution to the host susceptibility to SSPE. During chronic viral infection, virus-specific cytotoxic T lymphocytes display poor effector functions. Since co-inhibitory molecules are involved in the suppression of T lymphocytes, we investigated whether single nucleotide polymorphisms (SNPs) of genes encoding co-inhibitory molecules contributed to a susceptibility to SSPE. Association studies on a total of 20 SNPs in 8 genes (CTLA4, CD80, CD86, PD1, PDL1, PDL2, BTLA and HVEM) and subsequent haplotype analysis of 4 SNPs in the PD1 genes were performed in Japanese and Filipino SSPE patients and controls. Then, we investigated a functional difference in promoter activity of two haplotypes and compared the expression levels of PD1 between SSPE and controls. The frequency of GCG(C) haplotype of PD1 containing -606G allele was significantly higher in SSPE patients than in controls both in Japanese and in Filipinos. The promoter activity was significantly higher in the construct with -606G allele than in that with -606A allele. The expression levels of PD1 were significantly higher in SSPE patients than in the controls. Our results suggested that the PD1 gene contributed to a genetic susceptibility to SSPE.

Panencefalitis esclerosante subaguda: importancia de la prevención del sarampión / Subacute sclerosing panencephalitis: the importance of preventing measles

La panencefalitis esclerosante subaguda es la complicación más severa causada por el virus del sarampión, una infección persistente del sistema nervioso central. Se presenta el caso de un niño español de 11 años de edad, con cambio de comportamiento y pérdida de habilidades intelectuales. Como antecedentes personales destacaba que había padecido el sarampión a los 8 meses, y estaba adecuadamente vacunado. En la rápida progresión de la enfermedad presentó mioclonías rítmicas y simétricas con alteración inicial en el electroencefalograma y la resonancia magnética. En la electroforesis del suero y el líquido cefalorraquídeo se detectaron bandas oligoclonales, con niveles de anticuerpos antisarampión muy elevados. Se inició tratamiento con isoprinosina oral para intentar detener la progresión de la enfermedad. Se pretende mostrar una complicación poco frecuente del sarampión, pero con pronóstico fatal y una elevada morbimortalidad, aunque es una enfermedad prevenible mediante vacunación masiva. Cabe subrayar la importancia de incluirlo en el diagnóstico diferencial de los pacientes que consultan por presentar disminución del rendimiento escolar, deterioro cognitivo y de sus habilidades, junto con trastornos del movimiento. En los últimos años todavía se han detectado brotes de sarampión en muchos países desarrollados, incluida España, y la causa no sólo ha sido la emigración (AU)

Subacute sclerosing panencephalitis is the most severe complication caused by the measles virus, a persistent infection of the central nervous system. We present the case of an 11-year-old Spanish boy showing behavioural changes and a loss of intellectual abilities. Noteworthy in his medical history was measles suffered at the age of 8 months, and the fact that he was adequately vaccinated. The rapid progression of the disease involved rhythmic andsymmetric myoclonus with an initial alteration of the EEG and NMR. Oligoclonal bands were detected in the electrophoresis of the serum and CSF, with very high levels of anti-measles antibodies. A treatment with oral Isoprinosine was started with the aim of preventing the disease from progressing. The objective is to present a complication of measles that is rare, but with a fatal prognosis and high morbimortality, and that can be prevented by mass vaccination. It also highlights the importance of including the disease in the differential diagnosis of patients who seek medical advice because of a decline in academic performance, cognitive deterioration and the deterioration of their abilities, as well as movement disorders. In recent years, measles outbreaks have still been detected in many developed countries, including Spain, and emigration has not been the only cause (AU)

Bilateral retrobulbar optic neuritis, Guillain-Barré syndrome and asymptomatic central white matter lesions following adult measles infection.

A 28-year-old woman presented with classic signs of measles and subsequently developed bilateral retro-bulbar optic neuritis and Guillain-Barré syndrome. Her radiographic and CSF findings were consistent with acute measles encephalitis. However, encephalopathy, such as behavioral changes and alteration in consciousness, was not presented. Improvements in the clinical, radiographic, and electrophysiological studies were observed during the steroid therapy. The overlap of CNS and PNS involvement as neurological complications of measles infection is very rare.

Atypical presentations of subacute sclerosing panencephalitis in two neurologically handicapped cases.

Subacute sclerosing panencephalitis (SSPE) is a neurodegenerative disorder caused by persistent measles infection. Here, we report two neurologically handicapped cases presenting with atypical features of SSPE. Patient 1 who had mild mental retardation manifested acute encephalopathy with partial seizures and hemiplegia, mimicking encephalitis. He showed a fulminant course without myoclonia or a periodic electroencephalogram complex. Although SSPE is usually associated with an increased diffusion pattern, diffusion-weighted imaging of our patient showed decreased diffusion in the right hippocampus. Patient 2 with infantile hemiparesis presented with secondary generalized seizures, followed by asymettrical myoclonias involving the side contralateral to the hemiparesis. A periodic electroencephalogram complex was absent on the previously damaged brain regions. Our findings show that preexisting neurological disorders may modify the clinical or electrophysiological findings of SSPE, leading to atypical presentations. SSPE should be considered in the differential diagnosis of acute encephalopathy with lateralizing signs or unidentified seizures. Decreased diffusion resolution in diffusion-weighted-imaging may correlate with rapid clinical progression in SSPE.

[Development of animal model for understanding of pathogenesis of subacute sclerosing panencephalitis using non-human primates].

Many animal models using experimental small animals for subacute sclerosing panencephalitis (SSPE) had been reported. But these models were not enough for understanding of pathogenesis of SSPE. After pathogenic measles virus was isolated with highly susceptible B95a cells, mimic infection of measles in human beings became easily produced in non-human primates. In this article, our attempt to develop SSPE model using cynomolgus monkeys will be introduced.