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.

Panencefalitis esclerosante subaguda: reporte de un caso en Chile / Subacute sclerosing panencephalitis: a case report in Chile

La panencefalitis esclerosante subaguda postsarampión (PEES) es en la actualidad una entidad infrecuente en aquellos países donde existen programas regulares de vacunación contra el sarampión. Presentamos un caso, con evolución rápida a la muerte, en el cual fueron observados hallazgos característicos. Entre los más relevantes: títulos elevados de anticuerpos antisarampión en el líquido cefalorraquídeo (LCR), patrón periódico en el EEG, fenómenos de desmielinización progresiva en el scanner y resonancia nuclear magnética cerebral, asociados a la presencia constante de crisis mioclónicas. A pesar de una terapia continua con alfa-interferón intratecal, cimetidina en dosis inmunorreguladoras y con antiviral, se observó un deterioro progresivo del paciente. El estudio neuropatológico reveló compromiso a nivel de los centros semiovales de los hemisferios frontales, de predominio izquierdo

Panencefalitis esclerosante subaguda de inicio en edad adulta: presentación atípica en 2 pacientes / Adult onset subacute sclerosing panencephalitis: atypical presentation in 2 cases

Subacute sclerosing panencephalitis is an infrequent central nervous system viral disease and is a late manifestation of persistent infection by a mutant form of measles virus. Since it affects mainly children and teenagers, the diagnosis in older ages is difficult. Its main clinical symptoms are cognitive impairment, behavioral disturbances and myoclonia. We report two males, aged 21 and 22 years old, presenting with the disease with atypical manifestations. One had a catatonic syndrome and the other, amaurosis. The recognition of the different presentation forms of the disease, endemic in developing countries, allows an earlier diagnosis and a more efficient treatment, when available

Neuroimagem em panencefalite esclerosante subaguda - relato de um caso e diagnóstico diferencial / Subacute sclerosing panencephaling - a case report and differential diagnosis

Os autores apresentam um caso de panencefalite esclerosante subaguda, enfocando os aspectos da neuroimagem e o diagnóstico diferencial com outras doenças do sistema nervoso central que têm quadro clínico semelhante.

Vascular changes and blood-brain barrier damage in the pathogenesis of polycystic lipomembranous osteodysplasia with sclerosing leukoencephalopathy (membranous lipodystrophy).

The histopathological, immunohistochemical and electron microscopic findings in eight patients with polycystic lipomembranous osteodysplasia and sclerosing leukoencephalopathy (PLO-SL) are described. This autosomally recessively inherited disease is first manifested by multiple bone cysts, which are later followed around the age of 30 by severe neuropsychiatric syndrome. The pathogenesis of PLO-SL has not been established, and the search for the most suspected error in lipid metabolism has been unsuccessful. The typical macroscopic features were marked hydrocephalus ex vacuo due to severe destruction of the white matter (WM) with extensive secondary astrocytic gliosis, and with relatively better preserved gray matter (GM). The basement membranes of blood vessels with plump endothelium were thickened and often multiplied, most prominently in the WM. Extravasation of plasma constituents was demonstrated immunohistochemically. On the basis of the vascular changes, also present in bone lesions, it is proposed that severe chronic vasogenic brain edema is the main pathogenetic mechanism of the severe leukoencephalopathy in this disease entity.

Pan-encefalite esclerosante subaguda: uma demência mioclônica e a sua questäo causal - relato de série de casos / Subacute sclerosing panencephalitis: a myoclonic dementia and its causal question - a report of serial of cases

Este artigo descreve aspectos clínicos e epidemiológicos de 21 pacientes que preencheram os critérios diagnósticos de pan-encefalite esclerosante subaguda (PEES).Foram analisadas variáveis demográficas,clínicas e laboratoriais(eletroencefalográficas e do líquido cefalorraquiano).A partir deste relato de série de casos e revisäo de literatura, considerou-se a relaçäo de causa-efeito entre o vírus selvagem do sarampo e a PEES e os fatores de risco predisponentes à infecçäo subclínica, e, também, os fatores subjacentes aos eventos tardios(6/8 anos após a infecçäo aguda), tais como os clínicos (principalmente demência e mioclonias) e patológicos (baseados na reaçäo inflamatoria hiperimune e corpúsculos de inclusäo feitos de nucleocapsídeos do vírus do sarampo). Conclui-se que o vírus selvagem do sarampo é uma causa necessária mas näo suficiente para o desenvolvimento da PEES, e, também, que a vacinaçäo precoce, sistemática e homogênea da populaçäo contra o sarampo é a principal meta para a reduçäo ou eventualmente erradiaçäo da PEES

[A case of subacute sclerosing panencephalitis developing 8 years after immunosuppressive treatment for acute lymphocytic leukemia].

A 13-year-old girl developed subacute sclerosing panencephalitis (SSPE) with atypical absence attacks as an initial symptom. Eight years earlier she had been treated for acute lymphocytic leukemia with cytotoxic treatment and radiotherapy, which had resulted in complete remission. She was first treated with an anticonvulsant because the atypical absence attacks and the presence of epileptic discharges on an EEG suggested epilepsy. However, with this mode of treatment the epileptic discharges did not disappear, but periodic high-voltage slow-wave complex discharges were revealed on subsequent EEGs. The antibody titer for measles virus in the cerebrospinal fluid and serum was elevated, confirming the diagnosis of SSPE. SSPE may arise, though rarely, in an individual in an immunosuppressive state due to congenital immunodeficiency or various kinds of malignancies, and also may arise several years after the contraction of measles infection. Our patient, however, lacked a past history of measles infection or immunization, suggesting the possibility that she had contracted measles during or shortly after the course of treatment for ALL.

Pan-encefalite esclerosante subaguda (PEES): consideraçöes epidemiológicas e etiopatogênicas / Subacute sclerosing panencephalitis (SSPE): epidemiological and etiopathogenics considerations

Foram estudados dados de mortalidade sobre a pan-encefalite esclerosante subaguda (PEES) e de casos notificados de sarampo, em todo o Brasil. Os dados de mortalidade por PEES apresentaram distribuiçäo similar aos de morbidade descritos na literatura revisada e em nossa casuística hospitalar, tanto quanto ao sexo (dois masculinos x um feminino), quanto às faixas etárias (70 por cento de seis a 20 anos). A concentraçäo dos diagnósticos é dominante nas regiöes sul e sudeste. Embora haja nas regiöes norte e nordeste o predomínio relativo da mortalidade por sarampo e a populaçäo de zero a 19 anos corresponder a 37 por cento da do Brasil, apenas 5 por cento dos casos de PEELS (quatro dos 74) foram ai registrados pelo Sistema de Informaçäo sobre Mortalidade do Ministério da Saúde (SIM), nos anos de 1979 a 1986. Também neste trabalho säo feitas consideraçöes etiopatogênicas e epidemiológicas sobre a PEES, a partir dos dados sobre esta doença e o sarampo no Brasil

Subacute sclerosing panencephalitis in black children--a review of 18 cases.

Despite the fact that measles is severe and presents in very young Black children in Natal, South Africa, no case of subacute sclerosing panencephalitis was reported from this region prior to 1982. A retrospective study was therefore made over the six-year period 1982-1987 of 18 patients who presented to the King Edward VIII teaching hospital, Durban, with clinical and laboratory features of subacute sclerosing panencephalitis. The majority of patients (66 per cent) were between 8 and 12 years of age. The mean age of onset was 9.3 years, the youngest patient being four years nine months and the oldest 14 years. The male to female ratio was 1.25:1. A previous history of primary measles infection was obtained in 44.4 per cent of cases; 62.5 per cent occurred before the second birthday. The commonest mode of presentation was personality, intellectual and behaviour disorders (83 per cent) followed by myoclonic seizures (61 per cent) and choreiform movements (28 per cent). Measles antibody was present in the CSF in all cases. The EEG was abnormal in all recorded cases with pathognomonic periodic complexes being found in 56.2 per cent. Confirmation of the diagnosis was provided by brain biopsy in two cases and by necropsy in one case. The findings of this study suggest that subacute sclerosing panencephalitis may not be as uncommon in Black children as has hitherto been thought.

Mutated and hypermutated genes of persistent measles viruses which caused lethal human brain diseases.

Persistent measles viruses (MVs) causing lethal human brain diseases are defective, and the structure of several mutated matrix genes has been elucidated previously. The present study of four persistent MVs revealed a high number of differences from a consensus sequence also in other genes. Amino acid changes accumulated in the carboxyl terminus of the nucleocapsid protein and in the amino terminus of the phosphoprotein, but did not significantly alter these products, which are implicated in viral replication and transcription. The contrary is true for the envelope glycoproteins: In three of four cases, mutations caused partial deletion of the short intracellular domain of the fusion protein, most likely compromising efficient viral budding. Moreover, in the hemagglutinin gene of a strain showing strongly reduced hemadsorption, 20 clustered A to G mutations, resulting in 16 amino acid changes, were detected. This hypermutation might be due to unwinding modification of a part of the MV RNA genome accidentally present in a double-stranded form. Finally, we classified four lytic and seven persistent MV strains on the basis of their sequences. Surprisingly, the four lytic viruses considered belong to the same class. The persistent viruses form more loosely defined groups, which all differ from the vaccine strain Edmonston.

Search for virus nucleic acid sequences in postmortem human brain tissue using in situ hybridization technology with cloned probes: some solutions and results on progressive multifocal leukoencephalopathy and subacute sclerosing panencephalitis tissue.

In order to obtain a useful and readily applicable in situ hybridization (ISH) protocol for progressive central nervous system (CNS) diseases of unknown etiology that are possibly due to persistent viral infection, known and well described diseases were studied, namely, progressive multifocal leukoencephalopathy (PML) and subacute sclerosing panencephalitis (SSPE). The procedures described were validated by confirming results obtained by other investigators using histology, immunocytochemistry, electron microscopy, and ISH. A number of frequently encountered problems of tissue preparation are addressed as well as techniques to reduce autoradiography exposure times. A multi-staged specific, sensitive, reliable, and valid procedure for detection of viral genomes, mRNA and proteins is approached. Formalin-fixed and paraffin-embedded (FFPE) brain material from six patients who died with PML and one patient who died from SSPE were studied using ISH with a tritium-labeled cloned JC virus DNA probe and a measles-cloned nucleocapsid (NC) gene cDNA probe, respectively. This report constitutes a methodological framework as well as a detailed neuropathological analysis of identified brain cell populations within which in situ hybridization was detected. In early PML lesions, swollen nuclei or oligodendrocytes were the predominant cells labeled, whereas older lesions revealed increased numbers of reactive and bizarre hypertrophic astrocytes hybridized at the outer periphery of the demyelinated lesions. The hybridization varied greatly in intensity in different cells. Intense hybridization was noted very rarely in microglial cells, including rod cells and rarely in venular pericytes, intravascular mononuclear cells, or in vascular endothelial cells. These results, considered together with previous findings, indicate that in PML the viral infection runs different courses in the various cells: in astrocytes the viral genome persists for a long time inducing pathological changes in some cells. In oligodendrocytes the infection rapidly lyses the cells. There was a good correlation between chromatic changes observable in routinely stained sections and virus presence. In addition, in situ hybridization using a measles-NP-cloned probe in white matter from FFPE SSPE brain is presented confirming earlier results in SSPE cryopreserved brain.

Serious neurological complications of measles--a continuing preventable problem.

Eight children who presented to two Sydney children's hospitals in 1984 with the neurological complications of measles infection are described. Six of these children have either died or have serious residual neurological abnormalities. Experience in the United States indicates that such complications of measles can be virtually eliminated by a programme of compulsory immunization of pre-school children.

Growth of defective subacute sclerosing panencephalitis viruses in human neural cells and their neurovirulence in mice.

A defective subacute sclerosing panencephalitis (SSPE) virus which had been passaged in human embryonic lung cells was transferred to cultures of three neural cell types: neuroblastoma, oligodendroglioma and glioblastoma. The growth characteristics of the virus in these cells were essentially similar to those in non-neural cells. On the other hand, a marked difference in neurovirulence was noticed for the virus grown in neural cells when examined by intracerebral inoculation into mice. The virus passaged in neuroblastoma and oligodendroglioma cells showed high neurovirulence, inducing an acute encephalitis, whereas the virus passaged in human embryonic lung cells and that in glioblastoma cells did not show neurovirulence. These results suggest that the virus recovered its neurovirulence after passage in certain human neural cells.

Viral infections of the nervous system.

Neurotropic viruses cause a number of important infectious syndromes including encephalitis, myelitis, meningitis, and radiculopathy. In this review, the biology of conventional and unconventional viruses is examined. The host immune response to viruses is discussed, and patterns of viral pathogenesis are explained. The clinical features, laboratory findings, management of important viral infections, such as herpes simplex encephalitis and epidemic encephalitis, are presented. Post-infection syndromes, such as the Guillain-Barré syndrome, and chronic viral infections, such as those causing progressive multifocal leukoencephalopathy and subacute sclerosing panencephalitis, are discussed. Current knowledge concerning the nature of unconventional virus-like agents of the spongiform encephalopathies, including kuru and Creutzfeldt-Jakob disease, is summarized. Finally, viral infections of immunocompromised patients and the possible role of viruses in the newly described acquired immunodeficiency syndrome (AIDS) are examined.