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Abstract

Subacute sclerosing panencephalitis (SSPE), an uncommon disease usually affecting children and adolescents, is caused by persistent measles infection that progresses to chronic infection with fatal outcome. The debut of this disease in adults is rare, with a small number of cases in the medical literature. This article presents the clinical, radiologic and post-mortem neuropathologic findings in 2 new cases of women with SSPE (1 of them during pregnancy), which showed very atypical clinical characteristics, presentation and evolution. The influence of pregnancy on the course of the disease was unfavorable, in keeping with earlier reports. Our patients showed a very prolonged biphasal clinical course, with a period of disease-free remission that lasted several years. Histological study disclosed features of inflammatory disease associated with others of a neurodegenerative nature, such as the formation of neurofibrillary tangles, which would relate SSPE with other tauopathies.
... The diagnosis is based on the raised titers of anti-measles antibodies in CSF (2). Although SSPE has usual clinical properties in the childhood, adult-onset SSPE is rare and may have atypical course (3)(4)(5)(6)(7)(8). ...
... It has been known that spontaneous remission is possible in childhood-onset SSPE cases, however, it is rare in adult-onset SSPE cases. Although around 100 cases of adult onset SSPE cases have been published to date, only a few of them have been reported having spontaneous remission in the disease course (3,5,7,8). ...
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We report a 27 years old man who was admitted to our hospital with progressive dementia that had begun two years ago. In his past medical history, his family reported a transient period of frequent falling and drop attacks of the head without any change of conscious, started when he was at age 18 and continued over three years; then he had a symptom-free period between the ages of 21-25 years. He had neither myoclonus nor periodic sharp and slow-wave discharges on electroencephalography (EEG) during the second phase of the disease that we saw him at age 27. Cerebrospinal fluid investigation disclosed high anti-measles IgG antibodies titer (1/640) and the patient was diagnosed with subacute sclerosing panencephalitis (SSPE). To our knowledge, this is the first case who had biphasic course without typical EEG findings of SSPE in the later phase of the disease.
... Presence of tau may be because of co-existing other known tauopathy, as a part of "mixed proteinopathy" or be just because of old age. Similarly, tau pathology is also seen in post encephalitic parkinsonism (172), Niemann-Pick type C disease (173) subacute sclerosing panencephalitis (SSPE) (174) and in prion disease like Gerstmann-Straussler-Scheinker disease (GSS) (175) although the clinico-pathological significance is still unknown. ...
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The spectrum of tauopathy encompasses heterogenous group of neurodegenerative disorders characterized by neural or glial deposition of pathological protein tau. Clinically they can present as cognitive syndromes, movement disorders, motor neuron disease, or mixed. The heterogeneity in clinical presentation, genetic background, and underlying pathology make it difficult to classify and clinically approach tauopathy. In the literature, tauopathies are thus mostly highlighted from pathological perspective. From clinical standpoint, cognitive syndromes are often been focussed while reviewing tauopathies. However, the spectrum of tauopathy has also evolved significantly in the domain of movement disorders and has transgressed beyond the domain of primary tauopathies. Secondary tauopathies from neuroinflammation or autoimmune insults and some other “novel” tauopathies are increasingly being reported in the current literature, while some of them are geographically isolated. Because of the overlapping clinical phenotypes, it often becomes difficult for the clinician to diagnose them clinically and have to wait for the pathological confirmation by autopsy. However, each of these tauopathies has some clinical and radiological signatures those can help in clinical diagnosis and targeted genetic testing. In this review, we have exposed the heterogeneity of tauopathy from a movement disorder perspective and have provided a clinical approach to diagnose them ante mortem before confirmatory autopsy. Additionally, phenotypic variability of these disorders (chameleons) and the look-alikes (mimics) have been discussed with potential clinical pointers for each of them. The review provides a framework within which new and as yet undiscovered entities can be classified in the future.
... Age-related epigenetic changes in the MAPT gene (Coupland et al. 2014), such as DNA methylation of the MAPT promoter, could drive increase in gene expression in older individuals and therefore increase risk of these two diseases. Further, there are tauopathies with known environmental causes such as chronic traumatic encephalopathy associated with physical injury to the head (Buckland et al. 2019), and Subacute Sclerosing Panencephalitis associated with infection by the measles virus (Ortega-Aznar et al. 2003). ...
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Causative genes involved in familial forms of dementias, including Alzheimer's disease (AD), frontotemporal lobar degeneration (FTLD) and dementia with Lewy bodies (DLB), as well as amyotrophic lateral sclerosis and prion diseases where dementia is present as a significant clinical feature, are associated with distinct proteinopathies. This review summarizes the relationship between known genetic determinants of these dementia syndromes and variations in key neuropathological proteins in terms of three types of heterogeneity: (i) Locus Heterogeneity, whereby mutations in different genes cause a similar proteinopathy, as exemplified by mutations in APP, PSEN1 and PSEN2 leading to AD neuropathology; (ii) Allelic Heterogeneity, whereby different mutations in the same gene lead to different proteinopathies or neuropathological severity, as exemplified by different mutations in MAPT and PRNP giving rise to protein species that differ in their biochemistry and affected cell types; and (iii) Phenotypic Heterogeneity, where identical gene mutations lead to different proteinopathies, as exemplified by LRRK2 p.G2019S being associated with variable Lewy body presence and alternative AD neuropathology or FTLD-tau. Of note, the perceived homogeneity in histologic phenotypes may arise from laboratory-specific assessment protocols which can differ in the panel of proteins screened. Finally, the understanding of the complex relationship between genotype and phenotype in dementia families is highly relevant in terms of therapeutic strategies which range from targeting specific genes, to a broader strategy of targeting a downstream, common biochemical problem that leads to the histopathology.
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Subacute sclerosing panencephalitis is a late complication of measles infection and develops usually 6 to 15 years after the primary measles infection. Fulminant subacute sclerosing panencephalitis is an infrequently encountered form wherein the disease rapidly progresses to death. A six-year old male child presented with fever, abnormal movements of the left side of body followed by weakness of the left side of the body, and involuntary abnormal movements of right upper and lower limbs. On examination, he was drowsy and was unable to communicate. He had right-sided hemiballismus. He also had left-sided hemiparesis and the left plantar reflex was extensor. Cerebrospinal fluid examination revealed elevated protein and cells. In the serum and cerebrospinal fluid, anti-measles IgG antibodies were found to be positive. No other viral marker was noted in the cerebrospinal fluid. Magnetic resonance imaging of the brain showed extensive damage to the right temporal, parietal, and to a lesser extent, the frontal region as well as subcortical structures of these regions. Electroencephalography revealed generalized slowing of waves. Over a period of the next 3 days, the intensity and frequency of choreiform movements markedly reduced and the patient developed periodic generalized myoclonus, which was predominantly present on the right side. The patient succumbed to his illness and died after one month. Fulminant subacute sclerosing panencephalitis may have unusual clinical manifestations such as hemiballismus. In fulminant subacute sclerosing panencephalitis, neuroimaging may show extensive cortical damage.
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IntroductionSubacute sclerosing panencephalitis (SSPE) is a rare inflammatory and neurodegenerative disease caused by persistent brain infection with the measles virus (Singer et al. 1997; Gagnon and Bouchard 2003). SSPE is characterized by behavioral changes and mental deterioration, followed by myoclonic jerks, corticospinal signs, rigidity, frequently evolving to akinetic mutism. Death ensues in 1 to 3 years (Gutierrez et al. 2010; Garg 2008).Diagnosis is established by the characteristic clinical picture, intrathecal anti-measles antibody production, typical electroencephalographic, and brain histopathologic findings (Garg 2008; Eroglu et al. 2008). Neuropathology is characterized by parenchymal inflammatory infiltrates, demyelination, and neuronal, olygodendrocytic, and astrocytic viral inclusions, neuronal degeneration, and astrogliosis (Garg 2008).SSPE primarily affects children. Adult-onset SSPE is rare and often presents with atypical features (Fabian et al. 2010). We report t ...
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A 31-year-old man presented with Balint's syndrome. Radiology studies suggested an inflammatory demyelinating process within the occipital and parietal lobes. A cystic sellar/suprasellar mass was also found. Neuroimaging 2.5 years later showed progression of the lesions and growth of the tumor. Based on elevated antimeasles antibody titers in the cerebrospinal fluid subacute sclerosing panencephalitis (SSPE) was diagnosed. After 4 years of disease the patient died in a decerebrate state with tetraparesis. Neuropathological examination showed brain atrophy with discoloration and irregular induration of the white matter. The sellar tumor was a craniopharyngioma. Microscopically a chronic and active panencephalitis was revealed with intranuclear inclusions. Ultrastructural examination confirmed SSPE by demonstrating measles virus nucleocapsids within the inclusions. SSPE is a rare progressive neurological disorder caused by persistent defective measles virus infection and is usually seen in children and young adults. This disease has been eradicated in many countries by obligatory immunization. This case demonstrates, however, that SSPE should still be considered in the neurological and neuropathological differential diagnoses even in adult patients. Furthermore this is a first reported case of SSPE coexisting with a brain tumor (craniopharyngioma).
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The incidence of subacute sclerosing panencephalitis may be rising. This report describes three patients identified in New York City with atypical features including age of onset, prolonged prodrome, and lack of specific electroencephalographic changes. The diagnosis was confirmed with the identification of measles antibodies in the cerebrospinal fluid. Awareness of the possibility that the clinical presentation of subacute sclerosing panencephalitis may be changing may increase its timely diagnosis.
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We present a very rare case of adult onset subacute sclerosing panencephalitis (SSPE), and explain the characteristic sequential clinico-radiological findings. The patient, a twenty three-year-old man, had noticed unsteadiness in walking about two months previously. Although inosine pranobex and intrathecal interferon were administered, symptoms worsened insidiously and he became bedridden after four months. The levels of serum and CSF anti-measles IgG antibodies have not changed. Initially, supratentorial cortical atrophy was observed, especially of the left temporal lobe, but there were no other MRI signal alterations at the time. After three months, the supratentorial cortices produced low-signal intensities in T1-weighted images and in T2-weighted MRI, the cortical margin was very unclear and white matter signal intensities had become higher. Furthermore, cortices became thinner and ventricular size increased, especially for the lateral and third ventricles. SPECT examinations showed a marked reduction in cerebral blood flow and the perfusion deficits observed seemed to be closely correlated with the abnormal MRI signal patterns. Pathological examinations of biopsy samples revealed infiltration of inflammatory cells around the small vessels. As for immunohistochemical findings, CD68 positive cells were frequently observed, and this result implied the activation of microglia. Further studies are necessary to elucidate the pathogenic mechanisms of SSPE.
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In the realm of dementia, it is astonishing to note that neurofibrillary tangles (NFT) are microscopically identical in a childhood illness (SSPE) and in a dementia of late adult life (Alzheimer’s disease). The words “Alzheimer-type” NFT in peer reviewed scientific articles written by acknowledged experts underscore the striking similarities in “tangles” in two different diseases. Subacute Sclerosing Panencephalitis (SSPE) is caused by infection with atypical measles virus. Alzheimer’s disease has no known cause.
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We report a 25-year-old female who developed clinical and electroencephalographic (EEG) features of subacute sclerosing panencephalitis (SSPE) at the age of 17 years. After almost 17 months of progressive neurological deterioration to a level where she was bedridden and incapable of self-care (Risk and Haddad stage 3a), she experienced a substantial spontaneous clinical and EEG remission (stage 4c) which she has maintained for the last 8 years. The measles antibody titer in the cerebrospinal fluid (CSF), however, progressively increased during follow-up. There are only very few patients with well documented diagnosis of SSPE who have maintained such a prolonged remission. The age at onset of SSPE of > or = 12 years, disappearance of periodic complexes and a tendency for normalization of the background activity in the EEG, and a progressive increase in the measles antibody titer in the CSF appears to predict a favourable outcome of SSPE.
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A new case of subacute sclerosing panencephalitis with onset in adult life is reported. Clinical picture was characterized by a maculopathy, followed two years after by behavioural disturbances, psychomotor impairment, pyramidal signs and left-side myelonic jerks synchronously with the typical periodic R-complex in the EEG. CT-scan and MRI showed a wide demyelinative lesion in the right temporo-occipital area of the brain. Elevated antibody titers to measles virus in serum and CSF were present. Death occurred within 6 months while in coma. The neuropathologic findings confirmed the diagnosis of SSPE revealing widespread inflammatory lesions in the grey and white matter areas of demyelinization more evident in the right temporo-occipital regions and several Cowdry type A inclusions in glial cells and neurons.
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The supposed first adult patient with subacute sclerosing panencephalitis related to measles virus is described. Serum and cerebrospinal fluid measles antibody studies, immunofluorescence, and measles virus isolation confirmed the relationship of measles to the pathological findings. The adult patients reported in the literature are reviewed.
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Both neurons and oligodendroglia are preferentially infected in subacute sclerosing panencephalitis (SSPE). Massive argyrophilic and tau-positive glial fibrillary tangles (GFT) were found in oligodendroglia in two autopsy cases of SSPE with neurofibrillary tangles (NFT). GFT shared common phosphorylated tau-epitopes with NFT, but were negative for ubiquitin. Electron microscopically, GFT consisted of compact bundles of irregularly woven tubules. Thus, GFT in SSPE differed from NFT showing regular constriction of tubules and from GFT in some other cytoskeletal disorders in which GFT reportedly consisted of straight tubules.
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Neurofibrillary tangle formation, a cardinal characteristic of Alzheimer's disease, is also a feature of several other neurodegenerative disorders, including subacute sclerosing panencephalitis (SSPE). In the present study the association of measles virus genome with neurofibrillary tangle formation has been studied in five cases of SSPE, using in situ hybridization (measles genome) and immunocytochemistry (tau, ubiquitin and beta/A4 amyloid). In two cases with duration of disease less than one year, neurofibrillary tangle formation was not observed. However, in those cases in which the disease was of several years duration, numerous tau- and ubiquitin-positive neurofibrillary tangles were demonstrated. In the two cases of longest duration, double-labelling techniques demonstrated the frequent association of neurofibrillary tangle formation with neuronal measles virus genome positivity. Immunocytochemistry for beta/A4 amyloid failed to demonstrate amyloid in any of the five cases. These findings support the hypothesis that neurofibrillary tangle formation can occur independently of amyloid formation and that this mechanism may operate in both Alzheimer's disease and in virally-induced disease.
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A total of 72 EEGs from 57 patients with SSPE were studied. The EEG studies in SSPE revealed periodic high amplitude complexes in all except one. Besides periodic complexes, we found several atypical EEG findings including frontal rhythmic delta activity in intervals between periodic complexes, electrodecremental periods following EEG complexes, diffuse sharp waves and sharp-and-slow-wave complexes over frontal regions, and focal abnormalities, such as sharp wave and sharp and slow wave foci, which have been rarely reported previously. We also described a new finding characterized by high amplitude generalized rhythmic sharp wave activity following periodic complexes in one patient.
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Lack of major histocompatibility class I antigens on neurons has been implicated as a possible mechanism for viral persistence in the brain since these antigens are required for cytotoxic T-lymphocyte recognition of infected cells. In subacute sclerosing panencephalitis (SSPE), measles virus (MV) persists in neurons, resulting in a fatal chronic infection. MHC class I mRNA expression was examined in formalin-fixed brain tissue from 6 SSPE patients by in situ hybridization. In addition MHC class I protein expression in MV-infected neurons was examined in experimental Subacute Measles Encephalitis (SME) by double immunohistochemistry. MHC class I mRNA expression was found to be upregulated in SSPE tissues studied, and in 5 out of 6 cases the expression was definitively seen on neurons. The percentage of neurons expressing MHC class I mRNA ranged between 20 to 84% in infected areas. There was no correlation between the degree of infection and expression of MHC class I molecules on neurons. Importantly, the number of neurons co-expressing MHC class I and MV antigens was markedly low, varying between 2 to 8%. Similar results were obtained in SME where 20 to 30% of the neurons expressed MHC class I but <8% co-expressed MHC class I and MV antigens. Perivascular infiltrating cells in the infected regions in SME expressed IFNgamma immunoreactivity. The results suggest that MV may not be directly involved in the induction of MHC class I on neurons and that cytokines such as IFNgamma may play an important role. Furthermore, the paucity of neurons co-expressing MHC class I and MV antigens in SSPE and SME suggests that such cells are either rapidly cleared by cytotoxic T lymphocytes (CTL), or, alternatively, lack of co-expression of MHC class I on MV infected neurons favors MV persistence in these cells by escaping CTL recognition.
Article
We have studied the relationship between measles virus and the accumulation of abnormally phosphorylated tau (PHF-tau) in nine cases of subacute sclerosing panencephalitis (SSPE). By assessing the presence of viral intranuclear inclusions and neurofibrillary tangles (NFT) in each case, we found no correlation between presence and amount of measles virus and the numbers of neurons containing PHF-tau. Immunohistochemical double labeling in a case with long duration of disease and severe histopathologic change revealed no strict colocalization of measles virus antigen and PHF-tau throughout different brain regions. In areas containing both antigens, most neurons carrying measles virus did not have a tangle and vice versa, eventhough some colocalization beyond that expected by chance was observed in specific cortical areas. These results indicate that, although secondary to viral infection, NFT formation in SSPE is not restricted to cells carrying viral antigen. Conversely, measles virus infected cells do not necessarily accumulate PHF-tau. This lack of colocalization at the cellular level, throughout different brain areas and among different cases suggests that the formation of NFT in SSPE is not directly induced by the infectious agent. The formation of NFT in this disease appears to be elicited through a specific type of tissue damage and, thus, to be an epiphenomenon. This pathogenetic detail may be of interest for our understanding of the role of neurofibrillary degeneration in the pathogenesis of other more frequent neurodegenerative diseases with cytoskeletal pathology.