Approximately 30% of people with tuberculous meningitis (TBM) die despite modem treatment. Survival is dependent upon early treatment but diagnosis is difficult: the clinical features are non-specific, conventional bacteriology is widely regarded as insensitive, and newer diagnostic tests are incompletely evaluated. In addition, the pathogenesis of TBM remains so poorly understood that prospects for new interventions to improve outcome are few. This thesis examines the diagnosis and pathophysiology of TBM in adults admitted to an infectious disease hospital in Ho Chi Minh City, Vietnam. The aim was to address three questions: what is the best method for distinguishing TBM from other central nervous system disorders, how does disease pathophysiology relate to treatment and clinical outcome, and what other variables influence prognosis? Three methods for the diagnosis of TBM were studied: clinical, bacteriological and molecular. A diagnostic rule developed from five clinical features predictive of TBM was 86% sensitive and 79% specific when applied prospectively. A bacteriological diagnosis of TBM was confirmed in 107/132 (81%) adults: acid-fast bacilli were seen in 58% and cultured from 71%. Volume of CSF, duration of symptoms, CSF neutrophils, lactate and glucose all predicted bacteriological confirmation. The sensitivity and specificity of CSF Ziehl-Neelsen stain (52% and 100%) was greater than nucleic acid amplification (Gen-Probe Amplified Mycobacterium tuberculosis Direct test) (38% and 9 9%), although the combined performance of these tests on serial samples detected 83% of cases. The pathogenesis of TBM was investigated by identifying clinical and molecular markers of poor outcome. Treatment before the onset of coma independently predicted survival, and death was associated with high CSF concentrations of lactate, low numbers of white cells, in particular neutrophils, and low CSF glucose. CSF lactate concentration is a good indicator of disease severity and CSF bacterial load, and neutrophils may have a hitherto unreported protective role
