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

BACKGROUND: To evaluate serum antidiuretic hormone (ADH), its receptors, and renin levels in cerebral salt wasting (CSW) in tuberculous meningitis (TBM). METHODS: 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. RESULTS: 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. CONCLUSION: 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.

Diagnostic Model for Discrimination Between Tuberculous Meningitis and Bacterial Meningitis.

Background: The differential diagnosis between tuberculous meningitis (TBM) and bacterial meningitis (BM) remains challenging in clinical practice. This study aimed to establish a diagnostic model that could accurately distinguish TBM from BM. Methods: Patients with TBM or BM were recruited between January 2017 and January 2021 at Tongji Hospital (Qiaokou cohort) and Sino-French New City Hospital (Caidian cohort). The detection for indicators involved in cerebrospinal fluid (CSF) and T-SPOT assay were performed simultaneously. Multivariate logistic regression was used to create a diagnostic model. Results: A total of 174 patients (76 TBM and 98 BM) and another 105 cases (39 TBM and 66 BM) were enrolled from Qiaokou cohort and Caidian cohort, respectively. Significantly higher level of CSF lymphocyte proportion while significantly lower levels of CSF chlorine, nucleated cell count, and neutrophil proportion were observed in TBM group when comparing with those in BM group. However, receiver operating characteristic (ROC) curve analysis showed that the areas under the ROC curve (AUCs) produced by these indicators were all under 0.8. Meanwhile, tuberculosis-specific antigen/phytohemagglutinin (TBAg/PHA) ratio yielded an AUC of 0.889 (95% CI, 0.840-0.938) in distinguishing TBM from BM, with a sensitivity of 68.42% (95% CI, 57.30%-77.77%) and a specificity of 92.86% (95% CI, 85.98%-96.50%) when a cutoff value of 0.163 was used. Consequently, we successfully established a diagnostic model based on the combination of TBAg/PHA ratio, CSF chlorine, CSF nucleated cell count, and CSF lymphocyte proportion for discrimination between TBM and BM. The established model showed good performance in differentiating TBM from BM (AUC: 0.949; 95% CI, 0.921-0.978), with 81.58% (95% CI, 71.42%-88.70%) sensitivity and 91.84% (95% CI, 84.71%-95.81%) specificity. The performance of the diagnostic model obtained in Qiaokou cohort was further validated in Caidian cohort. The diagnostic model in Caidian cohort produced an AUC of 0.923 (95% CI, 0.867-0.980) with 79.49% (95% CI, 64.47%-89.22%) sensitivity and 90.91% (95% CI, 81.55%-95.77%) specificity. Conclusions: The diagnostic model established based on the combination of four indicators had excellent utility in the discrimination between TBM and BM.

Phenotype of Peripheral NK Cells in Latent, Active, and Meningeal Tuberculosis.

The mechanisms underlying the immunopathology of tuberculous meningitis (TBM), the most severe clinical form of extrapulmonary tuberculosis (TB), are not understood. It is currently believed that the spread of Mycobacterium tuberculosis (Mtb) from the lung is an early event that occurs before the establishment of adaptive immunity. Hence, several innate immune mechanisms may participate in the containment of Mtb infection and prevent extrapulmonary disease manifestations. Natural killer (NK) cells participate in defensive processes that distinguish latent TB infection (LTBI) from active pulmonary TB (PTB). However, their role in TBM is unknown. Here, we performed a cross-sectional analysis of circulating NK cellCID="C008" value="s" phenotype in a prospective cohort of TBM patients (n = 10) using flow cytometry. Also, we addressed the responses of memory-like NK cell subpopulations to the contact with Mtb antigens in vitro. Finally, we determined plasma levels of soluble NKG2D receptor ligands in our cohort of TBM patients by enzyme-linked immunosorbent assay (ELISA). Our comparative groups consisted of individuals with LTBI (n = 11) and PTB (n = 27) patients. We found that NK cells from TBM patients showed lower absolute frequencies, higher CD69 expression, and poor expansion of the CD45RO+ memory-like subpopulation upon Mtb exposure in vitro compared to LTBI individuals. In addition, a reduction in the frequency of CD56brightCD16- NK cells characterized TBM patients but not LTBI or PTB subjects. Our study expands on earlier reports about the role of NK cells in TBM showing a reduced frequency of cytokine-producing cells compared to LTBI and PTB.

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.

Serum and cerebrospinal fluid host proteins indicate stroke in children with tuberculous meningitis.

INTRODUCTION: Stroke is a common complication in children with tuberculous meningitis (TBM). Host proteins may give us insight into the mechanisms of stroke in TBM and serve as biomarkers for detection of stroke, however, they have not been widely explored. In this study, we compared the concentrations of cerebrospinal fluid (CSF) and serum proteins between children who had TBM-related stroke and children with TBM without stroke. METHODS: We collected CSF and serum from 47 children consecutively admitted to the Tygerberg Academic Hospital in Cape Town, South Africa between November 2016, and November 2017, on suspicion of having TBM. A multiplex platform was used to measure the concentrations of 69 host proteins in CSF and serum from all study participants. RESULTS: After classification of study participants, 23 (48.9%) out of the 47 study participants were diagnosed with TBM, of which 14 (60.9%) demonstrated radiological arterial ischemic infarction. The levels of lipocalin-2, sRAGE, IP-10/ CXCL10, sVCAM-1, MMP-1, and PDGF-AA in CSF samples and the levels of D-dimer, ADAMTS13, SAA, ferritin, MCP-1/ CCL2, GDF-15 and IL-13 in serum samples were statistically different between children who had TBM-related stroke and children with TBM without stroke. After correcting for multiple testing, only the levels of sVCAM-1, MMP-1, sRAGE, and IP-10/ CXCL10 in CSF were statistically different between the two groups. CSF and serum protein biosignatures indicated stroke in children diagnosed with TBM with up to 100% sensitivity and 88.9% specificity. CONCLUSION: Serum and CSF proteins may serve as biomarkers for identifying individuals with stroke amongst children diagnosed with TBM at admission and may guide us to understand the biology of stroke in TBM. This was a pilot study, and thus further investigations in larger studies are needed.

Is cerebral salt wasting related to sympathetic dysregulation in tuberculous meningitis?

BACKGROUND: Cerebral Salt wasting (CSW) is common in Tuberculous Meningitis (TBM) and is suggested to be due to sympathetic dysregulation of renal blood supply but has not been proven. OBJECTIVE: To evaluate plasma Catecholamines in TBM patients with CSW and correlate with the markers of stress. MATERIALS AND METHODS: The diagnosis of TBM was based on clinical, CSF and MRI criteria. Catecholamines level was measured by LC-MS on admission, at the time of hyponatremia and on correction of hyponatremia. Catecholamine levels were correlated with clinical and laboratory markers of stress, hyponatremia and severity of CSW using pre-defined criteria. RESULTS: There were 24 patients with TBM (12 with CSW) and 12 controls. The median age of patients was 31 (18-75) years and 12 (50 %) were females. TBM patients with CSW had significantly higher levels of catecholamines compared to controls (p < 0.001). TBM patients with CSW had higher levels of norepinephrine than those without CSW (p = 0.034). Sequential studies revealed that dopamine and epinephrine increased at the time of hyponatremia and declined on its correction. Severity of TBM was related to dopamine (p = 0.04) and severity of CSW was related to epinephrine (p = 0.016). CONCLUSION: CSW in TBM seems to be related to catecholamine dysregulation.

Lessons learnt from an old foe.

Neurotuberculosis usually responds well to standard antitubercular therapy. Some; patients have prolonged course A 11 year old boy diagnosed TBM, an immunocompetent patient, had an unusual course of illness in the form of prolonged fever, persistent hyponatremia and CSF; pleocytosis despite adequate treatment. Clinical course in the management of TBM can be; protracted with complications despite adequate therapy.

Pharmacokinetics and Pharmacodynamics of Intensive Antituberculosis Treatment of Tuberculous Meningitis.

The most effective antituberculosis drug treatment regimen for tuberculous meningitis is uncertain. We conducted a randomized controlled trial comparing standard treatment with a regimen intensified by rifampin 15 mg/kg and levofloxacin for the first 60 days. The intensified regimen did not improve survival or any other outcome. We therefore conducted a nested pharmacokinetic/pharmacodynamic study in 237 trial participants to define exposure-response relationships that might explain the trial results and improve future therapy. Rifampin 15 mg/kg increased plasma and cerebrospinal fluid (CSF) exposures compared with 10 mg/kg: day 14 exposure increased from 48.2 hour·mg/L (range 18.2-93.8) to 82.5 hour·mg/L (range 8.7-161.0) in plasma and from 3.5 hour·mg/L (range 1.2-9.6) to 6.0 hour·mg/L (range 0.7-15.1) in CSF. However, there was no relationship between rifampin exposure and survival. In contrast, we found that isoniazid exposure was associated with survival, with low exposure predictive of death, and was linked to a fast metabolizer phenotype. Higher doses of isoniazid should be investigated, especially in fast metabolizers.

Elevated Matrix Metalloproteinase Concentrations Offer Novel Insight Into Their Role in Pediatric Tuberculous Meningitis.

We collected lumbar and ventricular cerebrospinal fluid and serum from 40 children treated for tuberculous meningitis and measured the concentrations of gelatinases and their inhibitors. The concentrations of matrix metalloproteinase 9 (MMP-9), MMP-2, tissue inhibitor of metalloproteinase 1 (TIMP-1), and TIMP-2 were significantly elevated in the lumbar CSF samples, and we found interesting dynamics for MMP-9 that offer novel insight into its role in pediatric patients with tuberculous meningitis.

Tuberculous meningitis in children is characterized by compartmentalized immune responses and neural excitotoxicity.

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.

Role of Oxidative Stress in Tuberculous Meningitis: a Clinico-Radiological Correlation.

Central nervous system infection may be associated with oxidative stress and may influence clinical severity and outcome. We report oxidative stress markers in the patients with tuberculous meningitis (TBM) and correlate these with clinico-radiological severity and outcome. Fifty-six patients with TBM diagnosed on the basis of clinical, cerebrospinal fluid (CSF), and magnetic resonance (MRI) were included. Plasma glutathione (GSH), total antioxidant capacity (TAC), and malondialdehyde (MDA) were measured in the patients and 55 matched healthy controls. Hospital death was noted. Disabilities at 3 and 6 months were categorized using the modified Rankin Scale (mRS) as poor (mRS > 2) or good (mRS ≤ 2). The patients had lower levels of GSH (1.49 ± 0.49 vs 2.57 ± 0.39 mg/dL, p Ë‚ 0.001) and TAC (0.25 ± 0.17 vs 2.20 ± 0.31 mmol Trolox Eq/L, p Ë‚ 0.001), and higher level of MDA (6.61 ± 1.72 vs 3.09 ± 0.38 nmol/mL, p < 0.001) compared to controls. Total antioxidant capacity correlated with cranial nerve palsy and CSF pleocytosis. Patients with tuberculoma had lower GSH compared to those without. Six patients died in the hospital, and they had lower GSH (p < 0.01) and TAC (p = 0.02) levels compared to those who survived. Thirty-one and 36 patients had a good outcome at 3 and 6 months respectively. The patients with good outcome had higher GSH level.

Immune cell characteristics and cytokine responses in adult HIV-negative tuberculous meningitis: an observational cohort study.

Immunopathology contributes to high mortality in tuberculous meningitis (TBM) but little is known about the blood and cerebrospinal fluid (CSF) immune response. We prospectively characterised the immune response of 160 TBM suspects in an Indonesian cohort, including 67 HIV-negative probable or definite TBM cases. TBM patients presented with severe disease and 38% died in 6 months. Blood from TBM patients analysed by flow cytometry showed lower αßT and γδT cells, NK cells and MAIT cells compared to 26 pulmonary tuberculosis patients (2.4-4-fold, all p < 0.05) and 27 healthy controls (2.7-7.6-fold, p < 0.001), but higher neutrophils and classical monocytes (2.3-3.0-fold, p < 0.001). CSF leukocyte activation was higher than in blood (1.8-9-fold). CSF of TBM patients showed a predominance of αßT and NK cells, associated with better survival. Cytokine production after ex-vivo stimulation of whole blood showed a much broader range in TBM compared to both control groups (p < 0.001). Among TBM patients, high ex-vivo production of TNF-α, IL-6 and IL-10 correlated with fever, lymphocyte count and monocyte HLA-DR expression (all p < 0.05). TBM patients show a strong myeloid blood response, with a broad variation in immune function. This may influence the response to adjuvant treatment and should be considered in future trials of host-directed therapy.

Hypothalamic and pituitary dysfunction is common in tubercular meningitis: A prospective study from a tertiary care center in Northern India.

INTRODUCTION: Current literature is poor with respect to well conducted prospective studies of hypothalamic pituitary axis (HPA) dysfunction in tubercular meningitis (TBM). As hormonal deficiencies are associated with poor clinical outcome in various neurological and non-neurological disorders, we prospectively evaluated the hypothalamic pituitary axis (HPA) dysfunction in TBM. PATIENTS AND METHODS: Present study included newly diagnosed drug naive TBM patients (n = 63) at a tertiary care centre in Northern India. All patients underwent detailed clinical, radiological evaluation (Gadolinium enhanced magnetic resonance imaging of brain) and HPA hormonal profiles (electrochemiluminescence assay) both at initial presentation and at six month follow up. All the data was recorded on a predesigned proforma. RESULTS: 77.8% patients had definite and 22.2% had highly probable TBM. 84.2% of patients had pituitary hormonal abnormalities at presentation. These included hyperprolactinemia (49.2%), secondary adrenal deficiency (42.9%), secondary hypogonadism (38.1%) and central hypothyroidism (9.5%). At follow up, 42.1% patients had HPA abnormalities [hyperprolactinemia (13.2%), secondary hypogonadism (15.8%), secondary adrenal deficiency (10.5%) and central hypothyroidism (10.5%)]. On multivariate logistic regression analysis, secondary hypocortisolism (Odd ratio: 4.042; 95% CI = 1.074-15.22; P = .039) was associated with poor outcome in TBM. CONCLUSION: Abnormalities of HPA are common in TBM. Patients with TBM should be evaluated for dysfunction of HPA and treated accordingly.

Safety and Efficacy of Fludrocortisone in the Treatment of Cerebral Salt Wasting in Patients With Tuberculous Meningitis: A Randomized Clinical Trial.

Importance: Tuberculous meningitis is associated with high frequency of cerebral salt wasting. There is a paucity of objective information regarding the best method of treatment of this condition. Objective: To evaluate the efficacy and safety of fludrocortisone in the treatment of cerebral salt wasting in patients with tuberculous meningitis. Design, Setting, and Participants: This is a single-center, open-label, randomized clinical trial conducted from October 2015 to April 2017 in India. Patients were randomized in a 1:1 ratio to arms receiving saline only or saline plus fludrocortisone, in addition to a standard treatment of 4 antitubercular drugs, prednisolone, and aspirin. The 2 arms were matched for demographic, clinical, and magnetic resonance imaging findings. The patients were followed up for at least 6 months. Interventions: Patients were randomized to a 0.9% solution of intravenous saline with 5 to 12 g per day of oral salt supplementation, with or without the addition of 0.1 to 0.4 mg of fludrocortisone per day. Main Outcomes and Measures: The primary end point was the time needed to correct serum sodium levels; secondary end points were in-hospital deaths, disability at 3 months, disability at 6 months, occurence of stroke, and serious adverse reactions. Results: Ninety-three patients with suspected tuberculous meningitis were recruited; 12 did not meet the inclusion criteria, including 4 with alternate diagnoses. A total of 37 patients with cerebral salt wasting were eligible for the study. One refused to participate, and therefore 36 patients were included, with 18 randomized to each group. The median (range) age was 30 (20-46) years, and 19 were male (52.8%). Those receiving fludrocortisone regained normal serum sodium levels after 4 days, significantly earlier than those receiving saline only (15 days; P = .004). In an intention-to-treat analysis, hospital mortality, disability at 3 months, and disability at 6 months did not differ significantly, but fewer infarcts occurred in the deep border zone in the group receiving fludrocortisone (1 of 18 [6%]) vs those in the control arm (6 of 18 [33%]; P = .04). Fludrocortisone was associated with severe hypokalemia and hypertension in 2 patients each, and pulmonary edema occurred in 1 patient. These adverse reactions necessitated discontinuation of fludrocortisone in 2 patients. Conclusions and Relevance: Fludrocortisone results in earlier normalization of serum sodium levels, but did not affect outcomes at 6 months. Fludrocortisone had to be withdrawn in 2 patients because of severe adverse effects. This study provides class II evidence on the role of fludrocortisone in treatment of hyponatremia associated with cerebral salt wasting in patients with tuberculous meningitis. Trial Registration: Clinical Trials Registry of India (ctri.nic.in) Identifier: CTRI/2017/10/010255.

Progress on Diagnosis of Tuberculous Meningitis.

Central nervous system (CNS) disease caused by Mycobacterium tuberculosis (MTB) is highly devastating. Tuberculous meningitis (TBM) is the most common form of CNS tuberculosis (TB). Rapid, sensitive, and affordable diagnostic tests are not available. Ziehl-Neelsen (ZN) stain has a very low sensitivity in cases of TBM, the sensitivity rates is of about 10-20%.The detection rate can be improved by taking large volume CSF samples (>6 ml) and prolonged slide examination (30 min). Culture of MTB from the CSF is slow and insufficiently sensitive. The sensitivity is different, which varies from 36% to 81.8%. The microscopic observation drug susceptibility (MODS) assay was recommended by the World Health Organization in 2011. The sensitivity is 65%, which is more sensitive and faster than CSF smear. Commercial PCR assays were found to be insensitive at detecting MTB in CSF samples. Many research provided the value of ADA on the TBM diagnosis. Interferon-gamma release assays (IGRAs) are not recommended for diagnosis of active TB disease. Imaging is essential in diagnosis and showing complications of CNS TB. Thwaites criteria and the Lancet consensus scoring system (LCSS) were developed to improve the diagnosis of TBM. Clinicians will continue to make judgment based on clinical examination, inflammatory CSF examinations, imaging studies, and scoring systems.

A study of atrial and brain natriuretic peptides in tuberculous meningitis and acute encephalitis.

OBJECTIVE: To report atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) levels in patients with tuberculous meningitis (TBM) and acute encephalitis syndrome (AES), and evaluate their relationship with hyponatraemia. METHODS: Consecutive patients with TBM and AES were included in the study. Hyponatraemia was categorised as cerebral salt wasting (CSW), syndrome of inappropriate secretion of antidiuretic hormone (SIADH) and a miscellaneous group based on clinical and laboratory criteria. Serum ANP and BNP levels were measured upon hospital admission, at the time of diagnosis of hyponatraemia and upon correction of hyponatraemia. Outcome at 3 months was assessed using the modified Rankin scale (mRS) as good (mRS 2) and poor (mRS >2). RESULTS: There were 67 patients with TBM and 77 with AES. Hyponatraemia was more common in TBM than in AES (65.7% vs. 27%, P < 0.01). Forty-one (63.1%) patients had CSW, 6 (9.2%) SIADH and 18 (27.7%) had miscellaneous causes of hyponatraemia. During hyponatraemia, ANP (180 ± 45 vs. 106 ± 32 pg/ml, P < 0.01) and BNP (263 ± 118 vs. 163 ± 91 pg/ml, P  0.01) levels were significantly increased compared with baseline, and remained high even after Na+ correction. CONCLUSION: ANP and BNP levels were increased during hyponatraemia and remained high even after correction of hyponatraemia in TBM and AES, especially in patients with CSW. However, ANP and BNP levels could not be used to differentiate CSW from SIADH.

Blood-Brain Barrier and Intrathecal Immune Response in patients with neuroinfections.

Cerebrospinal fluid/serum albumin ratio is one of the most informative parameters for blood-brain barrier (BBB) integrity in cases of central nervous system (CNS) infectious diseases. Normally, CNS albumin concentration is a function of diffusion processes along with CSF drainage and resorption. In pathological processes CSF albumin levels are dependent only on the rate of CSF drainage resulting in non-linear reciprocal changes of albumin quotient (Qalb). IgG, IgA and IgM concentrations both in CSF and serum can be compared to Qalb, thus determining the intrathecal immune response. The aim of the study was to detect BBB permeability impairment and the intrathecal immune response in patients with CNS infections with various etiologies. CSF/serum ratios were calculated and related to IgG IgA and IgM concentrations in CSF and blood serum. The results were integrated and presented by Reibergrams. The results demonstrated typical patterns which prove albumin to be the main modulator of protein dynamics and at the same time explicates the complex pathophysiological mechanisms involved in BBB disruption and intrathecal immune response in CNS infections. The diagnostic model presented in our study seeks to explain the observations of meningitis and meningoencephalitis pathophysiology and points out the mandatory cooperation between clinicians and laboratory for accurate diagnosis and proper treatment.

Cytokines do play a role in pathogenesis of tuberculous meningitis: A prospective study from a tertiary care center in India.

BACKGROUND: Though animal studies have suggested a role for proinflammatory cytokines in pathogenesis their exact role in pathogenesis of human meningeal tuberculosis continues to be controversial with different studies yielding contradictory results. AIM AND OBJECTIVES: To study the levels of proinflammatory cytokines in serum and cerebrospinal fluid (CSF) of patients with tubercular meningitis (TBM) and to determine whether these correlate with disease severity. PATIENTS AND METHODS: Present study included 146 patients with TBM (90- Definite TBM; 56- Probable TBM), diagnosed according to criteria laid by Ahuja et al. which were modified to include CSF nucleic acid based tests. Serum (n=146) and CSF (n=140) levels of various proinflammatory cytokines (IL-1ß, IL-2, IL-6, TNF-α and IFNγ) were compared between TBM patients and healthy volunteers (n=99). These levels were correlated with various clinical, radiological and CSF parameters of TBM patients. RESULTS: Proinflammatory cytokines include cytokines which promote systemic inflammation. In current study, the serum and CSF levels of various cytokines (IL-2, IL-4, IL-6, IL-1ß, IFN-γ and TNF-α) were significantly elevated in TBM patients compared to controls. A significant correlation was found between a) Higher stage of TBM and various cytokines (except for serum IL-6 and CSF IFN-γ); b) High CSF TNF-α, IL-4 and IL-1ß with severity of hydrocephalus; c) High CSF IL1ß and IFN-γ with presence of exudates on MRI; d) Serum and CSF levels of all cytokines with poor outcome as determined by death or as defined by S and E ADL (Schwab and England activities of daily living) score or by GOS (Glasgow outcome scale) (except for interferon gamma); and e) Serum and CSF IL-4 and IL1ß with presence of infarcts on MRI brain. CONCLUSION: Proinflammatory cytokines play an important role in the pathogenesis of TBM and contribute significantly towards severity of disease.

Biomarkers of Cerebral Injury and Inflammation in Pediatric Tuberculous Meningitis.

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.

Interferon-Gamma Release Assay Performance of Cerebrospinal Fluid and Peripheral Blood in Tuberculous Meningitis in China.

The aim of this study was to examine the performance of T-SPOT.TB on cerebrospinal fluid (CSF) and peripheral blood (PB) in diagnosis of tuberculous meningitis (TBM) in China. Of 100 patients with presumed TBM prospectively enrolled from Sep 2012 to Oct 2014, 53 were TBM (21 definite and 32 probable TBM cases) and 37 were non-TBM cases; the other 10 patients were excluded from analysis due to inconclusive diagnosis, no sufficient CSF samples, or incomplete follow-up. T-SPOT.TB on CSF and PB and routine laboratory tests of CSF were performed simultaneously. The receiver operating characteristic (ROC) curve and cut-off value of CSF T-SPOT.TB and routine CSF parameters were established between TBM and non-TBM group. The area under ROC curve (AUC) of the T-SPOT.TB on CSF and PB was 0.81 and 0.89, which was higher than that of the routine CSF parameters (AUC 0.67-0.77). Although the sensitivity of CSF T-SPOT.TB was lower than that of PB T-SPOT.TB (60.8% versus 90.6%, P < 0.001), the specificity of CSF T-SPOT.TB was significantly higher than that of PB T-SPOT.TB (97.2% versus 75.7%, P = 0.007). These results indicated that the diagnostic accuracies of PB and CSF T-SPOT.TB are higher than routine laboratory tests. Furthermore, the higher specificity of CSF T-SPOT.TB makes it a useful rule-in test in rapid diagnosis of TBM.