Tuberculosis remains a global health problem, with an estimated 10.4 million cases and 1.8 million deaths resulting from the disease in 2015. The most lethal and disabling form of tuberculosis is tuberculous meningitis (TBM), for which more than 100,000 new cases are estimated to occur per year. In patients who are co-infected with HIV-1, TBM has a mortality approaching 50%. Study of TBM pathogenesis is hampered by a lack of experimental models that recapitulate all the features of the human disease. Diagnosis of TBM is often delayed by the insensitive and lengthy culture technique required for disease confirmation. Antibiotic regimens for TBM are based on those used to treat pulmonary tuberculosis, which probably results in suboptimal drug levels in the cerebrospinal fluid, owing to poor blood-brain barrier penetrance. The role of adjunctive anti-inflammatory, host-directed therapies-including corticosteroids, aspirin and thalidomide-has not been extensively explored. To address this deficit, two expert meetings were held in 2009 and 2015 to share findings and define research priorities. This Review summarizes historical and current research into TBM and identifies important gaps in our knowledge. We will discuss advances in the understanding of inflammation in TBM and its potential modulation; vascular and hypoxia-mediated tissue injury; the role of intensified antibiotic treatment; and the importance of rapid and accurate diagnostics and supportive care in TBM.
Bibliographical noteFunding Information:
Institute of Medical Sciences, New Delhi, India); Douwe H. Visser (VU University Medical Center, Amsterdam, The Netherlands); Robert J. Wilkinson (Imperial College and The Francis Crick Institute, London, UK and University of Cape Town, South Africa). R.J.W. is supported by the Francis Crick Institute, which receives its core funding from Cancer Research UK (FC00110218), the UK Medical Research Council (FC00110218), and the Wellcome Trust (FC00110218). He also receives support from the Wellcome Trust (104803, 203135) and the National Research Foundation Of South Africa (96841). G.T. is supported by the Wellcome Trust through a Major Overseas Programme grant (106680/Z/14/Z) and an Investigator Award (110179/Z/15/Z).
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