Behavioral variant of frontotemporal dementia in carriers of biallelic TREM2 variants: cases study.

INTRODUCTION: First reports associated mutations in triggering receptors expressed on myeloid cells 2 (TREM2) with autosomal recessive Nasu-Hakola disease characterized by painful bone cysts and progressive presenile dementia with psychotic symptoms; however, recent TREM2 biallelic rare variants are suggested to be causative also for the behavioral variant of frontotemporal dementia (bvFTD) without bone involvement. MATERIAL AND METHODS: Clinical data of three unrelated bvFTD patients carrying TREM2 biallelic variants were evaluated. All patients underwent neurological, psychiatric, and cognitive evaluation and neuroimaging. A full neuropsychological assessment was performed in two cases. RESULTS: Two patients carried compound heterozygous TREM2 variants, p.R62C and p.T66M, and one carried the homozygous p.D87N variant. Based on all obtained clinical and neuroimaging data, a behavioral variant of frontotemporal dementia was diagnosed in all cases. Their clinical manifestation was typical with neuropsychiatric and cognitive features, without bone abnormalities. CONCLUSIONS: Despite all three subjects partially resembling clinical manifestations of Nasu-Hakola disease with TREM2 mutations, we reveal some distinct features, including age of onset, neuroimaging findings, or disease course.

Homozygous TREM2 c.549del; p.(Leu184Serfs*5) variant causing Nasu-Hakola disease in three siblings in a consanguineous Iraqi family: Case report and review of literature.

BACKGROUND: The Triggering Receptor Expressed on Myeloid Cells 2 protein (TREM2) plays a crucial role in various biological processes, including osteoclast differentiation, and disease-associated microglia (DAM) activation to regulate neuroinflammation, and phagocytosis in the brain. Genetic variations in TREM2 are implicated in neurodegenerative disorders, such as Nasu-hakola disease (NHD), characterized by bone lesions, neuropsychiatric disorders, and early-onset dementia. METHODS: We studied 3 siblings with suspected NHD. Whole-exome sequencing was conducted on the proband to identify the possible genetic cause(s) and by Sanger sequencing to validate the identified variants in the two other affected siblings, a healthy sister, and the parents. RESULTS: We identified a novel homozygous deletion (c.549del; p.(Leu184Serfs*5)) in TREM2. Our literature review reveals 16 TREM2 mutations causing early-onset dementia and bone lesions. CONCLUSION: These findings, alongside previous research, elucidate the clinical spectrum of TREM2-related diseases, aiding accurate diagnosis and patient care. This knowledge is vital for understanding TREM2-dependent DAM and its involvement in the pathogenesis of neurodevelopmental disorders which can help to develop targeted therapies and improve outcomes for TREM2-affected individuals.

Movement Disorders in Patients with Subacute Sclerosing Panencephalitis: A Systematic Review.

BACKGROUND: Subacute sclerosing panencephalitis (SSPE) is a complication of measles, occurring after a latency of 4-10 years. It continues to occur in developing countries although resurgence is being reported from developed countries. Characteristic features include progressive neuropsychiatric issues, myoclonus, seizures, movement disorders and visual impairment. Electroencephalography (EEG) typically shows periodic generalized discharges, and elevated CSF anti-measles antibodies are diagnostic. Movement disorders are being increasingly recognized as part of the clinical spectrum, and range from hyperkinetic (chorea, dystonia, tremor, tics) to hypokinetic (parkinsonism) disorders and ataxia. OBJECTIVES: This article aims to comprehensively review the spectrum of movement disorders associated with SSPE. METHODS: A literature search was conducted in PubMed and EMBASE databases in December 2023 and articles were identified for review. RESULTS: Movement disorders reported in SSPE included hyperkinetic (chorea, dystonia, tremor and tics), hypokinetic (parkinsonism), ataxia and extraocular movement disorders. Myoclonus, a core clinical feature, was the most frequent "abnormal movement." Movement disorders were observed in all clinical stages, and could also be a presenting feature, even sans myoclonus. Hyperkinetic movement disorders were more common than hypokinetic movement disorders. An evolution of movement disorders was observed, with ataxia, chorea and dystonia occurring earlier, and parkinsonism later in the disease. Neuroradiological correlates of movement disorders remained unclear. CONCLUSION: A wide spectrum of movement disorders was observed throughout the clinical stages of SSPE. Most data were derived from case reports and small case series. Multicentric longitudinal studies are required to better delineate the spectrum and evolution of movement disorders in SSPE.

Subacute sclerosing panencephalitis presenting as severe depression in an adult.

Subacute sclerosing panencephalitis (SSPE) is a fatal disorder that occurs as a rare complication of childhood measles. Symptoms typically manifest between the ages of 5 and 15. While the incidence of SSPE is declining globally, it is still prevalent in regions where measles remains common and vaccination rates are low due to poverty and lack of health education. Diagnosing SSPE can be challenging, particularly when patients exhibit unusual symptoms. A thorough clinical evaluation, including vaccination history, physical examination, electroencephalogram (EEG) and Cerebrospinal fluid (CSF) analysis, can help in making a diagnosis. We present the case of a young woman in her early 20s who initially experienced depressive symptoms, followed by myoclonus, dementia and visual impairment. The patient was ultimately diagnosed with SSPE based on characteristic EEG findings, neuroimaging results, CSF analysis and elevated serum measles antibody levels.

Hyperkinetic and Hypokinetic Movement Disorders in SSPE: A Systematic Review of Case Reports and Case Series.

Background: Subacute Sclerosing Panencephalitis (SSPE) typically presents with periodic myoclonus; however, a spectrum of movement disorders including dystonia, chorea, tremor, and parkinsonism have also been described. This review aims to evaluate the array of movement disorders in SSPE, correlating them with neuroimaging findings, disease stages, and patient outcomes. Methods: A comprehensive review of published case reports and case series was conducted on patients with SSPE exhibiting movement disorders other than periodic myoclonus. PRISMA guidelines were followed, and the protocol was registered with PROSPERO (2023 CRD42023434650). A comprehensive search of multiple databases yielded 37 reports detailing 39 patients. Dyken's criteria were used for SSPE diagnosis, and the International Movement Disorders Society definitions were applied to categorize movement disorders. Results: The majority of patients were male, with an average age of 13.8 years. Approximately, 80% lacked a reliable vaccination history, and 39% had prior measles infections. Dystonia was the most common movement disorder (49%), followed by parkinsonism and choreoathetosis. Rapid disease progression was noted in 64% of cases, with a disease duration of ≤6 months in 72%. Neuroimaging showed T2/FLAIR MR hyperintensities, primarily periventricular, with 26% affecting the basal ganglia/thalamus. Brain biopsies revealed inflammatory and neurodegenerative changes. Over half of the patients (56%) reached an akinetic mute state or died. Conclusion: SSPE is associated with diverse movement disorders, predominantly hyperkinetic. The prevalence of dystonia suggests basal ganglia dysfunction.

Clinical features, pathogenesis, pathology, neuroimaging, clinical course and outcome of measles inclusion-body encephalitis: a systematic review of published case reports and case series.

Measles inclusion-body encephalitis (MIBE) is rare, with insights largely from case studies. We systematically analyzed subacute Sclerosing Panencephalitis (SSPE) cases in immunocompromised patients, identifying distinctive clinical and neuroimaging features. These findings could facilitate MIBE diagnosis without the need for brain biopsies. Our systematic review on MIBE and HIV-related SSPE adhered to PRISMA guidelines and was registered with PROSPERO. We searched multiple databases and followed a detailed inclusion process with independent reviews and quality assessment. Data on patient demographics, clinical features, and outcomes were compiled. A review of 39 studies on 49 MIBE patients and 8 reports on HIV-positive SSPE patients was conducted. Acute lymphoblastic leukemia, HIV, organ transplants, and malignancies were common precursors to MIBE. Perinatal HIV was prevalent among SSPE cases. Seizures were the primary symptom in MIBE, often drug-resistant and progressing to status epilepticus or epilepsia partialis continua, whereas periodic myoclonus was universal in SSPE. Neuroimaging showed distinct patterns for each group, and histopathology confirmed measles virus presence in 39% of MIBE cases. MIBE patients typically progressed to coma and death. In conclusion, MIBE and SSPE in HIV-infected patients present with distinct clinical pictures but identical brain pathological abnormalities.

Movement disorders associated with pediatric encephalitis.

New onset movement disorders are a common clinical problem in pediatric neurology and can be infectious, inflammatory, metabolic, or functional in origin. Encephalitis is one of the more important causes of new onset movement disorders, and movement disorders are a common feature (~25%) of all encephalitis. However, all encephalitides are not the same, and movement disorders are a key diagnostic feature that can help the clinician identify the etiology of the encephalitis, and therefore appropriate treatment is required. Movement disorders are a characteristic feature of autoimmune encephalitis such as anti-NMDAR encephalitis, herpes simplex virus encephalitis-induced autoimmune encephalitis, and basal ganglia encephalitis. Other rarer autoantibody-associated encephalitis syndromes with movement disorder associations include encephalitis associated with glycine receptor, DPPX, and neurexin-3 alpha autoantibodies. In addition, movement disorders can accompany acute disseminated encephalomyelitis with and without myelin oligodendrocyte glycoprotein antibodies. Extremely important infectious encephalitides that have characteristic movement disorder associations include Japanese encephalitis, dengue fever, West Nile virus, subacute sclerosing panencephalitis (SSPE), and SARS-CoV-2 (COVID-19). This chapter discusses how specific movement disorder phenomenology can aid clinician diagnostic suspicion, such as stereotypy, perseveration, and catatonia in anti-NMDAR encephalitis, dystonia-Parkinsonism in basal ganglia encephalitis, and myoclonus in SSPE. In addition, the chapter discusses how the age of the patients can influence the movement disorder phenomenology, such as in anti-NMDAR encephalitis where chorea is typical in young children, even though catatonia and akinesia is more common in adolescents and adults.

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.

Pediatric Subacute Sclerosing Panencephalitis: A Narrative Review on Measles and the Future of Vaccination.

Subacute sclerosing panencephalitis is a rare complication due to persistent measles infection, characterized by cognitive and motor deterioration. Because subacute sclerosing panencephalitis is considered a potentially fatal complication of measles and usually presents in young populations, particularly those with measles infection under the age of 2 years, new approaches to implement vaccination programs must be devised to help avoid the worsening of patient outcome. Until the disease is eradicated globally, children in all regions of the world remain at risk of measles infection and its respective complications, and therefore, the vaccine is considered the optimal preventative measure. The legacy of measles virus goes beyond the immediate complications. Our study, therefore, aims to provide a comprehensive review on the updated insights into subacute sclerosing panencephalitis as a complication, as well as the extent and future considerations pertaining to vaccination programs in the pediatric population.

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

OBJECTIVE: 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. METHODS: 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 interferon­α 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. RESULTS: The mean age was 13.9 ± 6.7 years, 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 JS III stage patients, with diffuse cerebral atrophy being a significant finding (p = 0.011). Basal ganglia involvement correlated with movement disorders. The 6­month 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 10 minutes correlated with normal neuroimaging, 10 patients died within the study period, 8 of whom had fulminant SSPE. CONCLUSION: 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.

Multimodal Imaging for Subacute Sclerosing Panencephalitis: Including Anterior Segment.

Subacute sclerosing panencephalitis (SSPE) is an irreversible and progressive neurological disorder. A 20-year-old woman with SSPE presented with a decline in visual acuity. Anterior segment was evaluated with slit lamp and in vivo confocal microscopy, revealing the presence of dendritiform keratic precipitates and +2 cells in the anterior chamber. In fundus examination, white-yellowish lesions involving the macula and periphery were observed, which gradually progressed into atrophy over time. Optical coherence tomography (OCT) imaging showed progression to atrophy of moth-eaten shaped cavities including all retinal layers due to necrotizing retinitis. OCT angiography (OCTA) further revealed reduced vessel densities and flow void areas. Notably, to the best of our knowledge, this is the first case documenting anterior segment findings in SSPE in detail. [Ophthalmic Surg Lasers Imaging Retina 2024;55:344-348.].

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.

Ongoing Measles in the Developed and Developing World.

Measles is a vaccine-preventable illness. Nevertheless, in recent years, measles is still endemic and epidemic in both the developed world and the developing world. The public perception of measles in the past was that it was not a big deal. However, measles is associated with a number of complications which can be places in three categories which are: acute(diarrhea, otitis media, pneumonia, encephalitis, seizures, and death) and delayed-subacute sclerosing panencephalitis (SSPE) and post-measles immune amnesia. Contrary to the beliefs of the anti-vaccine lobby, measles is bad. In acute measles, the death rate is 1-3 per 1000 and the risk of encephalitis is 1 per 1000. Relatively recent investigations indicate that SSPE is considerably more common than previously believed. The worldwide contribution of post-measles immune amnesia to morbidity and mortality is likely to be huge. In exposure situations, two doses of measles vaccine will prevent 99% of cases. Presently in the United States, the first dose is given at 12 through 15 months of age. The second dose is most often administered at 4 through 6 years of age. In my opinion, the second dose of measles vaccine should be given 4-6 weeks after the first dose rather than at 4-6 years of age. Children who don't have antibody to measles should not travel to risk areas.

The spectrum of psychiatric manifestations in subacute sclerosing panencephalitis: A systematic review of published case reports and case series.

Data related to psychiatric manifestations in subacute sclerosing panencephalitis (SSPE) is currently available only in the form of isolated case reports. In this systematic review, we evaluated the spectrum of psychiatric manifestations and their impact on the course and outcome of SSPE. Data were obtained from 4 databases (PubMed, Embase, Scopus, and Google Scholar), with the most recent search conducted on March 27, 2023. The PRISMA guidelines were followed, and the PROSPERO registration number for the protocol is CRD42023408227. SSPE was diagnosed using Dyken's criteria. Extracted data were recorded in an Excel spreadsheet. To evaluate the quality of the data, the Joanna Briggs Institute Critical Appraisal tool was employed. Our search resulted in 30 published reports of 32 patients. The mean age was 17.9 years. Schizophrenia, catatonia, and poorly characterized psychotic illnesses were the 3 most common psychiatric presentations that were seen in 63% (20/32) of cases. Catatonia was seen in 4 patients. Affective disorders, mania, and depression were reported among 22% (7/32) cases. In approximately 81% (26/32) cases, the course of SSPE was acute fulminant. Treatment with antipsychotic drugs had poor or no response. Out of 17 patients, who received antipsychotic drugs, 6 patients noted severe extrapyramidal adverse effects. SSPE often masquerades as a psychiatric disorder. Unresponsive psychiatric symptoms, early extrapyramidal signs, and progressive encephalopathy indicate SSPE.

Patients With Subacute Sclerosing Panencephalitis in Japan: A 2022 Nationwide Survey.

BACKGROUND: In Japan, the incidence of subacute sclerosing panencephalitis (SSPE) has reduced; however, the medical conditions and factors associated with disease progression remain unclear. METHODS: A nationwide survey of SSPE was conducted using a questionnaire in 2022. We conducted a descriptive analysis of the patients with SSPE in 2022 and Cox proportional hazards analyses for disease progression. We compared the patients with SSPE with those in a 2007 survey. RESULTS: A total of 37 surviving patients with SSPE were enrolled [median age: 32 years (range: 16-52 years)]. No new cases have been identified since 2017 in the survey. Jabbour stage IV was the most common stage (66.7%). The hazard ratios (95% confidence intervals) of male sex and age at the time of measles infection (years) were 2.56 (1.13-5.76) and 0.57 (0.34-0.93), respectively. Compared with those in 2007, the proportion of patients in hospitals decreased from 13.7% to 2.7%, whereas that of patients in nursing facilities increased from 17.6% to 29.7%. The proportions of patients prescribed inosine pranobex, interferon and ribavirin at the time of the survey decreased from 96.1% to 79.4%, 74.8% to 14.3% and 25.3% to 0%, respectively. The proportions of patients with gastrostomy, tracheostomy and ventilator use increased from 5.9% to 69.7%, 23.3% to 60.0% and 10.8% to 32.4%, respectively. CONCLUSIONS: Decreased measles cases in Japan reduced new SSPE cases. However, surviving patients in 2022 had advanced disease stages and needed medical care. Male sex and early measles infection were significantly associated with disease progression.

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.

Measles Virus and the Central Nervous System: An Update.

MEASLES VIRUS AND ASSOCIATED CENTRAL NERVOUS SYSTEM: Sequelae Renee Buchanan, Daniel J. Bonthius Seminars in Pediatric Neurology Volume 19, Issue 3, September 2012, Pages 107-114 Worldwide, measles remains one of the most deadly vaccine-preventable diseases. In the United States, enrollment in the public schools requires that each child receives 2 doses of measles-containing vaccine before entry, essentially eliminating this once endemic disease. Recent outbreaks of measles in the United States have been associated with importation of measles virus from other countries and subsequent transmission to intentionally undervaccinated children. The central nervous system complications of measles can occur within days or years of acute infection and are often severe. These include primary measles encephalitis, acute postinfectious measles encephalomyelitis, measles inclusion body encephalitis, and subacute sclerosing panencephalitis. These measles associated central nervous system diseases differ in their pathogenesis and pathologic effects. However, all involve complex brain-virus-immune system interactions, and all can lead to severe and permanent brain injury. Despite better understanding of the clinical presentations and pathogenesis of these illnesses, effective treatments remain elusive.