Review
Tuberculous meningitis: many questions, too few answers
Lancet Neurol 2005; 4: 160–70
Centre for Tropical Medicine,
Nuffield Department of Clinical
Medicine, Oxford University,
UK (G E Thwaites PhD);
and Oxford University
Clinical Research Unit
(G E Thwaites PhD), Hospital for
Tropical Diseases, Ho Chi Minh
City, Vietnam (T T Hien MD)
Correspondence to:
Dr Guy Thwaites, Brighton and
Sussex University Hospital,
Department of Infectious
Diseases and Microbiology,
Eastern Road, Brighton, Sussex,
BN2 5BE, UK
guy.thwaites@btinternet.com
160
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 “an inflammation of the meninges, with the deposit of
meningitis (TM) challenges physicians throughout the tubercular matter in the form of granulations, or cheesy
world (panel 1). Unlike pulmonary tuberculosis, which matter”. The author’s conclusion was controversial:
has been the subject of many clinical trials, the these findings represented “tubercular meningitis”, a
pathogenesis, diagnosis, and treatment of TM have new diagnosis, and one to join the growing number of
received little attention. How the disease kills or disables diseases marked by the presence of “tubercles”.
more than half of those it infects is not understood; the The unitary theory of tuberculosis was not widely
best diagnostic tests are controversial; the optimum accepted until 1882, when Robert Koch stained and
choice, dose, and treatment duration of antituberculosis cultured Mycobacterium tuberculosis for the first time and
drugs are not known; and the outcome from adjunctive showed it was the bacterium transmitted in
corticosteroids and neurosurgical intervention has been tuberculosis.2 Thereafter, controversy turned to whether
difficult to study. TM resulted from direct haematogenous invasion of the
meninges by the bacilli, or by inoculation from
Clinical features and pathogenesis of TM contiguous lesions resulting from earlier bacillaemia. In
Historical perspective 1933, Rich and McCordock3 reported a series of elegant
Controversy has dogged TM since 1836, when The experiments in rabbits and children post-mortem; they
Lancet published a description of six children with fatal found the disease developed after the release of bacilli
“acute hydrocephalus”.1 Assessment post-mortem found from old focal lesions in communication with the
meninges. These lesions, called Rich foci, were typically
subpial or subependymal and most commonly situated
Panel 1: TM in clinical practice
in the sylvian fissure.3
Associated with TM
Recent exposure to tuberculosis (especially in children) Clinical features
Evidence of tuberculosis elsewhere (especially miliary Understanding of the events that happen after the
tuberculosis on chest radiograph) release of bacilli from Rich foci has advanced little since
HIV infection Rich and McCordock’s studies, and although the
presenting clinical features of TM have been described
Diagnosis
extensively (panel 2)4–9 the mechanisms that cause them
Acute
are poorly understood. These mechanisms are
Meticulous microscopy (and then culture) of 5 ml of CSF
important for clinicians who need to understand the
After treatment commencement consequences of the disease, and may lead to new
PCR of CSF treatments.
Treatment
First 2 months Molecular and cellular pathogenesis
Four drugs: isoniazid, rifampicin, pyrazinamide and either An overview of the pathogenesis of TM and the variables
streptomycin, or ethambutol that might be associated with disease progression and
outcome is given in figure 1. The conflicting evidence on
Next 7–10 months
the role of tumour necrosis factor  (TNF ) in
Isoniazid and rifampicin
pathogenesis shows the complexity of this process. The
Patients without HIV release of M tuberculosis into the subarachnoid space
Give dexamethasone, regardless of patient’s age or disease results in a local T-lymphocyte-dependent response,
severity characterised macroscopically as caseating granulo-
matous 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 host-
mediated 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
Review
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
 Review

Pretreatment Treatment Post-treatment

HIV Pulmonary infection Coma

Death or
with M tuberculosis Cranial-nerve palsies
disability
Hemiparesis
Bacteraemia

Host Meningeal/subcortical M tuberculosis strain ↑ CSF lactate

genotype “Rich” focus ↑ CSF glucose

Rupture of Rich focus

Meningitis ↑ CSF IL8 Infarctions and tuberculomas

↑ CSF TNF ␣ Hydrocephulus
↑ CSF IFN ␥ Oedema
↑ Intracranial pressure

↑ Bacillary replication Vasculitis ↑ CSF lactate Coma

Encephalitis ↑ CSF protein Infarction Time to treatment
Meningitis ↑ BBB breakdown Hydrocephalus Drug resistance
↓ CSF glucose Oedema CSG drug levels
↑ Intracranial pressure HIV infection

↑ CSF WCC ↑ CSF matrix metalloproteinases ↓ Basal inflammation

(neutrophils and ↑ CSF tissue inhibitors of matrix ↓ Vasculitis
lymphocytes) metalloproteinases ↓ Intracranial pressure
↑ CSF IL10

↓ CSF lactate
Survival
↓ 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 demeclo-
nodular 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
50Ref number
years ago. The discovery of a syndrome Special
TLN_MAR_10003_Thwaites_1.eps meningeal
of instructions enhancement
(PLEASE MARK WITH RED SPOT IF and hydrocephalus on CT
URGENT)
inappropriate antidiuretic hormone as a cause Lancet might
of journal colours be less common andcolours
Specialty there could be more bacilli
Shapes
Editor GC 100% 10% 35% 100% 10% 35%
use for use for
background tint background tint
Author _
162 http://neurology.thelancet.com Vol 4 March 2005
Created by Steve
 Review

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 Figure 2: MRI showing the cerebral pathology of TM
findings predictive of TM.51,52 The first compared the 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
clinical findings at presentation of 110 Indian children
infarction (bottom right).
with TM with 94 with meningitis who either had
pyogenic bacteria isolated from the CSF or who
recovered without antituberculosis treatment. Five Panel 3: The modified British Medical Research Council
clinical variables were predictive of TM: report of clinical criteria for TM severity grades24
symptoms for longer than 6 days, optic atrophy, focal
Grade I
neurological deficit, abnormal movements, and
Alert and orientated without focal neurological deficit
neutrophils forming less than half the total CSF
leucocytes.51 From these findings a diagnostic rule was Grade II
developed and tested on a further 128 patients: Glasgow coma score* 14–10 with or without focal neurological
diagnostic sensitivity was 98%, specificity was 44% when deficit or Glasgow coma score 15 with focal neurological deficit
at least one feature was present; sensitivity was 55%, and
Grade III
specificity was 98% if three or more features were
Glasgow coma score less than 10 with or without focal
present. A second study compared the clinical outcomes
neurological deficit
of 143 Vietnamese adults with TM with 108 who had
either a pathogenic bacteria isolated from the CSF or a *The Glasgow coma score is between 3 and 15, where 3 is the worst and 15 the
CSF glucose to blood glucose ratio less than 0·5 and 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),
recovered without antituberculosis treatment.52 Thwaites best verbal response (1=no verbal response, 2=incomprehensible sounds,
and colleagues identified five variables predictive of TM 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
and developed a diagnostic rule (table 1) that had a
pain, 5=localising pain, 6=obeys commands).25
sensitivity of 86% and a specificity of 79% when it was
tested on a further 75 adults.

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 Review
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.53 However,
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).
164
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).
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.
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
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 Review

start of treatment careful bacteriology is as good as, or

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

be given throughout treatment,72 despite no supporting

Drug Daily dose Route
Children Adults
British Thoracic Society guidelines, 1998
Isoniazid 5 mg/kg 300 mg Oral
Rifampicin 10 mg/kg 450 mg (50 kg)
600 mg (50 kg) Oral
Pyrazinamide 35 mg/kg 1·5 g (50 kg)
2·0 g (50 kg) Oral
Ethambutol 15 mg/kg 15 mg/kg Oral
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
Rifampicin 10–20 mg/kg (MD 600 mg) 10 mg/kg (MD 600 mg) Oral
Pyrazinamide 15–30 mg/kg (MD 2000 mg) 40–55 kg person: 1000 mg Oral
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
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 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 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 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
Duration evidence from controlled trials. Indeed, data from
studies in pulmonary tuberculosis indicate
pyrazinamide has little effect on outcome after the first
9–12 months 2 months of therapy,65 except when there is initial
isoniazid resistance.73
9–12 months
2 months Adjunctive corticosteroids
2 months The use of adjunctive corticosteroids has been
controversial since they were suggested for the
9–12 months
management of TM more than 50 years ago.74 Early
9–12 months studies were too small to show an effect on survival, but
2 months suggested corticosteroids reduced CSF inflammation,
the incidence of neurological complications, and the
2 months
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

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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.
Girgis et al79
Age of patients 60% <14 years (median 8 years)
MRC Grade All grades
Drug Dexamethasone
Week 1 12 mg/kg/day im (8 mg/kg/day if 25 kg)
Week 2 12 mg/kg/day im (8 mg/kg/day if 25 kg)
Week 3 12 mg/kg/day im (8 mg/kg/day if 25 kg)
Week 4 Reducing over 3 weeks to stop†
Week 5
Week 6
*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
http://neurology.thelancet.com Vol 4 March 2005
Review
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
Schoeman et al80 Thwaites et al33 Thwaites et al33
14 years 14 years
Grade II and III Grade I Grade II and III
Prednisolone Dexamethasone Dexamethasone
4 mg/kg/day* 0·3 mg/kg/day iv 0·4 mg/kg/day iv
4 mg/kg/day 0·2 mg/kg/day iv 0·3 mg/kg/day iv
4 mg/kg/day 0·1 mg/kg/day oral 0·2 mg/kg/day iv
4 mg/kg/day 3 mg total/day oral 0·1 mg/kg/day iv
Reducing dose to stop‡ Reducing by 1 mg each week 4 mg total/day oral
Reducing by 1 mg each week
167
 Review
Search strategy and selection criteria
References for this review published between 1969 and
September 2004 were identified by searches of MEDLINE and
PubMed and from references from relevant papers; 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 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.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.
168
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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