Tuberculous Meningitis: An Endemic Cause of Intracranial Hypertension.

Tuberculous meningitis (TBM) presents a complex clinical scenario, often marked by delayed recognition and high mortality. Our case involves a 27-year-old woman from Nepal with no significant medical history, presented with a two-week history of fatigue, altered consciousness, dizziness, vomiting, fever, holocranial headache, and photophobia. Initial examination revealed signs consistent with meningitis, including fever, hypertensive state, prostration, bilateral exophthalmos, sixth cranial nerve paresis, and positive Kernig/Brudzinski signs. Cerebrospinal fluid (CSF) exhibited characteristics typical of TBM: turbidity, lymphocytic-predominant pleocytosis, low glucose, and elevated protein. The patient was promptly started on meningeal doses of vancomycin, ceftriaxone, and acyclovir. However, persistent fever, neurological deterioration, and signs of increased intracranial pressure led to the decision to initiate conventional empiric treatment of tuberculosis (TB) with isoniazid, rifampicin, pyrazinamide, and ethambutol (HRZE) and dexamethasone 1 week before cultural positivity for Mycobacterium tuberculosis of CSF. The case underscores the importance of considering TBM in patients from endemic regions, interpreting CSF findings, and initiating empirical treatment in critical scenarios, contributing to a positive patient outcome despite the diagnostic challenges.

Heparin Binding Protein in Early Differential Diagnosis of Bacterial Meningitis.

Heparin-binding protein is a serine protease that is mobilized rapidly from emigrating polymorphonuclear leukocytes that acts as a chemoattractant activator of monocyte and macrophages. We investigated the potential role and efficacy of serum and cerebrospinal fluid heparin binding protein in differentiating bacterial meningitis from tuberculosis and viral meningitis. A case diagnosed with acute bacterial meningitis (n:37), viral meningitis (n:30) and tuberculous meningitis (n:30) was included in this study. The diagnosis was based on history, clinical criteria, cerebrospinal fluid examination, latex agglutination and culture, and response to therapy. Heparin-binding protein was measured using enzyme-linked immunosorbent technique in both cerebrospinal fluid and serum. Cerebrospinal fluid heparin-binding protein levels were 7.81 ± 0.23 ng/mL in bacterial meningitis, 6.11 ± 0.3 ng/mL in tuberculosis meningitis and 5.75 ± 0.1 ng/mL in viral meningitis. The mean serum level was 14.98 ± 1.1 ng/mL in bacterial meningitis, 6.89 ± 0.4 ng/mL in tuberculosis meningitis, and 6.02 ± 0.4 ng/mL in viral meningitis. Both heparin-binding protein levels were significantly higher in patients with bacterial meningitis. We found that serum and cerebrospinal fluid heparin binding protein is a useful marker for differentiating bacterial meningitis from non-bacterial meningitis.

Linezolid Population Pharmacokinetic Model in Plasma and Cerebrospinal Fluid Among Patients With Tuberculosis Meningitis.

BACKGROUND: Linezolid is evaluated in novel treatment regimens for tuberculous meningitis (TBM). Linezolid pharmacokinetics have not been characterized in this population, particularly in cerebrospinal fluid (CSF), as well as, following its co-administration with high-dose rifampicin. We aimed to characterize linezolid plasma and CSF pharmacokinetics in adults with TBM. METHODS: In the LASER-TBM pharmacokinetic substudy, the intervention groups received high-dose rifampicin (35 mg/kg) plus 1200 mg/day of linezolid for 28 days, which was then reduced to 600 mg/day. Plasma sampling was done on day 3 (intensive) and day 28 (sparse). A lumbar CSF sample was obtained on both visits. RESULTS: Thirty participants contributed 247 plasma and 28 CSF observations. Their median age and weight were 40 years (range, 27-56) and 58 kg (range, 30-96). Plasma pharmacokinetics was described by a 1-compartment model with first-order absorption and saturable elimination. Maximal clearance was 7.25 L/h, and the Michaelis-Menten constant was 27.2 mg/L. Rifampicin cotreatment duration did not affect linezolid pharmacokinetics. CSF-plasma partitioning correlated with CSF total protein up to 1.2 g/L, where the partition coefficient reached a maximal value of 37%. The plasma-CSF equilibration half-life was ∼3.5 hours. CONCLUSIONS: Linezolid was readily detected in CSF despite high-dose rifampicin coadministration. These findings support continued clinical evaluation of linezolid plus high-dose rifampicin for the treatment of TBM in adults. Clinical Trials Registration. ClinicalTrials.gov (NCT03927313).

Central Nervous System Tuberculosis: Risk Factors for Mortality in a Propensity Score-Matched Case-Control Study.

Background: Despite advancements in tuberculosis (TB) control and treatment in the United States (US), patients with central nervous system TB (CNS-TB) continue to experience significantly higher mortality rates than those without CNS-TB. This raises concerns regarding clinical management and the need for a deeper understanding of the risk factors contributing to these deaths. This study aimed to determine the predictors of mortality in patients with CNS-TB. Methods: We conducted a retrospective 1:2 propensity score-matched case-control study. Cases were TB patients diagnosed with TB of the meninges, brain, spinal cord, or peripheral nerves, as documented in the Florida Department of Health (FDOH) TB registry, between 2009 and 2021. Controls were TB patients without CNS-TB, also reported in the FDOH TB registry during the same timeframe. We employed conditional logistic regression models to investigate the factors contributing to mortality in cases compared with controls. Results: We analyzed data from 116 cases and 232 matched controls. Patients with CNS-TB had a 5.69-fold higher risk of death than those without CNS-TB (adjusted odds ratio [aOR], 5.69 [95% confidence interval {CI}, 2.91-11.6]). Increased risk of death was associated with human immunodeficiency virus (HIV) coinfection (aOR, 1.93 [95% CI, .82-4.37]) and diabetes (aOR, 3.13 [95% CI, 1.28-7.47]). Miliary TB and non-HIV immunosuppression were significantly associated with being a case, while cavitary TB was less likely to be associated with being a case. Conclusions: Clinical management should prioritize screening and close monitoring of patients with HIV coinfection and diabetes to improve patient outcomes.

A preclinical model of TB meningitis to determine drug penetration and activity at the sites of disease.

Tuberculosis meningitis (TBM) is essentially treated with the first-line regimen used against pulmonary tuberculosis, with a prolonged continuation phase. However, clinical outcomes are poor in comparison, for reasons that are only partially understood, highlighting the need for improved preclinical tools to measure drug distribution and activity at the site of disease. A predictive animal model of TBM would also be of great value to prioritize promising drug regimens to be tested in clinical trials, given the healthy state of the development pipeline for the first time in decades. Here, we report the optimization of a rabbit model of TBM disease induced via inoculation of Mycobacterium tuberculosis into the cisterna magna, recapitulating features typical of clinical TBM: neurological deterioration within months post-infection, acid-fast bacilli in necrotic lesions in the brain and spinal cord, and elevated lactate levels in cerebrospinal fluid (CSF). None of the infected rabbits recovered or controlled the disease. We used young adult rabbits, the size of which allows for spatial drug quantitation in critical compartments of the central nervous system that cannot be collected in clinical studies. To illustrate the translational value of the model, we report the penetration of linezolid from plasma into the CSF, meninges, anatomically distinct brain areas, cervical spine, and lumbar spine. Across animals, we measured the bacterial burden concomitant with neurological deterioration, offering a useful readout for drug efficacy studies. The model thus forms the basis for building a preclinical platform to identify improved regimens and inform clinical trial design.

Role of Oxidative Stress in Tuberculosis Meningitis Infection in Diabetics.

Tuberculosis meningitis (TBM) is a result of the invasion of the meninges with the bacilli of Mycobacterium tuberculosis (Mtb), leading to inflammation of the meninges around the brain or spinal cord. Oxidative stress occurs when the body's cells become overwhelmed with free radicals, particularly reactive oxygen species (ROS). ROS plays a significant role in the pathogenesis of TBM due to their toxic nature, resulting in impairment of the body's ability to fight off infection. ROS damages the endothelial cells and impairs the defense mechanisms of the blood-brain barrier (BBB), which contributes to CNS susceptibility to the bacteria causing TBM. Diabetes mellitus (DM) is a common condition that is characterized by the impairment of the hormone insulin, which is responsible for modulating blood glucose levels. The increased availability of glucose in individuals with diabetes results in increased cellular activity and metabolism, leading to heightened ROS production and, in turn, increased susceptibility to TBM. In this review, we summarize our current understanding of oxidative stress and its role in both TBM and DM. We further discuss how increased oxidative stress in DM can contribute to the likelihood of developing TBM and potential therapeutic approaches that may be of therapeutic value.

Comparative performance of microbiological methods for the detection of tuberculous meningitis pathogens in cerebrospinal fluid.

The aim of this study was to comprehensively evaluate metagenomic next-generation sequencing (mNGS), Acid-fast bacillus stain (AFB), MGIT960 culture, polymerase-chain-reaction (PCR), and Xpert MTB/RIF in the diagnosis of tuberculous meningitis (TBM). A cohort of 280 patients who presented with suspected TBM (ie, headache or altered mental status with clinical signs of meningism) were analyzed. The sensitivities of the 5 assays for the diagnosis of TBM ranged from 10.0% to 70.0%. The AFB had the lowest sensitivity of 10.0% (0.5-45.9), while mNGS and PCR had the highest sensitivity, both at 70.0% (35.4-91.9). mNGS demonstrated a distinct advantage in identifying a wider array of pathogens, including viruses, in CSF samples. PCR was a cost-effective option with excellent sensitivity and specificity. However, no single method was statistically significantly better than any other in the diagnosis of TBM. New diagnostic techniques are urgently needed for the independent, rapid and accurate detection of Mycobacterium tuberculosis to guide the diagnosis of TBM.

Association of blood neutrophil-lymphocyte ratio with short-term prognosis and severity of tuberculosis meningitis patients without HIV infection.

BACKGROUND: Predicting the short-term prognosis and severity of tuberculosis meningitis (TBM) patients without HIV infection can be challenging, and there have been no prior studies examining the neutrophil lymphocyte ratio (NLR) as a potential predictor of short-term prognosis or its relationship to TBM severity. We hypothesized that NLR might serve as an independent indicator of short-term prognostic significance and that there might be a correlation between NLR and severity. The aim of this study was to investigate the role of NLR as a predictor of short-term prognosis and its relationship to severity of tuberculosis meningitis patients without HIV infection. METHODS: We retrospectively collected data from patients diagnosed with TBM in the West China Hospital, Sichuan University, from the period between January 1st, 2018 and August 1st, 2019. Multivariable analysis was executed by the logistic regression model to verify the independence of the 28-day mortality, the discriminative power for predicting short-term prognosis was evaluated using a Receiver Operating Characteristic (ROC) curve, survival outcomes were analyzed using the Kaplan-Meier method and Pearson's correlation analysis was performed to discuss correlation between NLR and the severity of TBM. RESULTS: We collected data from 231 TBM patients without HIV infection. 68 (29.4%) patients are classified as stage (I) 138(59.8%) patients are stage (II) 25(10.8%) patients are stage (III) 16(6.9%) patients died during the follow-up period of 28 days. By multiple logistic regression analyses, the NLR (OR = 1.065, 95% CI = 1.001-1.133, P = 0.045), peripheral neurological deficit (OR 7.335, 95% CI 1.964-27.385, P = 0 0.003) and hydrocephalus (OR 11.338, 95% CI 2.397-53.633, P = 0 0.002) are independent risk factors of 28-day mortality. The area under the ROC curve (AUC) for predicting short prognosis using NLR is 0.683 (95% CI 0.540-0.826, P = 0.015), the optimal cutoff value is 9.99(sensitivity: 56.3%, specificity: 80.9%). The Kaplan-Meier analysis demonstrated that patients with higher NLR(>9.99) had significantly worse survival outcomes(P<0.01).Pearson's correlation analysis presents a significant positive correlation between the severity of TBM and NLR (r = 0.234, P<0.01). CONCLUSIONS: NLR, peripheral neurological deficit, and hydrocephalus are independent risk factors of 28-day mortality, NLR can predict the short-term prognosis of TBM patients without HIV infection. NLR is also found to be significantly and positively correlated with the severity of TBM.

Missed Opportunities in the Diagnosis of Tuberculosis Meningitis.

Background: Tuberculosis meningitis (TBM) has high mortality and morbidity. Diagnostic delays can impact TBM outcomes. We aimed to estimate the number of potentially missed opportunities (MOs) to diagnose TBM and determine its impact on 90-day mortality. Methods: This is a retrospective cohort of adult patients with a central nervous system (CNS) TB International Classification of Diseases, Ninth/Tenth Revision (ICD-9/10) diagnosis code (013*, A17*) identified in the Healthcare Cost and Utilization Project, State Inpatient and State Emergency Department (ED) Databases from 8 states. Missed opportunity was defined as composite of ICD-9/10 diagnosis/procedure codes that included CNS signs/symptoms, systemic illness, or non-CNS TB diagnosis during a hospital/ED visit 180 days before the index TBM admission. Demographics, comorbidities, admission characteristics, mortality, and admission costs were compared between those with and without a MO, and 90-day in-hospital mortality, using univariate and multivariable analyses. Results: Of 893 patients with TBM, median age at diagnosis was 50 years (interquartile range, 37-64), 61.3% were male, and 35.2% had Medicaid as primary payer. Overall, 407 (45.6%) had a prior hospital or ED visit with an MO code. In-hospital 90-day mortality was not different between those with and without an MO, regardless of the MO coded during an ED visit (13.7% vs 15.2%, P = .73) or a hospitalization (28.2% vs 30.9%, P = .74). Independent risk of 90-day in-hospital mortality was associated with older age, hyponatremia (relative risk [RR], 1.62; 95% confidence interval [CI], 1.1-2.4; P = .01), septicemia (RR, 1.6; 95% CI, 1.03-2.45; P = .03), and mechanical ventilation (RR, 3.4; 95% CI, 2.25-5.3; P < .001) during the index admission. Conclusions: Approximately half the patients coded for TBM had a hospital or ED visit in the previous 6 months meeting the MO definition. We found no association between having an MO for TBM and 90-day in-hospital mortality.

Cerebrospinal fluid concentrations of fluoroquinolones and carbapenems in tuberculosis meningitis.

Background: Tuberculosis meningitis (TBM) is the most lethal form of TB. It is difficult to treat in part due to poor or uncertain drug penetration into the central nervous system (CNS). To help fill this knowledge gap, we evaluated the cerebrospinal fluid (CSF) concentrations of fluoroquinolones and carbapenems in patients being treated for TBM. Methods: Serial serum and CSF samples were collected from hospitalized patients being treated for TBM. CSF was collected from routine lumbar punctures between alternating timepoints of 2 and 6 h after drug administration to capture early and late CSF penetration. Rich serum sampling was collected after drug administration on day 28 for non-compartmental analysis. Results: Among 22 patients treated for TBM (8 with confirmed disease), there was high use of fluoroquinolones (levofloxacin, 21; moxifloxacin, 10; ofloxacin, 6) and carbapenems (imipenem, 11; meropenem, 6). Median CSF total concentrations of levofloxacin at 2 and 6 h were 1.34 mg/L and 3.36 mg/L with adjusted CSF/serum ratios of 0.41 and 0.63, respectively. For moxifloxacin, the median CSF total concentrations at 2 and 6 h were 0.78 mg/L and 1.02 mg/L with adjusted CSF/serum ratios of 0.44 and 0.62. Serum and CSF concentrations of moxifloxacin were not affected by rifampin use. Among the 76 CSF samples measured for carbapenem concentrations, 79% were undetectable or below the limit of detection. Conclusion: Fluoroquinolones demonstrated high CSF penetration indicating their potential usefulness for the treatment of TBM. Carbapenems had lower than expected CSF concentrations.

Pelvic and central nervous system tuberculosis complicated by a paradoxical response manifesting as a spinal tuberculoma: a case report.

BACKGROUND: The post-partum period is a risk factor for tuberculosis (TB), possibly including the period after miscarriage as illustrated here. This case demonstrates how non-specific symptoms can hide widely disseminated TB. CASE PRESENTATION: A healthy 26-year-old female with a history of recent miscarriage presented to the emergency department with non-specific symptoms of headache, abdominal pain, and sub-acute fevers. She had immigrated to the United States from the Marshall Islands 9 years prior. Two months prior to presentation she had a miscarriage at 18 weeks of pregnancy. On admission, transvaginal ultrasound revealed retained products of conception and abdominal computed tomography revealed findings consistent with tubo-ovarian abscesses and peritonitis. The obstetrics and gynecology service performed dilation and curettage (D&C) to remove retained products of conception. Acid-fast bacilli cultures from cerebrospinal fluid as well as specimens from D&C and intra-abdominal abscesses subsequently all grew TB. She was diagnosed with TB meningitis, peritonitis, endometritis, and tubo-ovarian abscesses. Her treatment course was complicated by a paradoxical response resulting in a spinal tuberculoma causing lower extremity weakness. The tuberculoma was treated with surgical decompression as well as continuation of treatment with anti-tubercular chemotherapy and steroids. CONCLUSION: Disseminated and extrapulmonary TB can present with non-specific symptoms. Recognition of risk factors for TB is critical for prompt diagnostic evaluation and treatment of this deadly disease. A paradoxical reaction needs to be taken into consideration when any new neurological symptoms occur during TB treatment.

Bayesian latent class analysis produced diagnostic accuracy estimates that were more interpretable than composite reference standards for extrapulmonary tuberculosis tests.

BACKGROUND: Evaluating the accuracy of extrapulmonary tuberculosis (TB) tests is challenging due to lack of a gold standard. Latent class analysis (LCA), a statistical modeling approach, can adjust for reference tests' imperfect accuracies to produce less biased test accuracy estimates than those produced by commonly used methods like composite reference standards (CRSs). Our objective is to illustrate how Bayesian LCA can address the problem of an unavailable gold standard and demonstrate how it compares to using CRSs for extrapulmonary TB tests. METHODS: We re-analyzed a dataset of presumptive extrapulmonary TB cases in New Delhi, India, for three forms of extrapulmonary TB. Results were available for culture, smear microscopy, Xpert MTB/RIF, and a non-microbiological test, cytopathology/histopathology, or adenosine deaminase (ADA). A diagram was used to define assumed relationships between observed tests and underlying latent variables in the Bayesian LCA with input from an inter-disciplinary team. We compared the results to estimates obtained from a sequence of CRSs defined by increasing numbers of positive reference tests necessary for positive disease status. RESULTS: Data were available from 298, 388, and 230 individuals with presumptive TB lymphadenitis, meningitis, and pleuritis, respectively. Using Bayesian LCA, estimates were obtained for accuracy of all tests and for extrapulmonary TB prevalence. Xpert sensitivity neared that of culture for TB lymphadenitis and meningitis but was lower for TB pleuritis, and specificities of all microbiological tests approached 100%. Non-microbiological tests' sensitivities were high, but specificities were only moderate, preventing disease rule-in. CRSs' only provided estimates of Xpert and these varied widely per CRS definition. Accuracy of the CRSs also varied by definition, and no CRS was 100% accurate. CONCLUSION: Unlike CRSs, Bayesian LCA takes into account known information about test performance resulting in accuracy estimates that are easier to interpret. LCA should receive greater consideration for evaluating extrapulmonary TB diagnostic tests.

Diagnostic and Prognostic Value of Cerebrospinal Fluid Lactate and Glucose in HIV-Associated Tuberculosis Meningitis.

The role of cerebrospinal fluid (CSF) lactate in tuberculosis meningitis (TBM) diagnosis and prognosis is unclear. The aim of this study was to evaluate the performance of CSF lactate alone and in combination with CSF glucose in predicting a diagnosis of TBM and 14-day survival. HIV-positive Ugandan adults were investigated for suspected meningitis. The baseline CSF tests included smear microscopy; Gram stain; cell count; protein; and point-of-care glucose, lactate, and cryptococcal antigen (CrAg) assays. Where CrAg was negative or there was suspicion of TBM, a CSF Xpert MTB/RIF Ultra (Xpert Ultra) test was performed. We recorded baseline demographic and clinical data and 2-week outcomes. Of 667 patients, 25% (n = 166) had TBM, and of these, 49 had definite, 47 probable, and 70 possible TBM. CSF lactate was higher in patients with definite TBM (8.0 mmol/L; interquartile ratio [IQR], 6.1 to 9.8 mmol/L) than in those with probable TBM (3.4 [IQR, 2.5 to 7.0] mmol/L), possible TBM (2.6 [IQR 2.1 to 3.8] mmol/L), and non-TBM disease (3.5 [IQR 2.5 to 5.0] mmol/L). A 2-fold increase in CSF lactate was associated with 8-fold increased odds of definite TBM (odds ratio, 8.3; 95% confidence interval [CI], 3.6 to 19.1; P < 0.01) and 2-fold increased odds of definite/probable TBM (odds ratio, 2.3; 95% CI, 1.4 to 3.7; P < 0.001). At a cut point of >5.5 mmol/L, CSF lactate could be used to diagnose definite TBM with a sensitivity of 87.7%, specificity of 80.7%, and a negative predictive value of 98.8%. CSF lactate was not predictive of 2-week mortality. IMPORTANCE Tuberculosis meningitis (TBM) is the most severe form of tuberculosis, and its fatality is largely due to delays in diagnosis. The role of CSF lactate has not been evaluated in patients with HIV presenting with signs and symptoms of meningitis. In this study, using a point-of-care handheld lactate machine in patients with HIV-associated meningitis, we showed that high baseline CSF lactate (>5.5 mmol) may be used to rapidly identify patients with TBM and shorten the time to initiate treatment with a similar performance to the Xpert Ultra assay for definite TBM. Elevated CSF lactate levels, however, were not associated with increased 2-week mortality in patients with HIV-associated TBM. Due to moderate specificity, other etiologies of meningitis should be investigated.

Cerebral Infarction and Evan's Ratio on MRI Affect the Severity and Prognosis of Tuberculosis Meningitis Patients.

Background: Magnetic resonance imaging (MRI) is widely used in the diagnosis of tuberculous meningitis (TBM) and its complications. We aimed to explore the relationship between MRI features and neurological deficits and TBM patients' prognosis. Methods: patients diagnosed with TBM were subjected to a neurological evaluation on admission and divided into groups based on the Medical Research Council (MRC) scale. After several years of follow-up, the patients were further divided into groups according to the Modified Rankin Score (MRS). Their MR images were analyzed for meningeal enhancement, tuberculomas, infarction, hydrocephalus, and abscess, including the location and size of the lesion. Any changes in MRI features during the follow-up were recorded. MRI features between groups were compared, and the relationship between dynamic changes in images and Rankin grading was explored. Results: We found significant differences in acute cerebral infarction (ACI) and old cerebral infarctions (OCI) between the MRC groups, and the ORs of ACI and OCI were 21.818 (95% CI: 2.440−195.075) and 6.788 (95% CI: 1.516−30.392), respectively. There were significant differences in ACI, OCI, and Evan's ratio between the MRS groups (p < 0.05), and the ORs of ACI, OCI, and hydrocephalus were 6.375 (95% CI: 1.501−27.080), 5.556 (95% CI: 1.332−23.177), and 9.139 (95% CI: 2.052−40.700), respectively. The changes of Evan's ratio were related to the MRS grading (r = 0.335, p = 0.040). Conclusions: For patients with TBM, the presence of ACI or OCI is associated with neurological deficits, and ACI, OCI, and hydrocephalus can be regarded as poor prognostic predictors. Changes in Evan's ratio will affect the outcome.

Safety and efficacy of high-dose rifampicin in the management of tuberculosis meningitis: Systematic review and meta-analysis.

Background: Mycobacterium tuberculosis (TB) practically affects any part of the body, but when the brain is involved, the consequences are devastating. Tuberculous meningitis (TBM) is the most severe form of drug-susceptible TB, with an estimation of more than 100,000 new cases occurring every year and a high mortality rate globally. The treatment strategy is based on pulmonary TB (PTB) management regimens which consider rifampicin as the backbone. Optimal treatment regimens for PTB may not be the most effective option for TBM due to difference in TB drug penetration across the blood-cerebrospinal fluid barrier, hence the need for other treatment options. This study aims to review the efficacy and safety of higher doses of rifampicin (>10 mg/kg) compared to 10 mg/kg rifampicin as part of standard therapy for the treatment of TBM. Methods: A systematic review and meta-analysis was conducted to assess the efficacy and safety of high-dose rifampicin for TBM. A search was done on PubMed, Google Scholar, and Cochrane library databases without publication date limit to identify studies providing data on the use of high-dose rifampicin for the treatment of TBM. Titles and abstracts were screened for relevance by three reviewers. Two reviewers used a predefined checklist on the inclusion criteria to assess full text for their eligibility in the review. A heterogeneity test was conducted to assess the variations among study outcomes. The risk ratio (RR) with a 95% confidence interval (CI) was calculated as a measure of intervention effect. The study is registered on PROSPERO and the registration number is CRD42020212737. Results: Five Phase 2 trials with a total of 1028 participants were included in this meta-analysis. All the five trials were used to analyze safety data, which found that there was no significant increase in the risk of Grade 3-5 adverse events in high-dose rifampicin (RR = 1.05; 95% CI = 0.95-1.18). Only four of them were included for the analysis of efficacy. The findings indicated that exposure to high-dose rifampicin is not associated with a reduced risk of mortality (RR = 0.95; 95% CI = 0.78-1.16). Conclusions: It can be concluded from this meta-analysis that there is no significant relation of high-dose rifampicin with adverse events and the reduction of mortality in TBM patients. Whether in future optimized TBM treatment regimen will include high-dose rifampicin or not should be determined by a large-scale clinical trial.

Evaluation of the molecular bacterial load assay for detecting viable Mycobacterium tuberculosis in cerebrospinal fluid before and during tuberculous meningitis treatment.

New tools to monitor treatment response and predict outcome from tuberculous meningitis (TBM) are urgently required. We retrospectively evaluated the 16S rRNA-based molecular bacterial load assay (MBLA) to quantify viable Mycobacterium tuberculosis in serial cerebrospinal fluid (CSF) from adults with TBM. 187 CSF samples were collected before and during the first two months of treatment from 99 adults TBM, comprising 56 definite, 43 probable or possible TBM, and 18 non-TBM and preserved at -80°C prior to MBLA. We compared MBLA against MGIT culture, GeneXpert MTB/RIF (Xpert) and Ziehl-Neelsen (ZN) smear. Before treatment, MBLA was positive in 34/99 (34.3%), significantly lower than MGIT 47/99 (47.5%), Xpert 51/99 (51.5%) and ZN smear 55/99 (55.5%). After one month of treatment, MBLA and MGIT were positive in 3/38 (7.9%) and 4/38 (10.5%), respectively, whereas Xpert and ZN smear remained positive in 19/38 (50.0%) and 18/38 (47.4%). In summary, MBLA was less likely to detect CSF bacteria before the start of treatment compared with MGIT culture, Xpert and ZN smear. MBLA and MGIT positivity fell during treatment because of detecting only viable bacteria, whereas Xpert and ZN smear remained positive for longer because of detecting both live and dead bacteria. Sample storage and processing may have reduced MBLA-detectable viable bacteria; and sampling earlier in treatment may yield more useful results. Prospective studies with CSF sampling after 1-2 weeks are warranted.

Population Pharmacokinetic Properties of Antituberculosis Drugs in Vietnamese Children with Tuberculous Meningitis.

Optimal dosing of children with tuberculous meningitis (TBM) remains uncertain and is currently based on the treatment of pulmonary tuberculosis in adults. This study aimed to investigate the population pharmacokinetics of isoniazid, rifampin, pyrazinamide, and ethambutol in Vietnamese children with TBM, to propose optimal dosing in these patients, and to determine the relationship between drug exposure and treatment outcome. A total of 100 Vietnamese children with TBM were treated with an 8-month antituberculosis regimen. Nonlinear mixed-effects modeling was used to evaluate the pharmacokinetic properties of the four drugs and to simulate different dosing strategies. The pharmacokinetic properties of rifampin and pyrazinamide in plasma were described successfully by one-compartment disposition models, while those of isoniazid and ethambutol in plasma were described by two-compartment disposition models. All drug models included allometric scaling of body weight and enzyme maturation during the first years of life. Cerebrospinal fluid (CSF) penetration of rifampin was relatively poor and increased with increasing protein levels in CSF, a marker of CSF inflammation. Isoniazid and pyrazinamide showed good CSF penetration. Currently recommended doses of isoniazid and pyrazinamide, but not ethambutol and rifampin, were sufficient to achieve target exposures. The ethambutol dose cannot be increased because of ocular toxicity. Simulation results suggested that rifampin dosing at 50 mg/kg of body weight/day would be required to achieve the target exposure. Moreover, low rifampin plasma exposure was associated with an increased risk of neurological disability. Therefore, higher doses of rifampin could be considered, but further studies are needed to establish the safety and efficacy of increased dosing.

Analysis of Tuberculosis Meningitis Pathogenesis, Diagnosis, and Treatment.

Tuberculosis (TB) is the most prevalent infectious disease in the world. In recent years there has been a significant increase in the incidence of TB due to the emergence of multidrug resistant strains of Mycobacterium tuberculosis (M. tuberculosis) and the increased numbers of highly susceptible immuno-compromised individuals. Central nervous system TB, includes TB meningitis (TBM-the most common presentation), intracranial tuberculomas, and spinal tuberculous arachnoiditis. Individuals with TBM have an initial phase of malaise, headache, fever, or personality change, followed by protracted headache, stroke, meningismus, vomiting, confusion, and focal neurologic findings in two to three weeks. If untreated, mental status deteriorates into stupor or coma. Delay in the treatment of TBM results in, either death or substantial neurological morbidity. This review provides latest developments in the biomedical research on TB meningitis mainly in the areas of host immune responses, pathogenesis, diagnosis, and treatment of this disease.

Decision-making in the diagnosis of tuberculous meningitis.

Tuberculous meningitis (TBM) is the most devastating form of tuberculosis (TB) but diagnosis is difficult and delays in initiating therapy increase mortality. All currently available tests are imperfect; culture of Mycobacterium tuberculosis from the cerebrospinal fluid (CSF) is considered the most accurate test but is often negative, even when disease is present, and takes too long to be useful for immediate decision making. Rapid tests that are frequently used are conventional Ziehl-Neelsen staining and nucleic acid amplification tests such as Xpert MTB/RIF and Xpert MTB/RIF Ultra. While positive results will often confirm the diagnosis, negative tests frequently provide insufficient evidence to withhold therapy. The conventional diagnostic approach is to determine the probability of TBM using experience and intuition, based on prevalence of TB, history, examination, analysis of basic blood and CSF parameters, imaging, and rapid test results. Treatment decisions may therefore be both variable and inaccurate, depend on the experience of the clinician, and requests for tests may be inappropriate. In this article we discuss the use of Bayes' theorem and the threshold model of decision making as ways to improve testing and treatment decisions in TBM. Bayes' theorem describes the process of converting the pre-test probability of disease to the post-test probability based on test results and the threshold model guides clinicians to make rational test and treatment decisions. We discuss the advantages and limitations of using these methods and suggest that new diagnostic strategies should ultimately be tested in randomised trials.