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Subacute and chronic meningitis (SCM) presents significant diagnostic challenges, with numerous infectious and non-infectious inflammatory causes. This study examined patients aged 16 and older with SCM admitted to referral centers for neuroinfections and neuroinflammations in Mashhad, Iran, between March 2015 and October 2022. Among 183 episodes, tuberculous meningitis was the most common infectious cause (46.5%), followed by Brucella meningitis (24.6%). The cause of SCM was definitively proven in 40.4%, presumptive in 35.0%, and unknown in 24.6% of cases. In-hospital mortality was 14.4%, and 30.5% of survivors experienced unfavorable outcomes (Glasgow Outcome Scale 2-4). Patients with unknown causes had a significantly higher risk of death compared to those with presumptive or proven diagnoses (risk ratio 4.18). This study emphasizes the diagnostic difficulties of SCM, with one-quarter of cases remaining undiagnosed and over one-third having only a presumptive diagnosis. Improving diagnostic methods could potentially enhance prognosis and reduce mortality.

Background: Tuberculous meningitis (TBM) emerges as a grave complication of tuberculosis in people living with HIV (PLWH). The diagnosis and treatment of TBM pose significant challenges, leading to elevated mortality rates. To comprehensively grasp the epidemiological landscape of TBM in PLWH, a systematic review and meta-analysis were meticulously undertaken., Methods: We performed a comprehensive search in PubMed, Embase, and Web of Science from database inception to September 19th, 2023, with no limitations on the publication type. The search terms were HIV/AIDS terms (AIDS OR HIV OR PLWH) and TBM-related terms (tuberculous meningitis OR TBM). Studies included in this meta-analysis evaluated the incidence of TBM among PLWH, or we were able to calculate the incidence of TBM among PLWH from the research., Results: The analysis revealed that the prevalence of TBM among PLWH was 13.6% (95% CI: 6.6-25.9%), with an incidence rate of 1.5 cases per 1000 persons per year. The case fatality rate was found to be 38.1% (95% CI: 24.3-54.1%). No significant publication bias was observed. Meta-regression analysis identified the proportion of females and finance situation as factors influencing the outcomes., Conclusions: Our study highlights TBM as a prevalent opportunistic infection that targets the central nervous system in PLWH. The elevated case fatality rate is especially prominent among PLWH in impoverished regions, underscores the pressing necessity for enhanced management strategies for PLWH suffering from TBM., Trial Registration: PROSPERO; No: CRD42022338586., (© 2024. The Author(s).)

Tuberculous meningitis (TBM) is a prevalent global intracranial infection and the most lethal and disabling form of tuberculosis. TBM with mixed intracranial infections is clinically rare but has a higher mortality rate. To investigate the clinical characteristics of TBM with mixed intracranial infections, demographic and clinical data of TBM and pulmonary tuberculosis (PTB) patients admitted to Shenzhen Third People's Hospital between January 2015 and October 2022 were collected anonymously. A total of 207 cases of TBM were diagnosed, of which 16 cases (7.73%) were TBM with mixed intracranial infections. The overall mortality rate of TBM cases was 16.4%, while the mortality rate of TBM cases with mixed intracranial infections was as high as 35.7%. Compared to simple TBM cases, TBM cases with mixed intracranial infections had severer clinical symptoms. The percentage of human immune deficiency virus (HIV)-positive TBM cases with mixed intracranial infections reached up to 68.8%. HIV co-infection, CD4 + /CD8 + T-cell counts less than 1, cranial nerve impairment, paralysis, cerebral infarction, PRO less than 450 mg/L, WBC less than 10 × 10 6 /L, and CL more than 120 mmol/L were risk factors for TBM cases with mixed intracranial infections. Compared to PTB, HIV co-infection, CD4 + T cell less than 550 /uL, and age less than 45 years were risk factors for TBM, and TBM was associated with higher mortality rates. Our study provides additional data to better understand single TBM and TBM with mixed intracranial infections. More than two-thirds of TBM cases with mixed intracranial infections were HIV-positive. Clinicians should consider the possibility of multiple infections in people with TBM/HIV co-infection., Importance: TBM can cause severe neurological damage and death, and TBM with mixed intracranial infections can exacerbate the damage and poor prognosis of the disease. TBM with mixed intracranial infections is a rare disease, which has led to an incomplete understanding of its clinical features. This study investigated the clinical features of TBM and its associated factors by comparing the characteristics of TBM with mixed intracranial infections, single TBM and pulmonary tuberculosis. This information will help to improve the understanding of TBM, diagnostic accuracy and treatment outcomes., Competing Interests: The authors declare no conflict of interest.

Objective: To investigate risk factors associated with long-term mortality in patients with stage II and III tuberculous meningitis (TBM)., Methods: This retrospective analysis examined patients who were first diagnosed with stage II and III TBM at West China Hospital of Sichuan University between January 1, 2018 and October 1, 2019. Patients were followed via telephone and categorized into survival and mortality groups based on 4-year outcomes. Multivariate logistic regression identified independent risk factors for long-term mortality in stage II and III TBM., Results: In total, 178 patients were included, comprising 108 (60.7%) males and 36 (20.2%) non-survivors. Mean age was 36 ± 17 years. Compared to survivors, non-survivors demonstrated significantly higher age, heart rate, diastolic blood pressure, blood glucose, rates of headache, neurological deficits, cognitive dysfunction, impaired consciousness, hydrocephalus, and basal meningeal inflammation. This group also exhibited significantly lower Glasgow Coma Scale (GCS) scores, blood potassium, albumin, and cerebrospinal fluid chloride. Multivariate analysis revealed age (OR 1.042; 95% CI 1.015-1.070; P = 0.002), GCS score (OR 0.693; 95% CI 0.589-0.814; P < 0.001), neurological deficits (OR 5.204; 95% CI 2.056-13.174; P < 0.001), and hydrocephalus (OR 2.680; 95% CI 1.081-6.643; P = 0.033) as independent mortality risk factors. The ROC curve area under age was 0.613 (95% CI 0.506-0.720; P = 0.036) and 0.721 (95% CI 0.615-0.826; P < 0.001) under GCS score., Conclusion: Advanced age, reduced GCS scores, neurological deficits, and hydrocephalus were identified as independent risk factors for mortality in stage II and III TBM patients., (© 2024. The Author(s).)

We conducted a prospective cohort study to determine the prevalence of leukotriene A4 hydrolase (LTA4H) polymorphisms in Zambian adults with tuberculous meningitis (TBM) and its association with mortality. We completed genotype testing on 101 definite cases of TBM and 119 consecutive non-TBM controls. The distribution of genotypes among TBM patients was as follows: C/C (0.83), C/T (0.14), T/T (0.03). There was no significant difference in genotype distribution between TBM and non-TBM patients. We found no relationship between LTA4H polymorphism and survival. Prospective studies are needed to determine the benefit of adjuvant steroids in TBM based upon population LTA4H genotype. ANN NEUROL 2021;90:994-998., (© 2021 American Neurological Association.)

Introduction: Tubercular bacterial meningitis continues to be an important cause of morbidity (especially neurologic handicap) in children from resource-poor countries. The present study was planned to assess the clinical and radiological presentation in cases of tubercular meningitis as well as to study the factors associated with mortality., Methodology: This study was done over a period of 12 months on children between 5 years and 13 years with suspected TBM. Staging of tubercular meningitis was done according to RNTCP Pediatric TB guideline 2019., Result: The study was conducted on a total of 47 pediatric patients with TBM. Mean age of children in present study was 8.77 ± 2.5 years. Our study documented male preponderance for TBM. Severe thinness was observed in 38.3% patients with TBM. Only 59.6% patients were immunized against tuberculosis and history of contact was documented in 40.5% patients. Maximum children belonged to stage I of TBM (59.6%) followed by stage III and stage II in 34% and 6.4% patients respectively. Montoux test positivity was observed in 14.9% patients only. CSF CBNAAT was positive in 6.4% patients. The most common finding was meningeal enhancement seen in 27.7% of patients followed by tuberculomas in 10.6%.Chest X ray was abnormal in 44.7% patients. In present study mortality was observed in 11 (23.4%) cases. Out of various risk factors, mortality was significantly associated with nutritional status and stage of TBM (p < 0.01)., Conclusion: TBM is associated with high morbidity and mortality in children especially in India where Burden of TB is high. Our study emphasized on the risk factors associated with mortality in children with TBM and need for early diagnosis and appropriate treatment., Competing Interests: Conflict of interest All authors have none to declare., (Copyright © 2021 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

There is a clear need to improve host-directed therapy for tuberculous meningitis (TBM), the most severe and deadly manifestation of tuberculosis. Corticosteroids represent the only host-directed therapy of proven benefit in TBM, yet their effect is modest, the mechanism by which they reduce mortality is unknown, and there is evidence for heterogeneity in their effect. Novel therapeutic approaches are therefore urgently needed. Cellular metabolism is critical for the function of immune cells; through unbiased metabolomics we recently found that high concentrations of cerebrospinal fluid (CSF) tryptophan are associated with increased mortality in Indonesian TBM patients, and that CSF tryptophan concentrations are under strong genetic regulation. Many questions remain. How exactly is tryptophan metabolism altered during TBM? How does it correlate with inflammation, immunopathology, and response to corticosteroids? How is tryptophan metabolism genetically regulated? What is the effect of HIV co-infection on tryptophan metabolism before and during TBM treatment? The ULTIMATE project addresses these questions by integrating data and specimens from large patient studies and clinical trials evaluating the effects of corticosteroids in Vietnam and Indonesia. Through its powerful and unbiased approach, ULTIMATE aims to identify which TBM patients benefit from corticosteroids and if novel therapeutic targets, such as the tryptophan pathway, could be targeted., (Copyright © 2021. Published by Elsevier Ltd.)

Adjunctive treatment with antiinflammatory corticosteroids like dexamethasone increases survival in tuberculosis meningitis. Dexamethasone responsiveness associates with a C/T variant in Leukotriene A4 Hydrolase ( LTA4H ), which regulates expression of the proinflammatory mediator leukotriene B 4 (LTB 4 ). TT homozygotes, with increased expression of LTA4H , have the highest survival when treated with dexamethasone and the lowest survival without. While the T allele is present in only a minority of the world's population, corticosteroids confer modest survival benefit worldwide. Using Bayesian methods, we examined how pretreatment levels of cerebrospinal fluid proinflammatory cytokines affect survival in dexamethasone-treated tuberculous meningitis. LTA4H TT homozygosity was associated with global cytokine increases, including tumor necrosis factor. Association between higher cytokine levels and survival extended to non-TT patients, suggesting that other genetic variants may also induce dexamethasone-responsive pathological inflammation. These findings warrant studies that tailor dexamethasone therapy to pretreatment cerebrospinal fluid cytokine concentrations, while searching for additional genetic loci shaping the inflammatory milieu., Competing Interests: Competing interest statement: D.M.T. and E.S. are coauthors on a 2018 meeting report., (Copyright © 2021 the Author(s). Published by PNAS.)

Inflammation contributes to the pathophysiology and high mortality of tuberculous meningitis. The IL-1β pathway has been implicated in immunopathology and could be a target for host-directed therapy. IL-1β was elevated in the cerebrospinal fluid (CSF) of 225 HIV-uninfected tuberculous meningitis patients in Indonesia compared to controls, but did not predict subsequent mortality, nor did IL-6 or IL-1Ra. Furthermore, genetic loci known to regulate IL1B gene expression did not predict mortality in 443 tuberculous meningitis patients, although two of these loci did predict CSF IL-1β concentrations. Collectively, these data argue against a role for IL-1β targeted host-directed therapy in tuberculous meningitis., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Background: Tuberculous meningitis (TBM) occurs in 1-5% of cases of tuberculosis. Without early treatment, mortality and permanent disability rates are high., Methods: A retrospective study performed at a tertiary hospital in Madrid (Spain) to describe clinical, diagnostic, and therapeutic aspects of TBM and analyze epidemiological trends over forty years, divided into two intervals (1979-1998 and 1999-2018)., Results: Overall, TBM was diagnosed in 65 patients (1.8% of new tuberculosis diagnoses), 48 in the first period and 17 in the second one. Median age at diagnosis increased from 38.5 to 77 years (p = 0.003). The proportion of non-HIV immunosuppressed patients increased (from 2.1% to 29.4%, p < 0.001), while the percentage of patients with a history of drug-abuse decreased (from 33.3% to 5.9%, p = 0.027). The median time between the onset of neurological symptoms and lumbar puncture increased from seven to 15 days (p = 0.040). The time between the onset of symptoms and the initiation of tuberculostatic treatment also increased from eleven to 18 days (p = 0.555). Results from image, biochemical, and microbiological tests showed no differences between both periods. A decreasing trend was observed in survival rates at 1-week (from 97.9% to 64.7%, p < 0.001), 1-month (from 91.7% to 58.8%, p = 0.002) and 1-year (from 85.4% to 47.1%, p = 0.002) after TBM diagnosis., Conclusions: The profile of patients diagnosed with TBM has changed from a young HIV-infected patient with a history of drug addiction to an elderly patient with non-HIV immunosuppression. Diagnosis and start of treatment both experienced a noticeable delay in the second period, which could help explain the increase in mortality observed across the two periods., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Patients with tuberculous meningitis (TBM) in any stage of the British Medical Research Council (BMRC) scale, if requiring mechanical ventilation (MV), are likely to have a poor outcome. We report the usefulness of BMRC, BMRC-MV, and BMRC-hydrocephalus (BMRC-HC) staging, and Haydarpasa Meningitis Severity Index (HAMSI) scoring in predicting the outcome of TBM. One hundred ninety-seven TBM patients were analyzed from a prospectively maintained TBM registry. The severity of meningitis was categorized using BMRC (stages I-III), BMRC-MV (I-IV [MV patients were grouped as stage IV]), and BMRC-HC (I-IV [BMRC stage III patients with hydrocephalus were grouped as stage IV]). Haydarpasa Meningitis Severity Index scoring was categorized as < 6 and ≥ 6. The outcome was defined at 6 months using the modified Rankin Scale (mRS) as death, poor (mRS score > 2), or good (mRS score ≤ 2). Forty-nine (25%) patients died. BMRC-mechanical ventilation stage IV had the highest predictive value for defining death, with a sensitivity of 88% and a specificity of 86%. About 81.7% of surviving patients had a good outcome at 6 months. BMRC-mechanical ventilation stages I-III had the highest predictive value for defining good outcome, with a sensitivity of 93% and a specificity of 61%. In TBM, BMRC-MV staging has the best predictive value for defining death and disability.

Background: Pediatric tuberculosis (TB) constitutes 8% of the total caseload of TB. Children are particularly vulnerable to dissemination of disease and mortality., Aim: To determine mortality rate, elucidate type of TB, causes and predictors of mortality, if any, in admitted pediatric TB patients., Methods: Present retrospective study was conducted in a tertiary referral center over last 6½ year on children who died out of total TB admissions., Results: Out of total 1380 pediatric (<15 years of age) TB admissions, 74 children died, a mortality rate of 5.36%. Mean age was 11.4 years with highest mortality 47 (63.51%) in patients from 11 to 14 years age group. Significant majority 58 (78.38%) patients were females (p < 0.011). Range of hospital stay was 0-113 days with 7 (9.5%), 9 (12.16%) and 27 (36.48%) children dying on day of admission, next day and 3rd-7th day respectively, therefore a total of 43 (58.11%) died within first week of admission. Most 60 (81.08%) patients belonged to poor socio-economic status. History of contact was present in 12 (16.22%) cases while none had diabetes. 31 (41.89%) patients had sepsis and severe anemia (Hb ≤ 6 g %) was present in 6 (8.11%) patients at admission, out of which 4 died on the same day of admission, even before blood could be arranged. Most patients 68 (91.89%) had pulmonary TB with 25 children having concomitant extrapulmonary involvement, while 4 (5.41%) had meningeal TB and 2 (2.70%) had disseminated TB with HIV. Microbiological confirmation was achieved in 51 (68.92%) (48 PTB and 3 EPTB) cases while 23 (31.08%) were clinically diagnosed. Bilateral extensive fibro-cavitary disease with infiltrations was the commonest. Drug resistance was confirmed in 21 (28.38%) with 2, 5, 8, 5 and 1 patient diagnosed with mono H, RR, MDR, pre-XDR and XDR respectively but results of 9 patients were received posthumously. Treatment given was category 1, category 2 and regimens for drug resistant TB in 24 (32.43%), 29 (39.19%) and 21 (28.37%) cases respectively based on prior history of ATT and drug sensitivity. Adverse drug reactions were noted in 12 (16.21%) cases. Noted immediate causes of mortality were cardio-respiratory failure, sudden pneumothorax, massive hemoptysis, sepsis, extensive pulmonary disease and aspiration pneumonia. The pointers towards mortality include female gender, severe malnutrition, anemia, extensive disseminated disease and drug resistant TB. Ignorance, dependency of children on parents, poor adherence and late referrals into the system lead to delayed diagnosis and initiation of proper regimen based treatment., Conclusion: Early referrals of non-responders and failures to centers equipped with programmatic management facilities are essential for proper, timely management of pediatric TB to reduce mortality., (Copyright © 2019 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Purpose of Review: Tuberculous meningitis (TBM) is associated with significant mortality and morbidity yet is difficult to diagnose and treat. We reviewed original research published in the last 2 years, since 1 January 2018, which we considered to have a major impact in advancing diagnosis, treatment and understanding of the pathophysiology of TBM meningitis in children and adults., Recent Findings: Studies have sought to identify a high sensitivity diagnostic test for TBM, with new data on modified Ziehl--Neelsen staining, urinary and cerebrospinal fluid (CSF) lipoarabinomannan and GeneXpert Ultra. Recent studies on CSF biomarkers provide a better understanding of the detrimental inflammatory cascade and neuromarkers of brain damage and suggest potential for novel host-directed therapy. Tryptophan metabolism appears to affect outcome and requires further study. Increased clinical trials activity in TBM focuses on optimizing antituberculosis drug regimens and adjuvant therapy; however, there are few planned paediatric trials., Summary: Tuberculous meningitis still kills or disables around half of sufferers. Although some progress has been made, there remains a need for more sensitive diagnostic tests, better drug therapy, improved management of complications and understanding of host-directed therapy if outcomes are to improve.

Background: Hydrocephalus is a common, life threatening complication of human immunodeficiency virus (HIV)-related central nervous system opportunistic infection which can be treated by insertion of a ventriculoperitoneal shunt (VPS). In HIV-infected patients there is concern that VPS might be associated with unacceptably high mortality. To identify prognostic indicators, we aimed to compare survival and clinical outcome following VPS placement between all studied causes of hydrocephalus in HIV infected patients., Methods: The following electronic databases were searched: The Cochrane Central Register of Controlled Trials, MEDLINE (PubMed), EMBASE, CINAHL Plus, LILACS, Research Registry, the metaRegister of Controlled Trials, ClinicalTrials.gov, African Journals Online, and the OpenGrey database. We included observational studies of HIV-infected patients treated with VPS which reported of survival or clinical outcome. Data was extracted using standardised proformas. Risk of bias was assessed using validated domain-based tools., Results: Seven Hunderd twenty-three unique study records were screened. Nine observational studies were included. Three included a total of 75 patients with tuberculous meningitis (TBM) and six included a total of 49 patients with cryptococcal meningitis (CM). All of the CM and two of the TBM studies were of weak quality. One of the TBM studies was of moderate quality. One-month mortality ranged from 62.5-100% for CM and 33.3-61.9% for TBM. These pooled data were of low to very-low quality and was inadequate to support meta-analysis between aetiologies. Pooling of results from two studies with a total of 77 participants indicated that HIV-infected patients with TBM had higher risk of one-month mortality compared with HIV non-infected controls (odds ratio 3.03; 95% confidence-interval 1.13-8.12; p = 0.03)., Conclusions: The evidence base is currently inadequate to inform prognostication in VPS insertion in HIV-infected patients. A population-based prospective cohort study is required to address this, in the first instance.

Background: Tuberculous meningitis (TBM) is one of the most life-threatening infectious diseases. We performed a systematic review and meta-analysis of the clinical features, outcomes, and prognostic factors for TBM in adults., Methods: PubMed, EMBASE, Cochrane CENTRAL, and Web of Science were searched for studies that reported the clinical outcomes and/or risk factors for death in adults with TBM between January 1990 and July 2018. A random-effects meta-analysis model was used to pool data on clinical features, outcomes, and risk factors for death., Results: Thirty-two studies that examined 5023 adults who had TBM met the inclusion criteria. Overall, the mortality was 22.8% [95% confidence interval (CI) 18.9-26.8] and the risk of neurological sequelae was 28.7% (95% CI 22.8-35.1). The major risk factors for death (OR > 2 and P < 0.05) were advanced stage of disease (OR = 6.06, 95% CI 4.31-8.53), hydrocephalus (OR = 5.27, 95% CI 2.25-12.37), altered consciousness (OR 3.33, 95% CI 1.51-7.36), altered sensorium (OR 3.31, 95% CI 2.20-4.98), advanced age (> 60 years; OR = 2.64, 95% CI 1.27-5.51), and cerebral infarction (OR = 2.35, 95% CI 1.63-3.38). The clinical features and diagnostic findings present in more than four-fifths of the patients were fever (86.3%, 95% CI 82.4-89.8) and low CSF/serum glucose ratio (80.6%, 95% CI 64.8-92.6)., Conclusions: Adults with TBM have high rates of mortality. Clinicians should maintain a high clinical suspicion for patients who present with certain clinical features, and should pay more attention to prognostic factors.

Background: Tuberculous meningitis is the most devastating presentation of disease with Mycobacterium tuberculosis. We sought to evaluate treatment outcomes for adult patients with this disease., Methods: The Ovid MEDLINE, EMBASE, Cochrane Library and Web of Science databases were searched to identify all relevant studies. We pooled appropriate data to estimate treatment outcomes at the end of treatment and follow-up., Results: Among the articles identified, 22 met our inclusion criteria, with 2437 patients. In a pooled analysis, the risk of death was 24.7% (95%CI: 18.7-31.9). The risk of neurological sequelae among survivors was 50.9% (95%CI: 40.2-61.5). Patients diagnosed in stage III or human immunodeficiency virus (HIV) positive were significantly more likely to die (64.8, 53.4% respectively) during treatment. The frequency of cerebrospinal fluid (CSF) acid-fast-bacilli smear positivity was 10.0% (95% CI 5.5-17.6), 23.8% (15.2-35.3) for CSF culture positivity, and 22.3% (17.8-27.5) for CSF polymerase chain reaction positivity. We found that the headache, fever, vomiting, and abnormal chest radiograph were the most common symptoms and diagnostic findings among tuberculous meningitis patients., Conclusions: Despite anti-tuberculosis treatment, adult tuberculous meningitis has very poor outcomes. The mortality rate of patients diagnosed in stage III or HIV co-infection increased significantly during treatment.

Intravenous (IV) dexamethasone is recommended for 14 days in stage 1 and 28 days in stage 2/3 tuberculous meningitis (TBM). We used a different steroid protocol. We shifted TBM patients to oral steroids after 48 hours of sustained improvement on IV steroids (oral group). Patients who worsened after shifting to oral steroids were reinitiated on IV steroids. Once they showed a consistent improvement for 48 hours, the IV steroids were overlapped with oral steroids for 7-10 days to taper off IV steroids (overlap group). We compared total IV steroid days in our patients with the recommended treatment and identified predictors that favored the oral group. This was a retrospective study. We included 98 patients with TBM (66 in the overlap group and 32 in the oral group) from January 2013 to July 2018. The median IV steroid days were 9 days (interquartile range of 4-12; 2-3.5 days in the oral group and 10-11.5 days in the overlap group). The mortality rate was 6.1%. The logistic regression model showed that TBM patients with basal exudate, tuberculoma, and modified Rankin scale (mRS) < 3 had a higher probability for going to the oral group. We conclude that total IV steroid days can be reduced in TBM patients by our method of steroid use. Presence of basal exudates and tuberculoma may favor early shifting from IV to oral steroid, whereas higher mRS may require a relatively longer course of IV steroid.

Most deaths in tuberculous meningitis occur in the early part of the illness. We assessed the determinants of early deaths, occurring within 2 months of intensive therapy. We prospectively included consecutive newly diagnosed adults with HIV-negative tuberculous meningitis. Patients were given WHO-recommended antituberculosis treatment and were followed up for 9 months. We enrolled 152 patients. A total of 26 deaths were recorded during 2 months. The logistic regression analysis revealed that papilledema ( P = 0.029, odds ratio (OR) = 4.8 [1.2-19.8]), increasing age ( P = 0.001, OR = 1.07 [1.03-1.1]), stage-III disease (Glasgow coma scale score ≤ 10; P = 0.01, OR = 4.2 [1.4-12.3]), and hydrocephalus ( P = 0.003, OR = 8.4 [2.1-33.6]) were independently associated with death. In addition, cerebral infarcts ( P = 0.012, OR = 5.6 [1.5-21.3]), paraparesis ( P = 0.004, OR = 8.8 [2.02-38.1]), and age ( P = 0.005, OR = 1.05 [1.02-1.09]) were associated with poor functional outcome. In conclusion, disease severity predicts early deaths in tuberculous meningitis.

Background: CNS infections are a leading cause of HIV-related deaths in sub-Saharan Africa, but causes and outcomes are poorly defined. We aimed to determine mortality and predictors of mortality in adults evaluated for meningitis in Botswana, which has an estimated 23% HIV prevalence among adults., Methods: In this prevalent cohort study, patient records from 2004-15 were sampled from the Botswana national meningitis survey, a nationwide audit of all cerebrospinal fluid (CSF) laboratory records from patients receiving a lumbar puncture for evaluation of meningitis. Data from all patients with culture-confirmed pneumococcal and tuberculous meningitis, and all patients with culture-negative meningitis with CSF white cell count (WCC) above 20 cells per μL were included in our analyses, in addition to a random selection of patients with culture-negative CSF and CSF WCC of up to 20 cells per μL. We used patient national identification numbers to link CSF laboratory records from the national meningitis survey to patient vital registry and HIV databases. Univariable and multivariable Cox proportional hazards models were used to evaluate clinical and laboratory predictors of mortality., Findings: We included data from 238 patients with culture-confirmed pneumococcal meningitis, 48 with culture-confirmed tuberculous meningitis, and 2900 with culture-negative CSF (including 1691 with CSF WCC of up to 20 cells per μL and 1209 with CSF WCC above 20 cells per μL). Median age was 37 years (IQR 31-46), 1605 (50%) of 3184 patients were male, 2188 (72%) of 3023 patients with registry linkage had documentation of HIV infection, and median CD4 count was 139 cells per μL (IQR 63-271). 10-week and 1-year mortality was 47% (112 of 238) and 49% (117 of 238) for pneumococcal meningitis, 46% (22 of 48) and 56% (27 of 48) for tuberculous meningitis, and 41% (1181 of 2900) and 49% (1408 of 2900) for culture-negative patients. When the analysis of patients with culture-negative CSF was restricted to those with known HIV infection, WCC (0-20 cells per μL vs >20 cells per μL) was not predictive of mortality (average hazard ratio 0·93, 95% CI 0·80-1·09)., Interpretation: Mortality from pneumococcal, tuberculous, and culture-negative meningitis was high in this setting of high HIV prevalence. There is an urgent need for improved access to diagnostics, to better define aetiologies and develop novel diagnostic tools and treatment algorithms., Funding: National Institutes of Health, President's Emergency Plan for AIDS Relief, National Institute for Health Research., (Copyright © 2019 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license. Published by Elsevier Ltd.. All rights reserved.)

Background: In 2000, we advised against insertion of a ventriculoperitoneal shunt (VPS) in human immunodeficiency virus (HIV)-positive patients with tuberculous meningitis (TBM) complicated by hydrocephalus. However, this was in the era when combination antiretroviral therapy (ART) was not freely available in South Africa. In this subsequent preliminary report, we describe the outcome of ventriculoperitoneal shunting in patients with TBM and hydrocephalus who are HIV positive and receiving ART., Methods: We compared a group of 15 HIV-positive patients with TBM and hydrocephalus on ART with a retrospective control group of 15 patients (demographically and clinically matched) but not on ART. All patients were otherwise managed similarly and evaluated at 1 month after VPS insertion., Results: In historical controls, 10 patients died (66.7%) and no patient showed any improvement 1 month after shunting. In contrast, in the current group on ART, 4 patients died (26.7%), with 11 patients (73.3%) having a good outcome. Eight of 12 patients with grade 3 TBM had a good outcome, whereas all 3 with grade 1 TBM made a good recovery., Conclusions: The outcome of VP shunting in HIV-positive patients with TBM and hydrocephalus is markedly improved in patients on ART. Based on limited data from this study, we recommend that better grades of TBM (1 and 2) undergo immediate VPS surgery. Patients with grade 4 TBM should undergo a trial of external ventricular drainage and those who improve should undergo a definitive procedure. Further research is required for patients with grade 3 TBM to identify characteristics associated with better outcomes to allow for effective use of limited resources., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Many approaches for variable selection with multiply imputed data in the development of a prognostic model have been proposed. However, no method prevails as uniformly best. We conducted a simulation study with a binary outcome and a logistic regression model to compare two classes of variable selection methods in the presence of MI data: (I) Model selection on bootstrap data, using backward elimination based on AIC or lasso, and fit the final model based on the most frequently (e.g. ≥ 50 % ) selected variables over all MI and bootstrap data sets; (II) Model selection on original MI data, using lasso. The final model is obtained by (i) averaging estimates of variables that were selected in any MI data set or (ii) in 50% of the MI data; (iii) performing lasso on the stacked MI data, and (iv) as in (iii) but using individual weights as determined by the fraction of missingness. In all lasso models, we used both the optimal penalty and the 1-se rule. We considered recalibrating models to correct for overshrinkage due to the suboptimal penalty by refitting the linear predictor or all individual variables. We applied the methods on a real dataset of 951 adult patients with tuberculous meningitis to predict mortality within nine months. Overall, applying lasso selection with the 1-se penalty shows the best performance, both in approach I and II. Stacking MI data is an attractive approach because it does not require choosing a selection threshold when combining results from separate MI data sets., (© 2018 The Authors. Biometrical Journal Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.)

Background: As the most severe form of tuberculosis (TB), TB meningitis (TBM) is still associated with high mortality even in developed countries. In certain areas of the United States (U.S.), more than 50% of the TBM patients die with TB or have neurological sequelae and complications despite the availability of advanced health care. This population-based analysis aimed to determine the risk factors and trends associated with TBM morbidity and mortality using state-wide surveillance data., Methods: De-identified surveillance data of all confirmed TB patients from the state of Texas between 01/2010 and 12/2017 reported to the National TB Surveillance System was analyzed. Spatial distribution of TBM cases was presented by Stata's Geographic Information Systems mapping. Univariate and multiple generalized linear modeling were used to identify risk factors associated with meningitis morbidity and mortality. Non-parametric testing was used to analyze morbidity and mortality trends., Results: Among 10,103 TB patients reported in Texas between 2010 and 2017, 192 (1.9%) had TBM. During this 8-year period, the TBM proportion fluctuated between 1.5% and 2.7% with peaks in 2011 (2.7%) and 2016 (2.1%) and an overall non-significant trend (z = -1.32, p = 0.19). TBM had a higher mortality at diagnosis (8.9%), during treatment (14.1%) and overall (22.9%) compared to non-TBM (1.9%, 5.3%, and 7.2%, respectively, p<0.001). While mortality during treatment was unchanged over time in non-TBM patients (z = 0.5, p = 0.62), it consistently increased in TBM patients after 2013 (z = 3.09, p = 0.002). TBM patients had nearly five times the risk for overall death in multivariate analysis [aRR 4.91 (95% CI 3.71, 6.51), p<0.001]. TBM patients were younger, and more likely to present with miliary TB or HIV (+). Age ≥45 years, resident of a long-term care facility, IDU, diabetes, chronic kidney disease, abnormal chest radiography, positive AFB smear or culture and HIV (+) were independently associated with higher mortality., Conclusion: TBM remains challenging in Texas with significantly high mortality. Risk factors determined by multivariate modeling will inform health professionals and lay a foundation for the development of more effective strategies for TBM prevention and management., Competing Interests: The authors have declared that no competing interests exist.

Background: The Mycobacterium tuberculosis load in the brain of individuals with tuberculous meningitis (TBM) may reflect the host's ability to control the pathogen, determine disease severity, and determine treatment outcomes., Methods: We used the GeneXpert assay to measure the pretreatment M. tuberculosis load in cerebrospinal fluid (CSF) specimens from 692 adults with TBM. We sought to understand the relationship between CSF bacterial load and inflammation, and their respective impact on disease severity and treatment outcomes., Results: A 10-fold higher M. tuberculosis load was associated with increased disease severity (odds ratio, 1.59; P = .001 for the comparison between grade 1 and grade 3 severity), CSF neutrophil count (r = 0.364 and P < .0001), and cytokine concentrations (r = 0.438 and P < .0001). A high M. tuberculosis load predicted new neurological events after starting treatment (P = .005, by multinomial logistic regression) but not death. Patients who died had an attenuated inflammatory response at the start of treatment, with reduced cytokine concentrations as compared to survivors. In contrast, patients with high pretreatment CSF bacterial loads, cytokine concentrations, and neutrophil counts were more likely to subsequently experience neurological events., Conclusions: The pretreatment GeneXpert-determined M. tuberculosis load may be a useful predictor of neurological complications occurring during TBM treatment. Given the evidence for the divergent pathogenesis of TBM-associated neurological complications and deaths, therapeutic strategies to reduce them may need reassessment., (© The Author(s) 2018. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: To evaluate the mortality in hospitalized patients with tuberculous meningitis and describe factors associated with an increased risk of mortality., Methods: Retrospective study of hospitalized patients with tuberculous meningitis between 2006 and 2015 in Peru performing a generalized linear regression to identify factors predictive of in-hospital mortality., Results: Of 263 patients, the median age was 35 years, 72.6% were men, 38% were positive for HIV upon admission, 24% had prior TB infections and 2.3% had prior MDR-TB infections. In-hospital mortality was 30.4% of all study patients with a final diagnosis of TBM. When multivariable analysis was applied, significant associations with in-hospital mortality were seen among patients with HIV (RR 2.06; Confidence Interval 95% (95% CI) 1.44-2.94), BMRC II (RR 1.78; 95% CI 1.07-2.97), BMRC III (RR 3.11; 95% CI 1.78-5.45) and positive CSF cultures (RR 1.95; 95% CI 1.39-2.74)., Conclusions: In-hospital mortality is higher among patients with HIV infections, age over 40 years, positive CSF TB culture and BMRC stage II or III.

High doses of rifampin may help patients with tuberculous meningitis (TBM) to survive. Pharmacokinetic pharmacodynamic evaluations suggested that rifampin doses higher than 13 mg/kg given intravenously or 20 mg/kg given orally (as previously studied) are warranted to maximize treatment response. In a double-blind, randomized, placebo-controlled phase II trial, we assigned 60 adult TBM patients in Bandung, Indonesia, to standard 450 mg, 900 mg, or 1,350 mg (10, 20, and 30 mg/kg) oral rifampin combined with other TB drugs for 30 days. The endpoints included pharmacokinetic measures, adverse events, and survival. A double and triple dose of oral rifampin led to 3- and 5-fold higher geometric mean total exposures in plasma in the critical early days (2 ± 1) of treatment (area under the concentration-time curve from 0 to 24 h [AUC 0-24 ], 53.5 mg · h/liter versus 170.6 mg · h/liter and 293.5 mg · h/liter, respectively; P  < 0.001), with proportional increases in cerebrospinal fluid (CSF) concentrations and without an increase in the incidence of grade 3 or 4 adverse events. The 6-month mortality was 7/20 (35%), 9/20 (45%), and 3/20 (15%) in the 10-, 20-, and 30-mg/kg groups, respectively ( P  = 0.12). A tripling of the standard dose caused a large increase in rifampin exposure in plasma and CSF and was safe. The survival benefit with this dose should now be evaluated in a larger phase III clinical trial. (This study has been registered at ClinicalTrials.gov under identifier NCT02169882.)., (Copyright © 2018 American Society for Microbiology.)

Background: Immunopathology contributes to the high mortality of tuberculous meningitis, but the biological pathways involved are mostly unknown. We aimed to compare cerebrospinal fluid (CSF) and serum metabolomes of patients with tuberculous meningitis with that of controls without tuberculous meningitis, and assess the link between metabolite concentrations and mortality., Methods: In this observational cohort study at the Hasan Sadikin Hospital (Bandung, Indonesia) we measured 425 metabolites using liquid chromatography-mass spectrometry in CSF and serum from 33 HIV-negative Indonesian patients with confirmed or probable tuberculous meningitis and 22 control participants with complete clinical data between March 12, 2009, and Oct 27, 2013. Associations of metabolite concentrations with survival were validated in a second cohort of 101 patients from the same centre. Genome-wide single nucleotide polymorphism typing was used to identify tryptophan quantitative trait loci, which were used for survival analysis in a third cohort of 285 patients., Findings: Concentrations of 250 (70%) of 351 metabolites detected in CSF were higher in patients with tuberculous meningitis than in controls, especially in those who died during follow-up. Only five (1%) of the 390 metobolites detected in serum differed between patients with tuberculous meningitis and controls. CSF tryptophan concentrations showed a pattern different from most other CSF metabolites; concentrations were lower in patients who survived compared with patients who died (9-times) and to controls (31-times). The association of low CSF tryptophan with patient survival was confirmed in the validation cohort (hazard ratio 0·73; 95% CI 0·64-0·83; p<0·0001; per each halving). 11 genetic loci predictive for CSF tryptophan concentrations in tuberculous meningitis were identified (p<0·00001). These quantitative trait loci predicted survival in a third cohort of 285 HIV-negative patients in a prognostic index including age and sex, also after correction for possible confounders (p=0·0083)., Interpretation: Cerebral tryptophan metabolism, which is known to affect Mycobacterium tuberculosis growth and CNS inflammation, is important for the outcome of tuberculous meningitis. CSF tryptophan concentrations in tuberculous meningitis are under strong genetic influence, probably contributing to the variable outcomes of tuberculous meningitis. Interventions targeting tryptophan metabolism could improve outcomes of tuberculous meningitis., Funding: Royal Dutch Academy of Arts and Sciences; Netherlands Foundation for Scientific Research; Radboud University; National Academy of Sciences; Ministry of Research, Technology, and Higher Education, Indonesia; European Research Council; and PEER-Health., (Copyright © 2018 Elsevier Ltd. All rights reserved.)

A placebo-controlled trial that compares the outcomes of immediate vs. deferred initiation of antiretroviral therapy in HIV +ve tuberculous meningitis (TBM) patients was conducted in Vietnam in 2011. Here, the pharmacokinetics of rifampicin, isoniazid, pyrazinamide, and ethambutol were investigated in the presence and absence of anti-HIV treatment in 85 patients. Pharmacokinetic analyses show that HIV therapy has no significant impact on the pharmacokinetics of TB drugs in this cohort. The same population, however, displayed generally low cerebrospinal fluid (CSF) and systemic exposures to rifampicin compared to previously reported HIV -ve cohorts. Elevated CSF concentrations of pyrazinamide, on the other hand, were strongly and independently correlated with increased mortality and neurological toxicity. The findings suggest that the current standard dosing regimens may put the patient at risk of treatment failure from suboptimal rifampicin exposure, and potentially increasing the risk of adverse central nervous system events that are independently correlated with pyrazinamide CSF exposure., (© 2017 American Society for Clinical Pharmacology and Therapeutics.)

Background: Tuberculous meningitis (TBM) is the most severe form of extrapulmonary tuberculosis. We developed and validated prognostic models for 9-month mortality in adults with TBM, with or without human immunodeficiency virus (HIV) infection., Methods: We included 1699 subjects from 4 randomized clinical trials and 1 prospective observational study conducted at 2 major referral hospitals in Southern Vietnam from 2001-2015. Modeling was based on multivariable Cox proportional hazards regression. The final prognostic models were validated internally and temporally and were displayed using nomograms and a Web-based app (https://thaole.shinyapps.io/tbmapp/)., Results: 951 HIV-uninfected and 748 HIV-infected subjects with TBM were included; 219 of 951 (23.0%) and 384 of 748 (51.3%) died during 9-month follow-up. Common predictors for increased mortality in both populations were higher Medical Research Council (MRC) disease severity grade and lower cerebrospinal fluid lymphocyte cell count. In HIV-uninfected subjects, older age, previous tuberculosis, not receiving adjunctive dexamethasone, and focal neurological signs were additional risk factors; in HIV-infected subjects, lower weight, lower peripheral blood CD4 cell count, and abnormal plasma sodium were additional risk factors. The areas under the receiver operating characteristic curves (AUCs) for the final prognostic models were 0.77 (HIV-uninfected population) and 0.78 (HIV-infected population), demonstrating better discrimination than the MRC grade (AUC, 0.66 and 0.70) or Glasgow Coma Scale score (AUC, 0.68 and 0.71) alone., Conclusions: The developed models showed good performance and could be used in clinical practice to assist physicians in identifying patients with TBM at high risk of death and with increased need of supportive care., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Objective: To determine the clinical presentations and outcomes of the children suffering from tuberculous meningitis., Methods: This prospective, descriptive study was conducted at the Children's Hospital and the Institute of Child Health, Multan, Pakistan, from February to December 2015. The Pakistan Paediatric Association scoring chart for tuberculosis was used as a tool for the probable diagnosis. The clinical symptoms with their durations were noted. Clinical stages of tuberculous meningitis, cerebrospinal fluid analysis and computerised tomography brain findings were noted for each patient. The outcomes in the form of death or neurological disabilities at the time of hospital discharge were noted. SPSS 19 was used for data analysis., Results: Of the 40 participants, 25(62.5%) were males and 15(37.5%) were females. The mean age of the patients was 4.24±3.32 years. Besides, 26(65%) patients were less than 5 years of age. All the patients (100%) were categorised as stage 3 tuberculous meningitis. The history of prolonged duration of fever 39(97.55%) and altered level of sensorium 40(100%) were the most common clinical presentations. Moreover, 2(5%) patients died during this study. All the 38(95%) survivors had neurological disabilities. There were motor deficits in 37(97.4%) patients, altered level of sensorium in 35(92%), cranial nerve palsies in 9(23.5%), epilepsy in 29(76.3%) and hydrocephalus in 32(84%) patients., Conclusions: The children were the most vulnerable group for the worst form of tuberculous meningitis and had a grave outcome.

Objectives: The predictors of poor outcome in tuberculous meningitis (TBM) remain to be delineated. We determined role of various clinical, radiological and cerebrospinal fluid (CSF) parameters in prediction of outcome in TBM., Patients and Methods: Current study was a prospective observational study including 209 patients of TBM. All patients underwent detailed evaluation including Gadolinium enhanced Magnetic resonance imaging (GdMRI) of brain as well as tests to detect evidence of tuberculosis elsewhere in body. They also underwent GdMRI at three and nine month follow up. All patients received treatment as per standard guidelines., Results: Mean age was 30.4±13.8years. 139 (66.5%) patients had definite TBM while 70 (34.5%) had highly probable TBM. 53 (25.4%) patients died. On univariate analysis, longer duration of illness, altered sensorium, stage III TBM, hydrocephalus and exudates correlated with poor outcome. On multivariate analysis presence of hydrocephalus (p=0.003; OR=3.2; 95% CI=1.5-6.7) and stage III TBM (p<0.0001; OR=8.7; 95% CI=3.7-20.2) correlated with higher risk of mortality. In addition, there was significant positive association between presence of hydrocephalus (p=0.05; OR=2.2; 95% CI=0.97-5.1), stage III TBM (p<0.0001; OR=28; 95% CI=4.9-158) and presence of altered sensorium (p=0.05; OR=22; 95% CI=0.99-4.8) with either death or survival with severe disability., Conclusions: It is possible to prognosticate TBM using a combination of clinical and radiological. The duration of illness (65.9±92days) before diagnosis of TBM continues to be unacceptably long and this stresses on need to educate primary care physicians about TBM. Future studies where intensity and duration of treatment is guided by these cues may help in sorting out some of the most difficult questions in TBM, namely duration of antitubercular therapy as well as dose and duration of steroid therapy etc., (Copyright © 2017 Elsevier B.V. All rights reserved.)

Introduction: This study aimed to investigate the factors which may predict mortality and neurological disability at one year follow up in patients of tuberculous meningitis (TBM) in India., Methodology: Patients with TBM were prospectively enrolled from July 2012 to September 2014 from four tertiary care hospitals of Delhi. The demographic characteristics, clinical features and laboratory findings were collected and patients were followed up till 1 year. These were analyzed by univariate and multivariate multinomial logistic regression analysis to identify predictors of adverse patient outcome at 1 year follow up., Results: Out of 478 patients enrolled, 391 patients could be followed up to 1 year. Sixty-four patients (16.3%) died and 150 patients (39%) survived with one or more neurological disability. Altered sensorium, motor deficit, cranial nerve palsy, seizures, isolation of M. tuberculosis and presence of multi-drug resistance were independently associated with any adverse outcome (death or disability) but by multivariate analysis only motor deficit, altered sensorium and isolation of M. tuberculosis on culture produced a statistically significant model for prediction of patient outcome., Conclusion: The three-predictor model with motor deficit, altered sensorium and isolation of M. tuberculosis produced a statistically significant model with correct prediction rate of 60.4%. These three variables predicted death with odds ratio of 39.2, 6.7 and 2.1 respectively in comparison to recovery whereas only motor deficit and isolation of M. tuberculosis predicted neurological disability at 1 year with odds ratio of 3.9, 2.4 respectively., (Copyright © 2017 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Background: Drug-resistant tuberculous meningitis (TBM) is difficult to diagnose and treat. Mortality is high and optimal treatment is unknown. We compared clinical outcomes of drug-resistant and -susceptible TBM treated with either standard or intensified antituberculosis treatment., Methods: We analyzed the influence of Mycobacterium tuberculosis drug resistance on the outcomes of patients with TBM enrolled into a randomized controlled trial comparing a standard, 9-month antituberculosis regimen (containing rifampicin 10 mg/kg/day) with an intensified regimen with higher-dose rifampicin (15 mg/kg/day) and levofloxacin (20 mg/kg/day) for the first 8 weeks. The primary endpoint of the trial was 9-month survival. In this subgroup analysis, resistance categories were predefined as multidrug resistant (MDR), isoniazid resistant, rifampicin susceptible (INH-R), and susceptible to rifampicin and isoniazid (INH-S + RIF-S). Outcome by resistance categories and response to intensified treatment were compared and estimated by Cox regression., Results: Of 817 randomized patients, 322 had a known drug resistance profile. INH-R was found in 86 (26.7%) patients, MDR in 15 (4.7%) patients, rifampicin monoresistance in 1 patient (0.3%), and INH-S + RIF-S in 220 (68.3%) patients. Multivariable regression showed that MDR (hazard ratio [HR], 5.91 [95% confidence interval {CI}, 3.00-11.6]), P < .001), was an independent predictor of death. INH-R had a significant association with the combined outcome of new neurological events or death (HR, 1.58 [95% CI, 1.11-2.23]). Adjusted Cox regression, corrected for treatment adjustments, showed that intensified treatment was significantly associated with improved survival (HR, 0.34 [95% CI, .15-.76], P = .01) in INH-R TBM., Conclusions: Early intensified treatment improved survival in patients with INH-R TBM. Targeted regimens for drug-resistant TBM should be further explored., Clinical Trials Registration: ISRCTN61649292., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America.)

Background: Damaging inflammation is thought to contribute to the high morbidity and mortality of tuberculous meningitis (TBM), but the link between inflammation and outcome remains unclear., Methods: We performed prospective clinical and routine laboratory analyses of a cohort of adult patients with TBM in Indonesia. We also examined the LTA4H promoter polymorphism, which predicted cerebrospinal fluid (CSF) leukocyte count and survival of Vietnamese patients with TBM. Patients were followed for >1 year., Results: We included 608 patients with TBM, of whom 67.1% had bacteriological confirmation of disease and 88.2% had severe (ie, grade II or III) disease. One-year mortality was 43.7% and strongly associated with decreased consciousness, fever, and focal neurological signs. Human immunodeficiency virus (HIV) infection, present in 15.3% of patients, was associated with higher mortality and different CSF characteristics, compared with absence of HIV infection. Among HIV-uninfected patients, mortality was associated with higher CSF neutrophil counts (hazard ratio [HR], 1.10 per 10% increase; 95% confidence interval [CI], 1.04-1.16), low CSF to blood glucose ratio (HR, 1.16 per 0.10 decrease; 95% CI, 1.04-1.30), CSF culture positivity (HR, 1.37; 95% CI, 1.02-1.84), and blood neutrophilia (HR, 1.06 per 109 neutrophils/L increase; 95% CI, 1.03-1.10). The LTA4H promoter polymorphism correlated with CSF mononuclear cell count but not with mortality (P = .915)., Conclusions: A strong neutrophil response and fever may contribute to or be a result of (immuno)pathology in TBM. Aggressive fever control might improve outcome, and more-precise characterization of CSF leukocytes could guide possible host-directed therapeutic strategies in TBM., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Background: Tuberculous meningitis (TBM) is the most devastating clinical presentation of infection with Mycobacterium tuberculosis; delayed initiation of effective antituberculosis therapy is associated with poor treatment outcomes. Our objective was to determine the relationship between drug resistance and 10-year mortality among patients with TBM., Methods: We conducted a retrospective cohort study of 324 patients with culture-confirmed TBM, susceptibility results reported for isoniazid and rifampin, and initiation of at least 2 antituberculosis drugs, reported to the tuberculosis registry in New York City between 1 January 1992 and 31 December 2001. Date of death was ascertained by matching the tuberculosis registry with death certificate data for 1992-2012 from the New York Office of Vital Statistics. Human immunodeficiency virus (HIV) status was ascertained by medical records review, matching with the New York City HIV Surveillance registry, and review of cause of death., Results: Among 257 TBM patients without rifampin-resistant isolates, isoniazid resistance was associated with mortality after the first 60 days of treatment when controlling for age and HIV infection (adjusted hazard ratio, 1.94 [95% confidence interval, 1.08-3.94]). Death occurred before completion of antituberculosis therapy in 63 of 67 TBM patients (94%) with rifampin-resistant disease., Conclusions: Among patients with culture-confirmed TBM, we observed rapid early mortality in patients with rifampin-resistant isolates, and an independent association between isoniazid-resistant isolates and death after 60 days of therapy. These findings support the continued evaluation of rapid diagnostic techniques and the empiric addition of second-line drugs for patients with clinically suspected drug-resistant TBM., (© The Author 2017. Published by Oxford University Press for the Infectious Diseases Society of America. All rights reserved. For permissions, e-mail: journals.permissions@oup.com.)

Aims: To assess the long-term outcome of childhood tuberculous meningitis treated with modern 4-drug antitubercular regimens and to determine predictors of survival and morbidity., Methods: In this single-center prospective cohort, outcome of children with tuberculous meningitis treated with standard regimens was assessed at 6 months and 12 months after discharge using the Pediatric Cerebral Performance Category Scale., Results: Of 130 children, 38 died in hospital and 34 were either severely disabled or comatose/vegetative at discharge. At 6 and 12 months, 87% of the survivors were either normal (n = 62) or mildly disabled (n = 17, on the Pediatric Cerebral Performance Category scale). On multivariate analysis, the factors associated with poor outcome at 12 months were stage III at admission (adjusted odds ratio 4.4, 95% confidence interval, 1.7-11.2, P = .002) and presence of infarcts on neuroimaging (adjusted odds ratio 2.6, 95% confidence interval, 1.1-6.6, P = .037)., Conclusions: Despite the high in-hospital mortality, in resource-constraint settings, the survivors showed remarkable improvement, with two-thirds returning to a normal functional status at 6 months' follow-up., (© The Author(s) 2016.)

Background: Tuberculous meningitis in adults is well characterized in Vietnam, but there are no data on the disease in children. We present a prospective descriptive study of Vietnamese children with TBM to define the presentation, course and characteristics associated with poor outcome., Methods: A prospective descriptive study of 100 consecutively admitted children with TBM at Pham Ngoc Thach Hospital, Ho Chi Minh City. Cox and logistic regression were used to identify factors associated with risk of death and a combined endpoint of death or disability at treatment completion., Results: The study enrolled from October 2009 to March 2011. Median age was 32.5 months; sex distribution was equal. Median duration of symptoms was 18.5 days and time from admission to treatment initiation was 11 days. Fifteen of 100 children died, 4 were lost to follow-up, and 27/81 (33 %) of survivors had intermediate or severe disability upon treatment completion. Microbiological confirmation of disease was made in 6 %. Baseline characteristics associated with death included convulsions (HR 3.46, 95CI 1.19-10.13, p = 0.02), decreased consciousness (HR 22.9, 95CI 3.01-174.3, p < 0.001), focal neurological deficits (HR 15.7, 95CI 1.67-2075, p = 0.01), Blantyre Coma Score (HR 3.75, 95CI 0.99-14.2, p < 0.001) and CSF protein, lactate and glucose levels. Neck stiffness, MRC grade (children aged >5 years) and hydrocephalus were also associated with the combined endpoint of death or disability., Conclusions: Tuberculous meningitis in Vietnamese children has significant mortality and morbidity. There is significant delay in diagnosis; interventions that increase the speed of diagnosis and treatment initiation are likely to improve outcomes.

Background: Tuberculous meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis., Objective: To assess hearing, visual, motor function, neurological and mental development outcomes in paediatric TBM., Methods: A retrospective cohort study was conducted among 139 children with TBM registered and treated at the Department of Child Health, Dr Hasan Sadikin Hospital, Bandung, Indonesia, from January 2007 to December 2010. Hearing and visual function, appearance of optic disc, motor function, and neurological and mental development were evaluated., Results: Of a final 128 patients (10 died during hospitalisation, 1 was excluded), 34 (26.5%) died after hospital discharge, the addresses of 58 patients could not be found and 7 parents refused to participate. The remaining 29 patients (16 males, 13 females) were available for evaluation; the mean age was 44 months (range 7-162). Hearing loss and visual impairment were identified in respectively 11/28 and 10/25 patients. Most patients had motor disorders. Delayed neurological and mental development was observed in nearly three quarters of patients, 11 of whom had normal or borderline intelligence quotient., Conclusions: TBM causes high mortality and sequelae involving hearing and visual impairment, and neurological and mental development.

Background: Central nervous system (CNS) infections are a significant contributor to morbidity and mortality globally. However, most published studies have been conducted in developed countries where the epidemiology and aetiology differ significantly from less developed areas. Additionally, there may be regional differences due to variation in the socio-economic levels, public health services and vaccination policies. Currently, no prospective studies have been conducted in Sabah, East Malaysia to define the epidemiology and aetiology of CNS infections. A better understanding of these is essential for the development of local guidelines for diagnosis and management., Methods: We conducted a prospective observational cohort study in patients aged 12 years and older with suspected central nervous system infections at Queen Elizabeth Hospital, Kota Kinabalu, Sabah, Malaysia between February 2012 and March 2013. Cerebrospinal fluid was sent for microscopy, biochemistry, bacterial and mycobacterial cultures, Mycobacterium tuberculosis polymerase chain reaction (PCR), and multiplex and MassCode PCR for various viral and bacterial pathogens., Results: A total of 84 patients with clinically suspected meningitis and encephalitis were enrolled. An aetiological agent was confirmed in 37/84 (44 %) of the patients. The most common diagnoses were tuberculous meningitis (TBM) (41/84, 48.8 %) and cryptococcal meningoencephalitis (14/84, 16.6 %). Mycobacterium tuberculosis was confirmed in 13/41 (31.7 %) clinically diagnosed TBM patients by cerebrospinal fluid PCR or culture. The acute case fatality rate during hospital admission was 16/84 (19 %) in all patients, 4/43 (9 %) in non-TBM, and 12/41 (29 %) in TBM patients respectively (p = 0.02)., Conclusion: TBM is the most common cause of CNS infection in patients aged 12 years or older in Kota Kinabalu, Sabah, Malaysia and is associated with high mortality and morbidity. Further studies are required to improve the management and outcome of TBM.

Aim: Tuberculous meningitis (TBM) is a lethal and commonly occurring form of extra-pulmonary tuberculosis in children, often complicated by hydrocephalus which worsens outcome. Despite high mortality and morbidity, little data on the impact on neurodevelopment exists. We examined the clinical characteristics, and clinical and neurodevelopmental outcomes of TBM and hydrocephalus., Method: Demographic and clinical data (laboratory and radiological findings) were prospectively collected on children treated for probable and definite TBM with hydrocephalus. At 6 months, clinical outcome was assessed using the Paediatric Cerebral Performance Category Scale and neurodevelopmental outcome was assessed with the Griffiths Mental Development Scale - Extended Version., Results: Forty-four patients (median age 3y 3mo, range 3mo-13y 1mo, [SD 3y 5mo]) were enrolled. The mortality rate was 16%, three patients (6.8%) were in a persistent vegetative state, two were severely disabled (4.5%), and 11 (25%) suffered mild-moderate disability. All cases demonstrated neurodevelopmental deficits relative to controls. Multiple or large infarcts were prognostic of poor outcome., Interpretation: Neurological and neurodevelopmental deficits are common after paediatric TBM with hydrocephalus, and appear to be related to ongoing cerebral ischaemia and consequent infarction. The impact of TBM on these children is multidimensional and presents short- and long-term challenges., (© 2016 The Authors. Developmental Medicine & Child Neurology published by John Wiley & Sons Ltd on behalf of Mac Keith Press.)

Background: Levofloxacin is an effective bactericidal category III antitubercular drug. There is paucity of studies comparing the role of additional levofloxacin to standard antitubercular regimen in the patients with tuberculous meningitis (TBM)., Aims: To compare the safety and efficacy of adding levofloxacin to standard four drug ATT regimen (RHZE)., Subjects and Methods: The patients with TBM diagnosed on the basis of clinical, cerebrospinal fluid (CSF) and MRI criteria were included. Children below 15 years, patients with pregnancy, seizures, liver failure, kidney failure and malignancy were excluded. The baseline clinical, CSF and MRI characteristics were noted and consciousness was evaluated by Glasgow Coma Scale (GCS). The patients were randomized to RHZE (rifampicin, isoniazid, pyrazinamide and ethambutol) and RHZEL (RHZE and levofloxacin) groups. Outcome was defined at 6 months. Primary outcome was death and secondary outcomes were disability as assess by Barthel Index score and adverse events., Results: Out of 110 TBM patients screened, 57 fulfilled the inclusion criteria. Their median age was 35 (15-75) years. 29 patients received RHZEL and 28 RHZE. The baseline clinical, biochemical and MRI characteristics were similar in the two groups. At 6 months, 11 (19.3%) patients died, 38 (66.7%) had good and 7 (12.3%) poor outcome. There was insignificant survival benefit in RHZEL group compared to RHZE (HR-2.61, 95% CI 0.73-9.36, P = 0.14), 25% patients died in RHZE where as 13.8% in RHZEL group. The disability was not significantly different between the two groups. The composite side effects were also similar between the two groups except for a higher frequency of seizure in RHZEL group (5 Vs 0) which resulted in withdrawal of levofloxacin., Conclusion: There was insignificant survival benefit in RHZEL which was associated with high frequency of seizures., (Copyright © 2016 Elsevier Ltd. All rights reserved.)

Background: Tuberculous meningitis is a serious form of tuberculosis (TB) that affects the meninges that cover a person's brain and spinal cord. It is associated with high death rates and with disability in people who survive. Corticosteroids have been used as an adjunct to antituberculous drugs to treat people with tuberculous meningitis, but their role has been controversial., Objectives: To evaluate the effects of corticosteroids as an adjunct to antituberculous treatment on death and severe disability in people with tuberculous meningitis., Search Methods: We searched the Cochrane Infectious Diseases Group Specialized Register up to the 18 March 2016; CENTRAL; MEDLINE; EMBASE; LILACS; and Current Controlled Trials. We also contacted researchers and organizations working in the field, and checked reference lists., Selection Criteria: Randomized controlled trials that compared corticosteroid plus antituberculous treatment with antituberculous treatment alone in people with clinically diagnosed tuberculous meningitis and included death or disability as outcome measures., Data Collection and Analysis: We independently assessed search results and methodological quality, and extracted data from the included trials. We analysed the data using risk ratios (RR) with 95% confidence intervals (CIs) and used a fixed-effect model. We performed an intention-to-treat analysis, where we included all participants randomized to treatment in the denominator. This analysis assumes that all participants who were lost to follow-up have good outcomes. We carried out a sensitivity analysis to explore the impact of the missing data., Main Results: Nine trials that included 1337 participants (with 469 deaths) met the inclusion criteria.At follow-up from three to 18 months, steroids reduce deaths by almost one quarter (RR 0.75, 95% CI 0.65 to 0.87; nine trials, 1337 participants, high quality evidence). Disabling neurological deficit is not common in survivors, and steroids may have little or no effect on this outcome (RR 0.92, 95% CI 0.71 to 1.20; eight trials, 1314 participants, low quality evidence). There was no difference between groups in the incidence of adverse events, which included gastrointestinal bleeding, invasive bacterial infections, hyperglycaemia, and liver dysfunction.One trial followed up participants for five years. The effect on death was no longer apparent at this time-point (RR 0.93, 95% CI 0.78 to 1.12; one trial, 545 participants, moderate quality evidence); and there was no difference in disabling neurological deficit detected (RR 0.91, 95% CI 0.49 to 1.69; one trial, 545 participants, low quality evidence).One trial included human immunodeficiency virus (HIV)-positive people. The stratified analysis by HIV status in this trial showed no heterogeneity, with point estimates for death (RR 0.90, 95% CI 0.67 to 1.20; one trial, 98 participants) and disability (RR 1.23, 95% CI 0.08 to 19.07; one trial, 98 participants) similar to HIV-negative participants in the same trial., Authors' Conclusions: Corticosteroids reduce mortality from tuberculous meningitis, at least in the short term.Corticosteroids may have no effect on the number of people who survive tuberculous meningitis with disabling neurological deficit, but this outcome is less common than death, and the CI for the relative effect includes possible harm. However, this small possible harm is unlikely to be quantitatively important when compared to the reduction in mortality.The number of HIV-positive people included in the review is small, so we are not sure if the benefits in terms of reduced mortality are preserved in this group of patients.

Objective: To evaluate headache severity, and its correlation with clinical, cerebrospinal fluid, and neuroimaging parameters of tuberculous meningitis (TBM) patients, and its impact on outcome., Methods: This prospective observational study was conducted at King George`s Medical University, Lucknow, India between October 2012 and March 2014. Ninety-five newly diagnosed TBM patients underwent detailed clinical, laboratory, and neuroimaging evaluation. A numeric rating scale was used to assess the headache severity, and patients were grouped into mild, moderate, severe, and intolerable groups. Patient outcome was evaluated at 6-months follow up., Results: Holocranial stabbing type headache (p=0.002), modified Barthel index &#8804;12 (p<0.001), diplopia (p=0.055), seizures (p<0.001), visual impairment (p=0.024), cranial nerve palsy (p=0.002), meningeal signs (p=0.016), definite cases of TBM (p=0.001), British Medical Research Council stage III (p<0.001), and CSF protein >2.5 g/l (p<0.001) were significantly associated with severity of headache. Neuroradiological features significantly associated with severity of headache were meningeal enhancement (p=0.015), basal exudates (p<0.001), and hydrocephalus (p=0.003). Eleven out of 15 patients who died had intolerable headache at admission. Significant predictors of poor outcome in severe and intolerable headache groups were CSF protein>2.5g/L, cranial nerve palsies, paraparesis, and infarcts. Patients of the mild and moderate headache group were headache free at 6 months follow up with good outcome., Conclusion: Severity of headache was associated with multiple clinical, CSF protein, and radiological factors. As intolerable and severe headache had an unfavorable impact on outcome, we could prognosticate the TBM patients on the basis of headache severity.

Background: Tuberculous meningitis is often lethal. Early antituberculosis treatment and adjunctive treatment with glucocorticoids improve survival, but nearly one third of patients with the condition still die. We hypothesized that intensified antituberculosis treatment would enhance the killing of intracerebral Mycobacterium tuberculosis organisms and decrease the rate of death among patients., Methods: We performed a randomized, double-blind, placebo-controlled trial involving human immunodeficiency virus (HIV)-infected adults and HIV-uninfected adults with a clinical diagnosis of tuberculous meningitis who were admitted to one of two Vietnamese hospitals. We compared a standard, 9-month antituberculosis regimen (which included 10 mg of rifampin per kilogram of body weight per day) with an intensified regimen that included higher-dose rifampin (15 mg per kilogram per day) and levofloxacin (20 mg per kilogram per day) for the first 8 weeks of treatment. The primary outcome was death by 9 months after randomization., Results: A total of 817 patients (349 of whom were HIV-infected) were enrolled; 409 were randomly assigned to receive the standard regimen, and 408 were assigned to receive intensified treatment. During the 9 months of follow-up, 113 patients in the intensified-treatment group and 114 patients in the standard-treatment group died (hazard ratio, 0.94; 95% confidence interval, 0.73 to 1.22; P=0.66). There was no evidence of a significant differential effect of intensified treatment in the overall population or in any of the subgroups, with the possible exception of patients infected with isoniazid-resistant M. tuberculosis. There were also no significant differences in secondary outcomes between the treatment groups. The overall number of adverse events leading to treatment interruption did not differ significantly between the treatment groups (64 events in the standard-treatment group and 95 events in the intensified-treatment group, P=0.08)., Conclusions: Intensified antituberculosis treatment was not associated with a higher rate of survival among patients with tuberculous meningitis than standard treatment. (Funded by the Wellcome Trust and the Li Ka Shing Foundation; Current Controlled Trials number, ISRCTN61649292.).

Purpose: There is paucity of information about the outcome of tuberculous meningitis (TBM) patients on mechanical ventilation (MV). In this communication, we report the clinical characteristics, predictors of MV, and outcome of TBM patients requiring MV., Method: Thirty-eight (18%) of 205 patients with TBM requiring MV were included; and their demographic, clinical, cerebrospinal fluid, and magnetic resonance imaging finding at admission and follow-up were noted. The ventilator-related and systemic complications, hospital death, and 3-month functional outcome were noted. The predictors of need of MV were derived by multivariate regression analysis., Results: There were 38 MV and 36 non-MV TBM patients who were matched for age, sex, and stage of meningitis on admission. The requirement of MV was independently related to leukocytosis, seizure, and cerebrospinal fluid pleocytosis on admission. Patients on MV had higher frequency of septicemia (9 vs 2), bedsores (6 vs 0), and gastric hemorrhage (4 vs 0) compared with non-MV patients. Only 29% of MV patients survived and had poor outcome at 3 months; but in the non-MV group, all the patients survived, and only 11% had poor outcome., Conclusion: Mechanical ventilation was needed in 18% TBM patients because of TBM-related or systemic complications. Those requiring MV had high mortality and may be categorized separately., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Background: Tuberculous meningitis (TBM) caused by Mycobacterium tuberculosis resistant to antituberculosis drugs is an increasingly common clinical problem. This study aimed to evaluate drug resistance profiles of TBM isolates in adult patients in nine European countries involving 32 centers to provide insight into the empiric treatment of TBM., Methods: Mycobacterium tuberculosis was cultured from the cerebrospinal fluid (CSF) of 142 patients and was tested for susceptibility to first-line antituberculosis drugs, streptomycin (SM), isoniazid (INH), rifampicin (RIF) and ethambutol (EMB)., Results: Twenty of 142 isolates (14.1 %) were resistant to at least one antituberculosis drug, and five (3.5 %) were resistant to at least INH and RIF, [multidrug resistant (MDR)]. The resistance rate was 12, 4.9, 4.2 and 3.5 % for INH, SM, EMB and RIF, respectively. The monoresistance rate was 6.3, 1.4 and 0.7 % for INH, SM and EMB respectively. There was no monoresistance to RIF. The mortality rate was 23.8 % in fully susceptible cases while it was 33.3 % for those exhibiting monoresistance to INH, and 40 % in cases with MDR-TBM. In compared to patients without resistance to any first-line drug, the relative risk of death for INH-monoresistance and MDR-TBM was 1.60 (95 % CI, 0.38-6.82) and 2.14 (95 % CI, 0:34-13:42), respectively., Conclusion: INH-resistance and MDR rates seemed not to be worrisome in our study. However, considering their adverse effects on treatment, rapid detection of resistance to at least INH and RIF would be most beneficial for designing anti-TB therapy. Still, empiric TBM treatment should be started immediately without waiting the drug susceptibility testing.

Predicting unfavorable outcome is of paramount importance in clinical decision making. Accordingly, we designed this multinational study, which provided the largest case series of tuberculous meningitis (TBM). 43 centers from 14 countries (Albania, Croatia, Denmark, Egypt, France, Hungary, Iraq, Italy, Macedonia, Romania, Serbia, Slovenia, Syria, Turkey) submitted data of microbiologically confirmed TBM patients hospitalized between 2000 and 2012. Unfavorable outcome was defined as survival with significant sequela or death. In developing our index, binary logistic regression models were constructed via 200 replicates of database by bootstrap resampling methodology. The final model was built according to the selection frequencies of variables. The severity scale included variables with arbitrary scores proportional to predictive powers of terms in the final model. The final model was internally validated by bootstrap resampling. A total of 507 patients' data were submitted among which 165 had unfavorable outcome. Eighty-six patients died while 119 had different neurological sequelae in 79 (16%) patients. The full model included 13 variables. Age, nausea, vomiting, altered consciousness, hydrocephalus, vasculitis, immunosuppression, diabetes mellitus and neurological deficit remained in the final model. Scores 1-3 were assigned to the variables in the severity scale, which included scores of 1-6. The distribution of mortality for the scores 1-6 was 3.4, 8.2, 20.6, 31, 30 and 40.1%, respectively. Altered consciousness, diabetes mellitus, immunosuppression, neurological deficits, hydrocephalus, and vasculitis predicted the unfavorable outcome in the scoring and the cumulative score provided a linear estimation of prognosis.

Background: Tuberculous meningitis disproportionately affects young children. We aimed to characterise treatment outcomes for this deadliest and most debilitating form of tuberculosis., Methods: We did a systematic review and meta-analysis of childhood tuberculous meningitis studies published up to Oct 12, 2012. We included study reports that applied predefined diagnostic criteria and described treatment regimens and outcomes. We pooled risks of death during treatment and neurological sequelae among survivors. As secondary objectives, we assessed study-level characteristics as sources of heterogeneity, and we pooled frequencies of presenting symptoms and diagnostic findings. For all meta-analyses we used random-effects models with the exact binomial likelihood method., Findings: 19 studies met our inclusion criteria, with reported treatment outcomes for 1636 children. Risk of death was 19·3% (95% CI 14·0-26·1) and probability of survival without neurological sequelae was 36·7% (27·9-46·4). Among survivors, risk of neurological sequelae was 53·9% (95% CI 42·6-64·9). Diagnosis in the most advanced disease stage (3) occurred in 307 (47%) of 657 patients and was associated with worse outcomes than was earlier diagnosis. The most common findings at presentation were cerebrospinal fluid (CSF) leucocytosis (frequency 99·9%, 95% CI 68·5-100·0), CSF lymphocytosis (97·9%, 51·9-100·0), fever (89·8%, 79·8-95·2), and hydrocephalus (86·1%, 68·6-94·6). Frequency of CSF acid-fast-bacilli smear positivity was 8·9% (95% CI 5·0-15·4), and frequency of CSF culture positivity for Mycobacterium tuberculosis was 35·1% (16·8-59·2)., Interpretation: Despite treatment, childhood tuberculous meningitis has very poor outcomes. Poor prognosis and difficult early diagnosis emphasise the importance of preventive therapy for child contacts of patients with tuberculosis and low threshold for empirical treatment of tuberculous meningitis suspects. Implementation of consensus definitions, standardised reporting of data, and high-quality clinical trials are needed to clarify optimum therapy., Funding: None., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Objectives: We report the efficacy and safety of levofloxacin versus rifampicin in tuberculous meningitis (TBM)., Patients and Methods: In this open-label, randomized controlled trial from India, patients with TBM diagnosed on the basis of clinical, MRI and CSF findings were included. Patients with hepatic or renal dysfunction, organ transplantation, malignancy, pregnancy, lactation, allergy, seizure, age <15 years and antitubercular treatment ≥1 month were excluded. Sixty patients each were randomized to levofloxacin (10 mg/kg, maximum 500 mg) or rifampicin (10 mg/kg, maximum 450 mg). They also received isoniazid, pyrazinamide, ethambutol, prednisolone and aspirin. The primary outcome was death and secondary outcome measures were 6 month disability, repeat MRI changes and serious adverse events (SAEs)., Results: The median age of the patients was 34.5 (16-75) years. The baseline clinical and MRI findings were similar between the two groups. At 6 months, 13 out of 60 (21.7%) patients in the levofloxacin arm and 23 out of 60 (38.3%) patients in the rifampicin arm had died (P = 0.07). On Cox regression analysis, survival in the levofloxacin group was significantly better than in the rifampicin group (hazard ratio 2.13, 95% CI 1.04-4.34, P = 0.04). The functional outcome (P = 0.47) was, however, not significantly different between the two groups. On intention-to-treat analysis, 10 out of 47 (21.3%) in the levofloxacin arm and 5 out of 37 (13.5%) in the rifampicin arm had poor recovery. Repeat MRI findings did not differ between the groups. Levofloxacin was discontinued more frequently than rifampicin due to SAEs (16 versus 4, P = 0.01)., Conclusions: Levofloxacin is superior to rifampicin in reducing 6 month death in TBM but not disability. Levofloxacin may be used in TBM especially in those patients with hepatotoxicity and without seizure., (© The Author 2014. Published by Oxford University Press on behalf of the British Society for Antimicrobial Chemotherapy. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.)