Tuberculous meningitis: where to from here?

Abstract

Purpose of review: Tuberculous meningitis (TBM) is associated with significant mortality and morbidity yet is difficult to diagnose and treat. We reviewed original research published in the last 2 years, since 1 January 2018, which we considered to have a major impact in advancing diagnosis, treatment and understanding of the pathophysiology of TBM meningitis in children and adults.

Recent findings: Studies have sought to identify a high sensitivity diagnostic test for TBM, with new data on modified Ziehl--Neelsen staining, urinary and cerebrospinal fluid (CSF) lipoarabinomannan and GeneXpert Ultra. Recent studies on CSF biomarkers provide a better understanding of the detrimental inflammatory cascade and neuromarkers of brain damage and suggest potential for novel host-directed therapy. Tryptophan metabolism appears to affect outcome and requires further study. Increased clinical trials activity in TBM focuses on optimizing antituberculosis drug regimens and adjuvant therapy; however, there are few planned paediatric trials.

Summary: Tuberculous meningitis still kills or disables around half of sufferers. Although some progress has been made, there remains a need for more sensitive diagnostic tests, better drug therapy, improved management of complications and understanding of host-directed therapy if outcomes are to improve.

Box 1

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FIGURE 1

Overview of the pathophysiology of tuberculosis meningitis^∗. Mortality of TBM is attributed to Mycobacterium tuberculosis and its interaction with the host immune response. Once M. tuberculosis enters the brain or meninges, a detrimental immunoinflammatory response including inflammatory cytokines, proteases, lipid mediators, neuromarkers and tryptophan metabolites, is triggered [–6]. This leads to the cerebral disorder and complications known to occur in TBM. Knowledge gaps exist in the mechanism of bacterial invasion into the CNS and the underlying biologic pathways (dotted arrows) leading to the disease process. CSF, cerebrospinal fluid; GFAP, glial fibrillary acidic protein; HIV, human immunodeficiency virus; ICP, intracranial pressure; IFN, interferon; IL, interleukin; LT, leukotriene; Lx, lipoxins; MDR, multidrug-resistant; MMP, matrix metalloproteinases; NSE, neuron-specific enolase; PG, prostaglandin; TB, tuberculosis; TIMP, tissue inhibitor of matrix metalloproteinases; TNF, tumour necrosis factor; Tx, thromboxane; VEGF, vascular endothelial growth factor; XDR, extensively drug-resistant. Adapted from Thwaites and Tran [27]. Figure references [,,^▪▪,–27].