Measles Inclusion Body Encephalitis Research Articles

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.

Vaccine Associated Measles Complicated by Suspected Measles Inclusion Body Encephalitis in a Pediatric Leukemia Patient and Stem Cell Transplant Recipient: A Focus on Clinical Evolution and Management.

Immunocompromised individuals are at increased risk for severe disease and complications from viral infections, highlighting the importance of vaccination. However, in extremely rare situations, vaccine associated viral infections can be associated with disseminated disease and complications in immunocompromised hosts. Herein, we present a case of a 1-year-old child diagnosed with acute myeloid leukemia less than 2 weeks after receiving live viral vaccines who developed acute vaccine-strain measles virus disease, later complicated by central nervous system involvement following hematopoietic stem cell transplantation. A brain biopsy specimen was positive for vaccine-strain measles virus detected by reverse transcriptase polymerase chain reaction. She was treated with intravenous ribavirin, inosine pranobex, intrathecal interferon-alpha and donor lymphocyte infusion following measles-mumps-rubella vaccine boost. Despite these measures, the patient suffered neurologic decline and dysautonomia, expiring after compassionate extubation. Management and ideal risk mitigation strategies are discussed within the context of existing literature for this rare complication.

Measles Virus and the Central Nervous System: An Update

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.

Uncommon histopathological features of cytomegalovirus encephalitis and measles inclusion body encephalitis on autopsy in two patients with primary immunodeficiency.

To describe the neuropathological findings in two patients with primary immunodeficiency who had fatal viral encephalitis. Severe combined immunodeficiency (SCID) was confirmed in case 1 by genetic testing, while case 2 had features suggestive of combined immunodeficiency; however, whole exome sequencing showed no pathogenic variants. Autopsies were performed in both cases after an informed consent. A detailed sampling of the brain including extracranial organs was conducted. Immunohistochemistry and electron microscopy was also performed to confirm the presence of viruses. Besides evidence of cystic encephalomalacia observed in both cases, the brain in case 1 revealed cytomegalovirus (CMV) ventriculoencephalitis accompanied by an exuberant gemistocytic response in the entire white matter. Nuclei of gemistocytes were loaded with several CMV nuclear inclusions, which was confirmed by immunohistochemistry. Case 2 demonstrated features of measles inclusion body encephalitis with several viral inclusions within neurons and astrocytes. Rare giant cells were also seen. Measles virus was confirmed on immunohistochemistry and electron microscopy. Plausibly, there was paucity of microglial nodules in both cases. Superadded bacterial pneumonia with diffuse alveolar damage was also seen in both cases. These cases add to the spectrum of unusual histological features of viral encephalitis seen in patients with underlying primary immunodeficiency diseases.

Measles-Associated CNS Complications: A Review

AbstractMeasles virus infection is a common infectious disease of childhood, incidence of which is still high in developing countries. Other than the morbidity associated with the acute systemic infection, the measles virus can cause serious fatal neural complications. It can either enter the brain leading to acute encephalitis like primary measles encephalitis and acute post infectious measles encephalomyelitis or it may persist in brain cells (as mutated virus) leading to long-term neurodegenerative diseases like measles inclusion body encephalitis and subacute sclerosing pan encephalitis. The patho-clinical features, treatment, and the outcomes of these complications are different and should be identified in time for early diagnosis and management.

ОСОБЛИВОСТІ КЛІНІЧНОГО ПЕРЕБІГУ ПІСЛЯКОРОВИХ ЕНЦЕФАЛІТІВ У ІМУНОСУПРЕСОВАНИХ ОСІБ

Primary acute measles encephalitis and acute postmeasles encephalitis are the most common neurological complications of measles. It is important to detect encephalitis, which develops a month or more after the manifestations of measles infection. These encephalitis are rare and occur mainly in people with immunodefi ciency. Multiple sclerosis is a chronic disease of the central nervous system for the treatment of which diseasemodifying therapy is used, namely monoclonal antibodies, that can lead to immunosuppression and immunodefi ciency. Nowadays, there is insuffi cient information about the course of postcortical encephalitis in patients with multiple sclerosis who are taking immunosuppressive drugs. The article presents data on the clinical classifi cation, diagnosis and treatment of measles encephalitis. A clinical case of measles inclusion body encephalitis in a thirty-threeyear-old patient with multiple sclerosis on the background of annual intake of monoclonal antibodies is presented. She also had viral-bacterial pneumonia and developed disseminated intravascular coagulation in the brain and lungs. These complications of measles infection led to the death of the person after a month and a half of intensive care. Thus, patients with multiple sclerosis who are taking drugs with immunosuppressive eff ects are among the risk group for measles inclusion body encephalitis. Measles inclusion body encephalitis in such patients can be severe, which complicates timely diagnosis, proper treatment and leads to death.

Fitness selection of hyperfusogenic measles virus F proteins associated with neuropathogenic phenotypes

Measles virus (MeV) is resurgent and caused >200,000 deaths in 2019. MeV infection can establish a chronic latent infection of the brain that can recrudesce months to years after recovery from the primary infection. Recrudescent MeV leads to fatal subacute sclerosing panencephalitis (SSPE) or measles inclusion body encephalitis (MIBE) as the virus spreads across multiple brain regions. Most clinical isolates of SSPE/MIBE strains show mutations in the fusion (F) gene that result in a hyperfusogenic phenotype in vitro and allow for efficient spread in primary human neurons. Wild-type MeV receptor-binding protein is indispensable for manifesting these mutant F phenotypes, even though neurons lack canonical MeV receptors (CD150/SLAMF1 or nectin-4). How such hyperfusogenic F mutants are selected and whether they confer a fitness advantage for efficient neuronal spread is unresolved. To better understand the fitness landscape that allows for the selection of such hyperfusogenic F mutants, we conducted a screen of ≥3.1 × 105 MeV-F point mutants in their genomic context. We rescued and amplified our genomic MeV-F mutant libraries in BSR-T7 cells under conditions in which MeV-F-T461I (a known SSPE mutant), but not wild-type MeV, can spread. We recovered known SSPE mutants but also characterized at least 15 hyperfusogenic F mutations with an SSPE phenotype. Structural mapping of these mutants onto the prefusion MeV-F trimer confirm and extend our understanding of the F regulatory domains in MeV-F. Our list of hyperfusogenic F mutants is a valuable resource for future studies into MeV neuropathogenesis and the regulation of paramyxovirus F.

Fatal Measles Inclusion-Body Encephalitis in Adult with Untreated AIDS, France.

We report a fatal case of measles inclusion-body encephalitis occurring in a woman from Romania with AIDS. After an extensive but unsuccessful diagnostic evaluation, a pan-pathogen shotgun metagenomic approach revealed a measles virus infection. We identified no mutations previously associated with neurovirulence.

A Major Regional Measles Outbreak: Description of Hospitalized Cases in 2017–2018 at Bordeaux University Hospital, France

BackgroundMeasles remains endemic worldwide, despite current vaccination recommendations, and is associated with high morbidity and mortality rates. We describe all cases hospitalized in Bordeaux University Hospital (BUH), the starting point of a national significant measles outbreak in 2017–2018.MethodsIn this retrospective study, we included all patients hospitalized in BUH from September 1, 2017, to May 31, 2018. Inclusion criteria were age >1 year, clinical symptoms, and biological confirmation by measles immunoglobulin M or measles reverse transcription polymerase chain reaction positivity.ResultsWe included 171 patients. Most patients were immunocompetent; only 19% had preexisting medical histories. Most patients had rash and fever (97%), but some cases were atypical and difficult to diagnose. Köplik’s spots were reported in 66 cases (38%). The most frequent biological markers were blood inflammation markers (96%) and lymphopenia (81%). Unexpectedly, we found hyponatremia (<135 mmol/L) in 40% of patients. We identified peaks in January and March, corresponding to 76 D8 genotypes and 28 B3 strains. The following complications were reported in 65 patients (38%): pneumonia, hepatitis, and keratitis; 10 had neurological symptoms. One patient had Guillain-Barré syndrome, and a young immunocompromised patient died from measles inclusion-body encephalitis. Most of the patients (80%) had not been correctly vaccinated, including 28 health care workers. Some patients (n = 43, 25%) developed measles despite having plasma IgG. These included 12 possible vaccination failure cases.ConclusionsDuring the BUH outbreak, measles was often complicated and sometimes atypical. Vaccination coverage was dramatically insufficient. We also describe vaccination failure cases that must be better investigated.

Primary Measles Encephalitis.

This scenario was developed to educate emergency medicine residents on the diagnosis and management of primary measles encephalitis. Measles is a highly infectious ribonucleic acid (RNA) virus whose prevalence in the United States has continued to increase despite being declared eliminated in 2000,1 and larger outbreaks have been noted among those who elect not to vaccinate.2 The recommended live-attenuated measles, mumps, and rubella (MMR) vaccine schedule for pediatrics includes one routine dose at 12-15 months of age and a second dose between 4-6 years of age with at least 28 days in between dose administration.1-2 Measles-associated complications include otitis media, pneumonia, laryngotracheobronchitis, diarrhea, and corneal ulceration.2 Patients may also develop central nervous system complications, including primary measles encephalitis, acute post-infectious measles encephalomyelitis, measles inclusion body encephalitis, and subacute sclerosing panencephalitis. Primary measles encephalitis and measles inclusion body encephalitis involve an active ongoing measles infection.3 We will focus on primary measles encephalitis for this case scenario. One out of every 1000 measles patients will develop primary measles encephalitis,1 with onset typically occurring within seven days of the measles prodrome. Treatment is largely supportive. Mortality from primary measles encephalitis is 10%-15%, with an additional 25% developing permanent neurodevelopmental sequalae.3 It is critical to maintain a high index of suspicion for this diagnosis, to place the patient in airborne precautions to protect other immunocompromised individuals, and to transfer to a pediatric intensive care unit (PICU). At the conclusion of the simulation session, learners will be able to: 1) Obtain a relevant focused history, including immunization status, associated symptoms, sick contacts, and travel history. 2) Develop a differential for fever, rash, and altered mental status in a pediatric patient. 3) Discuss management of primary measles encephalitis, including empiric broad spectrum antibiotics and antiviral treatment. 4) Discuss appropriate disposition of the patient from pediatric emergency departments, community hospitals, and freestanding emergency departments, including appropriate time to call for transfer and the appropriate time to transfer this patient during emergency department (ED) workup. 5) Review types of isolation and indications for each. This session was conducted using high-fidelity simulation, followed by a debriefing session and lecture on the diagnosis, differential diagnosis, and management of primary measles encephalitis. Debriefing methods may be left to the discretion of participants, but the authors have utilized advocacy-inquiry techniques. This scenario may also be run as an oral board case. Our residents are provided a survey at the completion of the debriefing session so they may rate different aspects of the simulation, as well as provide qualitative feedback on the scenario. Feedback from the residents was overwhelmingly positive with an average score of 7 (consistently effective/very good or extremely effective/outstanding) across all categories. The subsequent debriefings allowed for multiple areas of discussion, including differential diagnoses of fever and rash, the clinical presentation of measles, empiric treatment of meningitis/encephalitis, types and indications of isolation, when to call for transfer to a pediatric center, and when a child is deemed stable enough for transfer. This is a cost-effective method for reviewing primary measles encephalitis. There are multiple measles complications that may be reviewed via simulation, including pneumonia and dehydration from diarrhea. We encourage readers to utilize clinical photos of measles rashes, because this was difficult to capture via standard moulage techniques. Medical simulation, measles, primary measles encephalitis, encephalitis, infectious disease, emergency medicine, pediatric emergency medicine.

Neurological Complications of Measles (Rubeola).

Owing to vaccine hesitancy, there has been a resurgence of measles infections in developed countries. Practitioners can expect to see an increase in patients with neurologic complications of measles. These devastating disorders include primary measles encephalitis, acute post measles encephalitis, subacute sclerosing panencephalitis (SSPE), and measles inclusion body encephalitis (MIBE). Although there are many unanswered questions regarding the neurologic complications of measles, recent advances have led to better understanding of the mechanism of the spread of measles within the nervous system, particularly the disruption of F protein function, which raises the possibility of treatment with fusion-inhibiting molecules. Measles and its neurological complications are preventable and must be prevented. Neurologists must educate other clinicians and the public regarding the consequences of inadequate herd immunity to measles. More effective treatments for SSPE and MIBE may be available in the near future, but currently these remain lethal diseases.

Difficulties in diagnosing of measles inclusion body encephalitis in a child with acute lymphoblastic leukemia

The measles epidemic was observed in Ukraine during 20172019. According to WHO, in Ukraine there was registered the highest number of measles cases in Europe during that period [8]. Measles is characterized by an acute course with fever, maculopapular rash, cough, conjunctivitis and can lead to central nervous system complications (encephalitis, encephalomyelitis) and bronchopulmonary system complications (laryngotracheobronchitis, bronchiolitis, pneumonia). In immunocompetent patients, viremia ends after the end of clinical signs, in contrast to immunosuppressed individuals, who could develop viremia from one month up to a year. We have described a case of measles inclusion body encephalitis (MIBE) or subacute measles encephalitis (SME) in an unvaccinated child with an acute lymphoblastic leukemia (ALL). The diagnosis was confirmed by the synthesis of IgG antibodies to the measles virus in the cerebrospinal fluid and by the MRI results. The disease had a dramatic course and ended in death.

Measles Encephalitis: Towards New Therapeutics.

Measles remains a major cause of morbidity and mortality worldwide among vaccine preventable diseases. Recent decline in vaccination coverage resulted in re-emergence of measles outbreaks. Measles virus (MeV) infection causes an acute systemic disease, associated in certain cases with central nervous system (CNS) infection leading to lethal neurological disease. Early following MeV infection some patients develop acute post-infectious measles encephalitis (APME), which is not associated with direct infection of the brain. MeV can also infect the CNS and cause sub-acute sclerosing panencephalitis (SSPE) in immunocompetent people or measles inclusion-body encephalitis (MIBE) in immunocompromised patients. To date, cellular and molecular mechanisms governing CNS invasion are still poorly understood. Moreover, the known MeV entry receptors are not expressed in the CNS and how MeV enters and spreads in the brain is not fully understood. Different antiviral treatments have been tested and validated in vitro, ex vivo and in vivo, mainly in small animal models. Most treatments have high efficacy at preventing infection but their effectiveness after CNS manifestations remains to be evaluated. This review describes MeV neural infection and current most advanced therapeutic approaches potentially applicable to treat MeV CNS infection.

Measles Virus Bearing Measles Inclusion Body Encephalitis-Derived Fusion Protein Is Pathogenic after Infection via the Respiratory Route.

A clinical isolate of measles virus (MeV) bearing a single amino acid alteration in the viral fusion protein (F; L454W) was previously identified in two patients with lethal sequelae of MeV central nervous system (CNS) infection. The mutation dysregulated the viral fusion machinery so that the mutated F protein mediated cell fusion in the absence of known MeV cellular receptors. While this virus could feasibly have arisen via intrahost evolution of the wild-type (wt) virus, it was recently shown that the same mutation emerged under the selective pressure of small-molecule antiviral treatment. Under these conditions, a potentially neuropathogenic variant emerged outside the CNS. While CNS adaptation of MeV was thought to generate viruses that are less fit for interhost spread, we show that two animal models can be readily infected with CNS-adapted MeV via the respiratory route. Despite bearing a fusion protein that is less stable at 37°C than the wt MeV F, this virus infects and replicates in cotton rat lung tissue more efficiently than the wt virus and is lethal in a suckling mouse model of MeV encephalitis even with a lower inoculum. Thus, either during lethal MeV CNS infection or during antiviral treatment in vitro, neuropathogenic MeV can emerge, can infect new hosts via the respiratory route, and is more pathogenic (at least in these animal models) than wt MeV.IMPORTANCE Measles virus (MeV) infection can be severe in immunocompromised individuals and lead to complications, including measles inclusion body encephalitis (MIBE). In some cases, MeV persistence and subacute sclerosing panencephalitis (SSPE) occur even in the face of an intact immune response. While they are relatively rare complications of MeV infection, MIBE and SSPE are lethal. This work addresses the hypothesis that despite a dysregulated viral fusion complex, central nervous system (CNS)-adapted measles virus can spread outside the CNS within an infected host.

New Insights into Measles Virus Brain Infections.

Measles virus (MeV) may persist in the brain, causing fatal neurodegenerative diseases, subacute sclerosing panencephalitis, and measles inclusion-body encephalitis. However, the mechanism of MeV propagation in the brain remains unexplained because human neurons affected by the diseases do not express the known receptors for MeV. Recent studies have revealed that certain changes in the ectodomain of the MeV fusion (F) protein play a key role in MeV spread in the brain. These changes destabilize the prefusion form of the F protein and render it hyperfusogenic, which in turn allows the virus to propagate in neurons. Based on crystal structures of the F protein, effective fusion inhibitors could be developed to treat these diseases.

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A 26 year old, Caucasian, female student nurse presented with facial pains and vesicular rash, and over the following three days developed focal faciobrachial twitches. She was febrile, with an erythematous rash. Neurological examination was normal. MRI showed a non-enhancing lesion in the right medulla. CSF was normal with negative viral PCR. EEG demonstrated no seizure activity.A month earlier she was treated with steroids and antibiotics for acute liver injury and maculopapular rash, of presumed allergic aetiology. On that admission, deficiency of Immunoglobulins A and G was noted prompting diagnosis of Common Variable Immune Deficiency, treated with IVIg.Her conscious level deteriorated rapidly, requiring ventilation 10 days after admission. Repeat MRI showed a new subcortical inflammatory lesion. EEG showed new background slowing, and progressed to electrographic status, which continued despite six anticonvulsants, IV Propofol and Midazolam. Sequential imaging showed progressive deterioration with widespread inflammation and oedema, and consequent herniation. Life-support was withdrawn one month after presentation.Post-mortem demonstrated T-lymphocytic inflammation with inclusion bodies suggesting viral encephalitis. Electron microscopy demonstrated filamentous viral particles. Measles PCR was positive in brain tissue and CSF, diagnosing Measles Inclusion Body Encephalitis. Serum measles IgM, previously reported as negative, was re-evaluated and tested positive.

Structures of the prefusion form of measles virus fusion protein in complex with inhibitors

Measles virus (MeV), a major cause of childhood morbidity and mortality, is highly immunotropic and one of the most contagious pathogens. MeV may establish, albeit rarely, persistent infection in the central nervous system, causing fatal and intractable neurodegenerative diseases such as subacute sclerosing panencephalitis and measles inclusion body encephalitis. Recent studies have suggested that particular substitutions in the MeV fusion (F) protein are involved in the pathogenesis by destabilizing the F protein and endowing it with hyperfusogenicity. Here we show the crystal structures of the prefusion MeV-F alone and in complex with the small compound AS-48 or a fusion inhibitor peptide. Notably, these independently developed inhibitors bind the same hydrophobic pocket located at the region connecting the head and stalk of MeV-F, where a number of substitutions in MeV isolates from neurodegenerative diseases are also localized. Since these inhibitors could suppress membrane fusion mediated by most of the hyperfusogenic MeV-F mutants, the development of more effective inhibitors based on the structures may be warranted to treat MeV-induced neurodegenerative diseases.

The P gene of rodent brain-adapted measles virus plays a critical role in neurovirulence.

In rare cases, measles virus (MV) in children leads to fatal neurological complications such as primary measles encephalitis, post-acute measles encephalitis, subacute sclerosing panencephalitis and measles inclusion-body encephalitis. To investigate the pathogenesis of MV-induced encephalitis, rodent brain-adapted MV strains CAM/RB and CAMR40 were generated. These strains acquired mutations to adapt to the rodent brain during 40 passages in rat brain. However, it is still unknown which genes confer the neurovirulence of MV. We previously established a rescue system for recombinant MVs possessing the backbone of wild-type strain HL, an avirulent strain in mice. In the present study, to identify the genes in CAMR40 that elicit neurovirulence, we generated chimeric recombinant MVs based on strain HL. As a result, recombinant wild-type MV in which the haemagglutinin (H) gene was substituted with that of CAMR40 caused a non-lethal mild disease in mice, while additional substitution of the HL phosphoprotein (P) gene with that of strain CAMR40 caused lethal severe neurological signs comparable to those of CAMR40. These results clearly indicated that, in addition to the H gene, the P gene is required for the neurovirulence of MV CAMR40.

Measles.

Measles is an infectious disease in humans caused by the measles virus (MeV). Before the introduction of an effective measles vaccine, virtually everyone experienced measles during childhood. Symptoms of measles include fever and maculopapular skin rash accompanied by cough, coryza and/or conjunctivitis. MeV causes immunosuppression, and severe sequelae of measles include pneumonia, gastroenteritis, blindness, measles inclusion body encephalitis and subacute sclerosing panencephalitis. Case confirmation depends on clinical presentation and results of laboratory tests, including the detection of anti-MeV IgM antibodies and/or viral RNA. All current measles vaccines contain a live attenuated strain of MeV, and great progress has been made to increase global vaccination coverage to drive down the incidence of measles. However, endemic transmission continues in many parts of the world. Measles remains a considerable cause of childhood mortality worldwide, with estimates that >100,000 fatal cases occur each year. Case fatality ratio estimates vary from <0.01% in industrialized countries to >5% in developing countries. All six WHO regions have set goals to eliminate endemic transmission of MeV by achieving and maintaining high levels of vaccination coverage accompanied by a sensitive surveillance system. Because of the availability of a highly effective and relatively inexpensive vaccine, the monotypic nature of the virus and the lack of an animal reservoir, measles is considered a candidate for eradication.

Acute Measles Encephalitis: Primary Encephalitis or Postinfectious Encephalomyelitis

Measles remains an important vaccine-preventable disease, particularly in the developing countries. The disease at times is accompanied by numerous complications in the backdrop of malnutrition. Of these, the neurologic complications are the most devastating. The neurological involvement in measles encompasses at least four distinct conditions, namely, primary measles encephalitis (PME), acute postinfectious measles encephalomyelitis (APME), measles inclusion body encephalitis, and subacute sclerosing panencephalitis. The pathogenesis of PME or APME continues to be enigmatic with both immune mechanism and direct viral invasion being variously incriminated. We report a fatal case of measles encephalitis in a 3.5-year-old child, with a slow and indolent course over a 1-month period with laboratory evidence of acute measles infection without any demonstrable virus in the body fluid at the time of the encephalitis with typical magnetic resonance imaging features.