Defects in LC3B2 and ATG4A underlie HSV2 meningitis and reveal a critical role for autophagy in antiviral defense in humans.

Recurrent herpesvirus infections can manifest in different forms of disease, including cold sores, genital herpes, and encephalitis. There is an incomplete understanding of the genetic and immunological factors conferring susceptibility to recurrent herpes simplex virus 2 (HSV2) infection in the central nervous system (CNS). Here, we describe two adult patients with recurrent HSV2 lymphocytic Mollaret's meningitis that each carry a rare monoallelic variant in the autophagy proteins ATG4A or LC3B2. HSV2-activated autophagy was abrogated in patient primary fibroblasts, which also exhibited significantly increased viral replication and enhanced cell death. HSV2 antigen was captured in autophagosomes of infected cells, and genetic inhibition of autophagy by disruption of autophagy genes, including ATG4A and LC3B2, led to enhanced viral replication and cell death in primary fibroblasts and a neuroblastoma cell line. Activation of autophagy by HSV2 was sensitive to ultraviolet (UV) irradiation of the virus and inhibited in the presence of acyclovir, but HSV2-induced autophagy was independent of the DNA-activated STING pathway. Reconstitution of wild-type ATG4A and LC3B2 expression using lentiviral gene delivery or electroporation of in vitro transcribed mRNA into patient cells restored virus-induced autophagy and the ability to control HSV2 replication. This study describes a previously unknown link between defective autophagy and an inborn error of immunity that can lead to increased susceptibility to HSV2 infection, suggesting an important role for autophagy in antiviral immunity in the CNS.

Community-Acquired Meningitis in HIV-Infected Patients in the United States.

We conducted a retrospective study of 549 adults admitted with community-acquired meningitis (CAM) to several hospitals in New Orleans, LA and Houston, TX between 1999 and 2014 to characterize the current epidemiology, clinical manifestations, cerebrospinal fluid (CSF) characteristics, and outcomes of CAM between HIV-infected and uninfected patients and to identify risk factors for adverse outcomes in CAM. Bivariate analysis and logistic regression analysis were used to identify prognostic factors. A total of 1022 patients with CAM were screened. Only 549 (53.7%) subjects had an HIV test and were included in the study. Of those, 138 (25%) had HIV infection. HIV-infected patients presented with less meningeal symptoms (headache, neck stiffness, and Kernig sign), but with higher rates of hypoglycorrhachia, elevated CSF protein, and an abnormal cranial imaging (p < 0.05). More than 50% of all the patients had an unknown etiology. Cryptococcal meningitis was the most common identified etiology of CAM in HIV-infected patients followed by neurosyphilis and varicella-zoster virus (VZV). Viral and bacterial etiologies were the most frequent etiologies in non-HIV-infected patients. Streptococcus pneumoniae was the most common bacterial pathogen in both groups, but it was rare overall (2%). Adverse clinical outcomes were similar in both groups (27% vs. 24%). Logistic regression identified hypoglycorrhachia and an abnormal neurological examination as independent predictor factors of worse outcome in all patients with meningitis. Our results demonstrate that the etiology, clinical presentation, and CSF findings differ between HIV-infected and HIV-uninfected adults with CAM, but clinical outcomes are similar.

The Successful Treatment of a Cord Blood Transplant Recipient with Varicella Zoster Virus Meningitis, Radiculitis and Myelitis with Foscarnet.

Infections of the central nervous system (CNS) with varicella zoster virus (VZV) is a rare occurrence after allogeneic hematopoietic stem cell transplantation. We herein report a case of VZV meningitis, radiculitis and myelitis that developed 8 months after cord blood transplantation, shortly after the cessation of cyclosporine and low-dose acyclovir. Although treatment with acyclovir did not achieve a satisfactory response, the patient was successfully treated with foscarnet. Our report indicates that VZV infection should be considered in allo-hematopoietic stem cell transplantation (HSCT) patients with CNS symptoms and that foscarnet may be effective for the treatment of acyclovir-resistant VZV infections of the CNS. The development of optimal prophylactic strategies and vaccination schedules may eradicate post-transplant VZV disease.

Use of Testing for West Nile Virus and Other Arboviruses.

In the United States, the most commonly diagnosed arboviral disease is West Nile virus (WNV) infection. Diagnosis is made by detecting WNV IgG or viral genomic sequences in serum or cerebrospinal fluid. To determine frequency of this testing in WNV-endemic areas, we examined the proportion of tests ordered for patients with meningitis and encephalitis at 9 hospitals in Houston, Texas, USA. We identified 751 patients (567 adults, 184 children), among whom 390 (52%) experienced illness onset during WNV season (June-October). WNV testing was ordered for 281 (37%) of the 751; results indicated acute infection for 32 (11%). Characteristics associated with WNV testing were acute focal neurologic deficits; older age; magnetic resonance imaging; empirically prescribed antiviral therapy; worse clinical outcomes: and concomitant testing for mycobacterial, fungal, or other viral infections. Testing for WNV is underutilized, and testing of patients with more severe disease raises the possibility of diagnostic bias in epidemiologic studies.

Herpes Zoster Meningitis Presenting With a Cerebrospinal Fluid Leukemoid Reaction in an Adolescent With preB-ALL in Remission.

A 19-year-old girl with a history of precursor B acute lymphoblastic leukemia in remission presented with fever, headache, and a skin rash. Cerebrospinal fluid (CSF) examination reported pleocytosis with blast-like cells concerning for a central nervous system leukemic relapse. After the patient showed significant improvement on intravenous acyclovir, a repeat lumbar puncture revealed normalization of CSF. The abnormal CSF cells were reviewed and ultimately determined to be activated and atypical lymphocytes. The patient recovered uneventfully. Atypical lymphocytes resembling leukemic blasts are an unusual finding in viral meningitis. Varicella zoster virus reactivation should be considered during initial evaluation for central nervous system relapse of leukemia.

Clinical, neuropathological and radiological evidence for a rare complication of rituximab therapy.

We report a rare case of myofasciitis and meningitis with deafness caused by systemic enterovirus infection in the setting of hypogammaglobulinaemia induced by rituximab. Whilst effective and generally safe, anti- CD 20 antibody therapy is increasingly recognised to result in unusual infectious complications to be considered in a treated patient presenting with neurological symptoms. These cases may pose diagnostic difficulties and can have atypical presentations. We present this rare complication of rituximab therapy, with histopathological confirmation of myofasciitis. In the older literature, enterovirus associated myofasciitis may have erroneously been termed dermatomyositis and we review the literature to demonstrate this important nosological point.

Epidemiology of meningitis in an HIV-infected Ugandan cohort.

There is limited understanding of the epidemiology of meningitis among human immunodeficiency virus (HIV)-infected populations in sub-Saharan Africa. We conducted a prospective cohort study of HIV-infected adults with suspected meningitis in Uganda, to comprehensively evaluate the etiologies of meningitis. Intensive cerebrospiral fluid (CSF) testing was performed to evaluate for bacterial, viral, fungal, and mycobacterial etiologies, including neurosyphilis,16s ribosomal DNA (rDNA) polymerase chain reaction (PCR) for bacteria, Plex-ID broad viral assay, quantitative-PCR for HSV-1/2, cytomegalovirus (CMV), Epstein-Barr virus (EBV), and Toxoplasma gondii; reverse transcription-PCR (RT-PCR) for Enteroviruses and arboviruses, and Xpert MTB/RIF assay. Cryptococcal meningitis accounted for 60% (188 of 314) of all causes of meningitis. Of 117 samples sent for viral PCR, 36% were EBV positive. Among cryptococcal antigen negative patients, the yield of Xpert MTB/RIF assay was 22% (8 of 36). After exclusion of cryptococcosis and bacterial meningitis, 61% (43 of 71) with an abnormal CSF profile had no definitive diagnosis. Exploration of new TB diagnostics and diagnostic algorithms for evaluation of meningitis in resource-limited settings remains needed, and implementation of cryptococcal diagnostics is critical.

Community-acquired meningitis in older adults: clinical features, etiology, and prognostic factors.

OBJECTIVES: To investigate the epidemiology and outcomes of community-acquired meningitis in older adults. DESIGN: Retrospective study. SETTING: Participants adults in Houston, Texas, with community-acquired meningitis hospitalized between January 1, 2005, and January 1, 2010 (N = 619; n = 54, 8.7%, aged ≥65; n = 565 aged <65). METHODS: An adverse clinical outcome was defined as a Glasgow Outcome Scale score of 4 or less. RESULTS: Older adults had higher rates of comorbidities, abnormal neurological and laboratory (serum white blood cell count >12,000/µL, and cerebrospinal fluid protein >100 mg/dL) findings (P < .001), abnormalities on computed tomography and magnetic resonance imaging of the head (P = .002), and adverse clinical outcomes (ACOs) (P < .001). The majority of participants (65.8%) had meningitis of unknown etiology. Bacterial meningitis was an infrequent cause of community-acquired meningitis (7.4%). Of the known causes, bacterial meningitis and West Nile virus were more common in older than younger adults; younger participants more frequently had cryptococcal and viral meningitis. On logistic regression, female sex was predictive of a poor outcome in the older participants (P = .002), whereas abnormal neurological examination (P < .001), fever (P = .01), and a cerebrospinal fluid glucose level less than 45 mg/dL (P = .002) were significant poor prognostic factors in younger participants. CONCLUSION: Most cases of community-acquired meningitis are of unknown origin. Older adults are more likely than younger adults to have bacterial meningitis and West Nile virus infection when a cause can be identified. They also have more neurological abnormalities, laboratory and imaging abnormalities, and adverse clinical outcomes.

Maternal and perinatal factors associated with subsequent meningococcal, Haemophilus or enteroviral meningitis in children: database study.

We used a database of 248 659 births, with follow-up to subsequent disease, in the Oxford record linkage archive (1979-1999) to study the influence of family, maternal, and perinatal factors on subsequent hospital admission for meningococcal, Haemophilus, and enteroviral meningitis in the children. In this summary, we report key findings that were significant in multivariate analysis. Meningococcal meningitis was significantly associated with maternal smoking [odds ratio (OR) 2·1, 95% confidence interval (CI) 1·2-3·7]. Haemophilus meningitis was associated with having older siblings (e.g. second child compared to first-born, OR 3·3, 95% CI 2·0-5·6). Enteroviral meningitis was associated with low birth weight (OR 2·2, 95% CI 1·3-3·6) and male sex (OR 1·7, 95% CI 1·2-2·3). The mothers of six of the 312 children with enteroviral meningitis had previously had enteroviral meningitis themselves. We concluded that several maternal characteristics influence the risk of these types of meningitis.

Caso clínico de una meningitis por reactivación del virus varicela zóster en un paciente inmunocompetente / Case report of an inmunocompetent patient with reactivation of varicela zoster as meningitis

En este reporte presentamos el caso de un niño de 15 años sin antecedentes mórbidos, que consulta por un cuadro de cefalea febril, erupción cutánea de características herpéticas en tórax, en quien finalmente se confirma el diagnóstico de meningitis por varicela zóster. La literatura nos muestra que la reactivación del virus varicela zóster en forma de meningitis es rara y en general afecta a la población inmunocomprometida, sin embargo, existen algunos reportes de casos similares al que se presenta, por lo que se debiese considerar como germen causal de meningitis, en la población inmunocompetente.

This is a case report about a 15-year-old boy with no other previous medical history than chicken pox. His symptoms were headache, fever and a rash with vesicles in the dermatome that corresponds to T8. He was diagnosed with meningitis by the varicella-zoster virus. The information in the literature is scarce and shows that reactivation of the varicella-zoster virus as meningitis is rare and generally affects immunodeficient patients; however, there are some case reports similar to this case in which the varicella-zoster virus is the agent involved, so it should also be considered in immunocompetent patients diagnosed with meningitis.

Herpes simplex meningitis after removal of a vestibular schwannoma: case report and review of the literature.

OBJECTIVE: We present a case of postoperative herpes simplex type 1 viral meningitis after retrosigmoid craniotomy and uncomplicated removal of a vestibular schwannoma. This is a very rare complication that can mimic aseptic meningitis and could lead to devastating consequences for the patient, if unrecognized. PATIENT: A healthy 49-year-old woman underwent retrosigmoid craniotomy and resection of a 2.4-cm vestibular schwannoma. She developed worsening headache and low-grade fever on postoperative Day 10 and underwent lumbar puncture showing a lymphocyte predominant pleocytosis. Polymerase chain reaction was positive for herpes simplex type 1 virus; bacterial cultures were negative. The patient subsequently developed a pseudomeningocele and mild hydrocephalus. INTERVENTION: The patient was readmitted to the hospital, started on corticosteroids, and a lumbar drain was placed. She completed a 14-day course of antiviral therapy (4 d intravenous as an inpatient and 10 d oral outpatient therapy). RESULTS: At 1 month follow-up, she was completely asymptomatic, and her pseudomeningocele had resolved. CONCLUSION: The diagnosis of herpes simplex viral meningitis should be suspected in clinical cases of postsurgical meningitis with a lymphocyte predominant pleocytosis and negative bacterial cultures. Antiviral therapy should be initiated immediately after confirmatory polymerase chain reaction testing to avoid potential long-term sequelae of a herpes simplex infection of the central nervous system.

Acute urinary retention due to viral coinfections (HIV, HBV, VZV).

We report a case of acute urinary retention with meningoradiculoneuritis resulting from coinfection with varicella-zoster virus (VZV), HIV, and hepatitis B virus (HBV). The case is discussed in the context of other neurological syndromes associated with VZV and HIV infections, and of other viral causes of acute retention of urine.

Mollaret's meningitis due to human herpesvirus 6 in an adolescent.

We report the first pediatric case of Mollaret meningitis in an adolescent female with acute lymphoblastic leukemia in remission. This patient had signs and symptoms consistent with meningitis, with three episodes over a 3-month period. Human herpesvirus 6 (HHV-6) was identified during her last episode from polymerase chain reaction assay of a cerebrospinal fluid specimen. She was treated successfully with foscarnet, after which HHV-6 was undetectable in her cerebrospinal fluid.

Análisis de un brote de meningitis viral en la provincia de Tucumán, Argentina / Analysis of an outbreak of viral meningitis in the province of Tucuman, Argentina

OBJETIVO: Confirmar la existencia de un brote de meningitis viral en 1996 en la provincia de Tucumán, Argentina, y estudiar sus características epidemiológicas. MÉTODOS: Se analizó información obtenida del Sistema Nacional de Vigilancia Epidemiológica (SINAVE) del Ministerio de Salud de Argentina para el período de 1994-1998, la cual fue provista por la Dirección de Epidemiología de dicho ministerio. Para el cálculo de incidencias se usaron estimaciones poblacionales para los años 1994-1998 realizadas por el Instituto Nacional de Estadística y Censos (INDEC) sobre la base del censo de 1991. El estudio de frecuencias se realizó mediante el análisis de tablas de contingencia de doble entrada, según el método de ji cuadrado con la corrección de Yates. Se consideró significativo el resultado cuando P < 0,05. RESULTADOS: Se confirmó la presencia de un brote de 189 casos entre el 11 de febrero y el 18 de mayo de 1996. La incidencia de casos en la provincia mostró un aumento entre 1995 y 1996 (de 0,5 a 19,3 casos por 100000 años-persona) y dicha incidencia fue significativamenrte mayor que la observada en el resto del país (19,3 frente a 2,8 casos por 100000 años-persona). El 75,1 por ciento de los casos ocurrió en niños menores de 9 años (142/189). Se detectó la presencia de Enterovirus (EV) en 65 de las 111 muestras estudiadas (58,6 por ciento). Mediante la reacción en cadena de la polimerasa (RCP) anidada con transcripción inversa se logró detectar EV en 66,3 por ciento (53/80) de los casos estudiados por este método, en comparación con solo 29,6 por ciento (24/81) de los estudiados mediante aislamiento viral. Se identificó echovirus tipo 4 en 15 (68 por ciento) en las 22 muestras tipificadas (5 por aislamiento, 3 por secuenciación y 7 por ambos métodos). Este brote demuestra la capacidad de los EV para diseminarse y producir enfermedad en la población. Durante el brote, por lo menos 56 por ciento de los casos fueron hospitalizados. CONCLUSIONES: El uso de métodos moleculares permitió el diagnóstico rápido del virus etiológico y posibilitó un mejor control del brote. El reconocimiento temprano de este podría haber evitado la mayoría de las hospitalizaciones y el uso indiscriminado de antibióticos

Objective. To confirm the occurrence of an outbreak of viral meningitis in 1996 in the province of Tucuman, Argentina, and to study the outbreak's epidemiological characteristics. Methods. We analyzed information from the National Epidemiological Surveillance System of the Ministry of Health (MOH) of Argentina for 1994­1998 that had been provided by the MOH's Bureau of Epidemiology. We calculated incidence rates using population estimates for the years 1994­1998 developed by the National Statistics and Census Institute, based on the 1991 census. We studied frequencies with contingency tables, using the chi-square method with Yates' correction. Results were considered significant when P < 0.05. Results. We confirmed the occurrence of an outbreak of 189 cases of viral meningitis between 11 February and 18 May 1996. The incidence of cases in Tucuman province increased between 1995 and 1996, from 0.5 to 19.3 cases per 100 000 person-years. That 1996 rate in Tucuman was significantly higher than what was seen in the rest of the country (2.8 cases per 100 000 person-years). Of the 189 cases, 142 of them (75.1%) occurred in children less than 9 years old. Out of 111 samples studied, 65 of them (58.6%) were enterovirus-positive. Through reverse transcription-nested polymerase chain reaction, enteroviruses were found in 66.3% (53/80) of the cases studied by this method, versus in only 29.6% (24/81) of the cases studied through viral isolation. In the 22 samples that were serotyped, echovirus type 4 was identified in 15 of them (68%): 5 by isolation, 3 by sequencing, and 7 by both methods. During the Tucuman outbreak, at least 56% of the cases were hospitalized. This viral meningitis outbreak shows the capacity of enteroviruses to spread and cause disease. Conclusions. The use of molecular methods makes it possible to rapidly diagnose the etiological virus and to better control an outbreak. Recognizing this outbreak in Tucuman sooner could have averted the majority of the hospitalizations and the indiscriminate use of antibiotics.

Epstein-Barr virus infections of the central nervous system.

OBJECTIVE: Epstein-Barr virus (EBV), a lymphotropic herpes virus causing infectious mononucleosis (IM), also causes various central nervous system (CNS) infections. In the present study, EBV CNS infections were investigated. PATIENTS AND METHODS: For adult inpatients in our hospital and related hospitals between 1984-2002, CNS syndromes with IM symptoms were examined, and serologic positives were assessed according to established criteria. Polymerase chain reaction (PCR) was performed for cerebrospinal fluid (CSF) from seven patients. RESULTS: Ten patients with EBV-related CNS infections were found; their mean age was 36 years (20-79 years). The neurologic forms were as follows: acute encephalitis (4 patients), acute cerebellar ataxia (1), acute disseminated encephalomyelitis (ADEM) (2), myelitis (1), and meningitis (2). The PCR from CSF was positive in two patients with meningitis, one patient with ADEM, and one patient with encephalitis-associated chronic EVB infection. One case of encephalitis and another of relapsing ADEM were attributed to chronic EBV infection. CONCLUSION: Our study identified a variety of EBV-related CNS infections. EBV CNS infections are divided into two groups: 1) CNS syndromes associated with primary EBV or reactivated infection, and 2) those associated with chronic EBV infection; it is notable that in the former, diverse CNS syndromes including ADEM can occur, whereas in the latter, chronic or recurrent CNS syndromes are produced.

Serious infections of the central nervous system: encephalitis, meningitis, and brain abscess.

Central nervous system infections in adolescents range from the diffuse cerebritis of encephalitis to the regional inflammation of meningitis, and very focal disease of brain abscess. Clinical presentations reflect this wide spectrum, with encephalitis primarily characterized by altered mental status, meningitis by fever, headache, and neck stiffness, and brain abscess manifesting localizing findings. Encephalitis and viral meningitis are frequently caused by the seasonal enteroviruses and arboviruses, while most adolescent bacterial meningitis is due to Neisseria meningitidis and Streptococcus pneumoniae. The microbiology of brain abscess reflects underlying host risk factors. Gram-positive cocci are seen in patients with congenital heart disease, while respiratory flora including anaerobes are associated with sinus or otic disease. Lumbar puncture to characterize and culture the CSF remains the optimal test for the diagnosis and management of encephalitis and meningitis, while CT-guided needle biopsy may be both diagnostic and therapeutic for brain abscesses. New diagnostic tests include the use of PCR. A variety of safe and effective treatment regimens exists for most bacterial infections as well as for some herpesvirus infections. New vaccines are under study to further control bacterial meningitis.

Intracranial hypertension and HIV associated meningoradiculitis.

Two patients with meningoradiculitis associated with HIV presented with symptoms and signs of intracranial hypertension. In the patients described, the raised intracranial pressure resolved after lumbar puncture. After exclusion of opportunistic infection, such patients may be managed with therapeutic lumbar puncture alone.