You are on page 1of 11

Review

Tuberculous meningitis: many questions, too few answers
Lancet Neurol 2005; 4: 160–70
Centre for Tropical Medicine,
Nuffield Department of Clinical
Medicine, Oxford University,
UK (G E Thwaites PhD);
and Oxford University
Clinical Research Unit
(G E Thwaites PhD), Hospital for
Tropical Diseases, Ho Chi Minh
City, Vietnam (T T Hien MD)
Correspondence to:
Dr Guy Thwaites, Brighton and
Sussex University Hospital,
Department of Infectious
Diseases and Microbiology,
Eastern Road, Brighton, Sussex,
BN2 5BE, UK
guy.thwaites@btinternet.com

Guy E Thwaites, Tran Tinh Hien

Tuberculous meningitis (TM) is difficult to diagnose and treat; clinical features are non-specific, conventional
bacteriology is widely regarded as insensitive, and assessment of newer diagnostic methods is not complete.
Treatment includes four drugs, which were developed more than 30 years ago, and prevents death or disability in
less than half of patients. Mycobacterium tuberculosis resistant to these drugs threatens a return to the
prechemotherapeutic era in which all patients with TM died. Research findings suggest that adjunctive treatment
with corticosteroids improve survival but probably do not prevent severe disability, although how or why is not
known. There are many important unanswered questions about the pathophysiology, diagnosis, and treatment of
TM. Here we review the available evidence to answer some of these questions, particularly those on the diagnosis
and treatment of TM.
The diagnosis and management of tuberculous
meningitis (TM) challenges physicians throughout the
world (panel 1). Unlike pulmonary tuberculosis, which
has been the subject of many clinical trials, the
pathogenesis, diagnosis, and treatment of TM have
received little attention. How the disease kills or disables
more than half of those it infects is not understood; the
best diagnostic tests are controversial; the optimum
choice, dose, and treatment duration of antituberculosis
drugs are not known; and the outcome from adjunctive
corticosteroids and neurosurgical intervention has been
difficult to study.

Clinical features and pathogenesis of TM
Historical perspective
Controversy has dogged TM since 1836, when The
Lancet published a description of six children with fatal
“acute hydrocephalus”.1 Assessment post-mortem found
Panel 1: TM in clinical practice
Associated with TM
Recent exposure to tuberculosis (especially in children)
Evidence of tuberculosis elsewhere (especially miliary
tuberculosis on chest radiograph)
HIV infection
Diagnosis
Acute
Meticulous microscopy (and then culture) of 5 ml of CSF
After treatment commencement
PCR of CSF
Treatment
First 2 months
Four drugs: isoniazid, rifampicin, pyrazinamide and either
streptomycin, or ethambutol
Next 7–10 months
Isoniazid and rifampicin
Patients without HIV
Give dexamethasone, regardless of patient’s age or disease
severity

160

“an inflammation of the meninges, with the deposit of
tubercular matter in the form of granulations, or cheesy
matter”. The author’s conclusion was controversial:
these findings represented “tubercular meningitis”, a
new diagnosis, and one to join the growing number of
diseases marked by the presence of “tubercles”.
The unitary theory of tuberculosis was not widely
accepted until 1882, when Robert Koch stained and
cultured Mycobacterium tuberculosis for the first time and
showed it was the bacterium transmitted in
tuberculosis.2 Thereafter, controversy turned to whether
TM resulted from direct haematogenous invasion of the
meninges by the bacilli, or by inoculation from
contiguous lesions resulting from earlier bacillaemia. In
1933, Rich and McCordock3 reported a series of elegant
experiments in rabbits and children post-mortem; they
found the disease developed after the release of bacilli
from old focal lesions in communication with the
meninges. These lesions, called Rich foci, were typically
subpial or subependymal and most commonly situated
in the sylvian fissure.3

Clinical features
Understanding of the events that happen after the
release of bacilli from Rich foci has advanced little since
Rich and McCordock’s studies, and although the
presenting clinical features of TM have been described
extensively (panel 2)4–9 the mechanisms that cause them
are poorly understood. These mechanisms are
important for clinicians who need to understand the
consequences of the disease, and may lead to new
treatments.

Molecular and cellular pathogenesis
An overview of the pathogenesis of TM and the variables
that might be associated with disease progression and
outcome is given in figure 1. The conflicting evidence on
the role of tumour necrosis factor  (TNF ) in
pathogenesis shows the complexity of this process. The
release of M tuberculosis into the subarachnoid space
results in a local T-lymphocyte-dependent response,
characterised macroscopically as caseating granulomatous inflammation.10 In pulmonary tuberculosis,
http://neurology.thelancet.com Vol 4 March 2005

19. and more controversial. ballismus. an anti TNF  drug. through CT and MRI (figure 2) of the brain. These children had a diffuse cerebral disorder with coma. involuntary movements. such as the elderly and people with HIV. but chorea. neutrophils could have a role in pathogenesis. but little is known of their role in disease pathogenesis. improved survival and neurological outcome in rabbits16 and suggested a novel therapeutic approach in people. Pathological and clinical consequences of infection The macroscopic consequences of infection have been researched post mortem and. and an obliterative vasculitis can cause infarction and stroke syndromes. Neurological abnormalities occur with the development of an inflammatory exudate that affects mostly the sylvian fissures. tremor is the most common. particularly the roles of different lymphocyte subsets. in Indian children with disseminated tuberculosis.18 The numbers and types of white cells in the CSF help differentiate TM from other meningitides.14 although TNF  concentrations have not been correlated with disease severity or outcome in human beings.thelancet.15 Indeed.29 Less common. especially early in the disease.20 low counts have been associated with poor outcome.10 Three processes cause most of the common neurological deficits: the adhesive exudate can obstruct CSF causing hydrocephalus and compromise efferent cranial nerves. Dastur and Udani30 were the first to describe this variant of cerebral tuberculosis.12 Studies of pyogenic bacterial meningitis showed CSF concentrations of TNF  correlated with disease severity13 and study of rabbit models of TM found high CSF concentrations were associated with a worse outcome. and pyramidal signs but with normal CSF measurements.Review Panel 2: TM symptoms on presentation4–9 Symptom (proportion of patients affected) Headache (50–80%) Fever (60–95%) Vomiting (30–60%) Photophobia (5–10%) Anorexia (60–80%) Clinical sign (proportion of patients affected) Neck stiffness (40–80%) Confusion (10–30%) Coma (30–60%) Any cranial nerve palsy (30–50%) Cranial nerve III palsy (5–15%) Cranial nerve VI palsy (30–40%) Cranial nerve VII palsy (10–20%) Hemiparesis (10–20%) Paraparesis (5–10%) Seizures (children: 50%. demyelination. granulomas can coalesce to form tuberculomas (or an abscess in patients with uncharacteristic disease) which.26 Unusual clinical and pathological features of TM have been well described in previous research papers and can cause diagnostic uncertainty.23 but more data on these cells are needed. the severity of TM at presentation is classified into three grades according to the patient’s Glasgow coma score and the presence or absence of focal neurological signs (panel 3).21 and high proportions of neutrophils in the cell count have been associated with an increased likelihood of a bacteriological diagnosis and improved survival. Sadly. which is predominantly lymphocytic. total CSF white-cell count can be normal in those with TM and depressed cell-mediated immunity. convulsions.24 variables shown to be strongly predictive of death. adults: 5%) CSF (proportion or range) Appearance (80–90% clear) Opening pressure (50% 25 cm H20) Total leucocyte count (5–1000103/ml) Neutrophils (10–70%) Lymphocyte (30–90%) Protein (45–250 mg/dL)* Lactate (5–10 mmol/L) CSF glucose to blood glucose ratio (0·5 in 95%) *CSF protein can be 1000 mg/dL in patients with spinal block TNF  is thought to be crucial for granuloma formation. more recently.10 The severity of these complications may be dependent on the intracerebral inflammatory response and strongly predicts outcome. which they called “tuberculous encephalopathy”.11 but is also cited as a main factor in hostmediated destruction of infected tissue. and sometimes haemorrhage— features that may be more typical of a post-infectious 161 .com Vol 4 March 2005 glucose ratio. Preliminary research found that thalidomide was safe and well-tolerated17 and led to a controlled trial to assess the efficacy of adjunctive thalidomide in children with TM. However.28 Movement disorders can present after basal ganglia infarction.27. than patients who present with movement disorders are those who present with evidence of diffuse cerebral involvement but without clinical or CSF signs of meningitis. brainstem. basal cisterns.15. depending on their location.22 The kinetics of the lymphocyte response are probably also important. and myoclonus are all reported. cause diverse clinical consequences. Dastur31 has argued subsequently that the pathogenesis of tuberculous encephalopathy may differ from TM: post-mortem assessment of those with tuberculous encephalopathy found diffuse cerebral oedema. and cerebellum.15 Neutrophils can dominate. Typically the CSF shows a high CSF white-cell count.15 Treatment with antibiotics and thalidomide. with a high protein and low http://neurology. Hence. this trial was stopped early because there were many adverse events in the thalidomide arm and there did not seem to be any benefit from treatment.

39 However.41 whereas characterised by a subacute paraparesis.eps meningeal enhancement hydrocephalus on CT 50Ref number years ago. allergic encephalomyelitis.33 Vertebral tuberculosis (Pott’s disease) plasma atrial natriuretic peptide and sodium. TM can also cause metabolic complications.37 was described more than nature of complications.42 There is anecdotal evidence to suggest obliteration of the spinal subarachnoid space with fludrocortisone replacement therapy43 and demeclonodular intradural enhancement.TM. radicular pain.34 although tuberculomas can occur correcting the sodium concentration in the plasma is not in any part of the cord.32 Anecdotal reports suggest hyponatraemia associated originally with bronchial the disease is responsive to treatment with carcinoma38 led some to think a similar mechanism corticosteroids. Tuberculous radiculomyelitis known. IL10=interleukin 10. Although a accounts for about a quarter of patients with TM with role for antidiuretic hormone has not been excluded. spinal involvement and may be associated with fusiform “hyponatraemic natriuretic syndrome” is probably a para-vertebral abscesses or a gibbus. basal (PLEASE MARK WITH RED SPOT IF and URGENT) TLN_MAR_10003_Thwaites_1. cycline44 may be useful. MRI reveals loculation and are euvolaemic. affects more than Co-infection with HIV 50% of patients with the disease. BBB=blood–brain barrier.9 A “cerebral salt Research findings suggest HIV does not alter the clinical wasting syndrome” associated with TM and attributed to presentation of TM. which normal concentrations of antidiuretic hormone. hyponatraemia. The discovery of a syndrome Special of instructions might andcolours there could be more bacilli inappropriate antidiuretic hormone as a cause Lancet of journal Shapes Specialty colours be less common Editor 162 Author Created by GC _ Steve 100% 10% use for background tint 35% 100% 10% 35% use for background tint http://neurology. IFN =interferon .45 but may affect the number and a renal tubular defect36. sodium and fluid replacement is probably rarely occurs with tuberculous meningitis35 and is indicated in hypovolaemic hyponatraemia.com Vol 4 March 2005 . Tuberculous encephalopathy patients with TM-associated hyponatraemia have low has not been reported in adults. the commonest of which. Extradural cord better descriptive term for this common complication of tuberculomas cause more than 60% of cases of non. fluid restriction may be more appropriate in those who and bladder dysfunction. plasma volumes and persistent natriuresis despite TM with spinal involvement (figure 3).Review Pretreatment HIV Treatment Pulmonary infection with M tuberculosis Post-treatment Coma Cranial-nerve palsies Hemiparesis Death or disability Bacteraemia Host genotype M tuberculosis strain ↑ CSF lactate ↑ CSF glucose Meningitis ↑ CSF IL8 ↑ CSF TNF ␣ ↑ CSF IFN ␥ Infarctions and tuberculomas Hydrocephulus Oedema ↑ Intracranial pressure ↑ Bacillary replication Vasculitis Encephalitis Meningitis Meningeal/subcortical “Rich” focus Rupture of Rich focus ↑ CSF WCC (neutrophils and lymphocytes) ↑ CSF IL10 ↑ CSF lactate ↑ CSF protein ↑ BBB breakdown ↓ CSF glucose Coma Infarction Hydrocephalus Oedema ↑ Intracranial pressure Time to treatment Drug resistance CSG drug levels HIV infection ↓ Basal inflammation ↓ Vasculitis ↓ Intracranial pressure ↑ CSF matrix metalloproteinases ↑ CSF tissue inhibitors of matrix metalloproteinases ↓ CSF lactate ↓ CSF glucose Survival Figure 1: Overview of the pathophysiology of TM IL8=interleukin 8.40 Despite these investigations. occurs in less than is a stronger correlation between concentrations of 10% of cases. many data from controlled trials. WCC=total white cell count.31. but there are few recent reports and no causes TM-associated hyponatraemia.40 there commonly presents as paraplegia.thelancet. the best method of osseous paraplegia. In patients with HIV.

miliary tuberculosis strongly suggests multiorgan involvement. Five clinical variables were predictive of TM: report of symptoms for longer than 6 days. 3=inappropriate words.25 163 . Panel 3: The modified British Medical Research Council clinical criteria for TM severity grades24 Grade I Alert and orientated without focal neurological deficit Grade II Glasgow coma score* 14–10 with or without focal neurological deficit or Glasgow coma score 15 with focal neurological deficit Grade III Glasgow coma score less than 10 with or without focal neurological deficit *The Glasgow coma score is between 3 and 15. and specificity was 98% if three or more features were present. the presenting clinical features of the disease are non-specific. Diagnosis of TM The diagnosis and treatment of TM before the onset of coma is without question the greatest contribution a physician can make to improved outcome.46 Active extrameningeal tuberculosis is more common in people infected with HIV than in uninfected people. case fatality from TM is greater in people infected with HIV than in those who are uninfected. intense basal enhancement and infarction (bottom right). 6=obeys commands). best verbal response (1=no verbal response.33 although the role of other opportunistic infections upon case fatality is not known and there are no data from people taking antiretroviral drugs. alternative diagnostic methods are incompletely assessed. 2=extension to pain.52 Thwaites and colleagues identified five variables predictive of TM and developed a diagnostic rule (table 1) that had a sensitivity of 86% and a specificity of 79% when it was tested on a further 75 adults.49 Skin testing with purified protein derivative of M tuberculosis is probably of limited value. where 3 is the worst and 15 the best. Clinical diagnosis TM cannot be diagnosed on the history and clinical assessment alone.47. except in infants. 3=flexion to pain. although recall of recent exposure to tuberculosis can be helpful. optic atrophy.thelancet. 4=eyes open spontaneously). However. severe hydrocephalus secondary to TM (top right). First.6 as can signs of active extrameningeal tuberculosis on clinical assessment. particularly in children. sensitivity was 55%. 2=incomprehensible sounds. Second.4 but these findings lack specificity in settings with a high prevalence of pulmonary tuberculosis. abnormal movements. and best motor response (1=no motor response. 4=confused. Third.com Vol 4 March 2005 Figure 2: MRI showing the cerebral pathology of TM Post-contrast scan showing intense basal meningeal enhancement (top left). A second study compared the clinical outcomes of 143 Vietnamese adults with TM with 108 who had either a pathogenic bacteria isolated from the CSF or a CSF glucose to blood glucose ratio less than 0·5 and recovered without antituberculosis treatment. and neutrophils forming less than half the total CSF leucocytes. small numbers of bacilli in the CSF reduce the sensitivity of conventional bacteriology. Three factors are assessed: best eye response (1=no eye opening. 5=localising pain.Review in the meninges than in patients without HIV.20 More importantly. http://neurology. multiple basal tuberculomas and hydrocephalus (bottom left). 2=eye opening to pain. focal neurological deficit.52 The first compared the clinical findings at presentation of 110 Indian children with TM with 94 with meningitis who either had pyogenic bacteria isolated from the CSF or who recovered without antituberculosis treatment. 4=withdrawal from pain. specificity was 44% when at least one feature was present.51. 3=eye opening to verbal command.50 Two studies have tried to identify the clinical and CSF findings predictive of TM.20 Chest radiography finds active or previous tuberculosis infection in about 50% of those with TM.48 but three factors make this difficult. therefore it is very helpful when it is shown by chest radiograph. 5=orientated).51 From these findings a diagnostic rule was developed and tested on a further 128 patients: diagnostic sensitivity was 98%.

hydrocephalus. In summary. if the microscopist was prepared to look hard. the onset can be subtle behavioural changes that do not immediately suggest the diagnosis. such as those developed from the PCR. a common disease of people with HIV.61 According to these data. tuberculoma. and cultured from 94 (71%) patients. but the factors responsible for the large reported variation in the sensitivity of bacteriology have received little attention. 164 Whether molecular techniques can improve upon conventional bacteriology is unclear.56. there are few data to indicate whether findings can help discriminate between TM and other cerebral disorders.thelancet.54 A recent report suggested that precontrast hyperdensity in the basal cisterns might be the most specific radiological sign of TM in children.53 However. the local public health authority must be notified of suspected or proven cases of tuberculous meningitis. Kumar and colleagues54 compared the CT scans of 94 children with TM with those of 52 children with pyogenic meningitis and found basal enhancement. were 89% sensitive and 100% specific for the diagnosis of TM. Given the fatal consequences of delayed treatment. In some patients. In the UK. A recent systematic review and metaanalysis calculated that the sensitivity and specificity of commercial nucleic-acid-amplification assays for the diagnosis of TM was 56% (95% CI 46–66) and 98% (97–99) respectively. Molecular diagnosis Figure 3: MRI showing spinal tuberculosis associated with TM Vertebral tuberculosis causing impingement on the spinal cord (top left). In theory. and the extent of inflammatory exudates.58 but this is rarely the experience in contemporary laboratories. A recent study reported a bacteriological diagnosis of TM in 107 (81%) of 132 adults with the disease. Cryptococcal meningitis. whereas subdural collections were more common in those with pyogenic meningitis. Radiological diagnosis CT and MRI of the brain show the pathological changes of TM (figure 2) and provide diagnostic information at presentation and when complications occur. and lymphoma may be similar to TM on radiographic assessments (figure 4).57 but this might not be true in discrimination of TM from other disorders. Co-infection with HIV may alter the presenting features of TM. extensive vertebral tuberculosis with bilateral fusiform tuberculous paravertebral abscesses (top right). sarcoidosis.com Vol 4 March 2005 . with a sudden onset and polymorphonuclear cell predominance in the CSF. and laboratory findings. infarcts.59 Kennedy and Fallon60 showed that repeated CSF sampling improved the sensitivity of a Ziehl-Neelsen stain to over 80%. a high index of clinical suspicion is needed to diagnose TM. tuberculous radiculomyelitis showing loculation and obliteration of the spinal subarachnoid space with nodular intradural enhancement (bottom right). viral encephalitis. clinicians should be encouraged to initiate “empirical” therapy in the setting of compatible clinical. the http://neurology. Bacteriological diagnosis The comparative role of bacteriological and molecular techniques for the diagnosis of TM has been a source of much controversy.Review The results of these two diagnostic rules are affected by tuberculosis and HIV infection prevalence. cervical-cord tuberculoma causing quadriplegia (bottom left). tuberculoma. epidemiological. and infarction were all substantially more common in those with TM. tuberculomas. meningeal metastases. in others. commonly in children.55 Cranial MRI is better than CT for showing brain stem and cerebellum pathology. the disease can present as pyogenic bacterial meningitis. and changes the spectrum of disorders that present with similar clinical syndromes. Old reports suggested the acid-fast bacilli of M tuberculosis could be seen in the CSF after Zeihl-Neelsen staining in nearly every case. should improve with bacteriology. They suggested basal meningeal enhancement.22 These data suggest simple changes made at the bedside and in the laboratory can substantially improve the performance of conventional bacteriology. and further studies of these patients must be done. These studies were not designed to differentiate between tuberculous and cryptococcal meningitis.22 The likelihood of seeing or culturing M tuberculosis from the CSF was dependent upon meticulous microscopy and culture of a large volume (>5 mL) of CSF. nucleicacid-amplification assays. acid-fast bacilli were seen in 77 (58%) patients. or both. but attempts to clarify their diagnostic role have failed because of few cases and inadequate bacteriological diagnostic comparison.

Rifampicin kills low or non-replicating organisms and pyrazinamide kills those in sites hostile to the penetration and action of the other drugs. the Infectious Diseases Society of America and the American Thoracic Society (IDSA/ATS) recommend that the treatment of TM follow the model of short course chemotherapy of pulmonary tuberculosis: an “intensive phase” of treatment with four drugs. respectively (p=0·150). there are common principles of treatment. Similar findings have been reported63 and indicate molecular methods are sensitive for longer when there is antituberculosis chemotherapy. the diagnosis of TM cannot be excluded by these tests. Antituberculosis chemotherapy The British Thoracic Society (BTS). http://neurology. rifampicin and pyrazinamide become important because they “sterilise” lesions by killing organisms.67 Figure 4: Similar appearance of cryptococcal meningitis and TM on MRI Dilated ventricles with periventricular enhancement in TM (left) and in cryptococcal meningitis (right).66. Together. A study published after the meta-analysis supports this conclusion: the performance of bacteriology was compared with a commercial assay (the amplified mycobacterium tuberculosis direct test) in 79 adults with TM before and after starting antituberculosis drugs.com Vol 4 March 2005 165 . this fell to 2% and 28% (0·013) after 5–15 days of treatment. these data strongly suggest that before the start of treatment careful bacteriology is as good as.thelancet. or better than. Table 1: Maximum score of four for the diagnosis of TM on admission52 sensitivity of these assays is too low (about half those with a negative test will have the disease) and may not be better than bacteriology. with some additional help from streptomycin and ethambutol.64 The same is not true of TM—choice of drugs. Nevertheless. these two drugs are crucial for successful 6-month treatment regimens. followed by treatment with two drugs during a prolonged “continuation phase” (table 2).Review Variable Age (years) 36 36 Blood WCC (103/ml) 15000 15000 History of illness (days) 6 6 CSF total WCC (103/ml) 750 750 CSF % neutrophils 90 90 Score 2 0 4 0 –5 0 3 0 4 0 WCC=white cell count. doses. derived from the roles of the different antituberculosis drugs in the treatment of pulmonary disease. Treatment of TM The optimum treatment for pulmonary tuberculosis has been developed from the results of many controlled trials. Thereafter.65 Isoniazid kills most of the rapidly replicating bacilli in the first 2 weeks of treatment. total score 4=non-TM. However. but molecular methods may be more useful when antituberculosis drugs have started.62 Before the start of treatment the sensitivities of a Ziehl-Neelsen stain and the amplified mycobacterium tuberculosis direct test was 52% and 38%. and duration of treatment are unknown and there are few data to guide the clinician. the commercial nucleic-acid-amplification assays. even if both are negative. Suggested rule for diagnosis: total score 4=TM.

The study also found that treatment with dexamethasone was associated with less severe adverse events. although a recent systematic review concluded 6 months might be sufficient if the likelihood of drug resistance is low.70 Pyridoxine should be given with isoniazid therapy. Our controlled trial of adjunctive dexamethasone in 545 Vietnamese adults with TM addressed some of these trial shortcomings. particularly in South Africa. This finding is interesting and suggests that the affect of http://neurology. CDC=Centers for Disease Control. dispelling a previously held belief that corticosteroids only benefited those with more severe disease. Two facets of the study design warrant cautious interpretation of the poor effect on disability.72 despite no supporting evidence from controlled trials. The IDSA/ATS favour ethambutol.33 Analysis by intention-to-treat found that treatment with dexamethasone for was strongly associated with a reduced risk of death (relative risk 0·69.Review Drug Daily dose Children 35 mg/kg Ethambutol or streptomycin 15 mg/kg 15 mg/kg Duration Oral 9–12 months Oral 9–12 months Adults British Thoracic Society guidelines. Table 2: British and American guidelines for the treatment of TM66. but the effect on morbidity was not elucidated.com Vol 4 March 2005 . the incidence of neurological complications.73 Adjunctive corticosteroids The use of adjunctive corticosteroids has been controversial since they were suggested for the management of TM more than 50 years ago. IDSA.69 and both have substantial adverse effects.69 In contrast. but did not find a significant effect on death or disability in those infected with HIV. Some researchers advocate ethionamide. only 34% of patients’ diagnosis of TM was confirmed by bacteriological analysis. Indeed. and may not have had the discriminatory power to detect a true treatment effect. but suggested corticosteroids reduced CSF inflammation. p=0·01). pyrazinamide. the inclusion of patients with probable or possible TM may have affected the observed effect on disability. Ethionamide penetrates healthy and inflamed meninges. The BTS recommend streptomycin or ethambutol. and others recommend pyrazinamide 166 be given throughout treatment.71 Isoniazid and rifampicin are thought mandatory in the continuation phase.74 Early studies were too small to show an effect on survival. isoniazid and pyrazinamide pass freely into the CSF and some believe their use is crucial to a successful outcome. and further controlled trials were needed that included HIV-infected individuals and were large enough to show a clear effect on case fatality and morbidity in survivors. 2003 Isoniazid 10–15 mg/kg (MD 300 mg) 5 mg/kg (MD 300 mg) Rifampicin 10–20 mg/kg (MD 600 mg) 10 mg/kg (MD 600 mg) Pyrazinamide 15–30 mg/kg (MD 2000 mg) 40–55 kg person: 1000 mg 56–75 kg person: 1500 mg 76–90 kg: 2000 mg Ethambutol 15–20 mg/kg (MD 1000 mg) 40–55 kg person: 800 mg 56–75 kg person: 1200 mg 76–90 kg person: 1600 mg Oral 2 months Oral 2 months Intramuscular 2 months Oral Oral Oral 9–12 months 9–12 months 2 months Oral 2 months MD=maximum dose.67 These guidelines acknowledge the scarcity of evidence from controlled trials and show the main areas of uncertainty: the choice of the fourth drug in the intensive phase and the composition and duration of the continuation phase. but small trial sizes. although neither penetrates the blood–brain barrier well in the absence of inflammation68.65 except when there is initial isoniazid resistance. Many of the recommendations for the treatment of TM combine the principles of pulmonarytuberculosis treatment with pharmacokinetic data that predict the intracerebral concentrations of the antituberculosis drugs. but can cause severe nausea and vomiting.80 Prasad and co-workers81 did a meta-analysis and systematic review of all controlled trials published before 2000 and concluded that corticosteroids probably improved survival in children. rifampicin. and either streptomycin. and possible publication bias did not enable clear treatment recommendations. IDSA=Infectious Diseases Society of America. but did not prevent severe disability in the survivors. The BTS suggests therapy should be extended to 18 months in people who are unable to tolerate pyrazinamide in the intensive phase. or ethionamide. the scores used in assessment of disability were developed to assess outcome from stroke in the more developed world.thelancet. ATS=American Thoracic Society. and CDC.75–78 Later controlled trials from Egypt and South Africa indicated corticosteroids reduced case fatality in children with more severe disease. not TM in Vietnam. in particular hepatitis.79. There was no evidence of beneficial effect in adults or those co-infected with HIV. Subgroup analysis of our trial in Vietnam confirmed that the effect of dexamethasone on survival was consistent across all severity grades of disease. ethambutol. 1998 Isoniazid 5 mg/kg Rifampicin 10 mg/kg Pyrazinamide Route 300 mg 450 mg (50 kg) 600 mg (50 kg) 1·5 g (50 kg) 2·0 g (50 kg) 15 mg/kg 15 mg/kg (maximum 1 g) Guidelines of the joint committee of the ATS. 95% CI 0·52–0·92. and the time to recovery. and increasing prevalence of streptomycin resistance supports this recommendation. Second.82 First. although the role of rifampicin is uncertain because concentrations in CSF do not exceed 10% of those in plasma. data from studies in pulmonary tuberculosis indicate pyrazinamide has little effect on outcome after the first 2 months of therapy. poor treatment allocation concealment. The first 2 months of treatment should be with isoniazid. Both guidelines recommend 9–12 months total antituberculosis treatment.

An anti-inflammatory effect has been difficult to prove83 and corticosteroids might antagonise vascular endothelial growth factor and thereby reduce vasogenic cerebral oedema. why do corticosteroids improve survival but not reduce morbidity? How corticosteroids exert their effect in TM is very poorly understood.89 other research suggests monitoring of lumbar CSF pressure can predict response to medical treatment. In the absence of data. there are no reliable data to support or reject an effect of isoniazid resistance on outcome from TM.thelancet. should patients with TM and HIV infection be given adjunctive dexamethasone? The trial in Vietnamese adults did not find any clear benefit of treatment with dexamethasone in patients infected with HIV but did suggest it was safe and might improve survival. Resistance to isoniazid has been associated with longer times to CSF sterility. Isoniazid has potent early bactericidal activity65 and passes freely into the CSF.94 Whether these assays can Girgis et al79 Schoeman et al80 Thwaites et al33 60% <14 years (median 8 years) All grades Dexamethasone 12 mg/kg/day im (8 mg/kg/day if 25 kg) 12 mg/kg/day im (8 mg/kg/day if 25 kg) 12 mg/kg/day im (8 mg/kg/day if 25 kg) Reducing over 3 weeks to stop† 14 years 14 years Grade II and III Prednisolone 4 mg/kg/day* 4 mg/kg/day 4 mg/kg/day 4 mg/kg/day Reducing dose to stop‡ Grade I Dexamethasone 0·3 mg/kg/day iv 0·2 mg/kg/day iv 0·1 mg/kg/day oral 3 mg total/day oral Reducing by 1 mg each week Thwaites et al33 Grade II and III Dexamethasone 0·4 mg/kg/day iv 0·3 mg/kg/day iv 0·2 mg/kg/day iv 0·1 mg/kg/day iv 4 mg total/day oral Reducing by 1 mg each week *Route of administration not published. Table 3: Corticosteroid regimens associated with substantial improvements in survival in controlled trials http://neurology. However. †dexamethasone tapered to stop over 3 weeks: exact regimen not published. iv=into vein. A small prospective study failed to show a detrimental effect of isoniazid or streptomycin resistance on in-hospital survival.84 Understanding how dexamethasone exerts its substantial clinical effects could lead to more specific and potentially more effective adjunctive therapy. First. current evidence suggests only multidrug resistant TM needs treatment with second-line-antituberculosis drugs. Patients with multidrug resistant TM treated with first-line drugs are likely to be dead before the results of conventional susceptibility tests (which take 6–8 weeks) are available. Second. study findings suggest that all patients with TM who are not infected with HIV should be given dexamethasone.88 Without clear evidence. we suggest the duration of treatment for TM caused by isoniazid-resistant organisms may need to be extended and should include pyrazinamide throughout. but the affect on outcome and implications for treatment are not clear.com Vol 4 March 2005 167 . A history of previously treated tuberculosis or recent exposure to a known case of multidrug resistant pulmonary disease may identify those at high risk of multidrug resistant TM.91 but the series was under-powered (16/56 isoniazid resistant). but timely confirmation of the diagnosis is problematic.88 External ventricular drainage has been used to predict response to ventriculoperitoneal shunting but without success. However.33 Controlled trials including patients taking antiretroviral treatment are needed. regardless of age or disease severity. or ventriculoperitoneal or atrial shunting. Until larger studies are done.62 which suggests an attenuated bactericidal response. The regimens used in recent controlled trials are shown in table 3.90 The effect of resistance to one or both of isoniazid and streptomycin on outcome is more controversial. but until then dexamethasone should probably be used in such patients. several questions are unanswered. Multidrug resistant TM. Some advocate early shunting in all patients with hydrocephalus.87 whereas others only recommend shunting for patients with non-communicable hydrocephalus.Review dexamethasone on outcome may be more diverse than previously thought. Neurosurgical intervention Hydrocephalus is a common complication of TM and can be treated with drugs that have a diuretic effect.69 properties that suggest resistance might be detrimental to treatment. physicians must balance possible benefit with the resources and experience of their surgical unit and the substantial complications of shunt surgery. im=into muscle. has a far worse outcome than disease caused by susceptible organisms. In conclusion. The diagnosis and treatment of multidrug resistant TM is challenging.86 There are no data from controlled trials about which method of treatment is best. caused by organisms resistant to at least isoniazid and rifampicin. ‡ prednisolone tapered to stop over unspecified time: regimen not published. and did not report longer follow-up or morbidity in survivors.85 serial lumbar punctures. Age of patients MRC Grade Drug Week 1 Week 2 Week 3 Week 4 Week 5 Week 6 M tuberculosis resistant to antituberculosis drugs TM caused by M tuberculosis resistant to one or more first-line-antituberculosis drugs is an increasingly common clinical problem.92 Nucleic acid amplification assays that detect mutations in M tuberculosis rpoB gene93 have been used to rapidly diagnose multidrug resistant pulmonary tuberculosis.

Tuberculosis of the central nervous system in children: a 20-year survey. 22: 982–88. “pathophysiology”. Tuberculous meningitis: a 30-year review. there are many questions about its pathophysiology. Indeed. 13 Sharief MK. Farid Z. Clin Infect Dis 1996. Role of the funding source The Wellcome Trust. Freedman VH. 96: 5657–62. Di Sano C. 18 Schoeman JF. Gonzalez-Lahoz JM. Tuberculosis meningitis. Annu Rev Immunol 2001. Manghani DK. those published before 1969 were identified through searches of the old MEDLINE database and our own extensive files. Young RA. References 1 Green PH. Udani PM. 6: 1165–67. et al. 42: 378–79. Chevret S. Steele J. J Infect Dis 1998. 19: 93–129. J Infect 2000. Farrar JJ. Ciardi M. Tuberculous meningitis in adults: an eleven-year review. Sokol K. Geyik MF. 9 Davis LE. Crowe SM. Chan J. Abstracts and reports from meetings were not included. Acta Cytol 1982. drugs that penetrate less well.95 WHO recommends fluoroquinolones for the treatment of multidrug resistant pulmonary tuberculosis. Wolff M. 43: 1775–78. Q J Med 1998. Tuberculous meningitis with acellular cerebrospinal fluid in AIDS patients. Razali KA. streptomycin resistance does not confer resistance to other aminoglycosides. Predominance of Vgamma9/Vdelta2 T lymphocytes in the cerebrospinal fluid of children with tuberculous meningitis: reversal after chemotherapy. Valtchanova S. Die aetiologie der tuberculosis. Taverne J. 17: 987–94. 5: 301–12. 33: 733–52. Tumor necrosis factor alpha is a determinant of pathogenesis and disease progression in mycobacterial infection in the central nervous system. Leveton C. Proc Natl Acad Sci USA 1999. Authors’ contributions GET did the reference research. van Rensburg AJ. Egypt. 20 Karstaedt AS. Laissy JP. Tuberculous meningitis in the southwest United States: a community-based study.97 Until more data are available. and cycloserine are all reported to cross the blood–brain barrier well and may be effective. Holzel H. 21 Jeren T. dose. Than Ha Quyen N. McCordock HA. “diagnosis”. Novelli VM. 4 Girgis NI. Neurology 1993. Lucas CR. from 1976 to 1996. J Child Neurol 2004. 17 Schoeman JF. Sireci G. The pathogenesis of tuberculous meningitis. Berlin Klinische Wochenschrift 1882. use at least three previously unused drugs. Yung A. The best combination. Skipper BJ.97 Data on the CSF penetration and pharmacokinetics of these and other potential drugs are scant.com Vol 4 March 2005 .thelancet. Radiol Clin North Am 1995. Morgan G. 5 Hosoglu S. Barriere R. and duration of secondline drugs for the treatment of multidrug resistant TM are unknown. answers are needed urgently. 7 Kent SJ. vitamin D3 metabolites and tumour necrosis factor in the pathogenesis of tuberculosis. 188: 1105–15. 6 Farinha NJ. Sultan Y.96 but their published use in TM is restricted to case reports. Beus I. Kokoglu OF. have been given by intrathecal injection. Characteristics of cerebrospinal fluid in tuberculous meningitis. J Clin Microbiol 2004. Adrados M. 12 Rook GA. Freedman VH. the treatment of multidrug resistant TM should abide by the principles of treatment of multidrug resistant pulmonary disease: never add a single drug to a failing regimen. et al. Adjunctive thalidomide therapy for childhood tuberculous meningitis: results of a randomized study. The search terms used were: “tuberculous meningitis”. Springer P. and “therapy”. Simmons CP. 166: 350–58. 11 Flynn JL. The role of gammainterferon. such as the aminoglycosides.Review Search strategy and selection criteria References for this review published between 1969 and September 2004 were identified by searches of MEDLINE and PubMed and from references from relevant papers. Aids 1992. diagnosis. 91: 743–47. Pathology and pathogenetic mechanisms in neurotuberculosis. 2 Koch R. Clin Infect Dis 1993. Immunology 1987. Kaplan G. 26: 678–80. 16 Tsenova L. 8 Verdon R. Fournie JJ. 19: 221–30. Can the sensitivity of molecular diagnostic assays be improved? What is the best method of rapidly identifying disease caused by drug resistant organisms and what drugs should be used to treat them? Are adjunctive corticosteroids effective in people co-infected with HIV and should they be used in treatment when these patients are taking antiretroviral drugs? How do corticosteroids improve survival and can a greater understanding of the pathogenesis of TM lead to novel interventions? These are important questions because they threaten our ability to treat TM. Only papers published in English were reviewed. 15 Thwaites GE. Kaplan G. Both authors wrote the review. Lancet 1836. J Child Neurol 2000. Am J Trop Med Hyg 1998. Pathophysiology and prognosis in Vietnamese adults with tuberculous meningitis. Bull John Hopkins Hosp 1933. Ortega A. 19: 250–57. 62: 229–34. Salerno JI. “cerebral tuberculosis”.67 Future research TM is a formidable clinical challenge. The final reference list was generated from papers that were original and relevant to this review. “imaging”. J Infect Dis 1992. Ceviz A. Adjunctive thalidomide therapy of childhood tuberculous meningitis: possible anti-inflammatory role. and treat for at least 18 months. Bergtold A. diagnose multidrug resistant TM with sufficient speed needs urgent study. 10 Dastur DK. Mijch AM. Abbassia Fever Hospital Naval Medical Research Unit No 3. 15: 497–503. II: 232–35. Improving the bacteriological diagnosis of tuberculous meningitis. 168 Conflicts of interest We have no conflicts of interest. J Infect Dis 2003. Thompson EJ. http://neurology. Ravenscroft A. one of which should be a fluoroquinolone. A combination of thalidomide plus antibiotics protects rabbits from mycobacterial meningitis-associated death. 3 Rich AR. Immunology of tuberculosis.98 Ethionamide. Blood-brain barrier damage in patients with bacterial meningitis: association with tumor necrosis factor-alpha but not interleukin-1 beta. 41: 61–68. 58: 28–34. et al. there are no published controlled trials addressing this issue for any form of tuberculosis. et al. 23 Dieli F. Champagne E. Lambert LC. prothionamide. 22 Thwaites GE. Rastogi KR. Ayaz C. Mol Med 1999. Crewe-Brown HH. Tubercular meningitis. UK has funded our research into TM but was not involved in the writing of this review or the decision to submit it for publication. therefore amikacin or kanamycin can be used. Chau TT. Int J Tuberc Lung Dis 1998. 2: 553–57. 52: 5–37. Springer P. Tuberculous meningitis in South African urban adults. Tuberculous meningitis in adults: review of 48 cases. 177: 1563–72. 19 Laguna F. and treatment. 14 Tsenova L. Cairo.

Moschini M. Lancet 2002. 47: 577–81. Schwartz WB. 13: 1876–90. Raised intracranial pressure. Terken M. The bacteriological diagnosis of tuberculous meningitis. Lai MC. Rapoport S. Arribas JR. J Neurol Sci 1970. Chau TT. 143: 700–06. Tuberculous radiculomyelitis complicating tuberculous meningitis: case report and review. I: 582–97. Nagaraj R. Donald PR. Parsons M. 9: 309–13. J Lab Clin Med 1951. Treatment of tuberculosis. Bocchini J Jr. Douis H. Buck R. Brodsky WA. Diagnosis of adult tuberculous meningitis by use of clinical and laboratory features. Cevallos N. Trop Med Int Health 2004. Fallon RJ. 23: 529–42. 6: 311–26. et al. Tuberculosis of the central nervous system. Van Zyl LE. Katrak SM. Kennedy DH. Am J Med 1957. 2: 81–84. Teasdale G. 4. Kocen RS. Hyponatremic natriuretic syndrome in tuberculous meningitis: the probable role of atrial natriuretic peptide. Pediatr Infect Dis J 1991. three-times-weekly regimens for smear-positive pulmonary tuberculosis. 1946-1986. Cotton MF. Pai M. and 6 months of pyrazinamide in 6-month. 3: 261–65. Neurological complications of tuberculosis: some unusual manifestations. 266: 752–54. Singh SN. Nguyen DB. West CD. Lancet Infect Dis 2003. Kumar R. Mitchison DA. Lees AJ. Centers for Disease Control. 39: 17–30. 10: 541–61. Gouws E. Thwaites GE. Tuberculous meningitis. MRI in tuberculous meningoencephalitis: report of four cases and review of the neuroimaging literature. Donald PR. Movement disorders in 30 patients with tuberculous meningitis. Arch Dis Child 1999. 34: 876–85. Thavnani H. Predictors of outcome in patients with tuberculous meningitis. Parekh UC. Moreno S. JAMA 1979. Childs Nerv Syst 1993. Hosoglu S. the renal defect in tuberculous meningitis. 2: 13–19. Seifart HI. Hernandez-Albujar S. 53: 536–48. Childs Nerv Syst 1986. Udani PM. Rays 1998. et al. the syndrome of inappropriate antidiuretic hormone secretion. Kemp M. Aalbers C. 4: 796–806. BMJ 1948. Mitchison DA. J Pediatr 1989. Dastur DK. Stewart SM. Parizel PM. British Thoracic Society. Hyponatraemia and hypovolemic shock with tuberculous meningitis. Neurosurgery 1994. Chest 1972. Wilmshurst J. Dastur DK. Indian Pediatr 1996. 6: 64–70. including an assessment of a combined preparation of isoniazid. 10: 837–42. radiological and pathological profile of tuberculous meningitis in patients with and without human immunodeficiency virus infection. Allen BW. Lombard C. Q J Med 1970. Donald PR. van Dellen JR. Pena JM. Jennett B. 25: 613–17. Plasma arginine vasopressin and the syndrome of inappropriate antidiuretic hormone secretion in tuberculous meningitis. 6: 241–42. Tuberculous meningitis: is a 6-month treatment regimen sufficient? Int J Tuberc Lung Dis 2001. 33: 465–68. N Engl J Med 1992. Bernaerts A. Schoeman JF. Vazquez JJ. Dass R. 61: 629–32. Thwaites GE. Studies on the treatment of tuberculosis undertaken by the British Medical Research Council Tuberculosis Units. The pathology and pathogenesis of tuberculous encephalopathy and myeloradiculopathy: a comparison with allergic encephalomyelitis. Neurosurgically relevant aspects of pathology and pathogenesis of intracranial and intraspinal tuberculosis. Misra UK. J Neurol Sci 1971. J Neurol Sci 2000. Tuberculous encephalopathy with and without meningitis: clinical features and pathological correlations. Ypma L. Van Zyl LE. Diagnostic accuracy of nucleic acid amplification tests for tuberculous meningitis: a systematic review and meta-analysis. Sharma B. Schoeman JF. Donald PR. Dastur DK. Clin Infect Dis 2000. Value of CT scan in the diagnosis of meningitis. Assessment of coma and impaired consciousness: a practical scale. van der Meer JW. Neurosurg Rev 1983. Lancet 1974. Am Rev Respir Dis 1993. Salt losing conditions. Polymerase chain reaction in the diagnosis of tuberculous meningitis. Curelop S. Fazekas F. N Engl J Med 2004. Ethambutol in tuberculous meningitis. Mov Disord 2000. 56: 41–44. Thorax 1992. Royo A. Chemotherapy and management of tuberculosis in the United Kingdom: recommendations 1998. Cerebrospinal fluid concentrations of ethionamide in children with tuberculous meningitis. Outcome of tuberculous meningitis at 6 and 12 months: a multiple regression analysis. Bhandarkar LD. Definitive neuroradiological diagnostic features of tuberculous meningitis in children. 30: 915–21. Verbeek AL. Schmidt R. Indian J Pediatr 2003. 14: 341–57. The clinical. Dastur DK. Postgrad Med J 1980. Narotam PK. Udani PM. Ellard GA. Stepniewska K. Bijwe SR. 148: 650–55. Kohli N. Udani PM. http://neurology. Kohli N. Tuberculous meningitis and miliary tuberculosis in young children. Kumar A. Tuberculous meningitis in patients infected with the human immunodeficiency virus. Streptomycin treatment of tuberculous meningitis. Duenas G. 12: 769–71. 34: 982–88. Vanhoenacker FM. et al. Dastur DK. The pathology and pathogenesis of tuberculous encephalopathy. Berenguer J. 81: 221–24. discussion 15–16. Int J Tuberc Lung Dis 2000. Neurological and related syndromes in CNS tuberculosis: clinical features and pathogenesis. Chau TT. Pediatr Neurol 2002. Riley LW. Cerebrospinal fluid drug concentrations and the treatment of tuberculous meningitis. Laheij RJ. Geyik MF. Thorax 1998. 3: 39–44. Garg RK. 238: 340–44. 9: 10–15. Lui CC. Nguyen HD. Tuberculous meningitis in infancy. Hong Kong Chest Service/British Medical Research Council. Alarcon F. Eur Radiol 2003. The management of tuberculous meningitis. Andronikou S. 52: 1–77. 6: 103–10. Tuberculosis of the central nervous system: overview of neuroradiological findings. 3: 633–43. rifampin. Kalita J. Role of individual drugs in the chemotherapy of tuberculosis. Acta Neuropathol (Berl) 1966. 75: 133–40. 3: S231–79. Cerebral salt wasting. and arginine vasopressin in tuberculous meningitis. Humphries MJ. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. Hypersecretion of anti-diuretic hormone due to tuberculous meningitis. Lancet 1954. Hatherhill M. Di Lella GM. Am Rev Respir Dis 1991. Sakarcan A. Int J Tuberc Lung Dis 2002. et al. Bhoola KD.com Vol 4 March 2005 49 50 51 52 53 54 55 56 57 58 59 60 61 62 63 64 65 66 67 68 69 70 71 72 73 van den Bos F. Offenbacher H. Schoeman JF. 326: 668–72. Hubbard A. Jordaan AM. 42: 996–1002. and pyrazinamide: results at 30 months. et al. Flores LL. A diagnostic rule for tuberculous meningitis. Leone A. Controlled trial of 2. J Infect 1981.Review 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 British Medical Research Council. Int J Tuberc Lung Dis 1999. van Loenhout-Rooyackers JH. Gonzalez-Garcia JJ. et al. 15: 561–69. Cerase A. Int J Tuberc Lung Dis 1999. Tung YR. Laguna F. 70: 995–97. et al. Postgrad Med J 1999. 5: 1028–35. 27: 262–66. Singhi S. Keyser A. van Helden PD. Aalbers C. with relevant subsequent publications. Colosimo C. Smith B. Cort JH. Comparison of conventional bacteriology with nucleic acid amplification (amplified mycobacterium direct test) for diagnosis of tuberculous meningitis before and after inception of antituberculosis chemotherapy. 351: 1741–51. Pediatr Nephrol 1998. Humphries M. Fallon RJ. J Neurol 1991. Cotton MF. Kennedy DH. Murlidharan J. Godwin-Austen R. Bartter FC. Diagnostic imaging of neurotuberculosis. MMWR Recomm Rep 2003. 360: 1287–92. Treatment and prognosis in tuberculous meningitis. Kumar R. J Clin Microbiol 2004. Tartaglione T. Balik I. Fox W.thelancet. 115: 483–86. Colford JM. Smith J. Bennett W. Caws M. Lombard CJ. Shembalkar PK. Pediatr Radiol 2004. et al. Scand J Infect Dis 1993. Bobrowitz ID. The role of fludrocortisone in a child with cerebral salt wasting. 169 . Ellard GA. Thwaites GE. et al. 241: 264–68. 181: 118–26. Victor TC. 23: 164–80. Pai N. J Clinical Pathology 1953. A syndrome of renal sodium loss and hyponatremia probably resulting from inappropriate secretion of antidiuretic hormone. 37: 550–61.

Janse van Rensburg A. Multidrug-resistant tuberculous meningitis in KwaZulu-Natal. Menon GR. van Rensburg AJ. Lundgren B. Mortality from tuberculous meningitis reduced by steroid therapy.thelancet. Schoeman JF. Vascular endothelial growth factor and blood-brain barrier disruption in tuberculous meningitis. Pediatrics 1997. Hoppenreijs S. Ventriculoperitoneal shunting in childhood tuberculous meningitis. Dexamethasone in tuberculous meningitis: relationship of cerebrospinal fluid effects to therapeutic efficacy. Pediatr Infect Dis J 1991. Clin Infect Dis 2004. Vyshnevskiy B. Nau R. N Engl J Med 1953. Donald PR. Multidrug-resistant tuberculous meningitis in patients with AIDS. Medina P. Chau TT. 249: 829–34. Kolenda H. Cleary T. 3: CD00224. Caws M. Adjunctive steroids for tuberculous meningitis: more evidence. Maher D. Serial lumbar CSF presure measurements and cranial computed tomographic findings in childhood tuberculous meningitits. Ann Intern Med 1969. Clin Infect Dis 2001. Thornton GF. Novel treatment of meningitis caused by multidrug-resistant Mycobacterium tuberculosis with intrathecal levofloxacin and amikacin: case report. Schoeman J. Laubscher JA. Joseph T. Wait J. Donald P. van Zyl L. Lepper MH. Escobar JA. Sterling TR. 33: 396–405. Schoeman JF. Shunt surgery in poor grade patients with tuberculous meningitis and hydrocephalus: effects of response to external ventricular drainage and other variables on long term outcome. Daikos GL. 7: 394–98. Ashby M. Berning SE. Dye C. Prange HW. Lancet 1955. Donald PR. Riley C. Martell J. 1: 65–66. et al. Steroids for treating tuberculous meningitis. 21: 299–305. Donald P. 70: 39–48. Mathew JM. Duenas A. Chaulet P. 15: 119–25. Geneva: WHO TB. van der Flier M. Direct detection of multidrug-resistant Mycobacterium tuberculosis in clinical specimens in low. Sharifi S. Schoeman JF. Guidelines for the management of drug-resistant tuberculosis. Antimicrob Agents Chemother 2003.com Vol 4 March 2005 . South Africa. Lamprecht D. J Antimicrob Chemother 1990. Chandy MJ. Kilpatrick ME. Tuberculous hydrocephalus: comparison of different treatments with regard to ICP. Ann Trop Paediatr 2001. et al. Narvskaya O. and clinical outcome in young children with tuberculous meningitis. Dev Med Child Neurol 1991. Volmink J. Ann N Y Acad Med 1963. Pediatrics 1975. 25: 965–73. Girgis NI. Crofton J. http://neurology. 87 88 89 90 91 92 93 94 95 96 97 98 Palur R. 74: 64–69. Tuberculosis. computed tomographic findings. Donald PR. The present status of the treatment of tuberculosis of the central nervous system. Br J Neurosurg 2001. Iseman MD. The effect of adjuvant steroid treatment on serial cerebrospinal fluid changes in tuberculous meningitis. Laubscher JA. Tuberculous meningitis treated with cortisone. J Clin Microbiol 2003. Lancet 2003.and high-incidence countries by line probe assay. N Engl J Med 2004. 1997. ventricular size and clinical outcome. 32: 643–46. Munsiff SS. Isoniazid resistance. Cochrane Database Syst Rev 2000. Chandy MJ. 10: 179–83. Rodriguez A. Belsey MA. 99: 226–31. 38: 851–56. 23: 608–13. Mukherjee MK. Mikhail IA. Thwaites GE. Patel VB. Frieden TR. Laubscher JA. Tuberculous meningitis: combined therapy with cortisone and antimicrobial agents. Bircher J. Keet M. Thomsen Vs VO. Spies HW. Childs Nerv Syst 2000. Abraham J. Mokrousov I. 41: 4454–56. Sosnovskaja A. Padayatchi N. Rajshekhar V. Johansen IS. 16: 203–08. Nath RL. more questions. 106: 106–23.Review 74 75 76 77 78 79 80 81 82 83 84 85 86 170 Shane SJ. Shunt surgery for hydrocephalus in tuberculous meningitis: a long-term follow-up study. Otten T. Bhigjee AI. Dexamethasone adjunctive treatment for tuberculous meningitis. O’Toole RD. Effect of corticosteroids on intracranial pressure. Watt CJ. 65: 115–8. 6: 865–71. Allele-specific rpoB PCR assays for detection of rifampin-resistant Mycobacterium tuberculosis in sputum smears. Quagliarello V. J Neurol Neurosurg Psychiatry 1998. 362: 887–99. Int J Tuberc Lung Dis 2003. Prasad K. 351: 1792–94. Cherry TA. Rajshekhar V. Farid Z. mycobacterial genotype and outcome in Vietnamese adults with tuberculous meningitis. Fischl MA. Sultan Y.47: 2231–35. Penetration of ciprofloxacin into the cerebrospinal fluid of patients with uninflamed meninges. J Neurosurg 1991. Pediatr Infect Dis J 2004. Hartzenberg H. Elshof JW. et al. Van Zyl LE. Int J Tuberc Lung Dis 2002. 56: 1050–55. Schoeman J. Grant H.