Bridgette Jeanne Billioux

Neurological Complications of Ebola Virus Infection

Ebola virus disease is one of the deadliest pathogens known to man, with a mortality rate between 25–90% depending on the species and outbreak of Ebola. Typically, it presents with fever, headache, voluminous vomiting and diarrhea, and can progress to a hemorrhagic illness; neurologic symptoms, including meningoencephalitis, seizures, and coma, can also occur. Recently, an outbreak occurred in West Africa, affecting > 28,000 people, and killing > 11,000. Owing to the magnitude of this outbreak, and the large number (>17,000) of Ebola survivors, the medical and scientific communities are learning much more about the acute manifestations and sequelae of Ebola. A number of neurologic complications can occur after Ebola, such as seizures, memory loss, headaches, cranial nerve abnormalities, and tremor. Ebola may also persist in some immunologically privileged sites, including the central nervous system, and can rarely lead to relapse in disease. Owing to these findings, it is important that survivors are evaluated and monitored for neurologic symptoms. Much is unknown about this disease, and treatment remains largely supportive; however, with ongoing clinical and basic science, the mechanisms of how Ebola affects the central nervous system and how it persists after acute disease will hopefully become more clear, and better treatments and clinical practices for Ebola patients will be developed.

Cerebrospinal Fluid Examination in Survivors of Ebola Virus Disease

Cerebrospinal Fluid Examination in Survivors of Ebola Virus Disease With the extent of the recent Ebola virus disease (EVD) epidemic in West Africa (including >28 000 cases and ≤17 000 survivors), many aspects of Ebola virus have become clearer, including acute manifestations, sequelae, and the possibility of relapse and persistence.1 Neurologic complications are becoming more commonly recognized in EVD during the acute phase, with long-term sequelae.2-4 More remarkable, however, is the potential for persistence and relapse of EVD in the central nervous system (CNS), as in the case of a nurse who developed meningoencephalitis with seizures, cranial nerve involvement, and radiculitis 9 months after EVD recovery.5 Ebola virus was recovered from the cerebrospinal fluid (CSF) at higher levels than from the blood, indicating viral replication in the CNS.5 This case reveals the need to determine the role of the CNS as a potential reservoir for Ebola virus after initial clinical recovery.

Neurological Complications and Sequelae of Ebola Virus Disease

Purpose of ReviewThe recent 2014–2016 outbreak of Ebola virus disease (EVD) has led to many discoveries regarding Ebola. Although neurological symptoms during EVD had been previously described, many reports since this outbreak have made clear that EVD can lead to neurological issues. This article will review the various neurological manifestations of EVD.Recent FindingsRecently, many neurological symptoms have been described during acute EVD, including altered mental status, seizures, and meningoencephalitis, among others; survivors of EVD also may develop neurological sequelae, such as persistent headache and memory loss and can exhibit abnormalities on neurological exam. Additionally, it is now evident that in rare cases, survivors may experience relapses of EVD months after recovery, including the central nervous system (CNS).SummaryEVD can result in many clinical neurological manifestations, both acutely and after recovery. Research is ongoing to further clarify the nature of Ebola in the CNS.

Prevalence of salivary human herpesviruses in pediatric multiple sclerosis cases and controls

Background: Multiple sclerosis (MS) is a multifactorial disease of unknown origin. The current paradigm is that disease develops in genetically susceptible individuals, influenced by environmental factors. Epstein–Barr virus (EBV) and human herpesvirus 6 (HHV-6) have particularly strong associations with the disease. Both viruses are typically acquired during childhood, decades before MS presents. However, in patients with pediatric MS, the temporal window between viral acquisition and disease onset is shortened, which may provide insights into the association of herpesviruses with MS. Objective: To compare the frequency of EBV and HHV-6 in the saliva of a cohort of pediatric MS patients and age-matched controls. Methods: The study enrolled 32 pediatric MS patients and 42 controls and evaluated saliva for HHV-6 u57 and EBV lmp-1 amplification by droplet digital polymerase chain reaction (ddPCR). Results: Pediatric MS patients did not differ from controls in the frequency or magnitude of salivary viral shedding. During the assessment of EBV positivity, distinct profiles emerged that correlated with target amplicon mutations. Conclusions: None of these mutations were evident in EBV-positive samples from pediatric MS patients, whereas they were present in pediatric controls, in addition to MS and control adults, suggesting differential host-immune control of EBV in this pediatric MS cohort.

Development of HTLV-1 associated myelopathy/tropical spastic paraparesis in a patient with simian T-lymphotropic virus type 1-like infection.

Virus transmission from various wild and domestic animals contributes to increased risk of emerging infectious diseases in human populations. HTLV-1 is a human retrovirus associated with acute T-cell leukemia (ATL) and HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP), which originated from zoonotic transmission from various African and Asian nonhuman primates (NHPs). Similar to HTLV-1, the simian counterpart, STLV-1, causes chronic infection and leukemia and lymphoma in naturally infected monkeys. However, other clinical syndromes typically seen in human such as a chronic progressive myelopathy have not been observed in NHPs. Little is also known about the development of any neurologic and inflammatory diseases in human populations infected with STLV-1-like viruses following NHP exposure. We identified and analyzed the complete genome of a primate T lymphotropic virus type 1 (PTLV-1) isolated from a patient with typical HAM/TSP who resides in the United States but was born in Liberia. Using a novel droplet digital PCR for the detection of the HTLV-1 tax gene, the proviral load in PBMC was 14.01%; however there was a distinct difference in fluorescence amplitude compared to all other H!M/TSP patients, suggesting viral heterogeneity. A complete PTLV-1 proviral genome was amplified from DNA extracted from the PBMCs of the HAM/TSP patient using PCR to generate nine overlapping subgenomic fragments. Phylogenetic analysis of PTLV-1 env and LTR regions showed the virus was highly related with PTLV-1 from sooty mangabey monkeys and humans exposed from NHPs in West Africa. These results suggest the patient is likely infected with STLV-1, suggesting for the first time that viral transmission from monkey to human may be associated with a chronic progressive neurologic disease.

Herpesvirus trigger accelerates neuroinflammation in a nonhuman primate model of multiple sclerosis

Significance Inflammatory processes drive the autoimmune disease multiple sclerosis (MS). However, what triggers this inflammation remains unknown. Several herpesviruses (HHVs), such as HHV-6 typically acquired during childhood, are associated with MS. The temporal separation between HHV-6 acquisition and MS development complicates its study as a disease trigger. Because rodents are not susceptible to HHV-6 infection, we utilized nonhuman primates to examine the impact of HHV-6 infection on an experimental MS-like disease. The viral infections were asymptomatic; however, the MS-like disease was significantly accelerated in all virally inoculated animals. Our data support the hypothesis that viruses may act as triggers to lower the threshold for autoimmunity, and warrant trials of antiviral interventions in early disease stages. Pathogens, particularly human herpesviruses (HHVs), are implicated as triggers of disease onset/progression in multiple sclerosis (MS) and other neuroinflammatory disorders. However, the time between viral acquisition in childhood and disease onset in adulthood complicates the study of this association. Using nonhuman primates, we demonstrate that intranasal inoculations with HHV-6A and HHV-6B accelerate an MS-like neuroinflammatory disease, experimental autoimmune encephalomyelitis (EAE). Although animals inoculated intranasally with HHV-6 (virus/EAE marmosets) were asymptomatic, they exhibited significantly accelerated clinical EAE compared with control animals. Expansion of a proinflammatory CD8 subset correlated with post-EAE survival in virus/EAE marmosets, suggesting that a peripheral (viral?) antigen-driven expansion may have occurred post-EAE induction. HHV-6 viral antigen in virus/EAE marmosets was markedly elevated and concentrated in brain lesions, similar to previously reported localizations of HHV-6 in MS brain lesions. Collectively, we demonstrate that asymptomatic intranasal viral acquisition accelerates subsequent neuroinflammation in a nonhuman primate model of MS.

Immunophenotypic characterization of CSF B cells in virus-associated neuroinflammatory diseases

Intrathecal antibody synthesis is a well-documented phenomenon in infectious neurological diseases as well as in demyelinating diseases, but little is known about the role of B cells in the central nervous systems. We examined B cell and T cell immunophenotypes in CSF of patients with HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) compared to healthy normal donors and subjects with the other chronic virus infection and/or neuroinflammatory diseases including HIV infection, multiple sclerosis (MS) and progressive multifocal leukoencephalopathy. Antibody secreting B cells (ASCs) were elevated in HAM/TSP patients, which was significantly correlated with intrathecal HTLV-1-specific antibody responses. High frequency of ASCs was also detected in patients with relapsing-remitting multiple sclerosis (RRMS). While RRMS patients showed significant correlations between ASCs and memory follicular helper CD4+ T cells, CD4+CD25+ T cells were elevated in HAM/TSP patients, which were significantly correlated with ASCs and HTLV-1 proviral load. These results highlight the importance of the B cell compartment and the associated inflammatory milieu in HAM/TSP patients where virus-specific antibody production may be required to control viral persistence and/or may be associated with disease development.

Immunophenotyping of cerebrospinal fluid cells in virus-associated neurologic diseases

OBJECTIVE: To characterize the cellular immunophenotype of cells in cerebrospinal fluid (CSF) of patients with virus-associated neurologic diseases. BACKGROUND: Various inflammatory neurologic diseases are associated with viral infections. These agents may cause direct damage of infected cells associated with immunological alterations such as chronic activation, immunodeficiency and infiltration of inflammatory cells into the CNS that underlie the pathogenesis of inflammatory neurologic diseases. Therefore, characterization of local immune responses that are associated with the inflammatory milieu may provide evidence or pathogenic “signature” of an immunopathogenic process in virus-associated neurologic diseases. DESIGN/METHODS: Multicolor flow cytometry is used to characterize CD4+ and CD8+ T cells, B cells, monocytes and NK cells in the CSF and blood of patients with virus-associated neurologic diseases including HTLV-1 associated myelopathy/tropical spastic paraparesis (HAM/TSP; n=16), HIV adequately treated with antiretroviral drugs (n=16), multiple sclerosis (MS; n=4) and progressive multifocal leukoencephalopathy (PML; n=6) compared to healthy volunteers (n=6). RESULTS: In all patients, T cells were the predominant population in the CSF. CD4+ and CD8+ T cells were significantly altered among the groups, and the CD4/CD8 ratio reduced in HIV, HAM/TSP and a subset of PML, but elevated in MS. In patients with HAM/TSP, activated CD4+ T cells were significantly increased in the CSF as well as the blood and correlated with HTLV-1 proviral DNA loads. MS patients had a decreased frequency of effector/memory CD4+ and CD8+ T cells in the CSF. B cells and antibody producing plasma cells were elevated in patients with HAM/TSP, MS and PML whereas monocytes were reduced. CD56bright/CD56dim NK cell ratio was elevated in the CSF of patients with HAM/TSP. CONCLUSIONS: Immunophenotyping of CSF cells may reflect immune pathology in inflammatory neurologic diseases and can serve to highlight differential diagnoses that may lead to a better understanding of disease pathogenesis and clinical treatment. Disclosure: Dr. Akahata has nothing to disclose. Dr. Massoud has nothing to disclose. Dr. Caruso has nothing to disclose. Dr. Ohayon has nothing to disclose. Dr. Billioux has nothing to disclose. Dr. Von Geldern has nothing to disclose. Dr. Smith has nothing to disclose. Dr. Nath has nothing to disclose. Dr. Jacobson has nothing to disclose.

Human Herpes Virus 6 in human epilepsy: Data from surgical resections

and their dynamic changes roughly paralleled the clinical course of EAN. Compound 1, a synthetic compound that can specifically block the production of Th17 cells, suppressed the severity of EAN symptoms when it was administered from the immunization day. However, Compound 1 was incapable of obviously affecting the clinical signs of EAN when administered after the onset of EAN. In conclusion, Th17 cells are a neuritogenic T helper cell subset in GBS and EAN.