TUBERCULOUS Tuberculous meningitis

The rising incidence of HIV has seen a concomitant rise in the incidence of tuberculous meningitis.

P BILL Pierre Bill’s interests are neuromuscular MB ChB, FCP (SA), FRCP(Lond) disorders, tropical and under- graduate and postgraduate teaching. Emeritus Professor and Consultant He is currently President of the College Department of Neurology of Neurologists within the Colleges of Inkosi Albert Luthuli Central Hospital and Medicine of South Africa. University of KwaZulu-Natal Durban

Recently there has been a resurgence of (TB) an aerobic Gram-positive rod that stains poorly owing in developed and developing countries. This is due to the to its thick cell wall that contains lipids, peptoglycans, increasing prevalence of HIV, overcrowding in the urban and arabinomannans. The Ziehl-Neelsen stain uses the population and in abnormal communities (prisons, refugee properties of the cell wall to form a complex that prevents colonies, and concentration camps), poor nutritional status, decolourisation by acid or alcohol. appearance of drug-resistant strains of TB, ineffective TB control programmes, and increase in migration to the The development of TBM is a two-step process. M. developed world from countries where TB is prevalent. tuberculosis bacilli enter the body by droplet inhalation, the Compared with pulmonary TB, which has been the subject initial point of infection being the alveolar macrophage. of many clinical trials, the pathogenesis, diagnosis and During the localised infection within the lung (primary treatment of tuberculous meningitis (TBM) have received complex) there is a short but significant bacteraemia that little attention. How the disease kills or disables those can seed bacilli to other organs in the body. In about 10% it infects is poorly understood; the best diagnostic tests of cases the primary complex does not heal but progresses are controversial, and the optimum treatment with and tuberculous pneumonia develops, with heavier and antituberculosis drugs is not known. The only certainties more prolonged bacteraemia. Dissemination to the CNS lie in the fatal consequences of missed diagnoses and is more likely, particularly if miliary TB develops. In those management. It has been estimated that about 10% of who develop TBM, bacilli seed to the or patients with extrapulmonary TB have CNS involvement. parenchyma, forming small subpial or subependymal foci, Involvement of the CNS in TB is five times more frequent in called Rich foci, after the original studies of Rich and HIV-positive than in HIV-negative patients. McCordick. These foci may remain dormant for many years. The second step in the development of TBM is rupture of EPIDEMIOLOGY the into the subarachnoid space. This heralds the onset of TBM. Before HIV, the most important determinant for the development of TBM was age. In populations with a high The release of M. tuberculosis bacilli into the subarachnoid TB prevalence, the peak age for TBM is 0 - 4 years. In space results in a local T lymphocyte-dependent response, populations with a lower TB prevalence, most TBM cases characterised macroscopically as caseating granulomatous occur in adults, risk factors being alcoholism, diabetes inflammation. The numbers and types of white cells in the mellitus, malignancy, and recent corticosteroid use. Co- CSF help differentiate TBM from other forms of meningitis, infection with HIV now dwarfs these risk factors, and but little is known of their role in disease pathogenesis. increases the lifetime risk of developing clinical TB. HIV also increases the risk of developing extrapulmonary TB and in In 75% of children the onset of TBM is less than 12 months particular TBM – a risk which increases as the CD4 cell after the primary infection. count diminishes. Three general processes produce the subsequent AETIOLOGY, PATHOGENESIS AND PATHOLOGY neurological pathology: adhesion formation, an obliterative vasculitis, and an encephalitis or a myelitis. Adhesions TBM was first described as a pathological entity in 1836, result from the thick, gelatinous basal meningeal exudate and demonstrated that TB was caused by that develops after the inoculation of bacilli into the tuberculosis in 1882. M. tuberculosis is subarachnoid space. The exudate is particularly marked

September 2006 Vol.24 No.9 CME 505

pg505-511.indd 505 9/12/06 8:44:58 AM TUBERCULOUS MENINGITIS

Compared with pulmonary 1-β and tumour necrosis factor, fontanelles develop in infants. Nausea, which promote granuloma formation. vomiting and altered sensorium may TB, which has been the Tubercles consist of mononuclear develop. A continuous low-grade subject of many clinical cells surrounding a necrotic (caseous) is present in about 80% of patients. trials, the pathogenesis, centre. The complex cellular immune diagnosis and treatment response in TB determines whether Cranial nerve abnormalities occur of tuberculous meningitis the host develops active disease. in one-quarter of patients, most (TBM) have received little Progression and expansion of the commonly a 6th nerve palsy. Choroidal caseous lesion may result in different tubercles are present in less than attention. types of CNS involvement. Tubercles 10% of patients, but are diagnostic that rupture into the subarachnoid of TB. Visual loss may develop owing BCG vaccination pro- space cause meningitis. Those deeper to optochiasmatic , 3rd vides the best prophylaxis in the parenchyma of the brain or ventricular compression of optic chiasm spinal cord cause tuberculoma or from , optic nerve against severe forms of TB, abscess. granuloma, and toxicity. mainly meningitic and mil- Funduscopic examination may reveal iary. Most CNS TB is caused by papilloedema. Hemiplegia may occur M. tuberculosis. Non-tuberculous at the onset of the disease or at a later mycobacteria (NTM) are ubiquitous stage. Quadriplegia secondary to around the sylvian fissures, basal in the environment. They usually bilateral infarction or severe cerebral cisterns, brainstem and cerebellum, cause infection in persons with oedema is less common. Occasionally and contains lymphocytes, plasma immunosuppression, especially patients abnormal movements may be present, cells, macrophages and fibrin. with AIDS and very low CD4 counts including chorea , Blockage of the basal subarachnoid (< 10 cells/µl). Atypical bacteria athetosis, generalised tremors, cisterns, 4th ventricular outlet or infrequently produce meningitis or myoclonic jerks and ataxia. Seizures, aqueduct can result in obstruction of . Mycobacterium either focal or generalised, may occur the CSF and hydrocephalus. Adhesions avium is the most common aetiological during the illness. As the disease around the interpeduncular fossa and agent of this group. Mycobacterium progresses, increasing evidence of related structures can compromise fortuitum meningitis is a complication cerebral dysfunction sets in, with , particularly 2, 4 and of CNS surgery and trauma and apathy and irritability progressing to 6, and the internal carotid artery. is usually associated with abscess increasing lethargy, confusion, stupor An obliterative vasculitis may result and foreign bodies. Less frequently and . Spinal meningitis may in infarction and stroke syndromes. NTM infections are manifested result in root pain, spastic or flaccid These commonly occur in the territory as intracranial mass lesions, or paralysis and loss of sphincter control. of the internal carotid artery (ICA), rhombencephalitis. Diagnosis is made proximal middle cerebral artery (MCA) by culture of tissue, sputum, blood Although HIV-infected patients with TB and perforating vessels to the basal or CSF. Because NTM are ubiquitous are at increased risk of developing ganglia. Infarcts occur in about 30% bacteria, their isolation from a sample TBM, the clinical features and of cases, causing a range of disorders may represent contamination. However, outcome do not seem to be altered. ranging from hemiparesis to movement isolation from a sterile fluid such as These patients commonly have disorders. Haemorrhagic transformation CSF usually represents infection of the extrameningeal TB on admission. of infarcted tissue is not unusual. nervous system. In elderly patients with TBM, the The basal inflammatory process may presentation may be atypical. Signs extend into the parenchyma, resulting CLINICAL FEATURES of may be absent, seizures in encephalitis. Brain tissue underlying occur more commonly, and CSF the exudate shows oedema, which can TBM is usually preceded by a findings may be atypical, and the CSF be marked throughout the hemispheres, prodromal period of 2 - 4 weeks of may even be acellular. perivascular infiltration, and a nonspecific symptoms such as fever, microglial reaction (known as border malaise, myalgia, and . A rare complication of TBM is zone reaction). Fifty per cent of patients have chest tuberculous encephalopathy, radiographic abnormalities, a history usually occurring in a young child The pathogenesis of TBM at a cellular of contact with a TB patient, and a with progressive primary TB. level is poorly understood. During the positive skin test. In children The presentation is of reducing first 2 - 4 weeks of infection there is prodromal symptoms include irritability, consciousness level with few focal no immune response to the organism. poor feeding, drowsiness, and signs and minimal meningism. Thereafter CD4 T cells specific for abdominal pain. Eventually headache Diffuse oedema with white matter mycobacterial peptides appear, worsens and becomes continuous. demyelination is found pathologically. enabling more efficient intracellular Neck stiffness is reported by about The pathogenesis is presumed to be killing of tubercle bacilli. Activated 25% of patients, but meningismus is immune mediated. macrophages produce interleukin detected in a higher number. Bulging

506 CME September 2006 Vol.24 No.9

pg505-511.indd 506 9/12/06 8:44:59 AM TUBERCULOUS MENINGITIS

TBM can also cause metabolic • Non-infectious Neutrophils can dominate, especially complications of which the commonest, neoplasms early in the disease, and have been hyponatraemia, affects more than neurosarcoidosis associated with an increased likelihood 50% of patients with the disease. This Vasculitis of a bacteriological diagnosis ‘cerebral salt wasting syndrome’ is systemic lupus erythematosus and improved survival. In a small associated with low plasma volumes Behçet's disease. proportion of patients, neutrophils and persistent natriuresis despite persist. When therapy is initiated, the normal concentrations of antidiuretic DIAGNOSIS CSF pleocytosis may change transiently hormone (ADH). There is a stronger from lymphocyte to neutrophil correlation between concentrations of All series of TBM stress the importance predominance, a phenomenon atrial natriuretic peptide and sodium. of a high level of diagnostic suspicion, known as ‘therapeutic paradox’. CSF Treatment with sodium and fluid as delay in treatment either results examination in meningitis caused replacement is probably indicated, but in death or substantial neurological by NTM shows a mild lymphocytic fludrocortisone and democycline may morbidity. TBM cannot be diagnosed pleocytosis, with nearly normal be useful. Hyponatraemia may also be on history and clinical assessment concentrations of glucose and protein. due to inappropriate secretion of ADH. alone. Useful features are a history of recent exposure to TB (particularly Definitive diagnosis is based on the The frequency of symptoms and signs in children), and signs of active detection of bacilli in the CSF, either in TBM is shown in Table I. extrameningeal TB. A chest X-ray on the smear or by culture. Rates of showing active TB is present in about positivity for clinically diagnosed cases The severity of TBM at presentation 59% of patients with TBM, but lacks range from 25% to 75%. Acid-fast is classified into 3 grades according specificity where there is a high bacilli may be seen on Ziehl-Neelsen to the patient’s Glasgow Coma Scale prevalence of pulmonary TB. Miliary stain or cultured from the CSF in up (GCS) and the presence or absence of TB strongly suggests multi-organ to 81% of patients. The likelihood of focal signs – variables that are strongly involvement. Skin testing with purified seeing or culturing M. tuberculosis from predictive of death: protein derivative (PPD) of the CSF is dependent upon meticulous Grade 1. Alert and orientated without M. tuberculosis is of limited value, microscopy and culture of a large focal neurological deficit. except in children. volume of CSF (> 5 ml). The limit of Grade 2. GCS10 - 14 with or without detection of acid-fast bacilli on CSF focal neurological deficit or GCS 15 The CSF is clear or opalescent, and is 100 mycobacteria/ml. The success with focal neurological deficit. the opening pressure at initial lumbar of the test depends on the quality and Grade 3. GCS less than 10 with or puncture is elevated in about 50% of volume of the sample and the skill of without focal neurological deficit. patients. A ‘cobweb’-like appearance the technician, and his/her persistence on the surface of the CSF, when in examining for acid-fast bacilli. Relatively common causes of a chronic allowed to stand at room temperature Culture of M. tuberculosis bacilli is meningitis are listed below: or in the refrigerator, is a characteristic the gold standard for diagnosis, but is feature but not pathognomonic of TBM. insensitive and slow, and the decision • Infectious Typically there is a predominantly to treat the patient should not wait for M. tuberculosis lymphocytic pleocytosis (60 - 1 000 culture results. neurocyticercosis cells/ml), with a high protein (0.8 Cryptococcus neoformans - 4 g/l) and low glucose (< 50%) CSF polymerase chain reaction (PCR) Treponema pallidum concentration. However, total CSF for M. tuberculosis has a sensitivity of Herpes simplex viruses white cell count can be normal in those 56% and a specificity of 98%, and Borrelia burgdorferi with depressed cell-mediated immunity, should therefore not be used to exclude Brucella species such as the elderly and people with TBM. Molecular methods may be more Coccidioides immitis HIV infection. Low counts have been useful when antituberculosis drugs have Histoplasma capsulatum associated with a poor outcome. been started. Partially treated bacterial meningitis. An elevated CSF adenosine deaminase Table I. Frequency of symptoms and signs in TBM level supports the diagnosis in the Symptoms (%) Signs (%) appropriate clinical setting.

Headache (50 - 80) neck stiffness (40 - 80) CT and MRI changes that may be Fever (60 - 95) confusion (10 - 30) seen include basal enhancement, Vomiting (30 - 60) coma (30 - 60) hydrocephalus (especially in children), Photophobia (5 - 10) Any cranial nerve palsy (30 - 50) tuberculoma and infarction (25 - Anorexia (60 - 80) cn3 (5 - 15) 40% of patients). MRI may provide cn4 (30 - 40) more information regarding cerebral cn7 (10 - 20) miliary TB, with multiple small Hemiparesis (10 - 20) intraparenchymal granulomas. The

508 CME September 2006 Vol.24 No.9

pg505-511.indd 508 9/12/06 8:45:00 AM TUBERCULOUS MENINGITIS

carotid or MR angiogram may show (INH) kills most of the rapidly meningitis CSF levels are up to 29% of changes in the vessels of the circle of replicating bacilli in the first 2 weeks serum levels. penetrates Willis, such as segmental narrowing, of treatment, with some additional help well into the CSF, both in patients with irregular beaded appearance from streptomycin and ethambutol. meningeal inflammation and in those or complete occlusion (Figs. 1 Thereafter and pyrazinamide with normal meninges. and 2). Cryptococcal meningitis, become important. Rifampicin kills cytomegalovirus encephalitis, low or non-replicating organisms and Second-line drugs, which have less sarcoidosis, meningeal metastases, pyrazinamide kills those in sites hostile efficacy or greater toxicity, include and lymphoma may all produce similar to the penetration and action of other para-aminosalicylic acid, ethionamide radiological changes. drugs. Empirical therapy should be or prothionamide, cycloserine, instituted as early as possible to reduce aminoglycosides (amikacin and morbidity and mortality. The aim of kanamycin) and quinolones (ofloxacin treatment is to kill both intracellular and and ciprofloxacin). The first 4 penetrate extracellular organisms and requires well into the CSF, both in the presence the use of several drugs to avoid the or absence of meningeal inflammation. development of resistance. Treatment Aminoglycosides penetrate poorly into is hindered by the difficulty of access the CSF, and there is little information of antituberculosis agents to the CNS on the CSF penetration of quinolones. compartment, drug permeability, The efficacy, dosage, mode of action and the complex lipids that protect and major side-effects of the first-and the organism from the common second-line drugs are detailed further antituberculosis drugs. in Tables II and III.

First-line drugs include INH, rifampicin, A widely accepted regimen includes Fig. 1. Tuberculous meningitis. T1- ethambutol, pyrazinamide, and the use of 4 drugs on a daily basis in contrasted MRI scan showing streptomycin. INH diffuses readily into the first 2-month phase of treatment intense basal enhancement with the CSF in the presence or absence (INH, rifampicin, and pyrazinamide, ring-enhancing granulomas in the of meningeal inflammation, with CSF and a 4th drug, either streptomycin prepontine, and suprasellar cisterns, concentrations of approximately 20 or ethambutol). This is followed by a and along the middle cerebral artery. - 90% of serum levels. CSF levels prolonged continuation phase with INH Hydrocephalus is present. of rifampicin are approximately 20 and rifampicin for up to 12 months or - 50% of serum levels in the presence longer. Therapy should be continued of meningeal inflammation. Little or for 6 months after the patient becomes no ethambutol is detected in the CSF asymptomatic or after the CSF culture of patients with normal meninges. In becomes negative. In areas where patients with meningeal inflammation, resistance to INH is less than 4% and the ethambutol level approaches the patient does not come from an area 10 - 50% of serum levels. Similarly, of high prevalence of multiresistance streptomycin is not detectable in and has not had contact with a case normal meninges, while in patients with of multiresistance, ethambutol is not

Table II. First-line drugs

Drug Dosage (mg/kg/day) Efficacy Major side-effects Children Adult Maximum Fig. 2 . Tuberculous meningitis. T1- contrasted MRI image. Intense INH 5 - 15 5 300 bactericidal Hepatotoxicity, enhancement is seen in the right sylvian both intra- and peripheral neuropathy fissure with underlying right basal extracellular ganglion infarct. Hydrocephalus is Rifampicin 10 - 20 10 450 (< 50 kg) Bactericidal Hepatotoxicity, GI, present. 600 (> 50 kg) both intra- and fever, cutaneous rashes extracellular TREATMENT Pyrazinamide 15 - 30 1.5 g (< 50 kg) Bactericidal Hepatotoxicity, 2.0 g (> 50 kg) Both intra- and nausea, Compared with pulmonary TB, where extracellular arthralgia the optimum treatment has been Ethambutol 15 - 20 15 - 25 1.6 g Bacteriostatic Optic neuritis, developed from the results of many arthralgia controlled trials, the choice of drugs, Streptomycin 15 15 1.0 g Bacteriostatic Ototoxicity, renal, doses, and duration of treatment for extracellular only vertigo, vestibular TBM are unknown. There are however disturbances common principles of treatment. INH, rifampicin and pyrazinamide penetrate into CSF. Ethambutol and streptomycin penetrate when the meninges are inflamed.

September 2006 Vol.24 No.9 CME 509

pg505-511.indd 509 9/12/06 8:45:02 AM TUBERCULOUS MENINGITIS

Table III. Second-line drugs MDR pulmonary disease may identify those at high risk. MDR is of special Drug Dosage (mg/kg/day) Efficacy Major side- relevance in HIV-infected populations, Children Adult Maximum effects because of an impaired immune response against the bacilli. Ethionamide 10 - 20 15 - 20 1 g/day Bactericidal Hepatotoxicity, GI Cycloserine 10 - 20 750 mg/day Bacteriostatic Neurotoxic (fits, depression) In South Africa the mean prevalence Fluoroquinolones of MDR pulmonary TB is 1.6% among Ofloxacin 800 mg/day Bacteriostatic CNS effects, GI treatment-naïve patients, and 6.7% Ciprofloxacin 750 mg bd Bacteriostatic among patients previously treated for Aminoglycosides TB. In a study of 30 patients with Amikacin 15 15 1.5 g/day Bacteriostatic Ototoxicity, MDR TB organisms, 17 died, and the vertigo Kanamycin 15 Bacteriostatic Renal toxicity rest were left with significant functional impairment. Seventy-six per cent of the necessary. In children the substitution ventriculoperitoneal or atrial shunting. patients who died were HIV positive. of streptomycin for ethambutol should There are no data from controlled trials be considered because of the difficulty to indicate which is best. Current evidence suggests MDR TBM in monitoring visual acuity in the needs treatment with second-line paediatric group. In South Africa M. tuberculosis resistant to antituberculosis drugs, although there ethionamide is often used as the 4th antituberculosis drugs are insufficient data regarding the drug instead of ethambutol because of TBM caused by resistance to one effectiveness of second-line drugs poor penetration of ethambutol into the or more first-line antituberculosis against intracellular organisms. The CSF. When drug resistance is unlikely, drugs is an increasingly common WHO recommends fluoroquinolones a regimen of 3 drugs (INH, rifampicin clinical problem. The frequency of for the treatment of MDR TBM, but their and pyrazinamide) daily for 2 months, resistance varies with geographical published use in TBM is restricted to and 2 drugs (INH and rifampicin) region. In a study conducted in 35 case reports. Data on CSF penetration for an additional 4 months, may be countries, primary resistance to 1 of and pharmacokinetics are scant. adequate in adults. Therapy should the 4 first-line drugs was found in Ethionamide, prothionamide, and be prolonged to 9 months or longer 9.8% of the M. tuberculosis strains, cycloserine are all reported to cross the where there is a delayed response. most frequently to INH (7.3%) and blood-brain barrier well and may be For children with TBM, a 12-month streptomycin (6.5%), followed by effective. Aminoglycosides penetrate regimen is recommended with daily rifampicin (1.8%) and ethambutol (1%). less well and may have to be given by INH, rifampicin, pyrazinamide and The overall prevalence was 12.6% intrathecal injection. Occasionally up streptomycin for 2 months, followed to any of the 4 first-line drugs. In the to 5 – 7 drugs may be needed. by INH and rifampicin daily or twice case of primary resistance to INH, the weekly for 10 months. Pyridoxine British Thoracic Society recommend Until more data are available, the should be given with INH. rifampicin, pyrazinamide, ethambutol treatment of MDR TBM should follow and streptomycin for 2 months, the same guidelines as those used in Adjunctive corticosteroids followed by rifampicin and ethambutol the treatment of MDR pulmonary TB: The use of adjunctive corticosteroids for 7 months. In the case of secondary • Never add a single drug to a failing has been controversial since they were resistance, INH should be stopped and regimen. first suggested more than 50 years ethambutol and rifampicin should be • Use at least 3 previously unused ago. A meta-analysis concluded that administered for 12 months, together drugs, 1 of which should be a corticosteroids probably improved with pyrazinamide for 2 months. fluoroquinolone. survival in children. There was no • Streptomycin resistance does evidence of beneficial effects in Multidrug-resistant (MDR) TB is defined not confer resistance to other adults or in those co-infected with as resistance to at least INH and aminoglycosides, therefore amikacin or HIV. A later trial in adults showed rifampicin, with or without resistance kanamycin can be used. that dexamethasone was associated to other antituberculosis drugs. TBM • Treat for at least 18 months. with reduced risk of death but did not caused by MDR M. tuberculosis has The optimal regimens for the prevent severe disability in survivors. a fatality rate of 85%. Patients with treatment of CNS TB due to The beneficial effect of dexamethasone MDR TBM treated with first-line drugs atypical mycobacteria in persons was seen across all grades of severity. are likely to be dead before the with HIV infection have not been results of conventional susceptibility finally established, although a 4- Neurosurgical intervention tests (which take 6 - 8 weeks) are drug regimen is needed to treat Hydrocephalus is a common available, and thus timely confirmation M. avium intracellulare infection. complication of TBM, and can be of the diagnosis is problematic. A Current recommendations include treated with drugs that have a diuretic history of previously treated TB or azithromycin (500 –1 000 mg/day), effect, serial lumbar punctures, or recent exposure to a known case of and clarithromycin (500 –1 000 mg/

510 CME September 2006 Vol.24 No.9

pg505-511.indd 510 9/12/06 8:45:02 AM TUBERCULOUS MENINGITIS

day), in combination with ethambutol reactions might occur during the course IN A NUTSHELL (15 mg/kg/day) or clofazimine (100 of TB treatment when antiretroviral mg/day). Alternative regimens include therapy restores immune function. HIV- The incidence of TB is increasing, the use of ciprofloxacin and rifampicin. infected patients have an increased partly because of the increasing Overall, the prognosis for meningitis prevalence of infections caused by incidence of HIV. caused by NTM is poor, with a NTM. Aside from classic regimens Compared with pulmonary TB, which mortality rate close to 70%. of long duration, various regimens has been the subject of many clinical have been proposed for HIV-infected trials, the pathogenesis, diagnosis PREVENTION patients: and treatment of TBM have received • INH, rifabutin and pyrazinamide for little attention. BCG vaccination provides the best 2 months, and INH It has been estimated that about 10% prophylaxis against severe forms of and rifabutin for an additional 4 of patients with extrapulmonary TB TB, mainly meningitic and miliary. A months have CNS involvement. meta-analysis of published trials on the • INH, streptomycin, and The development of TBM is a two-step efficacy of BCG vaccination suggests a pyrazinamide daily for 2 months, process – the bacteria first enter the protective effect of 64% against TBM. and then 2 or 3 times weekly for 7 lungs and then the brain. Most CNS months HIV INFECTION AND CNS TB TB is due to M. tuberculosis. • INH, rifampicin, and either TBM is usually preceded by a ethambutol or pyrazinamide with HIV does not alter the clinical prodromal period of 2 - 4 weeks of a 4th drug, either streptomycin or presentation of TBM, but may affect the nonspecific symptoms such as fever, clofazimine, for a period of at least 6 number and nature of complications. malaise, myalgia, and headache. - 9 months. Basal meningeal enhancement and Neck stiffness is reported by about hydrocephalus may be less common, CONCLUSION 25% of patients, but meningismus is and there could be more bacilli in the detected in a higher number. meninges. Active extrameningeal TB is The diagnosis and management of TBM can also cause metabolic also more common, and case fatality TBM remain a major challenge for the complications; the commonest, from TBM is higher. The prognosis clinician. The current HIV epidemic hyponatraemia, affects more than of TB is poorer because of the contributes to the increasing TB disease 50% of patients with the disease. immunosuppression resulting from the burden and to consequent morbidity HIV infection. There is evidence that and mortality. CNS TB accounts for 5% TBM cannot be diagnosed on history the immune response to M. tuberculosis of extrapulmonary TB, and meningitis and clinical assessment alone. enhances HIV replication, resulting is the most frequent complication. Useful features are a history of in acceleration of the HIV disease. In recent exposure to TB (particularly treating HIV-infected patients, several Further reading in children), and signs of active extrameningeal TB. facts should be considered. First, Bashir HEL, Laundy M, Booy R. Diagnosis and controlling the infection will be difficult treatment of bacterial meningitis. Arch Dis Child Isoniazid kills most of the rapidly 2003; 88: 615-620. because of the associated immune replicating bacilli in the first 2 Garcia JC. Tuberculosis and other mycobacterial deficiency. Second, rifampicins interact infections. In: Noseworth JH, ed. Neurological weeks of treatment, with some with protease inhibitors, resulting Therapeutics: Principles and additional help from streptomycin Practice. M Dunitz, 2003: 904-912. in decreased activity of protease and ethambutol. Thereafter rifampicin inhibitors because of induction of Garg RK. Tuberculosis of the . Postgrad Med J 1999; 75:133-140. and pyrazinamide become important. cytochrome P450 by rifampicin. Golden MP, Vikram HR. Extrapulmonary Empirical therapy should be instituted Rifabutin has substantially less tuberculosis: an overview. Am Fam Physician as early as possible to reduce 2005; 72(9): 1761-1768. activity as an inducer of cytochrome Katti MK. Pathogenesis, diagnosis, treatment, morbidity and mortality. The aim of enzymes, and may be prescribed and outcome aspects of cerebral tuberculosis. treatment is to kill both intracellular for these patients. Conversely, if Med Sci Monit 2004; 10(9): RA215-229. and extracellular organisms and protease inhibitors, particularly Patel VB, Padayachee N, Bhigjee AI, et al. Multidrug-resistant tuberculous meningitis in requires the use of several drugs to ritonavir or saquinavir, which are KwaZulu-Natal, South Africa. Clin Infect Dis avoid the development of resistance. potent cytochrome P450 inhibitors, 2004; 38:851-856. Thwaites G, Chau TTH, Mai NT, et al. BCG vaccination provides the best are administered with rifabutin, blood Tuberculous meningitis. J Neurol Neurosurg prophylaxis against severe forms of concentrations of the latter increase Psychiatry 2000; 68:289-299. TB, mainly meningitic and miliary. markedly, as does the toxic effect. Thwaites G, Hien TT. tuberculous meningitis: many questions, too few answers. Lancet HIV does not alter the clinical Rifabutin is efficacious in non-resistant Neurology 2005; 4:160-170. presentation of TBM, but may TB and also against M. avium. Verma A, Solbrig M. Mycobacterial disease. In: affect the number and nature of Thirdly, HIV-infected patients can have Bradley WG, Daroff RB, Fenichel GM, Jankovic J, eds. Neurology in Clinical Practice. complications. malabsorption of antituberculosis Philadelphia Butterworth Heinemann, 2004: drugs and are prone to adverse drug 1490-1493. reactions. This makes drug monitoring particularly important. Paradoxical

September 2006 Vol.24 No.9 CME 511

pg505-511.indd 511 9/12/06 8:45:03 AM