Definite Tuberculous Meningitis Research Articles

The diagnostic performance of GeneXpert MTB/RIF in tuberculosis meningitis: A multicentre accuracy study

To evaluate the performance of GeneXpert MTB/RIF (Xpert) for tuberculous meningitis (TBM) and to identify additional indicators to improve diagnostic accuracy. An accuracy study was conducted. During 2011-2019, 243 TBM with 140 non-TBM in three TB-designated facilities in China were enrolled. Microbiological evidence of M tuberculosis (Mtb) in CSF was used as the reference. Additional indicators were identified by Boosted-Classification and Regression Tree (CART), the improvement of diagnostic performance was evaluated by ROC. The diagnostic sensitivity of Xpert was 71.1 % for definite TBM, and 5.5 % for probable/possible TBM. The positive rate of Xpert was improved with cerebrospinal fluid (CSF) increasing volume and was associated with CSF color (yellow). The additional indicators obtained by CART were CSF lactate and glucose and increased the sensitivity to 96.1 % (definite TBM) and 84.6 % (probable/possible TBM). The diagnostic performance of Xpert was satisfactory in definite TBM and would significantly be improved by the additional use of CSF lactate and glucose.

Performance of metagenomic next-generation sequencing in cerebrospinal fluid for diagnosis of tuberculous meningitis.

Purpose. Metagenomic next-generation sequencing (mNGS) has been widely used in the diagnosis of infectious diseases, while its performance in diagnosis of tuberculous meningitis (TBM) is incompletely characterized. The aim of this study was to assess the performance of mNGS in the diagnosis of TBM, and illustrate the sensitivity and specificity of different methods.Methods. We retrospectively recruited TBM patients between January 2021 and March 2023 to evaluate the performance of mNGS on cerebrospinal fluid (CSF) samples, in comparison with conventional microbiological testing, including culturing of Mycobacterium tuberculosis (MTB), acid-fast bacillus (AFB) stain, reverse transcription PCR and Xpert MTB/RIF.Results. Of the 40 enrolled, 34 participants were diagnosed with TBM, including 15(44.12 %) definite and 19(55.88 %) clinical diagnosis based upon clinical manifestations, CSF parameters, brain imaging, pathogen evidence and treatment response. The mNGS method identified sequences of Mycobacterium tuberculosis complex (MTBC) in 11 CSF samples. In patients with definite TBM, the sensitivity, specificity, positive predictive value, negative predictive value and accuracy of mNGS were 78.57, 100, 100, 66.67 and 85 %, respectively. Compared to conventional diagnostic methods, the sensitivity of mNGS (78.57 %) was higher than AFB (0 %), culturing (0 %), RT-PCR (60 %) and Xpert MTB/RIF (14.29 %).Conclusions. Our study indicates that mNGS of CSF exhibited an overall improved sensitivity over conventional diagnostic methods for TBM and can be considered a front-line CSF test.

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.

Tuberculostearic acid incorporated predictive model contributes to the clinical diagnosis of tuberculous meningitis

The conventional confirmation tests of tuberculous meningitis (TBM) are usually low in sensitivity, leading to high TBM mortality. Hence, sensitive methods for indicating the presence of bacilli are required. Tuberculostearic acid (TBSA), a constituent from Mycobacterium tuberculosis had been evaluated as a promising marker, but fails to demonstrate consistent results for definite TBM. This study retrospectively reviewed medical records of 113 TBM suspects, constructing a TBSA-combined scoring system based on multiple factors, which show sensitivity and specificity of 0.8148 and 0.8814, respectively, and the area under the receiver operating characteristic curve of 0.9010. Multivariate analyses revealed four co-predictive factors strongly associated with TBSA: extra-neural tuberculosis, basal meningeal enhancement, CSF glucose/Serum glucose <0.595, and coinfection in CNS (Total). The subsequent machine learning-based validation showed correspondent importance to factors in the TBSA model. This study demonstrates a simple scoring system to facilitate TBM prediction, yield reliable diagnoses and allow timely treatment initiation.

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.

Cerebrospinal fluid lactate as a predictive biomarker for tuberculous meningitis diagnosis.

The definitive diagnosis of tuberculous meningitis (TBM) is achieved by identifying Mycobacterium tuberculosis (MTb) in cerebrospinal fluid (CSF); however, diagnostic confirmation is difficult due to the inability ofcurrent tests for an effective diagnosis. Our objective was to retrospectively assess the characteristics of CSF lactate (CSF-LA) as an adjunct biomarker in the diagnosis of TBM. 608 CSF laboratory reports were assessed. Of these, 560 had clinically suspected TBM. These were classified as definite (n=36), probable (23), possible (278),or non-TBM (223) according to the international consensus TBM case definitions. An additional 48 CSF samples were negative controls with normal CSF. Against a reference standard of definite TBM, the cut-off value for CSF-LA was 4.0mmol/L, the area under the ROC curve was 0.88 (95% CI, 0.82-0.94; p=0.0001), sensitivity was 69%, specificity 90%, negative predictive value 98%. These diagnostic parameters decreased when calculated against those of the other categories of TBM. CSF-LA exhibited high specificity, efficiency, negative predictive value, and clinical utility index in all the groups studied. CSF-LA is a useful diagnostic marker to rule out TBM when associated with conventional microbiology tests, nucleic acid amplification assays, and clinical algorithms, particularly in endemic areas.

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.

Balancing between apoptosis and survival biomarkers in the patients with tuberculous meningitis

BackgroundThe balancing factor of apoptosis, survival, inflammatory and oxidative stress biomarkers may determine the clinico-radiological severity and death in the patients with tuberculous meningitis (TBM). AimWe report the relationship of death [caspase-3, malondialdehyde (MDA), tumor necrosis factor-α (TNFα), interleukin 6 (IL6)] and survival biomarkers [X-linked inhibitory apoptotic protein (XIAP), IL10, glutathione (GSH) and catalase] in TBM, and its role in determining disease severity and death. MethodsThe diagnosis of TBM was based on clinical, MRI and cerebrospinal fluid (CSF) findings. Their clinical and MRI findings were noted. The severity of TBM was categorized as stages I to III. Serum and CSF caspase-3 and XIAP were measured by ELISA, and TNFα, IL6 and IL10 gene expression in peripheral blood mononuclear cells using RT-PCR (reverse-transcriptase polymerase chain reaction). Plasma MDA, GSH and catalase were measured by spectrophotometer. ResultsThere were 40 patients with TBM whose mean age was 31.6 years and 50% were females. TBM patients had higher expression of death (caspase-3, TNFα, IL6, and MDA) and suppression of survival biomarkers (XIAP, catalase and GSH) compared to the healthy controls. Caspase-3 positively correlated with TNFα, IL6 and MDA, and negatively with XIAP, GSH and catalase. Patients with longer duration of illness and definite TBM had higher expression of caspase-3. Patients who died has higher expression of caspase-3 and suppression of XIAP compared to those who survived. ConclusionIt can be concluded from this study that there is up-regulation of death signals and suppression of survival signals in TBM.

10-Year Retrospective Review of the Etiologies for Meningitis With Elevated Adenosine Deaminase in Cerebrospinal Fluid: Etiologies Other Than TB.

PurposeAn elevated adenosine deaminase (ADA) level in the cerebrospinal fluid (CSF) is considered a reliable marker of tuberculous meningitis (TBM). However, CSF-ADA levels can also be elevated in other diseases. We aimed to find the most common diagnosis of patients with elevated CSF-ADA levels for the last 10 years.MethodsWe retrospectively investigated the diagnoses of all patients with elevated CSF-ADA (ADA ≥ 10 IU/L) levels between 2010 and 2019 at the Samsung Medical Center. Definite TBM was defined based on microbiological evidence. Clinical TBM was defined based on the brain imaging and response to the standard TB treatment. We compared the laboratory characteristics of the three most common diagnoses.ResultsCSF-ADA levels were elevated in 137 (5.6%) of 2,600 patients. The most common diagnoses included hematologic malignancy (HM; n = 36, 26.2%), TBM (n = 26, 19.0%), and viral meningitis (VM; n = 25, 18.2%). CSF-ADA levels did not differ significantly between TBM [median (interquartile range (IQR)), 20.2 IU/L (13.8–29.3)] and HM [16.5 (12.8–24.0)]. However, CSF-ADA levels were lower in VM [14.0 (11.0–16.1)] than in TBM (p = 0.027). Lymphocyte-dominant pleocytosis was more common in VM [77.0% (70.8–81.5)] than in TBM [16.0 (3.0–51.0), p = 0.015] or HM [36.0 (10.0–72.0); p = 0.032]. Interestingly, the CSF characteristics of clinical TBM were similar to those of VM but not definite TBM.ConclusionThe most common diagnoses with elevated CSF-ADA levels were HM, followed by TBM and VM. Clinicians should carefully consider the differential diagnoses in patients with elevated CSF-ADA levels, especially those in the early stage of meningitis without microbiological evidence for 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.

NMR based CSF metabolomics in tuberculous meningitis: correlation with clinical and MRI findings.

We report the potential role of 1H Nuclear Magnetic Resonance (NMR) based metabolomics in tuberculous meningitis (TBM). We also correlate the significant metabolites with clinical-radiological parameters. Forty-three patients with TBM were included, and their severity of meningitis was graded as stages I to III, and patients with positive Mycobacterium tuberculosis or its nucleic acid was considered as definite TBM. 1H NMR-based metabolomic study was performed on (CSF) samples, and the significant metabolites compared to healthy controls were identified. Outcome at three months was defined as death, poor and good based on the modified Rankin Scale. These metabolites were compared between definite and probable groups of TBM, and also correlated with MRI findings. About 11 metabolites were found to be significant for distinguishing TBM from the controls. In TBM, lactate, glutamate, alanine, arginine, 2-hydroxyisobutyrate, formate, and cis-aconitate were upregulated, and glucose, fructose, glutamine, and myo-inositol were downregulated compared to the controls. For differentiating TBM from the controls, the AUC of the ROC curve generated using these significant metabolites was 0.99, with a 95% confidence interval from 0.96 to 1, demonstrating that these metabolites were able to classify cases with good sensitivity and specificity. Lactate concentration in CSF correlated with hemoglobin, CSF glucose, and infarction. The outcome did not correlate with metabolomics parameters. NMR-based CSF metabolomics have a potential role in differentiating TBM from the controls.

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.

Paradoxical manifestations during tuberculous meningitis treatment among HIV-negative patients: a retrospective descriptive study and literature review.

Tuberculous meningitis (TBM) is the most frequent, severe, and disabling form of central nervous system (CNS) tuberculosis (TB). TBM paradoxical manifestations are characterized by clinical or paraclinical worsening after 1month of effective anti-TB treatment in patients who initially responded to treatment despite the use of adjunctive corticosteroids. Retrospective descriptive study of consecutive HIV-negative adult patients (≥ 18years) with definitive TBM who developed a paradoxical manifestation following anti-TB in a tertiary-care hospital in Mexico from 2009 to 2019; we also conducted a literature review of published cases/series of paradoxical manifestations in HIV-negative patients from 1980 to 2020. We detected 84 cases of definitive TBM; 55 (68.7%) HIV-negative patients and 29 (36.3%) HIV-infected patients. Among HIV-negative patients, four (7.3%), three female and one male (19-49years old), developed a paradoxical manifestation within 4-14weeks following treatment initiation despite receiving adequate corticosteroid doses; Mycobacterium bovis was isolated from the cerebrospinal fluid of three cases and Mycobacterium tuberculosis in one more. Two patients developed vasculopathy-related cerebral infarctions, one severe basilar meningitis, and hydrocephalus, one more a tuberculoma. Two were treated with intravenous cyclophosphamide, and two with steroids. One of the patients treated with steroids died; patients who received cyclophosphamide had a good clinical response. This case series illustrates the diverse clinical/radiologic paradoxical manifestations of TBM in HIV-negative patients. Cyclophosphamide may be safe and effective in treating TBM-associated paradoxical manifestations. Specific diagnostic and care protocols for these patients are needed.

18FDG-Positron Emission Tomography in patients with Tuberculous Meningitis: A Prospective Evaluation.

Lower yield of available diagnostic tests for tuberculous meningitis (TBM) frequently causes delay in diagnosis. Recently, 18F-fluorodeoxyglucose positron emission tomography (FDG PET) has been used in infectious disorders such as pulmonary tuberculosis; however, it is rarely used in TBM. This study was aimed to ascertain the role of FDG PET in the diagnosis and determination of the extent of disease and prognosis in patients with TBM. After excluding unsuitable patients, 25 patients were subjected to whole-body PET-computed tomography (CT) image acquisition along with separate brain protocol with an integrated PET-CT device. FDG PET was found to be abnormal in 92% patients. Extracranial FDG uptake was observed in 80% patients. Most common extracranial site of involvement was lymph nodes (60%), followed by lung (56%), vertebral body (8%), genitourinary organs (8%), and spleen (4%). FDG PET observed extracranial involvement had 80% sensitivity and 20% specificity in detecting definite TBM cases. In conclusion, FDG PET may be a useful test in TBM evaluation.

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.

Direct economic burden of patients with tuberculous meningitis in western China.

To estimate the direct economic burden of tuberculous meningitis (TBM) in China for the first time. Patients who were first diagnosed with TBM from December 2015 to December 2018 in Western China Hospital were enrolled. We retrospectively collected data on demographic and clinical features, resource utilization, costs, and long-term outcomes. The patients were followed up for 15-53months. We performed a cost-of-illness study and analyzed the cost contributors with a generalized linear model. In total, the cases of 154 TBM patients (95 males, 59 females, aged 14-82years) were reviewed. The average total direct cost per person was USD (United States dollars) 9,484 (range 1,822-67,285), with a mean direct medical cost of USD 8,901 (range 1,189-67,049). The average inpatient cost and drug cost after discharge were USD 6,837 (range 845-52,921) and USD 1,967 (range 0-60,423), respectively. The mean direct nonmedical cost was USD 583 (range 33-3,817), which accounted for 6.2% of the total direct cost. The average length of stay (LOS) in hospital was 25.0days (range 6-152). A total of 117 of the patients (76.0%) had good outcomes (mRS=0-2). There was no significant difference in the costs, LOS, or outcomes between rural and urban patients. Contributors to total direct cost were definite TBM, fever, coma, seizures, multidrug resistance, hydrocephalus, and poor long-term outcome. Although the accessibility of medical resources in remote and rural regions has significantly improved in China, the cost of TBM imposes a catastrophic burden on patients.

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.