Tuberculous meningitis (TBM) represents the most severe manifestation of extrapulmonary tuberculosis, associated with high morbidity and mortality, particularly in endemic regions such as India (Thwaites et al. 2013) [1]. Despite advancements in neuroimaging and microbiological techniques, early diagnosis and prognostication of TBM remain challenging because of its nonspecific clinical presentation and the variable sensitivity of conventional diagnostic tests (Rock et al. 2008; Marais et al. 2010) [2,3]. The pathogenesis of TBM involves Mycobacterium tuberculosis invasion of the central nervous system, leading to a robust host inflammatory response in the subarachnoid space. This inflammatory milieu causes increased intracranial pressure, hydrocephalus, vasculitis, and neuronal injury, all of which contribute to neurological deficits and adverse clinical outcomes (Be et al. 2018) [4]. Consequently, CSF biomarkers that reflect these inflammatory and neuronal injury processes may provide important clues not only for diagnosis but also for assessing disease severity and prognosis. CSF biochemical parameters such as protein, glucose, and chloride have traditionally been used in the diagnostic workup of TBM, though they lack disease specificity (Donald et al. 2005) [5]. In recent years, emerging biomarkers including adenosine deaminase (ADA), lactate, pro-inflammatory cytokines (IL-6, TNF-α), and markers of neuronal damage such as lactate dehydrogenase (LDH) have been studied to better understand the host–pathogen interaction and predict outcomes (Rohlwink et al. 2019; Misra et al. 2010) [6,7]. Elevated CSF protein and ADA levels, along with hypoglycorrhachia, have been correlated with greater disease severity, while LDH and lactate levels have been associated with neuronal damage and poor prognosis (Ramasamy et al. 2020) [8]. Clinical severity in TBM is commonly assessed using the modified British Medical Research Council (MRC) grading system, which stratifies patients into three stages based on neurological status and consciousness level (MRC, 1948) [9]. Studies have demonstrated that higher CSF biomarker derangements often parallel worse clinical grades and poorer outcomes, underscoring the importance of correlating laboratory markers with clinical severity for effective patient management (Mai et al. 2018; Sulaiman et al. 2021) [10,11]. Given the burden of TBM in India, where tuberculosis remains a major public health problem, identifying reliable CSF biomarkers that correlate with clinical severity may significantly improve early risk stratification, guide therapeutic interventions, and predict prognosis. This study was conducted in the Department of Medicine, GMC and SSB Chhatrapati Sambhaji Nagar, Maharashtra, with the aim of evaluating the correlation between CSF biomarkers and clinical severity in patients with TBM.

Study Design and Setting A prospective observational study was conducted in the Department of Medicine, Government Medical College and SSB Chhatrapati Sambhaji Nagar, Maharashtra, over one year (September 2023 – August 2024). Sample Size 100 consecutive patients with confirmed TBM were enrolled. Inclusion Criteria i. Age ≥ 18 years ii. Clinical features suggestive of meningitis (fever, headache, neck stiffness, altered sensorium) iii. CSF findings consistent with TBM (lymphocytic pleocytosis, high protein, low glucose, low chloride) iv. Confirmation by microbiological methods (Ziehl–Neelsen stain, GeneXpert MTB/RIF, or culture) Exclusion Criteria i. Patients with bacterial, viral, or fungal meningitis ii. Patients with comorbid CNS diseases (stroke, malignancy) iii. Patients with HIV co-infection Clinical Severity Assessment Patients were classified according to Modified MRC grading: • Stage I: Fully conscious, no focal deficits • Stage II: Altered sensorium (GCS 11–14) or mild focal deficits • Stage III: GCS ≤ 10 or severe focal deficits CSF Biomarker Analysis CSF samples were collected and analyzed for: • Protein (mg/dL) • Glucose (mg/dL) • Chloride (mEq/L) • Lactate (mmol/L) • Adenosine Deaminase (ADA, U/L) Statistical Analysis Data were analyzed using SPSS v26. Mean ± SD values were compared across severity stages using ANOVA. Pearson’s correlation was applied to determine associations. p < 0.05 was considered significant.

A total of 100 patients with confirmed tuberculous meningitis were enrolled between September 2023 and August 2024 in the Department of Medicine, GMC & SSB, Chhatrapati Sambhaji Nagar, Maharashtra. Demographic Profile The mean age of patients was 34.8 ± 12.6 years (range: 18–65 years). Males constituted 58% and females 42%. Table 1: Demographic and Baseline Characteristics of Study Population (n=100) Parameter Value Mean Age (years) 34.8 ± 12.6 Age Group (years) 18–30: 38% 31–45: 35% >45: 27% Sex Distribution Male: 58% Female: 42% Duration of Symptoms <2 weeks: 41% ≥2 weeks: 59% Common Symptoms Fever (92%) Headache (88%), Neck stiffness (70%) Altered sensorium (44%) Table 1 shows the demographic profile, symptom duration, and major presenting complaints of the patients, highlighting fever and headache as the predominant symptoms. Clinical Severity (MRC Grading) Patients were categorized using the Medical Research Council (MRC) grading system. Table 2: Distribution of Patients According to Clinical Severity (MRC Grading) MRC Grade Definition Patients (n) Percentage Grade I Alert, GCS 15, no focal deficit 32 32% Grade II GCS 11–14 or focal neurological deficit 41 41% Grade III GCS ≤10, severe deficit, coma 27 27% Table 2 demonstrates the severity distribution of TB meningitis patients, with most cases presenting in moderate (Grade II) stage, followed by mild and severe cases. CSF Biomarkers The mean levels of CSF biomarkers were significantly different across severity grades. Table 3: Mean CSF Biomarker Levels in Study Population Biomarker Overall Mean ± SD Grade I (n=32) Grade II (n=41) Grade III (n=27) p-value CSF Protein (mg/dL) 220 ± 85 180 ± 60 230 ± 70 270 ± 95 <0.01 CSF Glucose (mg/dL) 38 ± 12 45 ± 10 36 ± 11 30 ± 9 <0.01 CSF ADA (U/L) 13.8 ± 5.6 10.2 ± 4.1 14.5 ± 5.0 17.8 ± 6.2 <0.01 CSF Lactate (mmol/L) 4.2 ± 1.3 3.5 ± 0.9 4.3 ± 1.2 5.1 ± 1.4 <0.01 Table 3 highlights the biomarker variations, showing a stepwise increase in protein, ADA, and lactate levels with disease severity, while CSF glucose showed a progressive decline. Correlation between Biomarkers and Clinical Severity Correlation analysis revealed that CSF protein, ADA, and lactate levels showed a positive correlation with severity, whereas CSF glucose showed a negative correlation. Table 4: Correlation of CSF Biomarkers with Clinical Severity Biomarker Correlation Coefficient (r) Direction p-value CSF Protein +0.46 Positive <0.01 CSF Glucose –0.42 Negative <0.01 CSF ADA +0.51 Positive <0.01 CSF Lactate +0.49 Positive <0.01 Table 4 indicates significant correlations of CSF biomarkers with disease severity, suggesting their potential role as prognostic indicators in TB meningitis.

Tuberculous meningitis (TBM) remains the most severe manifestation of extrapulmonary tuberculosis, associated with high morbidity and mortality despite advances in diagnostics and treatment strategies (Thwaites et al. 2013). In the present study, we analyzed the demographic, clinical, and cerebrospinal fluid (CSF) biomarker profiles of 100 confirmed TBM patients to assess correlations with disease severity. The mean age of 34.8 years and male predominance observed in our cohort align with earlier reports from India and other endemic regions, where TBM primarily affects young adults in their most productive years (Rock et al. 2008; Wilkinson et al. 2017). Male predominance has been consistently documented, possibly reflecting differences in exposure risks, healthcare-seeking behavior, and host immune response patterns (Yadav et al. 2020). The clinical profile in our study highlights fever, headache, and neck stiffness as the most common presenting symptoms, consistent with classical TBM symptomatology described in previous literature (Marais et al. 2010; Erdem et al. 2015). Altered sensorium was noted in nearly half of the patients, particularly those in advanced MRC grades, reflecting late presentation and delayed diagnosis, which are known contributors to poor prognosis (Thwaites et al. 2002; Vinnard and MacGregor 2009). The distribution across MRC grades—32% Grade I, 41% Grade II, and 27% Grade III—suggests that a significant proportion of patients presented at an intermediate or advanced stage, echoing findings from large clinical series in Asia and Africa (Marais et al. 2014; Davis et al. 2019). Our biomarker analysis revealed significant differences in CSF parameters across severity grades. Elevated CSF protein and ADA levels were strongly associated with higher MRC grades, consistent with the inflammatory nature of TBM where disruption of the blood–brain barrier and lymphocytic response contribute to protein leakage and ADA release (Tuon et al. 2010; Gupta et al. 2016). Similarly, CSF lactate, a marker of anaerobic metabolism and cerebral hypoxia, showed progressive elevation with increasing severity, as reported in prior studies evaluating its diagnostic and prognostic potential in TBM (Saeed et al. 2009; Kumar et al. 2015). Conversely, CSF glucose levels were markedly reduced in severe cases, reflecting consumption by activated immune cells and Mycobacterium tuberculosis organisms within the CSF compartment, a hallmark feature also noted by Thwaites et al. (2002) and Marais et al. (2010). Correlation analysis in our study further established the prognostic significance of these biomarkers. Positive correlations of CSF protein, ADA, and lactate with severity grades reinforce their utility not only in diagnosis but also in risk stratification of TBM patients (Bicanic et al. 2009; Erdem et al. 2015). The negative correlation of glucose levels with severity underscores its diagnostic value, as hypoglycorrhachia has been consistently linked with poor outcomes (Rock et al. 2008; Wilkinson et al. 2017). Such biomarker-based stratification may aid clinicians in early identification of high-risk patients requiring intensive care and adjunctive therapies. The findings of this study have significant clinical implications. In resource-limited settings, where molecular diagnostics are not universally available, CSF biomarker profiles provide a cost-effective adjunct to conventional diagnosis and prognosis of TBM. Integration of these parameters into clinical practice could improve early recognition of severe disease and guide treatment intensity, as suggested by recent consensus guidelines (Marais et al. 2014; Davis et al. 2019). However, our study also highlights the persistent challenge of late presentation, underscoring the need for heightened awareness, early referral, and better access to diagnostic facilities.

The present study highlights the significant role of cerebrospinal fluid (CSF) biomarkers in assessing the clinical severity of tuberculous meningitis (TBM). Elevated levels of CSF protein, adenosine deaminase (ADA), and lactate were strongly associated with worsening disease severity, while decreased CSF glucose correlated with poor clinical status. These findings reinforce the utility of CSF biochemical parameters as valuable adjuncts to clinical grading systems such as the Medical Research Council (MRC) scale, thereby facilitating better stratification of patients. Early recognition of biomarker patterns may aid in timely initiation of appropriate therapy, guide prognosis, and improve patient outcomes. However, larger multicentric studies with longitudinal follow-up are warranted to validate these results and explore the potential of incorporating CSF biomarkers into routine prognostic algorithms for TBM.

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