Abstract
ObjectivesTuberculous 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.MethodsWe 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.ResultsWe 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).ConclusionOur 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.
Highlights
Tuberculous meningitis is the most lethal form of tuberculosis (TB), affecting about 1% of all people with TB [1]
matrix metalloproteinase 9 (MMP9) levels significantly correlated with cerebrospinal fluid (CSF) glucose levels and admission Glasgow coma scale score
The present study has several strengths—first, it was larger than previous studies, with sufficient number of patients in good as well as poor outcome groups; second, we studied the clinically relevant outcome of survival without neurological disability, and two observers independently scored the disability before estimating MMP9/TIMP1 levels to eliminate bias; third, we followed the recently proposed international consensus case-definition, in order to minimize difficulties in diagnosing tuberculous meningitis; and we studied the relationship between MMP9 levels and blood-brain barrier (BBB) permeability
Summary
Tuberculous meningitis is the most lethal form of tuberculosis (TB), affecting about 1% of all people with TB [1]. About 40% of adults with tuberculous meningitis succumb to the disease despite early treatment with standard anti-TB treatment and corticosteroids [2]. Intensified anti-TB treatment did not reduce the mortality in a recent clinical trial on adults with tuberculous meningitis [3]. There is a pressing need to develop host-directed therapies to improve treatment outcome in tuberculous meningitis. The role of matrix metalloproteinases (MMPs) in the pathogenesis of TB has generated considerable interest [4,5]. MMP9 plays an important role in macrophage recruitment, and destruction of extracellular matrix by MMPs could damage the blood-brain barrier (BBB) in patients with tuberculous meningitis [6,7]. MMP9 has been proposed as a potential therapeutic target in TB [4,5,6,7,8]
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