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121]

Review Article

Tuberculous meningitis: A narrative review

Pulikottil Wilson Vinny, Venugopalan Y. Vishnu1
Department of Neurology, INHS Asvini, Mumbai, Maharashtra, 1Department of Neurology, All India Institute of Medical Sciences,
New Delhi, India

Abstract Tuberculous meningitis (TBM) is a medical emergency. It is the most devastating manifestation of

tuberculosis (TB). The outcome depends on early diagnosis and appropriate treatment. Empirical
antituberculous therapy should be started if clinical suspicion is high. All patients should be tested for HIV.
The choice of antituberculous drugs is extrapolated from pulmonary TB regimen, and many drugs have
poor cerebrospinal fluid penetration. More evidence is required to guide on drug therapy in TBM. Steroids
should be used as adjunctive therapy and response may be modulated by host genotype. Active monitoring
should be done for complications such as hydrocephalus, hyponatremia, and stroke.

Keywords: Antituberculous therapy, guideline, tuberculoma, tuberculosis, tuberculous meningitis

Address for correspondence: Dr. Venugopalan Y. Vishnu, Department of Neurology, All India Institute of Medical Sciences, New Delhi, India.
E‑mail: vishnuvy16@yahoo.com
Received: 20.04.2019, Accepted: 23.04.2019

INTRODUCTION complementary or traditional medicine, inability to perform

Tuberculosis  (TB) is a major global health problem and
remains a major public health issue in India. Mycobacterium TB
can practically affect any part of the body but when the brain
is involved, the consequences are devastating. Tuberculous
meningitis (TBM) is the most devastating and disabling form
with around 1 lakh new cases appearing every year around
the world.[1] The incidence and prevalence of TBM varies
around the world depending on location, age group, and
prevalence of HIV. In 2017, eight countries (India, China,
Indonesia, Philippines, Pakistan, Nigeria, Bangladesh, and
South Africa) accounted for two‑thirds of all TB cases.[2] The
major risk factors causing the TB epidemic are urbanization,
crowding, poverty, malnutrition, injection drug use, chronic
use of steroids, chronic renal failure, incarceration, HIV,
diabetes, and alcoholism.[3] The major gaps in diagnosis and
treatment are caused by delayed presentation, reliance on
or refusal of lumbar puncture, lack of laboratory facilities,
and unavailability or unaffordability of antibiotics.[3] Indian
national guidelines for extrapulmonary TB estimates that
TBM constitutes 1% of all TB cases.[4] The diagnosis of
TBM is not easy and hence mostly underreported. The
neonatal bacillus Calmette–Guérin (BCG) vaccine might be
73% effective in preventing TBM.[5] The mortality rate of
TBM remains very high. A Cochrane review reported 41%
and 31% of mortality in TBM with or without steroids.[6]
Even with antiretroviral therapy (ART), the mortality of
TBM in HIV coinfection is around 40%.[7,8] The mortality is
near 100% in drug‑resistant TBM with HIV‑1 coinfection.[9]
PATHOGENESIS
Mycobacterium TB is an airborne infection with lung as the first
portal of entry. The infection initially replicates in the lungs

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DOI:
10.4103/jcrsm.jcrsm_17_19 How to cite this article: Vinny PW, Vishnu VY. Tuberculous meningitis: A
narrative review. J Curr Res Sci Med 2019;5:13-22.

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Vinny and Vishnu: Tuberculous meningitis
and then moves to the lymph nodes. The dissemination of TB
bacilli via blood accounts for the extrapulmonary TB, including
TBM. The bacilli settle and form a localized granuloma called
rich focus in the meninges or parameningeal areas. The rupture
of rich focus causes the bacilli to spill into subarachnoid space,
eventually involving the brain parenchyma and blood vessels.
The brain parenchymal involvement can be tuberculoma or
abscess. The inflammation of the meninges leads to basal
exudates in the base of the brain and causes inflammation of
vessels (vasculitis) that may result in vascular occlusion causing
strokes. The most commonly involved vessels are perforating
branches of the middle cerebral artery leading to infarcts in
the basal ganglia and internal capsule. The ischemia may be
further worsened by the raised intracranial pressure (ICP) and
hydrocephalus due to obstruction of cerebrospinal fluid (CSF)
flow by basal exudates.
In children and HIV‑1 coinfection, TBM can occur as part
of initial disseminated infection.[10] In HIV‑TB coinfection,
there is higher frequency of extrapulmonary TB, especially
TBM accompanied by occult meningeal disease and higher
blood culture positivity (40%) in HIV-1 co-infection.[11,12]
HIV‑1 coinfected individuals are more likely to experience
TBM‑associated Immune Reconstitution Inflammatory
Syndrome (IRIS) since initiation of antiretroviral therapy
might unmask the occult meningeal disease.
TBM pathogenesis involves both bacterial replication in
brain as well as dysregulated host immune response including
reactive oxygen species.[1] Mycobacterium TB bacilli are taken
up by microglia once they cross the blood–brain barrier.
Multiplication of bacilli inside the microglia leads to cytokine
and chemokine production. Many patients manifest pituitary
dysfunction which is significant considering that steroids
are used in treatment of TBM. interferon‑gamma (IFN‑γ),
tumor necrosis factor‑alpha (TNF‑α), interleukin‑1β, and
matrix metalloproteinases are the cytokines found to be
related to immunity and survival of TBM.
Genetic polymorphisms in various host response genes can
modulate the immune response in TBM. A single‑nucleotide
polymorphism in the leukotriene A4 hydrolase (LTA4H)
promoter can affect the balance between pro‑inflammatory
leukotriene B4 and immunosuppressive lipoxin A4.
LTA4H polymorphism is associated with inflammatory
cell recruitment, survival of TBM patients, and response
to anti‑inflammatory treatment.[13]
CLINICAL FEATURES
The clinical features of TBM are nonspecific. Important
differential diagnoses include partially treated pyogenic
14 Journal of Current Research in Scientific Medicine | Volume 5 | Issue 1 | January-June 2019
meningitis and cryptococcal meningitis. The common
symptoms and signs of TBM are fever, headache, vomiting,
neck stiffness, fatigue, loss of weight, loss of appetite,
altered sensorium, and focal deficits (cranial nerve palsies,
vision loss, hemiparesis, and paraparesis). The onset is
usually insidious with a prodromal stage lasting for days to
weeks (fatigue, loss of weight/appetite, and night sweats)
followed by features of meningitis (fever, headache, and
neck stiffness). If untreated, the patient can present with
various complications such as altered sensorium, cranial
nerve palsies, hemiparesis, or coma. TBM is a medical
emergency. Treatment before the onset of coma is the
greatest benefit a physician can give a patient with TBM. In
endemic region like India, the pretest probability of TBM
is high, and empirical treatment should be considered in a
patient suspected to have TBM.
The clinical features also depend on the host immune
response. In very young children  (<1  year of age) and
HIV‑1 coinfection, extrapulmonary dissemination and
TBM are common. Moreover, they can have an abrupt
and rapidly progressive presentation to coma with
high morbidity and mortality. The Medical Research
Council  (MRC) disease severity grade strongly predicts
outcome in TBM [Table 1].[14,15] The other important risk
factors for mortality include HIV‑1 coinfection, extremes
of age, and drug‑resistant TB.
Several clinical scoring systems have been studied to find
the diagnostic predictors of TBM depending on age group,
setting, and HIV status [Table 2]. Few have been externally
validated. However, not all externally validated scores have
fared well in terms of sensitivity and specificity. Thwaites
score, which was validated in multiple countries, did not
fare well in HIV coinfected Malawi population (sensitivity
78% and specificity of 43%) where most false‑positive
cases turned out to be cryptococcal meningitis.[18,20]
A consensus case definition for TBM was published
mainly for research purpose and was not very useful when
employed as a clinical diagnostic tool.[21,22]
IMAGING
Computed tomography  (CT) and magnetic resonance
imaging  (MRI) are the commonly used modalities
for imaging. MRI has better resolution in detecting
tuberculomas and infarct. The common brain imaging
features in TBM are basal exudates, tuberculomas, and
hydrocephalus[23] [Figure 1]. Ring‑enhancing lesions are
common presentation of tuberculomas and tubercular
abscess. The common differentials are neurocysticercosis,
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Vinny and Vishnu: Tuberculous meningitis

Table 1: Medical Research Council disease severity grade

MRC Definition Rate of death/severe disability in Rate of death/severe disability in
grade HIV‑1‑negative TBM patients (%) HIV‑1‑coinfected TBM patients (%)
I GCS score 15; no focal neurological signs 15 25
II GCS score 11‑14, or 15 with focal neurological signs 30 50
III GCS score ≤10 50 80
MRC: Medical Research Council, GCS: Glasgow Coma Scale, TBM: Tuberculous meningitis

Table 2: Various clinical scores for diagnostic predictors of tuberculous meningitis

Study Kumar et al. Arch Dis Youssef et al. Diagn Microbiol Thwaites et al. Lancet. Zhang et al. Intern Med
Child. 1999[16] Infect Dis 2006[17] 2002[18] 2013[19]
Setting India Egypt Vietnam China
Age group Children (1 month‑12 years) Children and adults (5 months‑years) Adults (16‑70 years) Adults (all HIV‑uninfected)
Variable that History of illness >6 days History of illness >5 days History of illness ≥6 days Female sex
predict TBM CSF lymphocytes >50% CSF lymphocytes >30% CSF lymphocytes >10% Reduced consciousness
Optic atrophy CSF WCC <1000×103/ml CSF WCC <750×103/ml No visual or hearing loss
Abnormal movements Clear CSF Age <36 years Evidence of extraneural TB
Focal neurological deficit CSF protein >100 mg/dl Blood WCC (103/ml) <15,000 CSF leukocytes ≥68/mm3
CSF protein >0.91 mg/dl
TBM: Tuberculous meningitis, CSF: Cerebrospinal fluid, WCC: White cell count, TB: Tuberculosis

Mycobacterium tuberculosis in clinical specimens and also

detect rifampicin resistance‑associated mutations. The
assay is approximately 60% sensitive and nearly 100%
specific. The test should be used to “rule‑in” and not
“rule‑out” the diagnosis of TBM.[28‑30] GeneXpert Ultra
is the second‑generation assay works on detection and
amplification of a multicopy gene target and is reported
by the WHO to have 95% sensitivity.[31]

Blood and CSF IFN‑γ release assays have a sensitivity of

78% and 77%, respectively, with specificity of 61% and
88%, respectively.[32] This limits its utility in clinical practice.

Figure 1: Magnetic resonance imaging brain T1 contrast imaging

showing basal exudates encasing the vessels
bacterial abscess, fungal abscess, metastasis, gliomas,
lymphomas, and toxoplasmosis [Tables 3‑5].[24]
DIAGNOSIS
The detection of TB bacilli by Ziehl–Neelsen staining has
been the main method of early diagnosis of TB. However,
its sensitivity in TBM is only 10%–20%. The sensitivity of
CSF microscopy can be augmented by taking large volume
CSF  (10  ml), centrifuging at 3000 RPM, and examining
for 30 min by experienced microbiologist.[25] The culture
takes minimum 10 days in liquid media and 8 weeks in
solid media. Hence, cultures in TBM rarely help in the
decision‑making process regarding treatment.
Many nucleic acid amplification tests have been developed,
but few are well validated.[26,27] GeneXpert is a real‑time
polymerase chain reaction‑based assay for detection of
Journal of Current Research in Scientific Medicine | Volume 5 | Issue 1 | January-June 2019 15
Similarly, CSF adenosine deaminase  (ADA) value of
1–4 U/l have a sensitivity of   >93% and specificity
of   <80%, while CSF ADA  >8 U/l have sensitivity
of  >96% and specificity of  <59%. These cutoff values,
however, could not consistently differentiate between TBM
and bacterial meningitis.[33,34]
The features detected on imaging may have good
specificity, but sensitivity remains low. A  combination
of basal exudates, hydrocephalus, and infarcts on CT
brain have high specificity (95%–100%), but these may
be absent in early stage of the disease, reducing its
sensitivity to around 40%. MRI might pick up more
tuberculomas and infarcts. More than 50% of TBM
have concomitant spinal cord involvement, and around
50% have chest X‑ray abnormalities.[35] Miliary mottling
of chest X‑ray suggests dissemination. CT or positron
emission tomography‑CT of chest, abdomen, and pelvis
can detect TB in other organs that may offer easier site
for biopsy.
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Vinny and Vishnu: Tuberculous meningitis

Table 3: Imaging characteristics of ring‑enhancing lesions

Wall Contrast DWI ADC SWI MRS
Bacterial abscess Smooth/lobulated wall + Central Low Can be present Acetate, succinate
Fungal Irregular wall + Wall and Low Complete smooth Lipids, lactate, amino
Intracavitary No enhancement of intracavitatory hypotense rim acid, trehalose
projections intracavitary projections projections
Tubercular Smooth/lobulated/crenated + Central Low Usually absent Lipid
Thick wall
Toxoplasmosis Basal ganglia + Not significant ‑ + Lipid/lactate but not
Target sign choline
+: Present, -: Absent. DWI: Diffusion‑weighted imaging, ADC: Apparent diffusion coefficients, MRS: Magnetic resonance spectroscopy, SWI:
Susceptibility weighted imaging

Table 4: Magnetic resonance imaging features of tuberculoma

T1W T2W FLAIR
Noncaseating granuloma Iso‑ to hypointense Hyperintense No suppression
Caseating granuloma Iso‑ to hypointense with hyperintense rim Hypointense No suppression
Caseating granuloma Isointense to hypointense with Hypointense rim with Partial suppression
with central liquefaction hyperintense rim central hyperintensity
Calcified granuloma Iso‑ to hypointense Hypointense No suppression
FLAIR: Fluid‑attenuated inversion recovery, T1W: T1‑weighted, T2W: T2‑weighted

Table 5: Imaging differentiation between neurocysticercosis duration of treatment in TBM. The treatment strategy is
and tuberculoma based on the pulmonary TB (PTB) management regimens.
Tuberculoma Neurocysticercosis
The characteristics of antituberculous agents are described
Lesions in the gray‑white matter Lesions in the sulcal
junction subarachnoid spaces
in Table 6.
T2 hypointense caseous T2 hyperintense cyst unless
granulomas calcified In central nervous system (CNS) TB, the major concerns
No/incomplete suppression on Complete suppression on FLAIR are poor CSF penetration of rifampicin and ethambutol.
FLAIR
No scolex visualized Eccentric T2 hypointense scolex Most of the guidelines and recommendations do not
T1W hyperintense rim on MT MRI No T1W hyperintense rim consider the poor CSF penetration of these drugs.
Size may be >2 cm Size usually <2 cm
Whether a higher dose of rifampicin should be used in
Conglomerate ring‑enhancing Diffusely distributed, various
lesions stage cysts TBM is not clear. An open‑label randomized controlled
Larger extent of perilesional edema Smaller extent of perilesional trial conducted in Indonesia with 60 TBM patients showed
edema
that use of 600  mg of rifampicin intravenously could
FLAIR: Fluid‑attenuated inversion recovery, MRI: Magnetic resonance
imaging, MT: Magnetisation transfer, T1W: T1‑weighted halve the mortality compared to 450 mg oral dosing.[38]
However, a larger trial with 817  patients in Vietnam
which tested higher dose of rifampicin  (15  mg/kg vs.
The main limitation of imaging as a diagnostic modality is
10  mg/kg orally) and levofloxacin  (first 2  months) did
that 30% of cases at MRC‑Grade I have normal CT scan
not show any survival benefit.[8] The probable reason for
and 15% have normal MRI brain. Age and HIV‑coinfection
failure may be higher dose requirement of rifampicin. In
significantly affect the imaging appearance. Children have
a dose‑ranging trial in PTB, doses up to 35 mg/kg were
more hydrocephalus. HIV‑coinfected TBM patients have
safe and highest doses (30 and 35 mg/kg) showed highest
less basal exudates, especially with low CD4 counts.[36,37]
bactericidal activity.[39]
MANAGEMENT
The choice of the fourth drug remains ambiguous. There
The management of TBM consists of three strategies: are no comparative trials available. Commonly used drugs
1. Killing the TB bacilli with antitubercular are ethambutol and streptomycin. Both have low CSF
treatment (ATT) penetration and exhibit adverse events in the form of
2. Manage the host immune response optic neuropathy and vestibular toxicity respectively. The
3. Supportive care and manage the complications. rationale in drug‑sensitive PTB is to prevent isoniazid
resistance, as it does not increase bacterial killing or improve
The greatest predictor of survival from TBM is the outcome. But in TBM, the rationale of the fourth drug is
initiation of ATT before the onset of coma. We still also to increase bacterial killing, and patient survival since
do not have high‑quality evidence regarding the ideal the CSF penetration of rifampicin is low. Ethionamide
combination, dosage, frequency of administration, or has better CSF penetration  (80%–90%). Levofloxacin
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Vinny and Vishnu: Tuberculous meningitis

Table 6: Characteristics of antituberculous drugs

Anti-Tuberculous Dose recommended by WHO Duration of treatment CSF penetration Adverse events
Therapy (ATT) in adults (WHO recommendation)
First‑line drug
RIF 10 mg/kg (range 8‑12 mg/kg); 12 months 10%‑20% Hepatotoxicity, orange urine, many drug
maximum 600 mg interactions
Isoniazid 5 mg/kg (range 4‑6 mg/kg); 12 months 80%‑90% Hepatotoxicity, peripheral neuropathy,
maximum 300 mg lupus‑like syndrome, confusion, seizures
Pyrazinamide 25 mg/kg (range 20‑30 mg/kg) First 2 months 90%‑100% Hepatotoxicity, arthralgia, gout
Ethambutol 15 mg/kg (range 15‑20 mg/kg) First 2 months 20%‑30% Dose‑related retrobulbar neuritis, more
common in renal impairment
Streptomycin 15 mg/kg (range 12‑18 mg/kg) First 2 months 10%–20% Monitor plasma concentrations when
possible; causes nephrotoxicity and
ototoxicity
Second‑line drugs
Levofloxacin 10–15 mg/kg Throughout treatment 70%–80% Nausea, headache, tremor, confusion,
tendon rupture (rare)
Moxifloxacin 400 mg Throughout treatment 70%–80% Nausea, headache, tremor, confusion,
tendon rupture (rare)
Amikacin 15 mg/kg maximum 1 g IV or Intensive phase only 10%–20% Monitor plasma concentrations when
IM possible; causes nephrotoxicity and
ototoxicity
Kanamycin 15 mg/kg maximum 1 g IV or Intensive phase only 10%–20% Monitor plasma concentrations when
IM possible; causes nephrotoxicity and
ototoxicity
Capreomycin 15 mg/kg maximum 1‑ g IV Intensive phase only No data Monitor plasma concentrations when
or IM possible; causes nephrotoxicity and
ototoxicity
Ethionamide 15‑20 mg/kg maximum 1 g Throughout treatment 80%‑90% Anorexia, nausea, vomiting,
gynecomastia, hypothyroidism,
confusion, seizures
Cycloserine 10‑15 mg/kg maximum 1 g Throughout treatment 80%‑90% CNS toxicity: depression, seizures,
neuropathy; coadministration with
pyridoxine recommended
Linezolid 600 mg Throughout treatment 30%‑70% Myelosuppression, optic neuropathy;
peripheral neuropathy, coadministration
with pyridoxine recommended
Other drugs used in
multi‑drug resistant TB
(uncertain benefit in
TBM)
Clofazimine 100‑200 mg OD No recommended Limited data Skin discoloration (orange/red),
Duration (probably low) photosensitivity
p‑aminosalicylic acid 8‑12 g No recommended No data (probably Vomiting, diarrhea, reversible
Duration very low) hypothyroidism (increased risk with
ethionamide)
Bedaquiline 400 mg for 2 weeks, followed New drug. Limited Probably very low Nausea, vomiting, arthralgia, QT
by 200 mg thrice weekly availability (but data from prolongation; metabolized through
one patient only) CYP3A4; RIF halves concentrations
Delamanid 200 mg New drug. Limited No data Nausea, vomiting, dizziness rarely; QT
availability prolongation
TB: Tuberculosis, ATT: Antitubercular treatment, TBM: Tuberculous meningitis, IV: Intravenous. IM: Intramuscular, CSF: Cerebrospinal fluid,
RIF: Rifampicin

and moxifloxacin also have better penetration (70%–80%)
with high activity against TB bacilli (drug susceptible and
drug‑resistant). The intensified regimen  (levofloxacin
as the 5th drug along with ethambutol and high‑dose
rifampicin) tested in a randomized controlled trial in
Vietnam failed to show any survival benefit, though there
was increased survival in patients with isoniazid‑resistant
TB bacilli. Hence, in drug‑susceptible TBM, choice of
the 4th drug might not influence patient outcome, but in
isoniazid resistance, high‑dose rifampicin (15 mg/kg) and
levofloxacin (as fifth drug) might improve the outcome.
Journal of Current Research in Scientific Medicine | Volume 5 | Issue 1 | January-June 2019 17
Drug‑resistant TBM has very poor outcome with
mortality  >80%. There is usually delay in detection of
drug resistance even with GeneXpert (sensitivity <60%).
CSF penetration and efficacy of second‑line drugs are not
well defined.
The Index TB guidelines recommend 2 months of HRZE
and 7 months of HRE[4] [Table 7]. The WHO guidelines
recommend 2  months HRZS followed by 10‑month
continuation phase with HR. The current RNTCP guidelines
recommend 2 months or HRZE and 9–12 months of HRE.
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Vinny and Vishnu: Tuberculous meningitis

Table 7: Summary of index tuberculosis guidelines regarding tuberculous meningitis[4]

Diagnosis of TBM using the Xpert
MTB/RIF test
Adjunctive steroids in the
treatment of HIV‑negative TBM
Adjunctive steroids in the
treatment of HIV‑coinfected TBM
Duration of treatment
TB: Tuberculosis, TBM: Tuberculous meningitis, CSF: Cerebrospinal fluid, ATT: Antitubercular treatment, MTB: Mycobacterium tuberculosis,
RIF: Rifampicin
Recommendation Strength of recommendation
“Xpert MTB/RIF may be used as an adjunctive test for TBM. Conditional recommendation,
A negative Xpert MTB/RIF result on a CSF specimen does not low‑quality evidence for
rule out TBM. The decision to give ATT should be based on the sensitivity estimate, high‑quality
clinical features and CSF profile evidence for specificity estimate
Duration of steroid treatment should be for at least 4 weeks Strong recommendation,
with tapering as appropriate high‑quality evidence
Steroids may be used for TB meningitis in HIV‑positive people, Conditional recommendation,
where other life‑threatening opportunistic infections are absent very low‑quality evidence
TB meningitis should be treated with standard first‑line ATT for Conditional
at least 9 months

There are various issues with these guidelines. There is
clinical equipoise regarding the duration of treatment in
TBM. Most of what is recommended in the guidelines are
expert opinion. The neurologists in general and also those
in the Index‑TB guideline panel feel that TBM should be
treated for minimum for 12–18  months. The Technical
Advisory Subcommittee for CNS TB who drafted
Index‑TB guidelines preferred pyrazinamide instead of
ethambutol. Many physicians and neurologists prefer
streptomycin instead of ethambutol, especially when TBM
threatens vision loss and due to risk of ethambutol‑related
optic neuropathy. However, both drugs have poor CSF
penetration.
Only high‑quality randomized controlled trials at a
larger scale can answer this question. It is ironic that the
streptomycin was the first drug in medicine to be tested in
a randomized controlled trial, and still half a century later,
we still do not have RCTs to guide us regarding treatment
of TBM.
ROLE OF ANTI‑INFLAMMATORY THERAPY
Adjunctive corticosteroids are hypothesized to reduce
inflammation in TBM and hence improve patient
outcomes. Cochrane Systematic Review and Meta‑analysis
in 2016 concluded that corticosteroids increase survival in
TBM (children and adults) who were HIV‑1 negative.[6] In
HIV‑1 coinfection, the benefit of steroids was uncertain.
There was no reduction in long‑term disability in
any group. In the Vietnam trial, however, there were
98 HIV‑1‑coinfected TBMs, and in this subgroup, there
was no significant effect of steroids on death or combined
end‑point of death and disability.
Delayed inflammatory reaction which occurs weeks
to months after starting ATT is called paradoxical
reaction.[40] In HIV‑coinfected patients, after starting
ART, it is called IRIS. Paradoxical reaction and IRIS
may present with fever, worsening headache, seizures,
18 Journal of Current Research in Scientific Medicine | Volume 5 | Issue 1 | January-June 2019
or altered sensorium. When suspected, hydrocephalus,
infarcts, or tuberculoma formation should be identified
by imaging. The most commonly described paradoxical
reaction is tuberculoma. They are commonly treated with
high‑dose steroids. When there is no response to steroids
or clinically patient worsens, other anti‑inflammatory
therapies may be tried, especially in the setting of
tuberculoma at optic chiasma or when optochiasmatic
arachnoiditis threatens vision. Thalidomide, infliximab,
and IFN‑γ have been tried in such scenarios. [41‑44]
Modi et  al. has reported use of thalidomide  (in a dose
of 2  mg/kg) for 4–6  months in  >50  patients with
TBM (who had already received  >2  months of ATT
and steroids) suffering from various inflammatory
complications (such as optochiasmatic arachnoiditis,
a paradoxical increase in the size of tuberculomas,
an increase in size and number of lesions, and spinal
arachnoiditis).[45] The authors have claimed clinical and
radiological improvement in >70% of patients.
Genetic polymorphism in some immune response genes
can modulate pro‑inflammatory and anti‑inflammatory
host responses. Much focus is on single polymorphism in
LTA4H promotor which modulates eicosanoids and thus
influencing TNF‑α expression.[13,46] In the Vietnam trial[8]
where all participants received steroids, survival benefit
was present in TT genotype  (hyperinflammatory), and
there was harm in CC genotype.[47] But in an Indonesian
study, LTA4H genotype did not show any survival benefit
in 427 HIV‑negative patients with TBM where all received
corticosteroids.[48] Hence, the clinical evidence on LTA4H
genotype guiding personalized anti‑inflammatory treatment
is ambiguous as of now.
Index TB recommendation for dosing of steroids in TBM
is “In hospital: intravenous dexamethasone 0.4 mg/kg/24 h
in 3–4 divided doses may be preferred with a slow switch
to oral therapy and taper. Currently, there is insufficient
evidence to recommend one formulation/regimen of
steroids over any other.”[4]
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Vinny and Vishnu: Tuberculous meningitis
Other than steroids, the only adjunctive treatment with
proven benefit in CNS TB is ART. There is ambiguity in
the timing of initiation of ART. The choice is between
reducing the risk of other opportunistic infections with
early ART versus risk of IRIS. A single trial comparing
early versus 2 months delayed initiation of ART in TBM
showed no survival difference, but severe adverse events
were more in early ART group.[49]
Tuberculomas
Tuberculomas can present along with TBM or occur
independently. The clinical features depend on site and
size. They can present with seizures, focal deficit, raised
ICP due to hydrocephalus, or mass effect. Tuberculomas
can appear a part of paradoxical worsening or IRIS. The
main treatment is ATT and duration of treatment is
uncertain. The usual practice is to continue treatment till
18 months or till tuberculoma disappears. When there is no
response to ATT and steroids, especially in locations such
as optochiasmatic region, other anti‑inflammatory agents
like thalidomide are used.
SUPPORTIVE MANAGEMENT
The various complications of TBM (increased ICP, infarct,
hydrocephalus, hyponatremia, and seizures) should be
detected early and managed appropriately. Raised ICP
is managed symptomatically by mannitol or hypertonic
saline.[50,51]
Hydrocephalus is the most common cause of increased
ICP, and 80% have communicating hydrocephalus due to
disruption of CSF flow due to basal exudates [Table 8].
Communicating hydrocephalus might be treated with diuretics
and serial lumbar punctures.[52,53] Noncommunicating
hydrocephalus is treated with ventriculoperitoneal  (VP)
shunt or endoscopic third ventriculostomy  (ETV).[54] A
systematic review of VP shunt in TBM concluded that
clinical severity determines the outcome and HIV‑1
coinfection had worse prognosis.[55] A trial on 48 patients
with TBM and hydrocephalus comparing VP shunt and
ETV, showed that ETV had higher risk of early recurrence,
but lesser long‑term complications than VP shunt.[56]
However, it is technically difficult to do ETV in TBM
Hydrocephalus in acute stage with inflamed, opaque, and
thick third ventricle.[57,58] The contrary viewpoint is that
aqueductal stenosis in early‑stage TBM should be managed
by ETV and VP shunt should be used for chronic burnt
out cases or those with communicating hydrocephalus.[59]
Ambiguity in selection of one procedure over other for
TBM hydrocephalus continues in the absence of robust
evidence.
Journal of Current Research in Scientific Medicine | Volume 5 | Issue 1 | January-June 2019 19
Hyponatremia in TBM could be due to syndrome of
inappropriate antidiuretic hormone secretion (SIADH)
or cerebral salt wasting syndrome  (CSWS), and it is
difficult to differentiate between them clinically. SIADH is
managed by fluid restriction, while CSW is treated by fluid
administration [Table 9].
Recently, a small trial with 36 patients assessed safety and
efficacy of fludrocortisone in the treatment of cerebral
salt wasting in patients with TBM.[60] It was published
as an open‑label randomized controlled trial with 0.9%
intravenous saline solution with 5–12 g per day of oral
salt supplementation, with or without the addition of
0.1–0.4 mg of fludrocortisone per day. Fludrocortisone
resulted in early normalization of serum sodium levels
but did not affect outcomes in 6  months. The study
was plagued by significant discrepancy between the
retrospectively registered trial protocol and the published
paper. The paper brought out fludrocortisone as a
treatment option in CSWS that is worth pursuing in future
randomized controlled trials.
Stroke due to TB vasculitis are usually multiple and bilateral
involving deep gray matter like caudate/ thalamus as also
anterior and genu of internal capsule (“tubercular zone”).
There is no proven treatment or prevention of stroke in
TBM. Corticosteroids were not found to be effective in
preventing brain infarction.[61] Aspirin might prevent stroke
in TBM as shown in two small trials.[62,63]
PREVENTION
Three most effective preventive strategies for TBM
are  (1) reducing transmission of Mycobacterium TB,
(2) BCG vaccination in neonates (reduces the incidence
of dissemination including TBM), and (3) ART in people
with HIV.
DRUG‑RESISTANT TUBERCULOUS MENINGITIS
Multidrug‑resistant TB is resistant to at least isoniazid and
rifampicin. Extensively drug‑resistant TB is resistant to
isoniazid and rifampicin, as well as any fluoroquinolones
and any of the three second‑line injectable ATT
drugs  (amikacin, kanamycin, or capreomycin). Drug
resistance could be primary (due to the transmission of
drug‑resistant strain in someone who was not taking
ATT) or acquired  (resistance developing in someone
who was already taking ATT). The WHO guidelines for
the treatment of multidrug‑resistant TBM recommend
that initially at least five effective drugs should be
used comprising a fluoroquinolone and an injectable
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Vinny and Vishnu: Tuberculous meningitis

Table 8: Modified Vellore Grading Scale for hydrocephalus in tuberculous meningitis and Glasgow Outcome Scale
Grade GCS Clinical features
Modified Vellore Grading Scale for hydrocephalus in TBM
I 15 Headache, vomiting±neck stiffness
No neurological deficit
II 15 Neurological deficit present
III 9‑14 Neurological deficit may or may not be present
IV 3‑8 Neurological deficit may or may not be present
Glasgow Outcome Scale
1 Death Severe injury or death without recovery of consciousness
2 Persistent vegetative state Severe damage with prolonged state of unresponsiveness and a lack of higher mental functions
3 Severe disability Severe injury with permanent need for help with daily living
4 Moderate disability No need for assistance in everyday life, employment is possible but may require special equipment
5 Low disability Light damage with minor neurological and psychological deficits
TBM: Tuberculous meningitis, GCS: Glasgow Coma Scale

Table 9: Features of cerebral salt wasting syndrome and REFERENCES

syndrome of inappropriate antidiuretic hormone
CSWS
Fluid balance Negative
Signs of dehydration + ‑
Signs of fluid overload ‑ +/‑
Serum osmolality Low
Urine osmolality High
Urine sodium High
+: Present, -: Absent. SIADH: Syndrome of inappropriate antidiuretic
hormone, CSWS: Cerebral salt wasting syndrome
second‑line agent and duration of treatment should be
18–24  months.[64] It is uncertain regarding the clinical
decision point of presumptive treatment failure in TBM.
It may not be acceptable to wait more than 3 months to
decide on presumptive treatment failure.[4]
CONCLUSION
TBM is a medical emergency associated with high morbidity
and mortality. Early empirical treatment with ATT
should be started if clinical suspicion is high. Ensuring
compliance with chosen ATT regimen and supportive
therapy cannot be overemphasized. Current ATT regimens
are extrapolated from PTB regimens and do not consider
poor CNS penetration of drugs such as ethambutol,
streptomycin, and rifampicin. Improvement in social
indicators of a country, namely, malnutrition, poverty, and
low income will play an important role in the prevention
and control of TB.
Acknowledgment
The authors would like to thank Dr. Rajesh Kumar Singh.
Financial support and sponsorship
Nil.
Conflicts of interest
There are no conflicts of interest.
SIADH 1. Wilkinson  RJ, Rohlwink  U, Misra  UK, van Crevel  R, Mai  NT,
Positive Dooley  KE, et al. Tuberculous meningitis. Nat Rev Neurol
2017;13:581‑98.
2. World Health Organization. Global Tuberculosis Report 2018. World
Low Health Organization. Available from: http://www.who.int/tb/
High publications/global_report/en/. [Last accessed on 2019 Apr 17].
High 3. Chin JH. Tuberculous meningitis: A neglected tropical disease ?. Neurol
Clin Pract 2019;9:152-4.
4. Sharma SK, Ryan H, Khaparde S, Sachdeva KS, Singh AD, Mohan A,
et al. Index‑TB guidelines: Guidelines on extrapulmonary tuberculosis
for India. Indian J Med Res 2017;145:448‑63.
5. Trunz BB, Fine P, Dye C. Effect of BCG vaccination on childhood
tuberculous meningitis and miliary tuberculosis worldwide:
A  meta‑analysis and assessment of cost‑effectiveness. Lancet
2006;367:1173‑80.
6. Prasad K, Singh MB, Ryan H. Corticosteroids for managing tuberculous
meningitis. Cochrane Database Syst Rev 2016;4:CD002244.
7. Marais S, Pepper DJ, Schutz C, Wilkinson RJ, Meintjes G. Presentation
and outcome of tuberculous meningitis in a high HIV prevalence
setting. PLoS One 2011;6:e20077.
8. Heemskerk  AD, Bang  ND, Mai  NT, Chau  TT, Phu  NH, Loc  PP,
et al. Intensified antituberculosis therapy in adults with tuberculous
meningitis. N Engl J Med 2016;374:124‑34.
9. Tho  DQ, Török ME, Yen  NT, Bang  ND, Lan  NT, Kiet  VS, et al.
Influence of antituberculosis drug resistance and Mycobacterium
tuberculosis lineage on outcome in HIV‑associated tuberculous
meningitis. Antimicrob Agents Chemother 2012;56:3074‑9.
10. Berenguer J, Moreno S, Laguna F, Vicente T, Adrados M, Ortega A,
et al. Tuberculous meningitis in patients infected with the human
immunodeficiency virus. N Engl J Med 1992;326:668‑72.
11. Rana FS, Hawken MP, Mwachari C, Bhatt SM, Abdullah F, Ng’ang’a LW,
et al. Autopsy study of HIV‑1‑positive and HIV‑1‑negative adult
medical patients in Nairobi, Kenya. J  Acquir Immune Defic Syndr
2000;24:23‑9.
12. Shafer RW, Goldberg R, Sierra M, Glatt AE. Frequency of Mycobacterium
tuberculosis bacteremia in patients with tuberculosis in an area endemic
for AIDS. Am Rev Respir Dis 1989;140:1611‑3.
13. Tobin DM, Roca FJ, Oh SF, McFarland R, Vickery TW, Ray JP, et al.
Host genotype‑specific therapies can optimize the inflammatory
response to mycobacterial infections. Cell 2012;148:434‑46.
14. Chiang  SS, Khan  FA, Milstein  MB, Tolman  AW, Benedetti  A,
Starke  JR, et al. Treatment outcomes of childhood tuberculous
meningitis: A systematic review and meta‑analysis. Lancet Infect Dis
2014;14:947‑57.
15. Brancusi F, Farrar J, Heemskerk D. Tuberculous meningitis in adults:
A review of a decade of developments focusing on prognostic factors
for outcome. Future Microbiol 2012;7:1101‑16.

20 Journal of Current Research in Scientific Medicine | Volume 5 | Issue 1 | January-June 2019

[Downloaded free from http://www.jcrsmed.org on Wednesday, August 11, 2021, IP: 27.61.234.121]
Vinny and Vishnu: Tuberculous meningitis
16. Kumar  R, Singh  SN, Kohli  N. A  diagnostic rule for tuberculous
meningitis. Arch Dis Child 1999;81:221‑4.
17. Youssef   FG, Afifi  SA, Azab  AM, Wasfy  MM, Abdel‑Aziz  KM,
Parker TM, et al. Differentiation of tuberculous meningitis from acute
bacterial meningitis using simple clinical and laboratory parameters.
Diagn Microbiol Infect Dis 2006;55:275‑8.
18. Thwaites  GE, Chau  TT, Stepniewska  K, Phu  NH, Chuong  LV,
Sinh DX, et al. Diagnosis of adult tuberculous meningitis by use of
clinical and laboratory features. Lancet 2002;360:1287‑92.
19. Zhang B, Lv K, Bao J, Lu C, Lu Z. Clinical and laboratory factors in
the differential diagnosis of tuberculous and cryptococcal meningitis
in adult HIV‑negative patients. Intern Med 2013;52:1573‑8.
20. Checkley  AM, Njalale  Y, Scarborough  M, Zjilstra  EE. Sensitivity
and specificity of an index for the diagnosis of TB meningitis in
patients in an urban teaching hospital in Malawi. Trop Med Int Health
2008;13:1042‑6.
21. Marais S, Thwaites G, Schoeman JF, Török ME, Misra UK, Prasad K.
Tuberculous meningitis: A uniform case definition for use in clinical
research. Lancet Infect Dis 2010;10:803‑12.
22. Solomons RS, Visser DH, Marais BJ, Schoeman JF, van Furth AM.
Diagnostic accuracy of a uniform research case definition for TBM in
children: A prospective study. Int J Tuberc Lung Dis 2016;20:903‑8.
23. Garg  RK, Malhotra  HS, Jain  A. Neuroimaging in tuberculous
meningitis. Neurol India 2016;64:219‑27.
24. Khatri GD, Krishnan V, Antil N, Saigal G. Magnetic resonance imaging
spectrum of intracranial tubercular lesions: One disease, many faces.
Pol J Radiol 2018;83:e524‑e535.
25. Thwaites  GE, Chau  TT, Farrar  JJ. Improving the bacteriological
diagnosis of tuberculous meningitis. J Clin Microbiol 2004;42:378‑9.
26. Pai  M, Flores  LL, Pai  N, Hubbard  A, Riley  LW, Colford JM Jr.
Diagnostic accuracy of nucleic acid amplification tests for tuberculous
meningitis: A systematic review and meta‑analysis. Lancet Infect Dis
2003;3:633‑43.
27. Pormohammad  A, Nasiri  MJ, McHugh  TD, Riahi  SM, Bahr  NC.
A systematic review and meta‑analysis of the diagnostic accuracy of
nucleic acid amplification tests in cerebrospinal fluid for tuberculous
meningitis. J Clin Microbiol 2019. pii: JCM.01113‑18.
28. Nhu NT, Heemskerk D, Thu do DA, Chau TT, Mai NT, Nghia HD,
et al. Evaluation of GeneXpert MTB/RIF for diagnosis of tuberculous
meningitis. J Clin Microbiol 2014;52:226‑33.
29. Bahr  NC, Tugume  L, Rajasingham  R, Kiggundu  R, Williams  DA,
Morawski  B, et al. Improved diagnostic sensitivity for tuberculous
meningitis with Xpert(®) MTB/RIF of centrifuged CSF. Int J Tuberc
Lung Dis 2015;19:1209‑15.
30. Patel VB, Theron G, Lenders L, Matinyena B, Connolly C, Singh R,
et al. Diagnostic accuracy of quantitative PCR (Xpert MTB/RIF) for
tuberculous meningitis in a high burden setting: A prospective study.
PLoS Med 2013;10:e1001536.
31. World Health Organization. WHO Meeting Report of a Technical
Expert Consultation. World Health Organization. Available from:
http://www.who.int/tb/publications/2017/XpertUltra/en/.  [Last
accessed on 2019 Apr 18].
32. Yu  J, Wang  ZJ, Chen  LH, Li  HH. Diagnostic accuracy of
interferon‑gamma release assays for tuberculous meningitis:
A meta‑analysis. Int J Tuberc Lung Dis 2016;20:494‑9.
33. Tuon  FF, Higashino  HR, Lopes  MI, Litvoc  MN, Atomiya  AN,
Antonangelo  L, et al. Adenosine deaminase and tuberculous
meningitis – A systematic review with meta‑analysis. Scand J Infect
Dis 2010;42:198‑207.
34. Xu  HB, Jiang  RH, Li  L, Sha  W, Xiao  HP. Diagnostic value of
adenosine deaminase in cerebrospinal fluid for tuberculous meningitis:
A meta‑analysis. Int J Tuberc Lung Dis 2010;14:1382‑7.
35. Solomons RS, Goussard P, Visser DH, Marais BJ, Gie RP, Schoeman JF,
et al. Chest radiograph findings in children with tuberculous meningitis.
Int J Tuberc Lung Dis 2015;19:200‑4.
36. Dekker  G, Andronikou  S, van Toorn  R, Scheepers  S, Brandt  A,
Journal of Current Research in Scientific Medicine | Volume 5 | Issue 1 | January-June 2019 21
Ackermann C. MRI findings in children with tuberculous meningitis:
A comparison of HIV‑infected and non‑infected patients. Childs Nerv
Syst 2011;27:1943‑9.
37. Rohlwink  UK, Kilborn  T, Wieselthaler  N, Banderker  E, Zwane  E,
Figaji AA. Imaging features of the brain, cerebral vessels and spine
in pediatric tuberculous meningitis with associated hydrocephalus.
Pediatr Infect Dis J 2016;35:e301‑10.
38. Ruslami R, Ganiem AR, Dian S, Apriani L, Achmad TH, van der Ven AJ,
et al. Intensified regimen containing rifampicin and moxifloxacin for
tuberculous meningitis: An open‑label, randomised controlled phase
2 trial. Lancet Infect Dis 2013;13:27‑35.
39. Boeree  MJ, Diacon  AH, Dawson  R, Narunsky  K, du Bois  J,
Venter A, et al. A dose‑ranging trial to optimize the dose of rifampin
in the treatment of tuberculosis. Am J Respir Crit Care Med
2015;191:1058‑65.
40. Singh AK, Malhotra HS, Garg RK, Jain A, Kumar N, Kohli N, et al.
Paradoxical reaction in tuberculous meningitis: Presentation, predictors
and impact on prognosis. BMC Infect Dis 2016;16:306.
41. Schoeman JF, Andronikou S, Stefan DC, Freeman N, van Toorn R.
Tuberculous meningitis‑related optic neuritis: Recovery of vision with
thalidomide in 4 consecutive cases. J Child Neurol 2010;25:822‑8.
42. Schoeman  JF, Fieggen  G, Seller  N, Mendelson  M, Hartzenberg  B.
Intractable intracranial tuberculous infection responsive to thalidomide:
Report of four cases. J Child Neurol 2006;21:301‑8.
43. Molton  JS, Huggan  PJ, Archuleta  S. Infliximab therapy in two
cases of severe neurotuberculosis paradoxical reaction. Med J Aust
2015;202:156‑7.
44. Lee  JY, Yim  JJ, Yoon  BW. Adjuvant interferon‑γ treatment in two
cases of refractory tuberculosis of the brain. Clin Neurol Neurosurg
2012;114:732‑4.
45. Modi  M, Goyal  MK, Jain  A, Sawhney  SS, Sharma  K, Vyas  S, et al.
Tuberculous meningitis: Challenges in diagnosis and management:
Lessons learnt from Prof. Dastur’s article published in 1970. Neurol
India 2018;66:1550‑71.
46. Tobin DM, Vary JC Jr., Ray JP, Walsh GS, Dunstan SJ, Bang ND, et al.
The lta4h locus modulates susceptibility to mycobacterial infection in
Zebrafish and humans. Cell 2010;140:717‑30.
47. Thuong NTT, Heemskerk D, Tram TT, Thao LT, Ramakrishnan L,
Ha VT, et al. Leukotriene A4 hydrolase genotype and HIV infection
influence intracerebral inflammation and survival from tuberculous
meningitis. J Infect Dis 2017;215:1020‑8.
48. van Laarhoven A, Dian S, Ruesen C, Hayati E, Damen MS, Annisa J,
et al. Clinical parameters, routine inflammatory markers, and LTA4H
genotype as predictors of mortality among 608  patients with
tuberculous meningitis in Indonesia. J Infect Dis 2017;215:1029‑39.
49. Török ME, Yen NT, Chau TT, Mai NT, Phu NH, Mai PP, et al. Timing
of initiation of antiretroviral therapy in human immunodeficiency
virus  (HIV)  –  Associated tuberculous meningitis. Clin Infect Dis
2011;52:1374‑83.
50. Oddo  M, Levine  JM, Frangos  S, Carrera  E, Maloney‑Wilensky  E,
Pascual  JL. Effect of mannitol and hypertonic saline on cerebral
oxygenation in patients with severe traumatic brain injury and
refractory intracranial hypertension. J Neurol Neurosurg Psychiatry
2009;80:916‑20.
51. Francony G, Fauvage B, Falcon D, Canet C, Dilou H, Lavagne P, et al.
Equimolar doses of mannitol and hypertonic saline in the treatment
of increased intracranial pressure. Crit Care Med 2008;36:795‑800.
52. Schoeman  J, Donald  P, van Zyl  L, Keet  M, Wait  J. Tuberculous
hydrocephalus: Comparison of different treatments with regard to
ICP, ventricular size and clinical outcome. Dev Med Child Neurol
1991;33:396‑405.
53. Visudhiphan  P, Chiemchanya  S. Hydrocephalus in tuberculous
meningitis in children: Treatment with acetazolamide and repeated
lumbar puncture. J Pediatr 1979;95:657‑60.
54. Figaji AA, Fieggen AG, Peter JC. Endoscopic third ventriculostomy
in tuberculous meningitis. Childs Nerv Syst 2003;19:217‑25.
[Downloaded free from http://www.jcrsmed.org on Wednesday, August 11, 2021, IP: 27.61.234.121]

Vinny and Vishnu: Tuberculous meningitis

55. Rizvi I, Garg RK, Malhotra HS, Kumar N, Sharma E, Srivastava C,
et al. Ventriculo‑peritoneal shunt surgery for tuberculous meningitis:
A systematic review. J Neurol Sci 2017;375:255‑63.
56. Goyal P, Srivastava C, Ojha BK, Singh SK, Chandra A, Garg RK, et al.
A randomized study of ventriculoperitoneal shunt versus endoscopic
third ventriculostomy for the management of tubercular meningitis
with hydrocephalus. Childs Nerv Syst 2014;30:851‑7.
57. Yadav YR, Parihar VS, Todorov M, Kher Y, Chaurasia ID, Pande S, et al.
Role of endoscopic third ventriculostomy in tuberculous meningitis
with hydrocephalus. Asian J Neurosurg 2016;11:325‑9.
58. Rajshekhar  V. Surgery for brain tuberculosis: A  review. Acta
Neurochir (Wien) 2015;157:1665‑78.
59. Kumar A, Singh K, Sharma V. Surgery in hydrocephalus of tubercular
origin: Challenges and management. Acta Neurochir  (Wien)
2013;155:869‑73.
60. Misra UK, Kalita J, Kumar M. Safety and efficacy of fludrocortisone
in the treatment of cerebral salt wasting in patients with tuberculous
meningitis: A randomized clinical trial. JAMA Neurol 2018;75:1383‑91.
61. Thwaites GE, Macmullen‑Price J, Tran TH, Pham PM, Nguyen TD,
Simmons CP, et al. Serial MRI to determine the effect of dexamethasone
on the cerebral pathology of tuberculous meningitis: An observational
study. Lancet Neurol 2007;6:230‑6.
62. Misra UK, Kalita J, Nair PP. Role of aspirin in tuberculous meningitis:
A  randomized open label placebo controlled trial. J  Neurol Sci
2010;293:12‑7.
63. Schoeman JF, Janse van Rensburg A, Laubscher JA, Springer P. The
role of aspirin in childhood tuberculous meningitis. J Child Neurol
2011;26:956‑62.
64. Falzon  D, Schünemann HJ, Harausz  E, González‑Angulo  L,
Lienhardt C, Jaramillo E, et al. World health organization treatment
guidelines for drug‑resistant tuberculosis, 2016 update. Eur Respir J
2017;49. pii: 1602308.

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