Evaluation of enterovirus concentration, species identification, and cerebrospinal fluid parameters in patients of different ages with aseptic meningitis in São Paulo, Brazil.

Human enteroviruses (EV) are the most common cause of aseptic meningitis worldwide. Data on EV viral load in cerebrospinal fluid (CSF) and related epidemiological studies are scarce in Brazil. This study investigated the influence of EV viral load on CSF parameters, as well as identifying the involved species. CSF samples were collected in 2018-2019 from 140 individuals at The Hospital das Clínicas, São Paulo. The EV viral load was determined using real-time quantitative polymerase chain reaction, while EV species were identified by 5'UTR region sequencing. Median viral load was 5.72 log10 copies/mL and did not differ by subjects' age and EV species. Pleocytosis was observed in 94.3% of cases, with the highest white blood cell (WBC) counts in younger individuals. Viral load and WBC count were correlated in children (p = 0.0172). Elevated lactate levels were observed in 60% of cases and correlated with the viral load in preteen-teenagers (p = 0.0120) and adults (p = 0.0184). Most individuals had normal total protein levels (70.7%), with higher in preteen-teenagers and adults (p < 0.0001). By sequencing, 8.2% were identified as EV species A and 91.8% as species B. Age-specific variations in CSF characteristics suggest distinct inflammatory responses in each group.

Síndrome de Ramsay-Hunt associada à meningite e vasculite em indivíduo imunocompetente / Ramsay-Hunt syndrome associated with meningitis and vasculitis in an immunocompetent individual

O vírus varicela zoster (VVZ) causa a varicela como infecção primária e sua reativação leva à herpes zóster, que é uma erupção cutânea vesicular dolorosa na distribuição de um dermátomo associado à neuralgia. A sua reativação no sistema nervoso central também é possível e acontece sob a forma de meningite, meningoradiculite, mielopatia, vasculite e síndrome de Ramsay-Hunt. Neste relato, descrevemos o caso de um paciente de 22 anos do sexo masculino e previamente hígido, que apresentou hemiplegia à direita e paralisia facial periférica associada a vesículas dolorosas em pavilhão auditivo ipsilateral, febre e cefaleia. A ressonância magnética de encéfalo com estudo dos vasos arteriais evidenciou achados compatíveis com vasculite em segmento longo da artéria carótida interna à esquerda. Apesar das pesquisas dos vírus da família herpes por biologia molecular terem sido negativas no líquor, pudemos documentar altos títulos de anticorpos IgG para varicela zoster em duas amostras diferentes de sangue periférico. Decorridas duas semanas do início do tratamento com aciclovir parenteral, o paciente já se encontrava assintomático e com melhora expressiva dos déficits neurológicos. O presente relato ressalta a importância de incluir a reativação do VVZ como causa de meningite e vasculite em indivíduos jovens, sem comorbidades e aparentemente imunocompetentes.

Diagnostic value of heparin-binding protein in the cerebrospinal fluid for purulent meningitis in children.

This study aimed to investigate the diagnostic value of heparin-binding protein (HBP) in the cerebrospinal fluid of children with purulent meningitis (PM). This study included 118 children with PM diagnosed at our hospital from January 2018 to January 2020, 110 children with viral meningitis (VM) and 80 children with suspected meningitis who were ruled out by cerebrospinal fluid (CSF) analysis during the same period. HBP and white blood cell (WBC) count in the CSF, and inflammatory factors, including C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and procalcitonin (PCT), were measured. Receiver-operator characteristic curves were used to analyze the predictive value of HBP, CRP, PCT, and TNF-α levels in the diagnosis of PM by CSF analysis. HBP levels in the CSF of children with PM were higher, while the CRP and serum PCT and TNF-α levels were elevated in all groups (P<0.05). In addition, HBP levels in the CSF were more accurate for the diagnosis of PM than traditional diagnostic indexes. HBP levels in the CSF can be used as an important reference for early diagnosis of PM.

The impact of viral infections on childhood central nervous system infections.

BACKGROUND: Viruses are a common cause of central nervous system (CNS) infections. However, studies of CNS viral pathogens in pediatric patients are poorly explored because viral infections are often erroneously diagnosed as bacterial infections. METHODS: 299 CNS samples were collected from pediatric patients aged from one month to 14 years old. A total of 140 viral meningitis cases that met the inclusion criteria were included in this study. In 38 of the 140 cerebral spinal fluid (CSF) samples (27.1%), conventional and real-time PCR were used to identify viruses commonly associated with CNS infections. RESULTS: Among them, 23 patients (16.5%) tested positive for flaviviruses such as dengue, Zika, and yellow fever virus, eight patients (5.7%) were positive for enterovirus (ENTV), and six patients (4.3%) were positive for human herpesvirus 1/2. We also identified one case of dengue virus and ENTV co-infection. CONCLUSIONS: A correlation between clinical symptoms and laboratory findings for the viruses was identified. Our study also reinforces the importance of including viruses in the laboratory diagnosis of CNS infections especially flaviviruses, which assists public health authorities in implementing early interventions.

Clinical performance of amperometry compared with enzymatic ultra violet method for lactate quantification in cerebrospinal fluid.

OBJECTIVES: The differential diagnosis between acute bacterial meningitis (BM) and viral meningitis (VM) is crucial for treatment and prognosis. Cerebrospinal fluid (CSF) lactate (LA) is considered a good biomarker for differentiating BM from VM. The objective of this study was to compare the clinical performance of amperometry, which is not validated for measurement of LA in CSF samples, with a validated method (enzymatic ultra violet), for their ability to discriminate between acute BM and VM. METHODS: It was a retrospective, descriptive comparative study, 320 CSF reports were included; LA was quantified in CSF using either Dimension AR machine (Dade Behring) or amperometry (RAPID Point 500, Siemens). All samples with bacteria (n=54) or virus (n=139) identified, compared with a control with normal CSF (n=127). RESULTS: CSF LA levels were comparable for amperometry or enzymatic methods on each group studied, in a wide range of LA levels; it was capable to distinguish BM from VM independent of the method used to quantify. CONCLUSIONS: The findings support the use of the amperometric method in measuring LA concentrations in CSF in a wide range of values. Amperometry is a less expensive method, validated for blood, easily available in small laboratories including in limited resources countries.

Diagnostic value of heparin-binding protein in the cerebrospinal fluid for purulent meningitis in children

This study aimed to investigate the diagnostic value of heparin-binding protein (HBP) in the cerebrospinal fluid of children with purulent meningitis (PM). This study included 118 children with PM diagnosed at our hospital from January 2018 to January 2020, 110 children with viral meningitis (VM) and 80 children with suspected meningitis who were ruled out by cerebrospinal fluid (CSF) analysis during the same period. HBP and white blood cell (WBC) count in the CSF, and inflammatory factors, including C-reactive protein (CRP), tumor necrosis factor (TNF)-α, and procalcitonin (PCT), were measured. Receiver-operator characteristic curves were used to analyze the predictive value of HBP, CRP, PCT, and TNF-α levels in the diagnosis of PM by CSF analysis. HBP levels in the CSF of children with PM were higher, while the CRP and serum PCT and TNF-α levels were elevated in all groups (P<0.05). In addition, HBP levels in the CSF were more accurate for the diagnosis of PM than traditional diagnostic indexes. HBP levels in the CSF can be used as an important reference for early diagnosis of PM.

Headache and pleocytosis in CSF associated with COVID-19: case report.

In December 2019, a new coronavirus infection was identified in China. Although the clinical presentation of COVID-19 is predominantly respiratory, more than 35%% of patients have neurological symptoms. We report an elderly female with asthenia, dry cough, anosmia, ageusia, fever, nausea, and a severe and persistent headache. She had confirmed COVID-19 using the nasal swab RT-PCR technique. Her cranial tomography was normal. The CSF analysis demonstrated a cell count of 21 cells/mm3 (80% lymphocytes and 20% monocytes), 34 mg/dl protein, and 79 mg/dl glucose. She improved after 4 days. Our report draws attention to the meningeal involvement of SARS-Cov-2.

Discriminating Tonate Virus from Dengue Virus Infection: A Matched Case-Control Study in French Guiana, 2003-2016.

Tonate virus (TONV) is an arbovirus discovered in 1973 in French Guiana (FG) belonging to the Venezuelan equine encephalitis virus complex, Alphavirus genus. Only few publications and cases have been reported in FG. The objectives of the present study were to describe the clinical picture of TONV and to compare its presentation with that of dengue virus (DENV). A retrospective study was performed in Cayenne hospital from 2003 to 2016 including all patients exclusively positive for TONV IgM and not for other alphaviruses. They were classified as high probability: typical clinical picture of arbovirus infection (i.e., fever, chills, headaches, muscle, and joint pains) and IgM seroconversion; medium probability: typical clinical picture + single positive IgM on a unique serum sample without control; and low probability: atypical clinical picture of infection and single positive IgM. Only patients with high and medium probability were included in the analysis and compared with a gender- and age-matched control group of DENV diagnosed by NS1 antigen (two controls per case). During the study period, 45 cases of TONV were included and compared with 90 cases of DENV. Twenty-eight (62.2%) were men; the median age was 34 years (IQ [22-49]). In the bivariate analysis, variables significantly associated with TONV versus DENV were the presence of cough (33.3% versus 10.3%) and anemia (32.5% versus 11.1%) and the absence of nausea (4.4% versus 32.2%), rash (2.2% versus 27.4%), fatigue (17.8% versus 41.0%), anorexia (6.7% versus 30.1%), muscle pain (42.2% versus 61.4%), headache (53.3% versus 70.8%), leukopenia (9.8% versus 44.4), and lymphopenia (42.5% versus 89.9%). There were no cases with severe neurological involvement, and there were no deaths. Tonate virus may be evoked as a cause of fever in patients living or returning from the Amazonian area. Positive TONV IgM does not prove the diagnosis and should not preclude from searching for alternative infectious diagnoses.

Herpes simplex virus type 2 meningitis as a manifestation of Good's syndrome.

Good's syndrome is a primary immunodeficiency phenocopy characterized for thymoma and immunodeficiency. The most frequent clinical presentation is recurrent or opportunistic infections, hematological alterations, and chronic diarrhea. We treated a 66-year-old man who consulted for 5 days of headache and diplopia with right sixth cranial nerve palsy at examination. Patient reported chronic diarrhea and prolonged febrile syndrome accompanied by weight loss of 23 kg in the last year. Exhaustive evaluation revealed Herpes simplex virus (HSV) type 2 meningitis, eosinophilic colitis, and type A thymoma. Severe antibody deficiency (hypogammaglobulinemia) associated with thymoma confirmed the diagnosis of Good's syndrome.

[Recurrent lymphocytic meningitis by herpes simplex virus type 2]. / Meningitis linfocítica recurrente por virus herpes simple tipo 2.

Recurrent lymphocytic meningitis or Mollaret's meningitis is a rare condition caused by a number of infectious, autoimmune, toxic and neoplastic diseases. Herpes simplex type 2 is the most commonly isolated agent. It usually compromises middle aged women, with a self-limited clinical presentation that resolves within a week leaving no sequelae. Its diagnosis is mainly based on nucleic acid detection on cerebrospinal fluid. Antiviral prophylaxis has not shown conclusive to avoid recurrences.

La meningitis linfocítica recurrente o meningitis de Mollaret es una entidad asociada a un gran número de etiologías infecciosas, autoinmunes, toxicológicas y neoplásicas. En la actualidad el virus herpes simple tipo 2 (HSV-2) es el agente más frecuentemente aislado. Afecta frecuentemente a mujeres de mediana edad y tiende a autolimitarse sin secuelas dentro de la primera semana de inicio de síntomas. El diagnóstico se basa en la detección de ácidos nucleicos virales en el líquido cefalorraquídeo. Al momento no se ha demostrado beneficio en el uso de tratamiento antiviral en la prevención de recurrencias.

Meningitis linfocítica recurrente por virus herpes simple tipo 2 / Recurrent lymphocytic meningitis by herpes simplex virus type 2

La meningitis linfocítica recurrente o meningitis de Mollaret es una entidad asociada a un gran número de etiologías infecciosas, autoinmunes, toxicológicas y neoplásicas. En la actualidad el virus herpes simple tipo 2 (HSV-2) es el agente más frecuentemente aislado. Afecta frecuentemente a mujeres de mediana edad y tiende a autolimitarse sin secuelas dentro de la primera semana de inicio de síntomas. El diagnóstico se basa en la detección de ácidos nucleicos virales en el líquido cefalorraquídeo. Al momento no se ha demostrado beneficio en el uso de tratamiento antiviral en la prevención de recurrencias.

Recurrent lymphocytic meningitis or Mollaret´s meningitis is a rare condition caused by a number of infectious, autoimmune, toxic and neoplastic diseases. Herpes simplex type 2 is the most commonly isolated agent. It usually compromises middle aged women, with a self-limited clinical presentation that resolves within a week leaving no sequelae. Its diagnosis is mainly based on nucleic acid detection on cerebrospinal fluid. Antiviral prophylaxis has not shown conclusive to avoid recurrences.

[Acute flaccid paralysis related to enterovirus with complete resolution of the neurological symptoms. A pediatric case report]. / Parálisis fláccida aguda por enterovirus con resolución completa del cuadro neurológico. A propósito de un caso pediátrico.

Since the wild poliovirus no longer circulates, the number of cases of acute flaccid paralysis decreased. However, cases related to non-polio enteroviruses and neurotrope viruses continue to occur. We present a nine-year-old patient with meningitis and myelitis with motor involvement in the lower limbs and neurogenic bladder associated with enterovirus, with complete resolution of the neurological symptoms following the administration of hyperimmune gammaglobulin.

Desde la eliminación de la circulación del virus polio salvaje, disminuyeron los casos de parálisis fláccida aguda. Sin embargo, continúan ocurriendo casos asociados a otros enterovirus no polio y virus neurotropos. Se presenta el caso de una paciente de 9 años con diagnóstico de meningitis y mielitis con compromiso motor en los miembros inferiores y vejiga neurogénica asociado a enterovirus, con resolución completa del cuadro neurológico posterior a la administración de gammaglobulina hiperinmune.

Human adenovirus meningoencephalitis: a 3-years' overview.

Human adenovirus (HAdV) has been recognized as a significant viral pathogen implicated in neurological diseases, particularly in immunocompromised patients. However, its involvement in meningoencephalitis remains unclear. The aim of this study was to investigate HAdV and other viral co-infections in the cerebrospinal fluid (CSF) of patients suspected of having either meningoencephalitis or encephalitis. A total of 373 CSF samples from patients under clinical suspicion of neurological viral infection were included in this study. HAdV was investigated by conventional or multiplex real-time PCR, for different time periods. The frequency of HAdV central nervous system (CNS) infection was 1.08%, predominating in female patients with a predisposing condition, and presented with HAdV encephalitis. HAdV CNS infection was found to occur during the months of autumn and winter. The frequency of HAdV detected in CSF positive samples increased after the change in the diagnostic method from conventional to multiplex real-time PCR. There were no specific NMRI or EEG characteristics and two CSF samples with HAdV encephalitis had normal CSF WBC count. There were two cases of co-infection with HIV; no other co-infections with enterovirus or herpes family viruses were detected. All patients had good outcome. Although HAdV is rarely observable in CNS infectious syndromes, it must be investigated particularly in immunocompromised patients.

Performance of lactate in discriminating bacterial meningitis from enteroviral meningitis.

The cytological and biochemical examination of cerebrospinal fluid (CSF) has been used for the presumed diagnosis of bacterial meningitis until the final microbiological results are achieved. We assessed the ability of CSF lactate in comparison with other CSF parameters to discriminate bacterial and enteroviral community acquired meningitis. We included 1,187 CSF samples of acute community-acquired meningitis, being 662 cases of bacterial and 525 of enteroviral meningitis. Lactate concentration (mg/dL), leukocyte count/mm3, protein (mg/dL), and glucose (mg/dL) were compared between bacterial and viral meningitis. Receiver operator characteristic (ROC) curves were used to assess diagnostic performance. CSF leukocytes, CSF protein and CSF lactate were significantly higher in bacterial meningitis cases (P<0.0001). CSF glucose was significantly lower in bacterial meningitis cases (P<0.0001). CSF lactate showed the best predictive ability with an area under the curve of 0.944 (95% CI 0.929 - 0.959). Considering a cut off of CSF lactate of 30 mg/dL, the sensitivity and specificity for bacterial meningitis were 84.1% and 99%, respectively. In the cytological and biochemical CSF analysis, CSF lactate was the most accurate marker for bacterial meningitis.

[Optochiasmatic tuberculomas as a paradoxical reaction to treatment for meningeal tuberculosis]. / Tuberculomas optoquiasmaticos como reaccion paradojica al tratamiento de tuberculosis meningea.

TITLE: Tuberculomas optoquiasmaticos como reaccion paradojica al tratamiento de tuberculosis meningea.

Cerebrospinal fluid lactate: a differential biomarker for bacterial and viral meningitis in children / Lactato no líquido cefalorraquidiano: um marcador diferencial para meningite bacteriana e meningite viral em crianças

Abstract Objective: To assess the performance of cerebrospinal fluid (CSF) lactate as a biomarker to differentiate bacterial meningitis from viral meningitis in children, and to define an optimal CSF lactate concentration that can be called significant for the differentiation. Methods: Children with clinical findings compatible with meningitis were studied. CSF lactate and other conventional CSF parameters were recorded. Results: At a cut-off value of 3 mmol/L, CSF lactate had a sensitivity of 0.90, specificity of 1.0, positive predictive value of 1.0, and negative predictive value of 0.963, with an accuracy of 0.972. The positive and negative likelihood ratios were 23.6 and 0.1, respectively. When comparing between bacterial and viral meningitis, the area under the curve for CSF lactate was 0.979. Conclusions: The authors concluded that CSF lactate has high sensitivity and specificity in differentiating bacterial from viral meningitis. While at a cut-off value of 3 mmol/L, CSF lactate has high diagnostic accuracy for bacterial meningitis, mean levels in viral meningitis remain essentially below 2 mmol/L.

Resumo Objetivo: Estudar o desempenho do lactato no líquido cefalorraquidiano como biomarcador para diferenciar a meningite bacteriana da meningite viral em crianças, e definir uma concentração de lactato ótima no líquido cefalorraquidiano que possa ser significativa para a diferenciação. Métodos: Foram estudadas crianças com achados clínicos compatíveis com meningite. O nível de lactato no líquido cefalorraquidiano e outros parâmetros convencionais do líquido cefalorraquidiano foram registrados. Resultados: Em um valor de corte de 3 mmol/L, o lactato no líquido cefalorraquidiano apresentou uma sensibilidade de 0,90, especificidade de 1,0, valor preditivo positivo de 1,0, valor preditivo negativo de 0,963, com uma precisão de 0,972. Os índices de probabilidade positivo e negativo foram 23,6 e 0,1, respectivamente. Para comparação entre a meningite bacteriana e viral, a área abaixo da curva do lactato no líquido cefalorraquidiano foi 0,979. Conclusões: Concluímos que o lactato no líquido cefalorraquidiano possui alta sensibilidade e especificidade na diferenciação da meningite bacteriana da meningite viral. Embora em um valor de corte de 3 mmol/L o lactato no líquido cefalorraquidiano possua alta precisão de diagnóstico da meningite bacteriana, os níveis médios na meningite viral permanecem basicamente abaixo de 2 mmol/L.

Cerebrospinal fluid lactate: a differential biomarker for bacterial and viral meningitis in children.

OBJECTIVE: To assess the performance of cerebrospinal fluid (CSF) lactate as a biomarker to differentiate bacterial meningitis from viral meningitis in children, and to define an optimal CSF lactate concentration that can be called significant for the differentiation. METHODS: Children with clinical findings compatible with meningitis were studied. CSF lactate and other conventional CSF parameters were recorded. RESULTS: At a cut-off value of 3mmol/L, CSF lactate had a sensitivity of 0.90, specificity of 1.0, positive predictive value of 1.0, and negative predictive value of 0.963, with an accuracy of 0.972. The positive and negative likelihood ratios were 23.6 and 0.1, respectively. When comparing between bacterial and viral meningitis, the area under the curve for CSF lactate was 0.979. CONCLUSIONS: The authors concluded that CSF lactate has high sensitivity and specificity in differentiating bacterial from viral meningitis. While at a cut-off value of 3mmol/L, CSF lactate has high diagnostic accuracy for bacterial meningitis, mean levels in viral meningitis remain essentially below 2mmol/L.

Impact of Enteroviral Polymerase Chain Reaction Testing on Length of Stay for Infants 60 Days Old or Younger.

OBJECTIVE: To determine the impact of a cerebrospinal fluid enterovirus polymerase chain reaction (PCR) test performance on hospital length of stay (LOS) in a large multicenter cohort of infants undergoing evaluation for central nervous system infection. STUDY DESIGN: We performed a planned secondary analysis of a retrospective cohort of hospitalized infants ≤60 days of age who had a cerebrospinal fluid culture obtained at 1 of 18 participating centers (2005-2013). After adjustment for patient age and study year as well as clustering by hospital center, we compared LOS for infants who had an enterovirus PCR test performed vs not performed and among those tested, for infants with a positive vs negative test result. RESULTS: Of 19 953 hospitalized infants, 4444 (22.3%) had an enterovirus PCR test performed and 945 (21.3% of tested infants) had positive test results. Hospital LOS was similar for infants who had an enterovirus PCR test performed compared with infants who did not (incident rate ratio 0.98 hours; 95% CI 0.89-1.06). However, infants PCR positive for enterovirus had a 38% shorter LOS than infants PCR negative for enterovirus (incident rate ratio 0.62 hours; 95% CI 0.57-0.68). No infant with a positive enterovirus PCR test had bacterial meningitis (0%; 95% CI 0-0.4). CONCLUSIONS: Although enterovirus PCR testing was not associated with a reduction in LOS, infants with a positive enterovirus PCR test had a one-third shorter LOS compared with infants with a negative enterovirus PCR test. Focused enterovirus PCR test use could increase the impact on LOS for infants undergoing cerebrospinal fluid evaluation.

Etiological agents of viral meningitis in children from a dengue-endemic area, Southeast region of Brazil.

Meningitis is a disease with a global distribution that constitutes a worldwide burden, with viruses as the primary etiologic agents. The range of viral meningitis severity depends mainly on age, immune status and etiological agent. The aim of this work was to investigate the suspected cases of viral meningitis using molecular techniques to confirm the viral infection. The diagnosed virus was correlated with clinical findings and cytochemical parameters in cerebrospinal liquid (CSF) of patients. CSF of 70 children with the presumptive diagnosis of viral meningitis was analyzed by real time PCR (qPCR). Viruses were identified by qPCR in 44 CSF samples (62.9%). Among them, 31 were identified as Enterovirus (ENTV) (70.4%), six as Human herpes virus 3 (HHV-3) (13.6%), five as Dengue virus (DENV) (11.7%), one as Human herpes virus 1-2 (2.3%) and one as Human herpes virus 5 (2.3%). Patients in the HHV-positive groups had increased percentage of polymorphonuclear neutrophils (PMN) (mean of 81%) while the groups of patients with DENV and ENTV had a mean of 30.9%. This study contributes to the knowledge of the epidemiological distribution of viral agents in CNS infections in children. In addition, it raises the relevance of DENV as an agent of CNS infection, and reinforces the importance for molecular in the cases of CNV infection.