Acta Neurol Scand 2010: 122: 75–90 DOI: 10.1111/j.1600-0404.2009.01316.

x Copyright  2009 The Author

Journal compilation  2009 Blackwell Munksgaard
ACTA NEUROLOGICA
SCANDINAVICA

Review article
Tuberculous meningitis
Garg RK. Tuberculous meningitis. R. K. Garg
Acta Neurol Scand: 2010: 122: 75–90. Department of Neurology, Chhatrapati Shahuji Maharaj
 2009 The Author Journal compilation  2009 Blackwell Munksgaard. Medical University, Uttar Pradesh, Lucknow, India

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 immunodeficiency virus-infected patients have a
high incidence of tuberculous meningitis. The hallmark pathological
processes are meningeal inflammation, basal exudates, vasculitis and
hydrocephalus. Headache, vomiting, meningeal signs, focal deficits,
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 fluid
changes (increased protein, low glucose and mononuclear cell
pleocytosis). Cerebrospinal fluid smear examination, mycobacterial
culture or polymerase chain reaction is mandatory for bacteriological
Key words: Bacillus Calmette-Gurin vaccination;
confirmation. The mortality and morbidity of tuberculous meningitis extrapulmonary tuberculosis; human immunodeficiency
are exceptionally high. Prompt diagnosis and early treatment are virus; dexamethasone; Mycobacterium tuberculosis
crucial. Decision to start antituberculous treatment is often empirical.
Dr Ravindra Kumar Garg, Department of Neurology,
WHO guidelines recommend a 6 months course of antituberculous Chhatrapati Shahuji Maharaj Medical University,
treatment; however, other guidelines recommend a prolonged Uttar Pradesh, Lucknow – 226003, India
treatment extended to 9 or 12 months. Corticosteroids reduce the Tel.: 91 522-4003496
number of deaths. Resistance to antituberculous drugs is associated Fax: 91 522-2258852
with a high mortality. Patients with hydrocephalus may need e-mail: garg50@yahoo.com
ventriculo-peritoneal shunting. Bacillus Calmette-Guérin vaccination
protects to some degree against tuberculous meningitis in children. Accepted for publication December 1, 2009

meningitis, which has been reported worldwide, is

Introduction
Tuberculous meningitis is a devastating disease of
central nervous system. It primarily affects the
meninges of brain and spinal cord along with
adjacent brain parenchyma. Human immunodefi-
ciency virus-infected patients have a high incidence
of tuberculous meningitis. Bacterial and hostÕs
genetic factors play a crucial role in its pathogen-
esis. Early diagnosis is important for the success of
the treatment (1). Diagnosis often remains prob-
lematic despite many significant advances in diag-
nostic 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 influence out-
come in patients with tuberculous meningitis, have
been identified (3). Multidrug-resistant tuberculous
difficult 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 regis-
tered worldwide. Of these 9.27 million new cases of

75
Garg
tuberculosis, an estimated 1.37 million (14%) were
human immunodeficiency virus-positive. In 2007,
approximately 1.3 million deaths (20 per 100 000
population) occurred in patients with tuberculosis.
The five countries, that have highest number of
tuberculosis cases, are India, China, Indonesia,
Nigeria and South Africa (4).
The exact incidence and prevalence of tubercu-
lous 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 tubercu-
losis cases, the proportion of extra-pulmonary
tuberculosis and tuberculous meningitis cases has
increased. In Germany, 26 302 tuberculosis cases
were registered during 1996–2000. 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 Ôthe Tuber-
culosis Mandatory Notification SystemÕ and the
ÔNational Reference CentreÕ total number of con-
firmed tuberculous meningitis cases were 91. The
number of culture-positive meningitis cases was
estimated to be 41 and the number of culture-
negative 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 fluid cultures for Myco-
bacterium tuberculosis, accounting for 1.5% of
culture-confirmed tuberculosis cases. All patients
were born in the United States, 31 (91%) were
black people and 16 (47%) were human immuno-
deficiency virus-infected patients (7). In poor and
developing countries with very high burden of
pulmonary tuberculosis, the incidence of tuber-
culous meningitis is expected to be proportionately
high.
The natural history and clinical manifestations
of tuberculosis in children are different as com-
pared with that of adults. Neonates have the
highest risk of progression to severe forms of
tuberculosis. Mortality is highest in early child-
hood 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 specific. The incidence in neonates was
76
31.5 per 100 000 as compared with 0.7 per 100 000
among older children (10–14 years) (9). Another
study from South Africa observed that in human
immunodeficiency virus-infected children dissemi-
nated tuberculosis was significantly more common
(6 ⁄ 25) as compared with human immunodeficiency
virus-negative children (12 ⁄ 414). In children with-
out human immunodeficiency virus infection
disseminated (miliary) disease (9 ⁄ 11) and tubercu-
lous meningitis (10 ⁄ 13) were predominantly seen in
those who were less than 3 years of age (10).
Tuberculosis, in human immunodeficiency virus-
infected patients, progresses to severe forms of
tuberculosis at a rate five times greater than that
for people not infected with human immuno-
deficiency virus (11). In a study, of 2205 patients
with all types of tuberculosis, 455 (21%) patients
were human immunodeficiency virus-infected. In
this study, 45 patients had culture-positive tuber-
culous meningitis. It was observed that of the 1750
patients without human immunodeficiency virus
infection only 2% had tuberculous meningitis, as
compared with 10% of the human immuno-
deficiency virus-infected patients. The majority of
human immunodeficiency 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 immu-
nodeficiency virus-positive patients. Under optimal
treatment conditions, the cure rate of multidrug-
resistant pulmonary tuberculosis is approximately
70–90%, but the cure rate averages to 50% in
diverse clinical conditions (13). The problem of
multidrug-resistant tuberculosis has also been
identified 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 1999–2002, 350
patients with tuberculous meningitis were identi-
fied by cerebrospinal fluid 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 signif-
icant morbidity. Eighteen of multidrug-resistant
tuberculous meningitis patients were human immu-
nodeficiency virus-positive (14). In a Vietnamese
study, Mycobacterium tuberculosis isolates from
the cerebrospinal fluid of 198 adults were com-
pared with 237 isolates from patients with pulmo-

nary tuberculosis. It was observed that drug
resistance rates were lower in the isolates from
cerebrospinal fluid (2.5% multidrug resistance)
than pulmonary isolates (5.9% multidrug resis-
tance) (15). Fortunately, multidrug-resistant tuber-
culous 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 tuber-
culosis is a gram-positive, aerobic, non-spore-
forming, non-motile, pleomorphic rod that is
distantly related to the Actinomycetes. Myco-
bacterium 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 tuber-
culous meningitis, like for any other forms of
tuberculosis, include poverty, overcrowding, illit-
eracy, malnutrition, alcoholism, substance abuse,
diabetes mellitus, immunosuppressive treatment,
malignancy, head trauma and human immunode-
ficiency virus infection (17). Transmission of bac-
teria Mycobacterium tuberculosis to a healthy
person is primarily by airborne droplet nuclei. In
the lungs, Mycobacterium tuberculosis bacteria
multiply in alveolar macrophages. Within 2–4
weeks, through blood circulation, bacilli spread to
extrapulmonary sites and produce small granulo-
mas in the meninges and adjacent brain paren-
chyma. These small granulomas are known as ÔRich
focusÕ. 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 (17–19).
Several reports suggest that, in children, miliary
tuberculosis is directly involved in the pathogenesis
Tuberculous meningitis
of tuberculous meningitis. The bacillaemia that
accompanies miliary dissemination increase the
likelihood that a meningeal or sub-cortical tubercu-
lous 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 blood–brain 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 Myco-
bacterium 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 Euro-
American 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 cere-
brospinal fluid. The East Asian ⁄ Beijing genotype
was strongly associated with drug-resistant tuber-
culosis and a high incidence of human immuno-
deficiency virus co-infection. It was suggested that
the association between the East Asian ⁄ Beijing
strain and disease progression and cerebrospinal
fluid leukocyte count might influence protective
inflammatory 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 macro-
phages is an effective hostÕs mechanism against
tuberculous bacilli. Virulent strains of Mycobacte-
rium tuberculosis have evolved several genetic
mechanisms to subvert host immune responses,
leading to their prolonged survival and growth in
the hostÕs macrophages (24, 25). The mechanisms
by which Mycobacterium tuberculosis manipulates
the host immune system are attributed to lipoara-
binomannans and their precursor lipomannans.
These two are important glycolipids of Mycobac-
terium tuberculosis cell wall. Lipoarabinomannan is
involved in the inhibition of phagosome matura-
tion, apoptosis, interferon-gamma signaling in
macrophages and interleukin-12 cytokine secretion
of dendritic cells. It has been observed that lipid
77
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 recep-
tor-4 and major histocompatibility complex class II
expression. In contrast, lipids from Mycobacterium
tuberculosis Canetti (a less virulent strain) do not
produce these inflammatory changes (26).
Several genetic abnormalities increase the hostÕs
susceptibility to Mycobacterium tuberculosis (27,
28). A group of authors identified polymorphisms
in the P2X7 receptor (an ATP-gated Ca2+ chan-
nel) 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 poly-
morphisms 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 hostÕs susceptibility to severe forms of tuber-
culosis like miliary tuberculosis and tuberculous
meningitis (30). Single nucleotide polymorphisms,
located at these genes, are thought to influence
cytokine levels and regulate resistance and suscep-
tibility of an individual to tuberculosis (21). Poly-
morphisms in interferon-gamma gene have also
been associated to individualÕs susceptibility to
tuberculous infection (31).
Immunopathogenesis
Once mycobacteria enter in the central nervous
system, macrophages recognize them and appro-
priate innate and adaptive immune responses are
initiated. Subsequent immunopathogenesis may
result in impairment of the blood–brain barrier,
development of cerebral edema and increased
intracranial pressure. The elevated level of tumor
necrosis factor-alpha produced during mycobacte-
rial infection is an important element in the
immunopathogenesis (32). Microglial cells (the
resident macrophages of the brain) are the princi-
pal cells producing immunological chemicals
against tubercle bacilli. Several studies have
shown that microglia produce a variety of chemo-
kines that act to initiate or promote inflammatory
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 fluid
tumor necrosis factor-alpha and interferon-gamma
78
have a positive correlation with the severity of the
tuberculous meningitis (35). Human immunodefi-
ciency virus co-infection with tuberculous menin-
gitis has been shown to attenuate cerebrospinal
fluid inflammatory changes. Low cerebrospinal
fluid interferon-gamma concentration was inde-
pendently associated with death, suggesting that
interferon-gamma contributes to hostÕs immunity
and survival (36).
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 inflammatory changes in
the cerebrospinal fluid. Histologically, severe men-
ingitis with thickening of the leptomeninges, prom-
inent 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 identified central nervous
system-specific Mycobacterium tuberculosis genes
that play an important role in the pathogenesis of
central nervous system tuberculosis (39).
Pathology
The tuberculous meningitis has a strong propensity
to affect the basal parts of the brain. Pathologic
changes diffusely affect the arachnoid membrane
and subarachnoid space. The hallmark pathologic
features are meningeal inflammation, fibrogelati-
nous basal exudates, vasculitis of the arteries
traversing the exudates and obstruction of flow of
cerebrospinal fluid resulting in hydrocephalus. The
brain tissue underlying the tuberculous exudates
shows varied degrees of edema, perivascular infil-
tration and a microglial reaction collectively
termed as ‘border zone encephalitisÕ. Microscopic
pathological feature of tuberculous meningitis is
formation of epithelioid cell granulomas with
Langhans giant cells, lymphocytic infiltrates and
caseous necrosis. Exudates are prominently present
around sylvian fissure, 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

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
inflammation, spasms, constriction and eventually
thrombosis of cerebral vessels. Occlusion of cere-
bral arteries leads to infarction of the underlying
tissue. The meningeal veins passing through the
inflammatory exudate show varying degree of
phlebitis. Obstruction to the flow of cerebrospinal
fluid 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. Infre-
quently, tuberculous meningitis may results in
formation of tuberculoma consisting of caseous
necrotic material, epithelioid cell granuloma and
mononuclear cell infiltration (17, 40).
Clinical features
Typically, tuberculous meningitis is preceded by
a variable period of non-specific symptoms.
Common non-specific symptoms include malaise,
anorexia, fatigue, weight loss, fever, myalgia and
headache. At first 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 deficits 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 admis-
sion 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 deficits
(24%) (43). Tuberculous meningitis in elderly
patients may present as a subacute dementia with
memory deficits and personality changes typical of
frontal lobe-like disease. In pediatric patients
coma, raised intracranial pressure, seizures and
focal neurological deficits dominate the clinical
manifestations. Generalized tonic and clonic sei-
zures are the commonest type of seizures followed
by focal seizures and tonic spasms (44). Hyponat-
remia in patients with tuberculous meningitis is a
Tuberculous meningitis
common metabolic abnormality. Hyponatremia is
often caused by repeated vomiting and cerebral salt
wasting syndrome. The advanced stages of tuber-
culous 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 affected cranial nerve. Third and fourth
cranial nerves are less frequently involved. Cranial
nerves are affected 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 men-
ingitis. There several possible reasons for optic
nerve involvement like optochiasmatic arachnoid-
itis, third ventricular compression of optic chiasma
in patients with a large hydrocephalus, optic nerve
granulomas or ethambutol toxicity (47). Opto-
chiasmatic tuberculoma is a rare cause of progres-
sive 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 tubercu-
lous radiculomyelitis or intramedullary tuberculo-
mas. Tuberculous radiculomyelopathy is char
acterized by the subacute paraparesis. Other mani-
festations of tuberculous radiculomyelopathy
include root pain, paraesthesias, bladder disturbance
and muscle wasting. Muscle wasting is a late mani-
festation. In the lower limbs, there is hypotonia and
deep tendon reflexes are usually absent. There may be
extensor plantar response. In most of the patients,
cerebrospinal fluid 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 syringo-
myelic cavities.
Infarcts are common in patients with tubercu-
lous 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 thalamoper-
forating 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. Symp-
tomatic strokes in tuberculous meningitis present
with dense hemiplegia (53, 54). In children, infarcts
of basal ganglia and internal capsule were associ-
ated with a poor outcome. Purely hemispheric
infarcts were associated with good prognosis (55).
Choroidal tubercles are infrequent fundoscopic
finding in patients with tuberculous meningitis.
These lesions are considered virtually pathogno-
monic of tuberculous meningitis. Choroidal tuber-
cles 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, cho-
roidal tubercles represent caseating granulomas.
Tubercle bacilli have also been demonstrated
within the choroidal tubercles (58).
Diagnosis
Cerebrospinal fluid examination
Cerebrospinal fluid examination is crucial for the
confirmation of the diagnosis. Characteristic cere-
brospinal fluid changes help in differentiating from
other causes of chronic meningitis. Typical cere-
brospinal fluid changes are mononuclear cell
pleocytosis, low glucose levels and elevated protein
levels (Table 1). However, the Ôgold standardÕ for
diagnosis is demonstration of Mycobacterium
tuberculosis bacilli in the cerebrospinal fluid
(Table 2). Unfortunately, smear for acid-fast bacil-
lus is positive only in 5–30% of patients. Culture of
Mycobacterium tuberculosis from cerebrospinal
fluid is also not always positive and it takes several
weeks for a positive result. Conventional cerebro-
spinal fluid culture on Lowenstein-Jensen medium
is positive in approximately 45–90% of cases. In
human immunodeficiency virus-associated tuber-
culous meningitis 69% positivity for smear and
Table 1 Cerebrospinal fluid diagnostic tests
Cerebrospinal fluid studies
Color Clear or xanthochromic*
Cerebrospinal fluid pressure Elevated
Glucose levels <400 mg ⁄ l (<2.22 mmol ⁄ l)
Protein levels 0.8–5 g ⁄ l
Cell contents 100–500 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 fluid is
collected and smear is examined for at least 30 min
(60). Cerebrospinal fluid sediments should always
be subjected for smear examination.
Several liquid culture systems have been evalu-
ated 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 reduc-
tion 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 identification of drug-resistant
Mycobacterium tuberculosis in patients with tuber-
culous meningitis (62).
The detection of Mycobacterium tuberculosis
DNA in cerebrospinal fluid samples using poly-
merase chain reaction is widely used diagnostic
method (63, 64). A meta-analysis found the sensi-
tivity of commercial nucleic acid amplification tests
to be only 56%; however, the specificity was as
high as 98%. Sensitivity of polymerase chain
reaction testing is higher in culture-positive
patients (65). A proper selection of Mycobacterium
tuberculosis-specific DNA and a caution against
contamination of cerebrospinal fluid specimens are
important for obtaining high specificity. A recent
study observed that cerebrospinal fluid ÔfiltratesÕ
contain a substantial amount of Mycobacterium
tuberculosis DNA. Authors suggests that the
ÔfiltratesÕ and not ÔsedimentsÕ are likely to reliably
provide a polymerase chain reaction-based diag-
nosis (66). A current review suggests that nucleic

acid amplification tests cannot replace conven-
tional tests such as microscopy, culture and biopsy.
Results of nucleic acid amplification 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 fluid
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 confirmation. Only 2% specimens
were smear-positive by the fluorochrome staining
method. None was positive by the Ziehl-Neelsen
staining method (68). In the similar study (in 57
samples) from India, the sensitivity of cerebrospi-
nal fluid microscopy, culture, computed tomogra-
phy 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 cerebro-
spinal fluid still remains a great diagnostic chal-
lenge. In response to this challenge, several newer
diagnostic tests have been devised. Among newly
devised methods, the ex vivo Mycobacterium tuber-
culosis-specific enzyme-linked immunospot assay
(ELISpot assay) is a novel assay for the rapid
detection of Mycobacterium tuberculosis-specific
T-lymphocytes. In an initial study, the ELISpot
assay detected Mycobacterium tuberculosis antigen-
specific interferon-gamma secreting T-cells in
A B
Figure 1. Contrast enhanced computed tomography showing (A, B) thick basal exudates, meningeal enhancement and ventricular
dilatation in adult patients with tuberculous meningitis.
Tuberculous meningitis
cerebrospinal fluid 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-Guérin anti-
body-secreting cell detection in cerebrospinal fluid
by an enzyme-linked immunospot assay was found
valuable because of its high degree of sensitivity.
The number of cerebrospinal fluid anti-Bacillus
Calmette-Guérin 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 diag-
nosis 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.
Neuroimaging
Both computed tomography and magnetic reso-
nance 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 specific imaging sign (73). A review
of computed tomographic findings of 289 patients
81
Garg
revealed that in 35 patients computed tomography
was normal. Remaining 254 patients had some
abnormality. Common abnormalities were hydro-
cephalus (204 patients), parenchymal enhancement
(62 patients), contrast enhancement of basal cis-
terns (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 hydro-
cephalus and infarcts) (76).
Magnetic resonance imaging is considered more
sensitive imaging modality in tuberculous menin-
gitis (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 substan-
tial number of patients with tuberculous menin-
gitis. In one study, chest roentgenography demon
strated abnormal findings in 43% (32 ⁄ 74) cases.
Hilar adenopathy, miliary pattern, bronchopneu-
monic infiltrate were most frequent abnormalities.
Chest computed tomography was more sensitive
(68 ⁄ 74) in detecting chest abnormalities. Mediasti-
nal and hilar lymphadenopathy, miliary pattern
and bronchopneumonic infiltrate were the most
A B
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
frequent computed tomographic findings (79).
Presence of tuberculosis elsewhere often helps in
making diagnosis of tuberculous meningitis.
Differential diagnosis
A variety of infective, inflammatory, neoplastic
and vascular diseases need to be considered in the
differential diagnosis of tuberculous meningitis.
Differential diagnosis from partially treated bacte-
rial meningitis is frequently difficult (80). Six
features (duration of illness more than 5 days,
presence of headache and cerebrospinal fluid white
blood cell count of <1000 per mm3, clear appear-
ance, lymphocyte count >30% and protein con-
tent of >100 mg ⁄ dl) favor tuberculous meningitis
(81). Several inflammatory or autoimmune diseases
(like Wegener granulomatosis, sarcoidosis, Behcet
disease, Vogt-Koyanagi-Harada syndrome and
acute posterior multifocal placoid pigment epithe-
liopathy), in addition to meningeal inflammation,
often cause inflammation of several other body
organs.
In human immunodeficiency virus-infected
patients, cryptococcal meningitis is the most
important differential 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. Neuro-
imaging studies are often normal. India ink prepa-
ration of cerebrospinal fluid is diagnostic. This test
demonstrates presence of fungal elements in the
C

cerebrospinal fluid. Patients with toxoplasmosis can
also present with diffuse meningoencephalitis.
If the cerebrospinal fluid 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 diffuse 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 anal-
ysis of cerebrospinal fluid, 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 immunodeficiency virus-
infected persons. In several studies, it has been
documented that human immunodeficiency virus
does not significantly alter the clinical manifesta-
tions, laboratory, or radiographic findings or the
response to therapy (12, 84). However, some
studies, on the contrary, suggest that differences
exist between immunodeficiency virus-infected and
immunodeficiency virus-negative patients of tuber-
culous meningitis. For example, it was observed
that a higher number of immunodeficiency virus-
infected patients had evidence of active tuberculo-
sis on chest radiography. The classic computed
tomographic signs of tuberculous meningitis
(obstructive hydrocephalus and basal enhance-
ment) were significantly less prominent (85). Intra-
cerebral mass lesions were more common (60% vs
14% in the non-immunodeficiency virus-infected
group) (86). A high frequency of non-inflammatory
cerebrospinal fluid (absence of pleocytosis) and of
infection by multidrug-resistant strains of Myco-
bacterium tuberculosis have been reported (87). In
an earlier study, authors observed neutrophil
predominance, high smear and culture positivity,
and high antituberculous drug resistance in cere-
brospinal fluid of human immunodeficiency virus-
infected patients of tuberculous meningtis (59).
These patients have a higher mortality rate (88).
Treatment
In patients with tuberculous meningitis antituber-
culous treatment should be started as quickly as
possible. Antimicrobial therapy often needs to be
instituted empirically, much before a bacteriological
Tuberculous meningitis
diagnosis is established. Treatment is started with
first-line antituberculous drugs which include isoni-
azid, rifampicin, pyrazinamide, streptomycin and
ethambutol. The second-line antituberculous drugs
(ethionamide, cycloserine, para-aminosalicylic acid,
aminoglycosides, capreomycin and thiacetazone)
are kept in reserve. Fluoroquinolones (levofloxacin,
gatifloxacin and moxifloxacin) are antimicrobial
agents which are used for the treatment of drug-
resistant tuberculosis. Substitution of older fluoro-
quinolones, especially ciprofloxacin, into a regimen
meant for treating drug-resistant tuberculosis
resulted in a higher rate of relapse (89, 90).
Most of the first-line antituberculous drugs
(except ethambutol) penetrate satisfactorily in to
the cerebrospinal fluid. In a study, the cerebrospi-
nal fluid concentrations of isoniazid and pyrazin-
amide 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 effect on cerebrospi-
nal fluid penetration of antituberculous drugs (91).
Antituberculous treatment regimens
World Health Organization recommends a cate-
gory-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 regi-
men includes a combination of four-first-line
drugs: isoniazid, rifampicin, streptomycin and
pyrazinamide. The intensive phase continues for
2 months. In continuation phase, two drug regi-
men (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
(9–12 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
immunodeficiency virus-infected patients remains
the same as for human immunodeficiency virus-
uninfected 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 anti-
microbial therapy despite adequate treatment. Avail-
able 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 max-
imum adult dose)
Tuberculous meningitis by drug-susceptible organisms (adult, children and human
immunodeficiency virus-infected patients)
Initiation phase: 2 months
Isoniazid (4–6 mg ⁄ kg, 300 mg)
Rifampicin (8–12 mg ⁄ kg, 600 mg)
Pyrazinamide (20–30 mg ⁄ kg, 1600 mg)
Streptomycin (12–18 mg ⁄ kg, 1000 mg)
Continuation phase: 4–7 months
Isoniazid (4–6 mg ⁄ kg, 300 mg)
Rifampicin (8–12 mg ⁄ kg, 600 mg)
Multidrug-resistant tuberculous meningitis
Initiation phase: 4 months
Amikacin or Kanamycin (intravenous or intramuscular 15–30 mg ⁄ kg,
1000 mg)
Ethionamide (15–20 mg ⁄ kg, 1000 mg)
Pyrazinamide (20–30 mg ⁄ kg, 1600 mg)
Ofloxacin (7.5–15 mg ⁄ kg, 800 mg)
Ethambutol or cycloserine (15–25 mg ⁄ kg, 1200 mg; 10–20 mg ⁄ kg, 1000 mg)
Continuation phase: 12–18 months
Ethionamide (5–10 mg ⁄ kg, 750 mg)
Ofloxacin (7.5–15 mg ⁄ kg, 800 mg)
Ethambutol or cycloserine (15–25 mg ⁄ kg, 1200 mg; 10–20 mg ⁄ kg, 1000 mg)
treatment regimen for these patients should include
at least five drugs. Treatment regimen should include
drugs that the patient has not received before and to
which the patientÕs organism is susceptible. The
regimen should also include an injectable medica-
tion. In five drug regimen, one of the antituberculous
drugs should be fluroquinolone. Second-line bacte-
riostatic agents as needed to bring the total number of
drugs in the regimen up to five. The initial phase of
6 months should be followed by the continuation
phase of 12–18 months (13). With emergence of
extensively drug-resistant tuberculosis (a form of
multidrug-resistant tuberculosis with resistance to at
least isoniazid and rifampicin, any fluoroquinolone,
and at least one of the injectable drugs like amikacin,
kanamycin and capreomycin), in future, treatment of
tuberculous meningitis may become much more
difficult.
Immune reconstitution inflammatory syndrome
is a potentially life-threatening condition which is
seen in human immunodeficiency virus-infected
patients of tuberculosis. This complication may be
seen within 3 months after starting highly active
antiretroviral therapy. Immune reconstitution
inflammatory syndrome is characterized by
improvement in CD4 cell counts. Differential
diagnoses of immune reconstitution inflammatory
syndrome include failure of antituberculous treat-
ment, drug reactions and alternative opportunistic
conditions. Infective forms of immune reconstitu-
tion inflammatory syndromes may manifest as
either an inflammatory ÔunmaskingÕ of previously
84
untreated tuberculosis or as the paradoxical clin-
ical deterioration of tuberculous meningitis (92,
94). Immune reconstitution inflammatory syn-
drome may be severe enough to cause death (95).
Concomitant administration of antituberculous
drugs and antiretroviral drugs may produce signif-
icant 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 poten-
tially results in the loss of antiretroviral drug
efficacy (96).
Drug-induced hepatitis following antituber-
culous 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 anti-
tuberculous 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 hep-
atotoxic effect (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 tuber-
culous meningitis because it significantly reduces
death and disabling residual neurological deficit
amongst survivors (98). In fact, the actual evidence
of benefit of corticosteroids in tuberculous menin-
gitis 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 dexa-
methasone or placebo. Patients with grade-II or
grade-III tuberculous meningitis received intra-
venous dexamethasone for 4 weeks and then oral
dexamethasone for 4 weeks. Patients with grade-I
disease received 2 weeks of intravenous dexameth-
asone and then 4 weeks of oral therapy. After
9 months of follow-up, treatment with dexametha-
sone was associated with a significantly 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 significant benefit for the combined
outcome. This observation suggested that early
treatment is important. As additional benefit, the
dexamethasone group experienced significantly
fewer number adverse effects of antituberculous

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. Corti-
costeroids are supposed to reduce cerebral and
meningeal inflammatory changes, cerebral edema
and increased intracranial pressure. Corticosteroids
are thought to operate via modulation of the
production of cytokines and chemokines by macro-
phages (33, 34). However, contrary to popular belief,
Simmons and coworkers demonstrated that
improved survival following corticosteroid treat-
mentwas possibly not mediated by favorable changes
in the immunological mediators of inflammation in
cerebrospinal fluid or by suppression of peripheral T
cell responses against mycobacteria (101). Matrix
metalloproteinases are mediators of extracellular
matrix degradation and are implicated in the path-
ogenesis of several inflammatory diseases of the
central nervous system. A recent study demonstrated
that dexamethasone decreased cerebrospinal fluid
matrix metalloproteinases-9 concentrations early in
course of the treatment. Authors suggested that this
might be one of the mechanisms by which corticos-
teroids improve outcome in tuberculous meningitis
(102).
Paradoxical response
Expansion of an existing tuberculoma or devel-
opment 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 fluid lymphocytic pleo-
cytosis or initial lymphocytic response may
change transiently in the direction of polymor-
phonuclear 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, tubercu-
lous meningitis and brain tuberculoma serial
magnetic resonance imaging revealed a paradox-
ical enlargement of existing cerebral tuberculo-
mas along with an aggravation of anterior
cerebral artery vasculitis, despite the appropriate
treatment (105). There was some evidence that
corticosteroid treatment might have a beneficial
effect in patients having paradoxical reaction
(106).
Tuberculous meningitis
Role of neurosurgery
Cerebrospinal fluid diversion procedures are often
employed in patients of tuberculous meningitis
with hydrocephalus. Shunt procedures are helpful
in reducing intracranial pressure. Ventriculoperi-
toneal shunting is most frequently used surgical
procedure for the drainage of cerebrospinal fluid.
Cerebrospinal fluid shunting is usually needed if
medical therapy does not produce desired result
and patient clinical condition deteriorated consid-
erably. 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 improve-
ment 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 com-
plication and is possibly because of the high
protein content of cerebrospinal fluid. Unfortu-
nately, no placebo-controlled trial, demonstrating
efficacy of shunt surgery in tuberculous meningitis,
is currently available.
Endoscopic third ventriculostomy creates a
communication between third ventricle and sub-
arachnoid space bypassing cerebral aqueduct. It is
now considered as a safe and long-lasting treat-
ment option for hydrocephalus in patient with
tuberculous meningitis. This procedure has most
frequently been used in patients who experienced
multiple episodes of shunt dysfunction. Endo-
scopic 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 unidentifiable third
ventricular floor anatomy (110).
Prognosis
In tuberculous meningitis, early diagnosis and
treatment is important for better prognosis. Unfor-
tunately, antituberculous treatment prevents death
or disability in less than 50% of the patients (111,
112). Administration of corticosteroids in adult
patients is associated with significant 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 neuro-
logical deficit; in stage 2 patient may be in altered
sensorium or has minor focal deficits such as
hemiparesis or cranial nerve palsy; and in stage 3
85
Garg
patient is comatose or may have severe focal
deficits 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% chil-
dren 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 mor-
tality (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 prog-
nostic factors (117). In another series, five factors
were associated with death which included stage-III
at presentation, low glucose levels, low cerebrospi-
nal fluid ⁄ 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 immunodeficiency virus-infected patients of
tuberculous meningitis, the mortality is quite high
(84). In a comparative study, among human immu-
nodeficiency virus-infected patients, 63.3%
(64 ⁄ 101) died while among human immunodefi-
ciency 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 deficit in
40%, and optic atrophy in 37% and other cranial
nerve palsies in 23% (117).
Prevention
Bacillus Calmette-Guérin (BCG) vaccination has
been shown to have a high efficacy in preventing
childhood tuberculous meningitis and miliary
tuberculosis. It is universally accepted that protec-
tive efficacy of BCG vaccination decreases with
age and there is insufficient protection against
tuberculosis in adults. A group of authors esti-
mated 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
first 5 years of lives (118). There are enough
evidences to suggest that a second dose of BCG
vaccine does not increase its efficacy.
It was observed that vaccinated children with
tuberculous meningitis had significantly lower rates
of altered sensorium and focal neurological deficits
and cerebrospinal fluid cell count. Short-term
outcomes (death and sequelae) were significantly
better in the vaccinated group (119). The mecha-
nism of protection by BCG vaccination is not
precisely known (120). Protective benefits of BCG
vaccine for human immunodeficiency virus-
infected persons are not known.
Conclusion
Tuberculous meningitis is associated with excep-
tionally high mortality and morbidity. Not much
has changed despite significant advances in the
recent years. Half of the patients either die during
treatment or they survive with significant disability.
The early diagnosis of tuberculous meningitis is
often difficult. In majority of patients, antitubercu-
lous treatment remains empirical. Available anti-
tuberculous drugs are moderately effective. Newer
drugs with better cerebrospinal fluid 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

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