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1Department of Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA

2Division of Pulmonary Sciences and Critical Care Medicine, University of Colorado Denver Anschutz Medical Campus, Aurora, CO 80045, USA

3Denver Veterans Affairs Medical Center, Denver, CO 80220-3808, USA

4Department of Medicine, National Jewish Health, Denver, CO 80206, USA

5Program in Cell Biology, National Jewish Health, Denver, CO 80206, USA

Received 3 September 2011; Revised 16 November 2011; Accepted 18 November 2011

Academic Editor: Carlo Garzelli

Copyright © 2011 Grace E. MARX and Edward D. Chan. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

Abstract

Tuberculous meningitis (TBM) is the most common form of central nervous system tuberculosis (TB) and has very high morbidity and mortality. TBM is typically a subacute disease with symptoms that may persist for weeks before diagnosis. Characteristic cerebrospinal fluid (CSF) findings of TBM include a lymphocytic-predominant pleiocytosis, elevated protein, and low glucose. CSF acid-fast smear and culture have relatively low sensitivity but yield is increased with multiple, large volume samples. Nucleic acid amplification of the CSF by PCR is highly specific but suboptimal sensitivity precludes ruling out TBM with a negative test. Treatment for TBM should be initiated as soon as clinical suspicion is supported by initial CSF studies. Empiric treatment should include at least four first-line drugs, preferably isoniazid, rifampin, pyrazinamide, and streptomycin or ethambutol; the role of fluoroquinolones remains to be determined. Adjunctive treatment with corticosteroids has been shown to improve mortality with TBM. In HIV-positive individuals with TBM, important treatment considerations include drug INTERACTIONS, development of immune reconstitution inflammatory syndrome, unclear benefit of adjunctive corticosteroids, and higher rates of drug-resistant TB. Testing the efficacy of second-line and new anti-TB drugs in ANIMAL models of experimental TBM is needed to help determine the optimal regimen for drug-resistant TB.

1. Introduction

Tuberculous meningitis (TBM) is caused by Mycobacterium tuberculosis (M. tuberculosis) and is the most common form of central nervous system (CNS) tuberculosis (TB). TBM is associated with a high frequency of neurologic sequelae and mortality if not treated promptly [1–5]. TBM is rare in developed countries with about 100 to 150 cases occurring annually in the US, less than 3% of the estimated 4,100 annual cases of bacterial meningitis [6, 7]. The disease occurs when subependymal or subpial tubercles, also known as “Rich foci” seeded during bacillemia of primary infection or disseminated disease, rupture into the subarachnoid space [8]. Individuals with increased risk for TBM include young children with primary TB and patients with immunodeficiency caused by aging, malnutrition, or disorders such as HIV and cancer [9, 10]. The use of antitumor necrosis factor-alpha (TNFα) neutralizing antibody has also been associated with increased risk of extrapulmonary TB including TBM [11]. Most have no known history of TB, but evidence of extrameningeal disease (e.g., pulmonary) can be found in about half of patients [3, 4]. The tuberculin skin test is positive in only about 50% of patients with TBM. In low TB prevalence areas, TBM is most commonly seen with reactivation TB.