Explore the vast range of titles available.

Tuberculous meningitis is characterized by elevated levels of matrix metalloproteinase 9 (MMP9) in the cerebrospinal fluid (CSF). However, it is unclear whether elevated MMP9 levels are associated with poor treatment outcome. We tested the hypothesis that pretreatment MMP9 levels in the CSF would be higher in tuberculous meningitis patients experiencing a poor treatment outcome. We prospectively assessed the treatment outcome in a consecutive sample of human immunodeficiency virus-negative patients with tuberculous meningitis. We defined good outcome as survival without severe neurological disability (modified Rankin scale scores 0-2). We estimated levels of MMP9 and its tissue inhibitor (TIMP1) on pretreatment CSF samples. We used albumin index to assess blood-brain barrier permeability. We studied 40 patients (23 males [58%]) with tuberculous meningitis. Sixteen patients (40%) had stage 3 disease. On follow-up, 18 (45%) patients had a poor treatment outcome-15 patients died and 3 had severe neurological disability. Pretreatment MMP9 levels were not associated with treatment outcome (median [interquartile range], 254 [115-389] vs. 192 [60-383] ng/mL in good vs. poor outcome groups; P = 0.693). MMP9 levels did not correlate with the albumin index (Spearman's rho = 0.142; P = 0.381). However, MMP9 levels significantly correlated with CSF glucose levels (rho = -0.419; P = 0.007) and admission Glasgow coma scale score (rho = 0.324; P = 0.032). Likewise, TIMP1 levels also did not differ by treatment outcome (1239 [889-1511] vs. 1522 [934-1949] ng/mL; P = 0.201). MMP9/TIMP1 ratio that reflects net proteolytic activity was also not different between the two groups (0.191 [0.107-0.250] vs. 0.163 [0.067-0.34]; P = 0.625). Our findings do not support the hypothesis that pretreatment levels of MMP9 would be higher in tuberculous meningitis patients experiencing a poor treatment outcome. Further, MMP9 levels in the CSF did not correlate with blood-brain barrier permeability in patients with tuberculous meningitis.

We assessed the performance of metagenomic next-generation sequencing (mNGS) in the diagnosis of infectious encephalitis and meningitis. This was a prospective multicenter study. Cerebrospinal fluid samples from patients with viral encephalitis and/or meningitis, tuberculous meningitis, bacterial meningitis, fungal meningitis, and non-central nervous system (CNS) infections were subjected to mNGS. In total, 213 patients with infectious and non-infectious CNS diseases were finally enrolled from November 2016 to May 2019; the mNGS-positive detection rate of definite CNS infections was 57.0%. At a species-specific read number (SSRN) ≥2, mNGS performance in the diagnosis of definite viral encephalitis and/or meningitis was optimal (area under the curve [AUC] = 0.659, 95% confidence interval [CI] = 0.566-0.751); the positivity rate was 42.6%. At a genus-specific read number ≥1, mNGS performance in the diagnosis of tuberculous meningitis (definite or probable) was optimal (AUC=0.619, 95% CI=0.516-0.721); the positivity rate was 27.3%. At SSRNs ≥5 or 10, the diagnostic performance was optimal for definite bacterial meningitis (AUC=0.846, 95% CI = 0.711-0.981); the sensitivity was 73.3%. The sensitivities of mNGS (at SSRN ≥2) in the diagnosis of cryptococcal meningitis and cerebral aspergillosis were 76.92 and 80%, respectively. mNGS of cerebrospinal fluid effectively identifies pathogens causing infectious CNS diseases. mNGS should be used in conjunction with conventional microbiological testing. Chinese Clinical Trial Registry, ChiCTR1800020442.

Background. Tuberculous meningitis (TBM) leads to death or disability in half the affected individuals. Tools to assess severity and predict outcome are lacking. Neurospecific biomarkers could serve as markers of the severity and evolution of brain injury, but have not been widely explored in TBM. We examined biomarkers of neurological injury (neuromarkers) and inflammation in pediatric TBM and their association with outcome. Methods. Blood and cerebrospinal fluid (CSF) of children with TBM and hydrocephalus taken on admission and over 3 weeks were analyzed for the neuromarkers S100B, neuron-specific enolase (NSE), and glial fibrillary acidic protein (GFAP), in addition to multiple inflammatory markers. Results were compared with 2 control groups: patients with (1) a fatty filum (abnormal filum terminale of the spinal cord); and (2) pulmonary tuberculosis (PTB). Imaging was conducted on admission and at 3 weeks. Outcome was assessed at 6 months. Results. Data were collected from 44 patients with TBM (cases; median age, 3.3 [min–max 0.3–13.1] years), 11 fatty filum controls (median age, 2.8 [min–max 0.8–8] years) and 9 PTB controls (median age, 3.7 [min–max 1.3–11.8] years). Seven cases (16%) died and 16 (36%) had disabilities. Neuromarkers and inflammatory markers were elevated in CSF on admission and for up to 3 weeks, but not in serum. Initial and highest concentrations in week 1 of S100B and NSE were associated with poor outcome, as were highest concentration overall and an increasing profile over time in S100B, NSE, and GFAP. Combined neuromarker concentrations increased over time in patients who died, whereas inflammatory markers decreased. Cerebral infarcts were associated with highest overall neuromarker concentrations and an increasing profile over time. Tuberculomas were associated with elevated interleukin (IL) 12p40, interferon-inducible protein 10, and monocyte chemoattractant protein 1 concentrations, whereas infarcts were associated with elevated tumor necrosis factor α, macrophage inflammatory protein 1α, IL-6, and IL-8. Conclusions. CSF neuromarkers are promising biomarkers of injury severity and are predictive of mortality. An increasing trend suggested ongoing brain injury, even though markers of inflammation declined with treatment. These findings could offer novel insight into the pathophysiology of TBM.

The epidemiology of infectious causes of meningitis in sub-Saharan Africa is not well understood, and a common cause of meningitis in this region, Mycobacterium tuberculosis (TB), is notoriously hard to diagnose. Here we show that integrating cerebrospinal fluid (CSF) metagenomic next-generation sequencing (mNGS) with a host gene expression-based machine learning classifier (MLC) enhances diagnostic accuracy for TB meningitis (TBM) and its mimics. 368 HIV-infected Ugandan adults with subacute meningitis were prospectively enrolled. Total RNA and DNA CSF mNGS libraries were sequenced to identify meningitis pathogens. In parallel, a CSF host transcriptomic MLC to distinguish between TBM and other infections was trained and then evaluated in a blinded fashion on an independent dataset. mNGS identifies an array of infectious TBM mimics (and co-infections), including emerging, treatable, and vaccine-preventable pathogens including Wesselsbron virus, Toxoplasma gondii, Streptococcus pneumoniae , Nocardia brasiliensis , measles virus and cytomegalovirus. By leveraging the specificity of mNGS and the sensitivity of an MLC created from CSF host transcriptomes, the combined assay has high sensitivity (88.9%) and specificity (86.7%) for the detection of TBM and its many mimics. Furthermore, we achieve comparable combined assay performance at sequencing depths more amenable to performing diagnostic mNGS in low resource settings. Tuberculous meningitis is difficult to differentiate from meningitis caused by other pathogens. Here, the authors combine metagenomics-based pathogen detection in cerebrospinal fluid with a host gene expression-based machine learning classifier for diagnosis.

Poor penetration of many anti-tuberculosis (TB) antibiotics into the central nervous system (CNS) is thought to be a major driver of morbidity and mortality in TB meningitis (TBM). While the amount of a particular drug that crosses into the cerebrospinal fluid (CSF) varies from person to person, little is known about the host factors associated with interindividual differences in CSF concentrations of anti-TB drugs. In patients diagnosed with TBM from the country of Georgia (n = 17), we investigate the association between CSF concentrations of anti-TB antibiotics and multiple host factors including serum drug concentrations and CSF concentrations of metabolites and cytokines. We found > 2-fold differences in CSF concentrations of anti-TB antibiotics from person to person for all drugs tested including cycloserine, ethambutol, imipenem, isoniazid, levofloxacin, linezolid, moxifloxacin, pyrazinamide, and rifampin. While serum drug concentrations explained over 30% of the variation in CSF drug concentrations for cycloserine, isoniazid, linezolid, and pyrazinamide (adjusted R 2  ≥ 0.3, p < 0.001 for all), there was no significant association between serum concentrations of imipenem and ethambutol and their respective CSF concentrations. CSF concentrations of carnitines were significantly associated with concentrations of ethambutol and imipenem (q < 0.05), and imipenem was the only antibiotic significantly associated with CSF cytokine concentrations. These results indicate that there is high interindividual variability in CSF drug concentrations in patients treated for TBM, which is only partially explained by differences in serum drug concentrations. With the exception of imipenem, there was no association between CSF drug concentrations and concentrations of cytokines and chemokines.

Tuberculosis (TB) which is caused by Mycobacterium tuberculosis poses a significant public health global treat. Tuberculosis meningitis (TBM) accounts for approximately 1% of all active TB cases. The diagnosis of Tuberculosis meningitis is notably difficult due to its rapid onset, nonspecific symptoms, and the difficulty of detecting Mycobacterium tuberculosis in cerebrospinal fluid (CSF). In 2019, 78,200 adults died of TB meningitis. This study aimed to assess the microbiological diagnosis TB meningitis using CSF and estimated the risk of death from TBM. Relevant electronic databases and gray literature sources were searched for studies that reported presumed TBM patients. The quality of included studies was assessed using the Joanna Briggs Institute Critical Appraisal tools designed for prevalence studies. Data were summarized using Microsoft excel ver 16. The proportion of culture confirmed TBM, prevalence of drug resistance and risk of death were calculated using the random-effect model. Stata version 16.0 was used perform the statistical analysis. Moreover, subgroup analysis was conducted. After systematic searching and quality assessment, 31 studies were included in the final analysis. Ninety percent of the included studies were retrospective studies in design. The overall pooled estimates of CSF culture positive TBM was 29.72% (95% CI; 21.42-38.02). The pooled prevalence of MDR-TB among culture positive TBM cases was 5.19% (95% CI; 3.12-7.25). While, the proportion of INH mono-resistance was 9.37% (95% CI; 7.03-11.71). The pooled estimate of case fatality rate among confirmed TBM cases was 20.42% (95%CI; 14.81-26.03). Based on sub group analysis, the pooled case fatality rate among HIV positive and HIV negative TBM individuals was 53.39% (95%CI; 40.55-66.24) and 21.65% (95%CI;4.27-39.03) respectively. Definite diagnosis of TBM still remains global treat. Microbiological confirmation of TBM is not always achievable. Early microbiological confirmation of TBM has great importance to reduce mortality. There was high rate of MDR-TB among confirmed TBM patients. All TB meningitis isolates should be cultured and drug susceptibility tested using standard techniques.

Meningeal tuberculosis (TBM) is the most severe form of extrapulmonary tuberculosis due to its high mortality and long-term sequelae in survivors. A cross-sectional study of diagnostic tests was carried out in a private clinical laboratory in Lima, Peru. All cerebrospinal fluid (CSF) samples from patients with suspected meningitis were analyzed with cytochemical and biochemical studies, as well as smear microscopy, India ink, the FilmArray Meningitis/Encephalitis panel, Xpert® MTB/RIF or Xpert MTB/RIF Ultra, and culture for common bacterias, fungi or mycobacterial. 450 CSF samples were included. The main microorganisms detected were Mycobacterium tuberculosis (8.9%), Cryptococcus neoformans (6.0%), and Streptococcus pneumoniae (2.4%). 97.5% of patients with TBM presented positive Xpert MTB/RIF or Ultra. The median number of red blood cells, leukocytes, and percentage of mononuclear cells, glucose, and proteins in the CSF was 57.5 cells/μl, 91.5 cells/μl, 70%, 22.5 mg/dL and 218.3 mg/dL, respectively. Likewise, patients with TMB had the lowest glucose levels (median: 22.5, IQR: 11 - 35) compared to other etiologies of meningitis. While bacterial meningitis had the highest leukocyte (median: 173 μl; IQR: 17 - 520) and protein levels (median: 289.7; IQR: 92 - 556). The characteristics of the cytochemical study of CSF can guide the differential diagnosis by identifying general trends of tuberculous meningitis and other meningitis etiologies. However, it remains necessary to establish methods with greater precision to properly define the etiological agent causing meningitis.

Background. Tuberculosis immune reconstitution inflammatory syndrome (IRIS) is a common cause of deterioration in human immunodeficiency virus (HIV)—infected patients receiving tuberculosis treatment after starting antiretroviral therapy (ART). Potentially life-threatening neurological involvement occurs frequently and has been suggested as a reason to defer ART. Methods. We conducted a prospective study of HIV-infected, ART-naive patients with tuberculous meningitis (TBM). At presentation, patients started tuberculosis treatment and prednisone; ART was initiated 2 weeks later. Clinical and laboratory findings were compared between patients who developed TBM-IRIS (TBM-IRIS patients) and those who did not (non-TBM-IRIS patients). A logistic regression model was developed to predict TBM-IRIS. Results. Forty-seven percent (16/34) of TBM patients developed TBM-IRIS, which manifested with severe features of inflammation. At TBM diagnosis, TBM-IRIS patients had higher cerebrospinal fluid (CSF) neutrophil counts compared with non-TBM-IRIS patients (median, 50 vs 3 cells ×10 6 /L, P = .02). Mycobacterium tuberculosis was cultured from CSF of 15 TBM-IRIS patients (94%) compared with 6 non-TBM-IRIS patients (33%) at time of TBM diagnosis; relative risk of developing TBM-IRIS if CSF was Mycobacterium tuberculosis culture positive = 9.3 (95% confidence interval [CI], 1.4–62.2). The combination of high CSF tumor necrosis factor (TNF)-α and low interferon (IFN)-γ at TBM diagnosis predicted TBM-IRIS (area under the curve = 0.91 [95% CI, .53–.99]). Conclusions. TBM-IRIS is a frequent, severe complication of ART in HIV-associated TBM and is characterized by high CSF neutrophil counts and Mycobacterium tuberculosis culture positivity at TBM presentation. The combination of CSF IFN-γ and TNF-α concentrations may predict TBM-IRIS and thereby be a means to individualize patients to early or deferred ART.

Tuberculous meningitis (TBM) is the most severe form of TB with high rates of mortality and morbidity. Here we conduct RNA-sequencing on whole blood as well as on ventricular and lumbar cerebrospinal fluid (CSF) of pediatric patients treated for TBM. Differential transcript expression of TBM cases are compared with healthy controls in whole blood and with non-TB cerebral infection controls in CSF. Whole blood RNA-Seq analysis demonstrates a distinct immune response pattern in TBM, with significant increase in both canonical and non-canonical inflammasome activation and decrease in T-cell activation. In ventricular CSF, a significant enrichment associated with neuronal excitotoxicity and cerebral damage is detected in TBM. Finally, compartmental comparison in TBM indicates that the ventricular profile represents brain injury whereas the lumbar profile represents protein translation and cytokine signaling. Together, transcriptomic analysis shows that disease processes differ between the periphery and the central nervous system, and within brain compartments. Tuberculosis meningitis (TBM) is a severe form of TB with limited treatment options. Here, the authors perform RNA sequencing on whole blood and on ventricular and lumbar cerebrospinal fluid (CSF) samples from pediatric patients treated for TBM to characterize the immune response and tissue damage.

Tuberculous meningitis (TBM) is the most serious type of tuberculosis infection, and there is a lack of accurate diagnostic targets for TBM. Therefore, it is of great clinical and public health significance to find a specific target for early diagnosis and prediction of the prognosis of TBM. From January 2021 to February 2024, 110 TBM patients and 122 patients with non-tumor, non-infectious headaches were admitted to Hunan Chest Hospital. To compare the two groups, cerebrospinal fluid (CSF) levels of sCD163 and MMP-9, as well as serum NCAM1 protein levels, were detected by ELISA. Multivariate logistic regression analysis or Spearman analysis was then performed to investigate the correlation between these protein levels and the MRC (Medical Research Council) stage or the short-term prognosis in TBM patients. sCD163 and MMP-9 were elevated in the CSF of TBM patients compared to controls. Oppositely, the protein levels of serum NCAM1 was decreased. The levels of CSF sCD163, MMP-9 and serum NCAM1 are associated with MRC stage and short-term prognosis of TBM patients, and the combined CSF sCD163, MMP-9 and serum NCAM1 have the best value in predicting the short-term prognosis of TBM patients.