Tuberculous Meningitis
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REVIEWS INFECTIONS OF THE CNS Tuberculous meningitis Robert J. Wilkinson1–3, Ursula Rohlwink4, Usha Kant Misra5, Reinout van Crevel6, Nguyen Thi Hoang Mai7, Kelly E. Dooley8, Maxine Caws9, Anthony Figaji4, Rada Savic10, Regan Solomons11 and Guy E. Thwaites7,12 on behalf of the Tuberculous Meningitis International Research Consortium 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. Extrapulmonary The absolute incidence of tuberculous meningitis a mortality of 19.3%, suggesting that several thousand 6 Tuberculosis occurring outside (TBM) and the overall proportion of meningitis cases very young children die of TBM every year . The neona‑ the lungs. that are attributable to TBM vary greatly by location, tal Bacillus Calmette–Guérin (BCG) vaccine is thought and are influenced by the overall incidence of tubercu‑ to be 73% effective in the prevention of TBM, and its use losis, age structure, and HIV‑1 seroprevalence within a is estimated to avert 30,000 childhood cases of the dis‑ popu lation. Population‑based estimates of TBM inci‑ ease annually3, consistent with the occurrence of around dence are infrequently reported, and are challenging to 100,000 cases of TBM per year overall. determine because the diagnosis of TBM is often not In adults, the best‑documented risk factor for TBM microbiologically confirmed. In 2013, a 7‑year national is HIV‑1 co‑infection. Among HIV‑infected individuals study conducted in Germany documented that 422 of who live in areas where tuberculosis is highly endemic, 46,349 (0.9%) patients with tuberculosis had meningitis, the proportion of HIV‑1‑associated meningitis cases with an increased risk of TBM in children younger than attributable to Mycobacterium tuberculosis can exceed 5 years of age (OR 4.90)1. This predisposition towards 50%7. In addition, in an autopsy study conducted in TBM in young children is commonly reported2,3. In 2015, Kenya, occult, undiagnosed TBM was found in 26% an estimated 10.4 million cases of tuberculosis occurred of individuals with disseminated HIV‑tuberculosis8. globally, and of 6.1 million incident cases reported, 15% Individuals with TBM and a HIV‑1 co‑infection have were extrapulmonary4. A large Brazilian study of 57,217 a twofold to threefold increase in relative risk of death cases of extrapulmonary tuberculosis estimated that from any cause9,10, with overall mortality around 40%, 7 Oxford University Clinical meningitis accounted for 6% of extrapulmonary pres‑ even in those individuals prescribed antiretroviral ther‑ Research Unit, 5 7,10 764 Vo Van Kiet, Quan 5, entations . A diagnosis of TBM is difficult to ascertain, apy . Drug‑resistant TBM in people co‑infected with Ho Chi Minh City, Vietnam. so the disease might be underreported, but extrapolation HIV‑1 has a particularly poor prognosis, approaching [email protected] suggests that the global burden of TBM could be at least 100% mortality11. doi:10.1038/nrneurol.2017.120 100,000 cases per year. A systematic review of treat‑ This Review capitalizes on knowledge shared in spe‑ Published online 8 Sep 2017 ment outcomes in 1,636 children with TBM estimated cialist meetings held in 2009 and 2015 to summarize NATURE REVIEWS | NEUROLOGY VOLUME 13 | OCTOBER 2017 | 581 ©2017 Mac millan Publishers Li mited, part of Spri nger Nature. All ri ghts reserved. REVIEWS Key points and McCordock produced what are now regarded as the definitive accounts of the extension of tuberculosis infec‑ • Tuberculous meningitis (TBM) causes death and disability, with especially high rates of tion to the meninges12. They showed that although TBM poor outcomes in children and individuals with an HIV‑1 co‑infection might occur as part of disseminated disease, only a single • Important risk factors for poor outcome are delayed diagnosis, delayed treatment, meningeal or parameningeal granuloma (now termed advanced disease, and antitubercular drug resistance the Rich focus) was usually found at autopsy and, thus, the • Intracerebral and spinal pathology in TBM is mediated by a dysregulated point of entry of bacilli into the cerebrospinal fluid (CSF) inflammatory response that contributes to meningitis, tuberculoma formation, could be located. Rupture of that focus was postulated to arteritis, obstruction of cerebrospinal fluid (CSF) flow, and vascular complications lead to further extension of inflammation throughout the including stroke meninges, leading to parenchymal tuberculoma formation • Diagnosis of TBM is insensitive and laborious; clinical scoring algorithms are or to vascular pathology characteristic of the disease. imperfect and few rigorous evaluations of diagnostics have been performed Ischaemia caused by vascular occlusion owing to inflam‑ • Multidrug antitubercular antibiotic therapy is the mainstay of treatment; however, mation both within and around vessels is compounded CSF penetration is probably a major limitation of these therapies, and evidence by raised intracranial pressure and hydrocephalus (espe‑ supporting dosage and treatment combinations is weak cially in children, in whom hydrocephalus is nearly invari‑ • The supportive management of TBM complications, which include hyponatraemia, able13), which can, in turn, compress or cause traction on hydrocephalus, hypoxic brain damage and infarction, is poorly understood and already inflamed vessels (FIG. 1). researched, but is vital to outcome Historically, the most widely used animal model of TBM consisted of rabbits infected via intracisternal inoculation of M. tuberculosis, resulting in histologi‑ historical and current research into TBM, and identifies cal, pathological and neurological features consistent key gaps in our comprehension of the disease. We will with TBM14. However, haematogenous spread cannot discuss current progress in our understanding of inflam‑ be investigated in this experimental setting and, thus, a mation in TBM and its potential modulation; vascular detailed understanding of pathogenesis — which should Miliary and hypoxia‑mediated tissue injury; the role of intensi‑ include CNS invasion — cannot be achieved using this Disseminated micronodular tuberculosis of the lungs. fied antibiotic treatment; and the importance of rapid model. Zebrafish have also been used to model TBM: and accurate diagnostics and supportive care in TBM. Mycobacterium marinum infection of zebrafish via the Rich focus bloodstream resulted in infection of the CNS and devel‑ The initial intracranial lesion of Pathogenesis opment of associated granulomas in 70% of the fish, with tuberculous meningitis, as described by Arnold Rich. Macroscopic pathology. Transmission of M. tubercu- CNS granulomas typically located in close proximity to losis is airborne and, consequently, the first focus of blood vessels15. Infection with a mutant M. marinum Tuberculoma infection is the lung. Following initial bacterial replica‑ lacking the homologue of EsxA, a gene associated with A clinical manifestation of tion, the infection disseminates to the lymph nodes. For M. tuberculosis virulence, resulted in substantial changes tuberculosis in which tubercles miliary and extrapulmonary presentations of the disease, in pathology without affecting the ability of the bacte‑ comglomerate into a firm lump, and so can mimic cancer dissemination of tuberculosis bacilli must then occur ria to penetrate the blood–brain barrier. High bacterial tumours of many types in through the blood, either via direct extension of local loads were observed, but no granulomas developed, medical imaging studies. infection or via lymph nodes. In the 1930s and 1940s, Rich and only small clusters and scattered isolated phago‑ cytes were detected, indicating that EsxA contributes to pathogenesis in this system. Author addresses In the context of disseminated childhood tuberculo‑ sis, the concept of the Rich focus has been re‑evaluated16. 1Department of Medicine, Imperial College London, Norfolk Place, London W2 1PG, UK. Specifically, although TBM can occur when a long- 2 The Francis Crick Institute, Midland Road, London NW1 2AT, UK. standing Rich focus bursts and discharges its contents 3 Wellcome