Elsevier

Journal of the Neurological Sciences

Volume 379, 15 August 2017, Pages 131-136
Journal of the Neurological Sciences

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

https://doi.org/10.1016/j.jns.2017.06.001Get rights and content

Highlights

  • Levels of proinflammatory cytokines are markedly raised in serum and cerebrospinal fluid (CSF) of patients with tubercular meningitis (TBM)

  • Levels of proinflammatory cytokines correlate with various clinical, radiological and biochemical markers of disease severity in TBM

  • A more exuberant cytokine response is associated with poor outcome in TBM

Abstract

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-1β, 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-1β, 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-1β with severity of hydrocephalus; c) High CSF IL1β 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 IL1β 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.

Introduction

The prognosis of tuberculous meningitis (TBM) continues to be dismal with mortality rate ranging from 20 to 50%. In addition 20–30% of survivors are left with significant residual impairment. This dismal scenario is due to several factors. While some of these (such as co-infection with human immunodeficiency virus and emergence of drug resistant strains) have been studied well, others have not been studied in detail [1]. One such factor is the extent of host immune response to the tubercular infection which can be both protective as well as detrimental [2]. If severe, this immune response leads to formation of dense basal exudates resulting in adhesions, hydrocephalus and obliterative vasculitis [3], [4].

Cytokines may play a major role in regulation of immune response in TBM. Produced by microglia in response to infection with tubercular bacilli, these hormone like soluble proteins induce formation of cell adhesion molecules, migration of neutrophils as well as release of inflammatory mediators (platelet activating factor, leukotrienes and prostaglandins) and toxic oxygen species resulting in breach of blood brain barrier, more robust inflammatory response, formation of thick exudates and cerebral edema, etc. [5].

Though animal studies have shown a role for tumor necrotic factor alpha (TNF-α) as well as various other cytokines and chemokines (IL-6, IL-1B, CCL21, CCL5 and CXCL10) in pathogenesis of TBM, their role in pathogenesis of human meningeal TB is still far from clear [6], [7], [8]. While some studies [9], [10] have found serum cytokines [(TNFα and interferon gamma (IFNγ)] to be elevated in TBM and correlating positively with severity of the disease, others did not report any correlation between cytokines and disease severity [5], [11]. In addition, all these studies suffered from limitations such as small sample size and methodological flaws such as lack of MRI (magnetic resonance imaging) brain in all the patients. Thus, we planned this study to delineate role of various pro-inflammatory cytokines in pathogenesis of TBM.

Section snippets

Aims and objectives

  • 1.

    To study the levels of proinflammatory cytokines in the serum and cerebrospinal fluid (CSF) of patients with TBM.

  • 2.

    To determine whether these correlate with severity of TBM.

Patients and methods

Present study was an institute based prospective study carried out from Jan 2010 to Dec 2014. Study group consisted of consecutive drug naive patients of TBM, diagnosed on basis of criteria laid by Ahuja et al. [12] which were slightly modified to include nucleic acid based CSF tests. The patients were included if they met the inclusion and exclusion criteria given below. Written informed consent was obtained from all the patients or their relatives (if patient was in altered sensorium or a

Statistical analysis

The data was entered in SPSS version 20 for analysis. The continuous variables were expressed as mean and median. Chi square test was used to compare difference between two groups (cases and controls). For comparing continuous variables, Mann Whitney test and Kruskal Wallis test was used. Linear regression analysis was used to compare CSF and serum cytokines with various CSF parameters. Two tailed p value of < 0.05, < 0.01 and < 0.001 were taken as significant, highly significant and very highly

Demographic and clinical data

Current study included 146 patients of TBM and 99 age and sex matched healthy volunteers. 90 (61.4%) (Culture based-39; PCR based-51) patients were classified as definitive TBM, while 56 (38.6%) patients were classified as highly probable TBM. The mean ± SD age of TBM patients was 31.8 ± 15.01 years (range: 13–69 years) in study group and 32.73 ± 17 years in control group. There were 78 (53.4%) men and 48 (46.6%) women in the study group and 54 (55.5%) men and 45 (44.5%) women in control group. 26

Discussion

The immunopathogenesis of TBM is poorly understood. A critical event in the pathogenesis of TBM is a T-cell mediated inflammatory reaction induced by the mycobacteria. Subsequent clinical picture and course of disease are determined, at least in part, by the severity of inflammatory response and resultant exudates in various CSF spaces leading to complications such as adhesions, hydrocephalus and obliterative vasculitis etc. Proinflammatory cytokines play an important role in exacerbation and

Conclusion

To conclude, proinflammatory cytokines play a highly significant role in pathogenesis of TBM. A more exuberant cytokine response is associated with poor outcome in TBM. Future studies employing serial measures of cytokines in serum and CSF as well as studies using treatment protocols based on cytokine inhibitor drugs may help further in clearing their role in pathogenesis of TBM.

The main strength of our study was a large sample size as well as adherence to a uniform protocol wherein all the

Funding sources

This research was funded supported by ICMR (Indian Council of Medical Research) (Sanction No. 5/4-5/14/Neuro/2009-NCD-I).

Acknowledgements

None.

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