A fatal case of tuberculous meningitis in a child with juvenile idiopathic arthritis: a diagnostic challenge

Abstract The prognosis of tuberculous meningitis, a rare form of extrapulmonary tuberculosis, depends on the stage of treatment initiation. We report a fatal case of tuberculous meningitis. The patient had received successive tumor necrosis factor (TNF) antagonists and abatacept to treat juvenile idiopathic arthritis, with negative results for polymerase chain reaction and acid-fast bacilli on smear, had normal cerebrospinal fluid (CSF) adenosine deaminase and glucose levels. Six weeks post-admission, the CSF culture demonstrated Mycobacterium tuberculosis. The altered immunological responses caused by anti-TNF treatment made the diagnosis challenging. Clinicians should bear this in mind and, if suspected, treatment should be initiated immediately.

Comparación de adenosina deaminasa y detección de anticuerpos anti-antígeno A60 para el diagnóstico de meningitis tuberculosa / A comparative study for adenosine deaminase and anti-antigen A-60 antibodies detection for the diagnosis of tuberculous meningitis

Background: Diagnosis of tuberculous meningitis (TBM) is hampered by the lack of rapid and accurate diagnostic tools. We evaluated the immunological response to Mycobacterium tuberculosis anti-A60 antibodies in cerebrospinal fluid (CSF) in comparison to adenosine deaminase (ADA) determination, for the diagnosis of TBM. Methods: A total of 63 CSF samples were analyzed by indirect ELISA for the detection of anti- A60 IgG, IgM and IgA. These include samples from 17 patients with confirmed TBM and 46 control patients with other infections. Results: The mean individual anti-A60 IgM, IgG and IgA CSF antibody titers were significantly higher in TBM in comparison with control groups (p < 0.01). The best discriminatory CSF antibody for confirming TBM diagnosis was IgM, with an area under the receiver operating characteristic curve of 0.928 (95%CI 0.834-0.978), compared to 0.863 (95% CI: 0.752-0.936) for ADA testing (p = NS). The sensitivity of anti- A60 IgM CSF antibody titers (cutoff > 0.06 U/ml) was 94.1% compared to 88.2% for ADA (cutoff > 6.2 U/ml), p = NS. Both anti A60 IgM and ADA showed the same moderate specificity (80.4%). Two cases of TBM were correctly identified by anti-A60 IgM but missed by ADA. Conclusion: The ELISA test for anti-antigen A60 antibodies (IgM) is a rapid and sensitive tool for the rapid diagnosis of TBM that can be a complement to ALDA determination. The specificity of both tests is still a limitation in TBM diagnosis.

Antecedentes: El diagnóstico de meningitis tuberculosa (MTBC) se ve limitado por la ausencia de técnicas diagnósticas rápidas y precisas en líquido cefalorraquídeo (LCR). En este estudio evaluamos la respuesta inmunoló-gica de anticuerpos anti-antígeno A60 de Mycobacterium tuberculosis en LCR en comparación a la determinación de adenosina deaminasa (ADA). Métodos: Un total de 63 muestras de LCR fueron estudiadas mediante ELISA indirecto para detección de IgG, IgM e IgA anti-A60. Estas muestras incluyeron 17 casos de MTBC confirmada y 46 controles con otras infecciones. Resultados: Los títulos de IgG, IgM e IgA anti A-60 resultaron significativamente superiores en casos de MTBC versus controles (p > 0,01). El anticuerpo con mej or poder discriminatorio resultó IgM, con un área bajo la curva ROC de 0,928 (95%IC 0,8340,978), comparado a 0,863 (95% IC: 0,752-0,936) para ADA (p = NS). La sensibilidad de IgM anti-A60 (nivel de corte > 0,06 U/ml) fue de 94,1% versus 88,2% para ADA (nivel de corte > 6,2 U/ml), p = NS. Ambos IgM anti-A60 y ADA presentaron la misma especificidad baja-moderada (80,4%). Dos casos de MMTBC fueron correctamente identificados por IgM anti-A60 pero no por ALDA. Conclusión: La detección de anticuerpos anti-A60 (IgM) puede ser de ayuda en el diagnostico de MTBC en forma complementaria a la determinación de ALDA. La baja especificidad de ambos tests constituye su principal limitante.

Tuberculous meningitis: a report of 60 adult cases / Meningitis tuberculosa: reporte de 60 casos adultos

OBJECTIVE: This was to evaluate the history, clinical and laboratory findings, outcome and prognosis of patients with tuberculous meningitis (TBM). METHOD: Between 1998 and 2009, 60 patients with TBM were evaluated, retrospectively. RESULT: Overall, 60 patients were selected, of which 33 (55%) were male. The patients' ages ranged from 14 to 62 years. In the majority of the patients, disease was in an advanced stage on admission (66% in stage III according to the British Research Council neurological criteria). The rate of complications was highest among patients in stages II and III with an overall mortality rate of 6.6% (n= 2 of stage II patients and n= 2 of stage III patients). CONCLUSIONS: Earlier admission of the patients with TBM could provide better outcomes with regard to sequelae and mortality. Fatal cases presented with rapid deterioration and were refractory to treatment.

OBJETIVO: El propósito de este trabajo fue evaluar la historia, los hallazgos clínicos y de laboratorio, la evolución, y la prognosis de pacientes con meningitis tuberculosa (MTB). MÉTODO: Entre 1998 y 2009, se evaluaron 60 pacientes con TBM, retrospectivamente. RESULTADOS: En general, se seleccionaron 60pacientes, de los cuales 33 (55%) fueron varones. La edad de los pacientes osciló de 14 a 62 años. En la mayoría de los pacientes, la enfermedad se encontraba en etapa avanzada al momento del ingreso (66% en la etapa III de acuerdo con los criterios neurológicos del Consejo Británico de Investigación). La tasa de complicaciones fue más alta entre los pacientes en las etapas IIy III con una tasa de mortalidad general de 6.6% (n = 2 en los pacientes de etapa IIy n = 2 en los pacientes de etapa III). CONCLUSIONES: El ingreso temprano de los pacientes con MTB podría proporcionar mejores resultados con respecto a las secuelas y la mortalidad. Los casos fatales se presentaron con deterioro rápido y fueron refractarios al tratamiento.

Tuberculous meningitis

To evaluate the role of cerebrospinal fluid [CSF] polymerase chain reaction [PCR] for Mycobacterium Tuberculosis in rapid diagnosis of tuberculous meningitis [TBM]. Prospective observational study. Medical A unit Hayat Abad Medical complex Peshawar from 1st September 2010 to 30th August 2011. A total of 20 Patients having fever, constitutional symptoms [malaise, vague ill health, headache, vomition], nuchal rigidity with altered mental and behavior changes were suspected as TBM and hence included in the study. Patients were divided into two groups based on direct and indirect evidence of tuberculosis in central nervous system [CNS] of patients. Group 1: Patients having direct evidence of mycobacterial infection in CNS as Acid Fast Bacilli smear positive in CSF. Group 2: Patients with indirect evidence of TB in CNS in form of typical CSF findings of TBM, positive sputum smear for Acid fast bacilli [AFB] or computed tomographic [CT] Scan brain findings suggestive of TBM or evidence of TB in x-ray chest or family History of tuberculosis and/or history of contact with TB patients or positive Mantoux Test or evidence of TB elsewhere in the body. Out of total 20 patients, 3 [15%] belonged to Group 1 having direct evidence of TBM the remaining 17 [85%] patients belonged to Group 2. Female patients were 60% while 40% patients were male. Mean age was 35.8 years. All patients had fever and headache. Productive cough was present in 40% patients. Thirty five percent had lost weight. Contact with TB patients was revealed in 35% patients. Signs of meningeal irritation were elicited in 90% patients. Cranial nerve palsies were seen in 25% patients, 10% had hemiparesis while 35% had impairment of consciousness. X-ray chest was normal in 65%. Computed tomographic scan was showing meningeal enhancement in 30% patients, hydrocephalus in 15% patients. PCR positive for mycobacterium tuberculosis. Of 17 patient in group 2, 64% patients had positive CSF PCR. Tuberculous meningitis is an important serious extrapulmonary complication of TB, related with high mortality and morbidity. The prompt and accurable diagnosis of TBM is a daunting challenge. CSF PCR for Mycobacterium tuberculosis is an excellent test for rapid diagnosis of TBM

Evaluation of Lionex TB kits and mycobacterial antigens for IgG and IgA detection in cerebrospinal fluid from tuberculosis meningitis patients

To evaluate commercial Lionex TB together with four antigens of Mycobacterium tuberculosis (MPT-64, MT10.3, 16 kDa and 38 kDa) for IgG and IgA cerebrospinal fluid (CSF) detection in the diagnosis of tuberculosis meningitis (TBM) with CSF negative acid-fast bacilli staining, 19 cases of TBM, 64 cases of other infectious meningoencephalitis and 73 cases of other neurological disorders were tested by enzyme linked immunosorbent assay. IgA-MPT-64 and IgG Lionex showed the highest sensitivities, specificities, positive predictive value and negative predictive value (63.2 percent, 47.4 percent; 95 percent, 93.7 percent; 40 percent, 98 percent and 28.4 percent, 97.1 percent, respectively). However, while grey zone was 12.7 percent and 6 percent, respectively, lowering sensitivity but maintains high specificity (> 95 percent). High protein concentration in CSF was associated with antibody positivity CSF/HIV+ which did not influence the sensitivity of both tests. To our knowledge, this is the first description of IgA-MPT-64 and IgG Lionex antibodies in CSF-TBM and, although there is good specificity, adjustments are needed based on antigen composition to enhance sensitivity.

Modified kenneth jones criteria for diagnosing tuberculous meningitis in children

To evaluate accuracy of modified Kenneth Jones scoring criteria [MKJSC] as a screening tool to diagnose tuberculous meningitis in children. Cross-sectional study. Paediatric Medicine, Unit-1, Bahawal Victoria Hospital, Bahawalpur, from May 2006 to March 2007. A total of 100 children admitted through emergency in Paediatric Medicine, Unit-l, were included who were having fever and features suggestive of central nervous system [CNS] infection. Lumbar puncture was done in all patients after written consent. Findings of lumbar puncture were taken as gold standard for the diagnosis of IBM. MKJSC was applied on each patient and accuracy determined against the gold standard. Out of 100 children, 47 were diagnosed as IBM on the basis of CSF results. All children had scored 0-7 or above according to MKJSC. A score 1-2, 3-4, 5-6 and 7 or more was obtained in 23, 25, 30 and 22 children respectively. Children who had scored 5 or more received ATT. Accuracy of MKJSC was calculated to be 91%. MKJSC is a simple and accurate tool to improve tuberculous meningitis case detection rate in children

Polymerase chain reaction as a useful and simple tool for rapid diagnosis of tuberculous meningitis in a Brazilian tertiary care hospital

Meningitis is a severe and potentially fatal form of tuberculosis. The diagnostic workup involves detection of acid-fast bacilli (AFB) in the cerebrospinal fluid (CSF) by microscopy or culture, however, the difficulty in detecting the organism poses a challenge to diagnosis. The use of the polymerase chain reaction (PCR) in the diagnostic approach to Mycobacterium tuberculosis (MTB) meningitis has been reported as a fast and accurate method, with several commercial kits available. As an alternative, some institutions have been developing inexpensive in house assays. In our institution, we use an in house PCR for tuberculosis. We analyzed the performance of our PCR for the diagnosis of MTB meningitis in 148 consecutive patients, using MTB culture as gold standard. The sensitivity and specificity of CSF PCR for the diagnosis of MTB meningitis was 50 percent and 98.6 percent respectively with a concordance with CSF mycobacterial culture of 96 percent (Kappa=0.52). In contrast to CSF cultures for MTB, our PCR test is a fast, simple and inexpensive tool to diagnose tuberculous meningitis with a performance similar to that obtained with the available commercial kits.

Multi drug resistant tuberculous meningitis in pediatric age group

Past decade has seen increase in cases of tuberculous meningitis [TBM] and multidrug resistance in such cases. The mortality rate for a mismanaged TBM is very high which increases manifold in presence of associated complicating factors. The present study was thus planned to evaluate the prevalence of MDR-TBM and look for associated complicating factors and carry out drug sensitivity pattern in all culture positive isolates. One hundred cerebro-spinal fluid [CSF] samples from children clinically suspected of having TBM were collected and processed for detection of Mycobacterium tuberculosis by conventional methods like Ziehl-Neelsen [ZN] staining, Lowenstein- Jensen [LJ] culture and newer method like BACTEC 460 TB culture. Antimicrobial susceptibility was performed on all culture positive isolates by BACTEC 460 TB system. Twenty two cases could be diagnosed as definitive TBM based on BACTEC culture. Of these 22 cases, six cases [27.3%] were positive by ZN staining and/or LJ culture. Of all isolates tested for drug sensitivity 18 were sensitive to all four drugs whereas 4 isolates were resistant to more than one drug. Since the prevalence of MDR-TBM is very high we conclude that all CSF samples should be subjected to sensitivity testing to diagnose it at an early time and determine its sensitivity pattern in view of its very high mortality

Factors associated to the positive cerebrospinal fuid culture in the tuberculous meningitis

Central nervous system involvement is the most common neurological complication in the course of tuberculosis. The lack of rapid and sensitive tests delays the early diagnosis. Here, we retrospectively reviewed the cerebrospinal fluid (CSF) examination of 30 patients with tuberculous meningitis confirmed by bacteriological tests (culture and/or polymerase chain reaction). The purpose of the present study was to determine the CSF parameters associated to the positive CSF culture for Mycobacterium tuberculosis in tuberculous meningitis. We found higher frequency of positive CSF culture in patients infected with HIV as well in patients with high number of neutrophils and high protein content (characteristic in the early or acute-stage patients), which suggests that the positive culture found in these patients may be associated with the presence of high bacillary load in CSF occurring in these stages.

A meningite tuberculosa é a complicação neurológica mais freqüente no curso da tuberculose. Entretanto, a carência de testes rápidos e sensíveis dificulta o diagnóstico precoce, contribuindo para o elevado índice de letalidade desta condição. Na presente análise, é feita revisão dos achados do líquido cefalorraquidiano (LCR) de 30 pacientes com o diagnóstico de meningite tuberculosa confirmado pelo exame bacteriológico. O objetivo do estudo consiste em caracterizar os parâmetros associados à positividade da cultura para Mycobacterium tuberculosis no LCR. Observamos maior freqüência de cultura positiva entre os pacientes infectados pelo HIV e naqueles que apresentam aumento de neutrófilos e da concentração de proteína no LCR. Nossos achados se justificam pelo fato de que na co-infecção com o HIV ocorre maior carga bacilífera em comparação aos pacientes não co-infectados. A presença de neutrofilorraquia e hiperproteinorraquia são marcadores de inflamação aguda, onde se supõe existir também maior concentração de bactérias no LCR.

Localização da lesão e achados do líquido cefalorraqueano na meningite tuberculosa: diferenças nos compartimentos lombar, cisternal e ventricular / Location of the lesion and the cerebrospinal fluid findings in tuberculous meningitis: differences in the lumbar, cisternal and ventricular compartiments

A tuberculose permanece como uma das doenças infecciosas mais freqüentes no mundo. No presente estudo, relatamos um caso de meningite tuberculosa, que evoluiu com bloqueio do fluxo do líquido cefalorraqueano (LCR), causando dificuldade diagnóstica. Discute-se a importância da localização da lesão e sua influência no exame do LCR como apoio ao diagnóstico da meningite tuberculosa. No caso relatado, a pesquisa do bacilo álcool-ácido resistente foi positiva no LCR cisternal e negativa no LCR lombar e ventricular, demonstrando que a maior acurácia do teste esteve relacionada a maior proximidade da lesão inflamatória.

Nested-PCR using MPB64 fragment improves the diagnosis of pleural and meningeal tuberculosis

O Mycobacterium tuberculosis é raramente encontrado em fluidos como o líquido pleural e o cerebroespinhal, tornando estas localizaçöes de difícil diagnóstico. Apresentamos nossa experiência com uma técnica de PCR aplicada a líquido pleural e cerebroespinhal com o uso do primer MPB64. Sessenta e três espécimes foram analisados: 30 líquidos pleurais (PF), 26 biópsias pleurais (PB) e 17 líquidos cerebroespinhais (CSF). O gold standard para o diagnóstico de meningite tuberculosa foi a cultura positiva para M. tuberculosis no CSF: Tuberculose pleural era diagnosticada quando culturas do PF e/ou PB eram positivas para M. tuberculosis, ou a histologia da PB mostrava granulomas. Nossos resultados, comparados aos gold standards empregados, mostram sensitividade de 70 por cento, especificidade de 88 por cento, valor preditivo positivo de 82 por cento e valor preditivo negativo de 80 por cento. A elevada especificidade e boa sensibilidade do fragmento MPB64 o transformam em um bom parâmetro para o diagnóstico de tuberculose pleural e do líquido cerebroespinhal

Características clínicas e laboratoriais de 62 casos de meningoencefalite tuberculosa / Clinical and laboratory characteristics of 62 tuberculous meningoencephalitis cases

Meningite tuberculosa se constitui em uma patologia endêmica há vários anos em várias cidades de países em desenvolvimento. Em Salvador foram estudados 62 pacientes com diagnóstico comprovado de meningoencefalite tuberculosa. A idade dos pacientes variou de 2 meses a 50 anos, 59,7 por cento dos casos se encontravam na faixa etária inferior a 4 anos. O tempo de doença antes do diagnóstico variou de horas a 90 dias, com média de 13 dias. Os sinais e sintomas clínicos mais comuns foram febre (86,7 por cento) e rigidez de nuca (81,8 por cento). O exame de líquido cefalorraquidiano mostrou: em média celularidade de 406/mm(3) (4 a 1509), glicose de 37,3 mg/dL (20 a 70) e proteínas de 203 mg/dL (30 a 500); predominância de linfócitos foi observada na maioria dos casos, mas em 21,3 por cento havia mais que 50 por cento de polimorfonucleares.

Utilidad de la determinación de adenosina deaminasa en líquido cefalorraquídeo para el diagnóstico de tuberculosis meníngea: experiencia de 4 años en un hospital de provincia / Usefulness of adenosine deaminase determination in cerebrospinal fluid for meningeal tuberculosis diagnosis: 4 years experience in a province hospital

The aim of this work was to study the usefulness of CSF adenosine deaminase determination in the diagnosis of tuberculous meningitis and determine if the proposed cutoff value of 7.1 IU/ml had the better sensitivitu and specificity. We retrospectively studied 148 patients, 12 with tuberculous meningitis and 136 with other central nervous system diseases. Adenosine deaminase values ranged from 3.6 to 31.2 IU/ml in patients with tuberculous meningitis and from 0.1 to 312 IU/ml in controls. The best sensitivity/specificity ratio (83.3 and 85.3 percent respectively) was obtained using a cutoff value of 6.5 IU/ml. It is concluded that CSF adenosine deaminase values are useful in the diagnosis of tuberculous meningitis and thet the cutoff value should be lowered to 6.5 IU/ml to improve its diagnostic yield

Tuberculous meningoencephalitis: a clinical study of 161 cases

This study deals with cases of tuberculous meningoenecephalitis [TBM] adimitted Tolbn-El-Khateeb Hospital for infectious diseases between Jan. 1986- Dec. 1992, and they were 161 cases. Diagnosis was based on the clinical presentation, cerebrospinal fluid [CSF] changes and theraputic response to antituberccolous therapy. The study contains detailed information on the epiderniological, clinical, and laboratory results, also a repeated prospective CSF analysis and comparison of the findings with their identicals among cases of pyogenic meningitis. For the difficulty in depending these results only for the final diagnosis of TB meningitis with an absence, or inefficiency of the laboratory procedures in our country in this concern, so it might be helpful to depend this study to help in [case definition] of TB meningitis, in order to haste-in its management

Kinetics of Isoniazid Transfer into Cerebrospinal Fluid in Patients with Tuberculous Meningitis

For the pharmacokinetic analysis of isoniazid transfer into CSF, steady-state isoniazid concentrations of plasma and CSF were measured in eleven tuberculous meningitis patients confirmed with findings of CSF and neuroimazing. Peak plasma levels (4.17-21.5 micrograms/mL) were achieved at 0.25 to 3 hours after multiple isoniazid dose (600 mg/day). Terminal half-life, total clearance (CI/F) and volume of distribution (Vd/F) were 1.42 +/- 0.41 hr, 0.47 +/- 0.22 L/kg/hr and 0.93 +/- 0.48 L/kg, respectively. Isoniazid concentrations in CSF collected intermittently were highest at 3 hr (Mean, 4.18 micrograms/mL) and were 0.54 +/- 0.21 micrograms/mL at 12 hrs after the last dose of isoniazid 10 mg/kg/day. CSF/plasma partitioning of isoniazid and equilibration rate were estimated using modified pharmacokinetic/pharmacodynamic model. Disposition rate constant from CSF to plasma and CSF/plasma partitioning ratio of isoniazid were estimated to be 0.39 h-1 and 1.17, respectively.