British Medical Bulletin Advance Access published February 18, 2015

British Medical Bulletin, 2015, 115

doi: 10.1093/bmb/ldv003

Tuberculous meningitis: advances in diagnosis

and treatment

Downloaded from http://bmb.oxfordjournals.org/ at Mahidol University / Library & Information Center on February 23, 2015
M. E. Trk,,,*

Department of Medicine, University of Cambridge, Addenbrookes Hospital, Box 157, Hills Road, Cambridge
CB2 0QQ, UK, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK,
and Public Health England, Clinical Microbiology and Public Health Laboratory, Addenbrookes Hospital,
Hills Road, Cambridge CB2 0QQ, UK
*Correspondence address. E-mail: et317@medschl.cam.ac.uk; estee.torok@addenbrookes.nhs.uk
Accepted 8 January 2015

Abstract
Introduction: Tuberculous meningitis (TBM) is the most severe form of
infection caused by Mycobacterium tuberculosis, causing death or disability
in more than half of those affected. The aim of this review is to examine
recent advances in our understanding of TBM, focussing on the diagnosis
and treatment of this devastating condition.
Sources of data: Papers on TBM published between 1891 and 2014 and
indexed in the NCBI Pubmed. The following search terms were used: TBM,
diagnosis, treatment and outcome.
Areas of agreement: The diagnosis of TBM remains difcult as its presenta-
tion is non-specic and may mimic other causes of chronic meningoenceph-
alitis. Rapid recognition of TBM is crucial, however, as delays in initiating
treatment are associated with poor outcome. The laboratory diagnosis of
TBM is hampered by the low sensitivity of cerebrospinal uid microscopy
and the slow growth of M. tuberculosis in conventional culture systems. The
current therapy of TBM is based on the treatment of pulmonary tuberculosis,
which may not be ideal. The combination of TBM and HIV infection poses
additional management challenges because of the need to treat both infec-
tions and the complications associated with them.
Areas of controversy: The pathogenesis of TBM remains incompletely
understood limiting the development of interventions to improve outcome.
The optimal therapy of TBM has not been established in clinical trials, and
increasing antimicrobial resistance threatens successful treatment of this
condition. The use of adjunctive anti-inammatory agents remains contro-
versial, and their mechanism of action remains incompletely understood.

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2 M. E. Trk, 2015, Vol. 0, No. 0

The role of surgical intervention is uncertain and may not be available in

areas where TBM is common.
Growing points: Laboratory methods to improve the rapid diagnosis of TBM
are urgently required. Clinical trials of examining the use of high-dose rifam-
picin and/or uoroquinolones are likely to report in the near future.
Areas timely for developing research: The use of biomarkers to improve the
rapid diagnosis of TBM warrants further investigation. The role of novel anti-

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tuberculosis drugs, such as bedaquiline and PA-824, in the treatment of TBM
remains to be explored. Human genetic polymorphisms may explain the het-
erogeneity of response to anti-inammatory therapies and could potentially
be used to tailor therapy.
Key words: tuberculosis, meningitis, tuberculous meningitis, diagnosis, treatment

Introduction mycolonus.14 Some children may present with tuber-

Tuberculous meningitis (TBM) is the most frequent culous encephalopathy with disseminated tubercu-
form of central nervous system (CNS) tuberculosis.1 losis but without clinical or CSF evidence of
CNS disease accounts for only 5% of all cases of meningitis.12,13 TBM with spinal involvement, which
extra-pulmonary tuberculosis and peak incidence is presents as paraplegia, occurs in <10% of cases.10
in children under 4 years of age.2 However, the Vertebral tuberculosis (Potts disease) accounts for
number of adults presenting with TBM has increased about a quarter of patients with spinal TBM and may
as a result of the HIV epidemic. The presenting clin- be associated with paravertebral abscess or a gibbus.
ical features and CSF features of TBM have been Extra-dural cord tuberculomas account for over 60%
extensively described39 and are summarized in of cases of non-osseous paraplegia, although tubercu-
Table 1. The classic presentation is with a subacute lomas may occur in any part of the cord.15 Tubercu-
meningitic illness, which can be difcult to distinguish lous radiculomyelitis rarely occurs in TBM and is
from other causes of meningoencephalitis. Once the characterized by subacute paraparesis, radicular pain
neurological symptoms of advanced disease are and bladder dysfunction.16
present (e.g. coma, seizures, raised intracranial pres- TBM can also cause metabolic complications, the
sure and hemiparesis), the diagnosis is apparent but commonest of which, hyponatraemia, affects >50%
the prognosis is poor. TBM is classied into three of patients with the disease.3 A cerebral salt-wasting
grades of severity according to the British Medical syndrome associated with TBM and attributed to a
Research Council TBM grade.10 Grade 1 TBM is renal tubular defect.17 The discovery of a syndrome
dened as a Glasgow coma score (GCS) of 15 with of inappropriate antidiuretic hormone as a cause of
no focal neurology, Grade 2 TBM as a GCS of 15 hyponatraemia led to speculation of a similar mech-
with a focal neurological decit, or a GCS of 1114 anism causing TBM-associated hyponatraemia.18
and Grade 3 TBM is dened as a GCS of 10. The However, many patients with TBM-associated hypo-
importance of this classication system is that it natraemia have low plasma volumes and persistent
enables stratication of patients and is useful to natriuresis despite normal concentrations of anti-
predict prognosis. diuretic hormone (ADH).19 Although a role for
Unusual neurological presentations of TBM may ADH has not been excluded, hyponatraemic natri-
result in diagnostic difculty.1113 Movement disor- uretic syndrome is probably a better term for this
ders may occur after infarction of the basal ganglia condition. Despite these investigations, the best
and present with tremor, chorea, ballismus or method of correcting the plasma sodium
Tuberculous meningitis, 2015, Vol. 0, No. 0 3

Table 1 Clinical features of tuberculous meningitis in children and adults

Symptoms Clinical ndings CSF ndings

Children Early symptoms are non-specic Apathy, irritability, meningitis, Usually clear and colourless, raised
and include fever, cough, reduced level of consciousness, white cell count (0.51 109/l)
vomiting, malaise and weight bulging anterior fontanelle with neutrophils and
loss. (infants), VI cranial nerve palsy, lymphocytes
Duration of symptoms >6 days optic atrophy, abnormal Raised protein (0.52.5 g/l)

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Seizures more common in movements and focal neurological CSF to plasma glucose ratio
children than in adults signs, e.g. hemiplegia <0.5 in 95% of cases
Adults Prodromal period with low-grade Neck stiffness, confusion, coma High opening pressure >25 cm
fever, malaise, weight loss Cranial nerve palsiesVI, III, IV H20 in 50% of cases, usually
followed by gradual onset of Focal neurological signs, e.g. clear and colourless
headache (12 weeks). monoplegia, hemiplegia, Raised white cell count
Worsening headache, vomiting, paraplegia (0.051 109/l) with
confusion, coma. Urinary retention neutrophils and lymphocytes
Duration of symptoms 6 days Raised protein (0.52.5 g/l)
CSF to plasma glucose ratio <0.5 in
95% of cases

concentration remains unknown; sodium and uid by release of M. tuberculosis bacilli into the menin-
replacement is probably indicated in hypovolaemic geal space from focal sub-pial or sub-ependymal
hyponatraemia,20 whereas uid restriction may be lesions, which were most commonly located in the
more appropriate in those who are euvolaemic.21 Sylvian ssure.26
There is anecdotal evidence to suggest that udrocor- Three pathological processes account for the com-
tisone replacement therapy22 and demeclocycline23 monly observed neurological decits: the exudate
may also be useful. may obstruct CSF ow resulting in hydrocephalus;
granulomas can coalesce to form tuberculomas or
abscesses resulting in focal neurological signs and an
Pathogenesis of TBM obliterative vasculitis can cause infarction and stroke
The rst description of TBM dates back to 1836 syndromes.27 More recently, a study examining the
when six cases of acute hydrocephalus in children radiological features of TBM showed that the most
characterized by an inammation of the meninges, common abnormalities seen on cerebral magnetic
with the deposit of tubercular matter in the form of resonance imaging (MRI) were basal meningeal
granulations, or cheesy matter were described in the enhancement and hydrocephalus.28 Tuberculomas
Lancet.24 The author concluded that the children developed in 74% of patients during the course of TB
had died of tubercular meningitis, a disease similar treatment and the basal ganglia were the most
in nature to other previously described conditions common site of infarction.
characterized by tubercles, such as tubercular peri- The numbers and types of white cells in the CSF
tonitis. The microbiological cause of tuberculosis may help to differentiate TM from other meningitides,
was not identied until 1882 when Robert Koch but little is known of their role in disease pathogenesis.
stained and cultured the bacterium that caused Typically, the CSF shows a high CSF white cell count,
tuberculosis25 and subsequently became known as which is predominantly lymphocytic, with a high
Mycobacterium tuberculosis. Fifty years later, two protein and low CSF to blood glucose ratio.9 However,
pathologists Rich and McCordock demonstrated, total CSF white cell count can be normal in those with
using a series of experiments in rabbits and post- TBM and depressed cell-mediated immunity, such as
mortem ndings in children, that TBM was caused the elderly and HIV-infected individuals.29,30 A low
4 M. E. Trk, 2015, Vol. 0, No. 0

CSF cell count has also been associated with poor

neuropathy (with high doses),

outcome.9 Neutrophils can predominate, especially

blindness, peripheral neuritis

Orange discolouration of bodily

Optic neuritis, red/green colour

gastrointestinal symptoms,

gastrointestinal symptoms
early in the disease,31 and a high proportion of neu-

Hepatotoxicity, peripheral
headache, drowsiness
trophils in the CSF has been associated with an

uids, hepatoxocity,

optic neuropathy,
Common side effects

increased likelihood of a bacteriological diagnosis

and improved survival.32,33 Thus, neutrophils may

Hepatoxicity
play a role in the pathogenesis of TBM. The kinetics
of the lymphocyte response are probably also

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important, particularly the roles of different lympho-
cyte subsets.34
Although TBM is associated with inammation in
the CNS, there is conicting evidence on the role of
12 months

12 months

tumour necrosis factor (TNF)- in the pathogenesis of

2 months

2 months
Duration

TBM. The release of M. tuberculosis into the sub-

arachnoid space results in a local T lymphocyte-
dependent response, characterized by caseating granu-
lomatous inammation.27 In pulmonary tuberculosis,
TNF- is thought to be important in granuloma for-
mation.35 Studies of acute bacterial meningitis showed
600 mg (weight <50 kg)

that CSF concentrations of TNF- correlated with

450 mg (weight <50 kg)

2 g (weight <50 kg)

disease severity,36 and study in a rabbit model of

1.5 g (weight <50 kg)

TBM found that high CSF concentrations were asso-

ciated with a worse outcome.37 In humans, however,
Dose in adults

TNF- concentrations were not correlated with

15 mg/kg
300 mg

disease severity or outcome.32 Treatment with antibio-

tics and thalidomide (a TNF- antagonist) improved
survival and neurological outcome in rabbits.38 Pre-
liminary research in humans found that thalidomide
was safe and well tolerated,39 but a clinical trial of
1020 mg/kg/day (maximum 600 mg/day)

1020 mg/kg/day (maximum 500 mg/day)

adjunctive thalidomide in children with TBM was

1530 mg/kg/day (maximum 2 g/day)

1520 mg/kg/day (maximum 1 g/day)

Table 2 Laboratory diagnosis of tuberculous meningitis

stopped early because of lack of benet and an excess

number of adverse events in the thalidomide arm.40
The role of other inammatory mediators in the
pathogenesis of TBM has also been explored.
Thwaites and colleagues32 measured concentrations
of pro- and anti-inammatory cytokines in serial
Dose in children

blood and CSF samples from 21 Vietnamese adults

with TBM. CSF concentrations of soluble TNF-
receptors, matrix metalloprotein-9 (MMP-9) and its
tissue inhibitor were measured, and bloodbrain
barrier permeability was assessed. Pre-treatment CSF
concentrations of lactate, IL-8 and IFN- were high
and then decreased rapidly during treatment, but
Pyrazinamide

Ethambutol
Rifampicin

signicant immune activation and bloodbrain

Isoniazid

barrier dysfunction were still apparent after 2-month

Drug

treatment. Death was associated with high CSF

Tuberculous meningitis, 2015, Vol. 0, No. 0 5

concentrations of lactate, low numbers of white A number of studies have sought to investigate the
blood cells, in particular neutrophils, and low CSF potential role of host genetic factors in the immuno-
glucose levels. A second study examined the relation- pathogenesis of TBM. Hawn and colleagues hypo-
ship between pre-treatment intracerebral and periph- thesized that polymorphisms in toll-interleukin 1
eral immune responses and outcome in Vietnamese receptor domain containing adaptor protein (TIRAP),
adults.41 Baseline CSF IL-6 concentrations were an adaptor protein that mediates signals from toll-like
independently associated with severe disease at receptors activated by mycobacteria, were associated
presentation. Surprisingly, however, elevated CSF with susceptibility to tuberculosis.45 They found that

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inammatory cytokines were not associated with the TIRAP single-nucleotide polymorphism (SNP)
death or disability in HIV-negative TBM patients. C558T was associated with increased susceptibility
HIV infection attenuated multiple cerebrospinal uid to TB. Subgroup analysis revealed that SNP 558T
inammatory indices. Low CSF IFN- concentrations was more strongly associated with susceptibility to
were independently associated with death in HIV- meningeal TB than to pulmonary TB. The 558TT
positive but not in HIV-negative individuals. A third genotype was associated with decreased whole-
study examined CSF inammatory markers in blood interleukin-6 production (compared with the
patients enrolled in a study of adjunctive corticoster- 558CC genotype), suggesting that TIRAP inuences
oids in TBM.42 Prolonged inammatory responses disease susceptibility by modulating the inamma-
were detected in all TBM patients irrespective of tory response. A second study examined the inu-
treatment assignment (placebo or dexamethasone). ence of polymorphisms in toll-like receptor 2 (TLR2)
Dexamethasone signicantly modulated acute cere- on bacterial dissemination and the development of
brospinal uid protein concentrations and marginally TBM.46 The TLR2 genotype 597CC was associated
reduced IFN- concentrations but did not affect with increased susceptibility to TB and was more
immunological and routine biochemical indices of strongly associated with meningeal than pulmonary
inammation or peripheral blood monocyte and TB. This association was strongest in patients with
T-cell responses to M. tuberculosis antigens. TBM and miliary TB. Furthermore, the association
increased with increasing disease severity, indicated
by TBM grade. These results demonstrate a strong
Host and pathogen genetics in TBM association of TLR2 SNP T597C with the develop-
The ndings reported above challenged previous ment of TBM and miliary TB and suggest that TLR2
assumptions about anti-inammatory effects of corti- inuences the dissemination of M. tuberculosis.
costeroids in this disease. A potential explanation for A third study compared host and bacterial geno-
this came from studies of mycobacterial infections in a type in Vietnamese adults with TBM and pulmonary
zebrash model.43 A polymorphism in the leukotriene tuberculosis.47 The host genotype of tuberculosis
A4 hydrolase (LTA4H) gene, which controls the cases was also compared with the genotype of cord
balance of pro-inammatory and anti-inammatory blood controls from the same population. Isolates of
eicosanoids, was found to inuence susceptibility of M. tuberculosis were genotyped by large sequence
zebrash to Mycobacterium marinum infection and polymorphisms. The hosts were dened by poly-
humans to tuberculosis.44 Furthermore, in humans morphisms in genes encoding TIRAP and TLR-2.
with TBM, the polymorphism was associated with The study found a signicant protective association
inammatory cell recruitment, patient survival and between the Euro-American lineage of M. tubercu-
response to adjunctive corticosteroids. These ndings losis and pulmonary (rather than meningeal tubercu-
provide a possible explanation for the failure to nd a losis), suggesting these strains were less capable of
mechanism by which corticosteroids improved sur- extra-pulmonary dissemination than others in the
vival in TBM and suggest the possibility of using study population. It also found that individuals with
host-directed therapies tailored to patient LTA4H TLR-2 T597C allele were more likely to have tuber-
genotypes. culosis caused by the East-Asian/Beijing genotype
6 M. E. Trk, 2015, Vol. 0, No. 0

than other individuals, thus providing evidence that 6 days), although drug susceptibility testing was not
M. tuberculosis genotype inuenced disease pheno- performed in this study.58
type and that there was a signicant interaction Nucleic acid amplication tests (NAAT) can
between host and bacterial genotypes and the devel- detect fewer than 10 organisms that can be used to
opment of tuberculosis. identify M. tuberculosis in clinical specimens or cul-
tures. The polymerase chain reaction (PCR) is the
most common methodology, but alternatives include
Laboratory diagnosis of TBM real-time PCR, isothermal, strain displacement or

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The laboratory diagnosis of TBM is summarised in transcription-mediated amplication and ligase
Table 2. Despite being developed over 100 years ago, chain reaction.59 The literature on NAATs has been
the acid-fast smear remains the most commonly used extensively reviewed, and has shown that the speci-
method to diagnose TB. A xed smear of a clinical city of NAATs is high but sensitivity is variable.59,60
specimen (e.g. sputum) is covered with carbol fuschin, Sensitivity is highest in smear-positive respiratory
heated and decolourized with acid-alcohol before samples and lower in smear-negative samples and in
being counterstained with methylene blue. Myco- non-respiratory disease. Thus, a negative result does
bacteria appear as red, slightly bent, beaded rods, not rule out the diagnosis of TB in these situations.
24 m in length and 0.20.5 m wide. An estimated Recently, line-probe assays (LPAs) and the Xpert
10 000 organisms are required for a smear positivity MTB/RIF (Cepheid, Sunnyvale, USA) have been for-
resulting in poor sensitivity of this test, particularly in mally endorsed by the World Health Organisation
paucibacillary disease. Fluorescent microscopy is and are now in routine use in middle- and high-
more sensitive and has a higher throughput than light income countries. The two LPAsINNO-LiPA Rif.
microscopy, but the equipment and bulbs are more TB (Innogenetics, Gent, Belgium) and Genotype
expensive.48 The development of light-emitting diode MTBDRplus (Hain LifescienceGbmH, Nehren
(LED) uorescent microscopy has overcome some Germany)are currently available for the detection
of these issues49,50 and is now recommended by the of M. tuberculosis in clinical specimens and culture
World Health Organisation.51 In TBM, early studies isolates. They are based on PCR of specic fragments
reported extremely high sensitivity rates for smear of the M. tuberculosis genome followed by hybrid-
microscopy,52,53 but these have proved difcult to ization of PCR products to oligonucleotide probes
reproduce in routine laboratories.54 Thwaites and col- immobilized on membranes. A single study from
leagues33 identied a number of factors associated China has evaluated the use of the Genotype
with improved diagnostic rates such as culture of a MTBDRplus assay in the diagnosis of TBM and
large volume (>5 ml) of CSF and examination of the found it to be useful in the rapid diagnosis of
slide for 30 min. A recent study from China reported drug-resistant tuberculosis.61
increased sensitivity with pre-treatment of CSF leuco- The Xpert MTB/RIF is a fully automated RT
cytes with triton prior to ZN staining.55 PCR based assay for the detection of M. tuberculosis
The microscopic observation drug-susceptibility and rifampicin resistance in clinical specimens. In
assay (MODS) is a liquid culture assay that uses sputum smear-positive samples, studies have
Middlebrook 7H9 broth culture and an inverted reported sensitivities ranging from 93 to 98% and
microscope to detect mycobacterial growth.56 This specicities if 8399%.62 The introduction of Xpert
technique has been evaluated in a number of studies MTB/RIF assays has increased the conrmation rate
and has been found to be useful for the diagnosis of in patients with suspected TB in high-burden coun-
tuberculosis and the detection of drug resistance, in a tries such as India, Uganda and South Africa.63 One
number of settings.57 It has also been evaluated for of the key concerns about rolling out this technology
the diagnosis of TBM and was found to be more sen- in areas with a low prevalence of rifampicin resist-
sitive than CSF smear, and more rapid than conven- ance, however, is the low positive predictive value of
tional TB culture (with a median time to positivity of the test, which means that most resistant results will
Tuberculous meningitis, 2015, Vol. 0, No. 0 7

be false positives. Several studies have evaluated the biomarkers to diagnose TBM. Cerebrospinal uid
use of Xpert MTB/RIF for the diagnosis of TBM.64 lactate levels have been used as a diagnostic marker
A South African study of 204 patients (87% HIV for central nervous system infections. Lactate is pro-
infected) found that the sensitivity of Xpert MTB/ duced by bacterial anaerobic metabolism, and
RIF was higher than that of smear microscopy (62 increased CSF levels have been reported in patients
versus 12%; P = 0.001), and for centrifuged com- with bacterial meningitis7781 and TBM.32 Clinical
pared with non-centrifuged specimens.64 A Vietnam- experience in Vietnam suggests that CSF lactate
ese study of 182 patients found that the sensitivity of levels of 510 mmol/l support a diagnosis of TBM,

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Xpert MTB/RIF was slightly higher than smear and that high initial levels are associated with
microscopy (59.3 versus 51.8%).65 There was one death.32 However, this marker has not been formally
false-positive result (giving a specicity of 99.5%) validated as a diagnostic test for TBM.
and four cases of rifampicin resistance, three of The adenosine deaminase (ADA) activity test is a
which were conrmed to be multidrug resistant by rapid test that has been used for the diagnosis of the
phenotypic tests. A third study compared the Xpert pleural, peritoneal and pericardial forms of tubercu-
MTB/RIF assay with the Roche Amplicor assay and losis. A systematic review of 522 studies of ADA
found similar rates of sensitivity and specicity.66 values in TBM cases and controls (diagnosed with
Interferon- release assays (IGRAs) for the diag- other types of meningitis) has been reported.82 Out
nosis of active and latent TB have been extensively of a total of 522 studies, 13 studies (380 patients
reviewed.67,68 While IGRAs have been shown to be with TBM) were included in the meta-analysis. The
of limited value in the diagnosis of pulmonary TB,69 sensitivity, specicity and diagnostic odds ratios
their application to site-specic lymphocytes may be (DOR) were calculated based on arbitrary ADA
of diagnostic benet.70 Several recent studies have cut-off values from 1 to 10 U/l. ADA values from 1
examined the utility of CSF IGRAs and found vari- to 4 U/l (sensitivity >93% and specicity <80%)
able sensitivity, a high rate of indeterminate results helped to exclude TBM; values between 4 and 8 U/l
and a requirement for large volumes of CSF.7174 were insufcient to conrm or exclude the diagnosis
Over the past 30 years, a number of studies have of TBM (P = 0.07), and values >8 U/l (sensitivity
investigated the detection of antibodies to M. tubercu- <59% and specicity >96%) improved the diagnosis
losis or its antigens within the CSF. While many of of TBM (P < 0.001). None of the cut-off values
these looked promising in preliminary studies, they could be used to discriminate between TBM and bac-
have failed to be translated into routine clinical care. terial meningitis. In conclusion, ADA cannot distin-
Two recent studies have reported interesting results. guish between bacterial meningitis and TBM, but
The rst study used a real-time quantitative PCR and using ranges of ADA values could be important to
ELISA to detect a panel of M. tuberculosis antigens improve TBM diagnosis, particularly after bacterial
(GlcB, HSpX, MPT51, Ag85B and PstS1) in 532 meningitis has been ruled out. However, the different
Indian children with TBM.75 In patients with denite methods used to measure ADA and the heterogeneity
TB, sensitivity and specicity were 100 and 9697%, of data limit the diagnostic use of this test.
respectively, and in those with probable/possible TB, A recent study evaluated the performance of
the sensitivity and specicity were 98%. The combin- number of diagnostic tests in 506 patients in with
ation of PCR with GlcB and HspX ELISAs accurately microbiologically conrmed TBM in Albania,
detected all patients with TBM with 90% specicity. Croatia, Denmark, Egypt, France, Hungary, Iraq,
A second study used a polyvalent rabbit IgG to M. Italy, Macedonia, Romania, Serbia, Slovenia, Syria
tuberculosis to stain antigen-specic CSF leucocytes.76 and Turkey between 2000 and 2012.83 The study
A diagnostic evaluation of 393 CSF samples revealed included the following tests: Ziehl Neelsen stain
a sensitivity of 73.5 and a specicity of 90.7%. (ZN), CSF M. tuberculosis polymerase chain reac-
Given the low sensitivity of standard diagnostic tion assay (CSF PCR), CSF automated culture system
methods, attempts have been made to investigate (CSF ACS) and Lowenstein Jensen (LJ) culture,
8 M. E. Trk, 2015, Vol. 0, No. 0

IGRA and ADA activity. The sensitivities of the tests and ethambutol) followed by a 10-month continuation
were as follows: IGRA 90.2%, ACS 81.8%, LJ phase of two drugs (rifampicin and isoniazid) (Table 3).
culture 72.7%, ADA 29.9% and ZN 27.3%. CSF In some settings such as South Africa93 and Vietnam,10
ACS was superior to CSF LJ culture and CSF PCR shorter continuation phases of 4 to 7 months are
(P < 0.05 for both), and CSF LJ culture was also recommended. The treatment of drug-resistant TBM
superior to CSF PCR (P < 0.05). The combination has likewise not been systematically investigated in clin-
CSF LJ and CSF ACS was superior to using these ical trials, and detailed recommendations are beyond
tests alone (P < 0.05). However, because of the the scope of this review. A prospective study of 180

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delays incurred by culture-based methods, the com- Vietnamese adults with TBM found resistance to at
bined use of non-culture tests could contribute to least one drug in 40% of patients and resistance to
early diagnosis. The authors concluded that diagnos- rifampicin and isoniazid (multidrug resistance) in 5.6%
tic approach to TBM should be individualized of patients.94 Resistance to isoniazid and/or streptomy-
according to the technical capacities of medical insti- cin was associated with slower clearance of bacteria
tutions, particularly in those with poor resources. from the CSF, but there were no differences in outcome.
A study by Kataria and colleagues performed prote- Multidrug resistance was independently associated with
omic analysis and two-dimensional electrophoresis on HIV infection and was strongly predictive of death
the CSF of patients with and without TBM.84 They (relative risk 11.63, 95% condence interval 5.21
identied 11 human proteins and 8 mycobacterial pro- 26.32). A larger retrospective study conducted in the
teins as possible diagnostic markers. One human USA between 1993 and 2005 included 1896 patients
protein, arachidonate 5-lipoxygenase (ALOX-5), with a clinical diagnosis of TBM and positive cultures
was validated in a second experiment and differen- from any site.95 Six per cent of patients had isoniazid-
tiated TBM from fungal meningitis. ALOX-5 is an resistant cultures on initial susceptibility testing. Among
enzyme in the metabolic pathway of leukotriene B4 1614 patients with positive cerebrospinal uid cultures,
and lipoxin and has been shown to have a role in the a signicant unadjusted association was found between
pathogenesis of TBM in mice.85,86 Genetic studies in initial isoniazid resistance and subsequent death (odds
humans have also shown higher susceptibility to pul- ratio 1.61, 1.082.40). This association increased after
monary tuberculosis in ALOX+ variants.87 adjustment for age, race, sex, and HIV status (odds
ratio 2.07, 1.303.29).
Two recent studies have investigated the role of
Treatment of TBM intensied therapy for TBM. The rst was randomized
The modern era of tuberculosis treatment began in controlled trial with three parallel arms that compared
1948 with the demonstration of the efcacy of strep- the effect of adding a uoroquinolone (ciprooxacin,
tomycin in the treatment of pulmonary tuberculosis.88 levooxacin or gatioxacin) with standard therapy in
This was followed by the introduction of isoniazid in 61 Vietnamese adults with TBM.96 The CSF penetra-
195289 and rifampicin in 1971,90 which revolutio- tion was greater for levooxacin than gatioxacin or
nized the treatment of TB. Over the next few years, a ciprooxacin. Surprisingly, worse outcomes were
number of clinical trials, using combinations of anti- recorded in patients with lower and higher uoro-
tuberculosis drugs, were conducted by the British quinolone exposures, than those with intermediate
Medical Research Council. Combination therapy exposures. Those with high exposures were older and
enabled the duration of treatment to be reduced from tended to have more severe disease, which may have
2 years, prior to rifampicin, to 6 months with rifampi- resulted in greater bloodbrain barrier breakdown.
cin, isoniazid and pyrazinamide.91 A second study conducted in Indonesia investigated
In contrast to pulmonary TB, the optimal therapy of the use of high (600 mg) or standard (450 mg) dose
TBM has not been determined in clinical trials. Current rifampicin and high (800 mg) or standard (400 mg)
guidelines92 recommend a 2-month initiation phase dose moxioxacin in 60 Indonesian adults with
with four drugs (rifampicin, isoniazid, pyrazinamide TBM.97 High-dose rifampicin resulted in an increase
Tuberculous meningitis, 2015, Vol. 0, No. 0 9

Table 3 Treatment of tuberculous meningitis

Diagnostic Principles of test Advantages Disadvantages

test

CSF smear CSF sample (10 ml) centrifuged and Universally available, quick, Low sensitivity in routine
deposit stained with Ziehl inexpensive diagnostic laboratories
Neelsen stain or uorescent stain Large CSF volumes, serial
and visualized under a light or samples, triton pre-treatment,

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uorescence microscopy uorescence microscopy
improves sensitivity
CSF culture CSF inoculated into liquid culture Faster and more sensitive than Only available at reference
media (e.g. Mycobacterial solid culturemedian time to laboratory level rather than
Growth Indicator Tube, Becton detection 1014 days; ability district/peripheral level.
Dickinson) and incubated for 42 to perform rst-line drug Requires containment Level
days. Growth detected by susceptibility testing 3 facilities and laboratory
uorescence resulting from expertise
consumption of oxygen by
mycobacteria.
MODS CSF deposit inoculated into a More sensitive than CSF smear Requires a containment Level 3
culture microtitre plate and incubated. and faster than commercial laboratory and laboratory
Growth examined using an liquid/solid culture; ability to expertise
inverted microscope. perform rst-line drug
susceptibility testing
Line probe DNA strip test than can detect Ability to detect M. tuberculosis Expensive. Requires a
assays Mycobacterium tuberculosis and and drug resistance in sputum containment Level 3
most common genetic mutations specimens or cultured isolates laboratory and laboratory
conferring resistance to certain published on TBM expertise including PCR.
antituberculosis drugs. Only one study
GeneXpert Automated cartridge-based system Ability to detect M. tuberculosis Disadvantages: Expensive. High
RIF/TB for sputum processing, DNA and drug resistance in sputum false positivity rate in areas
extraction and amplication, and other clinical specimens. with low prevalence of
detection of M. tuberculosis and Can be used in a district-level rifampicin resistance
rifampicin resistance. laboratory
Interferon- Whole-blood tests that detect Used for diagnosis of latent TB; Not recommended for diagnosis
release immune responses to a panel of results available within 24 h; of active TB disease.
assays M. tuberculosis antigens. not affected by BCG Requires large volumes of
vaccination CSF for diagnosis of TBM
and sensitivity variable
Antigen Detection of lipoarabinomannan Rapid, point-of-care test that can No data in TBM patients. Two
detection (LAM) antigen in urine. be conducted at community recent studies looking at
level. Currently being validated other M. tuberculosis
for diagnosis of pulmonary TB antigens in CSF (see text for
details)
Biomarkers Proteomic analysis of CSF samples. Potential novel diagnostic test Currently experimentala
single study has identied
ALOX-5 as a potential
biomarker (see text for
details)
10 M. E. Trk, 2015, Vol. 0, No. 0

in plasma and CSF levels and was associated with interferon- concentrations at baseline were pre-
reduced mortality (65 versus 35%). A large rando- dictive of the development of TBM-IRIS.
mized controlled trial of high-dose rifampicin and
levooxacin versus standard therapy is underway in
Vietnam and expected to report soon.98 Adjunctive anti-inammatory therapies
Over the past 60 years, a number of studies have inves-
tigated the use of adjunctive corticosteroids in the
HIV-associated TBM treatment of TBM.10,107112 The largest trial in 545

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HIV-associated TBM often presents in patients with Vietnamese adults showed a reduction in mortality
advanced HIV infection and is associated with a but not in neurological disability in patients treated
high mortality.99 The treatment of this condition is with dexamethasone, compared with placebo.10
complicated by the need to treat both conditions sim- A parallel immunological study showed that pro-
ultaneously, with the attendant drug interactions longed inammatory responses were detected in all
and toxicities, and the risk of immune reconstitution TBM patients, regardless of their treatment alloca-
inammatory syndrome (IRIS), a potentially fatal tion.42 The CSF response was characterized by a leuco-
condition.100 A number of studies have examined cytosis (predominantly CD3+ CD4+ T cells that were
the optimal timing of initiation of antiretroviral phenotypically distinct from those in the peripheral
therapy (ART) in HIV-associated tuberculosis.101104 blood), elevated concentrations of inammatory and
Most of these were conducted in patients with pul- anti-inammatory cytokines and chemokines, and evi-
monary tuberculosis and found that early initiation of dence of prolonged bloodbrain barrier dysfunction.
ART was benecial, particularly in those with low Although dexamethasone signicantly reduced CSF
CD4 counts, but it was associated with an increased protein concentrations and marginally reduced IFN-
risk of IRIS. In contrast, a study of immediate versus concentrations, all other immunological and routine
deferred in 253 Vietnamese adults with HIV- biochemical indices of inammation in the CSF were
associated TBM found that early ART did not reduce unaffected. The peripheral blood monocyte and T cell
mortality or time to new AIDS events or death.105 responses to M. tuberculosis antigens were also
Furthermore, there was an increased frequency of unaffected. Thus, dexamethasone did not appear to
severe adverse events in the immediate ART arm, sug- improve survival from TBM by attenuating immuno-
gesting that it may be better to defer initiation of ART logical mediators of inammation in the CSF, nor by
for 2 months in this setting. Of note, all patients suppressing peripheral T cell responses to mycobacter-
received adjunctive corticosteroids during the rst 68 ial antigens, challenging previously held views of the
weeks of the study, which may have prevented the pathogenesis of TBM. A study that looked at the long-
development of IRIS. term outcome recruited to the Vietnamese study found
The risk of TBM-associated IRIS remains a that adjunctive dexamethasone appeared to improve
major clinical concern. The clinical predictors of its the survival in patients with TBM, until at least 2 years
development were studied in a cohort of patients of follow-up, but failed to demonstrate a 5-year sur-
with HIV-associated TBM who started ART 2 vival benet.113
weeks after commencing TB treatment.106 16/34 Two recent studies have examined the possible
patients developed TBM-IRIS, a median of 14 days benets of aspirin in TBM treatment. The rst study
after commencing ART; the most common presen- was a randomized controlled trial of aspirin versus
tations were worsening headache and fever. Factors placebo in 118 Indian adults.114 Aspirin was asso-
associated with the development of TBM-IRIS ciated with a non-signicant reduction in stroke at 3
included longer duration of illness, the presence of months, and a signicant reduction in mortality
extra-neural TB, higher CSF neutrophil counts and (21.7 versus 43.4%, P = 0.02). The effects of aspirin
a positive CSF culture for M. tuberculosis. The are difcult to interpret, however, as prednisolone
combination of high CSF TNF- and low was also given to some patients such as those with
Tuberculous meningitis, 2015, Vol. 0, No. 0 11

severe disease at baseline, or those whose clinical devastating condition with a dismal prognosis, and
condition worsened during treatment. The second strategies to improve outcome are urgently required.
study was a randomized controlled trial with three The benet of adjunctive corticosteroids in HIV-
parallel arms (low- and high-dose aspirin and infected patients has not been established and is
placebo) in 146 South African children.115 Aspirin unlikely to be investigated in a large clinical trial. The
had no impact on morbidity (hemiparesis and devel- advances in diagnosis and treatment described in this
opmental outcome) or mortality. Aspirin was well review highlight the many challenges that clinicians
tolerated, but one death occurred and was probably face in managing this condition and a number of

Downloaded from http://bmb.oxfordjournals.org/ at Mahidol University / Library & Information Center on February 23, 2015
related to aspirin. Outcomes in the high-dose aspirin opportunities for research.
group compared favourably with the other treatment
groups despite younger age and more severe neuro- Funding
logical involvement.
M.E.T. is a Clinician Scientist Fellow supported by
the Academy of Medical Sciences and the Health
Conclusions Foundation, and the NIHR Cambridge Biomedical
Research Centre.
Despite advances in our understanding TBM over the
past few years, it remains the most lethal form of
tuberculosis. The best way to improve survival is by Conict of Interest statement
rapid accurate diagnosis and prompt initiation of
The authors have no potential conicts of interest.
therapy. The current rapid diagnostic methods for
TBM are inadequate but some recent developments
have shown promise. These include methods to References
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