Clinical presentation, management, and outcome of suspected central nervous system infections in Indonesia: a prospective cohort study.

BACKGROUND: Little is known about the etiology, clinical presentation, management, and outcome of central nervous system (CNS) infections in Indonesia, a country with a high burden of infectious diseases and a rising prevalence of HIV. METHODS: We included adult patients with suspected CNS infections at two referral hospitals in a prospective cohort between April 2019 and December 2021. Clinical, laboratory, and radiological assessments were standardized. We recorded initial and final diagnoses, treatments, and outcomes during 6 months of follow-up. RESULTS: Of 1051 patients screened, 793 were diagnosed with a CNS infection. Patients (median age 33 years, 62% male, 38% HIV-infected) presented a median of 14 days (IQR 7-30) after symptom onset, often with altered consciousness (63%), motor deficits (73%), and seizures (21%). Among HIV-uninfected patients, CNS tuberculosis (TB) was most common (60%), while viral (8%) and bacterial (4%) disease were uncommon. Among HIV-infected patients, cerebral toxoplasmosis (41%) was most common, followed by CNS TB (19%), neurosyphilis (15%), and cryptococcal meningitis (10%). A microbiologically confirmed diagnosis was achieved in 25% of cases, and initial diagnoses were revised in 46% of cases. In-hospital mortality was 30%, and at six months, 45% of patients had died, and 12% suffered from severe disability. Six-month mortality was associated with older age, HIV, and severe clinical, radiological and CSF markers at presentation. CONCLUSION: CNS infections in Indonesia are characterized by late presentation, severe disease, frequent HIV coinfection, low microbiological confirmation and high mortality. These findings highlight the need for earlier disease recognition, faster and more accurate diagnosis, and optimized treatment, coupled with wider efforts to improve the uptake of HIV services.

Central nervous system tuberculosis.

PURPOSE OF REVIEW: Central nervous system (CNS) tuberculosis is the most devastating form of tuberculosis (TB), with mortality and or neurological sequelae in over half of individuals. We reviewed original research and systematic reviews published since 1 January 2019 for new developments in CNS TB pathophysiology, diagnosis, management and prognosis. RECENT FINDINGS: Insight in the pathophysiology is increasing steadily since the landmark studies in 1933, focussing on granuloma type classification, the relevance of the M. tuberculosis bacterial burden and the wide range of immunological responses. Although Xpert/RIF has been recommended by the WHO for extrapulmonary TB diagnosis, culture is still needed to increase the sensitivity of TB meningitis diagnosis. Sequential MRIs can improve understanding of neurological deficits at baseline and during treatment. Pharmacokinetic/pharmacodynamic modelling suggests that higher doses of rifampicin and isoniazid in TB meningitis could improve survival. SUMMARY: Recent studies in the field of CNS-TB have largely focussed on TB meningitis. The outcome may improve by optimizing treatment dosing. This needs to be confirmed in clinical trials. Due to the important role of inflammation, these trials should be used as the platform to study the inflammatory and metabolomic responses. This could improve understanding of the biology of this disease and improve patient outlook by enabling individualised host-directed therapy.

Model-Based Meta-analysis of Rifampicin Exposure and Mortality in Indonesian Tuberculous Meningitis Trials.

BACKGROUND: Intensified antimicrobial treatment with higher rifampicin doses may improve outcome of tuberculous meningitis, but the desirable exposure and necessary dose are unknown. Our objective was to characterize the relationship between rifampicin exposures and mortality in order to identify optimal dosing for tuberculous meningitis. METHODS: An individual patient meta-analysis was performed on data from 3 Indonesian randomized controlled phase 2 trials comparing oral rifampicin 450 mg (~10 mg/kg) to intensified regimens including 750-1350 mg orally, or a 600-mg intravenous infusion. Pharmacokinetic data from plasma and cerebrospinal fluid (CSF) were analyzed with nonlinear mixed-effects modeling. Six-month survival was described with parametric time-to-event models. RESULTS: Pharmacokinetic analyses included 133 individuals (1150 concentration measurements, 170 from CSF). The final model featured 2 disposition compartments, saturable clearance, and autoinduction. Rifampicin CSF concentrations were described by a partition coefficient (5.5%; 95% confidence interval [CI], 4.5%-6.4%) and half-life for distribution plasma to CSF (2.1 hours; 95% CI, 1.3-2.9 hours). Higher CSF protein concentration increased the partition coefficient. Survival of 148 individuals (58 died, 15 dropouts) was well described by an exponentially declining hazard, with lower age, higher baseline Glasgow Coma Scale score, and higher individual rifampicin plasma exposure reducing the hazard. Simulations predicted an increase in 6-month survival from approximately 50% to approximately 70% upon increasing the oral rifampicin dose from 10 to 30 mg/kg, and predicted that even higher doses would further improve survival. CONCLUSIONS: Higher rifampicin exposure substantially decreased the risk of death, and the maximal effect was not reached within the studied range. We suggest a rifampicin dose of at least 30 mg/kg to be investigated in phase 3 clinical trials.

Large-scale genomic analysis shows association between homoplastic genetic variation in Mycobacterium tuberculosis genes and meningeal or pulmonary tuberculosis.

BACKGROUND: Meningitis is the most severe manifestation of tuberculosis. It is largely unknown why some people develop pulmonary TB (PTB) and others TB meningitis (TBM); we examined if the genetic background of infecting M. tuberculosis strains may be relevant. METHODS: We whole-genome sequenced M. tuberculosis strains isolated from 322 HIV-negative tuberculosis patients from Indonesia and compared isolates from patients with TBM (n = 106) and PTB (n = 216). Using a phylogeny-adjusted genome-wide association method to count homoplasy events we examined phenotype-related changes at specific loci or genes in parallel branches of the phylogenetic tree. Enrichment scores for the TB phenotype were calculated on single nucleotide polymorphism (SNP), gene, and pathway level. Genetic associations were validated in an independent set of isolates. RESULTS: Strains belonged to the East-Asian lineage (36.0%), Euro-American lineage (61.5%), and Indo-Oceanic lineage (2.5%). We found no association between lineage and phenotype (Chi-square = 4.556; p = 0.207). Large genomic differences were observed between isolates; the minimum pairwise genetic distance varied from 17 to 689 SNPs. Using the phylogenetic tree, based on 28,544 common variable positions, we selected 54 TBM and 54 PTB isolates in terminal branch sets with distinct phenotypes. Genetic variation in Rv0218, and absence of Rv3343c, and nanK were significantly associated with disease phenotype in these terminal branch sets, and confirmed in the validation set of 214 unpaired isolates. CONCLUSIONS: Using homoplasy counting we identified genetic variation in three separate genes to be associated with the TB phenotype, including one (Rv0218) which encodes a secreted protein that could play a role in host-pathogen interaction by altering pathogen recognition or acting as virulence effector.

Isoniazid exposures and acetylator status in Indonesian tuberculous meningitis patients.

The effect of acetylator status on the exposure to isoniazid in plasma and CSF in tuberculous meningitis (TBM) patients remains largely unexplored. Here, we describe isoniazid exposures and acetylator status of 48 subjects in the ReDEFINe study (NCT02169882). Fifty percentwere fast (half-life <130 min) or slow (half-life >130 min) acetylators. Slow acetylators had higher AUC0-24, Cmax and CSF concentrations than fast acetylators (GM AUC0-24 25.5 vs 10.6 mg/L*h, p < 0.001); plasma Cmax 5.5 vs 3.6 mg/L, p = 0.023; CSF concentration 1.9 vs 1.1 mg/L, p = 0.008). Higher isoniazid doses may benefit fast acetylators in TBM.

BA.5 sub-lineages associated with higher severity of COVID-19 infection: A cross-sectional study in Indonesia.

Objectives: We aimed to compare the clinical severity and outcome among laboratory-confirmed Omicron variant cases admitted between January and December 2022. Methods: This is a cross-sectional study conducted in Hasan Sadikin General Hospital between January and December 2022. We enrolled patients aged ≥18 years with laboratory-confirmed Omicron infection. Data were collected from clinical records and a whole genome sequencing database. We compared the risk of severe symptoms and mortality using a logistic regression analysis adjusted for sex, age, comorbidities, and vaccination status. Results: We enrolled 255 patients and the main sub-lineages were BA.1 (16.1%), BA.2 (11.4%), BA.5 (35.7%), XBB (22.7%), and BQ.1 (14.1%). Compared with BA.1/BA.2, BA.5 sub-lineages were associated with severe symptoms (adjusted odds ratio of 2.9, 95% confidence interval 1.1-8.2, P <0.05). The highest risk of severe symptoms and mortality was linked with a high number of comorbidities (adjusted odds ratio of 7.8, 95% confidence interval 1.7-22.4, P <0.05). Booster vaccination was protective of severity and mortality. Conclusions: Disease severity was associated with BA.5 sub-lineages and multiple comorbidities. Good management is particularly important for people with comorbidities. Furthermore, booster vaccination is also required to reduce severity and mortality.

Sequencing whole genomes of the West Javanese population in Indonesia reveals novel variants and improves imputation accuracy.

Existing genotype imputation reference panels are mainly derived from European populations, limiting their accuracy in non-European populations. To improve imputation accuracy for Indonesians, the world's fourth most populous country, we combined Whole Genome Sequencing (WGS) data from 227 West Javanese individuals with East Asian data from the 1000 Genomes Project. This created three reference panels: EAS 1KGP3 (EASp), Indonesian (INDp), and a combined panel (EASp+INDp). We also used ten West-Javanese samples with WGS and SNP-typing data for benchmarking. We identified 1.8 million novel single nucleotide variants (SNVs) in the West Javanese population, which, while similar to the East Asians, are distinct from the Central Indonesian Flores population. Adding INDp to the EASp reference panel improved imputation accuracy (R2) from 0.85 to 0.90, and concordance from 87.88% to 91.13%. These findings underscore the importance of including Indonesian genetic data in reference panels, advocating for broader WGS of diverse Indonesian populations to enhance genomic studies.

Diagnostic Prediction Model for Tuberculous Meningitis: An Individual Participant Data Meta-Analysis.

No accurate and rapid diagnostic test exists for tuberculous meningitis (TBM), leading to delayed diagnosis. We leveraged data from multiple studies to improve the predictive performance of diagnostic models across different populations, settings, and subgroups to develop a new predictive tool for TBM diagnosis. We conducted a systematic review to analyze eligible datasets with individual-level participant data (IPD). We imputed missing data and explored three approaches: stepwise logistic regression, classification and regression tree (CART), and random forest regression. We evaluated performance using calibration plots and C-statistics via internal-external cross-validation. We included 3,761 individual participants from 14 studies and nine countries. A total of 1,240 (33%) participants had "definite" (30%) or "probable" (3%) TBM by case definition. Important predictive variables included cerebrospinal fluid (CSF) glucose, blood glucose, CSF white cell count, CSF differential, cryptococcal antigen, HIV status, and fever presence. Internal validation showed that performance varied considerably between IPD datasets with C-statistic values between 0.60 and 0.89. In external validation, CART performed the worst (C = 0.82), and logistic regression and random forest had the same accuracy (C = 0.91). We developed a mobile app for TBM clinical prediction that accounted for heterogeneity and improved diagnostic performance (https://tbmcalc.github.io/tbmcalc). Further external validation is needed.

Cerebral toxoplasmosis in HIV-infected patients: a review.

Toxoplasma gondii infection in the central nervous system commonly occurs among immunodeficient patients. Its prevalence is high in countries with a high burden of HIV and low coverage of antiretroviral drugs. The brain is one of the predilections for T. gondii infection due to its low inflammatory reaction, and cerebral toxoplasmosis occurs solely due to the reactivation of a latent infection rather than a new infection. Several immune elements have recently been recognized to have an essential role in the immunopathogenesis of cerebral toxoplasmosis. Although real-time isothermal amplification, next-generation sequencing, and enzyme-linked aptamer assays from blood samples have been the recommended diagnostic tools in some in-vivo studies, a combination of clinical symptoms, serology examination, and neuroimaging are still the daily standard for the presumptive diagnosis of cerebral toxoplasmosis and early anti-toxoplasma administration. Clinical trials are needed to find a new therapy that is less likely to affect folate synthesis, have neuroprotective properties, or cure the latent phase of infection. The development of a vaccine is being extensively tested in animals, but its efficacy and safety for humans are still not proven.

Current Insights into Diagnosing and Treating Neurotuberculosis in Adults.

Neurotuberculosis has the highest morbidity and mortality risk of all forms of extrapulmonary tuberculosis (TB). Early treatment is paramount, but establishing diagnosis are challenging in all three forms of neurotuberculosis: tuberculous meningitis (TBM), spinal TB and tuberculomas. Despite advancements in diagnostic tools and ongoing research aimed at improving TB treatment regimens, the mortality rate for neurotuberculosis remains high. While antituberculosis drugs were discovered in the 1940s, TB treatment regimens were designed for and studied in pulmonary TB and remained largely unchanged for decades. However, new antibiotic regimens and host-directed therapies are now being studied to combat drug resistance and contribute to ending the TB epidemic. Clinical trials are necessary to assess the effectiveness and safety of these treatments, addressing paradoxical responses in neurotuberculosis cases and ultimately improving patient outcomes. Pharmacokinetic-pharmacodynamic analyses can inform evidence-based dose selection and exposure optimization. This review provides an update on the diagnosis and treatment of neurotuberculosis, encompassing both sensitive and resistant antituberculosis drug approaches, drawing on evidence from the literature published over the past decade.

Severe mononeuritis multiplex as a rare case of neuro leptospirosis: A case report.

Leptospirosis is a zoonotic bacterial disease caused by infection of spirochetes of the genus Leptospira. While typically self-limiting and non-fatal, severe manifestations can arise, including various neurological complications that are often overlooked. This case study presents a 59-year-old man with serologically positive Leptospirosis, who subsequently developed asymmetrical progressive leg weakness, severe back pain, and overflow incontinence suggestive of mononeuritis multiplex. Doxycycline treatment was started and intended to last for seven days. The patient had ongoing paraparesis, but all other problems were disappeared. The present case emphasizes the significance of identifying and treating neurological problems brought on by leptospirosis. To improve suitable treatment plans and patient outcomes, more research on these problems is necessary.

Single-Blind Randomized Controlled Trial: Comparative Efficacy of Dark Chocolate, Coconut Water, and Ibuprofen in Managing Primary Dysmenorrhea.

Dysmenorrhea, the pain experienced by women during menstruation, affects a significant proportion of women worldwide and often leads to decreased productivity. Various pharmacological and non-pharmacological treatments are available for pain relief, but information on their effectiveness, particularly regarding green coconut water, dark chocolate, and Ibuprofen, remains limited. This study aimed to compare the effectiveness of green coconut water, dark chocolate bars, and Ibuprofen in reducing the intensity of primary dysmenorrhea. In this research, a randomized controlled trial with a quantitative design was conducted, involving 45 participants randomly assigned to receive 330 mL of green coconut water, 35 g of 70% dark chocolate, or 400 mg Ibuprofen. The interventions were administered on the first day of menstruation when dysmenorrhea symptoms typically occur in subjects. This study used a single-dose approach to evaluate the immediate impact of each treatment. The subjects were instructed to consume the given interventional product within 15 min. The pain intensity was measured using a Numeric Rating Scale before the intervention and 2 h after the subjects finished consuming the interventional product. The multivariate Kruskal-Wallis test revealed a significant difference in effectiveness among the three interventions (p < 0.05). The study found that Ibuprofen was the most effective intervention compared to the other interventions. These findings contribute to understanding the treatment options for primary dysmenorrhea and emphasize the efficacy of Ibuprofen (trial registration: ClinicalTrials.gov: NCT05971186).

Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography mass-spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. Results: CSF tryptophan was associated with 60-day mortality from tuberculous meningitis (HR=1.16, 95%CI=1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and HIV-positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95%CI=1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. Conclusion: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of mortality. These findings may reveal new targets for host-directed therapy. Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).

Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis.

Background: Cellular metabolism is critical for the host immune function against pathogens, and metabolomic analysis may help understand the characteristic immunopathology of tuberculosis. We performed targeted metabolomic analyses in a large cohort of patients with tuberculous meningitis (TBM), the most severe manifestation of tuberculosis, focusing on tryptophan metabolism. Methods: We studied 1069 Indonesian and Vietnamese adults with TBM (26.6% HIV-positive), 54 non-infectious controls, 50 with bacterial meningitis, and 60 with cryptococcal meningitis. Tryptophan and downstream metabolites were measured in cerebrospinal fluid (CSF) and plasma using targeted liquid chromatography-mass spectrometry. Individual metabolite levels were associated with survival, clinical parameters, CSF bacterial load and 92 CSF inflammatory proteins. Results: CSF tryptophan was associated with 60-day mortality from TBM (hazard ratio [HR] = 1.16, 95% confidence interval [CI] = 1.10-1.24, for each doubling in CSF tryptophan) both in HIV-negative and -positive patients. CSF tryptophan concentrations did not correlate with CSF bacterial load nor CSF inflammation but were negatively correlated with CSF interferon-gamma concentrations. Unlike tryptophan, CSF concentrations of an intercorrelating cluster of downstream kynurenine metabolites did not predict mortality. These CSF kynurenine metabolites did however correlate with CSF inflammation and markers of blood-CSF leakage, and plasma kynurenine predicted death (HR 1.54, 95% CI = 1.22-1.93). These findings were mostly specific for TBM, although high CSF tryptophan was also associated with mortality from cryptococcal meningitis. Conclusions: TBM patients with a high baseline CSF tryptophan or high systemic (plasma) kynurenine are at increased risk of death. These findings may reveal new targets for host-directed therapy. Funding: This study was supported by National Institutes of Health (R01AI145781) and the Wellcome Trust (110179/Z/15/Z and 206724/Z/17/Z).

A Rarely Occurring Spinal Fracture Precipitated by Generalized Spasms of Tetanus Patient with Spondylitis Tuberculosis.

Background: The occurrence of spinal fracture due to tetanus nowadays is extremely rare, as compared to the 1950s, since the widely available anti-tetanus and antispasmodic therapy. The spinal fracture in tetanus patients is usually reported in higher thoracic vertebrae, previously with a rate as high as 57.5%. Spondylitis is the most common form of skeletal tuberculosis (TB) and can cause a spinal fracture. In Indonesia, tetanus is still reported, while tuberculosis is still endemic; however, co-infection of both diseases is rarely reported. Case Presentation: A 36-year-old male was brought to our hospital with jaw stiffness, accompanied by fever. A history of dental cavities was present, and 5 days prior, he experienced a fishing hook wound on his right index finger. There was no history of TB. Physical examination showed meningismus, 2 cm trismus, abdominal spasm, opisthotonus, and spontaneous muscle spasms, without dysautonomia. In the third week of hospitalization, while his tetanus condition improved, he complained of weakness in both legs. A thorough history taking revealed a history of backache for 3 years. A wedge-shaped fracture on his 11th and 12th thoracic vertebrae was observed on radiographic examination. A spinal TB diagnosis was made, and treatment was started. He refused to get spinal surgery, then went home with 4 out of 5 motor strength scale. After three months, he returned to his routine activity as a food hawker with no motor deficits. Conclusion: Tetanus spinal fracture is extremely rare nowadays; a thorough history of spinal problems/medication is compulsory for anticipation. This patient's spinal fracture was deemed due to a preexisting TB spinal infection that was precipitated by prolonged continuous tetanic spasm due to general tetanus.

A Bayesian analysis of the association between Leukotriene A4 Hydrolase genotype and survival in tuberculous meningitis.

Tuberculous meningitis has high mortality, linked to excessive inflammation. However, adjunctive anti-inflammatory corticosteroids reduce mortality by only 30%, suggesting that inflammatory pathophysiology causes only a subset of deaths. In Vietnam, the survival benefit of anti-inflammatory corticosteroids was most pronounced in patients with a C/T promoter variant in the leukotriene A4 hydrolase (LTA4H) gene encoding an enzyme that regulates inflammatory eicosanoids. LTA4H TT patients with increased expression had increased survival, consistent with corticosteroids benefiting individuals with hyper-inflammatory responses. However, an Indonesia study did not find an LTA4H TT genotype survival benefit. Here using Bayesian methods to analyse both studies, we find that LTA4H TT genotype confers survival benefit that begins early and continues long-term in both populations. This benefit is nullified in the most severe cases with high early mortality. LTA4H genotyping together with disease severity assessment may target glucocorticoid therapy to patients most likely to benefit from it.

Tuberculous meningitis is a serious infection of the lining of the brain, which affects over 100,000 people a year. Without treatment, it is always fatal: even with proper antibiotics, about a quarter of patients do not survive and many will have permanent brain damage. Overactive inflammation is thought to contribute to this process. Corticosteroid drugs, which dampen the inflammatory process, are therefore often used during treatment. However, they merely reduce mortality by 30%, suggesting that only some people benefit from them. Two recent studies have linked the genetic makeup of individuals who have tuberculous meningitis to how they respond to corticosteroids. There were, in particular, differences in the LTA4H gene that codes for an inflammation-causing protein. According to these results, only individuals carrying high-inflammation versions of the LTA4H gene would benefit from the treatment. Yet a third study did not find any effect of the genetic background of patients. All three papers used frequentist statistics to draw their conclusions, only examining the percentage of people who survived in each group. Yet, this type of analysis can miss important details. It also does not work well when the number of patients is small, or when the effectiveness of a drug varies during the course of an illness. Another method, called Bayesian statistics, can perform better under these limitations. In particular, it takes into account the probability of an event based on prior knowledge ­ for instance, that the risk of dying varies smoothly with time. Here, Whitworth et al. used Bayesian statistics to reanalyse the data from these studies, demonstrating that death rates were correlated with the type of LTA4H gene carried by patients. In particular, corticosteroid treatment worked best for people with the high inflammation versions of the gene. However, regardless of genetic background, corticosteroids were not effective if patients were extremely sick before being treated. The work by Whitworth et al. demonstrates the importance of using Bayesian statistics to examine the effectiveness of medical treatments. It could help to design better protocols for tuberculous meningitis treatment, tailored to the genetic makeup of patients.

Microbiological Testing of Gastric Aspirate Improves the Diagnosis of Pulmonary Tuberculosis in Unconscious Adults with TB Meningitis.

Conventional sputum collection for TB diagnosis is difficult in TB meningitis patients since most of them are admitted with decreased consciousness. It is assumed that unconscious patients swallow their sputum; therefore, gastric aspiration can replace sputum collection in unconscious patients. A prospective study was conducted to see whether examining gastric aspirate could increase the diagnosis certainty of pulmonary TB in such subjects. The inclusion criteria were age 18-60 years, decreased level of consciousness, and use of a nasogastric tube. Subjects who had taken antituberculosis drugs for more than 3 days were excluded. Gastric lavage was performed in the morning after an overnight fast. Specimens were examined for direct smear, culture, and rapid molecular testing. Demographic, clinical, chest X-ray, and laboratory data were also recorded. During the study period, 31 subjects were available. The positivity rates for microbiological tests were 19.3%, 41.9%, and 48.4% for smear, culture, and rapid molecular testing, respectively. All positive smears were confirmed by either culture or rapid molecular testing. Gastric lavage can be considered a tool for improving extraneural TB diagnosis in unconscious patients.