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Background: The World Health Organization predicted 10.6 million new tuberculosis cases and 1.5 million deaths in 2022. Tuberculous meningitis, affecting 1% of active TB cases, is challenging to diagnose due to sudden onset, vague symptoms, and limited laboratory tests. Nanopore-targeted sequencing (NTS) is an emerging third-generation sequencing technology known for its sequencing capabilities. We compared its detection efficiency with Xpert, MTB culture, PCR, and AFB smear in cerebrospinal fluid samples to highlight the substantial potential of NTS in detecting intracranial tuberculosis. Methods: This study included 122 patients suspected of having intracranial tuberculosis at the Second Hospital of Nanjing in Jiangsu Province, China, between January 2021 and January 2024. The Univariate logistic regression and random forest regression identified risk factors and clinical markers. A chi-square test evaluated diagnostic accuracy for different image types of intracranial tuberculosis. Results: The research involved 100 patients with intracranial tuberculosis. Among them, 41 had tuberculous meningitis, 27 had cerebral parenchymal tuberculosis, and 32 had mixed intracranial tuberculosis. Besides, 22 patients were diagnosed with other brain conditions. In diagnosing intracranial tuberculosis, NTS demonstrated a sensitivity of 60.0% (95% CI: 49.7-69.5%) and a specificity of 95.5% (95% CI:75.1-99.8%), with an AUC value of 0.78 (95% CI: 0.71 to 0.84), whose overall performance was significantly better than other detection methods. There was no notable difference (P > 0.05) in diagnostic accuracy between NTS and the final diagnosis for intracranial tuberculosis patients with varying imaging types. Furthermore, patients who tested positive had a 31.500 (95% CI: 6.205-575.913) times higher risk of having intracranial tuberculosis compared to those with negative results. Conclusion: Due to its convenience, efficiency, quick turnaround time, and real-time sequencing analysis, NTS might become a promising and reliable method for providing microbiological diagnoses for patients with intracranial tuberculosis and for screening populations at risk. [ABSTRACT FROM AUTHOR]

Abstract Background The World Health Organization predicted 10.6 million new tuberculosis cases and 1.5 million deaths in 2022. Tuberculous meningitis, affecting 1% of active TB cases, is challenging to diagnose due to sudden onset, vague symptoms, and limited laboratory tests. Nanopore-targeted sequencing (NTS) is an emerging third-generation sequencing technology known for its sequencing capabilities. We compared its detection efficiency with Xpert, MTB culture, PCR, and AFB smear in cerebrospinal fluid samples to highlight the substantial potential of NTS in detecting intracranial tuberculosis. Methods This study included 122 patients suspected of having intracranial tuberculosis at the Second Hospital of Nanjing in Jiangsu Province, China, between January 2021 and January 2024. The Univariate logistic regression and random forest regression identified risk factors and clinical markers. A chi-square test evaluated diagnostic accuracy for different image types of intracranial tuberculosis. Results The research involved 100 patients with intracranial tuberculosis. Among them, 41 had tuberculous meningitis, 27 had cerebral parenchymal tuberculosis, and 32 had mixed intracranial tuberculosis. Besides, 22 patients were diagnosed with other brain conditions. In diagnosing intracranial tuberculosis, NTS demonstrated a sensitivity of 60.0% (95% CI: 49.7-69.5%) and a specificity of 95.5% (95% CI:75.1-99.8%), with an AUC value of 0.78 (95% CI: 0.71 to 0.84), whose overall performance was significantly better than other detection methods. There was no notable difference (P > 0.05) in diagnostic accuracy between NTS and the final diagnosis for intracranial tuberculosis patients with varying imaging types. Furthermore, patients who tested positive had a 31.500 (95% CI: 6.205-575.913) times higher risk of having intracranial tuberculosis compared to those with negative results. Conclusion Due to its convenience, efficiency, quick turnaround time, and real-time sequencing analysis, NTS might become a promising and reliable method for providing microbiological diagnoses for patients with intracranial tuberculosis and for screening populations at risk.

Abstract Tuberculous meningitis (TBM)—the extrapulmonary form of tuberculosis, is the most severe complication associated with tuberculosis, particularly in infants and children. The gold standard for the diagnosis of TBM requires cerebrospinal fluid (CSF) through lumbar puncture—an invasive sample collection method, and currently available CSF assays are often not sufficient for a definitive TBM diagnosis. Urine is metabolite-rich and relatively unexplored in terms of its potential to diagnose neuroinfectious diseases. We used an untargeted proton magnetic resonance (1H-NMR) metabolomics approach to compare the urine from 32 patients with TBM (stratified into stages 1, 2 and 3) against that from 39 controls in a South African paediatric cohort. Significant spectral bins had to satisfy three of our four strict cut-off quantitative statistical criteria. Five significant biological metabolites were identified—1-methylnicotinamide, 3-hydroxyisovaleric acid, 5-aminolevulinic acid, N-acetylglutamine and methanol—which had no correlation with medication metabolites. ROC analysis revealed that methanol lacked diagnostic sensitivity, but the other four metabolites showed good diagnostic potential. Furthermore, we compared mild (stage 1) TBM and severe (stages 2 and 3) TBM, and our multivariate metabolic model could successfully classify severe but not mild TBM. Our results show that urine can potentially be used to diagnose severe TBM.

Abstract 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

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. [ABSTRACT FROM AUTHOR]

Abstract Background The pathogenesis of tuberculous meningitis (TBM) involves infection by Mycobacterium tuberculosis in the meninges and brain. However, recent studies have shown that the immune response and inflammatory processes triggered by TBM can have significant effects on gut microbiota. Disruptions in the gut microbiome have been linked to various systemic consequences, including altered immunity and metabolic dysregulation. Inflammation caused by TBM, antibiotic treatment, and changes in host immunity can all influence the composition of gut microbes. This complex relationship between TBM and the gut microbiome is of great importance in clinical settings. To gain a deeper understanding of the intricate interactions between TBM and the gut microbiome, we report innovative insights into the development of the disease in response to treatment. Ultimately, this could lead to improved outcomes, management strategies and quality of life for individuals affected by TBM. Method We used a targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) approach to investigate metabolites associated with gut metabolism in paediatric participants by analysing the urine samples collected from a control group (n = 40), and an experimental group (n = 35) with confirmed TBM, which were subdivided into TBM stage 1 (n = 8), stage 2 (n = 11) and stage 3 (n = 16). Findings Our metabolomics investigation showed that, of the 78 initially selected compounds of microbiome origin, eight unique urinary metabolites were identified: 2-methylbutyrlglycine, 3-hydroxypropionic acid, 3-methylcrotonylglycine, 4-hydroxyhippuric acid, 5-hydroxyindoleacetic acid, 5-hydroxyhexanoic acid, isobutyrylglycine, and phenylacetylglutamine as urinary markers of dysbiosis in TBM. Conclusion These results – which are supported by previous urinary studies of tuberculosis – highlight the importance of gut metabolism and of identifying corresponding microbial metabolites as novel points for the foundation of improved management of TBM patients.

Background: The pathogenesis of tuberculous meningitis (TBM) involves infection by Mycobacterium tuberculosis in the meninges and brain. However, recent studies have shown that the immune response and inflammatory processes triggered by TBM can have significant effects on gut microbiota. Disruptions in the gut microbiome have been linked to various systemic consequences, including altered immunity and metabolic dysregulation. Inflammation caused by TBM, antibiotic treatment, and changes in host immunity can all influence the composition of gut microbes. This complex relationship between TBM and the gut microbiome is of great importance in clinical settings. To gain a deeper understanding of the intricate interactions between TBM and the gut microbiome, we report innovative insights into the development of the disease in response to treatment. Ultimately, this could lead to improved outcomes, management strategies and quality of life for individuals affected by TBM. Method: We used a targeted liquid chromatography–tandem mass spectrometry (LC-MS/MS) approach to investigate metabolites associated with gut metabolism in paediatric participants by analysing the urine samples collected from a control group (n = 40), and an experimental group (n = 35) with confirmed TBM, which were subdivided into TBM stage 1 (n = 8), stage 2 (n = 11) and stage 3 (n = 16). Findings: Our metabolomics investigation showed that, of the 78 initially selected compounds of microbiome origin, eight unique urinary metabolites were identified: 2-methylbutyrlglycine, 3-hydroxypropionic acid, 3-methylcrotonylglycine, 4-hydroxyhippuric acid, 5-hydroxyindoleacetic acid, 5-hydroxyhexanoic acid, isobutyrylglycine, and phenylacetylglutamine as urinary markers of dysbiosis in TBM. Conclusion: These results – which are supported by previous urinary studies of tuberculosis – highlight the importance of gut metabolism and of identifying corresponding microbial metabolites as novel points for the foundation of improved management of TBM patients. [ABSTRACT FROM AUTHOR]

Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed. [ABSTRACT FROM AUTHOR]

Tuberculous meningitis (TBM) is a severe form of tuberculosis with high neuro-morbidity and mortality, especially among the paediatric population (aged ≤12 years). Little is known of the associated metabolic changes. This study aimed to identify characteristic metabolic markers that differentiate severe cases of paediatric TBM from controls, through non-invasive urine collection. Urine samples selected for this study were from two paediatric groups. Group 1: controls (n = 44): children without meningitis, no neurological symptoms and from the same geographical region as group 2. Group 2: TBM cases (n = 13): collected from paediatric patients that were admitted to Tygerberg Hospital in South Africa on the suspicion of TBM, mostly severely ill; with a later confirmation of TBM. Untargeted 1H NMR-based metabolomics data of urine were generated, followed by statistical analyses via MetaboAnalyst (v5.0), and the identification of important metabolites. Twenty nine urinary metabolites were identified as characteristic of advanced TBM and categorized in terms of six dysregulated metabolic pathways: 1) upregulated tryptophan catabolism linked to an altered vitamin B metabolism; 2) perturbation of amino acid metabolism; 3) increased energy production–metabolic burst; 4) disrupted gut microbiota metabolism; 5) ketoacidosis; 6) increased nitrogen excretion. We also provide original biological insights into this biosignature of urinary metabolites that can be used to characterize paediatric TBM patients in a South African cohort.

Tuberculous meningitis (TBM), the most severe form of tuberculosis, causes death in approximately 25% cases despite antibiotic therapy, and half of survivors are left with neurological disability. Mortality and morbidity are contributed to by a dysregulated immune response, and adjunctive host-directed therapies are required to modulate this response and improve outcomes. Developing such therapies relies on improved understanding of the host immune response to TBM. The historical challenges in TBM research of limited in vivo and in vitro models have been partially overcome by recent developments in proteomics, transcriptomics, and metabolomics, and the use of these technologies in nested substudies of large clinical trials. We review the current understanding of the human immune response in TBM. We begin with M. tuberculosis entry into the central nervous system (CNS), microglial infection and blood-brain and other CNS barrier dysfunction. We then outline the innate response, including the early cytokine response, role of canonical and non-canonical inflammasomes, eicosanoids and specialised pro-resolving mediators. Next, we review the adaptive response including T cells, microRNAs and B cells, followed by the role of the glutamate-GABA neurotransmitter cycle and the tryptophan pathway. We discuss host genetic immune factors, differences between adults and children, paradoxical reaction, and the impact of HIV-1 co-infection including immune reconstitution inflammatory syndrome. Promising immunomodulatory therapies, research gaps, ongoing challenges and future paths are discussed.

Tuberculosis (TB) is still one of the most challenging infectious diseases worldwide. Coinfection with HIV increases the likelihood of extrapulmonary involvement, including the tuberculosis of the central nervous system (CNS-TB). CNS-TB often presents as tuberculomas or tuberculous meningitis. Although tuberculomas can be single or multiple, asymptomatic carriage of numerous tuberculomas is seldom reported. We present a case of a 55-year-old man who carried at least 34 tuberculomas of different sizes asymptomatically before developing and succumbing to tuberculous meningitis. Furthermore, we highlight several possible public health challenges that might have complicated his clinical course, suggesting that future studies also focus on these variables alongside more traditional clinical issues., Competing Interests: Human subjects: Consent was obtained or waived by all participants in this study. Conflicts of interest: In compliance with the ICMJE uniform disclosure form, all authors declare the following: Payment/services info: All authors have declared that no financial support was received from any organization for the submitted work. Financial relationships: All authors have declared that they have no financial relationships at present or within the previous three years with any organizations that might have an interest in the submitted work. Other relationships: All authors have declared that there are no other relationships or activities that could appear to have influenced the submitted work., (Copyright © 2024, Alavidze et al.)

Tuberculous meningitis (TBM) is a severe form of tuberculosis with high neuro-morbidity and mortality, especially among the paediatric population (aged ≤12 years). Little is known of the associated metabolic changes. This study aimed to identify characteristic metabolic markers that differentiate severe cases of paediatric TBM from controls, through non-invasive urine collection. Urine samples selected for this study were from two paediatric groups. Group 1: controls (n = 44): children without meningitis, no neurological symptoms and from the same geographical region as group 2. Group 2: TBM cases (n = 13): collected from paediatric patients that were admitted to Tygerberg Hospital in South Africa on the suspicion of TBM, mostly severely ill; with a later confirmation of TBM. Untargeted 1H NMR-based metabolomics data of urine were generated, followed by statistical analyses via MetaboAnalyst (v5.0), and the identification of important metabolites. Twenty nine urinary metabolites were identified as characteristic of advanced TBM and categorized in terms of six dysregulated metabolic pathways: 1) upregulated tryptophan catabolism linked to an altered vitamin B metabolism; 2) perturbation of amino acid metabolism; 3) increased energy production-metabolic burst; 4) disrupted gut microbiota metabolism; 5) ketoacidosis; 6) increased nitrogen excretion. We also provide original biological insights into this biosignature of urinary metabolites that can be used to characterize paediatric TBM patients in a South African cohort., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Isaiah, Loots, van Reenen, Solomons, van Elsland, Tutu van Furth, van der Kuip and Mason.)

Objective: To better characterize the cerebrospinal fluid (CSF) metabolic profile of tuberculous meningitis (TBM) cases using a South African paediatric cohort.Methods: 1H NMR metabolomics was used to analyse the CSF of a South African paediatric cohort. Univariate and multivariate statistical analyses were performed to compare a homogeneous control group with a well-defined TBM group.Results: Twenty metabolites were identified to discriminate TBM cases from controls. As expected, reduced glucose and elevated lactate were the dominating discriminators. A closer investigation of the CSF metabolic profile yielded 18 metabolites of statistical significance. Ten metabolites (acetate, alanine, choline, citrate, creatinine, isoleucine, lysine, myo-inositol, pyruvate and valine) overlapped with two other prior investigations. Eight metabolites (2-hydroxybutyrate, carnitine, creatine, creatine phosphate, glutamate, glutamine, guanidinoacetate and proline) were unique to our paediatric TBM cohort.Conclusions: Through strict exclusion criteria, quality control checks and data filtering, eight unique CSF metabolites associated with TBM were identified for the first time and linked to: uncontrolled glucose metabolism, upregulated proline and creatine metabolism, detoxification and disrupted glutamate-glutamine cycle in the TBM samples. Associated with oxidative stress and chronic neuroinflammation, our findings collectively imply destabilization, and hence increased permeability, of the blood-brain barrier in the TBM cases. [ABSTRACT FROM AUTHOR]

Keywords: lactate; neurology; traumatic brain injury (TBI); neurodegenerative disease; tuberculous meningitis (TBM) EN lactate neurology traumatic brain injury (TBI) neurodegenerative disease tuberculous meningitis (TBM) 1 5 5 05/21/20 20200515 NES 200515 Introduction Lactate has become one of the most re-evaluated metabolites in energy metabolism, particularly as a shuttle in neuroenergetics (Mason, [21]; Ferguson et al., [10]). New insights into lactate cellular compartmentation have been gained by measuring great variations in lactate diffusion properties I in vivo i (Ligneul et al., [17]), which show that intracellular lactate is predominantly present within astrocytes under control conditions, but comes to be predominate in neurons during "pure" astrocyte reactivity (in the absence of both neuronal death and microglial activation). Therapeutic Role of Lactate in Acute Brain Injuries The therapeutic role of lactate in acute brain injuries such as subarachnoid hemorrhage and traumatic brain injury (TBI) - identified by a high lactate/pyruvate ratio despite adequate brain glucose and oxygenation - was recently reviewed by Killen et al. ([14]). (2) Transcriptional analysis of gene expression modulation in neurons evoked by exposure to L-lactate indicated that lactate effectively regulates activity-dependent and synaptic genes and highlighted new signaling effects of lactate in plasticity and neuroprotection (Margineanu et al., [20]). [Extracted from the article]

From the World Health Organization’s global TB report for 2020, it is estimated that in 2019 at least 80,000 children (a particularly vulnerable population) developed tuberculous meningitis (TBM)—an invariably fatal disease if untreated—although this is likely an underestimate. As our latest technologies have evolved—with the unprecedented development of the various “omics” disciplines—a mountain of new data on infectious diseases have been created. However, our knowledge and understanding of infectious diseases are still trying to keep pace. Metabolites offer much biological information, but the insights they permit can be difficult to derive. This review summarizes current metabolomics studies on cerebrospinal fluid (CSF) from TBM cases and collates the metabolic data reported. Collectively, CSF metabolomics studies have identified five classes of metabolites that characterize TBM: amino acids, organic acids, nucleotides, carbohydrates, and “other”. Taken holistically, the information given in this review serves to promote the mechanistic action of hypothesis generation that will drive and direct future studies on TBM.

Neurotuberculosis remains a mystery and presents a formidable challenge in diagnosis and management. While pulmonary tuberculosis has a well understood pathophysiology and well researched management strategies, CNS tuberculosis still has plenty of unanswered questions. The purpose of this review is to highlight the debatable issues in the current understanding of the clinical, diagnostic, and therapeutic aspects of Neurotuberculosis., (Copyright © 2023 Tuberculosis Association of India. Published by Elsevier B.V. All rights reserved.)

Background: Timely diagnosis of tuberculous meningitis (TBM) remains challenging. Molecular diagnostic tools are necessary, particularly in low- and middle-income countries. There is no approved commercial polymerase chain reaction (PCR) assay that can be used to detect Mycobacterium tuberculosis in non-respiratory samples, such as the cerebrospinal fluid (CSF). We aimed to validate the threshold cycle (Ct) cut-off points; calculate the operational characteristics of real-time PCR for detection of M. tuberculosis (MTb qPCR) in the CSF; and the inhibitory affect of CSF red blood cells (RBC) and total proteins on MTb qPCR. Methods: A total of 334 consecutive participants were enrolled. Based on clinical, laboratory and imaging data, cases of suspected TBM were categorized as definite, probable, possible or not TBM cases. Receiver operating characteristic curve analysis was used to select the best discriminating Ct value. Results: For TBM cases categorized as definite or probable (n=21), the Ct validated for CSF (≤39.5) improved the diagnostic performance of MTb qPCR on CSF samples. The sensitivity was 29%, specificity was 95%, positive predictive value was 26%, negative predictive value was 95%, efficiency was 90% and positive likelihood was 5.3. The CSF RBC and total protein did not affect the positivity of the MTb qPCR. Conclusions: These data support the validation of a highly specific but low sensitive MTb qPCR assay for the TBM diagnosis using CSF samples. MTb qPCR contributes significantly to the diagnosis, mainly when associated with conventional microbiology tests and clinical algorithms. [ABSTRACT FROM AUTHOR]

Background: Molecular methods which allow for rapid and reliable detection of drug resistance have yet not been sufficiently evaluated for timely management of patients with tuberculous meningitis. Aims: We aimed to evaluate Geno Type MTBDRplus line probe assay for early detection of drug resistance in Mycobacterium tuberculosis isolates and CSF samples of confirmed tuberculous meningitis patients. Settings and Design: This was a multicentric prospective study carried out from July 2011 to December 2013 in tertiary care hospitals of Delhi. Materials and Methods: The assay was performed on 89 M. tuberculosis isolates and 31 direct CSF samples from microbiologically confirmed tuberculous meningitis patients. The sensitivity and specificity of this assay was calculated in comparison to drug susceptibility testing by BACTEC MGIT 960 system. Results: The sensitivity, specificity for detection of resistance to Isoniazid was 93%, 97% and to Rifampicin was 80%, 98.8%, respectively by this assay in comparison with the phenotypic drug susceptibility testing. The line probe assay could detect M. tuberculosis in 55% of CSF samples from patients with microbiologically confirmed tuberculous meningitis. Only 5/89 isolates (5.6%) were resistant to both Isoniazid and Rifampicin while 9/89 (10%) isolates were additionally resistant to Isoniazid. Resistance to any of the drugs, namely Isoniazid, Rifampicin, Streptomycin or Ethambutol, was seen in 24.7% of strains. Conclusion: The line probe assay has a good sensitivity and specificity for detection of drug resistance to Isoniazid and Rifampicin in M. tuberculosis culture isolates. However, this assay has limited role in detection of M. tuberculosis and drug resistance from direct samples with confirmed diagnosis of tuberculous meningitis.

Background: In Africa, tuberculosis is generally regarded as persisting as one of the most devastating infectious diseases. The pediatric population is particularly vulnerable, with infection of the brain in the form of tuberculous meningitis (TBM) being the most severe manifestation. TBM is often difficult to diagnose in its early stages because of its non-specific clinical presentation. Of particular concern is that late diagnosis, and subsequent delayed treatment, leads to high risk of long-term neurological sequelae, and even death. Using advanced technology and scientific expertise, we are intent on further describing the biochemistry behind this devastating neuroinflammatory disease, with the goal of improving upon its early diagnosis.Method: We used the highly sensitive analytical platform of gas chromatography-mass spectrometry (GC-MS) to analyze amino acid profiles of cerebrospinal fluid (CSF) collected from a cohort of 33 South African pediatric TBM cases, compared to 34 controls.Results: Through the use of a stringent quality assurance procedure and various statistical techniques, we were able to confidently identify five amino acids as being significantly elevated in TBM cases, namely, alanine, asparagine, glycine, lysine, and proline. We found also in an earlier untargeted metabolomics investigation that alanine can be attributed to increased CSF lactate levels, and lysine as a marker of lipid peroxidation. Alanine, like glycine, is an inhibitory neurotransmitter in the brain. Asparagine, as with proline, is linked to the glutamate-glutamine cycle. Asparagine is associated with the removal of increased nitrites in the brain, whereas elevated proline coincides with the classic biochemical marker of increased CSF protein in TBM. All five discriminatory amino acids are linked to ammonia due to increased nitrites in TBM.Conclusion: A large amount of untapped biochemical information is present in CSF of TBM cases, of which amino acid profiling through GC-MS has potential in aiding in earlier diagnosis, and hence crucial earlier treatment.

Background: In Africa, tuberculosis is generally regarded as persisting as one of the most devastating infectious diseases. The pediatric population is particularly vulnerable, with infection of the brain in the form of tuberculous meningitis (TBM) being the most severe manifestation. TBM is often difficult to diagnose in its early stages because of its non-specific clinical presentation. Of particular concern is that late diagnosis, and subsequent delayed treatment, leads to high risk of long-term neurological sequelae, and even death. Using advanced technology and scientific expertise, we are intent on further describing the biochemistry behind this devastating neuroinflammatory disease, with the goal of improving upon its early diagnosis. Method: We used the highly sensitive analytical platform of gas chromatography-mass spectrometry (GC-MS) to analyze amino acid profiles of cerebrospinal fluid (CSF) collected from a cohort of 33 South African pediatric TBM cases, compared to 34 controls. Results: Through the use of a stringent quality assurance procedure and various statistical techniques, we were able to confidently identify five amino acids as being significantly elevated in TBM cases, namely, alanine, asparagine, glycine, lysine, and proline. We found also in an earlier untargeted metabolomics investigation that alanine can be attributed to increased CSF lactate levels, and lysine as a marker of lipid peroxidation. Alanine, like glycine, is an inhibitory neurotransmitter in the brain. Asparagine, as with proline, is linked to the glutamate-glutamine cycle. Asparagine is associated with the removal of increased nitrites in the brain, whereas elevated proline coincides with the classic biochemical marker of increased CSF protein in TBM. All five discriminatory amino acids are linked to ammonia due to increased nitrites in TBM. Conclusion: A large amount of untapped biochemical information is present in CSF of TBM cases, of which amino acid profiling through GC-MS has potential in aiding in earlier diagnosis, and hence crucial earlier treatment. [ABSTRACT FROM AUTHOR]

The diagnosis of tuberculous meningitis cannot be made or excluded on the basis of clinical findings. Definite laboratory diagnosis is cumbersome and time consuming. Delay in diagnosis and institution of proper treatment is directly related to poor outcome and sequalae. Adenosine deaminase activity (ADA) was estimated in cerebrospinal fluid (CSF) in addition to routine CSF analysis of 32 patients of tuberculous meningitis (TBM) and 7 patients of partially treated pyomeningitis (PTM), 10 patients aseptic meningitis (AM) and 13 patients pyogenic meningitis (PM). Mean ADA levels in CSF of TBM patients were higher (15.42 U/L) as compared to 7.21 U/L, 6.41 U/L and 7.50 U/L in PTM, AM and PM respectively. This difference of ADA values in CSF between TBM and other types of meningitis was statistically significant (p Journal of College of Medical Sciences-Nepal,2012,Vol-8,No-2, 17-23 DOI: http://dx.doi.org/10.3126/jcmsn.v8i2.6833

Context Tuberculosis (TB) is India's major public health problem. The profile of childhood TB in the northeast region of India is still limited. Aim To analyze the clinical, radiological, and bacteriological profiles of children with TB at a tertiary health care facility. Materials and methods A three years retrospective descriptive analysis of children admitted to a tertiary centre with TB before the introduction of cartridge-based nucleic acid amplification test (CBNAAT) for testing. Children below 18 years who were admitted from 2012 to 2014 and were diagnosed with TB were included. Relevant data were extracted in a predesigned format and entered into a Microsoft Excel sheet. Descriptive statistic was used for analysis. The results of variables are given in proportions and means and a Chi-square test was done for the test of significance using Epi-info tools. The study was done after getting ethical approval from the institute. Results A total of 150 children were included in the analysis with a Male: Female ratio of 1.1:1. A majority of the cases were under five years (n=46) and 11 to 15 years old (n=45) with a mean age of 9.3 ± 4.4 years. Fever was a common presentation (70%). Disseminated TB was seen in 31.3%, isolated central nervous system (CNS) TB was found in 30.6%, and all CNS TB with dissemination was found in 46 cases (40.7%) making extra-pulmonary TB a common finding in our study (83.3%). Isolated pulmonary TB was seen in 16.7% and total pulmonary cases along with dissemination was seen in 60 cases (40%). A bacteriological diagnosis was made in 23%. Overall mortality was 9.3%, out of which mortality in CNS TB was 13% with a p-value of 0.004 as compared to mortality other than CNS TB which was significant and mortality in under-five years was significant with a p-value of 0.001. Conclusions Pulmonary and extra-pulmonary were both causes of admission in the pediatric age group. We found that extra-pulmonary TB was the most common cause of admission in children, with CNS manifestation and disseminated TB, being the most common presentations and significant mortality was seen in under-five years and in children diagnosed with CNS TB., Competing Interests: The authors have declared that no competing interests exist., (Copyright © 2023, Ksoo et al.)

Objective: To determine the frequency of positive results of Bacille Calmette Gurein and Mantoux skin tests in suspected cases of childhood pulmonary tuberculosis. Patients and Methods: This prospective interventional study was conducted on 160 children from outpatient and inpatient departments of Pediatrics in Services institute of medical sciences, Lahore. An informed consent was taken from their parents for using their data in research and to keep the results confidential. Cases were diagnosed on the basis of history, examination and investigations. Each patient was given 0.1 ml BCG intradermally on left shoulder and 5 IU of PPD intradermally on volar aspect of right forearm. The results were observed after 48 hours of application in the form of induration (in mm). The diagnostic BCG >8 and Mantoux test >10 after 48hrs was taken as positive. All the information was recorded in a predesigned proforma. Results: Out of 160 patients, 83 (51.9%) were males and 77 (48.1%) were females. It was found that 72 (45%) patients showed positive response to both mantoux test and BCG. While alone BCG test was positive in 56 (35%) patients. Both BCG and mantoux tests were negative in rest of 32 (20%) patients. 131(81.9%) patients had variable degree of malnutrition. Severe malnutrition was present in 54 patients; out of these, 50 (92.6%) patients were BCG positive while only 10 (18.5%) patients showed positive response to mantoux test. Conclusion: BCG is more reliable than the tuberculin test in the diagnosis of childhood pulmonary tuberculosis. [ABSTRACT FROM AUTHOR]

Background: The defining feature of the cerebrospinal fluid (CSF) collected from infants and children with tuberculous meningitis (TBM), derived from an earlier untargeted nuclear magnetic resonance (NMR) metabolomics study, was highly elevated lactic acid. Undetermined was the contribution from host response (L-lactic acid) or of microbial origin (D-lactic acid), which was set out to be determined in this study.Methods: In this follow-up study, we used targeted ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS/MS) to determine the ratio of the L and D enantiomers of lactic acid in these CSF samples.Results: Here we report for the first time that the lactic acid observed in the CSF of confirmed TBM cases was in the L-form and solely a response from the host to the infection, with no contribution from any bacteria. The significance of elevated lactic acid in TBM appears to be that it is a crucial energy substrate, used preferentially over glucose by microglia, and exhibits neuroprotective capabilities.Conclusion: These results provide experimental evidence to support our conceptual astrocyte-microglia lactate shuttle model formulated from our previous NMR-based metabolomics study - highlighting the fact that lactic acid plays an important role in neuroinflammatory diseases such as TBM. Furthermore, this study reinforces our belief that the determination of enantiomers of metabolites corresponding to infectious diseases is of critical importance in substantiating the clinical significance of disease markers. [ABSTRACT FROM AUTHOR]

Tuberculosis meningitis (TBM) is the most severe form of extra-pulmonary tuberculosis and is particularly intense in small children; there is no universally accepted algorithm for the diagnosis and substantiation of TB infection, which can lead to delayed intervention, a high risk factor for morbidity and mortality. In this study a proton magnetic resonance (H NMR)-based metabolomics analysis and several chemometric methods were applied to data generated from lumber cerebrospinal fluid (CSF) samples from three experimental groups: (1) South African infants and children with confirmed TBM, (2) non-meningitis South African infants and children as controls, and (3) neurological controls from the Netherlands. A total of 16 NMR-derived CSF metabolites were identified, which clearly differentiated between the controls and TBM cases under investigation. The defining metabolites were the combination of perturbed glucose and highly elevated lactate, common to some other neurological disorders. The remaining 14 metabolites of the host's response to TBM were likewise mainly energy-associated indicators. We subsequently generated a hypothesis expressed as an 'astrocyte-microglia lactate shuttle' (AMLS) based on the host's response, which emerged from the NMR-metabolomics information. Activation of microglia, as implied by the AMLS hypothesis, does not, however, present a uniform process and involves intricate interactions and feedback loops between the microglia, astrocytes and neurons that hamper attempts to construct basic and linear cascades of cause and effect; TBM involves a complex integration of the responses from the various cell types present within the CNS, with microglia and the astrocytes as main players. [ABSTRACT FROM AUTHOR]

Background: Molecular methods which allow for rapid and reliable detection of drug resistance have yet not been sufficiently evaluated for timely management of patients with tuberculous meningitis. Aims: We aimed to evaluate Geno Type MTBDRplus line probe assay for early detection of drug resistance in Mycobacterium tuberculosis isolates and CSF samples of confirmed tuberculous meningitis patients. Settings and Design: This was a multicentric prospective study carried out from July 2011 to December 2013 in tertiary care hospitals of Delhi. Materials and Methods: The assay was performed on 89 M. tuberculosis isolates and 31 direct CSF samples from microbiologically confirmed tuberculous meningitis patients. The sensitivity and specificity of this assay was calculated in comparison to drug susceptibility testing by BACTEC MGIT960 system. Results: The sensitivity, specificity for detection of resistance to Isoniazid was 93%, 97% and to Rifampicin was 80%, 98.8%, respectively by this assay in comparison with the phenotypic drug susceptibility testing. The line probe assay could detect M. tuberculosis in 55% of CSF samples from patients with microbiologically confirmed tuberculous meningitis. Only 5/89 isolates (5.6%) were resistant to both Isoniazid and Rifampicin while 9/89 (10%) isolates were additionally resistant to Isoniazid. Resistance to any of the drugs, namely Isoniazid, Rifampicin, Streptomycin or Ethambutol, was seen in 24.7% of strains. Conclusion: The line probe assay has a good sensitivity and specificity for detection of drug resistance to Isoniazid and Rifampicin in M. tuberculosis culture isolates. However, this assay has limited role in detection of M. tuberculosis and drug resistance from direct samples with confirmed diagnosis of tuberculous meningitis. [ABSTRACT FROM AUTHOR]

To study the cerebrospinal fluid (CSF) protein profiles of tuberculous meningitis (TBM) and discover potential biomarkers for TBM, differential expression of proteins in the CSF of patients with TBM, patients with cryptococcal meningitis, and a control group were compared using isobaric tags for relative and absolute quantitation labelling (iTRAQ) coupled with 2-dimensional liquid chromatography-tandem mass spectrometry (LC-MS). As a result, a total of 208 unique proteins with a molecular weight ranging from 10 KD to 135 KD were identified and quantified in CSF samples from patients with TBM. Of the proteins, 9 were expressed at levels differing 2.0 fold, 6 were up-regulated, and 3 were down-regulated. These proteins appear to be involved in calcium ion binding, lipoprotein metabolism, immune response, and signal conduction. Two differentially expressed proteins were identified using ELISA. The present study represents the successful use of iTRAQ to examine CSF from patients with TBM. The differentially expressed proteins identified may be potential diagnostic biomarkers and provide valuable insight into the underlying mechanisms of TBM. This study also demonstrated that the differential protein profiles of diseases can be quickly determined using iTRAQ-LC-MS, a potential method for quantitative comparative proteomics. [ABSTRACT FROM AUTHOR]

In this letter, we propose a novel method for diagnosis of tuberculous meningitis using Raman spectroscopy. The silicate Raman signature obtained from Mycobacterium tuberculosis positive cases enables specific and sensitive detection of tuberculous meningitis from acquired cerebrospinal fluid samples. The association of silicates with the tuberculosis mycobacterium is discussed. We envision that this new method will facilitate rapid diagnosis of tuberculous meningitis without application of exogenous reagents or dyes and can be aptly used as a complementary screening tool to the existing gold standard methods. (© 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim) [ABSTRACT FROM AUTHOR]

Objective: To find out the association of lateral rectus palsy in patients with tuberculous meningitis (TBM). Material and Methods: This study was conducted at Department of Neurology, Lady Reading Hospital, Peshawar from January 2008 to December 2009 on 43 diagnosed patients of TBM. The diagnosis was made on the basis of history, clinical presentation, laboratory and radiological findings. Patients of tuberculous meningitis with or without intracranial tuberculomas or having any extra cranial tuberculosis were included while cases presenting with similar clinical picture but having non tuberculous CNS pathology were excluded from the study. Results: Out of 43 patients, 27 (62.8%) patients were females and 16 (37.3) were males. The age range was from 7 years to 65 years with mean age of 36 years. Out of 43 patients, 11 (25.58%) patients were assigned stage I, 23 (53.48%) stage II and 9 (20.93%) stage III, according to Medical Research Council classification for tuberculous meningitis. Fourteen out of 43 (32.6%) were found to have unilateral or bilateral lateral rectus palsy. Conclusion: The presence of recent onset lateral rectus palsy is an important sign towards the diagnosis of TBM. However more studies are needed to establish the diagnostic value of lateral rectus palsy in diagnosing TBM. [ABSTRACT FROM AUTHOR]

Tuberculous meningitis (TBM) results from the haematogenous dissemination of Mycobacterium tuberculosis from the lung to the brain. Dissemination is believed to occur early during infection, before the development of adaptive immunity. Toll-like receptor 2 (TLR2) mediates recognition of M. tuberculosis and initiates the innate immune response to infection. We hypothesized that polymorphisms in the TLR2 gene influence bacterial dissemination and the development of TBM. A case–control study was designed to test the hypothesis. Cases of bacteriologically confirmed pulmonary tuberculosis (TB) (n=183) and TBM (n=175), and cord blood controls (n=389) were enrolled in Vietnam. TLR2 genotype 597CC was associated with susceptibility to TB (odds ratio (OR)=2.22, 95% confidence interval (CI): 1.23−3.99). The association was found with meningeal rather than pulmonary TB (TBM vs control, OR=3.26, 95% CI: 1.72−6.18), and was strongest when miliary TB was found on chest radiography (controls vs TBM with miliary TB, OR=5.28, 95% CI: 2.20−12.65). Furthermore, the association increased with the severity of neurologic symptoms (grade I TBM, OR=1.93, 95% CI: 0.54−6.92; grade II, OR=3.32, 95% CI: 0.84−13.2; and grade III, OR=5.70, 95% CI: 1.81−18.0). These results demonstrate a strong association of TLR2 SNP T597C with the development of TBM and miliary TB and indicate that TLR2 influences the dissemination of M. tuberculosis.Genes and Immunity (2007) 8, 422–428. doi:10.1038/sj.gene.6364405; published online 7 June 2007 [ABSTRACT FROM AUTHOR]

From the World Health Organization's global TB report for 2020, it is estimated that in 2019 at least 80,000 children (a particularly vulnerable population) developed tuberculous meningitis (TBM)—an invariably fatal disease if untreated—although this is likely an underestimate. As our latest technologies have evolved—with the unprecedented development of the various "omics" disciplines—a mountain of new data on infectious diseases have been created. However, our knowledge and understanding of infectious diseases are still trying to keep pace. Metabolites offer much biological information, but the insights they permit can be difficult to derive. This review summarizes current metabolomics studies on cerebrospinal fluid (CSF) from TBM cases and collates the metabolic data reported. Collectively, CSF metabolomics studies have identified five classes of metabolites that characterize TBM: amino acids, organic acids, nucleotides, carbohydrates, and "other". Taken holistically, the information given in this review serves to promote the mechanistic action of hypothesis generation that will drive and direct future studies on TBM. [ABSTRACT FROM AUTHOR]

Objective: To better characterize the cerebrospinal fluid (CSF) metabolic profile of tuberculous meningitis (TBM) cases using a South African paediatric cohort., Methods: 1 H NMR metabolomics was used to analyse the CSF of a South African paediatric cohort. Univariate and multivariate statistical analyses were performed to compare a homogeneous control group with a well-defined TBM group., Results: Twenty metabolites were identified to discriminate TBM cases from controls. As expected, reduced glucose and elevated lactate were the dominating discriminators. A closer investigation of the CSF metabolic profile yielded 18 metabolites of statistical significance. Ten metabolites (acetate, alanine, choline, citrate, creatinine, isoleucine, lysine, myo-inositol, pyruvate and valine) overlapped with two other prior investigations. Eight metabolites (2-hydroxybutyrate, carnitine, creatine, creatine phosphate, glutamate, glutamine, guanidinoacetate and proline) were unique to our paediatric TBM cohort., Conclusions: Through strict exclusion criteria, quality control checks and data filtering, eight unique CSF metabolites associated with TBM were identified for the first time and linked to: uncontrolled glucose metabolism, upregulated proline and creatine metabolism, detoxification and disrupted glutamate-glutamine cycle in the TBM samples. Associated with oxidative stress and chronic neuroinflammation, our findings collectively imply destabilization, and hence increased permeability, of the blood-brain barrier in the TBM cases., (Copyright © 2020. Published by Elsevier Ltd.)

Here, we evaluated the potential activity of rapid Mycobacterium tuberculosis detection with loop-mediated isothermal amplification (LAMP), for the early diagnosis of tuberculous meningitis (TBM). Patients with suspected TBM from January 2014 to December 2015 were reviewed retrospectively. The cerebrospinalfluid(CSF) was collected. Acid-fast bacillus (AFB) staining, MGIT 960 culture, real-time fluorescent quantitative polymerase chain reaction (RTFQ PCR) and LAMP were performed. A total of 200 patients were included in the study. Of which, 172 of them were diagnosed with TBM (86.00%). The sensitivities of AFB staining, MGIT 960 culture, LAMP and RTFQ PCR for TBM diagnosis were 2.91% (5/172), 12.79% (22/172), 43.02% (74/172), and 34.30% (59/172), respectively. The sensitivity of LAMP for TBM was significantly higher than those of AFB staining and MGIT960 culture ( χ2 = 75.11, P < 0.001; χ2 = 43.88, P = 0.002). LAMP's sensitivity was however comparable to RTFQ PCR assay ( χ2 = 2.08, P = 0.130). The specificity, positive predictive value and negative predictive value of LAMP in the diagnosis of TBM were 92.86% (26/28), 97.37% (74/76) and 20.97 % (26/124), respectively. The overall consistency between LAMP and RTFQ PCR in the diagnosis of TBM was 88.5% (177/200), with Kappa value of 0.870. The consistency between LAMP and MGIT960 culture was 71% (142/200), with Kappa value of 0.730. Among all the methods, LAMP had high sensitivity, specificity and positive predictive value, showing high consistency with MGIT960 culture and RTFQ PCR., Competing Interests: CONFLICTS OF INTEREST The listed authors have no conflict of interests.

Objective: Tuberculous meningitis (TBM) frequently is complicated by hydrocephalus and cerebral infarction. Previous studies have shown radiologic evidence of cerebral infarction in TBM to be an indicator of poor outcome in both adults and children. Our objective was to assess short-term mortality in adult patients with TBM and hydrocephalus treated with an external ventricular drain and to assess the prognostic value of cerebral infarction on admission computed tomography imaging within this cohort. Methods: This was a retrospective case series based on an adult intensive care unit admissions database, analyzing demographic, clinical, diagnostic, and radiologic data against short-term mortality. Results: A total of 25 patients managed from 2005 to 2011 were identified. Three patients were excluded. Mean age was 31 years. British Medical Research Council clinical severity grading was grade I in 9.1%, grade II in 31.8%, and grade III in 59.1%. Short-term mortality was 68.2% overall. Cerebral infarction on admission scanning was seen in 10 patients (45.5%). Prevalence of infarcts was not significantly higher in HIV-positive patients (50.0% vs. 42.9%). Mortality in the group with infarcts was 100%, compared with 41.7% in the group without infarcts. Mortality in patients with an admission Glasgow Coma Scale of 8 or less was 91.7%. Mortality in the HIV-positive group was slightly greater, but this increase did not reach statistical significance (71.4% vs. 57.1% P = 0.6). Univariate analysis showed presence of infarcts at admission, Glasgow Coma Scale ≤8 at admission and age of 30 years or more to be significantly related to mortality. There was also a statistically significantly increased mortality according to British Medical Research Council grade. Conclusion: TBM with hydrocephalus requiring cerebrospinal diversion carries a significant short-term mortality. Within this cohort, the group of patients who have computed tomography-evident cerebral infarcts at admission has an even worse outcome, with a significantly greater short-term mortality prevalence. [ABSTRACT FROM AUTHOR]

CCL1, one of the members of the CC chemokine family, is an inflammatory mediator that stimulates the migration of human monocytes. CCL1 expression is induced by Mycobacterium tuberculosis and TLR ligands in macrophage. TLR2 plays critical role in host immune response against M. tuberculosis infection by regulating the macrophage activation and cytokine secretion. M. tuberculosis causes different clinical forms of tuberculosis (TB) disease. Single-nucleotide polymorphisms (SNPs) in the CCL1 gene and TLR2 gene may be associated with the development of different clinical forms of TB, depending on the different immune mechanisms. This study was to evaluate the possible association between CCL1 rs2072069 G/A or/and TLR2 rs3804099 T/C (T597C) polymorphisms and pulmonary tuberculosis (PTB) or/and tuberculous meningitis (TBM) in a sample of the Chinese adult population. A case-control study was designed to compare the allele frequency and genotype distribution between control (n=386) and TB (n=341) who had either PTB (n=230) or TBM (n=111). The genotype typing was performed using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) technique. TLR2 variant genotype 597CC was associated with susceptibility to PTB rather than to TBM. In the male PTB subgroup, 597CC genotype was identified in a higher rate, compared with male control subgroup. This study demonstrates that T597C polymorphism of TLR2 is a risk factor for susceptibility to PTB rather than to TBM in a sample of Chinese adult population. Patient gender may affect the outcome of M. tuberculosis infection. TLR2 gene may influence the development of PTB and TBM by different immune mechanisms.