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 a, macrophage inflammatory protein 1 alpha, 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.