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 [email protected]
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
“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
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%; 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,11 but is also cited as a main factor in hostmediated destruction of infected tissue.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,14 although TNF concentrations have not been correlated with disease severity or outcome in human beings.15 Treatment with antibiotics and thalidomide, an anti TNF drug, improved survival and neurological outcome in rabbits16 and suggested a novel therapeutic approach in people. 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. Sadly, 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.18 The numbers and types of white cells in the CSF help differentiate TM from other meningitides, but little is known of their role in disease pathogenesis. Typically the CSF shows a high CSF white-cell count, which is predominantly lymphocytic, with a high protein and low http://neurology.thelancet.com Vol 4 March 2005
glucose ratio. However, total CSF white-cell count can be normal in those with TM and depressed cell-mediated immunity, such as the elderly and people with HIV;19,20 low counts have been associated with poor outcome.15 Neutrophils can dominate, especially early in the disease,21 and high proportions of neutrophils in the cell count have been associated with an increased likelihood of a bacteriological diagnosis and improved survival. Hence, neutrophils could have a role in pathogenesis.15,22 The kinetics of the lymphocyte response are probably also important, particularly the roles of different lymphocyte subsets,23 but more data on these cells are needed.
Pathological and clinical consequences of infection The macroscopic consequences of infection have been researched post mortem and, more recently, through CT and MRI (ﬁgure 2) of the brain. Neurological abnormalities occur with the development of an inﬂammatory exudate that affects mostly the sylvian ﬁssures, basal cisterns, brainstem, and cerebellum.10 Three processes cause most of the common neurological deﬁcits: the adhesive exudate can obstruct CSF causing hydrocephalus and compromise efferent cranial nerves; granulomas can coalesce to form tuberculomas (or an abscess in patients with uncharacteristic disease) which, depending on their location, cause diverse clinical consequences; and an obliterative vasculitis can cause infarction and stroke syndromes.10 The severity of these complications may be dependent on the intracerebral inﬂammatory response and strongly predicts outcome.15 Indeed, 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),24 variables shown to be strongly predictive of death.26 Unusual clinical and pathological features of TM have been well described in previous research papers and can cause diagnostic uncertainty.27,28 Movement disorders can present after basal ganglia infarction; tremor is the most common, but chorea, ballismus, and myoclonus are all reported.29 Less common, and more controversial, 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. Dastur and Udani30 were the ﬁrst to describe this variant of cerebral tuberculosis, which they called “tuberculous encephalopathy”, in Indian children with disseminated tuberculosis. These children had a diffuse cerebral disorder with coma, convulsions, involuntary movements, and pyramidal signs but with normal CSF measurements. 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, demyelination, and sometimes haemorrhage— features that may be more typical of a post-infectious 161
Pulmonary infection with M tuberculosis
Coma Cranial-nerve palsies Hemiparesis
Death or disability
Bacteraemia Host genotype
M tuberculosis strain
↑ CSF lactate ↑ CSF glucose
↑ 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
Figure 1: Overview of the pathophysiology of TM IL8=interleukin 8; IL10=interleukin 10; IFN =interferon ; WCC=total white cell count; BBB=blood–brain barrier.
allergic encephalomyelitis.31,32 Anecdotal reports suggest hyponatraemia associated originally with bronchial the disease is responsive to treatment with carcinoma38 led some to think a similar mechanism corticosteroids, but there are few recent reports and no causes TM-associated hyponatraemia.39 However, many data from controlled trials. Tuberculous encephalopathy patients with TM-associated hyponatraemia have low has not been reported in adults. plasma volumes and persistent natriuresis despite TM with spinal involvement (ﬁgure 3), which normal concentrations of antidiuretic hormone;40 there commonly presents as paraplegia, occurs in less than is a stronger correlation between concentrations of 10% of cases.33 Vertebral tuberculosis (Pott’s disease) plasma atrial natriuretic peptide and sodium. 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. Extradural cord better descriptive term for this common complication of tuberculomas cause more than 60% of cases of non- TM.40 Despite these investigations, the best method of osseous paraplegia,34 although tuberculomas can occur correcting the sodium concentration in the plasma is not in any part of the cord. Tuberculous radiculomyelitis known; sodium and ﬂuid replacement is probably rarely occurs with tuberculous meningitis35 and is indicated in hypovolaemic hyponatraemia,41 whereas characterised by a subacute paraparesis, radicular pain, ﬂuid restriction may be more appropriate in those who and bladder dysfunction. MRI reveals loculation and are euvolaemic.42 There is anecdotal evidence to suggest obliteration of the spinal subarachnoid space with ﬂudrocortisone replacement therapy43 and demeclonodular intradural enhancement. cycline44 may be useful. TM can also cause metabolic complications, the commonest of which, hyponatraemia, affects more than Co-infection with HIV 50% of patients with the disease.9 A “cerebral salt Research ﬁndings suggest HIV does not alter the clinical wasting syndrome” associated with TM and attributed to presentation of TM,45 but may affect the number and a renal tubular defect36,37 was described more than nature of complications. In patients with HIV, basal (PLEASE MARK WITH RED SPOT IF and URGENT) TLN_MAR_10003_Thwaites_1.eps meningeal enhancement hydrocephalus on CT 50Ref number years ago. 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
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in the meninges than in patients without HIV.46 Active extrameningeal tuberculosis is more common in people infected with HIV than in uninfected people.20 More importantly, case fatality from TM is greater in people infected with HIV than in those who are uninfected,33 although the role of other opportunistic infections upon case fatality is not known and there are no data from people taking antiretroviral drugs.
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,47,48 but three factors make this difﬁcult. First, the presenting clinical features of the disease are non-speciﬁc. Second, small numbers of bacilli in the CSF reduce the sensitivity of conventional bacteriology. Third, alternative diagnostic methods are incompletely assessed.
Clinical diagnosis TM cannot be diagnosed on the history and clinical assessment alone, although recall of recent exposure to tuberculosis can be helpful, particularly in children,6 as can signs of active extrameningeal tuberculosis on clinical assessment.20 Chest radiography ﬁnds active or previous tuberculosis infection in about 50% of those with TM,4 but these ﬁndings lack speciﬁcity in settings with a high prevalence of pulmonary tuberculosis. However, miliary tuberculosis strongly suggests multiorgan involvement; therefore it is very helpful when it is shown by chest radiograph.49 Skin testing with puriﬁed protein derivative of M tuberculosis is probably of limited value, except in infants.50 Two studies have tried to identify the clinical and CSF ﬁndings predictive of TM.51,52 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. Five clinical variables were predictive of TM: report of symptoms for longer than 6 days, optic atrophy, focal neurological deﬁcit, abnormal movements, and neutrophils forming less than half the total CSF leucocytes.51 From these ﬁndings a diagnostic rule was developed and tested on a further 128 patients: diagnostic sensitivity was 98%, speciﬁcity was 44% when at least one feature was present; sensitivity was 55%, and speciﬁcity was 98% if three or more features were present. 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.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. http://neurology.thelancet.com Vol 4 March 2005
Figure 2: MRI showing the cerebral pathology of TM Post-contrast scan showing intense basal meningeal enhancement (top left); severe hydrocephalus secondary to TM (top right); multiple basal tuberculomas and hydrocephalus (bottom left); intense basal enhancement and infarction (bottom right).
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, where 3 is the worst and 15 the best. Three factors are assessed: best eye response (1=no eye opening, 2=eye opening to pain, 3=eye opening to verbal command, 4=eyes open spontaneously), best verbal response (1=no verbal response, 2=incomprehensible sounds, 3=inappropriate words, 4=confused, 5=orientated), and best motor response (1=no motor response, 2=extension to pain, 3=ﬂexion to pain, 4=withdrawal from pain, 5=localising pain, 6=obeys commands).25
The results of these two diagnostic rules are affected by tuberculosis and HIV infection prevalence. Co-infection with HIV may alter the presenting features of TM, and changes the spectrum of disorders that present with similar clinical syndromes. These studies were not designed to differentiate between tuberculous and cryptococcal meningitis, a common disease of people with HIV, and further studies of these patients must be done. In summary, a high index of clinical suspicion is needed to diagnose TM. In some patients, commonly in children, the onset can be subtle behavioural changes that do not immediately suggest the diagnosis; in others, the disease can present as pyogenic bacterial meningitis, with a sudden onset and polymorphonuclear cell predominance in the CSF. Given the fatal consequences of delayed treatment, clinicians should be encouraged to initiate “empirical” therapy in the setting of compatible clinical, epidemiological, and laboratory ﬁndings. In the UK, the local public health authority must be notiﬁed of suspected or proven cases of tuberculous meningitis.
there are few data to indicate whether ﬁndings can help discriminate between TM and other cerebral disorders. Kumar and colleagues54 compared the CT scans of 94 children with TM with those of 52 children with pyogenic meningitis and found basal enhancement, hydrocephalus, tuberculoma, and infarction were all substantially more common in those with TM, whereas subdural collections were more common in those with pyogenic meningitis. They suggested basal meningeal enhancement, tuberculoma, or both, were 89% sensitive and 100% speciﬁc for the diagnosis of TM.54 A recent report suggested that precontrast hyperdensity in the basal cisterns might be the most speciﬁc radiological sign of TM in children.55 Cranial MRI is better than CT for showing brain stem and cerebellum pathology, tuberculomas, infarcts, and the extent of inﬂammatory exudates,56,57 but this might not be true in discrimination of TM from other disorders. Cryptococcal meningitis, viral encephalitis, sarcoidosis, meningeal metastases, and lymphoma may be similar to TM on radiographic assessments (ﬁgure 4).
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.53 However,
Bacteriological diagnosis The comparative role of bacteriological and molecular techniques for the diagnosis of TM has been a source of much controversy. Old reports suggested the acid-fast bacilli of M tuberculosis could be seen in the CSF after Zeihl-Neelsen staining in nearly every case, if the microscopist was prepared to look hard,58 but this is rarely the experience in contemporary laboratories.59 Kennedy and Fallon60 showed that repeated CSF sampling improved the sensitivity of a Ziehl-Neelsen stain to over 80%, but the factors responsible for the large reported variation in the sensitivity of bacteriology have received little attention. A recent study reported a bacteriological diagnosis of TM in 107 (81%) of 132 adults with the disease; acid-fast bacilli were seen in 77 (58%) patients, and cultured from 94 (71%) patients.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.22 These data suggest simple changes made at the bedside and in the laboratory can substantially improve the performance of conventional bacteriology.
Figure 3: MRI showing spinal tuberculosis associated with TM Vertebral tuberculosis causing impingement on the spinal cord (top left); extensive vertebral tuberculosis with bilateral fusiform tuberculous paravertebral abscesses (top right); cervical-cord tuberculoma causing quadriplegia (bottom left); tuberculous radiculomyelitis showing loculation and obliteration of the spinal subarachnoid space with nodular intradural enhancement (bottom right).
Whether molecular techniques can improve upon conventional bacteriology is unclear. In theory, nucleicacid-ampliﬁcation assays, such as those developed from the PCR, should improve with bacteriology; but attempts to clarify their diagnostic role have failed because of few cases and inadequate bacteriological diagnostic comparison. 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.61 According to these data, the http://neurology.thelancet.com Vol 4 March 2005
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. Suggested rule for diagnosis: total score 4=TM; total score 4=non-TM.
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. 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.62 Before the start of treatment the sensitivities of a Ziehl-Neelsen stain and the ampliﬁed mycobacterium tuberculosis direct test was 52% and 38%, respectively (p=0·150); this fell to 2% and 28% (0·013) after 5–15 days of treatment. Similar ﬁndings have been reported63 and indicate molecular methods are sensitive for longer when there is antituberculosis chemotherapy. Together, these data strongly suggest that before the
start of treatment careful bacteriology is as good as, or better than, the commercial nucleic-acid-ampliﬁcation assays, but molecular methods may be more useful when antituberculosis drugs have started. However, the diagnosis of TM cannot be excluded by these tests, even if both are negative.
Treatment of TM The optimum treatment for pulmonary tuberculosis has been developed from the results of many controlled trials.64 The same is not true of TM—choice of drugs, doses, and duration of treatment are unknown and there are few data to guide the clinician. Nevertheless, there are common principles of treatment, derived from the roles of the different antituberculosis drugs in the treatment of pulmonary disease.65 Isoniazid kills most of the rapidly replicating bacilli in the ﬁrst 2 weeks of treatment, with some additional help from streptomycin and ethambutol. Thereafter, rifampicin and pyrazinamide become important because they “sterilise” lesions by killing organisms; these two drugs are crucial for successful 6-month treatment regimens. Rifampicin kills low or non-replicating organisms and pyrazinamide kills those in sites hostile to the penetration and action of the other drugs.
Antituberculosis chemotherapy The British Thoracic Society (BTS), 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, followed by treatment with two drugs during a prolonged “continuation phase” (table 2).66,67
Figure 4: Similar appearance of cryptococcal meningitis and TM on MRI Dilated ventricles with periventricular enhancement in TM (left) and in cryptococcal meningitis (right).
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Daily dose Children
Ethambutol or streptomycin
15 mg/kg 15 mg/kg
British Thoracic Society guidelines, 1998 Isoniazid 5 mg/kg Rifampicin 10 mg/kg Pyrazinamide
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, IDSA, and CDC, 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
MD=maximum dose. ATS=American Thoracic Society; IDSA=Infectious Diseases Society of America; CDC=Centers for Disease Control.
Table 2: British and American guidelines for the treatment of TM66,67
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. 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. The ﬁrst 2 months of treatment should be with isoniazid, rifampicin, pyrazinamide, and either streptomycin, ethambutol, or ethionamide. The BTS recommend streptomycin or ethambutol, although neither penetrates the blood–brain barrier well in the absence of inﬂammation68,69 and both have substantial adverse effects. The IDSA/ATS favour ethambutol, and increasing prevalence of streptomycin resistance supports this recommendation. Some researchers advocate ethionamide, particularly in South Africa. Ethionamide penetrates healthy and inﬂamed meninges, but can cause severe nausea and vomiting.70 Pyridoxine should be given with isoniazid therapy. Both guidelines recommend 9–12 months total antituberculosis treatment; although a recent systematic review concluded 6 months might be sufﬁcient if the likelihood of drug resistance is low.71 Isoniazid and rifampicin are thought mandatory in the continuation phase, although the role of rifampicin is uncertain because concentrations in CSF do not exceed 10% of those in plasma.69 In contrast, isoniazid and pyrazinamide pass freely into the CSF and some believe their use is crucial to a successful outcome. The BTS suggests therapy should be extended to 18 months in people who are unable to tolerate pyrazinamide in the intensive phase, and others recommend pyrazinamide 166
be given throughout treatment,72 despite no supporting evidence from controlled trials. Indeed, data from studies in pulmonary tuberculosis indicate pyrazinamide has little effect on outcome after the ﬁrst 2 months of therapy,65 except when there is initial isoniazid resistance.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.74 Early studies were too small to show an effect on survival, but suggested corticosteroids reduced CSF inﬂammation, the incidence of neurological complications, and the time to recovery.75–78 Later controlled trials from Egypt and South Africa indicated corticosteroids reduced case fatality in children with more severe disease, but the effect on morbidity was not elucidated.79,80 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, but small trial sizes, poor treatment allocation concealment, and possible publication bias did not enable clear treatment recommendations. There was no evidence of beneﬁcial effect in adults or those co-infected with HIV, 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. Our controlled trial of adjunctive dexamethasone in 545 Vietnamese adults with TM addressed some of these trial shortcomings.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, 95% CI 0·52–0·92, p=0·01), but did not prevent severe disability in the survivors. Two facets of the study design warrant cautious interpretation of the poor effect on disability.82 First, only 34% of patients’ diagnosis of TM was conﬁrmed by bacteriological analysis; the inclusion of patients with probable or possible TM may have affected the observed effect on disability. Second, the scores used in assessment of disability were developed to assess outcome from stroke in the more developed world, not TM in Vietnam, and may not have had the discriminatory power to detect a true treatment effect. Subgroup analysis of our trial in Vietnam conﬁrmed that the effect of dexamethasone on survival was consistent across all severity grades of disease, dispelling a previously held belief that corticosteroids only beneﬁted those with more severe disease, but did not ﬁnd a signiﬁcant effect on death or disability in those infected with HIV. The study also found that treatment with dexamethasone was associated with less severe adverse events, in particular hepatitis. This ﬁnding is interesting and suggests that the affect of http://neurology.thelancet.com Vol 4 March 2005
dexamethasone on outcome may be more diverse than previously thought. In conclusion, study ﬁndings suggest that all patients with TM who are not infected with HIV should be given dexamethasone, regardless of age or disease severity. The regimens used in recent controlled trials are shown in table 3. However, several questions are unanswered. First, 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.33 Controlled trials including patients taking antiretroviral treatment are needed, but until then dexamethasone should probably be used in such patients. Second, why do corticosteroids improve survival but not reduce morbidity? How corticosteroids exert their effect in TM is very poorly understood. An anti-inﬂammatory effect has been difﬁcult to prove83 and corticosteroids might antagonise vascular endothelial growth factor and thereby reduce vasogenic cerebral oedema.84 Understanding how dexamethasone exerts its substantial clinical effects could lead to more speciﬁc and potentially more effective adjunctive therapy.
Neurosurgical intervention Hydrocephalus is a common complication of TM and can be treated with drugs that have a diuretic effect,85 serial lumbar punctures, or ventriculoperitoneal or atrial shunting.86 There are no data from controlled trials about which method of treatment is best. Some advocate early shunting in all patients with hydrocephalus,87 whereas others only recommend shunting for patients with non-communicable hydrocephalus.88 External ventricular drainage has been used to predict response to ventriculoperitoneal shunting but without success,89 other research suggests monitoring of lumbar CSF pressure can predict response to medical treatment.88 Without clear evidence, physicians must balance possible beneﬁt with the resources and experience of their surgical unit and the substantial complications of shunt surgery.
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, but the affect on outcome and implications for treatment are not clear. Multidrug resistant TM, caused by organisms resistant to at least isoniazid and rifampicin, has a far worse outcome than disease caused by susceptible organisms.90 The effect of resistance to one or both of isoniazid and streptomycin on outcome is more controversial. Isoniazid has potent early bactericidal activity65 and passes freely into the CSF,69 properties that suggest resistance might be detrimental to treatment. Resistance to isoniazid has been associated with longer times to CSF sterility,62 which suggests an attenuated bactericidal response. However, there are no reliable data to support or reject an effect of isoniazid resistance on outcome from TM. A small prospective study failed to show a detrimental effect of isoniazid or streptomycin resistance on in-hospital survival,91 but the series was under-powered (16/56 isoniazid resistant), and did not report longer follow-up or morbidity in survivors. Until larger studies are done, current evidence suggests only multidrug resistant TM needs treatment with second-line-antituberculosis drugs. In the absence of data, we suggest the duration of treatment for TM caused by isoniazid-resistant organisms may need to be extended and should include pyrazinamide throughout. The diagnosis and treatment of multidrug resistant TM is challenging. 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, but timely conﬁrmation of the diagnosis is problematic. 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.92 Nucleic acid ampliﬁcation assays that detect mutations in M tuberculosis rpoB gene93 have been used to rapidly diagnose multidrug resistant pulmonary tuberculosis.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†
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; †dexamethasone tapered to stop over 3 weeks: exact regimen not published; ‡ prednisolone tapered to stop over unspeciﬁed time: regimen not published. im=into muscle; iv=into vein.
Table 3: Corticosteroid regimens associated with substantial improvements in survival in controlled trials
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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; those published before 1969 were identiﬁed through searches of the old MEDLINE database and our own extensive ﬁles. The search terms used were: “tuberculous meningitis”, “cerebral tuberculosis”, “pathophysiology”, “diagnosis”, “imaging”, and “therapy”. Abstracts and reports from meetings were not included. Only papers published in English were reviewed. The ﬁnal reference list was generated from papers that were original and relevant to this review.
diagnose multidrug resistant TM with sufﬁcient speed needs urgent study. The best combination, dose, and duration of secondline drugs for the treatment of multidrug resistant TM are unknown. Indeed, there are no published controlled trials addressing this issue for any form of tuberculosis.95 WHO recommends ﬂuoroquinolones for the treatment of multidrug resistant pulmonary tuberculosis,96 but their published use in TM is restricted to case reports.97 Data on the CSF penetration and pharmacokinetics of these and other potential drugs are scant.98 Ethionamide, prothionamide, and cycloserine are all reported to cross the blood–brain barrier well and may be effective; drugs that penetrate less well, such as the aminoglycosides, have been given by intrathecal injection.97 Until more data are available, 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; use at least three previously unused drugs, one of which should be a ﬂuoroquinolone; streptomycin resistance does not confer resistance to other aminoglycosides, therefore amikacin or kanamycin can be used; and treat for at least 18 months.67
Future research TM is a formidable clinical challenge; there are many questions about its pathophysiology, diagnosis, and treatment. 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; answers are needed urgently. Authors’ contributions GET did the reference research. Both authors wrote the review.
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