Novel Methods of Investigating Disease Mechanisms and Treatment in Children with Tuberculous Meningitis

Tuberculous meningitis (TBM) is the most severe form of tuberculosis and accounts for substantial neurological disability and loss of life in affected children. The infection initiates secondary cerebral injury mechanisms that worsen outcome. Our understanding of these mechanisms is poor because our clinical and research methods are limited. To date, studies of these injury mechanisms have relied on proxy measures, sampling from remote sites, and single-point-in-time methods, usually relying on spinal cerebrospinal fluid (CSF) samples. Our previous work has shown considerable differences exist between spinal and brain CSF but analysis of high frequency samples directly from the brain has not been possible. Recently, we developed a novel method that addresses these limitations, by accessing brain CSF and enabling serial sampling to examine dynamic molecular changes and drug kinetics. In vitro and in vivo results have demonstrated safety and feasibility, enabling a foundation for novel mechanistic brain research that is scalable beyond our primary research questions. Leveraging opportunities from standard clinical procedures, we aim to recruit children with TBM to perform, for the first time, high frequency serial sampling directly from the brain to interrogate the cerebral metabolome, neuroimmunology, and neuropharmacokinetics in humans.