Tuberculous meningitis: many questions, too few answers

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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 Lancetpublished a description of six children with fatal

“acute hydrocephalus”.¹Assessment post-mortem found

“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 tuberculosisfor the first time and showed it was the bacterium transmitted in tuberculosis.²Thereafter, 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 McCordock³reported 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)^4–9the 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 granulo- matous inflammation.¹⁰ In pulmonary tuberculosis,

Lancet Neurol2005; 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

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.

Tuberculous meningitis: many questions, too few answers

Guy E Thwaites, Tran Tinh Hien

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

TNF is thought to be crucial for granuloma formation,¹¹but is also cited as a main factor in host- mediated destruction of infected tissue.¹² Studies of pyogenic bacterial meningitis showed CSF concentrations of TNF correlated with disease severity¹³and 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 rabbits¹⁶and suggested a novel therapeutic approach in people. Preliminary research found that thalidomide was safe and well-tolerated¹⁷and 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

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,²¹and 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,²³but 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.¹⁰The 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.²⁹Less 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 Udani³⁰were 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 Panel 2: TM symptoms on presentation^4–9

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

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allergic encephalomyelitis.^31,32Anecdotal reports suggest the disease is responsive to treatment with corticosteroids, but there are few recent reports and no data from controlled trials. Tuberculous encephalopathy has not been reported in adults.

TM with spinal involvement (figure 3), which commonly presents as paraplegia, occurs in less than 10% of cases.³³ Vertebral tuberculosis (Pott’s disease) accounts for about a quarter of patients with TM with spinal involvement and may be associated with fusiform para-vertebral abscesses or a gibbus. Extradural cord tuberculomas cause more than 60% of cases of non- osseous paraplegia,³⁴although tuberculomas can occur in any part of the cord. Tuberculous radiculomyelitis rarely occurs with tuberculous meningitis³⁵ and is characterised by a subacute paraparesis, radicular pain, and bladder dysfunction. MRI reveals loculation and obliteration of the spinal subarachnoid space with nodular intradural enhancement.

TM can also cause metabolic complications, the commonest of which, hyponatraemia, affects more than 50% of patients with the disease.⁹ A “cerebral salt wasting syndrome” associated with TM and attributed to a renal tubular defect^36,37 was described more than 50 years ago. The discovery of a syndrome of inappropriate antidiuretic hormone as a cause of

hyponatraemia associated originally with bronchial carcinoma³⁸ led some to think a similar mechanism causes TM-associated hyponatraemia.³⁹However, many patients with TM-associated hyponatraemia have low plasma volumes and persistent natriuresis despite normal concentrations of antidiuretic hormone;⁴⁰there is a stronger correlation between concentrations of plasma atrial natriuretic peptide and sodium. Although a role for antidiuretic hormone has not been excluded,

“hyponatraemic natriuretic syndrome” is probably a better descriptive term for this common complication of TM.⁴⁰Despite these investigations, the best method of correcting the sodium concentration in the plasma is not known; sodium and fluid replacement is probably indicated in hypovolaemic hyponatraemia,⁴¹ whereas fluid restriction may be more appropriate in those who are euvolaemic.⁴²There is anecdotal evidence to suggest fludrocortisone replacement therapy⁴³ and demeclo- cycline⁴⁴may be useful.

Co-infection with HIV

Research findings suggest HIV does not alter the clinical presentation of TM,⁴⁵ but may affect the number and nature of complications. In patients with HIV, basal meningeal enhancement and hydrocephalus on CT might be less common and there could be more bacilli

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Shapes Pulmonary infection

with M tuberculosis HIV

Meningeal/subcortical

“Rich” focus Bacteraemia

Rupture of Rich focus Meningitis

↑ Bacillary replication

Coma

Cranial-nerve palsies Hemiparesis

Death or disability

Pretreatment Treatment Post-treatment

Survival

↑ CSF lactate

↑ CSF glucose

Time to treatment Drug resistance CSG drug levels HIV infection M tuberculosis strain

↑ CSF IL8

↑ CSF TNF ␣

↑ CSF IFN ␥

↑ CSF lactate

↑ CSF protein

↑ BBB breakdown

↓ CSF glucose

Coma Infarction Hydrocephalus Oedema

↑ Intracranial pressure

Infarctions and tuberculomas Hydrocephulus

Oedema

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↓ Basal inflammation

↓ Vasculitis

↓ Intracranial pressure

↓ CSF lactate

↓ CSF glucose Vasculitis

Encephalitis Meningitis

↑ CSF WCC (neutrophils and lymphocytes)

↑ CSF IL10

↑ CSF matrix metalloproteinases

↑ CSF tissue inhibitors of matrix metalloproteinases Host

genotype

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.

in the meninges than in patients without HIV.⁴⁶Active 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,^47,48but 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,⁶as can signs of active extrameningeal tuberculosis on clinical assessment.²⁰Chest radiography finds active or previous tuberculosis infection in about 50% of those with TM,⁴but 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.⁴⁹Skin testing with purified protein derivative of M tuberculosisis 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.⁵¹From 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.⁵²Thwaites 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.

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

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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.

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.⁵³However,

there are few data to indicate whether findings can help discriminate between TM and other cerebral disorders.

Kumar and colleagues⁵⁴compared 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.⁵⁴A recent report suggested that precontrast hyperdensity in the basal cisterns might be the most specific radiological sign of TM in children.⁵⁵Cranial MRI is better than CT for showing brain stem and cerebellum pathology, tuberculomas, infarcts, and the extent of inflammatory exudates,^56,57but 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).

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 tuberculosiscould 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 tuberculosisfrom the CSF was dependent upon meticulous microscopy and culture of a large volume (>5 mL) of CSF.²²These data suggest simple changes made at the bedside and in the laboratory can substantially improve the performance of conventional bacteriology.

Molecular diagnosis

Whether molecular techniques can improve upon conventional bacteriology is unclear. In theory, nucleic- acid-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 meta- analysis 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

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).

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 tuberculosisdirect test) in 79 adults with TM before and after starting antituberculosis drugs.⁶²Before the start of treatment the sensitivities of a Ziehl-Neelsen stain and the amplified mycobacterium tuberculosisdirect 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 reported⁶³and 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.⁶⁴The 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.⁶⁵Isoniazid 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

Variable Score

Age (years)

36 2

36 0

Blood WCC (103/ml)

15000 4

15000 0

History of illness (days)

6 –5

6 0

CSF total WCC (103/ml)

750 3

750 0

CSF % neutrophils

90 4

90 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

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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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 pulmonary- tuberculosis 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 inflammation^68,69 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

be given throughout treatment,⁷²despite 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.^75–78Later 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-workers⁸¹did 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.³³Analysis 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

Drug Daily dose Route Duration

Children Adults

British Thoracic Society guidelines, 1998

Isoniazid5 mg/kg 300 mg Oral 9–12 months

Rifampicin 10 mg/kg 450 mg (50 kg)

600 mg (50 kg) Oral 9–12 months

Pyrazinamide 35 mg/kg 1·5 g (50 kg)

2·0 g (50 kg) Oral 2 months

Ethambutol 15 mg/kg 15 mg/kg Oral 2 months

or streptomycin 15 mg/kg 15 mg/kg (maximum 1 g) Intramuscular 2 months Guidelines of the joint committee of the ATS, IDSA, and CDC, 2003

Isoniazid10–15 mg/kg (MD 300 mg) 5 mg/kg (MD 300 mg) Oral 9–12 months Rifampicin 10–20 mg/kg (MD 600 mg) 10 mg/kg (MD 600 mg) Oral 9–12 months Pyrazinamide 15–30 mg/kg (MD 2000 mg) 40–55 kg person: 1000 mg Oral 2 months

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 Oral 2 months 56–75 kg person: 1200 mg

76–90 kg person: 1600 mg

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 TM^66,67

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 prove⁸³and corticosteroids might antagonise vascular endothelial growth factor and thereby reduce vasogenic cerebral oedema.⁸⁴Understanding 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.

M tuberculosisresistant to antituberculosis drugs TM caused by M tuberculosisresistant 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,⁶²which 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 Thwaites et al³³

Age of patients 60% <14 years (median 8 years) 14 years 14 years

MRC Grade All grades Grade II and III Grade I Grade II and III

Drug Dexamethasone Prednisolone Dexamethasone Dexamethasone

Week 1 12 mg/kg/day im (8 mg/kg/day if 25 kg) 4 mg/kg/day* 0·3 mg/kg/day iv 0·4 mg/kg/day iv Week 2 12 mg/kg/day im (8 mg/kg/day if 25 kg) 4 mg/kg/day 0·2 mg/kg/day iv 0·3 mg/kg/day iv Week 3 12 mg/kg/day im (8 mg/kg/day if 25 kg) 4 mg/kg/day 0·1 mg/kg/day oral 0·2 mg/kg/day iv

Week 4 Reducing over 3 weeks to stop† 4 mg/kg/day 3 mg total/day oral 0·1 mg/kg/day iv

Week 5 Reducing dose to stop‡ Reducing by 1 mg each week 4 mg total/day oral

Week 6 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

168 http://neurology.thelancet.com Vol 4 March 2005

diagnose multidrug resistant TM with sufficient speed needs urgent study.

The best combination, dose, and duration of second- line 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.⁹⁸Ethionamide, 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.

Conflicts of interest

We have no conflicts of interest.

Role of the funding source

The Wellcome Trust, 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.

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