Copyright  2009 The Author

Journal compilation  2009 Blackwell Munksgaard

Acta Neurol Scand 2010: 122: 7590 DOI: 10.1111/j.1600-0404.2009.01316.x

ACTA NEUROLOGICA
SCANDINAVICA

Review article

Tuberculous meningitis
Garg RK. Tuberculous meningitis.
Acta Neurol Scand: 2010: 122: 7590.
 2009 The Author Journal compilation  2009 Blackwell Munksgaard.
Tuberculous meningitis is a severe form of extrapulmonary
tuberculosis. The exact incidence and prevalence are not known. In
countries with high burden of pulmonary tuberculosis, the incidence is
expected to be proportionately high. Children are much more
vulnerable. Human immunodeciency virus-infected patients have a
high incidence of tuberculous meningitis. The hallmark pathological
processes are meningeal inammation, basal exudates, vasculitis and
hydrocephalus. Headache, vomiting, meningeal signs, focal decits,
vision loss, cranial nerve palsies and raised intracranial pressure are
dominant clinical features. Diagnosis is based on the characteristic
clinical picture, neuroimaging abnormalities and cerebrospinal uid
changes (increased protein, low glucose and mononuclear cell
pleocytosis). Cerebrospinal uid smear examination, mycobacterial
culture or polymerase chain reaction is mandatory for bacteriological
conrmation. The mortality and morbidity of tuberculous meningitis
are exceptionally high. Prompt diagnosis and early treatment are
crucial. Decision to start antituberculous treatment is often empirical.
WHO guidelines recommend a 6 months course of antituberculous
treatment; however, other guidelines recommend a prolonged
treatment extended to 9 or 12 months. Corticosteroids reduce the
number of deaths. Resistance to antituberculous drugs is associated
with a high mortality. Patients with hydrocephalus may need
ventriculo-peritoneal shunting. Bacillus Calmette-Guerin vaccination
protects to some degree against tuberculous meningitis in children.

Introduction

Tuberculous meningitis is a devastating disease of

central nervous system. It primarily aects the
meninges of brain and spinal cord along with
adjacent brain parenchyma. Human immunodeciency virus-infected patients have a high incidence
of tuberculous meningitis. Bacterial and hosts
genetic factors play a crucial role in its pathogenesis. Early diagnosis is important for the success of
the treatment (1). Diagnosis often remains problematic despite many signicant advances in diagnostic techniques. The mortality and morbidity of
tuberculous meningitis are exceptionally high.
Corticosteroids reduce the number of deaths and
increase the survival in adult patients (2). Gene
polymorphisms, which appear to inuence outcome in patients with tuberculous meningitis, have
been identied (3). Multidrug-resistant tuberculous

R. K. Garg
Department of Neurology, Chhatrapati Shahuji Maharaj
Medical University, Uttar Pradesh, Lucknow, India

Key words: Bacillus Calmette-Gurin vaccination;

extrapulmonary tuberculosis; human immunodeficiency
virus; dexamethasone; Mycobacterium tuberculosis
Dr Ravindra Kumar Garg, Department of Neurology,
Chhatrapati Shahuji Maharaj Medical University,
Uttar Pradesh, Lucknow 226003, India
Tel.: 91 522-4003496
Fax: 91 522-2258852
e-mail: garg50@yahoo.com
Accepted for publication December 1, 2009

meningitis, which has been reported worldwide, is

difcult to diagnose and treat. This review focuses
on the various aspects of tuberculous meningitis.
Special emphasis is given to recent developments in
the early detection and treatment of this dreaded
disease. An extensive review of the literature,
published in English, was carried out using the
PubMed and Google Scholar databases. The
search terms those were used included tuberculosis,
tuberculous meningitis, meningeal tuberculosis and
central nervous system tuberculosis.
Epidemiology

Globally, there were an estimated 13.7 million

prevalent cases of tuberculosis in 2007 (206 per
100 000 population). During this period, estimated
9.27 million new cases of tuberculosis were registered worldwide. Of these 9.27 million new cases of
75

Garg
tuberculosis, an estimated 1.37 million (14%) were
human immunodeciency virus-positive. In 2007,
approximately 1.3 million deaths (20 per 100 000
population) occurred in patients with tuberculosis.
The ve countries, that have highest number of
tuberculosis cases, are India, China, Indonesia,
Nigeria and South Africa (4).
The exact incidence and prevalence of tuberculous meningitis in the most parts of the world are
not exactly known. Some epidemiological details
of extra-pulmonary tuberculosis are available from
developed countries. In developed countries,
despite an overall decrease in numbers of tuberculosis cases, the proportion of extra-pulmonary
tuberculosis and tuberculous meningitis cases has
increased. In Germany, 26 302 tuberculosis cases
were registered during 19962000. The proportion
of patients with extrapulmonary tuberculosis
(including tuberculous meningitis) was 21.6%.
Extrapulmonary tuberculosis was frequent among
females, children aged less than 15 years and
persons migrated from Africa and Asia (5) The
incidence of tuberculous meningitis in France (in
the year 2000) was estimated as 1.55 cases per
million. The incidence rate was 0.7 cases per
million when only culture-positive cases were
counted. Among 143 tuberculous meningitis cases
reported to two agencies of France the Tuberculosis Mandatory Notication System and the
National Reference Centre total number of conrmed tuberculous meningitis cases were 91. The
number of culture-positive meningitis cases was
estimated to be 41 and the number of culturenegative meningitis cases was 50 (6). In United
States, at a large inner-city medical center, during
an 11.5-year period, 34 patients were found to have
positive cerebrospinal uid cultures for Mycobacterium tuberculosis, accounting for 1.5% of
culture-conrmed tuberculosis cases. All patients
were born in the United States, 31 (91%) were
black people and 16 (47%) were human immunodeciency virus-infected patients (7). In poor and
developing countries with very high burden of
pulmonary tuberculosis, the incidence of tuberculous meningitis is expected to be proportionately
high.
The natural history and clinical manifestations
of tuberculosis in children are dierent as compared with that of adults. Neonates have the
highest risk of progression to severe forms of
tuberculosis. Mortality is highest in early childhood because of a high incidence of disseminated
forms of tuberculosis in this population (8). In a
study from South Africa, the incidence rate of
tuberculous meningitis, in children, was observed
to be age specic. The incidence in neonates was
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31.5 per 100 000 as compared with 0.7 per 100 000
among older children (1014 years) (9). Another
study from South Africa observed that in human
immunodeciency virus-infected children disseminated tuberculosis was signicantly more common
(6 25) as compared with human immunodeciency
virus-negative children (12 414). In children without human immunodeciency virus infection
disseminated (miliary) disease (9 11) and tuberculous meningitis (10 13) were predominantly seen in
those who were less than 3 years of age (10).
Tuberculosis, in human immunodeciency virusinfected patients, progresses to severe forms of
tuberculosis at a rate ve times greater than that
for people not infected with human immunodeciency virus (11). In a study, of 2205 patients
with all types of tuberculosis, 455 (21%) patients
were human immunodeciency virus-infected. In
this study, 45 patients had culture-positive tuberculous meningitis. It was observed that of the 1750
patients without human immunodeciency virus
infection only 2% had tuberculous meningitis, as
compared with 10% of the human immunodeciency virus-infected patients. The majority of
human immunodeciency virus-infected patients
with culture-positive tuberculous meningitis had
clinical or radiologic evidence of extra-meningeal
tuberculosis as well (12).
Multidrug-resistant tuberculous meningitis

In 2007, there were an estimated 0.5 million cases

of multidrug-resistant tuberculosis worldwide (4).
Drug resistance is more common in human immunodeciency virus-positive patients. Under optimal
treatment conditions, the cure rate of multidrugresistant pulmonary tuberculosis is approximately
7090%, but the cure rate averages to 50% in
diverse clinical conditions (13). The problem of
multidrug-resistant tuberculosis has also been
identied in patients with tuberculous meningitis.
Multidrug-resistant tuberculous meningitis is often
associated with poor prognosis (13). In a center of
South Africa, during the period of 19992002, 350
patients with tuberculous meningitis were identied by cerebrospinal uid culture. In this group, 30
patients (8.6%) had tuberculous meningitis that
was resistant to at least isoniazid and rifampicin.
The majority of multidrug-resistant tuberculous
meningitis cases either died or experienced significant morbidity. Eighteen of multidrug-resistant
tuberculous meningitis patients were human immunodeciency virus-positive (14). In a Vietnamese
study, Mycobacterium tuberculosis isolates from
the cerebrospinal uid of 198 adults were compared with 237 isolates from patients with pulmo-

Tuberculous meningitis
nary tuberculosis. It was observed that drug
resistance rates were lower in the isolates from
cerebrospinal uid (2.5% multidrug resistance)
than pulmonary isolates (5.9% multidrug resistance) (15). Fortunately, multidrug-resistant tuberculous meningitis is still not a serious problem in
some of the endemic countries. In a study from
India, a total of 366 isolates were analyzed for
multidrug-resistant tuberculous meningitis. Among
these, 301 (82.2%) were sensitive to all four
primary drugs tested, whereas 65 (17.8%) showed
resistance. There were 46 (12.5%) isolates resistant
to isoniazid, whereas only nine isolates (2.4%)
demonstrated multidrug resistance (16).
Etiology

Tuberculous meningitis is caused by bacteria

Mycobacterium tuberculosis. Mycobacterium tuberculosis is a gram-positive, aerobic, non-sporeforming, non-motile, pleomorphic rod that is
distantly related to the Actinomycetes. Mycobacterium tuberculosis is an acid-fast bacterium.
One of the most widely used acid-fast staining
method for Mycobacterium tuberculosis is the
Ziehl-Neelsen stain. Lowenstein-Jensen medium is
most popular and widely available culture medium
to grow Mycobacterium tuberculosis.
Pathogenesis

Predisposing factors for the development of tuberculous meningitis, like for any other forms of
tuberculosis, include poverty, overcrowding, illiteracy, malnutrition, alcoholism, substance abuse,
diabetes mellitus, immunosuppressive treatment,
malignancy, head trauma and human immunodeciency virus infection (17). Transmission of bacteria Mycobacterium tuberculosis to a healthy
person is primarily by airborne droplet nuclei. In
the lungs, Mycobacterium tuberculosis bacteria
multiply in alveolar macrophages. Within 24
weeks, through blood circulation, bacilli spread to
extrapulmonary sites and produce small granulomas in the meninges and adjacent brain parenchyma. These small granulomas are known as Rich
focus. These lesions are usually present in the
meninges and on the subpial or subependymal
surface of the brain. Rich foci remain dormant for
years. Tuberculous meningitis develops when a
caseating Rich focus discharges its contents into
the subarachnoid space. Decreased immunity is
believed to play a role, however, the exact trigger for
the rupture of Rich foci is not known (1719).
Several reports suggest that, in children, miliary
tuberculosis is directly involved in the pathogenesis

of tuberculous meningitis. The bacillaemia that

accompanies miliary dissemination increase the
likelihood that a meningeal or sub-cortical tuberculous focus will be formed, which may eventually
caseate and give rise to tuberculous meningitis (19,
20). The bacilli enter the central nervous system by
traversing the bloodbrain barrier.
Pathogen factors

Some strains of Mycobacterium tuberculosis are

considered more virulent and capable of causing
disseminated and meningeal forms of tuberculosis
than others. For example, Beijing strain of Mycobacterium tuberculosis (highly prevalent in Asia
and in the countries of the former Soviet Union) is
strongly associated with tuberculous meningitis;
however, the tuberculosis caused by the EuroAmerican strain (the most prevalent strain in
Europe and the Americas) is more likely to be
pulmonary rather meningeal (21). In addition,
these two different genotypes of Mycobacterium
tuberculosis may manifest with variable clinical
manifestations in the host. For example, meningitis
caused by the East Asian Beijing genotype was
associated with a shorter duration of illness and
presence of lesser number of leukocytes in cerebrospinal uid. The East Asian Beijing genotype
was strongly associated with drug-resistant tuberculosis and a high incidence of human immunodeciency virus co-infection. It was suggested that
the association between the East Asian Beijing
strain and disease progression and cerebrospinal
uid leukocyte count might inuence protective
inammatory responses of the brain (22, 23).
Host factors

Mycobacterium tuberculosis is an intracellular

pathogen that survives within the phagosome of
host macrophages. Apoptosis of infected macrophages is an eective hosts mechanism against
tuberculous bacilli. Virulent strains of Mycobacterium tuberculosis have evolved several genetic
mechanisms to subvert host immune responses,
leading to their prolonged survival and growth in
the hosts macrophages (24, 25). The mechanisms
by which Mycobacterium tuberculosis manipulates
the host immune system are attributed to lipoarabinomannans and their precursor lipomannans.
These two are important glycolipids of Mycobacterium tuberculosis cell wall. Lipoarabinomannan is
involved in the inhibition of phagosome maturation, apoptosis, interferon-gamma signaling in
macrophages and interleukin-12 cytokine secretion
of dendritic cells. It has been observed that lipid
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Garg
fractions from the virulent Beijing strain induce
macrophages to secrete large amounts of tumor
necrosis factor-alpha and interleukin-10, but
downregulate toll-like receptor-2, toll-like receptor-4 and major histocompatibility complex class II
expression. In contrast, lipids from Mycobacterium
tuberculosis Canetti (a less virulent strain) do not
produce these inammatory changes (26).
Several genetic abnormalities increase the hosts
susceptibility to Mycobacterium tuberculosis (27,
28). A group of authors identied polymorphisms
in the P2X7 receptor (an ATP-gated Ca2+ channel) gene. Normally, activation of the P2X7
receptor leads to the induction of apoptosis and
death of the infecting mycobacteria. Macrophages
from subjects who have these polymorphisms fail
to undergo macrophage apoptosis and show defect
in mycobacterial killing (27). Another recent
investigation revealed that single nucleotide polymorphisms in toll-interleukin-1 receptor domain
containing adaptor protein gene were more
strongly associated with the risk of meningeal
tuberculosis (29). Presence of toll-like receptor-2
gene polymorphisms has been shown to increase
the hosts susceptibility to severe forms of tuberculosis like miliary tuberculosis and tuberculous
meningitis (30). Single nucleotide polymorphisms,
located at these genes, are thought to inuence
cytokine levels and regulate resistance and susceptibility of an individual to tuberculosis (21). Polymorphisms in interferon-gamma gene have also
been associated to individuals susceptibility to
tuberculous infection (31).

have a positive correlation with the severity of the

tuberculous meningitis (35). Human immunodeciency virus co-infection with tuberculous meningitis has been shown to attenuate cerebrospinal
uid inammatory changes. Low cerebrospinal
uid interferon-gamma concentration was independently associated with death, suggesting that
interferon-gamma contributes to hosts immunity
and survival (36).

Immunopathogenesis

Pathology

Once mycobacteria enter in the central nervous

system, macrophages recognize them and appropriate innate and adaptive immune responses are
initiated. Subsequent immunopathogenesis may
result in impairment of the bloodbrain barrier,
development of cerebral edema and increased
intracranial pressure. The elevated level of tumor
necrosis factor-alpha produced during mycobacterial infection is an important element in the
immunopathogenesis (32). Microglial cells (the
resident macrophages of the brain) are the principal cells producing immunological chemicals
against tubercle bacilli. Several studies have
shown that microglia produce a variety of chemokines that act to initiate or promote inammatory
responses in the central nervous system through
facilitating the recruitment of peripheral immune
cells into the brain parenchyma (33, 34). The
elevated levels of serum and cerebrospinal uid
tumor necrosis factor-alpha and interferon-gamma

The tuberculous meningitis has a strong propensity

to aect the basal parts of the brain. Pathologic
changes diusely aect the arachnoid membrane
and subarachnoid space. The hallmark pathologic
features are meningeal inammation, brogelatinous basal exudates, vasculitis of the arteries
traversing the exudates and obstruction of ow of
cerebrospinal uid resulting in hydrocephalus. The
brain tissue underlying the tuberculous exudates
shows varied degrees of edema, perivascular inltration and a microglial reaction collectively
termed as border zone encephalitis. Microscopic
pathological feature of tuberculous meningitis is
formation of epithelioid cell granulomas with
Langhans giant cells, lymphocytic inltrates and
caseous necrosis. Exudates are prominently present
around sylvian ssure, basal cisterns, brainstem
and cerebellum. The optic chiasma and the roots of
other cranial nerves arising from the ventral aspect
of the brainstem are usually entrapped in thick

78

Animal models

Animal models have played an important role in

the understanding of pathogenesis of tuberculous
meningitis. Currently, the rabbit is being used as a
model of human tuberculosis because of its close
resemblance to human tuberculosis. In 1998,
the rabbit model of tuberculous meningitis was
prepared by introducing a virulent strain of
Mycobacterium bovis by intracranial route.
Authors observed acute inammatory changes in
the cerebrospinal uid. Histologically, severe meningitis with thickening of the leptomeninges, prominent vasculitis and encephalitis was apparent by
day 8 (37). Recently, a murine model has been
developed to study the pathogenesis of tuberculous
meningitis. Mice were intracerebrally injected with
Mycobacterium tuberculosis. Later on bacilli could
be cultured from brain homogenates (38). In the
murine model, authors identied central nervous
system-specic Mycobacterium tuberculosis genes
that play an important role in the pathogenesis of
central nervous system tuberculosis (39).

Tuberculous meningitis
exudates. Exudates can be seen surrounding the
lower part of spinal cord and cauda equina
resulting in tuberculous rediculomyelopathy.
Changes in cerebral vessels are characterized by
inammation, spasms, constriction and eventually
thrombosis of cerebral vessels. Occlusion of cerebral arteries leads to infarction of the underlying
tissue. The meningeal veins passing through the
inammatory exudate show varying degree of
phlebitis. Obstruction to the ow of cerebrospinal
uid occurs in the posterior fossa, as thick exudate
blocks the openings of fourth ventricles, at sylvian
aqueduct or at the opening of the tentorium. As a
consequence, hydrocephalus develops. Infrequently, tuberculous meningitis may results in
formation of tuberculoma consisting of caseous
necrotic material, epithelioid cell granuloma and
mononuclear cell inltration (17, 40).
Clinical features

Typically, tuberculous meningitis is preceded by

a variable period of non-specic symptoms.
Common non-specic symptoms include malaise,
anorexia, fatigue, weight loss, fever, myalgia and
headache. At rst consultation, most of the
patients are already in the advanced stages of the
disease (41). Fever, headache, vomiting, alteration
in sensorium and nuchal rigidity are the most
frequent presenting manifestations. Cranial nerve
palsies, vision loss, focal neurological decits and
signs of raised intracranial pressure are common in
advanced stages. In a series of 101 adult patients,
frequent presenting neurologic features included
headache (96.0%), fever (91.1%), nuchal rigidity
(91.1%), vomiting (81.2%), meningism (79.2%)
and abnormal mental state (72.3%). In this series,
the mean duration of the symptoms before admission was 12 days (42). Atypical clinical features in
elderly often lead to a delayed diagnosis. In elderly,
meningeal signs are less frequently present. In a
study conducted on 53 adults patients (over of
50 years), the major clinical presentations were:
fever (81%), headache (47%), vomiting (34%),
neck rigidity (51%), altered sensorium (64%),
seizures (28%) and focal neurological decits
(24%) (43). Tuberculous meningitis in elderly
patients may present as a subacute dementia with
memory decits and personality changes typical of
frontal lobe-like disease. In pediatric patients
coma, raised intracranial pressure, seizures and
focal neurological decits dominate the clinical
manifestations. Generalized tonic and clonic seizures are the commonest type of seizures followed
by focal seizures and tonic spasms (44). Hyponatremia in patients with tuberculous meningitis is a

common metabolic abnormality. Hyponatremia is

often caused by repeated vomiting and cerebral salt
wasting syndrome. The advanced stages of tuberculous meningitis are marked by deep coma,
hemiplegia or paraplegia, decerebrate posturing,
deterioration in vital signs, and, eventually, death.
Cranial nerve palsies are seen in approximately
25% of cases. The sixth cranial nerve is most
commonly aected cranial nerve. Third and fourth
cranial nerves are less frequently involved. Cranial
nerves are aected either because of entrapment of
nerve trunk in thick basilar exudates or because of
increased intracranial pressure (45, 46). Vision loss
is a devastating complication of tuberculous meningitis. There several possible reasons for optic
nerve involvement like optochiasmatic arachnoiditis, third ventricular compression of optic chiasma
in patients with a large hydrocephalus, optic nerve
granulomas or ethambutol toxicity (47). Optochiasmatic tuberculoma is a rare cause of progressive visual failure in tuberculous meningitis.
Magnetic resonance imaging in optochiasmatic
tuberculoma demonstrates ring enhancing lesions
in optic chiasma and brainstem (48). Papilledema is
an unusual feature of tuberculous meningitis.
In tuberculous meningitis, several types of
movement disorders like chorea, hemiballismus,
athetosis, generalized tremors, myoclonic jerks and
ataxia have been described. Movement disorders
are more common in children than in adults. On
imaging, deep periventricular vascular lesions are
frequently present (49).
Paraplegia frequently complicates tuberculous
meningitis. Paraplegia is either caused by tuberculous radiculomyelitis or intramedullary tuberculomas. Tuberculous radiculomyelopathy is char
acterized by the subacute paraparesis. Other manifestations of tuberculous radiculomyelopathy
include root pain, paraesthesias, bladder disturbance
and muscle wasting. Muscle wasting is a late manifestation. In the lower limbs, there is hypotonia and
deep tendon reexes are usually absent. There may be
extensor plantar response. In most of the patients,
cerebrospinal uid examination often reveals a very
high protein content (probably as a consequence of
spinal block) (50, 51). Other possible causes of
paraplegia are an intradural, extramedullary spinal
cord tuberculoma or intramedullary spinal syringomyelic cavities.
Infarcts are common in patients with tuberculous meningitis (52). Infarcts are frequently located
at internal capsule, basal ganglion and thalamic
regions. Infarcts are much more common in the
areas supplied by medial striate and thalamoperforating arteries. The regions supplied by lateral
striate, anterior choroidal and thalamogeniculate
79

Garg
arteries are less frequently affected. Infracts can
either be asymptomatic or symptomatic. Symptomatic strokes in tuberculous meningitis present
with dense hemiplegia (53, 54). In children, infarcts
of basal ganglia and internal capsule were associated with a poor outcome. Purely hemispheric
infarcts were associated with good prognosis (55).
Choroidal tubercles are infrequent fundoscopic
nding in patients with tuberculous meningitis.
These lesions are considered virtually pathognomonic of tuberculous meningitis. Choroidal tubercles are often associated with miliary tuberculosis
(56). On fundoscopic examination, choroidal
tubercles are white, gray or yellow lesions and
have indistinct borders with surrounding edema.
Their size varies from about 0.5 to 3 mm in
diameter (57) (Fig. S1). Histopathologically, choroidal tubercles represent caseating granulomas.
Tubercle bacilli have also been demonstrated
within the choroidal tubercles (58).

Diagnosis
Cerebrospinal fluid examination

Cerebrospinal uid examination is crucial for the

conrmation of the diagnosis. Characteristic cerebrospinal uid changes help in dierentiating from
other causes of chronic meningitis. Typical cerebrospinal uid changes are mononuclear cell
pleocytosis, low glucose levels and elevated protein
levels (Table 1). However, the gold standard for
diagnosis is demonstration of Mycobacterium
tuberculosis bacilli in the cerebrospinal uid
(Table 2). Unfortunately, smear for acid-fast bacillus is positive only in 530% of patients. Culture of
Mycobacterium tuberculosis from cerebrospinal
uid is also not always positive and it takes several
weeks for a positive result. Conventional cerebrospinal uid culture on Lowenstein-Jensen medium
is positive in approximately 4590% of cases. In
human immunodeciency virus-associated tuberculous meningitis 69% positivity for smear and

Table 1 Cerebrospinal fluid diagnostic tests

Cerebrospinal fluid studies
Color
Cerebrospinal fluid pressure
Glucose levels
Protein levels
Cell contents

Clear or xanthochromic*
Elevated
<400 mg l (<2.22 mmol l)
0.85 g l
100500 cells ll (0.10 to 0.50 109 l)
Predominance of lymphocytes

*In the presence of subarachnoid block.

Cerebrospinal fluid and blood glucose ratio < 0.5.

80

Table 2 Other diagnostic tests used for the diagnosis of tuberculous meningitis
Currently available diagnostic tests
Cerebrospinal fluid smear examination
Culture of Mycobacterium tuberculosis
Polymerase chain reaction
Enzyme-linked immunosorbent assay
Microscopic observation drug susceptibility assay
Mycobacterial growth indicator tube
Dot enzyme-linked immunosorbent method
Newly devised methods
Ex vivo Mycobacterium tuberculosis-specific enzyme-linked immunospot assay
(ELISpot assay)
Anti-Bacillus Calmette-Gurin antibody-secreting cell detection
Adenosine deaminase assays
Gen-Probe amplified Mycobacterium tuberculosis direct test

87.9% positivity for bacterial culture have been

demonstrated (59). To increase the yield of smear
examination at least 6 ml of cerebrospinal uid is
collected and smear is examined for at least 30 min
(60). Cerebrospinal uid sediments should always
be subjected for smear examination.
Several liquid culture systems have been evaluated extensively in tuberculous meningitis and
seem to provide comparable results to the solid
media-based tests with the advantage of rapid
results. MB BacT Mycobacterium detection system
is a fully automated and non-radiometric system
that utilizes a bottle containing a colorimetric
sensor embedded in its bottom. Carbon dioxide
produced by microbial metabolism causes reduction in pH of medium and changes the sensor color
from dark green to yellow. The color change is
continuously monitored and promptly reported by
the instrument (61). Microscopic observation drug
susceptibility assay is an also newer technique for
the cheap, rapid identication of drug-resistant
Mycobacterium tuberculosis in patients with tuberculous meningitis (62).
The detection of Mycobacterium tuberculosis
DNA in cerebrospinal uid samples using polymerase chain reaction is widely used diagnostic
method (63, 64). A meta-analysis found the sensitivity of commercial nucleic acid amplication tests
to be only 56%; however, the specicity was as
high as 98%. Sensitivity of polymerase chain
reaction testing is higher in culture-positive
patients (65). A proper selection of Mycobacterium
tuberculosis-specic DNA and a caution against
contamination of cerebrospinal uid specimens are
important for obtaining high specicity. A recent
study observed that cerebrospinal uid ltrates
contain a substantial amount of Mycobacterium
tuberculosis DNA. Authors suggests that the
ltrates and not sediments are likely to reliably
provide a polymerase chain reaction-based diagnosis (66). A current review suggests that nucleic

Tuberculous meningitis
cerebrospinal uid from nine of 10 prospectively
recruited patients with tuberculous meningitis (70).
Later on, the sensitivity of ELISpot assay was
found to vary in patients with different forms of
tuberculosis, with highest sensitivity in patients
with sputum positive pulmonary tuberculosis
(89.89%) and lowest in tuberculous meningitis
(62.5%) (71). Anti-Bacillus Calmette-Guerin antibody-secreting cell detection in cerebrospinal uid
by an enzyme-linked immunospot assay was found
valuable because of its high degree of sensitivity.
The number of cerebrospinal uid anti-Bacillus
Calmette-Guerin antibody-secreting cells was
higher in the early phase of tuberculous meningitis
and then gradually declined, suggesting that this
assay was particularly effective for the early diagnosis of tuberculous meningitis (72). At present,
these immunological tests are not recommended for
routine diagnosis of tuberculous meningitis because
no proper evaluation of these tests exists.

acid amplication tests cannot replace conventional tests such as microscopy, culture and biopsy.
Results of nucleic acid amplication tests should be
interpreted in conjunction with conventional tests
and clinical data (67).
In several studies, the results of smear, culture
and polymerase chain reaction were compared (63,
68, 69). In one such study, 105 cerebrospinal uid
specimens (from clinically suspected cases of
tuberculous meningitis) were subjected to various
diagnostic tests. Polymerase chain reaction test was
positive in 31.42% of specimens, whereas by
conventional culture 3.8% specimens provided
bacteriological conrmation. Only 2% specimens
were smear-positive by the uorochrome staining
method. None was positive by the Ziehl-Neelsen
staining method (68). In the similar study (in 57
samples) from India, the sensitivity of cerebrospinal uid microscopy, culture, computed tomography and polymerase chain reaction was only 3.3%,
26.7%, 60.0% and 66.7%, respectively (63). It was
observed that the yields of all these diagnostic tests
were much better when a combination of tests were
performed on serial samples (69).
Demonstration of tuberculous bacilli in cerebrospinal uid still remains a great diagnostic challenge. In response to this challenge, several newer
diagnostic tests have been devised. Among newly
devised methods, the ex vivo Mycobacterium tuberculosis-specic enzyme-linked immunospot assay
(ELISpot assay) is a novel assay for the rapid
detection of Mycobacterium tuberculosis-specic
T-lymphocytes. In an initial study, the ELISpot
assay detected Mycobacterium tuberculosis antigenspecic interferon-gamma secreting T-cells in

Neuroimaging

Both computed tomography and magnetic resonance are valuable in tuberculous meningitis for
the diagnosis and evaluation of complications. The
characteristic computed tomographic changes
include basal enhancement, presence of exudates,
hydrocephalus and periventricular infarcts (Fig. 1).
Basal meningeal enhancement and hydrocephalus
are the most frequent imaging abnormalities.
Hyperdensity in the basal cisterns on non-contrast
computed tomography has been considered a
sensitive and specic imaging sign (73). A review
of computed tomographic ndings of 289 patients

Figure 1. Contrast enhanced computed tomography showing (A, B) thick basal exudates, meningeal enhancement and ventricular
dilatation in adult patients with tuberculous meningitis.

81

Garg
revealed that in 35 patients computed tomography
was normal. Remaining 254 patients had some
abnormality. Common abnormalities were hydrocephalus (204 patients), parenchymal enhancement
(62 patients), contrast enhancement of basal cisterns (49 patients), cerebral infarct and focal or
diffuse brain edema (39 patients), and tuberculoma
(14 patients) (74). Presence of hydrocephalus was
shown to be associated with a higher risk of stroke
and poor prognosis (75). Follow-up imaging may
be valuable as it may demonstrate some new
feature that is not initially present (like hydrocephalus and infarcts) (76).
Magnetic resonance imaging is considered more
sensitive imaging modality in tuberculous meningitis (77). A gadolinium-enhanced study can detect
meningeal enhancement early in course of illness.
On magnetic resonance imaging focal meningeal
enhancement is much more frequently encountered
than diffuse meningeal enhancement. Basal pial
areas, particularly the interpeduncular fossa, were
noted as the most preferred site of focal meningeal
enhancement (78) (Fig. 2).
Chest radiography may be abnormal in substantial number of patients with tuberculous meningitis. In one study, chest roentgenography demon
strated abnormal ndings in 43% (32 74) cases.
Hilar adenopathy, miliary pattern, bronchopneumonic inltrate were most frequent abnormalities.
Chest computed tomography was more sensitive
(68 74) in detecting chest abnormalities. Mediastinal and hilar lymphadenopathy, miliary pattern
and bronchopneumonic inltrate were the most

frequent computed tomographic ndings (79).

Presence of tuberculosis elsewhere often helps in
making diagnosis of tuberculous meningitis.
Differential diagnosis

A variety of infective, inammatory, neoplastic

and vascular diseases need to be considered in the
dierential diagnosis of tuberculous meningitis.
Dierential diagnosis from partially treated bacterial meningitis is frequently dicult (80). Six
features (duration of illness more than 5 days,
presence of headache and cerebrospinal uid white
blood cell count of <1000 per mm3, clear appearance, lymphocyte count >30% and protein content of >100 mg dl) favor tuberculous meningitis
(81). Several inammatory or autoimmune diseases
(like Wegener granulomatosis, sarcoidosis, Behcet
disease, Vogt-Koyanagi-Harada syndrome and
acute posterior multifocal placoid pigment epitheliopathy), in addition to meningeal inammation,
often cause inammation of several other body
organs.
In human immunodeciency virus-infected
patients, cryptococcal meningitis is the most
important dierential diagnosis of tuberculous
meningitis. In cryptococcal meningitis, headache
is often the most dominant and sometimes may be
the sole manifestation. In cryptococcal meningitis,
meningeal signs may not be demonstrable. Neuroimaging studies are often normal. India ink preparation of cerebrospinal uid is diagnostic. This test
demonstrates presence of fungal elements in the

Figure 2. (A) Gadolinium-enhanced cranial magnetic resonance imaging showing thick basilar exudates in pontine region,
multiple small tuberculoma ventricular dilatation; (B) T2-weighted magnetic resonance image showing in right basal ganglion and
thalamus; (C) gadolinium-enhanced cranial magnetic resonance imaging showing multiple tuberculoma in a patient with tuberculous
meningitis.

82

Tuberculous meningitis
cerebrospinal uid. Patients with toxoplasmosis can
also present with diuse meningoencephalitis.
If the cerebrospinal uid glucose concentration
is very low, then possibility of neoplastic meningitis
(metastasis, lymphoma, leukemia) should always
be considered. Neoplastic meningitis occurs in
approximately 5% of all patients with cancer.
Primary diuse leptomeningeal gliomatosis is a
rare condition whereby a glioma arises from
heterotopic cell nests in the leptomeninges and
produces a clinical picture similar to chronic
infective meningitis. A meticulous cytologic analysis of cerebrospinal uid, neuroimaging of brain
and spine, and an appropriate clinical setting are
the key factors which help in the diagnosis of
neoplastic meningitis (82, 83).
Tuberculous meningitis and human immunodeficiency
virus

There is an increased incidence of tuberculous

meningitis in human immunodeciency virusinfected persons. In several studies, it has been
documented that human immunodeciency virus
does not signicantly alter the clinical manifestations, laboratory, or radiographic ndings or the
response to therapy (12, 84). However, some
studies, on the contrary, suggest that differences
exist between immunodeciency virus-infected and
immunodeciency virus-negative patients of tuberculous meningitis. For example, it was observed
that a higher number of immunodeciency virusinfected patients had evidence of active tuberculosis on chest radiography. The classic computed
tomographic signs of tuberculous meningitis
(obstructive hydrocephalus and basal enhancement) were signicantly less prominent (85). Intracerebral mass lesions were more common (60% vs
14% in the non-immunodeciency virus-infected
group) (86). A high frequency of non-inammatory
cerebrospinal uid (absence of pleocytosis) and of
infection by multidrug-resistant strains of Mycobacterium tuberculosis have been reported (87). In
an earlier study, authors observed neutrophil
predominance, high smear and culture positivity,
and high antituberculous drug resistance in cerebrospinal uid of human immunodeciency virusinfected patients of tuberculous meningtis (59).
These patients have a higher mortality rate (88).
Treatment

In patients with tuberculous meningitis antituberculous treatment should be started as quickly as

possible. Antimicrobial therapy often needs to be
instituted empirically, much before a bacteriological

diagnosis is established. Treatment is started with

rst-line antituberculous drugs which include isoniazid, rifampicin, pyrazinamide, streptomycin and
ethambutol. The second-line antituberculous drugs
(ethionamide, cycloserine, para-aminosalicylic acid,
aminoglycosides, capreomycin and thiacetazone)
are kept in reserve. Fluoroquinolones (levooxacin,
gatioxacin and moxioxacin) are antimicrobial
agents which are used for the treatment of drugresistant tuberculosis. Substitution of older uoroquinolones, especially ciprooxacin, into a regimen
meant for treating drug-resistant tuberculosis
resulted in a higher rate of relapse (89, 90).
Most of the rst-line antituberculous drugs
(except ethambutol) penetrate satisfactorily in to
the cerebrospinal uid. In a study, the cerebrospinal uid concentrations of isoniazid and pyrazinamide were well above the minimum inhibitory
concentrations. Concentrations of rifampin and
streptomycin, 3 h after administration, were above
the minimal inhibitory concentration but declined
later. Corticosteroids had no eect on cerebrospinal uid penetration of antituberculous drugs (91).
Antituberculous treatment regimens

World Health Organization recommends a category-based treatment for tuberculosis.

Tuberculous meningitis falls under category-1 of
World Health Organization treatment category.
For the patients of category-I, antituberculosis
treatment regimen is divided into two phases: an
intensive (initial) phase and a continuation phase.
In intensive phase, antituberculous therapy regimen includes a combination of four-rst-line
drugs: isoniazid, rifampicin, streptomycin and
pyrazinamide. The intensive phase continues for
2 months. In continuation phase, two drug regimen (isoniazid and rifampicin) is given at least for
4 months. In patients with tuberculous meningitis,
the continuation phase is usually extended to 7
or 10 months (92). American Thoracic Society
guideline also recommends a longer duration
(912 months) of antituberculous therapy for
tuberculous meningitis. Optimal length of therapy
for tuberculous meningitis is not yet established
(93). (Table 3) Antituberculous therapy in human
immunodeciency virus-infected patients remains
the same as for human immunodeciency virusuninfected patients (93).
Multidrug-resistant
tuberculous meningitis
should be considered if there is a history of contact
with a patient of multidrug-resistant pulmonary
tuberculosis or a poor clinical response to antimicrobial therapy despite adequate treatment. Available guidelines recommend that antituberculous
83

Garg
Table 3 Antituberculous treatment regimen for tuberculous meningitis (92, 93)
(dosage of antituberculous drugs is given in mg kg for children along with maximum adult dose)
Tuberculous meningitis by drug-susceptible organisms (adult, children and human
immunodeficiency virus-infected patients)
Initiation phase: 2 months
Isoniazid (46 mg kg, 300 mg)
Rifampicin (812 mg kg, 600 mg)
Pyrazinamide (2030 mg kg, 1600 mg)
Streptomycin (1218 mg kg, 1000 mg)
Continuation phase: 47 months
Isoniazid (46 mg kg, 300 mg)
Rifampicin (812 mg kg, 600 mg)
Multidrug-resistant tuberculous meningitis
Initiation phase: 4 months
Amikacin or Kanamycin (intravenous or intramuscular 1530 mg kg,
1000 mg)
Ethionamide (1520 mg kg, 1000 mg)
Pyrazinamide (2030 mg kg, 1600 mg)
Ofloxacin (7.515 mg kg, 800 mg)
Ethambutol or cycloserine (1525 mg kg, 1200 mg; 1020 mg kg, 1000 mg)
Continuation phase: 1218 months
Ethionamide (510 mg kg, 750 mg)
Ofloxacin (7.515 mg kg, 800 mg)
Ethambutol or cycloserine (1525 mg kg, 1200 mg; 1020 mg kg, 1000 mg)

treatment regimen for these patients should include

at least ve drugs. Treatment regimen should include
drugs that the patient has not received before and to
which the patients organism is susceptible. The
regimen should also include an injectable medication. In ve drug regimen, one of the antituberculous
drugs should be uroquinolone. Second-line bacteriostatic agents as needed to bring the total number of
drugs in the regimen up to ve. The initial phase of
6 months should be followed by the continuation
phase of 1218 months (13). With emergence of
extensively drug-resistant tuberculosis (a form of
multidrug-resistant tuberculosis with resistance to at
least isoniazid and rifampicin, any uoroquinolone,
and at least one of the injectable drugs like amikacin,
kanamycin and capreomycin), in future, treatment of
tuberculous meningitis may become much more
difcult.
Immune reconstitution inammatory syndrome
is a potentially life-threatening condition which is
seen in human immunodeciency virus-infected
patients of tuberculosis. This complication may be
seen within 3 months after starting highly active
antiretroviral therapy. Immune reconstitution
inammatory syndrome is characterized by
improvement in CD4 cell counts. Dierential
diagnoses of immune reconstitution inammatory
syndrome include failure of antituberculous treatment, drug reactions and alternative opportunistic
conditions. Infective forms of immune reconstitution inammatory syndromes may manifest as
either an inammatory unmasking of previously
84

untreated tuberculosis or as the paradoxical clinical deterioration of tuberculous meningitis (92,

94). Immune reconstitution inammatory syndrome may be severe enough to cause death (95).
Concomitant administration of antituberculous
drugs and antiretroviral drugs may produce significant drug interactions. For example, induction of
cytochrome P-450 enzymes and P-glycoprotein by
rifampicin results in reduced concentrations of
non-nucleoside reverse-transcriptase inhibitors
and, particularly, protease inhibitors. This potentially results in the loss of antiretroviral drug
ecacy (96).
Drug-induced hepatitis following antituberculous therapy often poses a great challenge to
successful treatment. No separate guidelines exist
to counter drug-induced hepatitis in patients with
tuberculous meningitis. If a patient of pulmonary
tuberculosis develops drug-induced hepatitis antituberculous treatment should be withdrawn
temporarily. After hepatitis has resolved, same
regimen may be reintroduced. In patients with
tuberculous meningitis it is recommended that at
least two antituberculous drugs having least hepatotoxic eect (like ethambutol and streptomycin)
should always be continued (92, 97).
Role of corticosteroids

The recent Cochrane review recommends that

corticosteroids should routinely be used in tuberculous meningitis because it signicantly reduces
death and disabling residual neurological decit
amongst survivors (98). In fact, the actual evidence
of benet of corticosteroids in tuberculous meningitis came from a well-designed, randomized,
double-blind, placebo-controlled trial conducted
in Vietnam. In this trial, a total of 545 patients
were randomly assigned to receive either dexamethasone or placebo. Patients with grade-II or
grade-III tuberculous meningitis received intravenous dexamethasone for 4 weeks and then oral
dexamethasone for 4 weeks. Patients with grade-I
disease received 2 weeks of intravenous dexamethasone and then 4 weeks of oral therapy. After
9 months of follow-up, treatment with dexamethasone was associated with a signicantly improved
survival. However, treatment with corticosteroids
did not alter the combined outcome of death and
severe disability. However, subgroup analysis
revealed that for the patients in stage-I there was a
slight statistically signicant benet for the combined
outcome. This observation suggested that early
treatment is important. As additional benet, the
dexamethasone group experienced signicantly
fewer number adverse effects of antituberculous

Tuberculous meningitis
drugs than in the placebo group (99). Later, in
same group of patients, same group of authors
demonstrated that dexamethasone affected the
outcome of tuberculous meningitis, possibly, by
reducing the incidence of hydrocephalus and cerebral
infarctions (100).
The mechanism of action of corticosteroids in
tuberculous meningitis is not exactly known. Corticosteroids are supposed to reduce cerebral and
meningeal inammatory changes, cerebral edema
and increased intracranial pressure. Corticosteroids
are thought to operate via modulation of the
production of cytokines and chemokines by macrophages (33, 34). However, contrary to popular belief,
Simmons and coworkers demonstrated that
improved survival following corticosteroid treatmentwas possibly not mediated by favorable changes
in the immunological mediators of inammation in
cerebrospinal uid or by suppression of peripheral T
cell responses against mycobacteria (101). Matrix
metalloproteinases are mediators of extracellular
matrix degradation and are implicated in the pathogenesis of several inammatory diseases of the
central nervous system. A recent study demonstrated
that dexamethasone decreased cerebrospinal uid
matrix metalloproteinases-9 concentrations early in
course of the treatment. Authors suggested that this
might be one of the mechanisms by which corticosteroids improve outcome in tuberculous meningitis
(102).
Paradoxical response

Expansion of an existing tuberculoma or development of multiple new brain lesions during

antimicrobial treatment of tuberculous meningitis
has been recognized as a paradoxical response.
Sometimes, paradoxical reaction manifests as an
increase in cerebrospinal uid lymphocytic pleocytosis or initial lymphocytic response may
change transiently in the direction of polymorphonuclear predominance (103, 104). However,
the exact timing and frequency of paradoxical
response are not known. A paradoxical response
is often interpreted as a clinical deterioration.
Citing an example of paradoxical response, a
patient having pulmonary tuberculosis, tuberculous meningitis and brain tuberculoma serial
magnetic resonance imaging revealed a paradoxical enlargement of existing cerebral tuberculomas along with an aggravation of anterior
cerebral artery vasculitis, despite the appropriate
treatment (105). There was some evidence that
corticosteroid treatment might have a benecial
effect in patients having paradoxical reaction
(106).

Role of neurosurgery

Cerebrospinal uid diversion procedures are often

employed in patients of tuberculous meningitis
with hydrocephalus. Shunt procedures are helpful
in reducing intracranial pressure. Ventriculoperitoneal shunting is most frequently used surgical
procedure for the drainage of cerebrospinal uid.
Cerebrospinal uid shunting is usually needed if
medical therapy does not produce desired result
and patient clinical condition deteriorated considerably. Shunting is often performed in the acute
stage if the hydrocephalus is obstructive type. In
patients with communicating hydrocephalus, shunt
surgery is recommended following failed medical
therapy (107). In advanced stages of tuberculous
meningitis, shunt surgery should be considered if
external ventricular drainage causes an improvement in sensorium (108). Early shunt procedures
have been reported to reduce the morbidity and
mortality in childhood tuberculous meningitis as
well (109). Shunt malfunction is a common complication and is possibly because of the high
protein content of cerebrospinal uid. Unfortunately, no placebo-controlled trial, demonstrating
efcacy of shunt surgery in tuberculous meningitis,
is currently available.
Endoscopic third ventriculostomy creates a
communication between third ventricle and subarachnoid space bypassing cerebral aqueduct. It is
now considered as a safe and long-lasting treatment option for hydrocephalus in patient with
tuberculous meningitis. This procedure has most
frequently been used in patients who experienced
multiple episodes of shunt dysfunction. Endoscopic third ventriculostomy is likely to fail in the
presence of advanced clinical grade, extra-central
nervous system tuberculosis, dense adhesions in
prepontine cisterns and an unidentiable third
ventricular oor anatomy (110).
Prognosis

In tuberculous meningitis, early diagnosis and

treatment is important for better prognosis. Unfortunately, antituberculous treatment prevents death
or disability in less than 50% of the patients (111,
112). Administration of corticosteroids in adult
patients is associated with signicant decrease in
the mortality (99). Medical Research Council
staging is used to assess the severity of tuberculous
meningitis. In this system of staging, in stage 1
patient is fully conscious and without focal neurological decit; in stage 2 patient may be in altered
sensorium or has minor focal decits such as
hemiparesis or cranial nerve palsy; and in stage 3
85

Garg
patient is comatose or may have severe focal
decits like multiple cranial nerve palsy, hemiplegia
and or paraplegia (113).
Mortality is highest in patients younger than
5 years, those older than 50 years, and those in
whom illness has been present for longer than
2 months (114). A pediatric study (123 patients)
observed that following treatment only 20% children recovered completely, 80% of the patients
either died or survived with disability (115). In most
of the studies, the stage of disease emerged as the
single most important factor associated with mortality (42, 116). In a large series of 434 adult patients,
101 patients (23.3%) died and 67 (27%) of survivors
had neurological sequelae. Coma, seizures and
delayed or irregular treatment were adverse prognostic factors (117). In another series, ve factors
were associated with death which included stage-III
at presentation, low glucose levels, low cerebrospinal uid blood glucose ratio, high protein levels
and computed tomographic abnormality (42). In
series of 554 pediatric patients of tuberculous
meningitis, mortality after 6 months was 13%. All
of the patients diagnosed with stage-I tuberculous
meningitis had normal outcome. Ethnicity, stage of
disease, headache, convulsions, motor function,
brainstem dysfunction and cerebral infarctions
were independently associated with poor outcome
in multivariate logistic regression analysis (41). In
human immunodeciency virus-infected patients of
tuberculous meningitis, the mortality is quite high
(84). In a comparative study, among human immunodeciency virus-infected patients, 63.3%
(64 101) died while among human immunodeciency virus-negative patients mortality was only
17.5% (7 40) (87).
Various neurological sequelae, like hemiplegia,
paraplegia, quadriplegia, aphasia and vision loss,
are common among survivors. In a study, complete
neurological recovery was observed only in 21.5%
of the surviving patients. Common sequelae were
cognitive impairment in 55%, motor decit in
40%, and optic atrophy in 37% and other cranial
nerve palsies in 23% (117).
Prevention

Bacillus Calmette-Guerin (BCG) vaccination has

been shown to have a high ecacy in preventing
childhood tuberculous meningitis and miliary
tuberculosis. It is universally accepted that protective ecacy of BCG vaccination decreases with
age and there is insucient protection against
tuberculosis in adults. A group of authors estimated that 100.5 million BCG vaccinations given
to infants in 2002 will have prevented 29 729 cases
86

Table 4 Current research questions

Epidemiology of tuberculous meningitis in highly endemic countries is not known
Efforts should be made to estimate the magnitude of problem
Not all persons exposed to tuberculosis develop tuberculous meningitis. There is
need to explore the factors (including genetic factors) which make a person
susceptible to tuberculous meningitis
Host and bacterial factors determining the clinical variability (like variable
frequency of disabling complications) need to be explored
For better understanding of pathogenesis, appropriate animal models should be
developed and immunological profile of disease should be studied
Risk factors of some of the devastating complications like stroke, paraplegia and
blindness should be studied
Currently available drugs are not universally effective. Newer drugs effective even
against resistant cases with better penetration in cerebrospinal fluid are needed
New low-cost techniques for bacteriological diagnosis are required. Polymerase
chain reaction test is still unaffordable
New low-cost techniques to rapidly detect drug resistance are required to insure
adequate treatment without delay
Optimum duration and an optimum antituberculous regimen need to be worked out
Factors responsible for failure of treatment need to be identified
An effective anti-tuberculosis vaccine to prevent tuberculous meningitis in adults
need to be developed
Do other immunosuppressives have a role in the management of tuberculous
meningitis need to be explored?
Use of ventriculo-peritoneal shunts is still empirical. A randomized trial is needed

of tuberculous meningitis in children during their

rst 5 years of lives (118). There are enough
evidences to suggest that a second dose of BCG
vaccine does not increase its efcacy.
It was observed that vaccinated children with
tuberculous meningitis had signicantly lower rates
of altered sensorium and focal neurological decits
and cerebrospinal uid cell count. Short-term
outcomes (death and sequelae) were signicantly
better in the vaccinated group (119). The mechanism of protection by BCG vaccination is not
precisely known (120). Protective benets of BCG
vaccine for human immunodeciency virusinfected persons are not known.
Conclusion

Tuberculous meningitis is associated with exceptionally high mortality and morbidity. Not much
has changed despite signicant advances in the
recent years. Half of the patients either die during
treatment or they survive with signicant disability.
The early diagnosis of tuberculous meningitis is
often dicult. In majority of patients, antituberculous treatment remains empirical. Available antituberculous drugs are moderately eective. Newer
drugs with better cerebrospinal uid penetration
are urgently needed (Table 4). Effective vaccination
against tuberculosis seems to be the only hope
available today. Several new vaccines are showing
promising results in preclinical studies and a few of
them have already entered clinical trials.

Tuberculous meningitis
Supporting Information
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Figure S1. Fundus photograph showing a choroid tubercle.
Please note: Wiley-Blackwell are not responsible for the
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References
1. Thwaites G, Fisher M, Hemingway C, Scott G, Solomon T,
Innes J. British Infection Society guidelines for the diagnosis and treatment of tuberculosis of the central nervous
system in adults and children. J Infect 2009;59:16787.
2. Jubelt B. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. Curr Neurol
Neurosci Rep 2006;6:4512.
3. Be NA, Kim KS, Bishai WR, Jain SK. Pathogenesis of
central nervous system tuberculosis. Curr Mol Med
2009;9:949.
4. World Health Organization. Global tuberculosis control
surveillance, planning, nancing. WHO Report 2009,
WHO HTM TB 2009.411. Available at: http://www.
who.int/tb/publications/global_report/2009/key_points/
en/index.html.
5. Forssbohm M, Zwahlen M, Loddenkemper R, Rieder HL.
Demographic characteristics of patients with extrapulmonary tuberculosis in Germany. Eur Respir J
2008;31:99105.
6. Cailhol J, Che D, Jarlier V, Decludt B, Robert J. Incidence of tuberculous meningitis in France, 2000: a capturerecapture analysis. Int J Tuberc Lung Dis 2005;
9:8038.
7. Porkert MT, Sotir M, Parrott-Moore P, Blumberg HM.
Tuberculous meningitis at a large inner-city medical
center. Am J Med Sci 1997;313:32531.
8. Datta M, Swaminathan S. Global aspects of tuberculosis
in children. Paediatr Respir Rev 2001;2:916.
9. Berman S, Kibel MA, Fourie PB, Strebel PM. Childhood
tuberculosis and tuberculous meningitis: high incidence
rates in the Western Cape of South Africa. Tuber Lung
Dis 1992;73:34955.
10. Marais BJ, Gie RP, Schaaf HS, Hesseling AC, Enarson
DA, Beyers N. The spectrum of disease in children treated
for tuberculosis in a highly endemic area. Int J Tuberc
Lung Dis 2006;10:7328.
11. Ghate M, Deshpande S, Tripathy S et al. Incidence of
common opportunistic infections in HIV-infected individuals in Pune, India: analysis by stages of immunosuppression represented by CD4 counts. Int J Infect Dis
2009;13:e18.
12. 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.
13. Byrd TF, Davis LE. Multidrug-resistant tuberculous
meningitis. Curr Neurol Neurosci Rep 2007;7:4705.
14. Patel VB, Padayatchi N, Bhigjee AI et al. Multidrugresistant tuberculous meningitis in KwaZulu-Natal,
South Africa. Clin Infect Dis 2004;38:8516.
15. Caws M, Thwaites GE, Duy PM et al. Molecular analysis
of Mycobacterium tuberculosis causing multidrug-resistant tuberculosis meningitis. Int J Tuberc Lung Dis
2007;11:2028.

16. Nagarathna S, Rafi W, Veenakumari HB, Mani R, Satishchandra P, Chandramuki A. Drug susceptibility proling
of tuberculous meningitis. Int J Tuberc Lung Dis 2008;
12:1057.
17. Garg RK. Tuberculosis of the central nervous system.
Postgrad Med J 1999;75:13340.
18. Rich AR, McCordick HA. The pathogenesis of tuberculous
meningitis. Bull Johns Hopkins Hospital 1933;52:537.
19. Donald PR, Schaaf HS, Schoeman JF. Tuberculous meningitis and miliary tuberculosis: the Rich focus revisited.
J Infect 2005;50:1935.
20. Garcia-Monco JC. Central nervous system tuberculosis.
Neurol Clin 1999;17:73759.
21. Caws M, Thwaites G, Dunstan S et al. The inuence of
host and bacterial genotype on the development of disseminated disease with Mycobacterium tuberculosis. PLoS
Pathog 2008;4:e1000034.
22. Thwaites G, Caws M, Chau TT et al. Relationship
between Mycobacterium tuberculosis genotype and the
clinical phenotype of pulmonary and meningeal tuberculosis. J Clin Microbiol 2008;46:13638.
23. Caws M, Thwaites G, Stepniewska K et al. Beijing genotype of Mycobacterium tuberculosis is signicantly associated with human immunodeciency virus infection and
multidrug resistance in cases of tuberculous meningitis.
J Clin Microbiol 2006;44:39349.
24. Porcelli SA, Jacobs WR Jr. Tuberculosis: unsealing the
apoptotic envelope. Nat Immunol 2008;9:11012.
25. Lee J, Hartman M, Kornfeld H. Macrophage apoptosis in
tuberculosis. Yonsei Med J 2009;50:111.
26. Rocha-Ramrez LM, Estrada-Garca I, Lopez-Marn LM
et al. Mycobacterium tuberculosis lipids regulate cytokines, TLR-2 4 and MHC class II expression in human
macrophages. Tuberculosis (Edinb) 2008;88:21220.
27. Britton WJ, Fernando SL, Saunders BM, Sluyter R,
Wiley JS. The genetic control of susceptibility to Mycobacterium tuberculosis. Novartis Found Symp 2007;281:
7989.
28. Fernando SL, Saunders BM, Sluyter R et al. A polymorphism in the P2X7 gene increases susceptibility to
extrapulmonary tuberculosis. Am J Respir Crit Care Med
2007;175:3606.
29. Hawn TR, Dunstan SJ, Thwaites GE et al. A polymorphism in Toll-interleukin 1 receptor domain containing
adaptor protein is associated with susceptibility to meningeal tuberculosis. J Infect Dis 2006;194:112734.
30. Thuong NT, Hawn TR, Thwaites GE et al. A polymorphism in human TLR2 is associated with increased susceptibility to tuberculous meningitis. Genes Immun
2007;8:4228.
31. Sallakci N, Coskun M, Berber Z et al. Interferon-gamma
gene+874T-A polymorphism is associated with tuberculosis and gamma interferon response. Tuberculosis (Edinb)
2007;87:22530.
32. 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.
33. Rock RB, Hu S, Gekker G et al. Mycobacterium tuberculosis-induced cytokine and chemokine expression by
human microglia and astrocytes: eects of dexamethasone. J Infect Dis 2005;192:20548.
34. Rock RB, Olin M, Baker CA, Molitor TW, Peterson PK.
Central nervous system tuberculosis: pathogenesis and
clinical aspects. Clin Microbiol Rev 2008;21:24361.

87

Garg
35. Nagesh Babu G, Kumar A, Kalita J, Misra UK. Proinammatory cytokine levels in the serum and cerebrospinal uid of tuberculous meningitis patients. Neurosci Lett
2008;436:4851.
36. Simmons CP, Thwaites GE, Quyen NT et al. Pretreatment
intracerebral and peripheral blood immune responses in
Vietnamese adults with tuberculous meningitis: diagnostic
value and relationship to disease severity and outcome.
J Immunol 2006;176:200714.
37. 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.
38. van Well GT, Wieland CW, Florquin S, Roord JJ, van der
Poll T, van Furth AM. A new murine model to study the
pathogenesis of tuberculous meningitis. J Infect Dis 2007;
195:6947.
39. Be NA, Lamichhane G, Grosset J et al. Murine model to
study the invasion and survival of Mycobacterium tuberculosis in the central nervous system. J Infect Dis 2008;
198:15208.
40. Molavi A, LeFrock JL. Tuberculous meningitis. Med Clin
North Am 1985;69:31531.
41. van Well GT, Paes BF, Terwee CB et al. Twenty years of
pediatric tuberculous meningitis: a retrospective cohort
study in the western cape of South Africa. Pediatrics
2009;123:e18.
42. Hosoglu S, Ayaz C, Geyik MF, Kokoglu OF, Ceviz A.
Tuberculous meningitis in adults: an eleven-year review.
Int J Tuberc Lung Dis 1998;2:5537.
43. Srikanth SG, Taly AB, Nagarajan K, Jayakumar PN,
Patil S. Clinicoradiological features of tuberculous meningitis in patients over 50 years of age. J Neurol Neurosurg Psychiatry 2007;78:5368.
44. Patwari AK, Aneja S, Ravi RN, Singhal PK, Arora SK.
Convulsions in tuberculous meningitis. J Trop Pediatr
1996;42:917.
45. Hanna LS, Girgis NI, Abu el Ella AH, Farid Z. Ocular
complications in meningitis: fteen years study. Metab
Pediatr Syst Ophthalmol 1988;11:1602.
46. Amitava AK, Alarm S, Hussain R. Neuro-ophthalmic
features in pediatric tubercular meningoencephalitis. J
Pediatr Ophthalmol Strabismus 2001;38:22934.
47. Lamba PA, Bhalla JS, Mullick DN. Ocular manifestations of tubercular meningitis: a clinico-biochemical
study. J Pediatr Ophthalmol Strabismus 1986;23:1235.
48. Akhaddar A, El Hassani MY, Chakir N, Jiddane M.
Optochiasmatic tuberculoma: complication of tuberculous meningitis. Report of a case and review of the literature. J Neuroradiol 2001;28:13742.
49. Alarcon F, Duenas G, Cevallos N, Lees AJ. Movement
disorders in 30 patients with tuberculous meningitis. Mov
Disord 2000;15:5619.
50. Hernandez-Albujar S, Arribas JR, Royo A, GonzalezGarca JJ, Pena JM, Vazquez JJ. Tuberculous radiculomyelitis complicating tuberculous meningitis: case report
and review. Clin Infect Dis 2000;30:91521.
51. Wadia NH. Radiculomyelopathy associated with spinal
meningitis (arachnoiditis) with special reference to the
spinal tuberculous variety. In: Spillane JD, ed. Tropical
Neurology. Oxford: Oxford University Press, 1973;639.
52. Chan KH, Cheung RT, Lee R, Mak W, Ho SL. Cerebral
infarcts complicating tuberculous meningitis. Cerebrovasc Dis 2005;19:3915.
53. Hsieh FY, Chia LG, Shen WC. Locations of cerebral
infarctions in tuberculous meningitis. Neuroradiology
1992;34:1979.

88

54. Koh SB, Kim BJ, Park MH, Yu SW, Park KW, Lee DH.
Clinical and laboratory characteristics of cerebral
infarction in tuberculous meningitis: a comparative study.
J Clin Neurosci 2007;14:10737.
55. Andronikou S, Wilmshurst J, Hatherill M, VanToorn R.
Distribution of brain infarction in children with tuberculous meningitis and correlation with outcome score at
6 months. Pediatr Radiol 2006;36:128994.
56. Biswas J, Shome D. Choroidal tubercles in disseminated
tuberculosis diagnosed by the polymerase chain reaction
of aqueous humor. A case report and review of the literature. Ocul Immunol Inamm 2002;10:2938.
57. Thompson MJ, Albert DM. Ocular tuberculosis. Arch
Ophthalmol 2005;123:8449.
58. Helm CJ, Holland GN. Ocular tuberculosis. Surv Ophthalmol 1993;38:22956.
59. Torok ME, Chau TT, Mai PP et al. Clinical and microbiological features of HIV-associated tuberculous meningitis in Vietnamese adults. PLoS ONE 2008;3:e1772.
60. Thwaites GE, Chau TT, Farrar JJ. Improving the bacteriological diagnosis of tuberculous meningitis. J Clin
Microbiol 2004;42:3789.
61. Tortoli E, Cichero P, Piersimoni C, Simonetti MT, Gesu G,
Nista D. Use of BACTEC MGIT 960 for recovery of
Mycobacteria from clinical specimens: multicenter study.
J Clin Microbiol 1999;37:357882.
62. Caws M, Dang TM, Torok E et al. Evaluation of the
MODS culture technique for the diagnosis of tuberculous
meningitis. PLoS ONE 2007;2:e1173.
63. Desai D, Nataraj G, Kulkarni S et al. Utility of the
polymerase chain reaction in the diagnosis of tuberculous
meningitis. Res Microbiol 2006;157:96770.
64. Rafi W, Venkataswamy MM, Nagarathna S, Satishchandra P, Chandramuki A. Role of IS6110 uniplex PCR in the
diagnosis of tuberculous meningitis: experience at a tertiary neurocentre. Int J Tuberc Lung Dis 2007; 11:20914.
65. Pai M, Flores LL, Hubbard A et al. Diagnostic accuracy
of nucleic acid amplication tests for tuberculous meningitis: a systematic review and meta-analysis. Lancet
Infect Dis 2003;3:63343.
66. Haldar S, Sharma N, Gupta VK, Tyagi JS. Ecient
diagnosis of tuberculous meningitis by detection of
Mycobacterium tuberculosis DNA in cerebrospinal uid
ltrates using PCR. J Med Microbiol 2009;58:61624.
67. Pai M, Ling DI. Rapid diagnosis of extrapulmonary
tuberculosis using nucleic acid amplication tests: what is
the evidence? Future Microbiol 2008;3:14.
68. Desai MM, Pal RB. Polymerase chain reaction for the
rapid diagnosis of tuberculous meningitis. Indian J Med
Sci 2002;56:54652.
69. 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.
70. Thomas MM, Hinks TS, Raghuraman S et al. Rapid
diagnosis of Mycobacterium tuberculosis meningitis by
enumeration of cerebrospinal uid antigen-specic Tcells. Int J Tuberc Lung Dis 2008;12:6517.
71. Chen X, Yang Q, Zhang M et al. Diagnosis of active
tuberculosis in china using an in-house interferon-gamma
enzyme-linked immunospot assay. Clin Vaccine Immunol
2009;16:87984.
72. Quan C, Lu CZ, Qiao J, Xiao BG, Li X. Comparative
evaluation of early diagnosis of tuberculous meningitis by
dierent assays. J Clin Microbiol 2006;44:31606.

Tuberculous meningitis
73. Andronikou S, Smith B, Hatherhill M, Douis H, Wilmshurst J. Denitive neuroradiological diagnostic features
of tuberculous meningitis in children. Pediatr Radiol
2004;34:87685.
74. Ozates M, Kemaloglu S, Gurkan F, Ozkan U, Hosoglu S,
Simsek MM. CT of the brain in tuberculous meningitis. A
review of 289 patients. Acta Radiol 2000;41:137.
75. Chan KH, Cheung RT, Fong CY, Tsang KL, Mak W, Ho
SL. Clinical relevance of hydrocephalus as a presenting
feature of tuberculous meningitis. QJM 2003;96:6438.
76. Andronikou S, Wieselthaler N, Smith B et al. Value of
early follow-up CT in paediatric tuberculous meningitis.
Pediatr Radiol 2005;35:10929.
77. Gupta RK, Gupta S, Singh D, Sharma B, Kohli A, Gujral
RB. MR imaging and angiography in tuberculous meningitis. Neuroradiology 1994;36:8792.
78. Oztoprak I, Gumus C, Oztoprak B, Engin A. Contrast
medium-enhanced MRI ndings and changes over time in
stage I tuberculous meningitis. Clin Radiol 2007;62:1206
15.
79. Yaramis A, Bukte Y, Katar S, Ozbek MN. Chest computerized tomography scans ndings in 74 children with
tuberculous meningitis in southeastern Turkey. Turk J
Pediatr 2007;49:3659.
80. Thwaites GE, Chau TT, Stepniewska K et al. Diagnosis of
adult tuberculous meningitis by use of clinical and laboratory features. Lancet 2002;360:128792.
81. Youssef FG, Afifi SA, Azab AM et al. Dierentiation of
tuberculous meningitis from acute bacterial meningitis
using simple clinical and laboratory parameters. Diagn
Microbiol Infect Dis 2006;55:2758.
82. Chamberlain MC. Neoplastic meningitis. Curr Neurol
Neurosci Rep 2008;8:24958.
83. Aparicio A, Chamberlain MC. Neoplastic meningitis. Curr
Neurol Neurosci Rep 2002;2:22535.
84. Thwaites GE, Duc Bang N, Huy Dung N et al. The
inuence of HIV infection on clinical presentation,
response to treatment, and outcome in adults with
tuberculous meningitis. J Infect Dis 2005; 192:213441.
85. Dube MP, Holtom PD, Larsen RA. Tuberculous meningitis in patients with and without human immunodeciency virus infection. Am J Med 1992;93:5204.
86. van der Weert EM, Hartgers NM, Schaaf HS et al.
Comparison of diagnostic criteria of tuberculous meningitis in human immunodeciency virus-infected and
uninfected children. Pediatr Infect Dis J 2006;25:659.
87. Cecchini D, Ambrosioni J, Brezzo C et al. Tuberculous
meningitis in HIV-infected and non-infected patients:
comparison of cerebrospinal uid ndings. Int J Tuberc
Lung Dis 2009;13:26971.
88. Cecchini D, Ambrosioni J, Brezzo C et al. Tuberculous
meningitis in HIV-infected patients: drug susceptibility
and clinical outcome. AIDS 2007;21:3734.
89. Ziganshina LE, Squire SB. Fluoroquinolones for treating tuberculosis. Cochrane Database Syst Rev 2008;
Art. No.: CD004795. DOI: 10.1002/14651858.CD004795.
pub3.
90. Moadebi S, Harder CK, Fitzgerald MJ, Elwood KR,
Marra F. Fluoroquinolones for the treatment of pulmonary tuberculosis. Drugs 2007;67:207799.
91. Kaojarern S, Supmonchai K, Phuapradit P, Mokkhavesa C,
Krittiyanunt S. Eect of steroids on cerebrospinal uid
penetration of antituberculous drugs in tuberculous
meningitis. Clin Pharmacol Ther 1991;49:612.
92. World Health Organization. Treatment of tuberculosis:
guidelines for national programmes, 3rd edn. Geneva,
Switzerland: World Health Organization, 2002.

93. Blumberg HM, Burman WJ, Chaisson RE, Daley CL,

Etkind SC, American Thoracic Society, Centers for Disease Control and Prevention and the Infectious Diseases
Society. American Thoracic Society Centers for Disease
Control and Prevention Infectious Diseases Society of
America: treatment of tuberculosis. Am J Respir Crit
Care Med 2003;167:60362.
94. Pepper DJ, Marais S, Maartens G et al. Neurologic
manifestations of paradoxical tuberculosis-associated
immune reconstitution inammatory syndrome: a case
series. Clin Infect Dis 2009;48:e96107.
95. Huttner HB, Kollmar R, Hug A, Meisel F, Kress B,
Schwab S. Fatal tuberculous meningitis caused by immune restoration disease. J Neurol 2004;251:15223.
96. McIlleron H, Meintjes G, Burman WJ, Maartens G.
Complications of antiretroviral therapy in patients with
tuberculosis: drug interactions, toxicity, and immune
reconstitution inammatory syndrome. J Infect Dis 2007;
196(Suppl 1):S6375.
97. Saukkonen JJ, Cohn DL, Jasmer RM et al. ATS (American Thoracic Society) hepatotoxicity of Antituberculosis
Therapy Subcommittee. An ocial ATS statement: hepatotoxicity of antituberculosis therapy. Am J Respir Crit
Care Med 2006;174:93552.
98. Prasad K, Singh MB. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev 2008; Art.
No.: CD002244. DOI: 10.1002/14651858.CD002244.pub3.
99. 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.
100. Thwaites GE, Macmullen-Price J, Tran TH et al. Serial
MRI to determine the eect of dexamethasone on the
cerebral pathology of tuberculous meningitis: an observational study. Lancet Neurol 2007;6:2306.
101. Simmons CP, Thwaites GE, Quyen NT et al. The clinical
benet of adjunctive dexamethasone in tuberculous
meningitis is not associated with measurable attenuation
of peripheral or local immune responses. J Immunol
2005;175:57990.
102. Green JA, Tran CT, Farrar JJ et al. Dexamethasone,
cerebrospinal uid matrix metalloproteinase concentrations and clinical outcomes in tuberculous meningitis.
PLoS ONE 2009;4:e7277.
103. Afghani B, Lieberman JM. Paradoxical enlargement or
development of intracranial tuberculomas during therapy: case report and review. Clin Infect Dis 1994;19:1092
9.
104. Garcia-Monco JC, Ferreira E, Gomez-Beldarrain M. The
therapeutic paradox in the diagnosis of tuberculous
meningitis. Neurology 2005;65:19912.
105. Lee SI, Park JH, Kim JH. Paradoxical progression of
intracranial tuberculomas and anterior cerebral artery
infarction. Neurology 2008;71:68.
106. Nicolls DJ, King M, Holland D, Bala J, del Rio C.
Intracranial tuberculomas developing while on therapy
for pulmonary tuberculosis. Lancet Infect Dis 2005;
5:795801.
107. Lamprecht D, Schoeman J, Donald P, Hartzenberg H.
Ventriculoperitoneal shunting in childhood tuberculous
meningitis. Br J Neurosurg 2001;15:11925.
108. 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;
74:649.
109. Kemaloglu S, Ozkan U, Bukte Y, Ceviz A, Ozates M. Timing
of shunt surgery in childhood tuberculous meningitis with
hydrocephalus. Pediatr Neurosurg 2002; 37:1948.

89

Garg
110. Jha DK, Mishra V, Choudhary A et al. Factors aecting
the outcome of neuroendoscopy in patients with tuberculous meningitis hydrocephalus: a preliminary study.
Surg Neurol 2007;68:3541.
111. Thwaites GE, Tran TH. Tuberculous meningitis: many
questions, too few answers. Lancet Neurol 2005;4:
16070.
112. Sutlas PN, Unal A, Forta H, Senol S, Kirbas D.
Tuberculous meningitis in adults: review of 61 cases.
Infection 2003;31:38791.
113. Medical Research Council. Streptomycin treatment of
tuberculous meningitis. Lancet 1948;I:58296.
114. Golden MP, Vikram HR. Extrapulmonary tuberculosis:
an overview. Am Fam Physician 2005;72:17618.
115. Karande S, Gupta V, Kulkarni M, Joshi A. Prognostic
clinical variables in childhood tuberculous meningitis: an
experience from Mumbai, India. Neurol India 2005; 53:
1915.

90

116. Hosoglu S, Geyik MF, Balik I et al. Predictors of outcome in patients with tuberculous meningitis. Int J Tuberc Lung Dis 2002;6:6470.
117. Kalita J, Misra UK, Ranjan P. Predictors of long-term
neurological sequelae of tuberculous meningitis: a multivariate analysis. Eur J Neurol 2007;14:337 (Erratum in:
Eur J Neurol 2007;14:357).
118. Trunz BB, Fine P, Dye C. Eect of BCG vaccination on
childhood tuberculous meningitis and miliary tuberculosis worldwide: a meta-analysis and assessment of costeectiveness. Lancet 2006;367:117380.
119. Kumar R, Dwivedi A, Kumar P, Kohli N. Tuberculous
meningitis in BCG vaccinated and unvaccinated children.
J Neurol Neurosurg Psychiatry 2005;76:15504.
120. Sterling TR, Martire T, de Almeida AS et al. Immune
function in young children with previous pulmonary or
miliary meningeal tuberculosis and impact of BCG vaccination. Pediatrics 2007;120:e91221.