Persistent Measles Virus Infection Research Articles

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.

Adult onset subacute sclerosing panencephalitis presenting with acute ischemic stroke

Subacute sclerosing panencephalitis (SSPE) is a progressive, invariably fatal inflammatory disease of the brain, owing to persistent measles virus infection. It generally presents in childhood or adolescence, and usual presentation is with progressive cognitive decline and myoclonic jerks. An adult male, with an uneventful past medical history, presented with a rapidly progressive dementia and generalised myoclonus. During the course of his admission, he developed right sided spastic hemiparesis with evidence of subcortical infarct on brain imaging with focal narrowing of left middle cerebral artery. Subsequently diagnosed as SSPE, he was managed conservatively, without improvement. Intrathecal interferon could not be given owing to lack of consent from the patient’s relatives. Histopathological confirmation could not be done for the same reason. A medium to small vessel intracranial vasculitis, secondary to measles virus infiltration was a proposed explanation of the vascular event. Persistence of measles virus in the brain may be a potential risk factor for intracranial vasculitis and strokes.

A CASE REPORT OF PAEDIATRIC SUBACUTE SCLEROSING PANENCEPHALITIS

Subacute sclerosing panencephalitis (SSPE) is a devastating disease of the central nervous system (CNS) caused by persistent measles virus infection. The diagnosis of SSPE is based on characteristic clinical and EEG findings and demonstration of elevated antibody titres against measles in cerebrospinal fluid. Subacute sclerosing panencephalitis can have atypical clinical features at the onset.We report a 10 year old boy presented with convulsions and visual disturbances. The disease progressed with behavioural and cognitive disturbances and periodic high amplitude generalised complexes on EEG, and elevated titers of measles antibodies in cerebrospinal fluid leading to the final diagnosis of subacute sclerosing panencephalitis.

Spectrum of movement disorders among children with subacute sclerosing panencephalitis (SSPE): A cross-sectional study

Subacute sclerosing panencephalitis (SSPE) is a rare neurodegenerative disorder due to persistent mutant measles virus infection, affecting children and young adults. Although movement disorders are known to occur in SSPE, their spectrum is poorly described in literature. We aimed to assess spectrum of movement disorders associated with pediatric SSPE.

Articles of Significant Interest In This Issue

Subacute sclerosing panencephalitis (SSPE), a fatal complication of measles, is caused by persistent measles virus (MeV) infection in the brain. Shirogane et al. (e00528-21) show that host proteins, the cell adhesion molecule 1 (CADM1) and CADM2, are involved in MeV spread in neurons. Remarkably, these molecules interact in cis with the MeV attachment protein on the same cell membrane, which in turn triggers the fusion protein-mediated membrane fusion. This novel molecular mechanism, receptor-mimicking cis-acting fusion triggering, enables MeV to spread transsynaptically between neurons, thereby causing SSPE.

Clinical and Neuroimaging Changes of Subacute Sclerosing Panencephalitis – Experience 30 Cases in Tertiary Care Center in Bangladesh

Background: Subacute sclersing panencephalitis (SSPE) is a very rare progressive, fatal neurodegenerative disease of the control nervous system of childhood and early adolescence. It is a slow virus disease caused by persistent defective measles virus infection of the brain
 Objective: To see the clinical andneuro-imaging findings in children with Subacute sclerosing panencephalitis.
 Methods: This retrospective study was conducted at Bangabandhu Sheikh Mujib Medical University (BSMMU), Dhaka, a tertiary care premier Postgraduate Medical Institution in Bangladesh. Thirty (30) Subacute sclerosing panencephalitis (SSPE) children were evaluated at paediatric neurology ward during the period January 2010 to December 2017. Diagnosis was based on typical clinical characteristic features, the presence of periodic discharges on EEG, demonstration of raised antibody titer against measles in the plasma and cerebrospinal fluid Detected by ELISA in all patients.
 Results: Total number of studied children were 30. Mean age was 10.2±3.1 year and Male female ratio was 5:1. Most of the patient arrived from poor socio-economic (83.33%) background of rural area (66.67%) of Bangladesh. Among them 46.67% had history of measles infection during early childhood. Progressive deterioration of school performance (50%), gait disturbance (70%), myoclonus (83%) dysarthria (43%) and Ocular manifestations like optic atrophy & papilledema (83.33%) were the main presenting feature of our studied children. All of the patients (100%) showed positive measles specific antibody IgG in CSF and On electroencephalographic findings showed periodic burst suppression in 90.90% cases. Most of the children (56.6%) were in stage II category and other 3.3%, 33.3%,6.6%, were stage I, stage III, stage IV category respectively. Neuroimaging study showed abnormalities in 45.83% cases included periventricular white matter hyper intense signal changes, cortical atrophy and ischaemic change.
 Conclusion: In our study most of the SSPE patient were in stage II.About half of the patient had history of measles infection during early childhood. Neuroimaging abnormalities found in about half of the cases and majority cases were in stage II. Common neuroimaging abnormalities were periventricular white matter hyper intense signal changes and cortical atrophy.

CADM1 and CADM2 Trigger Neuropathogenic Measles Virus-Mediated Membrane Fusion by Acting in cis.

Measles virus (MeV), an enveloped RNA virus in the family Paramyxoviridae, is still an important cause of childhood morbidity and mortality worldwide. MeV usually causes acute febrile illness with skin rash, but in rare cases persists in the brain, causing a progressive neurological disorder, subacute sclerosing panencephalitis (SSPE). The disease is fatal, and no effective therapy is currently available. Although transsynaptic cell-to-cell transmission is thought to account for MeV propagation in the brain, neurons do not express the known receptors for MeV. Recent studies have shown that hyperfusogenic changes in the MeV fusion (F) protein play a key role in MeV propagation in the brain. However, how such mutant viruses spread in neurons remains unexplained. Here, we show that cell adhesion molecule 1 (CADM1; also known as IGSF4A, Necl-2, and SynCAM1) and CADM2 (also known as IGSF4D, Necl-3, SynCAM2) are host factors that enable MeV to cause membrane fusion in cells lacking the known receptors and to spread between neurons. During enveloped virus entry, a cellular receptor generally interacts in trans with the attachment protein on the envelope. However, CADM1 and CADM2 interact in cis with the MeV attachment protein on the same cell membrane, causing the fusion protein triggering and membrane fusion. Knockdown of CADM1 and CADM2 inhibits syncytium formation and virus transmission between neurons that are both mediated by hyperfusogenic F proteins. Thus, our results unravel the molecular mechanism (receptor-mimicking cis-acting fusion triggering) by which MeV spreads transsynaptically between neurons, thereby causing SSPE. IMPORTANCE Measles virus (MeV), an enveloped RNA virus, is the causative agent of measles, which is still an important cause of childhood morbidity and mortality worldwide. Persistent MeV infection in the brain causes a fatal progressive neurological disorder, subacute sclerosing panencephalitis (SSPE), several years after acute infection. However, how MeV spreads in neurons, which are mainly affected in SSPE, remains largely unknown. In this study, we demonstrate that cell adhesion molecule 1 (CADM1) and CADM2 are host factors enabling MeV spread between neurons. During enveloped virus entry, a cellular receptor generally interacts in trans with the attachment protein on the viral membrane (envelope). Remarkably, CADM1 and CADM2 interact in cis with the MeV attachment protein on the same membrane, triggering the fusion protein and causing membrane fusion, as viral receptors usually do in trans. Careful screening may lead to more examples of such "receptor-mimicking cis-acting fusion triggering" in other viruses.

Atypical subacute sclerosing panencephalitis presenting in a toddler with a short latency period: Evolving epidemiological trend

Subacute sclerosing panencephalitis (SSPE) is a slowly progressive degeneration of the central nervous system (CNS) caused by a persistent defective measles virus infection. We report the case of a 2.5-year-old girl who presented with complaints of sudden onset frequent falls while walking, myoclonic jerks, and loss of speech. The electroencephalogram showed generalized slowing with irregular activity and cerebral magnetic imaging revealed T2 hyperintensities in the periventricular region in the parietal and occipital lobes. SSPE was considered and the diagnosis was confirmed with the identification of measles antibodies in cerebrospinal fluid. Our findings show that SSPE should be in mind in the differential diagnosis of meningoencephalitis even when a short latency period with measles infection.

Diagnostic Approaches and Management of Subacute Sclerosing Panencephalitis in Children

Abstract: Subacute Sclerosing Panencephalitis (SSPE) is a progressive neurodegenerative disease that attacks the central nervous system, especially in the population of children and early adolescents, due to persistent measles virus infection. The incidence of SSPE is quite rare, and data shows that in developing countries it is still quite high compared to developed countries. Diagnosis is based on clinical, supporting examinations such as EEG, as well as increased antibodies against measles virus in serum and cerebrospinal fluid. Symptoms can include changes in behavior, myoclonus, memory problems, and persistent pyramidal or extrapyramidal movements. Management to date has not provided satisfactory results and is individualized. Most SSPE patients experience a progressive and gradual course, leading to death within 1-3 years. The challenge of SSPE in children is the approach to diagnosis and management. Until now, the approach to treating SSPE in children is still based on the pathophysiological mechanisms from several existing research studies. That why therapy guidelines for children with SSPE are still varied. This paper aims to discuss the topic of SSPE in children with a major focus on diagnostic and therapeutic approaches based on the latest scientific evidence. Keywords: Subacute Sclerosing Panencephalitis (SSPE), children, diagnosis, therapy

Otosclerosis and Measles: Do Measles Have a Role in Otosclerosis? A Review Article

Otosclerosis is a common cause of conductive hearing loss which is an autoimmune inflammatory disorder related to abnormal bone remodeling of the human otic capsule that has complex etiopathogenesis attributed to genetics, autoimmunity, viral infection, inflammation, hormonal factor, environmental factor, and disturbed bone metabolism. It has a prevalence of 0.3%-0.4% in Caucasians, which makes up 5-9% of all hearing loss and 18-22% of all conductive hearing loss. This review article aims to study the postulated role of sustained measles virus infection in the etiopathogenesis of otosclerosis, among others. A PubMed search of the related topic identified 97,990 articles. After we applied the inclusion and exclusion criteria, it was determined that 52 articles were relevant, which included 38 observational studies, 13 review articles, and a systematic review. Among them, 33 observational studies, 13 review articles and a systematic review spotted a positive association between persistent measles virus infection and otosclerosis. On the contrary, five observational studies reported no evidence of the association. The majority of the current literature supported the presence of the measles virus component in the otosclerotic stapes samples and its role in the etiopathogenesis of otosclerosis. Measles virus infection may have the amplitude to initiate a pathological process, which in the presence of other factors like autoimmunity and genes plays a significant role in causing otosclerosis. However, other studies have failed to show the presence of the measles virus component in otosclerotic stapes. So, more studies are needed to probe the role of persistent measles virus infection in the etiopathogenesis of otosclerosis.

Triphasic Waves in EEG, an Atypical Finding in a Subacute Sclerosing Panencephalitis (SSPE) Adult Patient

Subacute sclerosing panencephalitis (SSPE) is a known rare cause of progressive myoclonic encephalitis of childhood and young adults due to a persistent measles virus infection. It is usually characterised by myoclonic jerks, cognitive decline , typical EEG findings that clinches its diagnosis and further supported by a high CSF and serum measles antibody titre.

Subacute Sclerosing Panencephalitis


 Subacute sclerosing panencephalitis (SSPE) is chronic progressive encephalitis of childhood and young adoloscent due to persistent measles virus infection. This case illustrates a 14 year old girl presented with short history of intellectual decline, abnormal behavior, myoclonus and altered consciousness with suggestive neuroimaging mimicking metachromatic leucodystrophy. Subsequently she was diagnosed to be a case of Subacute sclerosing panencephalitis (SSPE) on the basis of Electroencephalography (EEG) and Cerebrospinal fluid(CSF) measles antibody titer.
 J Bangladesh Coll Phys Surg 2019; 37(4): 205-208

A long-term subacute sclerosing panencephalitis survivor treated with intraventricular interferon-alpha for 13 years

Subacute sclerosing panencephalitis (SSPE) is a rare, progressive, and fatal central nervous system disorder resulting from persistent measles virus infection. Long-term data are scarce, with a maximum follow-up period of 10 years. Interferon-alpha (IFN-α) is a protein that exerts its antiviral activity via enhancement of cellular immune response and is reported to be an effective drug for the treatment of SSPE. However, there is currently no consensus regarding the optimal duration of IFN-α therapy. Here, we present a case report of a patient with SSPE treated with long-term intraventricular IFN-α therapy, which facilitated clinical improvement and neurological stabilization without causing serious adverse effects. To the best of our knowledge, this is one of the longest follow-up studies investigating a patient with SSPE receiving intraventricular INF-α treatment. Further studies are necessary to validate the benefits and safety of long-term intraventricular IFN-α treatment in patients with SSPE.

IL28B, IL29 and micro-RNA 548 in subacute sclerosing panencephalitis as a rare disease

Subacute sclerosing panencephalitis (SSPE) is a progressive neurodegenerative disease which affects children and young adults, caused by a persistent infection of defective measles virus. IFN-λs (IL-28A, IL-28B and IL-29) are a group of cytokines mediating antiviral responses. It has been shown that IL-29 levels are significantly higher in infected cells with defective measles virus. IL-29 expression is thought to be regulated at post-transcriptional level and miRNA-548 family targets the 3′UTR of the IFNL1 gene. Impaired immune system has an important role as well as viral factors in SSPE. The aim of our study investigates whether IL-28B, IL-29 levels and gene polymorphisms contribute to the damaged immune response leading to the development of SSPE. Also possible association of miR-548 family with IL-29 and SSPE is explored.Frequencies of rs12979860, rs8099917, rs30461, serum levels of IL-28B, IL-29 and expression levels of miR-548b, miR-548c, miR-548i are determined at 64 SSPE patients and 68 healthy controls. Serum IL-29 levels are statistically significant higher in SSPE patients. Allele frequencies of rs8099917 are statistically significant higher in SSPE patients and resulted G allele is found to increase 2.183-fold risk of SSPE. The expression levels of miR-548b-5p, miR-548c-5p and miR-548i are found to be statistically significant higher in SSPE patients.Dramatically increased level of IL-29 seen in patient group indicates that the elevated miR-548 expression is compensatory result of the over-activated immune system response. Further studies referred to IL28, IL29 and related miRNA's will be enlightened the pathogenesis of SSPE.

Measles Virus Persistent Infection of Human Induced Pluripotent Stem Cells.

In this study, we found that the measles virus (MV) can infect human-induced pluripotent stem cells (hiPSCs). Wild-type MV strains generally use human signaling lymphocyte activation molecule (SLAM; CD150) as a cellular receptor, while vaccine strains such as the Edmonston strain can use both CD150 and CD46 as receptors. It is not yet known how early in the embryonal differentiation stages these receptors are expressed. We established two hiPSCs (BGU-iPSCs and EMF-iPSCs) which express CD46 and CD150. Both cell types can be infected by MV to form persistent, noncytopathic cell lines that release infectious MV particles. Following MV persistent infection, BGU-iPSCs and EMF-iPSCs remain pluripotent and can differentiate in vitro into the three germ layers. This includes cells expressing the neuronal differentiation markers: NF68 and miRNA-124. Since the MV does not integrate into the cell's genome, it can be utilized as a vehicle to systematically introduce genes into iPSC, to dissect and to define factors regulating lineage differentiation.

MiRNA-124 is a link between measles virus persistent infection and cell division of human neuroblastoma cells.

Measles virus (MV) infects a variety of lymphoid and non-lymphoid peripheral organs. However, in rare cases, the virus can persistently infect cells within the central nervous system. Although some of the factors that allow MV to persist are known, the contribution of host cell-encoded microRNAs (miRNA) have not been described. MiRNAs are a class of noncoding RNAs transcribed from genomes of all multicellular organisms and some viruses, which regulate gene expression in a sequence-specific manner. We have studied the contribution of host cell-encoded miRNAs to the establishment of MV persistent infection in human neuroblastoma cells. Persistent MV infection was accompanied by differences in the expression profile and levels of several host cell-encoded microRNAs as compared to uninfected cells. MV persistence infection of a human neuroblastoma cell line (UKF-NB-MV), exhibit high miRNA-124 expression, and reduced expression of cyclin dependent kinase 6 (CDK6), a known target of miRNA-124, resulting in slower cell division but not cell death. By contrast, acute MV infection of UKF-NB cells did not result in increased miRNA-124 levels or CDK6 reduction. Ectopic overexpression of miRNA-124 affected cell viability only in UKF-NB-MV cells, causing cell death; implying that miRNA-124 over expression can sensitize cells to death only in the presence of MV persistent infection. To determine if miRNA-124 directly contributes to the establishment of MV persistence, UKF-NB cells overexpressing miRNA-124 were acutely infected, resulting in establishment of persistently infected colonies. We propose that miRNA-124 triggers a CDK6-dependent decrease in cell proliferation, which facilitates the establishment of MV persistence in neuroblastoma cells. To our knowledge, this is the first report to describe the role of a specific miRNA in MV persistence.

Adult Onset Subacute Sclerosing Panencephalitis: A case report

Subacute sclerosing panencephalitis (SSPE) is a chronic encephalitis of childhood and young adolescence due to persistent measles virus infection of the central nervous system (CNS). In majority of cases, onset occurs between 5-10 years of age. SSPE generally occurs 5-10 years after measles virus infection1. The diagnosis of SSPE is based on characteristic clinical and electroencephalogram (EEG) findings, increase measles antibody titer in cerebrospinal fluid (CSF) and serum. As onset of SSPE in adults is rare and may have atypical feature it requires high index of suspicion for early and accurate diagnosis. Herein, we report a case of SSPE in a male of 26 years with recurrent episodes of myoclonic jerks. Journal of National Institute of Neurosciences Bangladesh, 2016;2(1): 40-42

A Novel Peptide Derived from the Fusion Protein Heptad Repeat Inhibits Replication of Subacute Sclerosing Panencephalitis Virus In Vitro and In Vivo.

Subacute sclerosing panencephalitis (SSPE) is a persistent, progressive, and fatal degenerative disease resulting from persistent measles virus (MV) infection of the central nervous system. Most drugs used to treat SSPE have been reported to have limited effects. Therefore, novel therapeutic strategies are urgently required. The SSPE virus, a variant MV strain, differs virologically from wild-type MV strain. One characteristic of the SSPE virus is its defective production of cell-free virus, which leaves cell-to-cell infection as the major mechanism of viral dissemination. The fusion protein plays an essential role in this cell-to-cell spread. It contains two critical heptad repeat regions that form a six-helix bundle in the trimer similar to most viral fusion proteins. In the case of human immunodeficiency virus type-1 (HIV-1), a synthetic peptide derived from the heptad repeat region of the fusion protein enfuvirtide inhibits viral replication and is clinically approved as an anti-HIV-1 agent. The heptad repeat regions of HIV-1 are structurally and functionally similar to those of the MV fusion protein. We therefore designed novel peptides derived from the fusion protein heptad repeat region of the MV and examined their effects on the measles and SSPE virus replication in vitro and in vivo. Some of these synthetic novel peptides demonstrated high antiviral activity against both the measles (Edmonston strain) and SSPE (Yamagata-1 strain) viruses at nanomolar concentrations with no cytotoxicity in vitro. In particular, intracranial administration of one of the synthetic peptides increased the survival rate from 0% to 67% in an SSPE virus-infected nude mouse model.

Identification of target proteins involved in cochlear otosclerosis.

Investigation of differential protein expression will provide clues to pathophysiology in otosclerosis. Otosclerosis is a bone remodeling disorder limited to the endochondral layer of the otic capsule within the temporal bone. Some authors have suggested an inflammatory etiology for otosclerosis resulting from persistent measles virus infection involving the otic capsule. Despite numerous genetic studies, implication of candidate genes in the otosclerotic process remains elusive. We employed liquid chromatography-mass spectrometry (LC-MS) analysis on formalin-fixed celloidin-embedded temporal bone tissues for postmortem investigation of otosclerosis. Proteomic analysis was performed using human temporal bones from a patient with severe otosclerosis and a control temporal bone. Sections were dissected under microscopy to remove otosclerotic lesions and normal otic capsule for proteomic analysis. Tandem 2D chromatography mass spectrometry was employed. Data analysis and peptide matching to FASTA human databases was done using SEQUEST and proteome discoverer software. TGFβ1 was identified in otosclerosis but not in the normal control temporal bone specimen. Aside from TGFβ1, many proteins and predicted cDNA-encoded proteins were observed, with implications in cell death and/or proliferation pathways, suggesting a possible role in otosclerotic bone remodeling. Immunostaining using TGFβ1 monoclonal revealed marked staining of the spongiotic otosclerotic lesions. Mechanisms involved in cochlear extension of otosclerosis are still unclear, but the implication of TGFβ1 is supported by the present proteomic data and immunostaining results. The established role of TGFβ1 in the chondrogenesis process supports the theory of a reaction targeting the globulae interossei within the otic capsule.