J Neurol Neurosurg Psychiatry 2000;68:289–299 289 J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.3.289 on 1 March 2000. Downloaded from NEUROLOGICAL ASPECTS OF TROPICAL DISEASE Tuberculous meningitis G Thwaites, T T H Chau, N T H Mai, F Drobniewski, K McAdam, J Farrar Uncertainty and doubt dominate all aspects of infection is under debate.11 Certain ethnic tuberculous meningitis (TBM). The variable groups seem to be more susceptible to M natural history and accompanying clinical fea- tuberculosis than others. Studies using tubercu- tures of TBM hinders the diagnosis. Ziehl- lin conversion as a surrogate marker suggest Neelsen staining lacks sensitivity and culture that black skinned people are more susceptible results are often insuYciently timely to aid to infection than white people.12 Recently it has clinical judgement. New rapid diagnostic been proposed that certain polymorphisms in methods are incompletely evaluated, and many the human NRAMP1 gene may aVect suscep- are not suitable for laboratories in low income tibility to pulmonary tuberculosis in West countries. The duration of chemotherapy for Africans.13 Whether genetic factors influence TBM is unclear and the benefits of adjuvant prevalence of TBM within a population is corticosteroids remain in doubt. The only unknown. uncomfortable certainties lie in the fatal conse- The extent to which BCG vaccination Department of Microbiology, St quences of missed diagnoses and delayed treat- aVords protection against TBM is still debated. Thomas’s Hospital, ment. A meta-analysis of the published trials on the London UK This review will discuss the current uncer- eYcacy of BCG vaccination suggested a G Thwaites tainties surrounding TBM. More attention will protective eVect of 64% against TBM.14 This be given to diagnosis and management, as figure is higher than that suggested for pulmo- Centre for Tropical these areas have a direct bearing on patient nary TB (50%), but may only reflect more Diseases, 190 Ben Ham Tu, Quan 5 Ho Chi outcome. accurate case ascertainment of TBM given the Minh City Viet Nam universal requirement for admission to hospi- T T H Chau tal. Overall, these and other studies support the NTHMai Epidemiology About 2000 million people in the world today view that BCG vaccination is protective against are infected with tuberculosis,1 but only 10% TBM. PHLS Mycobacterium Close correlation exists between the ob- Reference Unit, King’s develop clinical disease. Why some people College School of develop clinical disease remains unclear. The served incidence of TBM in children aged 0–4 Medicine, London UK reasons are likely to be multifactorial: inherent years, and the population’s annual average risk http://jnnp.bmj.com/ F Drobniewski not just to the individual person, but to their of infection with M tuberculosis. The incidence of TBM has been calculated to represent 1% of Medical Research given population and environment. 15 Before HIV the most important determinant the annual risk of infection. Risk of infection Council Laboratories depends on the prevalence of infectious cases Banjul The Gambia for the development of TBM was age. In K McAdam populations with high TB prevalence TBM in a given community. Prevalence of infectious diVers from pulmonary, and other extra- cases is dependant not only on the risks perti- Wellcome Trust pulmonary tuberculosis, in that the peak age is nent to each person for developing disease, but Clinical Research 2 to the factors inherent in the community on October 2, 2021 by guest. Protected copyright. Unit, Centre for from 0–4 years. In populations with lower TB prevalence, most cases of TBM are in adults. encouraging spread of infection. The main rea- Tropical Diseases, Ho son for the spread of tuberculosis is poverty, Chi Minh City, Viet Risk factors identified for these people are Nam alcoholism, diabetes mellitus, malignancy, and with resulting homelessness, malnutrition, and G Thwaites recent corticosteroid use.3–5 Coinfection with breakdown of public health infrastructure. J Farrar HIV now dwarfs these risk factors. HIV The total number of tuberculosis cases in the world is increasing.16 17 It is estimated that most Centre for Tropical increases the lifetime risk of developing clinical 16 TB postinfection to 1 in 3.6 HIV also of these new cases will be in south east Asia Medicine, NuYeld fuelled by the rapid spread of HIV. It has been Department of predisposes to the development of extra- Medicine, University 7 predicted that without intervention 200 million pulmonary TB, and in particular TBM, a risk 1 of Oxford, UK which increases as the CD4 count declines.8 people alive today will develop TB. The physi- J Farrar The disease constitutes either reactivation of cian needs to be aware of these changes, as less latent infection, or new infection. Evidence common forms of tuberculosis such as TBM Correspondence to: will be encountered more often. Dr Guy Thwaites, from DNA fingerprinting of strains using Department of Microbiology, restriction fragment length polymorphism St Thomas’s Hospital, London SE1 7EH, UK suggests that in the United States up to 40% of Causative agent email Guy.Thwaites@ new disease in both HIV positive and non- HIV Tuberculous meningitis was first described as a gstt.sthames.nhs.uk patients is due to recent infection.910 distinct pathological entity in 1836,18 and Rob- Received 4 October 1999 The extent to which a person’s genetic con- ert Koch demonstrated that tuberculosis was Accepted 11 October 1999 stitution eVects resistance or susceptibility to caused by Mycobacterium tuberculosis in 1882.19 290 Thwaites, Chau, Mai, et al J Neurol Neurosurg Psychiatry: first published as 10.1136/jnnp.68.3.289 on 1 March 2000. Downloaded from M tuberculosis is an aerobic gram positive rod tuberculous bacteraemia. Dissemination to the that stains poorly due to its thick cell wall con- CNS is more likely, particularly if miliary TB taining lipids, peptidoglycans, and arabi- develops. nomannans. The Ziehl-Neelsen stain uses the The second step in the development of TBM properties of the cell wall to form a complex is rupture of a Rich focus into the subarachnoid that prevents decolourisation by acid or space. This heralds the onset of meningitis, alcohol.20 which if left untreated, will result in severe and The characteristics of M tuberculosis enabling irreversible neurological pathology. In 75% of it to cause disease are complex and incom- children the onset of TBM is less than 12 pletely understood. It is accepted that those months after the primary infection.29 with active pulmonary infection vary consider- Three general processes produce the subse- ably in their ability to transmit the disease to quent neurological pathology: adhesion forma- others.21 Part of the variability is explained by tion, an obliterative vasculitis, and an encepha- diVerences in environment, infectious burden, litis or myelitis.30 Adhesions result from a dense and host immunity. Experimental evidence basal meningeal exudate that develops after suggests that the virulence of individual strains inoculation of bacilli into the subarachnoid is also significant, and selected gene mutations space. The exudate contains lymphocytes, have been shown to aVect virulence.22 23 plasma cells, and macrophages, with increasing Whether there are stains which cause more quantities of fibrin. Blockage, through adhe- disease of the CNS is not known. The sion formation, of the basal subarachnoid predominance of one strain typed using cisterns can result in obstruction of the CSF restriction fragment length polymorphism has and hydrocephalus. Adhesions around the been reported from a series of patients with M interpendicular fossa and related structures tuberculosis,24 however the mechanisms by can compromise cranial nerves, particularly II, which neurovirulence may occur is unknown. IV, and VI, and the internal carotid artery. An As the contribution of strain variation and obliterative vasculitis of both large and small virulence becomes more apparent, so tech- vessels develops that can result in infarction niques are developing to determine the genetic and stroke syndromes. These commonly occur components of mycobacterial virulence. in the territories of the internal carotid, “Molecular” Koch’s postulates have been proximal middle cerebral, and the perforating applied to advance a hypothesis for a single vessels to the basal ganglia.31 Infarction gene basis for a virulent phenotype. The through vasculitis is the mechanism by which phenotype is analogous to the disease, the gene many of the diverse clinical neurological analogous to the organism.25 Only a few abnormalities in TBM occur, and accounts for virulence genes have currently satisfied these an appreciable part of the irreversible neuro- methods.26 The recent determination of the logical sequelae. The intensity of the basal complete genomic sequence for M tuberculosis inflammatory process extends into the paren- should expand our understanding in this area.27 chyma resulting in encephalitis. Oedema oc- curring as a consequence can be marked throughout both hemispheres. This will con- Pathogenesis tribute to rising intracranial pressure and the A discussion on the pathogenesis of tubercu- global clinical neurological deficit. lous meningitis can be directed on two levels. A rare complication of TBM is tuberculous http://jnnp.bmj.com/ On a macroscopic level there are the mecha- encephalopathy.32 Usually occurring in a young nisms by which the tuberculous bacilli dissemi- child with progressive primary TB, the presen- nate to the CNS. This is discussed alongside tation is of reducing conscious level with few the role of granulomatous inflammation, the focal signs and minimal meningism. DiVuse currency of tuberculous pathology, in causing oedema and white matter pallor with demyeli- gross pathological changes within the CNS. On nation are found pathologically. The pathogen- a microscopic level there are the cellular and esis is uncertain, but is presumed to be immune immune mechanisms that can result in both mediated. Diagnosis is important as anecdotal on October 2, 2021 by guest.