TM lancet 2005

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Review

The diagnosis and management of tuberculous

meningitis (TM) challenges physicians throughout theworld (panel 1). Unlike pulmonary tuberculosis, whichhas been the subject of many clinical trials, thepathogenesis, diagnosis, and treatment of TM havereceived little attention. How the disease kills or disablesmore than half of those it infects is not understood; thebest diagnostic tests are controversial; the optimumchoice, dose, and treatment duration of antituberculosisdrugs are not known; and the outcome from adjunctivecorticosteroids and neurosurgical intervention has beendifficult to study.

Clinical features and pathogenesis of TM

Historical perspectiveControversy has dogged TM since 1836, when TheLancet published a description of six children with fatal“acute hydrocephalus”.1 Assessment post-mortem found

“an inflammation of the meninges, with the deposit of

tubercular matter in the form of granulations, or cheesymatter”. The author’s conclusion was controversial:these findings represented “tubercular meningitis”, anew diagnosis, and one to join the growing number of diseases marked by the presence of “tubercles”.

The unitary theory of tuberculosis was not widelyaccepted until 1882, when Robert Koch stained andcultured Mycobacterium tuberculosis for the first time andshowed it was the bacterium transmitted intuberculosis.2 Thereafter, controversy turned to whetherTM resulted from direct haematogenous invasion of themeninges by the bacilli, or by inoculation fromcontiguous lesions resulting from earlier bacillaemia. In

1933, Rich and McCordock

3

reported a series of elegantexperiments in rabbits and children post-mortem; theyfound the disease developed after the release of bacillifrom old focal lesions in communication with themeninges. These lesions, called Rich foci, were typicallysubpial or subependymal and most commonly situatedin the sylvian fissure.3

Clinical featuresUnderstanding of the events that happen after therelease of bacilli from Rich foci has advanced little sinceRich and McCordock’s studies, and although thepresenting clinical features of TM have been describedextensively (panel 2)4–9 the mechanisms that cause them

are poorly understood. These mechanisms areimportant for clinicians who need to understand theconsequences of the disease, and may lead to newtreatments.

Molecular and cellular pathogenesisAn overview of the pathogenesis of TM and the variablesthat might be associated with disease progression andoutcome is given in figure 1. The conflicting evidence onthe role of tumour necrosis factor ␣ (TNF ␣) inpathogenesis shows the complexity of this process. Therelease of M tuberculosis into the subarachnoid spaceresults in a local T-lymphocyte-dependent response,

characterised macroscopically as caseating granulo-matous inflammation.10 In pulmonary tuberculosis,

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]

Tuberculous meningitis (TM) is difficult to diagnose and treat; clinical features are non-specific, conventionalbacteriology 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 inless than half of patients. Mycobacterium tuberculosis resistant to these drugs threatens a return to theprechemotherapeutic era in which all patients with TM died. Research findings suggest that adjunctive treatmentwith corticosteroids improve survival but probably do not prevent severe disability, although how or why is notknown. 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 diagnosisand treatment of TM.

Tuberculous meningitis: many questions, too few answersGuy 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

AcuteMeticulous microscopy (and then culture) of у5 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

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TNF ␣ is thought to be crucial for granulomaformation,11 but is also cited as a main factor in host-mediated destruction of infected tissue.12 Studies of pyogenic bacterial meningitis showed CSFconcentrations of TNF ␣ correlated with diseaseseverity13 and study of rabbit models of TM found highCSF concentrations were associated with a worseoutcome,14 although TNF ␣ concentrations have notbeen correlated with disease severity or outcome in

human beings.15 Treatment with antibiotics andthalidomide, an anti TNF ␣ drug, improved survival andneurological outcome in rabbits16 and suggested a noveltherapeutic approach in people. Preliminary researchfound that thalidomide was safe and well-tolerated17 andled to a controlled trial to assess the efficacy of adjunctivethalidomide in children with TM. Sadly, this trial wasstopped early because there were many adverse events inthe thalidomide arm and there did not seem to be anybenefit from treatment.18

The numbers and types of white cells in the CSF helpdifferentiate TM from other meningitides, but little isknown of their role in disease pathogenesis. Typicallythe CSF shows a high CSF white-cell count, which ispredominantly 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-mediatedimmunity, 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 thedisease,21 and high proportions of neutrophils in the cellcount have been associated with an increased likelihoodof a bacteriological diagnosis and improved survival.Hence, neutrophils could have a role in pathogenesis.15,22

The kinetics of the lymphocyte response are probablyalso important, particularly the roles of differentlymphocyte subsets,23 but more data on these cells areneeded.

Pathological and clinical consequences of infection

The macroscopic consequences of infection have beenresearched post mortem and, more recently, through CTand MRI (figure 2) of the brain. Neurologicalabnormalities occur with the development of aninflammatory exudate that affects mostly the sylvianfissures, basal cisterns, brainstem, and cerebellum.10

Three processes cause most of the common neurologicaldeficits: the adhesive exudate can obstruct CSF causinghydrocephalus and compromise efferent cranial nerves;granulomas can coalesce to form tuberculomas (or anabscess in patients with uncharacteristic disease) which,depending on their location, cause diverse clinicalconsequences; and an obliterative vasculitis can cause

infarction and stroke syndromes.

10

The severity of thesecomplications may be dependent on the intracerebralinflammatory response and strongly predicts outcome.15

Indeed, the severity of TM at presentation is classifiedinto three grades according to the patient’s Glasgowcoma score and the presence or absence of focalneurological signs (panel 3),24 variables shown to bestrongly predictive of death.26

Unusual clinical and pathological features of TM havebeen well described in previous research papers and cancause diagnostic uncertainty.27,28 Movement disorderscan present after basal ganglia infarction; tremor is themost common, but chorea, ballismus, and myoclonusare all reported.29 Less common, and more controversial,

than patients who present with movement disorders arethose who present with evidence of diffuse cerebralinvolvement but without clinical or CSF signs of meningitis. Dastur and Udani30 were the first to describethis variant of cerebral tuberculosis, which they called“tuberculous encephalopathy”, in Indian children withdisseminated tuberculosis. These children had a diffusecerebral disorder with coma, convulsions, involuntarymovements, and pyramidal signs but with normal CSFmeasurements. Dastur31 has argued subsequently thatthe pathogenesis of tuberculous encephalopathy maydiffer from TM: post-mortem assessment of those withtuberculous encephalopathy found diffuse cerebraloedema, demyelination, and sometimes haemorrhage—features that may be more typical of a post-infectious

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%Ͼ25 cm H20)

Total leucocyte count (5–1000ϫ103/ml)

Neutrophils (10–70%)

Lymphocyte (30–90%)

Protein (45–250 mg/dL)*

Lactate (5–10 mmol/L)

CSF glucose to blood glucose ratio (Ͻ0·5 in 95%)

*CSF protein can beϾ1000 mg/dL in patients with spinal block

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allergic encephalomyelitis.31,32 Anecdotal reports suggestthe disease is responsive to treatment withcorticosteroids, but there are few recent reports and nodata from controlled trials. Tuberculous encephalopathyhas not been reported in adults.

TM with spinal involvement (figure 3), whichcommonly presents as paraplegia, occurs in less than10% of cases.33 Vertebral tuberculosis (Pott’s disease)accounts for about a quarter of patients with TM withspinal involvement and may be associated with fusiformpara-vertebral abscesses or a gibbus. Extradural cord

tuberculomas cause more than 60% of cases of non-osseous paraplegia,34 although tuberculomas can occurin any part of the cord. Tuberculous radiculomyelitisrarely occurs with tuberculous meningitis35 and ischaracterised by a subacute paraparesis, radicular pain,and bladder dysfunction. MRI reveals loculation andobliteration of the spinal subarachnoid space withnodular intradural enhancement.

TM can also cause metabolic complications, thecommonest of which, hyponatraemia, affects more than50% of patients with the disease.9 A “cerebral saltwasting syndrome” associated with TM and attributed toa renal tubular defect36,37 was described more than50 years ago. The discovery of a syndrome of inappropriate antidiuretic hormone as a cause of

hyponatraemia associated originally with bronchialcarcinoma38 led some to think a similar mechanismcauses TM-associated hyponatraemia.39 However, manypatients with TM-associated hyponatraemia have lowplasma volumes and persistent natriuresis despitenormal concentrations of antidiuretic hormone;40 thereis a stronger correlation between concentrations of plasma atrial natriuretic peptide and sodium. Although arole for antidiuretic hormone has not been excluded,“hyponatraemic natriuretic syndrome” is probably abetter descriptive term for this common complication of

TM.40 Despite these investigations, the best method of correcting the sodium concentration in the plasma is notknown; sodium and fluid replacement is probablyindicated in hypovolaemic hyponatraemia,41 whereasfluid restriction may be more appropriate in those whoare euvolaemic.42 There is anecdotal evidence to suggestfludrocortisone replacement therapy43 and demeclo-cycline44 may be useful.

Co-infection with HIVResearch findings suggest HIV does not alter the clinicalpresentation of TM,45 but may affect the number andnature of complications. In patients with HIV, basalmeningeal enhancement and hydrocephalus on CTmight be less common and there could be more bacilli

Ref number

Editor

Special instructions (PLEASE MARK WITH RED SPOT IF URG ENT)LN_MAR_10003_Thwaites_1.eps

GCSpecialty coloursancet journal colours

100% 10%use for

background tint

35% 100% 10%use for

background tint

35%

Shapes

Pulmonary infection

with M tuberculosisHIV

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

ComaInfarction

Hydrocephalus

Oedema

↑ Intracranial pressure

Infarctions and tuberculomas

Hydrocephulus

Oedema

↑ Intracranial pressure

↓ Basal inflammation

↓ Vasculitis

↓ Intracranial pressure

↓ CSF lactate

↓ CSF glucose

VasculitisEncephalitis

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.

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in the meninges than in patients without HIV.46 Active

extrameningeal tuberculosis is more common in peopleinfected with HIV than in uninfected people.20 Moreimportantly, case fatality from TM is greater in peopleinfected with HIV than in those who are uninfected,33

although the role of other opportunistic infections uponcase fatality is not known and there are no data frompeople taking antiretroviral drugs.

Diagnosis of TMThe diagnosis and treatment of TM before the onset of coma is without question the greatest contribution aphysician can make to improved outcome,47,48 but threefactors make this difficult. First, the presenting clinicalfeatures of the disease are non-specific. Second, small

numbers of bacilli in the CSF reduce the sensitivity of conventional bacteriology. Third, alternative diagnosticmethods are incompletely assessed.

Clinical diagnosisTM cannot be diagnosed on the history and clinicalassessment alone, although recall of recent exposure totuberculosis can be helpful, particularly in children,6 ascan signs of active extrameningeal tuberculosis onclinical assessment.20 Chest radiography finds active orprevious tuberculosis infection in about 50% of thosewith TM,4 but these findings lack specificity in settingswith a high prevalence of pulmonary tuberculosis.

However, miliary tuberculosis strongly suggestsmultiorgan involvement; therefore it is very helpfulwhen it is shown by chest radiograph.49 Skin testing withpurified protein derivative of M tuberculosis is probably of limited value, except in infants.50

Two studies have tried to identify the clinical and CSFfindings predictive of TM.51,52 The first compared theclinical findings at presentation of 110 Indian childrenwith TM with 94 with meningitis who either hadpyogenic bacteria isolated from the CSF or whorecovered without antituberculosis treatment. Fiveclinical variables were predictive of TM: report of symptoms for longer than 6 days, optic atrophy, focalneurological deficit, abnormal movements, and

neutrophils forming less than half the total CSFleucocytes.51 From these findings a diagnostic rule wasdeveloped and tested on a further 128 patients:diagnostic sensitivity was 98%, specificity was 44% whenat least one feature was present; sensitivity was 55%, andspecificity was 98% if three or more features werepresent. A second study compared the clinical outcomesof 143 Vietnamese adults with TM with 108 who hadeither a pathogenic bacteria isolated from the CSF or aCSF glucose to blood glucose ratio less than 0·5 andrecovered without antituberculosis treatment.52 Thwaitesand colleagues identified five variables predictive of TMand developed a diagnostic rule (table 1) that had asensitivity of 86% and a specificity of 79% when it wastested 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-infectionwith HIV may alter the presenting features of TM, andchanges the spectrum of disorders that present withsimilar clinical syndromes. These studies were notdesigned to differentiate between tuberculous andcryptococcal meningitis, a common disease of people withHIV, and further studies of these patients must be done.

In summary, a high index of clinical suspicion isneeded to diagnose TM. In some patients, commonly inchildren, the onset can be subtle behavioural changesthat do not immediately suggest the diagnosis; in others,the disease can present as pyogenic bacterial meningitis,with a sudden onset and polymorphonuclear cellpredominance in the CSF. Given the fatal consequences

of delayed treatment, clinicians should be encouraged toinitiate “empirical” therapy in the setting of compatibleclinical, epidemiological, and laboratory findings. In theUK, the local public health authority must be notified of suspected or proven cases of tuberculous meningitis.

Radiological diagnosisCT and MRI of the brain show the pathological changesof TM (figure 2) and provide diagnostic information atpresentation and when complications occur.53 However,

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 94children with TM with those of 52 children withpyogenic meningitis and found basal enhancement,hydrocephalus, tuberculoma, and infarction were allsubstantially more common in those with TM, whereassubdural collections were more common in those withpyogenic meningitis. They suggested basal meningealenhancement, tuberculoma, or both, were 89% sensitiveand 100% specific for the diagnosis of TM.54 A recentreport suggested that precontrast hyperdensity in thebasal cisterns might be the most specific radiologicalsign of TM in children.55 Cranial MRI is better than CTfor showing brain stem and cerebellum pathology,

tuberculomas, infarcts, and the extent of inflammatoryexudates,56,57 but this might not be true in discriminationof TM from other disorders. Cryptococcal meningitis,viral encephalitis, sarcoidosis, meningeal metastases,and lymphoma may be similar to TM on radiographicassessments (figure 4).

Bacteriological diagnosisThe comparative role of bacteriological and moleculartechniques for the diagnosis of TM has been a source of much controversy. Old reports suggested the acid-fastbacilli of M tuberculosis could be seen in the CSF afterZeihl-Neelsen staining in nearly every case, if the

microscopist was prepared to look hard,

58

but this israrely the experience in contemporary laboratories.59

Kennedy and Fallon60 showed that repeated CSFsampling improved the sensitivity of a Ziehl-Neelsenstain to over 80%, but the factors responsible for thelarge reported variation in the sensitivity of bacteriologyhave received little attention. A recent study reported abacteriological diagnosis of TM in 107 (81%) of 132adults 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 fromthe CSF was dependent upon meticulous microscopyand culture of a large volume (>5 mL) of CSF. 22 Thesedata suggest simple changes made at the bedside and

in the laboratory can substantially improve theperformance of conventional bacteriology.

Molecular diagnosisWhether molecular techniques can improve uponconventional bacteriology is unclear. In theory, nucleic-acid-amplification assays, such as those developed fromthe PCR, should improve with bacteriology; but attemptsto clarify their diagnostic role have failed because of fewcases and inadequate bacteriological diagnosticcomparison. A recent systematic review and meta-analysis calculated that the sensitivity and specificity of commercial nucleic-acid-amplification assays for thediagnosis 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 spacewith nodular intradural enhancement (bottom right).

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sensitivity of these assays is too low (about half thosewith a negative test will have the disease) and may not bebetter than bacteriology. A study published after themeta-analysis supports this conclusion: the performanceof bacteriology was compared with a commercial assay(the amplified mycobacterium tuberculosis direct test) in79 adults with TM before and after startingantituberculosis drugs.62 Before the start of treatment the

sensitivities of a Ziehl-Neelsen stain and the amplifiedmycobacterium 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 beenreported63 and indicate molecular methods are sensitivefor 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-amplificationassays, but molecular methods may be more usefulwhen antituberculosis drugs have started. However, thediagnosis of TM cannot be excluded by these tests, evenif both are negative.

Treatment of TMThe optimum treatment for pulmonary tuberculosis hasbeen developed from the results of many controlledtrials.64 The same is not true of TM—choice of drugs,doses, and duration of treatment are unknown and thereare few data to guide the clinician. Nevertheless, thereare common principles of treatment, derived from theroles 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 streptomycinand ethambutol. Thereafter, rifampicin andpyrazinamide become important because they “sterilise”lesions by killing organisms; these two drugs are crucialfor successful 6-month treatment regimens. Rifampicinkills low or non-replicating organisms and pyrazinamidekills those in sites hostile to the penetration and action of the other drugs.

Antituberculosis chemotherapyThe British Thoracic Society (BTS), the Infectious

Diseases Society of America and the American ThoracicSociety (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 withtwo drugs during a prolonged “continuation phase”(table 2).66,67

Variable Score

Age (years)

Ͼ36 2

Ͼ36 0

Blood WCC (103/ml)

Ͼ15000 4

Ͻ15000 0

History of illness (days)

у6 –5

Ͻ6 0

CSF total WCC (103/ml)

у750 3

Ͻ750 0

CSF % neutrophils

у90 4

Ͻ90 0

WCC=white cell count. Suggested rule for diagnosis: total score р4=TM; total

scoreϾ4=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 MRIDilated ventricles with periventricular enhancement in TM (left) and in cryptococcal meningitis (rig ht).

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These guidelines acknowledge the scarcity of evidencefrom controlled trials and show the main areas of uncertainty: the choice of the fourth drug in the intensivephase and the composition and duration of thecontinuation phase. Many of the recommendations for thetreatment of TM combine the principles of pulmonary-

tuberculosis treatment with pharmacokinetic data thatpredict the intracerebral concentrations of theantituberculosis drugs.

The first 2 months of treatment should be withisoniazid, rifampicin, pyrazinamide, and eitherstreptomycin, ethambutol, or ethionamide. The BTSrecommend streptomycin or ethambutol, althoughneither penetrates the blood–brain barrier well in theabsence of inflammation68,69 and both have substantialadverse effects. The IDSA/ATS favour ethambutol, andincreasing prevalence of streptomycin resistancesupports this recommendation. Some researchersadvocate 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 systematicreview concluded 6 months might be sufficient if thelikelihood of drug resistance is low.71 Isoniazid andrifampicin are thought mandatory in the continuationphase, although the role of rifampicin is uncertainbecause concentrations in CSF do not exceed 10% of those in plasma.69 In contrast, isoniazid andpyrazinamide pass freely into the CSF and some believetheir use is crucial to a successful outcome. The BTSsuggests therapy should be extended to 18 months inpeople who are unable to tolerate pyrazinamide in theintensive phase, and others recommend pyrazinamide

be given throughout treatment,72 despite no supporting

evidence from controlled trials. Indeed, data fromstudies in pulmonary tuberculosis indicatepyrazinamide has little effect on outcome after the first2 months of therapy,65 except when there is initialisoniazid resistance.73

Adjunctive corticosteroidsThe use of adjunctive corticosteroids has beencontroversial since they were suggested for themanagement of TM more than 50 years ago.74 Earlystudies were too small to show an effect on survival, butsuggested corticosteroids reduced CSF inflammation,the incidence of neurological complications, and thetime to recovery.75–78 Later controlled trials from Egypt

and South Africa indicated corticosteroids reduced casefatality in children with more severe disease, but theeffect on morbidity was not elucidated.79,80 Prasad andco-workers81 did a meta-analysis and systematic reviewof all controlled trials published before 2000 andconcluded that corticosteroids probably improvedsurvival in children, but small trial sizes, poortreatment allocation concealment, and possiblepublication bias did not enable clear treatmentrecommendations. There was no evidence of beneficialeffect in adults or those co-infected with HIV, andfurther controlled trials were needed that includedHIV-infected individuals and were large enough to

show a clear effect on case fatality and morbidity insurvivors. Our controlled trial of adjunctivedexamethasone in 545 Vietnamese adults with TMaddressed some of these trial shortcomings.33 Analysisby intention-to-treat found that treatment withdexamethasone for was strongly associated with areduced risk of death (relative risk 0·69, 95% CI0·52–0·92, p=0·01), but did not prevent severedisability in the survivors. Two facets of the studydesign warrant cautious interpretation of the pooreffect on disability.82 First, only 34% of patients’diagnosis of TM was confirmed by bacteriologicalanalysis; the inclusion of patients with probable orpossible TM may have affected the observed effect on

disability. Second, the scores used in assessment ofdisability were developed to assess outcome fromstroke in the more developed world, not TM inVietnam, and may not have had the discriminatorypower to detect a true treatment effect.

Subgroup analysis of our trial in Vietnam confirmedthat the effect of dexamethasone on survival wasconsistent across all severity grades of disease, dispellinga previously held belief that corticosteroids onlybenefited those with more severe disease, but did notfind a significant effect on death or disability in thoseinfected with HIV. The study also found that treatmentwith dexamethasone was associated with less severeadverse events, in particular hepatitis. This finding isinteresting and suggests that the affect of

Drug Daily dose Route Duration

Children Adults

British Thoracic Society guidelines, 1998

Isoniazid 5 mg/kg 300 mg Oral 9–12 months

Rifampicin 10 mg/kg 450 mg (Ͻ50 kg)

600 mg (Ͼ50 kg) Oral 9–12 months

Pyrazinamide 35 mg/kg 1·5 g (Ͻ50 kg)

2·0 g (Ͼ50 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

Isoniazid 10–15 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

Pyrazina mide 15–30 mg/ kg (MD 2000 mg ) 40–55 kg person: 1000 mg Or al 2 mont hs

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



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

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dexamethasone on outcome may be more diverse than

previously thought.In conclusion, study findings suggest that all patientswith TM who are not infected with HIV should be givendexamethasone, regardless of age or disease severity.The regimens used in recent controlled trials are shownin table 3. However, several questions are unanswered.First, should patients with TM and HIV infection begiven adjunctive dexamethasone? The trial inVietnamese adults did not find any clear benefit of treatment with dexamethasone in patients infected withHIV but did suggest it was safe and might improvesurvival.33 Controlled trials including patients takingantiretroviral treatment are needed, but until thendexamethasone should probably be used in such

patients. Second, why do corticosteroids improvesurvival but not reduce morbidity? How corticosteroidsexert their effect in TM is very poorly understood. Ananti-inflammatory effect has been difficult to prove83 andcorticosteroids might antagonise vascular endothelialgrowth factor ␤ and thereby reduce vasogenic cerebraloedema.84 Understanding how dexamethasone exerts itssubstantial clinical effects could lead to more specificand potentially more effective adjunctive therapy.

Neurosurgical interventionHydrocephalus is a common complication of TM andcan be treated with drugs that have a diuretic effect,85

serial lumbar punctures, or ventriculoperitoneal or atrialshunting.86 There are no data from controlled trialsabout which method of treatment is best. Some advocateearly shunting in all patients with hydrocephalus,87

whereas others only recommend shunting for patientswith non-communicable hydrocephalus.88 Externalventricular drainage has been used to predict responseto ventriculoperitoneal shunting but without success,89

other research suggests monitoring of lumbar CSFpressure can predict response to medical treatment.88

Without clear evidence, physicians must balancepossible benefit with the resources and experience of their surgical unit and the substantial complications of shunt surgery.

M tuberculosis resistant to antituberculosis drugs

TM caused by M tuberculosis resistant to one or morefirst-line-antituberculosis drugs is an increasinglycommon clinical problem, but the affect on outcomeand implications for treatment are not clear. Multidrugresistant TM, caused by organisms resistant to at leastisoniazid and rifampicin, has a far worse outcome thandisease caused by susceptible organisms.90 The effectof resistance to one or both of isoniazid andstreptomycin on outcome is more controversial.Isoniazid has potent early bactericidal activity65 andpasses freely into the CSF,69 properties that suggestresistance might be detrimental to treatment.Resistance to isoniazid has been associated with longertimes to CSF sterility,62 which suggests an attenuated

bactericidal response. However, there are no reliabledata to support or reject an effect of isoniazidresistance on outcome from TM. A small prospectivestudy failed to show a detrimental effect of isoniazid orstreptomycin resistance on in-hospital survival,91 butthe series was under-powered (16/56 isoniazidresistant), and did not report longer follow-up ormorbidity in survivors. Until larger studies are done,current evidence suggests only multidrug resistant TMneeds treatment with second-line-antituberculosisdrugs. In the absence of data, we suggest the durationof treatment for TM caused by isoniazid-resistantorganisms may need to be extended and should

include pyrazinamide throughout.The diagnosis and treatment of multidrug resistantTM is challenging. A history of previously treatedtuberculosis or recent exposure to a known case of multidrug resistant pulmonary disease may identifythose at high risk of multidrug resistant TM, but timelyconfirmation of the diagnosis is problematic. Patientswith multidrug resistant TM treated with first-linedrugs are likely to be dead before the results of conventional susceptibility tests (which take 6–8 weeks)are available.92 Nucleic acid amplification assays thatdetect mutations in M tuberculosis rpoB gene93 havebeen used to rapidly diagnose multidrug resistantpulmonary 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) Ͻ14 years Ͼ14 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 Ͻ25 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 Ͻ25 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 Ͻ25 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

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diagnose multidrug resistant TM with sufficient speedneeds urgent study.

The best combination, dose, and duration of second-line drugs for the treatment of multidrug resistant TMare unknown. Indeed, there are no published controlledtrials addressing this issue for any form of tuberculosis.95

WHO recommends fluoroquinolones for the treatmentof multidrug resistant pulmonary tuberculosis,96 buttheir 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 crossthe 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 moredata are available, the treatment of multidrug resistantTM should abide by the principles of treatment of multidrug resistant pulmonary disease: never add asingle drug to a failing regimen; use at least threepreviously unused drugs, one of which should be afluoroquinolone; streptomycin resistance does notconfer resistance to other aminoglycosides, thereforeamikacin or kanamycin can be used; and treat for at least18 months.67

Future researchTM is a formidable clinical challenge; there are many

questions about its pathophysiology, diagnosis, andtreatment. Can the sensitivity of molecular diagnosticassays be improved? What is the best method of rapidlyidentifying disease caused by drug resistant organismsand what drugs should be used to treat them? Areadjunctive corticosteroids effective in people co-infectedwith HIV and should they be used in treatment whenthese patients are taking antiretroviral drugs? How docorticosteroids improve survival and can a greaterunderstanding of the pathogenesis of TM lead to novelinterventions? These are important questions becausethey threaten our ability to treat TM; answers areneeded urgently.

Authors’ contributionsGET 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 notinvolved in the writing of this review or the decision to submit it forpublication.

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The final reference list was generated from papers that were

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