Tuberculous meningitis

Abstract

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.

Can improved diagnostics reduce mortality from Tuberculous meningitis? Findings from a 6.5-year cohort in Uganda

“…Here we report clinical outcomes among hospitalized Ugandans treated for TB meningitis over a 6.5-year period. In-hospital mortality was high in the cohort overall (44%), similar to other research settings with high HIV prevalence 7, 19, 22, 23 . The adjusted model on imputed data found odds of in-hospital mortality were almost two fold higher in the earliest cohort, tested by CSF smear microscopy only, than that of that of the most recent cohort in whom Xpert (and culture) are routinely performed.…”

“…Initiating treatment in the early stage of disease is the single most important factor in improving outcomes 7 . Earlier presentation to the hospital is essential for prompt diagnosis and treatment initiation, yet, 83% of our cohort presented with MRC grade II or III disease.…”

“…Insidious symptom onset in persons with TBM leads to delay in seeking care and increasing disease severity at presentation correlates with higher mortality 7 . Further, the paucibacillary nature of TBM increases the difficulty in confirming diagnosis once care is sought, also contributing to high mortality 8 .…”

“…Further, the paucibacillary nature of TBM increases the difficulty in confirming diagnosis once care is sought, also contributing to high mortality 8 . Cerebrospinal fluid (CSF) smear microscopy for acid-fast bacilli (AFB smear) has poor sensitivity (~10–20%) in routine practice 7 . Culture has improved sensitivity (~50–60%) but is not widely available in many resource constrained settings and commonly takes at least 2–3 weeks for liquid culture growth, which is too slow to guide decision-making at the time of presentation 8 .…”

Mycobacteria employ two different mechanisms to cross the blood-brain barrier

“…Invasion of Mycobacterium tuberculosis , the causative agent of TB, into the central nervous system (CNS) occurs in 1% of all cases (Thwaites, van Toorn, & Schoeman, 2013; Wilkinson et al, 2017). Major risk groups for developing TBM include young children and HIV‐positive individuals in TB endemic areas (van Well et al, 2009; Wilkinson et al, 2017). Despite extensive research efforts, the diagnosis and treatment of TBM is often delayed because of its insidious onset (Wilkinson et al, 2017).…”