Review

Tuberculous meningitis: many questions, too few answers

Lancet Neurol 2005; 4: 16070
Centre for Tropical Medicine,
Nufeld Department of Clinical
Medicine, Oxford University,
UK (G E Thwaites PhD);
and Oxford University
Clinical Research Unit
(G E Thwaites PhD), Hospital for
Tropical Diseases, Ho Chi Minh
City, Vietnam (T T Hien MD)
Correspondence to:
Dr Guy Thwaites, Brighton and
Sussex University Hospital,
Department of Infectious
Diseases and Microbiology,
Eastern Road, Brighton, Sussex,
BN2 5BE, UK
guy.thwaites@btinternet.com

Guy E Thwaites, Tran Tinh Hien

Tuberculous meningitis (TM) is difcult to diagnose and treat; clinical features are non-specic, 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 ndings suggest that adjunctive treatment
with corticosteroids improve survival but probably do not prevent severe disability, although how or why is not
known. There are many important unanswered questions about the pathophysiology, diagnosis, and treatment of
TM. Here we review the available evidence to answer some of these questions, particularly those on the diagnosis
and treatment of TM.
The diagnosis and management of tuberculous
meningitis (TM) challenges physicians throughout the
world (panel 1). Unlike pulmonary tuberculosis, which
has been the subject of many clinical trials, the
pathogenesis, diagnosis, and treatment of TM have
received little attention. How the disease kills or disables
more than half of those it infects is not understood; the
best diagnostic tests are controversial; the optimum
choice, dose, and treatment duration of antituberculosis
drugs are not known; and the outcome from adjunctive
corticosteroids and neurosurgical intervention has been
difcult to study.

Clinical features and pathogenesis of TM

Historical perspective
Controversy has dogged TM since 1836, when The
Lancet published a description of six children with fatal
acute hydrocephalus.1 Assessment post-mortem found
Panel 1: TM in clinical practice
Associated with TM
Recent exposure to tuberculosis (especially in children)
Evidence of tuberculosis elsewhere (especially miliary
tuberculosis on chest radiograph)
HIV infection
Diagnosis
Acute
Meticulous microscopy (and then culture) of 5 ml of CSF
After treatment commencement
PCR of CSF
Treatment
First 2 months
Four drugs: isoniazid, rifampicin, pyrazinamide and either
streptomycin, or ethambutol
Next 710 months
Isoniazid and rifampicin
Patients without HIV
Give dexamethasone, regardless of patients age or disease
severity

160

an inammation of the meninges, with the deposit of

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

Clinical features
Understanding of the events that happen after the
release of bacilli from Rich foci has advanced little since
Rich and McCordocks studies, and although the
presenting clinical features of TM have been described
extensively (panel 2)49 the mechanisms that cause them
are poorly understood. These mechanisms are
important for clinicians who need to understand the
consequences of the disease, and may lead to new
treatments.

Molecular and cellular pathogenesis

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

Review

Panel 2: TM symptoms on presentation49

Symptom (proportion of patients affected)
Headache (5080%)
Fever (6095%)
Vomiting (3060%)
Photophobia (510%)
Anorexia (6080%)
Clinical sign (proportion of patients affected)
Neck stiffness (4080%)
Confusion (1030%)
Coma (3060%)
Any cranial nerve palsy (3050%)
Cranial nerve III palsy (515%)
Cranial nerve VI palsy (3040%)
Cranial nerve VII palsy (1020%)
Hemiparesis (1020%)
Paraparesis (510%)
Seizures (children: 50%; adults: 5%)
CSF (proportion or range)
Appearance (8090% clear)
Opening pressure (50% 25 cm H20)
Total leucocyte count (51000103/ml)
Neutrophils (1070%)
Lymphocyte (3090%)
Protein (45250 mg/dL)*
Lactate (510 mmol/L)
CSF glucose to blood glucose ratio (05 in 95%)
*CSF protein can be 1000 mg/dL in patients with spinal block

TNF  is thought to be crucial for granuloma

formation,11 but is also cited as a main factor in hostmediated destruction of infected tissue.12 Studies of
pyogenic
bacterial
meningitis
showed
CSF
concentrations of TNF  correlated with disease
severity13 and study of rabbit models of TM found high
CSF concentrations were associated with a worse
outcome,14 although TNF  concentrations have not
been correlated with disease severity or outcome in
human beings.15 Treatment with antibiotics and
thalidomide, an anti TNF  drug, improved survival and
neurological outcome in rabbits16 and suggested a novel
therapeutic approach in people. Preliminary research
found that thalidomide was safe and well-tolerated17 and
led to a controlled trial to assess the efcacy 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
benet from treatment.18
The numbers and types of white cells in the CSF help
differentiate TM from other meningitides, but little is
known of their role in disease pathogenesis. Typically
the CSF shows a high CSF white-cell count, which is
predominantly lymphocytic, with a high protein and low
http://neurology.thelancet.com Vol 4 March 2005

glucose ratio. However, total CSF white-cell count can be

normal in those with TM and depressed cell-mediated
immunity, such as the elderly and people with HIV;19,20
low counts have been associated with poor outcome.15
Neutrophils can dominate, especially early in the
disease,21 and high proportions of neutrophils in the cell
count have been associated with an increased likelihood
of a bacteriological diagnosis and improved survival.
Hence, neutrophils could have a role in pathogenesis.15,22
The kinetics of the lymphocyte response are probably
also important, particularly the roles of different
lymphocyte subsets,23 but more data on these cells are
needed.

Pathological and clinical consequences of infection

The macroscopic consequences of infection have been
researched post mortem and, more recently, through CT
and MRI (gure 2) of the brain. Neurological
abnormalities occur with the development of an
inammatory exudate that affects mostly the sylvian
ssures, basal cisterns, brainstem, and cerebellum.10
Three processes cause most of the common neurological
decits: 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
inammatory response and strongly predicts outcome.15
Indeed, the severity of TM at presentation is classied
into three grades according to the patients 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 rst 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
HIV

Treatment

Pulmonary infection
with M tuberculosis

Post-treatment

Coma
Cranial-nerve palsies
Hemiparesis

Death or
disability

Bacteraemia
Host
genotype

M tuberculosis strain

CSF lactate
CSF glucose

Meningitis

CSF IL8
CSF TNF
CSF IFN

Infarctions and tuberculomas

Hydrocephulus
Oedema
Intracranial pressure

Bacillary replication

Vasculitis
Encephalitis
Meningitis

Meningeal/subcortical
Rich focus
Rupture of Rich focus

CSF WCC
(neutrophils and
lymphocytes)
CSF IL10

CSF lactate
CSF protein
BBB breakdown
CSF glucose

Coma
Infarction
Hydrocephalus
Oedema
Intracranial pressure

Time to treatment
Drug resistance
CSG drug levels
HIV infection
Basal inflammation
Vasculitis
Intracranial pressure

CSF matrix metalloproteinases

CSF tissue inhibitors of matrix
metalloproteinases

CSF lactate
CSF glucose

Survival

Figure 1: Overview of the pathophysiology of TM

IL8=interleukin 8; IL10=interleukin 10; IFN =interferon ; WCC=total white cell count; BBB=bloodbrain 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 (gure 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 (Potts 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 uid replacement is probably
rarely occurs with tuberculous meningitis35 and is indicated in hypovolaemic hyponatraemia,41 whereas
characterised by a subacute paraparesis, radicular pain, uid 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 udrocortisone replacement therapy43 and demeclonodular intradural enhancement.
cycline44 may be useful.
TM can also cause metabolic complications, the
commonest of which, hyponatraemia, affects more than Co-infection with HIV
50% of patients with the disease.9 A cerebral salt Research ndings suggest HIV does not alter the clinical
wasting syndrome associated with TM and attributed to presentation of TM,45 but may affect the number and
a renal tubular defect36,37 was described more than nature of complications. In patients with HIV, basal
(PLEASE MARK
WITH RED SPOT IF and
URGENT)
TLN_MAR_10003_Thwaites_1.eps
meningeal
enhancement
hydrocephalus on CT
50Ref number
years ago.
The discovery of a syndrome Special
of instructions
might
andcolours
there could be more bacilli
inappropriate antidiuretic hormone as a cause Lancet
of journal
Shapes
Specialty
colours be less common
Editor

162

Author
Created by

GC
_

Steve

100%

10%
use for
background tint

35%

100%

10%

35%

use for
background tint

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

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 difcult. First, the presenting clinical
features of the disease are non-specic. 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 nds active or
previous tuberculosis infection in about 50% of those
with TM,4 but these ndings lack specicity 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
puried protein derivative of M tuberculosis is probably of
limited value, except in infants.50
Two studies have tried to identify the clinical and CSF
ndings predictive of TM.51,52 The rst compared the
clinical ndings 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 decit, abnormal movements, and
neutrophils forming less than half the total CSF
leucocytes.51 From these ndings a diagnostic rule was
developed and tested on a further 128 patients:
diagnostic sensitivity was 98%, specicity was 44% when
at least one feature was present; sensitivity was 55%, and
specicity 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 05 and
recovered without antituberculosis treatment.52 Thwaites
and colleagues identied ve variables predictive of TM
and developed a diagnostic rule (table 1) that had a
sensitivity of 86% and a specicity of 79% when it was
tested on a further 75 adults.
http://neurology.thelancet.com Vol 4 March 2005

Figure 2: MRI showing the cerebral pathology of TM

Post-contrast scan showing intense basal meningeal enhancement (top left); severe hydrocephalus secondary to
TM (top right); multiple basal tuberculomas and hydrocephalus (bottom left); intense basal enhancement and
infarction (bottom right).

Panel 3: The modied British Medical Research Council

clinical criteria for TM severity grades24
Grade I
Alert and orientated without focal neurological decit
Grade II
Glasgow coma score* 1410 with or without focal neurological
decit or Glasgow coma score 15 with focal neurological decit
Grade III
Glasgow coma score less than 10 with or without focal
neurological decit
*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=exion to pain, 4=withdrawal from
pain, 5=localising pain, 6=obeys commands).25

163

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 ndings. In the
UK, the local public health authority must be notied of
suspected or proven cases of tuberculous meningitis.

there are few data to indicate whether ndings 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% specic for the diagnosis of TM.54 A recent
report suggested that precontrast hyperdensity in the
basal cisterns might be the most specic 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 inammatory
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 (gure 4).

Radiological diagnosis
CT and MRI of the brain show the pathological changes
of TM (gure 2) and provide diagnostic information at
presentation and when complications occur.53 However,

Bacteriological diagnosis
The comparative role of bacteriological and molecular
techniques for the diagnosis of TM has been a source of
much controversy. Old reports suggested the acid-fast
bacilli of M tuberculosis could be seen in the CSF after
Zeihl-Neelsen staining in nearly every case, if the
microscopist was prepared to look hard,58 but this is
rarely the experience in contemporary laboratories.59
Kennedy and Fallon60 showed that repeated CSF
sampling improved the sensitivity of a Ziehl-Neelsen
stain to over 80%, but the factors responsible for the
large reported variation in the sensitivity of bacteriology
have received little attention. A recent study reported a
bacteriological diagnosis of TM in 107 (81%) of 132
adults with the disease; acid-fast bacilli were seen in 77
(58%) patients, and cultured from 94 (71%) patients.22
The likelihood of seeing or culturing M tuberculosis from
the CSF was dependent upon meticulous microscopy
and culture of a large volume (>5 mL) of CSF.22 These
data suggest simple changes made at the bedside and
in the laboratory can substantially improve the
performance of conventional bacteriology.

Molecular diagnosis

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

Whether molecular techniques can improve upon

conventional bacteriology is unclear. In theory, nucleicacid-amplication assays, such as those developed from
the PCR, should improve with bacteriology; but attempts
to clarify their diagnostic role have failed because of few
cases and inadequate bacteriological diagnostic
comparison. A recent systematic review and metaanalysis calculated that the sensitivity and specicity of
commercial nucleic-acid-amplication assays for the
diagnosis of TM was 56% (95% CI 4666) and 98%
(9799) respectively.61 According to these data, the
http://neurology.thelancet.com Vol 4 March 2005

Review

Variable
Age (years)
36
36
Blood WCC (103/ml)
15000
15000
History of illness (days)
6
6
CSF total WCC (103/ml)
750
750
CSF % neutrophils
90
90

Score
2
0
4
0
5
0
3
0
4
0

WCC=white cell count. Suggested rule for diagnosis: total score 4=TM; total
score 4=non-TM.

Table 1: Maximum score of four for the diagnosis of TM on

admission52

sensitivity of these assays is too low (about half those

with a negative test will have the disease) and may not be
better than bacteriology. A study published after the
meta-analysis supports this conclusion: the performance
of bacteriology was compared with a commercial assay
(the amplied mycobacterium tuberculosis direct test) in
79 adults with TM before and after starting
antituberculosis drugs.62 Before the start of treatment the
sensitivities of a Ziehl-Neelsen stain and the amplied
mycobacterium tuberculosis direct test was 52% and 38%,
respectively (p=0150); this fell to 2% and 28% (0013)
after 515 days of treatment. Similar ndings have been
reported63 and indicate molecular methods are sensitive
for longer when there is antituberculosis chemotherapy.
Together, these data strongly suggest that before the

start of treatment careful bacteriology is as good as, or

better than, the commercial nucleic-acid-amplication
assays, but molecular methods may be more useful
when antituberculosis drugs have started. However, the
diagnosis of TM cannot be excluded by these tests, even
if both are negative.

Treatment of TM
The optimum treatment for pulmonary tuberculosis has
been developed from the results of many controlled
trials.64 The same is not true of TMchoice of drugs,
doses, and duration of treatment are unknown and there
are few data to guide the clinician. Nevertheless, there
are common principles of treatment, derived from the
roles of the different antituberculosis drugs in the
treatment of pulmonary disease.65 Isoniazid kills most of
the rapidly replicating bacilli in the rst 2 weeks of
treatment, with some additional help from streptomycin
and
ethambutol.
Thereafter,
rifampicin
and
pyrazinamide become important because they sterilise
lesions by killing organisms; these two drugs are crucial
for successful 6-month treatment regimens. Rifampicin
kills low or non-replicating organisms and pyrazinamide
kills those in sites hostile to the penetration and action of
the other drugs.

Antituberculosis chemotherapy
The British Thoracic Society (BTS), the Infectious
Diseases Society of America and the American Thoracic
Society (IDSA/ATS) recommend that the treatment of
TM follow the model of short course chemotherapy of
pulmonary tuberculosis: an intensive phase of
treatment with four drugs, followed by treatment with
two drugs during a prolonged continuation phase
(table 2).66,67

Figure 4: Similar appearance of cryptococcal meningitis and TM on MRI

Dilated ventricles with periventricular enhancement in TM (left) and in cryptococcal meningitis (right).

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

165

Review

Drug

Daily dose
Children

35 mg/kg

Ethambutol
or streptomycin

15 mg/kg
15 mg/kg

Duration

Oral

912 months

Oral

912 months

Adults

British Thoracic Society guidelines, 1998

Isoniazid
5 mg/kg
Rifampicin
10 mg/kg
Pyrazinamide

Route

300 mg
450 mg (50 kg)
600 mg (50 kg)
15 g (50 kg)
20 g (50 kg)
15 mg/kg
15 mg/kg (maximum 1 g)

Guidelines of the joint committee of the ATS, IDSA, and CDC, 2003
Isoniazid
1015 mg/kg (MD 300 mg) 5 mg/kg (MD 300 mg)
Rifampicin
1020 mg/kg (MD 600 mg) 10 mg/kg (MD 600 mg)
Pyrazinamide
1530 mg/kg (MD 2000 mg) 4055 kg person: 1000 mg
5675 kg person: 1500 mg
7690 kg: 2000 mg
Ethambutol
1520 mg/kg (MD 1000 mg) 4055 kg person: 800 mg
5675 kg person: 1200 mg
7690 kg person: 1600 mg

Oral
2 months
Oral
2 months
Intramuscular 2 months
Oral
Oral
Oral

912 months
912 months
2 months

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

These guidelines acknowledge the scarcity of evidence

from controlled trials and show the main areas of
uncertainty: the choice of the fourth drug in the intensive
phase and the composition and duration of the
continuation phase. Many of the recommendations for the
treatment of TM combine the principles of pulmonarytuberculosis treatment with pharmacokinetic data that
predict the intracerebral concentrations of the
antituberculosis drugs.
The rst 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 bloodbrain barrier well in the
absence of inammation68,69 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 inamed
meninges, but can cause severe nausea and vomiting.70
Pyridoxine should be given with isoniazid therapy.
Both guidelines recommend 912 months total
antituberculosis treatment; although a recent systematic
review concluded 6 months might be sufcient if the
likelihood of drug resistance is low.71 Isoniazid and
rifampicin are thought mandatory in the continuation
phase, although the role of rifampicin is uncertain
because concentrations in CSF do not exceed 10% of
those in plasma.69 In contrast, isoniazid and
pyrazinamide pass freely into the CSF and some believe
their use is crucial to a successful outcome. The BTS
suggests therapy should be extended to 18 months in
people who are unable to tolerate pyrazinamide in the
intensive phase, and others recommend pyrazinamide
166

be given throughout treatment,72 despite no supporting

evidence from controlled trials. Indeed, data from
studies
in
pulmonary
tuberculosis
indicate
pyrazinamide has little effect on outcome after the rst
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 inammation,
the incidence of neurological complications, and the
time to recovery.7578 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 benecial
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 069, 95% CI
052092, p=001), 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 conrmed 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 conrmed
that the effect of dexamethasone on survival was
consistent across all severity grades of disease, dispelling
a previously held belief that corticosteroids only
beneted those with more severe disease, but did not
nd a signicant 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 nding is
interesting and suggests that the affect of
http://neurology.thelancet.com Vol 4 March 2005

Review

dexamethasone on outcome may be more diverse than

previously thought.
In conclusion, study ndings 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 nd any clear benet 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-inammatory effect has been difcult 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 specic
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 benet with the resources and experience of
their surgical unit and the substantial complications of
shunt surgery.

Age of patients
MRC Grade
Drug
Week 1
Week 2
Week 3
Week 4
Week 5
Week 6

M tuberculosis resistant to antituberculosis drugs

TM caused by M tuberculosis resistant to one or more
rst-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
conrmation of the diagnosis is problematic. Patients
with multidrug resistant TM treated with rst-line
drugs are likely to be dead before the results of
conventional susceptibility tests (which take 68 weeks)
are available.92 Nucleic acid amplication assays that
detect mutations in M tuberculosis rpoB gene93 have
been used to rapidly diagnose multidrug resistant
pulmonary tuberculosis.94 Whether these assays can

Girgis et al79

Schoeman et al80

Thwaites et al33

60% <14 years (median 8 years)

All grades
Dexamethasone
12 mg/kg/day im (8 mg/kg/day if 25 kg)
12 mg/kg/day im (8 mg/kg/day if 25 kg)
12 mg/kg/day im (8 mg/kg/day if 25 kg)
Reducing over 3 weeks to stop

14 years

14 years

Grade II and III

Prednisolone
4 mg/kg/day*
4 mg/kg/day
4 mg/kg/day
4 mg/kg/day
Reducing dose to stop

Grade I
Dexamethasone
03 mg/kg/day iv
02 mg/kg/day iv
01 mg/kg/day oral
3 mg total/day oral
Reducing by 1 mg each week

Thwaites et al33
Grade II and III
Dexamethasone
04 mg/kg/day iv
03 mg/kg/day iv
02 mg/kg/day iv
01 mg/kg/day iv
4 mg total/day oral
Reducing by 1 mg each week

*Route of administration not published; dexamethasone tapered to stop over 3 weeks: exact regimen not published; prednisolone tapered to stop over unspecied 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

167

Review

Search strategy and selection criteria

References for this review published between 1969 and
September 2004 were identied by searches of MEDLINE and
PubMed and from references from relevant papers; those
published before 1969 were identied through searches of
the old MEDLINE database and our own extensive les. 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 nal reference list was generated from papers that were
original and relevant to this review.

diagnose multidrug resistant TM with sufcient speed

needs urgent study.
The best combination, dose, and duration of secondline drugs for the treatment of multidrug resistant TM
are unknown. Indeed, there are no published controlled
trials addressing this issue for any form of tuberculosis.95
WHO recommends uoroquinolones 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 bloodbrain 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
uoroquinolone; 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

Conicts of interest
We have no conicts 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.
References
1
Green PH. Tubercular meningitis. Lancet 1836; II: 23235.
2
Koch R. Die aetiologie der tuberculosis.
Berlin Klinische Wochenschrift 1882; 19: 22130.
3
Rich AR, McCordock HA. The pathogenesis of tuberculous
meningitis. Bull John Hopkins Hosp 1933; 52: 537.
4
Girgis NI, Sultan Y, Farid Z, et al. Tuberculosis meningitis,
Abbassia Fever Hospital Naval Medical Research Unit No 3, Cairo,
Egypt, from 1976 to 1996. Am J Trop Med Hyg 1998; 58: 2834.
5
Hosoglu S, Ayaz C, Geyik MF, Kokoglu OF, Ceviz A. Tuberculous
meningitis in adults: an eleven-year review. Int J Tuberc Lung Dis
1998; 2: 55357.
6
Farinha NJ, Razali KA, Holzel H, Morgan G, Novelli VM.
Tuberculosis of the central nervous system in children: a 20-year
survey. J Infect 2000; 41: 6168.
7
Kent SJ, Crowe SM, Yung A, Lucas CR, Mijch AM. Tuberculous
meningitis: a 30-year review. Clin Infect Dis 1993; 17: 98794.
8
Verdon R, Chevret S, Laissy JP, Wolff M. Tuberculous meningitis
in adults: review of 48 cases. Clin Infect Dis 1996; 22: 98288.
9
Davis LE, Rastogi KR, Lambert LC, Skipper BJ. Tuberculous
meningitis in the southwest United States: a community-based
study. Neurology 1993; 43: 177578.
10 Dastur DK, Manghani DK, Udani PM. Pathology and pathogenetic
mechanisms in neurotuberculosis. Radiol Clin North Am 1995;
33: 73352.
11 Flynn JL, Chan J. Immunology of tuberculosis. Annu Rev Immunol
2001; 19: 93129.
12 Rook GA, Taverne J, Leveton C, Steele J. The role of gammainterferon, vitamin D3 metabolites and tumour necrosis factor
in the pathogenesis of tuberculosis. Immunology 1987;
62: 22934.
13 Sharief MK, Ciardi M, Thompson EJ. Blood-brain barrier damage
in patients with bacterial meningitis: association with tumor
necrosis factor-alpha but not interleukin-1 beta. J Infect Dis 1992;
166: 35058.
14 Tsenova L, Bergtold A, Freedman VH, Young RA, Kaplan G.
Tumor necrosis factor alpha is a determinant of pathogenesis and
disease progression in mycobacterial infection in the central
nervous system. Proc Natl Acad Sci USA 1999; 96: 565762.
15 Thwaites GE, Simmons CP, Than Ha Quyen N, et al.
Pathophysiology and prognosis in Vietnamese adults with
tuberculous meningitis. J Infect Dis 2003; 188: 110515.
16 Tsenova L, Sokol K, Freedman VH, Kaplan G. A combination of
thalidomide plus antibiotics protects rabbits from mycobacterial
meningitis-associated death. J Infect Dis 1998; 177: 156372.
17 Schoeman JF, Springer P, Ravenscroft A, et al. Adjunctive
thalidomide therapy of childhood tuberculous meningitis: possible
anti-inammatory role. J Child Neurol 2000; 15: 497503.
18 Schoeman JF, Springer P, van Rensburg AJ, et al. Adjunctive
thalidomide therapy for childhood tuberculous meningitis: results
of a randomized study. J Child Neurol 2004; 19: 25057.
19 Laguna F, Adrados M, Ortega A, Gonzalez-Lahoz JM. Tuberculous
meningitis with acellular cerebrospinal uid in AIDS patients. Aids
1992; 6: 116567.
20 Karstaedt AS, Valtchanova S, Barriere R, Crewe-Brown HH.
Tuberculous meningitis in South African urban adults. Q J Med
1998; 91: 74347.
21 Jeren T, Beus I. Characteristics of cerebrospinal uid in
tuberculous meningitis. Acta Cytol 1982; 26: 67880.
22 Thwaites GE, Chau TT, Farrar JJ. Improving the bacteriological
diagnosis of tuberculous meningitis. J Clin Microbiol 2004;
42: 37879.
23 Dieli F, Sireci G, Di Sano C, Champagne E, Fournie JJ, Salerno JI.
Predominance of Vgamma9/Vdelta2 T lymphocytes in the
cerebrospinal uid of children with tuberculous meningitis:
reversal after chemotherapy. Mol Med 1999; 5: 30112.

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

Review

24
25
26

27
28

29

30
31

32

33

34

35

36

37
38

39

40

41

42

43
44

45

46

47
48

British Medical Research Council. Streptomycin treatment of

tuberculous meningitis. BMJ 1948; I: 58297.
Teasdale G, Jennett B. Assessment of coma and impaired
consciousness: a practical scale. Lancet 1974; 2: 8184.
Hosoglu S, Geyik MF, Balik I, et al. Predictors of outcome in
patients with tuberculous meningitis. Int J Tuberc Lung Dis 2002;
6: 6470.
Kocen RS, Parsons M. Neurological complications of tuberculosis:
some unusual manifestations. Q J Med 1970; 39: 1730.
Udani PM, Parekh UC, Dastur DK. Neurological and related
syndromes in CNS tuberculosis: clinical features and pathogenesis.
J Neurol Sci 1971; 14: 34157.
Alarcon F, Duenas G, Cevallos N, Lees AJ. Movement disorders in
30 patients with tuberculous meningitis. Mov Disord 2000;
15: 56169.
Dastur DK, Udani PM. The pathology and pathogenesis of
tuberculous encephalopathy. Acta Neuropathol (Berl) 1966; 6: 31126.
Dastur DK. The pathology and pathogenesis of tuberculous
encephalopathy and myeloradiculopathy: a comparison with
allergic encephalomyelitis. Childs Nerv Syst 1986; 2: 1319.
Udani PM, Dastur DK. Tuberculous encephalopathy with and
without meningitis: clinical features and pathological correlations.
J Neurol Sci 1970; 10: 54161.
Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for
the treatment of tuberculous meningitis in adolescents and adults.
N Engl J Med 2004; 351: 174151.
Dastur DK. Neurosurgically relevant aspects of pathology and
pathogenesis of intracranial and intraspinal tuberculosis.
Neurosurg Rev 1983; 6: 10310.
Hernandez-Albujar S, Arribas JR, Royo A, Gonzalez-Garcia JJ,
Pena JM, Vazquez JJ. Tuberculous radiculomyelitis complicating
tuberculous meningitis: case report and review. Clin Infect Dis
2000; 30: 91521.
Rapoport S, West CD, Brodsky WA. Salt losing conditions; the
renal defect in tuberculous meningitis. J Lab Clin Med 1951;
37: 55061.
Cort JH. Cerebral salt wasting. Lancet 1954; 266: 75254.
Schwartz WB, Bennett W, Curelop S, Bartter FC. A syndrome of
renal sodium loss and hyponatremia probably resulting from
inappropriate secretion of antidiuretic hormone. Am J Med 1957;
23: 52942.
Cotton MF, Donald PR, Schoeman JF, Van Zyl LE, Aalbers C,
Lombard CJ. Raised intracranial pressure, the syndrome of
inappropriate antidiuretic hormone secretion, and arginine
vasopressin in tuberculous meningitis. Childs Nerv Syst 1993;
9: 1015; discussion 1516.
Narotam PK, Kemp M, Buck R, Gouws E, van Dellen JR,
Bhoola KD. Hyponatremic natriuretic syndrome in tuberculous
meningitis: the probable role of atrial natriuretic peptide.
Neurosurgery 1994; 34: 98288.
Dass R, Nagaraj R, Murlidharan J, Singhi S. Hyponatraemia and
hypovolemic shock with tuberculous meningitis. Indian J Pediatr
2003; 70: 99597.
Cotton MF, Donald PR, Schoeman JF, Aalbers C, Van Zyl LE,
Lombard C. Plasma arginine vasopressin and the syndrome of
inappropriate antidiuretic hormone secretion in tuberculous
meningitis. Pediatr Infect Dis J 1991; 10: 83742.
Sakarcan A, Bocchini J Jr. The role of udrocortisone in a child
with cerebral salt wasting. Pediatr Nephrol 1998; 12: 76971.
Smith J, Godwin-Austen R. Hypersecretion of anti-diuretic
hormone due to tuberculous meningitis. Postgrad Med J 1980;
56: 4144.
Berenguer J, Moreno S, Laguna F, et al. Tuberculous meningitis in
patients infected with the human immunodeciency virus.
N Engl J Med 1992; 326: 66872.
Katrak SM, Shembalkar PK, Bijwe SR, Bhandarkar LD. The
clinical, radiological and pathological prole of tuberculous
meningitis in patients with and without human immunodeciency
virus infection. J Neurol Sci 2000; 181: 11826.
Fallon RJ, Kennedy DH. Treatment and prognosis in tuberculous
meningitis. J Infect 1981; 3: 3944.
Kalita J, Misra UK. Outcome of tuberculous meningitis at
6 and 12 months: a multiple regression analysis.
Int J Tuberc Lung Dis 1999; 3: 26165.

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

49

50
51
52

53

54

55

56

57

58
59
60
61

62

63

64

65
66

67
68
69

70

71

72
73

van den Bos F, Terken M, Ypma L, et al. Tuberculous meningitis

and miliary tuberculosis in young children. Trop Med Int Health
2004; 9: 30913.
Tung YR, Lai MC, Lui CC, et al. Tuberculous meningitis in
infancy. Pediatr Neurol 2002; 27: 26266.
Kumar R, Singh SN, Kohli N. A diagnostic rule for tuberculous
meningitis. Arch Dis Child 1999; 81: 22124.
Thwaites GE, Chau TT, Stepniewska K, et al. Diagnosis of adult
tuberculous meningitis by use of clinical and laboratory features.
Lancet 2002; 360: 128792.
Bernaerts A, Vanhoenacker FM, Parizel PM, et al. Tuberculosis of
the central nervous system: overview of neuroradiological ndings.
Eur Radiol 2003; 13: 187690.
Kumar R, Kohli N, Thavnani H, Kumar A, Sharma B.
Value of CT scan in the diagnosis of meningitis. Indian Pediatr
1996; 33: 46568.
Andronikou S, Smith B, Hatherhill M, Douis H, Wilmshurst J.
Denitive neuroradiological diagnostic features of tuberculous
meningitis in children. Pediatr Radiol 2004; 34: 87685.
Offenbacher H, Fazekas F, Schmidt R, et al. MRI in tuberculous
meningoencephalitis: report of four cases and review of the
neuroimaging literature. J Neurol 1991; 238: 34044.
Tartaglione T, Di Lella GM, Cerase A, Leone A, Moschini M,
Colosimo C. Diagnostic imaging of neurotuberculosis. Rays 1998;
23: 16480.
Stewart SM. The bacteriological diagnosis of tuberculous
meningitis. J Clinical Pathology 1953; 6: 24142.
Garg RK. Tuberculosis of the central nervous system.
Postgrad Med J 1999; 75: 13340.
Kennedy DH, Fallon RJ. Tuberculous meningitis. JAMA 1979;
241: 26468.
Pai M, Flores LL, Pai N, Hubbard A, Riley LW, Colford JM.
Diagnostic accuracy of nucleic acid amplication tests for
tuberculous meningitis: a systematic review and meta-analysis.
Lancet Infect Dis 2003; 3: 63343.
Thwaites GE, Caws M, Chau TT, et al. Comparison of conventional
bacteriology with nucleic acid amplication (amplied
mycobacterium direct test) for diagnosis of tuberculous meningitis
before and after inception of antituberculosis chemotherapy.
J Clin Microbiol 2004; 42: 9961002.
Donald PR, Victor TC, Jordaan AM, Schoeman JF, van Helden PD.
Polymerase chain reaction in the diagnosis of tuberculous
meningitis. Scand J Infect Dis 1993; 25: 61317.
Fox W, Ellard GA, Mitchison DA. Studies on the treatment
of tuberculosis undertaken by the British Medical
Research Council Tuberculosis Units, 1946-1986, with relevant
subsequent publications. Int J Tuberc Lung Dis 1999;
3: S23179.
Mitchison DA. Role of individual drugs in the chemotherapy of
tuberculosis. Int J Tuberc Lung Dis 2000; 4: 796806.
British Thoracic Society. Chemotherapy and management of
tuberculosis in the United Kingdom: recommendations 1998.
Thorax 1998; 53: 53648.
Centers for Disease Control. Treatment of tuberculosis.
MMWR Recomm Rep 2003; 52: 177.
Bobrowitz ID. Ethambutol in tuberculous meningitis. Chest 1972;
61: 62932.
Ellard GA, Humphries MJ, Allen BW. Cerebrospinal uid drug
concentrations and the treatment of tuberculous meningitis.
Am Rev Respir Dis 1993; 148: 65055.
Donald PR, Seifart HI. Cerebrospinal uid concentrations of
ethionamide in children with tuberculous meningitis. J Pediatr
1989; 115: 48386.
van Loenhout-Rooyackers JH, Keyser A, Laheij RJ, Verbeek AL,
van der Meer JW. Tuberculous meningitis: is a 6-month treatment
regimen sufcient? Int J Tuberc Lung Dis 2001; 5: 102835.
Humphries M. The management of tuberculous meningitis.
Thorax 1992; 47: 57781.
Hong Kong Chest Service/British Medical Research Council.
Controlled trial of 2, 4, and 6 months of pyrazinamide in 6-month,
three-times-weekly regimens for smear-positive pulmonary
tuberculosis, including an assessment of a combined preparation
of isoniazid, rifampin, and pyrazinamide: results at 30 months.
Am Rev Respir Dis 1991; 143: 70006.

169

Review

74

75
76

77

78

79

80

81
82
83

84

85

86

170

Shane SJ, Riley C. Tuberculous meningitis: combined therapy with

cortisone and antimicrobial agents. N Engl J Med 1953;
249: 82934.
Ashby M, Grant H. Tuberculous meningitis treated with cortisone.
Lancet 1955; 1: 6566.
Lepper MH, Spies HW. The present status of the treatment of
tuberculosis of the central nervous system. Ann N Y Acad Med
1963; 106: 10623.
OToole RD, Thornton GF, Mukherjee MK, Nath RL.
Dexamethasone in tuberculous meningitis: relationship of
cerebrospinal uid effects to therapeutic efcacy. Ann Intern Med
1969; 70: 3948.
Escobar JA, Belsey MA, Duenas A, Medina P. Mortality from
tuberculous meningitis reduced by steroid therapy. Pediatrics 1975;
56: 105055.
Girgis NI, Farid Z, Kilpatrick ME, Sultan Y, Mikhail IA.
Dexamethasone adjunctive treatment for tuberculous meningitis.
Pediatr Infect Dis J 1991; 10: 17983.
Schoeman JF, Van Zyl LE, Laubscher JA, Donald PR. Effect of
corticosteroids on intracranial pressure, computed tomographic
ndings, and clinical outcome in young children with tuberculous
meningitis. Pediatrics 1997; 99: 22631.
Prasad K, Volmink J, Menon GR. Steroids for treating tuberculous
meningitis. Cochrane Database Syst Rev 2000; 3: CD00224.
Quagliarello V. Adjunctive steroids for tuberculous meningitis:
more evidence, more questions. N Engl J Med 2004; 351: 179294.
Schoeman JF, Elshof JW, Laubscher JA, Janse van Rensburg A,
Donald PR. The effect of adjuvant steroid treatment on serial
cerebrospinal uid changes in tuberculous meningitis.
Ann Trop Paediatr 2001; 21: 299305.
van der Flier M, Hoppenreijs S, van Rensburg AJ, et al. Vascular
endothelial growth factor and blood-brain barrier disruption in
tuberculous meningitis. Pediatr Infect Dis J 2004; 23: 60813.
Schoeman J, Donald P, van Zyl L, Keet M, Wait J. Tuberculous
hydrocephalus: comparison of different treatments with regard to
ICP, ventricular size and clinical outcome. Dev Med Child Neurol
1991; 33: 396405.
Lamprecht D, Schoeman J, Donald P, Hartzenberg H.
Ventriculoperitoneal shunting in childhood tuberculous
meningitis. Br J Neurosurg 2001; 15: 11925.

87

88

89

90

91

92

93

94

95
96
97

98

Palur R, Rajshekhar V, Chandy MJ, Joseph T, Abraham J. Shunt

surgery for hydrocephalus in tuberculous meningitis: a long-term
follow-up study. J Neurosurg 1991; 74: 6469.
Schoeman JF, Laubscher JA, Donald PR. Serial lumbar CSF
presure measurements and cranial computed tomographic
ndings in childhood tuberculous meningitits. Childs Nerv Syst
2000; 16: 20308.
Mathew JM, Rajshekhar V, Chandy MJ. Shunt surgery in poor
grade patients with tuberculous meningitis and hydrocephalus:
effects of response to external ventricular drainage and other
variables on long term outcome. J Neurol Neurosurg Psychiatry
1998; 65: 1158.
Patel VB, Padayatchi N, Bhigjee AI, et al. Multidrug-resistant
tuberculous meningitis in KwaZulu-Natal, South Africa.
Clin Infect Dis 2004; 38: 85156.
Thwaites GE, Chau TT, Caws M, et al. Isoniazid resistance,
mycobacterial genotype and outcome in Vietnamese adults with
tuberculous meningitis. Int J Tuberc Lung Dis 2002; 6: 86571.
Daikos GL, Cleary T, Rodriguez A, Fischl MA. Multidrug-resistant
tuberculous meningitis in patients with AIDS.
Int J Tuberc Lung Dis 2003; 7: 39498.
Mokrousov I, Otten T, Vyshnevskiy B, Narvskaya O. Allele-specic
rpoB PCR assays for detection of rifampin-resistant Mycobacterium
tuberculosis in sputum smears. Antimicrob Agents Chemother
2003;47: 223135.
Johansen IS, Lundgren B, Sosnovskaja A, Thomsen Vs VO. Direct
detection of multidrug-resistant Mycobacterium tuberculosis in
clinical specimens in low- and high-incidence countries by line
probe assay. J Clin Microbiol 2003; 41: 445456.
Frieden TR, Sterling TR, Munsiff SS, Watt CJ, Dye C.
Tuberculosis. Lancet 2003; 362: 88799.
Crofton J, Chaulet P, Maher D. Guidelines for the management of
drug-resistant tuberculosis. Geneva: WHO TB, 1997.
Berning SE, Cherry TA, Iseman MD. Novel treatment of
meningitis caused by multidrug-resistant Mycobacterium
tuberculosis with intrathecal levooxacin and amikacin: case report.
Clin Infect Dis 2001; 32: 64346.
Nau R, Prange HW, Martell J, Shari S, Kolenda H, Bircher J.
Penetration of ciprooxacin into the cerebrospinal uid of patients
with uninamed meninges. J Antimicrob Chemother 1990;
25: 96573.

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