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Concept: Tuberculous meningitis

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PURPOSE: To study the incidence and clinical characteristics of delayed cerebral thrombosis in bacterial meningitis patients. METHODS: We assessed the incidence and clinical characteristics of delayed cerebral thrombosis in adults with cerebrospinal fluid (CSF) culture-proven community-acquired bacterial meningitis included in a prospective nationwide study in The Netherlands performed from 2006 to 2012. RESULTS: Delayed cerebral thrombosis occurred in 11 of 1,032 episodes (1.1 %). CSF culture yielded Streptococcus pneumoniae in ten patients and Listeria monocytogenes in one. Adjunctive dexamethasone therapy was administered before or with the first dose of antibiotics in 9 of 11 patients; two patients were initially not treated with dexamethasone. All patients made good initial recovery, followed by sudden deterioration after 7-42 days. Cranial imaging studies showed multiple cerebral infarctions in all patients. The outcome was unfavorable in all but one patient. In an explorative analysis, patients with delayed cerebral thrombosis had eightfold higher complement C5a CSF concentrations on the diagnostic lumbar puncture as compared in those without delayed cerebral thrombosis (p = 0.04). CONCLUSION: Delayed cerebral thrombosis is a rare but devastating complication of bacterial meningitis. Adjunctive dexamethasone therapy seems to predispose patients with bacterial meningitis to this complication. We found some evidence that this thrombotic complication is associated with activation of the complement system.

Concepts: Bacteria, Streptococcus pneumoniae, Cerebrospinal fluid, Meningitis, Listeria monocytogenes, Listeriosis, Tuberculous meningitis, Lumbar puncture

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BACKGROUND: Intensified antibiotic treatment might improve the outcome of tuberculous meningitis. We assessed pharmacokinetics, safety, and survival benefit of several treatment regimens containing high-dose rifampicin and moxifloxacin in patients with tuberculous meningitis in a hospital setting. METHODS: In an open-label, phase 2 trial with a factorial design in one hospital in Indonesia, patients (aged >14 years) with tuberculous meningitis were randomly assigned to receive, according to a computer-generated schedule, first rifampicin standard dose (450 mg, about 10 mg/kg) orally or high dose (600 mg, about 13 mg/kg) intravenously, and second oral moxifloxacin 400 mg, moxifloxacin 800 mg, or ethambutol 750 mg once daily. All patients were given standard-dose isoniazid, pyrazinamide, and adjunctive corticosteroids. After 14 days of treatment all patients continued with standard treatment for tuberculosis. Endpoints included pharmacokinetic analyses of the blood and cerebrospinal fluid, adverse events attributable to tuberculosis treatment, and survival. Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01158755. FINDINGS: 60 patients were randomly assigned to receive rifampicin standard dose (12 no moxifloxacin, ten moxifloxacin 400 mg, and nine moxifloxacin 800 mg) and high dose (ten no moxifloxacin, nine moxifloxacin 400 mg, and ten moxifloxacin 800 mg). A 33% higher dose of rifampicin, intravenously, led to a three times higher geometric mean area under the time-concentration curve up to 6 h after dose (AUC(0-6); 78·7 mg.h/L [95% CI 71·0-87·3] vs 26·0 mg.h/L [19·0-35·6]), maximum plasma concentrations (C(max); 22·1 mg/L [19·9-24·6] vs 6·3 mg/L [4·9-8·3]), and concentrations in cerebrospinal fluid (0·60 mg/L [0·46-0·78] vs 0·21 mg/L [0·16-0·27]). Doubling the dose of moxifloxacin resulted in a proportional increase in plasma AUC(0-6) (31·5 mg.h/L [24·1-41·1] vs 15·1 mg.h/L [12·8-17·7]), C(max) (7·4 mg/L [5·6-9·6] vs 3·9 mg/L [3·2-4·8]), and drug concentrations in the cerebrospinal fluid (2·43 mg/L [1·81-3·27] vs 1·52 mg/L [1·28-1·82]). Intensified treatment did not result in increased toxicity. 6 month mortality was substantially lower in patients given high-dose rifampicin intravenously (ten [35%] vs 20 [65%]), which could not be explained by HIV status or severity of disease at the time of presentation (adjusted HR 0·42; 95% CI 0·20-0·91; p=0·03). INTERPRETATION: These data suggest that treatment containing a higher dose of rifampicin and standard-dose or high-dose moxifloxacin during the first 2 weeks is safe in patients with tuberculous meningitis, and that high-dose intravenous rifampicin could be associated with a survival benefit in patients with severe disease. FUNDING: Royal Dutch Academy of Arts and Sciences, Netherlands Foundation for Scientific Research, and Padjadjaran University, Bandung, Indonesia.

Concepts: Tuberculosis, Cerebrospinal fluid, Meningitis, Tuberculous meningitis, Lumbar puncture, Tuberculosis treatment, Pyrazinamide, Rifampicin

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To assess the diagnostic validity of laboratory cerebrospinal fluid (CSF) parameters for discriminating between tuberculous meningitis (TBM) and other causes of meningeal syndrome in high tuberculosis incidence settings.

Concepts: AIDS, Diagnosis, Tuberculosis, Cerebrospinal fluid, Meningitis, Meninges, Tuberculous meningitis, Lumbar puncture

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Tuberculous meningitis (TBM) comprises a significant proportion of TB cases globally and causes substantial morbidity and mortality, especially in children and HIV-infected patients. It is a challenging condition to diagnose due to its non-specific clinical presentation and the limited sensitivity of existing laboratory techniques. Smear microscopy and culture are the most widely available diagnostic tools yet are negative in a significant proportion of TBM cases. Simplified and more affordable nucleic acid amplification tests (NAATs) are increasing in use in resource-limited settings but have not been optimised for cerebrospinal fluid (CSF) samples. Novel diagnostic methods such as CSF interferon-gamma release assays and various biomarkers have been developed but require further evaluation to establish their utility as diagnostic tools. There is an urgent need for further research into optimal diagnostic strategies to decrease the morbidity and mortality as a result of delayed or missed diagnosis of TBM. In this review, we discuss current and novel diagnostic tests in TBM and areas where future research should be prioritised.

Concepts: Diagnosis, Tuberculosis, Cerebrospinal fluid, Meningitis, Laboratory techniques, Tuberculous meningitis, Lumbar puncture

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BACKGROUND: Hydrocephalus of tubercular origin is one of the most dreaded and difficult to manage complications of brain tuberculosis. Traditionally, the management has been ventriculoperitoneal shunting, but in recent years emerging interest is in endoscopic ventriculostomy. In this article, we discuss the management protocol of hydrocephalus in various stages of disease. METHODS: A total of 424 cases of tubercular origin hydrocephalus were managed between years 2000 and 2009. Initially the cases were managed by ventriculoperitoneal shunting, which was followed by use of endoscopic third ventriculostomy. Drug-resistant cases were also encountered and managed according to drug sensitivity. RESULTS: The results provided through evaluation of retrospective data showed a high mortality in cases of hydrocephalus of acute origin if endoscopic third ventriculostomy was performed. The cerebrospinal fluid protein level and neurological status of the patient determined the success or failure of the procedure. For better management, patients were divided into six groups and their management underlined. CONCLUSION: The cases of tubercular meningitis with aqueductal stenosis presenting in early stages should be given a trial of endoscopic third ventriculostomy where chronic burnt-out cases or cases with communicating hydrocephalus should be managed by ventriculoperitoneal shunting.

Concepts: Brain, Intracranial pressure, Neurology, Cerebrospinal fluid, Hydrocephalus, Meningitis, Ventricular system, Tuberculous meningitis

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PURPOSE OF REVIEW: Early diagnosis and treatment of tuberculous meningitis (TBM) saves lives, but current laboratory diagnostic tests lack sensitivity and the best treatment regimens are uncertain. This article reviews the advances towards better TBM diagnosis and treatments made over the last 2 years. RECENT FINDINGS: A modified Ziehl-Neelsen stain, interferon-gamma release assays and Mycobacterium tuberculosis antigen detection assays have all shown promise as new TBM diagnostic tests. HIV-associated TBM carries an especially grave prognosis and there are new data describing the optimal timing of antiretroviral treatment initiation and the clinical predictors of TBM immune reconstitution inflammatory syndrome. The pharmacokinetic and pharmacodynamic properties of different fluoroquinolones for TBM treatment have been compared, and there are intriguing new data to suggest higher doses of rifampicin given intravenously may improve the survival. Finally, there are preliminary data to suggest that the beneficial effect of adjunctive corticosteroids on TBM survival may be augmented by aspirin and predicted by a polymorphism in a gene responsible for eicosanoid synthesis. SUMMARY: Much remains to be done to improve the outcome from TBM. There have been important advances in the treatment, which may influence treatment guidelines in the near future, but there remains an urgent need for better diagnostic tests.

Concepts: AIDS, Immune system, Inflammation, Tuberculosis, Mycobacterium tuberculosis, Meningitis, Ziehl-Neelsen stain, Tuberculous meningitis

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Tuberculous meningitis, the most destructive form of tuberculosis, continues to be associated with considerable mortality and morbidity; among children, it is the major cause of death resulting from tuberculosis. The consequences of tuberculous meningitis are yet again clearly shown in the article by Heemskerk et al. in this issue of the Journal.(1) This randomized, controlled study of tuberculous meningitis in Vietnamese adults, probably the largest ever undertaken, was carefully planned and executed and evaluated an intensified regimen that included both a higher dose of oral rifampin than the standard dose (15 mg per kilogram of body weight vs. 10 . . .

Concepts: AIDS, Death, Mass, Tuberculosis, Meningitis, Major, Tuberculous meningitis, Rifampicin

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Using a combination of aspirin, anti-tuberculosis drugs and steroids may help to reduce the number of strokes and deaths in patients with tuberculous meningitis.

Concepts: Stroke, Tuberculosis, Meningitis, Tuberculous meningitis, Lumbar puncture

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David Boulware discusses the challenges of diagnosing tuberculous meningitis and the implications of the study by Patel and colleagues using the Xpert MTB/RIF assay for diagnosis. Please see later in the article for the Editors' Summary.

Concepts: Diagnosis, Tuberculosis, Meningitis, Tuberculous meningitis, Editors

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Tuberculous meningitis (TBM) leads to death or disability in half the affected individuals. Tools to assess severity and predict outcome are lacking. Neuro-specific biomarkers could serve as markers of the severity and evolution of brain injury, but have not been widely explored in TBM. We examined biomarkers of neurological injury (neuromarkers) and inflammation in pediatric TBM and their association with outcome.

Concepts: Medicine, Brain, Traumatic brain injury, Tuberculosis, Cerebrospinal fluid, Meningitis, Tuberculous meningitis, Lumbar puncture