Probable Tuberculous Meningitis Research Articles

Clinical characteristics, radiological pointers and outcomes of central nervous system tuberculosis

BackgroundCentral nervous system tuberculosis (CNS-TB) is a severe and aggressive form of tuberculosis with a high mortality. With early identification and appropriate therapy, it carries a good outcome. Aim: To identify the clinical characteristics, radiological pointers, and outcomes of central nervous system tuberculosis. MethodsSingle-center retrospective study was conducted from January 01, 2018 to December 31, 2022 on patients diagnosed with CNS-TB.Adult patients with at least nine months of follow-up were included. Those seropositive for HIV or lost to follow-up before treatment completion were excluded. Variables were expressed as mean with standard deviation, median, and range. Chi-square and student's t-test for qualitative and quantitative variables were used. Results158 records were reviewed, and 56 were excluded. 102 patients were included with 90(88.23 %) cases of tubercular meningitis(TBM) and 12 (11.76 %) cases of isolated tuberculoma. There were 22(24.44 %) and 63(70.00%) cases of definite and probable tuberculous meningitis. Leptomeningeal enhancement (79.41%)and hydrocephalus (42.22%)were noted commonly. All cases of TBM and tuberculoma completed 9–12 months of anti-tubercular treatment. Dexamethasone was given to all patients with TBM for 6–12 weeks. One patient with biopsy-proven isolated tuberculoma received up to 24 months of ATT. Nine patients with TBM died(9/102,8.82 %). Grade III TBM, age >60 years, hydrocephalus,drug-induced hepatitis, and extra-neural tuberculosis were significant in the expired versus survivors comparison (p < 0.05). ConclusionsEarly identification, appropriate ATT regimen, and duration of treatment are associated with a good outcome in this fatal and disabling disease.

Disease spectrum and prognostic factors in patients treated for tuberculous meningitis in Shaanxi province, China.

Tuberculous meningitis (TBM) is the most severe form of tuberculosis (TB) and can be difficult to diagnose and treat. We aimed to describe the clinical presentation, diagnosis, disease spectrum, outcome, and prognostic factors of patients treated for TBM in China. A multicenter retrospective study was conducted from 2009 to 2019 enrolling all presumptive TBM patients referred to Xijing tertiary Hospital from 27 referral centers in and around Shaanxi province, China. Patients with clinical features suggestive of TBM (abnormal CSF parameters) were included in the study if they had adequate baseline information to be classified as "confirmed," "probable," or "possible" TBM according to international consensus TBM criteria and remained in follow-up. Patients with a confirmed alternative diagnosis or severe immune compromise were excluded. Clinical presentation, central nervous system imaging, cerebrospinal fluid (CSF) results, TBM score, and outcome-assessed using the modified Barthel disability index-were recorded and compared. A total of 341 presumptive TBM patients met selection criteria; 63 confirmed TBM (25 culture positive, 42 Xpert-MTB/RIF positive), 66 probable TBM, 163 possible TBM, and 49 "not TBM." Death was associated with BMRC grade III (OR = 5.172; 95%CI: 2.298-11.641), TBM score ≥ 15 (OR = 3.843; 95%CI: 1.372-10.761), age > 60 years (OR = 3.566; 95%CI: 1.022-12.442), and CSF neutrophil ratio ≥ 25% (OR = 2.298; 95%CI: 1.027-5.139). Among those with confirmed TBM, nearly one-third (17/63, 27.0%) had a TBM score < 12; these patients exhibited less classic meningitis symptoms and signs and had better outcomes compared with those with a TBM score ≥ 12. In this group, signs of disseminated/miliary TB (OR = 12.427; 95%CI: 1.138-135.758) and a higher TBM score (≥15, OR = 8.437; 95%CI: 1.328-53.585) were most strongly associated with death. TBM patients who are older (>60 years) have higher TBM scores or CSF neutrophil ratios, have signs of disseminated/miliary TB, and are at greatest risk of death. In general, more effort needs to be done to improve early diagnosis and treatment outcome in TBM patients.

Risk Factors for Stroke in Children with Tuberculous Meningitis: A Prospective Observational Study.

The purpose of the study is to establish the prevalence of stroke as well as the clinical and radiological correlates of stroke in children with tuberculous meningitis (TBM). A prospective observational study was conducted at the Pediatric Department, King George's Medical University (KGMU), Lucknow, Uttar Pradesh, India. Using a computed tomography (CT) scan/brain magnetic resonance imaging (MRI), patients were divided into stroke and non-stroke groups. Demographic characteristics, clinical presentations, cerebrospinal fluid examination, basal meningeal enhancement, hydrocephalus, tuberculoma, and clinical outcome were compared between the two groups. Seventy-eight TBM patients, aged between 6 months and 14 years, were included. Out of 78 enrolled patients, 3 (3.8%) had definite TBM, 73 (91%) had probable TBM, and 4 (5.1%) had possible TBM (LCS). As per the Medical Research Council (MRC) staging, 13% had Stage 1 TBM, 26% had stage 2, and 61% had stage 3 TBM. Out of 78 patients with chest X-ray findings, 42 (53%) had findings suggestive of tuberculosis (TB), which included 33 (42%) with hilar lymphadenopathy and 9 (11%) with a miliary pattern. On neuroimaging, hydrocephalous was seen in 62.8% of cases, basal meningeal enhancement in 64.1%, tuberculoma in 6.4% of cases, and infarction in 53.8% of cases. There was no statistically significant association found between the staging of TBM and the presence of infarction as the majority of cases involved were in stage 3 of the disease (61.5%). TBM patients with stroke had poor clinical outcomes. Age, altered sensorium, focal neurological deficits, vomiting, and basal meningeal enhancement can predict the occurrence of stroke in young adults with TBM.

Assessment of the Diagnostic Utility of GeneXpert Mycobacterium tuberculosis/Rifampicin (MTB/RIF) Assay in the Suspected Cases of Tuberculous Meningitis.

Tuberculous meningitis (TBM) is a manifestation of extrapulmonary tuberculosis (EPTB) caused by Mycobacterium tuberculosis (MTB). The central nervous system is involved in about 1%-2% of all current tuberculosis (TB) cases and about 7%-8% of all EPTB. if not treated early, TBM leads to a high rate of neurological sequelae and mortality. This study aimed to assess the diagnostic performance of the GeneXpert MTB/rifampicin (RIF) assay in patients with TBM. A total of 100 suspected TBM cases were enrolled from various departments at tertiary care hospital, Bhopal, Madhya Pradesh, India, and classified as definite, possible, or probable TBM. The clinical samples were tested for microbiological and other cerebrospinal fluid(CSF) testing. Out of 100 cases, 14 (14%) were classified as definite TBM, 15 (15%) were having probable TBM, and 71 (71%) were having possible TBM.Out of a total of 100 participants, all were negative for acid-fast bacilli (AFB) staining. Of the 100 cases, 11 (11%) were positive by mycobacterium growth indicator tube (MGIT) culture, of which only four (36.36%) were positive by GeneXpert MTB/RIF. GeneXpert MTB/RIF detected three (3%) cases that were negative by MGIT culture. Ten (90.9%) of the 11 MGIT-positive culture isolates were found to be RIFsensitive while one (9.1%) was found to be RIF resistant. Three cases tested positive/sensitive by the GeneXpert MTB/RIF but negative by MGIT culture. Six (85%) of the seven GeneXpert MTB/RIF positive cases were RIF sensitive while one (15%) was RIF resistant. The sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and diagnostic accuracy were 36.36% (95% Confidence Interval (CI) (10.93% to 69.21%)), 96.63% (95% CI (90.46% to 99.30%)), 57.14% (95% CI (25.50% to 83.85%)), 92.47% (95% CI (88.70% to 95.06%)) and 90% (95% CI (82.38% to 95.10%)) for GeneXpert MTB/RIF assay, compared with MGIT culture as the reference standard. Our study found that the sensitivity is lower when compared to culture, so using GeneXpert MTB/RIF alone is not recommended. Overall performance of GeneXpert MTB/RIF assay is noteworthy. The GeneXpert MTB/RIF assay is a potentially accepted test for obtaining an earlier diagnosis, and if it tested positive, the treatment should begin immediately. However, culture must be performed in GeneXpert MTB/RIF negative cases.

Molecular diagnosis of Tuberculous meningitis: sdaA-based multi-targeted LAMP and GeneXpert Ultra

SettingNucleic acid amplification techniques like GeneXpert and GeneXpert Ultra (Xpert Ultra), the first-line tests for diagnosing Tuberculous meningitis (TBM), are expensive and depend on sophisticated equipment. ObjectiveThe diagnostic potential of multitargeted loop-mediated isothermal assay (MLAMP), a low-cost simple test using novel gene combination, was evaluated for TBM. Design300 CSF specimen (200 TBM patients, 100 controls) processed between January 2017 and December 2021 were subjected to MLAMP (using sdaA, IS1081 and IS6110 gene targets), sdaA PCR and Xpert Ultra. The performance was evaluated against uniform case definition as per Marais criteria, and against culture. ResultsUniform case definition classified 50 as definite TBM and 150 as probable or definite TBM. Against this uniform case definition, the sensitivity and specificity of MLAMP was 88% and 100%, respectively. The sensitivity was 96% against culture-positive cases and 85.3% against culture-negative cases. The sensitivity of sdaA-LAMP, IS1081-LAMP, IS6110-LAMP, Xpert Ultra and sdaA-PCR was 82.5%, 80.5%, 85.3%, 67% and 71%, respectively against uniform case definition. sdaA-LAMP detected additional two cases and IS1081-LAMP detected nine. 11 of 134 (8.2%) cases were reported rifampicin resistant by Xpert Ultra. ConclusionMLAMP, incorporating sdaA and IS1081, is a cheap, easy and accurate first-line diagnostic test for TBM.

Diagnostic performance of real time PCR for the detection of Mycobacterium tuberculosis in cerebrospinal fluid samples.

We aimed this study to standardize real time - polymerase chain reaction (RT-PCR) for the detection of Mycobacterium tuberculosis (Mtb) in cerebrospinal fluid (CSF) samples and compare its diagnostic performance with GeneXpert (Xpert), Mycobacteria Growth Indicator Tube (MGIT) and Multiplex PCR (MPCR) for tuberculous meningitis (TBM). A total of 217 CSF samples were obtained from patients with suspected TBM during the study period between January 2019 and December 2021. The optimal cycle threshold (CT) of RT-PCR was determined by comparing different gene targets of Mtb (IS6110, 16SrRNA, HSP65 and Ag85B). Sensitivity, specificity, positive predictive value (PPV) and negative predictive value (NPV) was determined for RT-PCR, Xpert, MGIT960 and MPCR. Diagnostic accuracy of these assays was compared by using clinical diagnosis as reference standard. IS6110RT-PCR was found to be highly sensitive as compared to other gene targets. Sensitivities of IS6110RT-PCR, MPCR, Xpert and MGIT against a reference standard of definite, probable and possible TBM were 36.7%, 21.1%, 16.7% and 6.7%, respectively; specificities were 97.6%, 100%, 100% and 100%, respectively. Xpert, RT-PCR, MPCR and MGIT960 detected 6.91% (n = 15), 5.99% (n = 13), 5.99% (n = 13) and 2.76% (n = 6) of definite TBM, respectively. RT-PCR detected 6.45% (n = 14) and 2.76% (n = 6) of possible TBM and probable TBM, respectively and MPCR detected 1.38% (n = 3) of possible and probable TBM each. IS6110RT-PCR is highly sensitive for primary screening of suspected TB cases, which may help clinicians to start appropriate patient's treatment with clinical suspicion of TBM.

A study of risk factors for tuberculous meningitis among patients with tuberculosis in China: An analysis of data between 2012 and 2019.

The present study aimed to explore the risk factors for tuberculous meningitis (TBM) among patients with tuberculosis (TB). This retrospective study was conducted on patients with TB who were hospitalized in Beijing Chest Hospital between January 2012 and December 2019. Demographic and clinical data of patients with TB were extracted from electronic medical records using a standardized data collection system. Logistic regression was used to analyze the risk factors associated with TBM. Of the total number of 22,988 cases enrolled, 3.1% were cases of TBM, which included 127 definite and 581 probable TBM, respectively. Multivariate analysis showed that definite TBM was significantly associated with patients aged < 30 years [adjusted odds ratio (aOR) = 3.015, 95% confidence interval (CI): (1.451-6.266)], who were farmers [aOR = 1.490, 95%CI: (1.020-2.177)], with miliary pulmonary TB [aOR = 105.842, 95%CI: (71.704-156.235)], and with malnutrition [aOR = 2.466, 95%CI: (1.110-5.479)]. Additionally, probable TBM was significantly associated with patients aged < 30 years [aOR = 2.174, 95% CI: (1.450-3.261)], aged 30-59 years [aOR = 1.670, 95% CI: (1.222-2.282)], who were farmers [aOR = 1.482, 95%CI: (1.203-1.825)], with miliary pulmonary TB [aOR = 108.696, 95%CI: (87.122-135.613)], and with a digestive system TB [aOR = 2.906, 95%CI: (1.762-4.793)]. An age of < 30 years, being a farmer, and having miliary pulmonary TB were risk factors for TBM among patients with TB. Further screening of patients with TB with aforementioned characteristics could facilitate clinicians to identify patients with TBM at an early stage.

Identification of protein biomarkers in host cerebrospinal fluid for differential diagnosis of tuberculous meningitis and other meningitis.

Background and purposeThe diagnosis of tuberculous meningitis (TBM) is difficult due to the lack of sensitive methods. Identification of TBM-specific biomarkers in the cerebrospinal fluid (CSF) may help diagnose and improve our understanding of TBM pathogenesis.Patients and methodsOf the 112 suspected patients with TBM prospectively enrolled in the study, 32 patients with inconclusive diagnosis, non-infectious meningitis, and long-term treatment with hormones and immunosuppressants were excluded. The expression of 8 proteins in the CSF was analyzed using ELISA in 22 patients with definite TBM, 18 patients with probable TBM, and 40 patients with non-TBM.ResultsSignificant differences in the expression of 7 proteins were detected between the TBM and non-TBM groups (P < 0.01). Unsupervised hierarchical clustering (UHC) analysis revealed a disease-specific profile consisting of 7 differentially expressed proteins for TBM diagnosis, with an accuracy of 82.5% (66/80). Logistic regression with forward stepwise analysis indicated that a combination of 3 biomarkers (APOE_APOAI_S100A8) showed a better ability to discriminate TBM from patients with non-TBM [area under the curve (AUC) = 0.916 (95%CI: 0.857–0.976)], with a sensitivity of 95.0% (95%CI: 83.1–99.4%) and a specificity of 77.5% (95%CI: 61.5–89.2%).ConclusionOur results confirmed the potential ability of CSF proteins to distinguish TBM from patients with non-TBM and provided a useful panel for the diagnosis of TBM.

Vascular Manifestations of Tuberculous Meningitis: MR Angiography and Venography Study.

Purpose The purpose of this study is to evaluate magnetic resonance (MR) angiography (MRA) and venography (MRV) findings in tuberculous meningitis (TBM). Methods Thirty consecutive patients of clinically diagnosed TBM were enrolled. Apart from T2-weighted imaging, T1-weighted imaging (T1WI), diffusion-weighted imaging, susceptibility-weighted imaging, fluid-attenuated inversion recovery, and postcontrast T1WI, time-of-flight (TOF) MRA and postcontrast MRV were done in all the patients. MRV was done after intravenous administration of gadolinium-based contrast agent followed by postcontrast T1WI. MRA and MRV findings were analyzed. Results Mean age of the patients was 33.13 ± 14.93 years. Duration of symptom was 34.90 ± 33.82 (range: 10–150) days. Out of 30 patients, 11 were categorized as definite TBM and 19 probable TBM. Eighteen (60%) were grade I, 7 (23%) grade II, and 5 (16%) grade III TBM based on severity. MR abnormalities were in varying combinations of leptomeningeal enhancement in 24 (80%), pachymeningeal in 2, both in 3, tuberculomas in 13 (43.3%), ventriculitis in 1, hydrocephalus in 16 (53.3%), and infarcts in 10 (33.3%) patients out of which the tubercular zone infarct in 9 patients. TOF MRA showed arterial abnormality in 13 patients. Anterior cerebral artery and middle cerebral artery have commonly involved vessels. Dural sinus thrombosis was noted in two patients. Both were female. One patient had subacute thrombus in the posterior part of superior sagittal sinus, left transverse sinus, and proximal right transverse sinus. The second patient had a filling defect in the transverse sinus. Conclusion In TBM, there is predominant arterial involvement causing infarcts which are usually seen in the tubercular zone. However, occasionally, there may be venous involvement causing cerebral venous sinus thrombosis.

The Sensitivity of Diagnostic Criteria of Marais S, et al. in Confirmed Childhood Tuberculous Meningitis.

BackgroundTo establish the sensitivity of the diagnostic criteria published by Marais and co-workers in 2010 for childhood tuberculous meningitis (TBM), a retrospective study on children with confirmed TBM was conducted.MethodsBetween January 2006 and December 2019, children consecutively diagnosed with TBM were recruited retrospectively at our center. TBM was defined in cases where any of the following criteria were met: the presence of acid-fast bacilli (AFB) in cerebrospinal fluid (CSF) microscopy, CSF nucleic acid amplification test (NAAT, +), or M.tuberculosis cultured from CSF. The demographic and clinical features of all enrolled patients were recorded including clinical characteristics, CSF findings, cerebral imaging features, and other evidence of TB.ResultsA total of 30 children with confirmed diagnosis of TBM over an 14-year period were recruited. The mean age of patients was 7.2 ± 5.1 years and 16 (53.3%) were male. The estimated mean diagnostic score was 12.7 ± 2.4. Twenty-three (76.7%; 95% CI: 59.1–88.2%) patients were classified as “probable TBM” according to the Marais criteria and 7 (23.3%; 95% CI: 11.8–40.9%) as “possible TBM.” Further statistical analysis revealed significant differences in CSF scores between probable and possible TBM groups. Other variables reported at a relatively low frequency, such as symptoms and imaging features, made little contribution to TBM diagnosis according to the Marais criteria.ConclusionChildhood TBM could be effectively identified by the criteria defined by Marais et al. However, further revision is required to ensure that the system is more sensitive and easier to perform in practice.

Renin, antidiuretic hormone (ADH), and ADH receptor levels in cerebral salt wasting associated with tuberculous meningitis.

To evaluate serum antidiuretic hormone (ADH), its receptors, and renin levels in cerebral salt wasting (CSW) in tuberculous meningitis (TBM). Patients diagnosed with definite (n = 30) or probable TBM (n = 47) who developed hyponatremia (CSW, SIADH, or miscellaneous causes) were included. Sequential measurement of serum ADH, ADH-R, and renin activity by enzyme-linked immunosorbent assay was done and correlated with serum sodium level, urinary output, and fluid balance. Out of 79 TBM patients, CSW was observed in 36, SIADH in four, and miscellaneous hyponatremia in eight patients. CSW patients had a longer hospital stay (P < 0.001), lower GCS score (P < 0.007), higher MRC grade (P < 0.007), and a lower serum Na (P < 0.001) compared to non-CSW TBM patients. In severe CSW patients, serum ADH and ADH-R were correlated with hyponatremia and returned to baseline on correction; however, serum renin levels remained elevated. Serum ADH was related to hyponatremia but ADH-R and renin were not. ADH-R and renin levels did not significantly differ in CSW and SIADH. CSW is the commonest cause of hyponatremia in TBM and correlates with disease severity. ADH is related to hyponatremia, but ADH receptor and renin are not.

Comparative analysis of Truenat™ MTB Plus and Xpert® Ultra in diagnosing tuberculous meningitis.

BACKGROUND: Diagnostic delay and drug resistance not only worsen the outcomes of tuberculous meningitis (TBM), but are also important impediments to TB elimination efforts. Given the need for a near point-of-care test suitable for primary healthcare centres and simultaneous detection of resistance, Truenat™ MTB Plus assay was evaluated on a large cohort of TBM patients.METHODS: Truenat assay was performed on 148 cerebrospinal fluid specimens (76 definite TBM, 32 probable TBM and 40 non-TBM controls) and its performance was compared with Xpert® Ultra.RESULTS: The overall sensitivity of Truenat and Ultra was respectively 78.7% and 67.6% in diagnosing TBM, and respectively 85.5% and 96% in diagnosing definite TBM. Twenty-three additional cases were detected using Truenat and 11 using Ultra. Truenat missed seven cases of rifampicin (RIF) resistance and indicated false RIF resistance in four cases.CONCLUSION: Performance of Truenat was comparable to that of Ultra in diagnosing TBM and inferior to Xpert Ultra in determining RIF resistance.

The association between serum sodium level and tuberculous meningitis compared with viral and bacterial meningitis

We evaluated the association between hyponatremia and tuberculous meningitis (TBM) with the aim of providing additional information for differential diagnosis from other types of infectious meningitis, especially viral meningitis (VM). Cross-sectional and longitudinal data involving 5026 participants older than 18 years were analyzed in the total population and a propensity-matched population. The initial and lowest sodium levels and longitudinal changes in TBM, bacterial meningitis (BM), and VM patients were compared. Participants in the TBM group were enrolled when they were diagnosed as possible, probable, or definite TBM according to the Marais’ criteria. The initial serum sodium level was significantly lower in TBM patients than in BM and VM patients (136.9 ± 5.9 vs. 138.3 ± 4.7 mmol/L, p < 0.001 for TBM vs. BM, and 139.0 ± 3.1, p < 0.001 for TBM vs. VM), and it decreased significantly more steeply to lower levels in both the TBM and BM patients compared with VM patients. The lowest serum sodium level was in the order of TBM < BM < VM patients, and the change was statistically significant in all subgroups (131.8 ± 6.4, 133.1 ± 5.1, 137.4 ± 3.7, respectively, p < 0.001). Participants with lower serum sodium level were more likely to have a diagnosis of TBM rather than VM, and this association was more pronounced for the lowest sodium level than the initial sodium level [OR 4.6 (95% CI 2.4–8.8, p < 0.001)]. These findings indicate that baseline and longitudinal evaluation of serum sodium level can provide information for differential diagnosis of TBM from BM or VM.

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.

Predictors Modifying the Outcome of Tuberculous Meningitis (TBM) in Adults: A Hospital Based Study in Bangladesh

Background: Outcome of TBM can be modified by several predictors.&#x0D; Objective: This study was undertaken to evaluate the predictors of outcome of tuberculous meningitis (TBM) at 6 and 9 months.&#x0D; Methodology: This hospital based prospective cohort study was carried out from October, 2016 to September, 2017 (1 year) in the in-patient Department of Neurology at the National Institute of Neurosciences &amp; Hospital (NINS &amp; H), Dhaka, Bangladesh. All the patients with age 18 years or more of both sexes with features of TBM fulfilling the case definition criteria was included as the study population. The outcome was measured at 6 and 9 months by modified Rankin Scale (mRS) with no disability (score=0-1), mild disability (score = 2), moderate disability (score=3-4), severe disability (score=5) and dead (score=6). For statistical analysis outcome was classified as death and survival group. A number of clinical, laboratory and radiological parameters were evaluated initially by univariate and finally multiple regression analysis.&#x0D; Results: A total 54 TBM patients were included in this study. Over 70% of the patients were adolescent or young adult (&lt; 30 years) with mean age of 28.2 ± 12.3 years and 63% were female. Staging of the TBM showed that nearly half (48.1%) were at stage II and 37% cases were in stage III disease. Baseline imaging (CT-scan and MRI) showed basal meningeal enhancement in 40.7% cases, hydrocephalus in 40.7%, infarction 46.3% and tuberculoma in 29.6% cases. Final diagnosis was established as definite TBM in 3(5.6%) cases, probable TBM 30(55.6%) and possible TBM in 21(38.9%) cases. In terms of 6-months outcome, 16(29.6%) cases died and 10(18.5%) had recovered without any neurological sequelae; however, mild, moderate and severe disability were in11.1%, 27.8% and 13% cases respectively. At the 9 months of evaluation 13 (24.0%) had complete recovery without any neurological sequelae, 22 (40.9%) patients survived with various degree of disabilities like visual impairment, hemi or paraplegia, cognitive impairment, rests died giving a total mortality of 19(35.1%). In univariate analysis, age &gt;50 years (p=0.019), duration of illness before initiation of treatment (&gt;45 d) (p = 0.041), convulsion (p = 0.010), altered sensorium (p&lt;0.001), delayed initiation of treatment &gt;1 month (p=0.041) and stage III TBM (p&lt;0.001) were significantly associated with mortality. In multivariate analyses stage III TBM (p=0.004), altered sensorium (p=0.036), delayed initiation of treatment &gt;1 month (p=0.043) emerged as independent predictors of mortality.&#x0D; Conclusions: In conclusion stage III TBM, altered sensorium and delayed initiation of treatment more than 1 month are the independent predictors of mortality in TBM patients.&#x0D; Journal of National Institute of Neurosciences Bangladesh, January 2021, Vol. 7, No. 1, pp. 14-19

Machine-Learning-Based Approach to Differential Diagnosis in Tuberculous and Viral Meningitis.

BackgroundTuberculous meningitis (TBM) is the most severe form of tuberculosis, but differentiating between the diagnosis of TBM and viral meningitis (VM) is difficult. Thus, we have developed machine-learning modules for differentiating TBM from VM.Material and MethodsFor the training data, confirmed or probable TBM and confirmed VM cases were retrospectively collected from five teaching hospitals in Korea between January 2000 - July 2018. Various machine-learning algorithms were used for training. The machine-learning algorithms were tested by the leave-one-out cross-validation. Four residents and two infectious disease specialists were tested using the summarized medical information.ResultsThe training study comprised data from 60 patients with confirmed or probable TBM and 143 patients with confirmed VM. Older age, longer symptom duration before the visit, lower serum sodium, lower cerebrospinal fluid (CSF) glucose, higher CSF protein, and CSF adenosine deaminase were found in the TBM patients. Among the various machine-learning algorithms, the area under the curve (AUC) of the receiver operating characteristics of artificial neural network (ANN) with ImperativeImputer for matrix completion (0.85; 95% confidence interval 0.79 - 0.89) was found to be the highest. The AUC of the ANN model was statistically higher than those of all the residents (range 0.67 - 0.72, P <0.001) and an infectious disease specialist (AUC 0.76; P = 0.03).ConclusionThe machine-learning techniques may play a role in differentiating between TBM and VM. Specifically, the ANN model seems to have better diagnostic performance than the non-expert clinician.

Diagnostic accuracy of Xpert MTB/RIF for tuberculous meningitis: systematic review and meta-analysis.

This systematic review evaluated the diagnostic accuracy of Xpert MTB/RIF to detect tuberculous meningitis (TBM). PubMed and five other databases were systematically searched through March 2019. All studies evaluating diagnostic accuracy of Xpert MTB/RIF on cerebrospinal fluid (CSF) samples were included. Reference standards were definitive or definite plus probable TBM. The quality of studies was assessed by the QUADAS-2 tool. We performed bivariate random-effects meta-analysis and calculated summary diagnostic statistics. We identified 30 studies (n=3972 participants), including 5 cohort studies and 25 cross-sectional studies. Reference standards were definite TB (n=28 studies) or definite plus probable TBM (n=6 studies). The pooled Xpert MTB/RIF sensitivity was 85% (95% CI, 70-93%), and specificity was 98% (95% CI, 97-99%) with a negative likelihood ratio of 0.15 (95% CI, 0.04-0.27) for definite TBM. For probable TBM cases, pooled sensitivity was 81% (95% CI, 66-90%), and specificity was 99% (95% CI, 97-99%).For both reference standard types, meta-analyses showed a C-statistic area under the curve of 0.98. The QUADAS-2 tool revealed low risk of bias as well as low concerns regarding applicability. Methodological heterogeneity was high among studies. Xpert MTB/RIF showed high accuracy for TBM diagnosis, but a negative Xpert MTB/RIF test does not rule out TBM. Repeat Xpert testing may be necessary. In clinical practice, Xpert MTB/RIF adds speed and sensitivity when compared to classic TBM diagnostic methods or previous commercial nucleic acid amplification techniques. More studies and better strategies for rapidly confirming a diagnosis of TBM in children are urgently needed.

Diagnostic characteristics of Xpert MTB/RIF assay for the diagnosis of tuberculous meningitis and rifampicin resistance in Southern Brazil.

The timely diagnosis of tuberculous meningitis (TBM) is challenging. Molecular diagnostic tools are necessary for TBM, particularly in low- and middle-income countries. We aimed to calculate the diagnostics characteristics of Xpert MTB/RIF for the detection of Mycobacterium tuberculosis in the cerebrospinal fluid (CSF) and the frequency of rifampicin (RIF)-resistance in the CSF samples. A total of 313 consecutive CSF samples were studied and categorized into TBM definite, probable, possible, or not TBM cases based on the clinical, laboratory, and imaging data. For the definite TBM cases (n=7), the sensitivity, specificity, efficiency, and positive likelihood ratio were 100, 97, 97, and 38%, respectively. However, for the TBM definite associated with the probable cases (n=24), the sensitivity decreased to 46%. All CSF samples that were Xpert MTB/RIF-positive were RIF susceptible. Xpert MTB/RIF showed high discriminating value among the microbiology-proven TBM cases, although the values for the probable and possible TBM cases were reduced. Xpert MTB/RIF contributes significantly to the diagnosis of TBM, mainly when coupled with the conventional microbiological tests and clinical algorithms.

Cerebrospinal Fluid Bacillary Load by Xpert MTB/RIF Ultra Polymerase Chain Reaction Cycle Threshold Value Predicts 2-Week Mortality in Human Immunodeficiency Virus-Associated Tuberculous Meningitis.

BackgroundThe World Health Organization recommends GeneXpert MTB/RIF Ultra (Xpert Ultra), a fully automated polymerase chain reaction (PCR) assay, as the initial tuberculous meningitis (TBM) diagnostic test. The assay’s PCR cycle threshold (Ct) values represent the number of PCR cycles required for probe signal to be detected (low Ct value = high bacillary load) and may approximate tuberculosis (TB) bacillary load. We measured the relationship between cerebrospinal fluid (CSF) TB bacillary load with mortality. MethodsWe prospectively enrolled 102 human immunodeficiency virus (HIV)–positive Ugandans with probable or definite TBM from April 2015 to August 2019. Xpert Ultra Ct tertiles and semi-quantitative categories were separately analyzed as predictors of 2-week mortality. We investigated associations between Ct and baseline clinical and CSF parameters. ResultsSubjects with Ct values in the low tertile (ie, high bacillary load) had 57% 2-week mortality—worse than the intermediate (17%) and high (25%) Ct tertiles and Xpert Ultra–negative (30%) probable TBM cases (P = .01). In contrast, the reported semi-quantitative Xpert Ultra categorization was less precise; with the medium to low category trending toward worse 2-week survival (42%) compared with very low (28%), trace (26%), and negative (30%) categories (P = .48). Ct tertile was significantly associated with baseline CSF lactate (P = .03). ConclusionsHigh CSF TB bacillary load, as measured by Xpert Ultra Ct tertile, is associated with an almost 2-fold higher 2-week mortality in HIV-associated TBM and is a better predictor than the reported Xpert Ultra semi-quantitative category. Xpert Ultra Ct values could identify TBM patients at increased risk of death who may benefit from enhanced supportive care.

Xpert MTB/RIF ultra for the diagnosis of tuberculous meningitis: A diagnostic accuracy study from India

SettingStudies evaluating Xpert MTB/RIF Ultra assay (Xpert Ultra) for diagnosing tuberculous meningitis (TBM) are scarce and have reported contrasting results in comparison to Xpert MTB/RIF assay (Xpert). ObjectiveTo evaluate the performance of Xpert Ultra in diagnosing TBM and compare it with Xpert and multiplex polymerase chain reaction (MPCR). DesignXpert Ultra was performed on 244 cerebrospinal fluid (CSF) samples: 56 definite TBM, 148 probable TBM and 40 non-TBM controls. 105/244 CSF samples were also subjected to Xpert and MPCR (IS6110, MPB64, protein B). ResultsThe overall sensitivity of Xpert Ultra in diagnosing TBM from 244 CSF samples was 72.05% (96.42% - definite TBM, 62.83% - probable TBM) with a specificity of 100%. 18 (12.24%) cases [8 definite TBM, 10 probable TBM] were reported rifampicin resistant (RifR) by Xpert Ultra and confirmed by rpoB sequencing. 60 (40.81%) cases [9 definite TBM, 51 probable TBM] were reported rifampicin indeterminate (RifI) by Xpert Ultra (all trace category), out of which 45 [8 definite, 37 probable) were rifampicin susceptible (RifS) and 5 probable cases were RifR on rpoB sequencing. Out of 105 CSF samples subjected to all three techniques, TBM was diagnosed in 70.66%, 28% and 88% by Xpert Ultra, Xpert and MPCR, respectively. ConclusionXpert Ultra detected TBM with higher sensitivity than Xpert. Among trace category, constituting 40% of TBM cases, rpoB gene sequencing confirmed 5 RifR cases.