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Tuberculous meningitis

Key Points

  • Tuberculous meningitis (TBM) causes death and disability, with especially high rates of poor outcomes in children and individuals with an HIV-1 co-infection

  • Important risk factors for poor outcome are delayed diagnosis, delayed treatment, advanced disease, and antitubercular drug resistance

  • Intracerebral and spinal pathology in TBM is mediated by a dysregulated inflammatory response that contributes to meningitis, tuberculoma formation, arteritis, obstruction of cerebrospinal fluid (CSF) flow, and vascular complications including stroke

  • Diagnosis of TBM is insensitive and laborious; clinical scoring algorithms are imperfect and few rigorous evaluations of diagnostics have been performed

  • Multidrug antitubercular antibiotic therapy is the mainstay of treatment; however, CSF penetration is probably a major limitation of these therapies, and evidence supporting dosage and treatment combinations is weak

  • The supportive management of TBM complications, which include hyponatraemia, hydrocephalus, hypoxic brain damage and infarction, is poorly understood and researched, but is vital to outcome

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.

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Figure 1: Pathogenesis of tuberculous meningitis.
Figure 2: MRI scans from a patient with stage II tuberculous meningitis.

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Acknowledgements

Tuberculous Meningitis International Research Consortium members include: Rob Aarnoutse, Reinout Van Crevel, Aarjan van Laarhoven, Sofiati Dian (Radboud University Nijmegen Medical Center, Nijmegen, The Netherlands); Nathan C. Bahr (University of Kansas Medical Center, Kansas City, USA); David R. Boulware (University of Minnesota, Minneapolis, USA); Maxine Caws (Liverpool School of Tropical Medicine, Liverpool, UK); Mark R. Cronan, David Tobin (Duke University School of Medicine, Durham, USA); Kelly Dooley (Johns Hopkins University School of Medicine, Baltimore, USA); Sarah Dunstan (University of Melbourne, Melbourne, Australia); Guo-dong Feng, Xiaodan Shi, Ting Wang (Fourth Military Medical University, Xi'an, People's Republic of China); Anthony Figaji, Suzaan Marais, Helen McIlleron, Graeme Meintjes, Ursula Rohlwink (University of Cape Town, Cape Town, South Africa); Ahmad Rizal, Rovina Ruslami (Padjadjaran University, Bandung, Indonesia); Ravindra K. Garg (King George Medical University, Lucknow, India); Mudit Gupta, Rakesh K. Gupta (Fortis Memorial Research Institute, Gurgaon, India); Sneha Gupta, Rada Savic (University of California, San Francisco, USA); Anna D. Heemskerk, Thuong Thuy Thuong Nguyễn, Mai Thi Hoàng Nguyễn, Vijay Srinivasan, Guy Thwaites, Trâm Thi Bích Trân, Thinh Thi Vân Trân, Anh Thi Ngoc Trân, Trang Hồng Yêng Võ, Marcel Wolbers (Oxford University Clinical Research Unit, Ho Chi Minh City, Vietnam); Jayantee Kalita, Usha K. Misra (Sanjay Gandhi Postgraduate Institute of Medical Sciences, Lucknow, India); Rachel Lai (The Francis Crick Institute, London, UK); Ben J. Marais, Mai Quỳnh Trinh (University of Sydney, Sydney, Australia); Bằng Đức Nguyễn, Yến Bích Nguyễn (Pham Ngoc Thach Hospital for Tuberculosis & Lung Diseases, Ho Chi Minh City, Vietnam); Vinod Patel (University of KwaZulu-Natal, Durban, South Africa); Thomas Pouplin (Mahidol-Oxford Tropical Medicine Research Unit, Bangkok, Thailand); Lalita Ramakrishnan (University of Cambridge, Cambridge, UK); Johan F. Schoeman, Regan Solomons, Ronald Van Toorn (University of Stellenbosch, Cape Town, South Africa); James Seddon (Imperial College, London, UK); Javeed Shah (University of Washington, Washington, USA); Jaya S. Tyagi (All India 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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R.J.W, U.R., U.K.M., R.v.C., N.T.H.M., K.E.D., M.C., A.F., and G.T. researched data for the article, R.J.W, U.R., U.K.M., R.v.C., K.E.D., M.C., A.F., R. Savic, R. Solomons, and G.T made a substantial contribution to discussion of content, R.J.W., U.R., U.K.M., R.v.C., wrote the article, and all authors contributed to the review and editing of the manuscript before submission.

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Correspondence to Guy E. Thwaites.

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Glossary

Extrapulmonary

Tuberculosis occurring outside the lungs.

Miliary

Disseminated micronodular tuberculosis of the lungs.

Rich focus

The initial intracranial lesion of tuberculous meningitis, as described by Arnold Rich.

Tuberculoma

A clinical manifestation of tuberculosis in which tubercles comglomerate into a firm lump, and so can mimic cancer tumours of many types in medical imaging studies.

Basal exudates

An inflammatory reaction to tuberculosis in the basal cisterns of the brain.

Paradoxical worsening

The worsening of a tuberculosis lesion during otherwise effective antirtubercular or antiretroviral therapy.

Ziehl–Neelsen staining

A technique to visualize Mycobacterium tuberculosis directly by microscopy in pathological samples.

Paucibacillary

Disease associated with very low numbers of bacteria in clinical specimens.

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Wilkinson, R., Rohlwink, U., Misra, U. et al. Tuberculous meningitis. Nat Rev Neurol 13, 581–598 (2017). https://doi.org/10.1038/nrneurol.2017.120

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