Subacute Sclerosing Panencephalitis Research Articles

A measles virus collective infectious unit that caused lethal human brain disease includes many locally restricted and few widespread copy-back defective genomes.

During virus replication in cultured cells, copy-back defective viral genomes (cbDVGs) can arise. CbDVGs are powerful inducers of innate immune responses in vitro, but their occurrence and impact on natural infections of human hosts remain poorly defined. We asked whether cbDVGs were generated in the brain of a patient who succumbed to subacute sclerosing panencephalitis (SSPE) about 20 years after acute measles virus (MeV) infection. Previous analyses of 13 brain specimens of this patient indicated that a collective infectious unit (CIU) drove lethal MeV spread. In this study, we identified 276 replication-competent cbDVG species, each present in over 100 copies in the brain. Six species were detected in multiple forebrain locations, implying that they travelled long-distance with the CIU. The cbDVG to full-length genomes ratio was often close to 1 (0.6-1.74). Most cbDVGs were 324-2,000 bases in length, corresponding to 2%-12% of the full-length genome; all are predicted to have complementary terminal sequences. If improperly encapsidated, these sequences have the potential to form double-stranded structures that can induce innate immune responses. To assess this, we examined the transcriptome of all brain specimens. Several interferon and inflammatory response genes were upregulated, but upregulation levels did not correlate with cbDVG levels in the specimens. Thus, the CIU that drove MeV pathogenesis in this brain includes, in addition to two complementary full-length genome populations, many locally restricted and few widespread cbDVG species. The widespread cbDVG species may have been positively selected but how they impacted pathogenesis remains to be determined.IMPORTANCECopy-back defective viral genomes (cbDVGs) can drive virus-host interactions. They can suppress virus replication directly, by competing with full-length genomes, or indirectly by stimulating antiviral immunity. In vitro, cbDVG can slow down infections and promote persistence, but there is limited documentation of their presence in human hosts or of their impact on disease. We had the unique opportunity to analyze the brain of a patient who succumbed to subacute sclerosing panencephalitis, a rare but lethal consequence of measles. We detected more than 270 distinct cbDVG species; most were restricted to one specimen, but several reached all lobes of the forebrain, suggesting positive selection. Our analyses provide the missing knowledge of the diversity of cbDVG in a natural infection of a human host. They also reveal that a collective infectious unit that caused lethal human brain disease includes few widespread cbDVG, in addition to two ubiquitous complementary full-length genome populations.

Indocyanine green angiography reveals choroidal hypoperfusion in subacute sclerosing panencephalitis (SSPE).

We report the choroidal findings on indocyanine green angiography (ICGA) in two cases of subacute sclerosing panencephalitis (SSPE). The two immunocompetent patients (31-year-old and 30-year-old Asian Indian males) presented with acute-onset rapidly progressing vision loss with findings of necrotizing retinitis involving the central macula. Both patients tested negative for serological evidence of herpes or varicella, and toxoplasma antibodies. The patients demonstrated high serum and cerebrospinal fluid titers of anti-measles antibody (and abnormal electroencephalogram in one patient) leading to the diagnosis of SSPE. ICGA of both patients revealed distinct "dark dots" which showed hypofluorescence in the early and late phases suggestive of choroidal involvement/hypoperfusion. Choroidal involvement in SSPE has not been evaluated before and must be considered in the pathological manifestations of the disease.

Central Nervous System Disorders of Marine Mammals: Models for Human Disease?

This article deals with Central Nervous System (CNS) disorders of marine mammals as putative neuropathology and neuropathogenesis models for their human and, to some extent, their animal "counterparts" in a dual "One Health" and "Translational Medicine" perspective. Within this challenging context, special emphasis is placed upon Alzheimer's disease (AD), provided that AD-like pathological changes have been reported in the brain tissue of stranded cetacean specimens belonging to different Odontocete species. Further examples of potential comparative pathology interest are represented by viral infections and, in particular, by "Subacute Sclerosing Panencephalitis" (SSPE), a rare neurologic sequela in patients infected with Measles virus (MeV). Indeed, Cetacean morbillivirus (CeMV)-infected striped dolphins (Stenella coeruleoalba) may also develop a "brain-only" form of CeMV infection, sharing neuropathological similarities with SSPE. Within this framework, the global threat of the A(H5N1) avian influenza virus is another major concern issue, with a severe meningoencephalitis occurring in affected pinnipeds and cetaceans, similarly to what is seen in human beings. Finally, the role of Brucella ceti-infected, neurobrucellosis-affected cetaceans as putative neuropathology and neuropathogenesis models for their human disease counterparts is also analyzed and discussed. Notwithstanding the above, much more work is needed before drawing the conclusion marine mammal CNS disorders mirror their human "analogues".

Subacute sclerosing panencephalitis with a fulminant course: Case series

ABSTRACT Subacute sclerosing panencephalitis (SSPE) is a life-threatening and delayed complication of measles. It may rarely follow a fulminant course, with rapid progression to a vegetative state. There have been case reports of this challenging and aggressive form of SSPE in previously immunised children. The cause of the rapid progression in many patients is unknown. However, it is postulated that genetically determined immune dysfunction can prevent cell-mediated immune clearance of the measles virus. This was a retrospective study of five patients who presented with clinical features and laboratory investigations suggestive of fulminant SSPE over the previous year. The diagnosis of SSPE was established using Radermecker’s complexes in electroencephalogram, encephalitis on brain magnetic resonance imaging and elevated titres of immunoglobulin (Ig) M and IgG measles antibodies in the serum and cerebrospinal fluid. Treatment included isoprinosine, intravenous Igs, sodium valproate, levetiracetam and clobazam. The outcome was dismal in all patients, with progression to a bedridden state despite timely intervention. In our series of five cases, the diagnosis of SSPE was often missed because the children were immunised and healthy before the onset of symptoms. However, after excluding other central nervous system viral infections, the clinical presentation and laboratory findings corroborated the fulminant course of SSPE. This article captures the presentation and outcomes of five patients and emphasises the importance of clinicians’ awareness of this condition.

A Rare Case of Subacute Sclerosing Panencephalitis Presenting as Generalized Seizure (P9-4.002)

A Rare Case of Subacute Sclerosing Panencephalitis Presenting as Generalized Seizure (P9-4.002)

Cardiac Rhythm Aberrations in Subacute Sclerosing Panencephalitis: Insights From Heart Rate Variability Analysis.

Subacute sclerosing panencephalitis (SSPE) is a fatal neurological disorder resulting from persistent measles virus infection within the brain. Although neurological manifestations have been well-documented, the impact of SSPE on cardiac autonomic function, assessed through heart rate variability (HRV), remains understudied. In this prospective single-center study conducted from January 2022 to March 2023 in Southern India, 30 consecutive SSPE patients and age- and sex-matched controls underwent electrocardiogram recordings for HRV analysis. Various HRV parameters were assessed, including time-domain metrics (SD of normal-to-normal intervals, root mean square of successive differences between normal heartbeats, percentage of successive normal interbeat intervals greater than 50 msec), SD1 and SD2 for Poincaré plot analysis, and frequency-domain metrics (low frequency %, high frequency %, low frequency:high frequency ratio). In the study, SSPE patients exhibited markedly reduced HRV. Specifically, SD of normal-to-normal intervals (P = 0.003), percentage of successive normal interbeat intervals greater than 50 msec (P = 0.03), and SD2 (P = 0.0016) were significantly lower compared with controls. Frequency-domain analysis did not reveal significant distinctions. Correlation analysis demonstrated a negative relationship between percentage of successive normal interbeat intervals greater than 50 msec and SSPE severity (r = -0.37, P = 0.042). Heart rate variability did not significantly differ between SSPE stages or with clinical variables. The interbeat interval range showed a narrower distribution in SSPE subjects. Our study highlights the clinical relevance of HRV analysis in SSPE and autonomic dysfunction throughout the disease course underscoring its importance in SSPE. This investigation provides valuable insights into cardiac autonomic dysfunction probably because of affliction of the central autonomic networks caused by the disease process and may be a contributing factor to mortality in SSPE.

A rare complication of measles infection presented with subacute sclerosing panencephalitis: Report of two cases in India

Rationale: Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder caused by persistent measles virus infection. SSPE predominantly affects children and adolescents. The symptoms usually develop 6-15 years after measles infection and ultimately leading to death in many cases. Patient concerns: Patient 1 presented with cognitive decline and myoclonus and the Patient 2 presented with diminution of vision with myoclonic jerks. Diagnosis: Based on the clinical features with a characteristic electroencephalogram pattern and the presence of a high titer of anti-measles IgG in serum and cerebrospinal fluid, these patients were diagnosed as SSPE. Interventions: Antiepileptics were started for controlling myoclonus along with supportive treatment. Outcomes: Both patients were discharged on antiepileptics and supportive care. Lessons: Whenever there are unusual clinical manifestations with unknown vaccination status, SSPE can be suspected and the cerebrospinal fluid should be examined for anti-measles antibodies. Our case study also highlights the importance of universal coverage of measles vaccination. To reduce the incidence of measles and associated deaths, it is important to maintain a high level of immunization coverage for the measles vaccine and to strengthen all the integral components of the national immunization program.

Atypical Presentation of Subacute Sclerosing Panencephalitis in a Child

Background: Subacute sclerosing panencephalitis (SSPE) is a rare complication of measles, which emerges long after the initial infection. The diagnosis of SSPE can be challenging, especially when initial presentation is atypical. Clinical Description: A 6-year-old boy, apparently healthy previously, presented with a sudden onset of generalized myoclonic jerks with intact cognitive and scholastic skills. Past history revealed that the child had measles infection at 7 months of age. Clinical examination, including memory and intellect assessment, was normal except for the generalized myoclonus. Management and Outcome: Diagnosis of SSPE was confirmed with positive antimeasles antibodies and characteristic pseudoperiodic pattern on electroencephalogram. The child was started on standard treatment as per the existing guidelines. However, the child showed marked deterioration over the next 4 weeks with loss of cognition and intellect, causing hopelessness and grief in the family, leading to their self-withdrawal from further treatment. Conclusion: This case report describes the importance of considering SSPE as a potential diagnosis in patients with myoclonic jerks but intact cognitive and intellectual function. Furthermore, the case portrays the progressive deterioration and profound emotional impact on the family of child with this disease.

TDP-43 pathology in subacute sclerosing panencephalitis.

Subacute sclerosing panencephalitis (SSPE) is a fatal, slowly progressive brain disorder caused by a mutated measles virus. Both subacute inflammatory and neurodegenerative mechanisms appear to play significant roles in the pathogenesis. TAR DNA-binding protein 43 (TDP-43) inclusions are a common co-pathology in several neurodegenerative disorders with diverse pathogenesis. In the present study, we examined brains of 16 autopsied SSPE patients for the presence of TDP-43 pathology and possible associations with tau pathology. Immunohistochemical staining identified TDP-43 inclusions in 31% of SSPE cases. TDP-43 pathology was widely distributed in the brains, most severely in the atrophied cerebral cortex (temporal and parietal), and most frequently as tangle- and thread-like neuronal cytoplasmic inclusions. It was associated with longer disease duration (>4 years) and tau pathology (all TDP-43-positive cases had tau-positive neurofibrillary tangles). This study demonstrates for the first time an association between TDP-43 pathology and SSPE. The co-occurrence of TDP-43 and tau aggregates and correlation with the disease duration suggest that both pathological proteins are involved in the neurodegenerative process induced by viral inflammation.

Neuroimaging Abnormalities in Patients with Subacute Sclerosing Panencephalitis : Prospective Follow-up Study.

This study aimed to assess the neuroimaging abnormalities and their progression in patients with Subacute sclerosing panencephalitis (SSPE) and identify clinical predictors of these imaging findings. This prospective observational study evaluated clinical and neuroimaging features in patients with SSPE. Patients were categorized using Dyken's criteria, Jabbour's staging system, and the definition of fulminant SSPE. They underwent comprehensive clinical assessments, cerebrospinal fluid examination, Electroencephalogram (EEG), and Magnetic Resonance Imaging (MRI) scans. Treatment involved intrathecal interferon‑α and antiepileptic medications. Functional disability was assessed using the modified Barthel index. Follow-ups were performed at 6 months, including reassessment of Modified Barthel Index (MBI) and Jabbour's staging and EEG and MRI scans. The mean age was 13.9 ± 6.7years, with males comprising 81.5% (44/54) of the cohort. Fulminant SSPE was noted in 33% (18/54) of cases. Disease duration before presentation varied significantly between fulminant and non-fulminant forms (p = 0.001). Neuroimaging abnormalities were more prevalent in JSIII stage patients, with diffuse cerebral atrophy being asignificant finding (p = 0.011). Basal ganglia involvement correlated with movement disorders. The 6‑month follow-up showed increased cerebral atrophy (p = 0.004). Increasing disease duration was an independent predictor of cerebral atrophy. An Intercomplex interval (ICI) of more than 10minutes correlated with normal neuroimaging, 10 patients died within the study period, 8 of whom had fulminant SSPE. Parieto-occipital White matter hyperintensity (WMH) is the most prevalent and sensitive neuroimaging finding for the diagnosis of SSPE. Despite interferon treatment, cerebral atrophy progressed in both aggressive and fulminant SSPE. Increasing disease duration is an independent predictor of cerebral atrophy.

Measles to Misfortune: A Case Report on Subacute Sclerosing Panencephalitis

Subacute sclerosing panencephalitis (SSPE) is a progressive neurological disorder of children or young adults caused by measles infection. An abnormal immune response to the virus is said to cause brain inflammation, which may last for years. Mortality rate of the disease is around 95%. In this case report, we present the case of a 15-year-old unimmunized boy from rural Assam who presented with progressive sudden jerky movements of his limbs for 2 months, along with difficulty in doing his daily activities and forgetfulness. Although he was initially admitted with a provisional diagnosis of seizure disorder and treated with tab sodium valproate and tab clobazam, his mother, revealed a history of measles infection at 7 years of age. His Electroencephalogram (EEG) reports and CSF IgG measles antibody findings were suggestive of SSPE. He was immediately started on Tab Isoprinosine at adequate doses, but he later succumbed to his illness within 3 months of the onset of symptoms. Immunization of children with the measles vaccine plays a significant role in averting this deadly condition.

Adult Onset of Subacute Sclerosing Section Panencephalitis- A Case Report

Subacute Sclerosing Panencephalitis (SSPE) is a rare, slowly progressive disorder that affects the entire nervous system. It primarily involves the cerebral cortex, subcortex and optic nerves. Caused by a mutated strain of the measles virus, the disease is mostly irreversible and devastating. It presents with gradually progressive cognitive impairment, extrapyramidal symptoms and sometimes seizures. Although commonly seen in unvaccinated children, SSPE of adult onset is uncommon. The disease is fatal and currently has no treatment. There have been many different presentations of this disorder, ranging from optic nerve involvement to gradual cognitive decline, but none have a good prognosis; ultimately, patients may become akinetic and mute. Here, the authors present an uncommon case of SSPE occurring at an older age (26-year-old male), with a rapid and atypical presentation resembling severe post-viral syndrome, which was later diagnosed as SSPE.

The history of the Japanese Society for Neuro-infectious Diseases: Foundation, objectives, and legacy.

The Japanese Research Group for Neuro-infectious Diseases was founded in August 1996, and by 2004 it had evolved into the Japanese Society for Neuro-infectious Diseases. The Society focuses on neuroinfectious conditions (e.g., encephalitis/encephalopathy, myelitis, and meningitis), providing a venue for academic presentations and exchanges. Clinical guidelines for major neurological infectious diseases are also published by the Society, in order to meet the social demands of each era. Although the threat of herpes simplex encephalitis has declined due to acyclovir's introduction, the frequency of encephalitis or peripheral neuropathy caused by varicella-zoster virus is increasing. In Japan, prion disease, human T-cell leukemia virus-1 (HTLV-1)-associated myelopathy (HAM), subacute sclerosing panencephalitis (SSPE), and progressive multifocal leukoencephalopathy (PML) are designated as intractable diseases. The incidence of prion disease is 1.8/1,000,000 individuals, with the sporadic type accounting for 80%. Prion disease is fatal, and effective medications are awaited. HAM's prevalence is ~3/100,000 individuals, with a male-to-female ratio of 1:2-3. HAM is common in western Japan, including Kyushu and Okinawa. The prevalence of PML is rising with the spread of both immunosuppressive therapy for transplantation and treatment for multiple sclerosis. From late 2019 through 2020, the world faced a global outbreak of coronavirus disease 2019 (COVID-19) due to virus mutations, and the threat of new mutations persists. Close attention should be paid to the emergence of new neurological infections that could arise from abnormal weather patterns and/or a decline in immune function due to aging.

Brain tropism acquisition: The spatial dynamics and evolution of a measles virus collective infectious unit that drove lethal subacute sclerosing panencephalitis.

It is increasingly appreciated that pathogens can spread as infectious units constituted by multiple, genetically diverse genomes, also called collective infectious units or genome collectives. However, genetic characterization of the spatial dynamics of collective infectious units in animal hosts is demanding, and it is rarely feasible in humans. Measles virus (MeV), whose spread in lymphatic tissues and airway epithelia relies on collective infectious units, can, in rare cases, cause subacute sclerosing panencephalitis (SSPE), a lethal human brain disease. In different SSPE cases, MeV acquisition of brain tropism has been attributed to mutations affecting either the fusion or the matrix protein, or both, but the overarching mechanism driving brain adaptation is not understood. Here we analyzed MeV RNA from several spatially distinct brain regions of an individual who succumbed to SSPE. Surprisingly, we identified two major MeV genome subpopulations present at variable frequencies in all 15 brain specimens examined. Both genome types accumulated mutations like those shown to favor receptor-independent cell-cell spread in other SSPE cases. Most infected cells carried both genome types, suggesting the possibility of genetic complementation. We cannot definitively chart the history of the spread of this virus in the brain, but several observations suggest that mutant genomes generated in the frontal cortex moved outwards as a collective and diversified. During diversification, mutations affecting the cytoplasmic tails of both viral envelope proteins emerged and fluctuated in frequency across genetic backgrounds, suggesting convergent and potentially frequency-dependent evolution for modulation of fusogenicity. We propose that a collective infectious unit drove MeV pathogenesis in this brain. Re-examination of published data suggests that similar processes may have occurred in other SSPE cases. Our studies provide a primer for analyses of the evolution of collective infectious units of other pathogens that cause lethal disease in humans.

Assessing Implicit and Explicit Polarizable Solvation Models for Nuclear-Electronic Orbital Systems: Quantum Proton Polarization and Solvation Energetics.

Accurate simulations of many chemical processes require the inclusion of both nuclear quantum effects and a solvent environment. The nuclear-electronic orbital (NEO) approach, which treats electrons and select nuclei quantum mechanically on the same level, combined with a polarizable continuum model (PCM) for the solvent environment, addresses this challenge in a computationally practical manner. In this work, the NEO-PCM approach is extended beyond the IEF-PCM (integral equation formalism PCM) and C-PCM (conductor PCM) approaches to the SS(V)PE (surface and simulation of volume polarization for electrostatics) and ddCOSMO (domain decomposed conductor-like screening model) approaches. IEF-PCM, SS(V)PE, C-PCM, and ddCOSMO all exhibit similar solvation energies as well as comparable nuclear polarization within the NEO framework. The calculations show that the nuclear density does not leak out of the molecular cavity because it is much more localized than the electronic density. Finally, the polarization of quantized protons is analyzed in both continuum solvent and explicit solvent environments described by the polarizable MB-pol model, illustrating the impact of specific hydrogen-bonding interactions captured only by explicit solvation. These calculations highlight the relationship among solvation formalism, nuclear polarization, and energetics.

Jaw Opening Myoclonus in Subacute Sclerosing Panencephalitis: A New Phenotypic Observation.

Jaw Opening Myoclonus in Subacute Sclerosing Panencephalitis: A New Phenotypic Observation.

Subacute sclerosing panencephalitis: current threat

The relevance of this problem is associated with a predicted increased incidence of subacute sclerosing panencephalitis, a steadily progressive and difficult to diagnose fatal brain disease. Subacute sclerosing panencephalitis develops after measles and it does not correlate with clinical type of an acute measles infection: it affects both persons with manifest measles and ones who have had an asymptomatic or abortive disease. WHO estimates the incidence of subacute sclerosing panencephalitis as 4–11 per 100,000 measles cases. The latency period from measles to the onset of subacute sclerosing panencephalitis is between 2.5 and 34 years. As a result of measles outbreaks in 2011–2014 and 2017–2019 an increase in the number of subacute sclerosing panencephalitis cases in Russia is expected soon. Diagnostic difficulties are caused by multiplicity of subacute sclerosing panencephalitis clinical manifestation and the absence of MRI changes in early stages. Thereby, it is important to exclude SSPE in patients with neurological symptoms. Screening tests for subacute sclerosing panencephalitis should be conducted in children with acute cognitive impairment, myoclonus, or a new onset of epileptic syndrome. The specific cure for subacute sclerosing panencephalitis has not been developed yet. Most treatments aim at reducing symptoms. Up to date, the only way to conquer this disease is routine measles vaccination.

Subacute sclerosing panencephalitis (SSPE): Late onset of measles complication - Case of IVIG treatment failure

Subacute sclerosing panencephalitis (SSPE) is characterized by gradual deterioration of cognitive motor and cognitive functions. SSPE more often occurs in individuals who had a history of measles viral infection. We present a case of 8 year old male child who was presented with generalized progressive weakness, recurrent falls to one side, multiple episodes of seizure, urinary incontinence. On liaison it was understood that he had a history of measles at the age of 3 years. Examination showed elevated serum measles antibody titer, electro-encephalogram (EEG) analysis revealed stereotyped polymorphic discharge seen periodically, suggestive of SSPE. He was treated with IVIG and other symptomatic treatment. However he had recurrent episodes of vomiting after IVIG administration, Ribavirin administration caused multiple oral lesions. Upon discharge he was given Syr. Valproate, Oral Steroid (Prednisolone) tapering therapy, THP 2 mg BD, PPI and Laxatives. Parents were advised to maintain RT feed of 150 mL, once in 3 hours. After 1 week, he succumbed to his illness at his residence.

Seizures as Presenting Feature of Subacute Sclerosing Panencephalitis: a Systematic Review of Case Reports and Case Series

Seizures as Presenting Feature of Subacute Sclerosing Panencephalitis: a Systematic Review of Case Reports and Case Series

Atypical early presentation of subacute sclerosing panencephalitis in children: A case series

Subacute sclerosing panencephalitis (SSPE) is a progressive neurodegenerative disease of children and young adults that may occur as an uncommon complication 7–10 years after a measles infection. In measles – endemic countries like India, the incidence of this fatal disease is high and more number of new cases are detected in recent times. In this case series, we have presented three cases of SSPE between the 4 and 5 years age group, presented with abnormal movement and neuroregression and diagnosed by characteristic clinical features, raised anti-measles antibody titer in CSF, and typical Electroencephalography findings. All of them had a history of measles infection before the vaccination and very short latency period between measles infection and the development of SSPE. They were discharged in stable condition after the treatment with oral Isoprinosine and intrathecal Interferon alfa 2b. Early age of presentation, short latency period, and apparently good response to treatment for the time being prompted us to present these cases.