A pilot study of inflammatory mediators in brain extracellular fluid in paediatric TBM

Abstract

Tuberculous meningitis (TBM) is the most fatal form of tuberculosis and frequently occurs in children. The inflammatory process initiates secondary brain injury processes that lead to death and disability. Much remains unknown about this cerebral inflammatory process, largely because of the difficulty in studying the brain. To date, studies have typically examined samples from sites distal to the site of disease, such as spinal cerebrospinal fluid (CSF) and blood. In this pilot study, we examined the feasibility of using direct brain microdialysis (MD) to detect inflammatory mediators in brain extracellular fluid (ECF) in TBM. MD was used to help guide neurocritical care in 7 comatose children with TBM by monitoring brain chemistry for up to 4 days. Remnant ECF fluid was stored for offline analysis. Samples of ventricular CSF, lumbar CSF and blood were collected at clinically indicated procedures for comparison. Inflammatory mediators were quantified using multiplex technology. All inflammatory markers, with the exception of interleukin (IL)-10 and IL-12p40, were detected in the ECF. Cytokine concentrations were generally lower in ECF than ventricular CSF in time-linked specimens. Individual cases showed ECF cytokine increases coinciding with marked increases in ECF glycerol or decreases in ECF glucose. Cytokine levels and glycerol were generally higher in patients with more severe disease. This is the first report of inflammatory marker analysis from samples derived directly from the brain and in high temporal resolution, demonstrating feasibility of cerebral MD to explore disease progression and possibly therapy response in TBM.

Recent advances in understanding the human host immune response in tuberculous meningitis

“…Several limitations to existing data, and future challenges in TBM research exist. In a small brain microdialysis study in paediatric TBM, brain extracellular fluid (ECF) cytokine levels were lower than ventricular CSF, which were in turn lower than lumbar CSF ( 133 ). In addition, Rohlwink et al.…”

An integrated cytokine and kynurenine network as the basis of neuroimmune communication

“…However, levels of cytokines in the tissues and organs can be highly variable. A cytokine panel used in patients with tuberculous meningitis indicated that all (except IL-10) were present in brain at levels lower than in CSF ( Loxton et al, 2021 ), while a panel of 36 cytokines used by Lepennetier et al (2019) exhibited little correlation between serum and CSF levels in a variety of neurological disorders. Similarly, measurements of TNF, IFN-γ, IL-6, IL-8, and IL-10 revealed no correlation between plasma and CSF levels ( Ellison et al, 2005 ), and a meta-analysis of patients with MDD found no relationships between IL-6 or TNF levels in blood and CSF or with PET-scan markers of inflammation ( Enache et al, 2019 ).…”