NEUROL-2102; No.

of Pages 7

revue neurologique xxx (2019) xxx–xxx

Available online at

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www.sciencedirect.com

International meeting of the French society of neurology & SPILF 2019

Tuberculous meningitis: Challenges in

diagnosis and management

F. Méchaı̈ *, O. Bouchaud
Infectious disease Unit, Avicenne Hospital, Université Paris 13, IAME, Inserm, 125, route de Stalingrad, 93017,
Bobigny, France

info article abstract

Article history: Tuberculous meningitis (TBM) is the most lethal and disabling form of tuberculosis. In 2017,
Received 10 July 2019 approximately 10 million people developed TB worldwide, of whom more than 100,000 new
Received in revised form cases of TBM are estimated to occur per year. In patients who are co-infected with HIV-1,
16 July 2019 TBM has a mortality approaching 50%. Diagnosis of TBM is often delayed by the insensitive
Accepted 18 July 2019 and lengthy culture technique required for disease confirmation. GeneXpert represents the
Available online xxx most significant advance in TBM diagnostics over the past decade, but it lacks sensitivity and
cannot be used to rule out the diagnosis. Higher volume of cerebrospinal fluid (CSF) seems to
Keywords: be interesting to improve the diagnosis performances. New rapid and accurate diagnostic
Tuberculosis tools are necessary. Better advances have been made concerning the anti-tuberculosis
Meningitis chemotherapy of TBM, with the publication of clinical trials and pharmacokinetic studies
Diagnosis exploring the use of higher rifampicin doses and fluoroquinolones. The rise of drug-resistant
Xpert TBM is another challenge for management because TBM caused by multidrug resistant
Management organisms results in death or severe disability in almost all sufferers.
# 2019 Elsevier Masson SAS. All rights reserved.

[3,4]. TBM occurs when M. tuberculosis invades the mem-

1. Introduction
Mycobacterium tuberculosis (M. tuberculosis) is the leading
infectious cause of death globally. In 2017, approximatively
10 million people developed tuberculosis (TB) worldwide, of
whom an estimated 1.6 million deaths were caused by TB [1].
Tuberculous meningitis (TBM) is the most severe form of TB.
Over half of treated TBM patients die or suffer severe
neurological sequelae, largely due to late diagnosis [2].
For HIV co-infected patients TBM mortality is around 60%
branes and fluid surrounding the brain and spinal cord.
Central nervous system (CNS) TB, including tuberculous
meningitis and brain tuberculomas, is challenging to
diagnose. Early diagnosis and prompt initiation of TB
treatment offer the best chance of a good neurological
outcome. Without appropriate treatment, the disease will
invariably progress, resulting in neurologic impairment, CNS
damage and often death. In this review, we focus on the
main aspects relevant to diagnosis and management of
patients with TBM.

* Corresponding author.
E-mail address: frederic.mechai@aphp.fr (F. Méchaı̈).
https://doi.org/10.1016/j.neurol.2019.07.007
0035-3787/# 2019 Elsevier Masson SAS. All rights reserved.

Please cite this article in press as: Méchaı̈ F, Bouchaud F. Tuberculous meningitis: Challenges in diagnosis and management. Revue
neurologique (2019), https://doi.org/10.1016/j.neurol.2019.07.007
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2 revue neurologique xxx (2019) xxx–xxx

during early disease in patients of all ages. Occasionally, TBM

2. Epidemiology
TBM represents roughly 1% of all cases of TB and approxi-
mately 5% of extra-pulmonary TB cases, but is disproportio-
nately important because it kills or severely disables about
half of the people affected [2]. In many parts of the world,
tuberculosis is the most common cause of bacterial meningi-
tis. Indeed, mass vaccination policies have significantly
reduced the incidence of meningitis related to pyogenic
bacteria. TBM affects all age groups, but is especially common
in young children and in people with untreated HIV infection.
Furthermore, HIV co-infected patients are five times more
likely to develop CNS TB, which causes poor clinical outcomes
including death [3–5]. Incidence is directly related to the
prevalence of pulmonary TB; therefore, optimization of global
TB control is the key to prevention. The neonatal Bacillus
Calmette–Guérin (BCG) vaccine is thought to be 73% effective
in the prevention of TBM, and its use is estimated to avert
30,000 childhood cases of the disease annually, consistent
with the occurrence of around 100,000 cases of TBM per year
overall [6]. Several new TB vaccines are promising with the
aim of providing enhanced protection against pulmonary TB,
which if successful will also reduce the incidence of TBM.
screening and treatment of individuals with latent TB also
could help to prevent TBM [2].
3. Diagnosis
Diagnosing TBM is more difficult than other forms of bacterial
meningitis, partially because symptoms generally do not
develop as suddenly as with classic bacterial meningitis and
because TB produces a paucibacillary infection that is difficult
to detect in CSF.
3.1. Clinical features
TBM typically presents as a sub-acute or chronic meningitis,
with many days or weeks of headache, fever and vomiting,
culminating in loss of consciousness, focal neurological deficit
and death, unless anti-TB chemotherapy is given (Table 1)
[2,7]. The difficulty is that neck stiffness is usually absent
can present acutely, with these normally late signs already
apparent and without a distinct prodromal period. Organism
genotype drug resistance, HIV co-infection, and BCG immu-
nization status do not consistently modify disease presenta-
tion [2]. Several studies have defined the clinical features most
predictive of TBM (Table 1). The strongest of these features,
across all studies, is symptom duration longer than 5 days.
Also, clinical diagnostic algorithms have been developed, but
their use outside of populations in which algorithms were
derived is largely untested [8].
3.2. Radiology
Neuroimaging may be helpful for TBM diagnosis. An expert
consensus case definition (CCD) and set of imaging criteria for
diagnosing basal meningeal enhancement (BME) were pro-
posed in 2009 [8]. Infarcts and hydrocephalus revealed by brain
computed tomography lack diagnostic specificity for TBM, as
other infectious and noninfectious diseases can cause similar
features. An increased specificity (95–100%) can be achieved
via detection of the combination of hydrocephalus, basal
enhancement and infarction; however, these features can be
absent in early disease, which reduces diagnostic sensitivity to
around 40% [6,9]. Magnetic resonance imaging (MRI) is
superior to CT at defining the neuroradiological features of
TBM, especially when they involve the brainstem (Fig. 1). MRI
with diffusion weighted imaging enhances the detection of
early infarcts and border-zone encephalitis. Gadolinium-
enhanced MRI allows visualization of leptomeningeal tuber-
cles, which are present in about 90% of children and 70% of
adults with the disease [2].
3.3. Microbiology
Rapid TBM diagnosis and treatment is a strong prognostic
indicator for reduced death and neurologic deficit. Available
TBM diagnostic tests are inadequate, for the most part due to
low bacillary loads in CSF. CSF Ziehl–Neelsen staining is rapid,
but sensitivity is poor (approximately 10%–20%) [10]. Myco-
bacterial culture is more sensitive (approximately 60%–70%)
but culture often takes  2 weeks [11]. Given the lack of
adequate TBM diagnostics, Xpert appeals as a new diagnostic

Table 1 – Common clinical features of tuberculous meningitis in children and adults [2].
Symptoms
Children Early symptoms are non-specific and
include cough, fever, vomiting
(without diarrhea), malaise, and
weight faltering
Adults Non-specific prodrome of malaise,
weight loss, low-grade fever, and
gradual onset of headache over 1–2
weeks; followed by worsening
headache, vomiting, and confusion,
leading to coma and death if
untreated
Clinical signs
Initial apathy or irritability that
progresses to meningism, decreased level
of consciousness, signs of raised
intracranial pressure (often bulging
anterior fontanelle and abducens nerve
palsy), and focal neurological signs (most often
hemiplegia)
Variable degrees of neck stiffness; cranial
nerve palsies (VI > III > IV > VII) develop
as disease progresses and confusion and
coma deepen; monoplegia, hemiplegia,
or paraplegia in about 20% of cases
CSF examination
Usually clear and colorless; raised
numbers of white cells (0.05  10exp9–
1.00  10exp9/L), with mixture of
neutrophils and lymphocytes; raised
protein (0.5–2.5 g/L); ratio of CSF to
plasma glucose < 0.5 in 95% of cases
High opening pressure (> 25 cm H2O)
in 50% of cases; raised numbers of
white cells (0.05  10exp9–
100  10exp9/L), with mixture of
neutrophils and lymphocytes; raised
protein (0.5–2.5 g/L); ratio of CSF to
plasma glucose < 0.5 in 95% of cases

Please cite this article in press as: Méchaı̈ F, Bouchaud F. Tuberculous meningitis: Challenges in diagnosis and management. Revue
neurologique (2019), https://doi.org/10.1016/j.neurol.2019.07.007
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Fig. 1 – Tuberculous meningitis-associated optochiasmatic arachnoiditis [2]. A. Initial T1-weighted post-gadolinium MRI
scan of a 7-year-old boy with blindness caused by severe tuberculous meningitis-related optochiasmatic arachnoiditis
shows enhancement of the whole suprasellar cistern with displacement and compression of the optic nerve anteriorly. A
ring-enhancing tuberculous abscess is also visible in the right temporal lobe. B. After 3 months of adjuvant thalidomide the
patient regained full vision and follow-up MRI shows a substantial improvement of the optochiasmatic arachnoiditis
despite asymptomatic enlargement of suprasellar and temporal lobe abscesses.

tool. In 2013, the World Health Organization endorsed
GeneXpert MTB/RIF (Cepheid, Sunnyvale, CA USA) for the
diagnosis of extra-pulmonary TB in adults and children,
including for CSF in patients with suspected TBM [12]. The
GeneXpert MTB/RIF is an automated closed-cartridge system
used to simultaneously detect M. tuberculosis and rifampicin
(RIF) resistance within 2 hours.
However, polymerase chain reaction testing of CSF for TBM
diagnosis has important limitations. The WHO 2013 meta-
analysis to assess the diagnostic performance of Xpert for TBM
included the cohorts by Patel and by Nhu and numerous
studies with small numbers of meningitis cases among
extrapulmonary TB cohorts (total 117 cases in 16 studies)
[11–13]. The pooled Xpert sensitivity in this meta-analysis was
79.5% [95% confidence interval (CI) 62.0%–90.2%] with culture
as the gold standard. When a clinical gold standard was used,
sensitivity was only 55% with 84% negative predictive value
(NPV). In high prevalence TBM settings, this NPV equates to 1
in 6 persons with TBM tested by Xpert being missed.
Pormohammad et al. undertook a systematic review and
meta-analysis to evaluate the diagnostic accuracy of Nucleic
Acid Amplification Tests (NAAT) with CSF samples [14]. Sixty-
three studies comprising 1,381 cases of confirmed TBM and
5,712 non-TBM controls were included in the final analysis.
The overall pooled estimates of sensitivity, specificity, positive
likelihood ratio (PLR), and negative likelihood ratio (NLR) of the
NAA tests against culture were 82% [75–87%), 99% [98–99%],
58.6 [35.3–97.3], and 0.19 [0.14–0.25], respectively. The pooled
sensitivity, specificity, PLR, and NLR of NAA tests against
CRS (Combined Reference Standard) were 68% [41–87%], 98%
[95–99%], 36.5 [15.6–85.3], and 0.32 [0.15–0.70], respectively.
Even when using large volumes of centrifuged CSF, the NPV
was 94% (77/82) in a moderate TB setting [10]. Nevertheless, for
Heemskerk et al., testing large CSF volumes improves
performances of TBM diagnosis [15]. Even next generation
molecular tests (e.g. Xpert Ultra) are unlikely to exceed the
sensitivity of culture. So, the use of Xpert as the sole diagnostic
test for TBM may lead to missed TBM cases and deaths. It
seems useful to encourage clinicians for using large CSF
volumes with Xpert, but to remember that a negative Xpert
test does not exclude TBM. WHO now recommends the use of
Xpert Ultra as the initial diagnostic test for suspected TBM.
Chin JE et al. have included Xpert Ultra testing of CSF as part of
diagnostic investigation of 11 patients fulfilling uniform case
definition criteria for probable or definite TBM. Xpert Ultra
detected M. tuberculosis in 7 of the 11 CSF samples [16]. In HIV
patients, Bahr et al. have tested Xpert Ultra in patients with
probable or definite TBM by uniform case definition. Xpert
Ultra sensitivity was 70% compared with 43% for Xpert and
43% for culture [17].
Thus, even the best current testing may miss up to 30% of
cases. Clinicians are often left to treat empirically with
prolonged regimens with significant side effects or risk a
missed case that would result in death. So, new diagnostic
tests for TBM are necessary.
3.4. Adenosine deaminase
The measurement of adenosine deaminase (ADA) level in CSF
has been demonstrated to be a suitable test for TBM diagnosis.

Please cite this article in press as: Méchaı̈ F, Bouchaud F. Tuberculous meningitis: Challenges in diagnosis and management. Revue
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NEUROL-2102; No. of Pages 7
4 revue neurologique xxx (2019) xxx–xxx
Pormohammad et al. performed a meta-analysis in 2017 to
evaluate the accuracy of ADA. Twenty studies were eligible for
inclusion within the meta-analysis. The pooled sensitivity and
specificity for TBM diagnosis hallmarks were 89% and 91%
respectively [18]. It was shown that ADA testing has a
relatively high accuracy for TBM diagnosis. This test is also
recommended for TBM diagnosis in IDSA/CDC/ATS (Infectious
Disease Society of America/Control Disease Center/American
Thoracic Society) and NICE (National Institute for Health and
Care Excellence) guidelines [19,20].
4. Management
4.1. Antimicrobial therapy
Antitubercular treatment before the onset of coma is the
strongest predictor of survival from TBM. The current
guidelines recommend treatment with four anti-TB drugs
for at least the first 2 months of therapy, followed by treatment
with two drugs (rifampicin and isoniazid) for an additional 7 to
10 months. These recommendations are based on data from
pulmonary TB and do not take into account the differential
ability of anti-TB drugs to penetrate the brain [21]. Rifampicin
is a key component in TB treatment, but concentrations of the
drug in CSF are less than 30% of the concentration in plasma.
In pulmonary TB, an increase in the oral dose of rifampicin
from 10 to 13 mg per kilogram of body weight had an
acceptable side effect profile and led to a 65% increase
in plasma concentrations of the drug [22]. A recent randomi-
zed comparison of higher-dose intravenous rifampicin
(approximately 13 mg per kilogram per day) versus a standard
oral dose (10 mg per kilogram per day) in 60 Indonesian adults
with TBM showed that mortality among patients who received
the higher intravenous dose was 50% lower than that among
patients who received the standard dose [22]. Fluoroquino-
lones are active anti-TB agents with good penetration of the
blood–brain barrier. For example, the concentration of levo-
floxacin in CSF reaches 70% of the concentration in plasma,
and the drug has early bactericidal activity approaching that of
isoniazid [23]. A randomized study involving Vietnamese
adults with TNM suggested that the initial addition of
levofloxacin to a standard four-drug anti-TB regimen impro-
ved the survival rate, especially among patients who were
treated before the onset of coma [23]. Heemskerk et al.
compared a standard, 9-month anti-TB regimen (which
included 10 mg of rifampin per kilogram of body weight per
day) with an intensified regimen that included higher-dose
rifampin (15 mg per kilogram per day) and levofloxacin (20 mg
per kilogram per day) for the first 8 weeks of treatment in 819
Vietnamese patients with TBM [21]. Intensified anti-TB
treatment was not associated with a higher rate of survival
among patients with TBM than standard treatment. Never-
theless, there is today good evidence from preclinical, clinical,
and modeling studies to support the use of high-dose
rifampicin in TBM, likely to be at least 30 mg/kg. Higher-dose
isoniazid could be beneficial, especially in rapid acetylators.
The role of other first- and second-line drugs is unclear, but
observational data suggest that linezolid, which has good
brain penetration, may be beneficial [24].
Please cite this article in press as: Méchaı̈ F, Bouchaud F. Tuberculous meningitis: Challenges in diagnosis and management. Revue
neurologique (2019), https://doi.org/10.1016/j.neurol.2019.07.007
Also, if rifampicin and isoniazid resistance (multidrug
resistance) is suspected, then at least four second-line anti-TB
drugs with an adequate CSF penetration must be started as
early as possible.
4.2. Adjunctive host–directed therapies
Intracerebral inflammation has long been recognized as an
important determinant of TBM outcome. The hypothesis
that adjunctive corticosteroids reduce inflammation and
thereby improve outcome from TBM was first postulated in
the early 1950s, but it took nearly 50 years for sufficient
randomized controlled trial evidence to accumulate before
this treatment was widely recommended in guidelines [6]. A
2016 Cochrane systematic review and meta-analysis of all
relevant published trials concluded that corticosteroids
increase survival in HIV–1–negative children and adults
with TBM, but that the benefit of corticosteroids
was uncertain in individuals co–infected with HIV–1 [25].
A randomized control trial is in progress in Indonesia and
Vietnam to study corticosteroids in HIV-patients [26]. The
optimal dose and administration route, and whether
prednisolone and dexamethasone are equally effective,
remain unknown [27]. Thwaites GE et al. performed a
randomized controlled trial in 545 Vietnamese patients
over 14 years who had TBM, with or without HIV infection. In
this study, adjunctive treatment with dexamethasone
improved survival in patients over 14 years of age with
TBM but probably did not prevent severe disability [28]. The
role of adjunctive anti-inflammatory, host-directed thera-
pies–including aspirin and thalidomide–has not been
extensively explored. Occasionally, tuberculomas do not
respond to corticosteroids, with persistence or progression
of symptoms associated with tuberculomas despite therapy.
Case reports and small case series suggest adjunctive
thalidomide, infliximab, and interferon gamma might be
effective in this circumstance [27].
4.3. Supportive management
Supportive care is indispensable in severe TBM. Supportive
therapies include optimization of patient position for CSF and
cerebral venous drainage, control of hyperthermia and
hypotension, management of seizures, and appropriate
mechanical ventilation. Drug therapies include acetazolamide
for reducing CSF production, adjunctive anti-inflammatory
therapy and anti-TB chemotherapy. Coma in TBM is associa-
ted with raised intracranial pressure. Hydrocephalus but also
cerebral edema and tuberculoma formation can elevate
intracranial pressure (ICP) in patients with TBM [27]. A
sustained ICP of more than 20 mm Hg is considered abnormal
in adults. Lumbar puncture is essential to provide opening
pressure measurement. CSF opening pressure is elevated in
approximately half of adult TBM cases, although no evidence
yet supports opening pressure as a predictor of ICP or outcome
in patients with TBM [27]. Hydrocephalus is the most common
cause of raised ICP. In the majority (80%) of patients with TBM,
communicating hydrocephalus is observed, caused by exu-
dates in the basal cisterns and resulting in disruption of
CSF flow. In that case, reasonable evidence suggests that
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hydrocephalus in TBM can be treated medically with repeated
lumbar punctures. Non-communicating hydrocephalus, cau-
sed by obstruction at the level of the cerebral aqueduct and/or
the outlet foramina of the fourth ventricle, is less common in
this population, and should be treated with ventriculoperito-
neal shunting or endoscopic third ventriculostomy [6]. In fact,
no optimum management strategy for TB hydrocephalus is
universally accepter (Fig. 2 and Table 2).
For patients with TBM, early-onset seizures were
associated with cerebral edema and meningeal irritation,
whereas late-onset seizures were associated with hydro-
cephalus, cerebral infarction, and tuberculomas [27].
Seizure risk can be increased by fluoroquinolone
coadministration. To our knowledge, The optimum
treatment of seizures in patients with TBM has not been
studied.

Fig. 2 – Potential strategies for management of intracranial pressure and maintenance of brain perfusion in critically ill
individuals with tuberculous meningitis [27].

Table 2 – CSF penetration of first-line and second-line antituberculous drugs [2].

Standard daily dose for Estimated ratio Comments
adults of CSF to plasma
concentration
Isoniazid 300 mg 80–90% Essential drug; good CSF penetration throughout
treatment
Rifampicin 450 mg (weight < 50 kg) or 10–20% Essential drug, despite relatively poor CSF
600 mg (weight  50 kg) penetration; higher doses might improve
effectiveness
Pyrazinamide 1.5 g (weight < 50 kg) or 2.0 g 90–100% Excellent CSF penetration throughout treatment
(weight  50 kg)
Ethambutol 15 mg/kg 20–30% Poor CSF penetration once meningeal
inflammation resolves
Streptomycin 15 mg/kg (1 g maximum) 10–20% Poor CSF penetration once meningeal
inflammation resolves
Kanamycin 15 mg/kg 10–20% Poor CSF penetration once meningeal
inflammation resolves
Amikacin 15–20 mg/kg 10–20% Poor CSF penetration once meningeal
inflammation resolves
Moxifloxacin 400 mg 70–80% Good CSF penetration
Levofloxacin 1000 mg 70–80% Good CSF penetration
p-Aminosalicylic acid 10–12 g No data Probably very poor CSF penetration unless
meninges are inflamed
Ethionamide or Protionamide 15–20 mg/kg (1 g maximum) 80–90% Good CSF penetration
Cycloserine 10–15 mg/kg 80–90% Good CSF penetration
Linezolid 1200 mg 40–70% Variable interindividual CSF pharmacokinetics
Capreomycin 15–20 mg/kg No data

Please cite this article in press as: Méchaı̈ F, Bouchaud F. Tuberculous meningitis: Challenges in diagnosis and management. Revue
neurologique (2019), https://doi.org/10.1016/j.neurol.2019.07.007
NEUROL-2102; No. of Pages 7
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5. Conclusion
TBM remains the most lethal form of TB. The best way to
improve survival is through early diagnosis and treatment, but
this goal will remain elusive without replacement of the poor
diagnostic tests currently available. GeneXpert represents the
most significant advance in TBM diagnostics over the past
decade, but it lacks sensitivity and cannot be used to rule out
the diagnosis. Higher volume of CSF seems to be interesting to
improve the diagnosis performances. So, new diagnostic
approaches are urgently needed.
Better advances have been made concerning the anti-TB
chemotherapy of TBM, with the publication of clinical trials
and pharmacokinetic studies exploring the use of higher
rifampicin doses and fluoroquinolones.
Disclosure of interest
The authors declare that they have no competing interest.
references
[1] WHO | Global tuberculosis report 2018 [Internet]. WHO. [cité
29 mars 2019]. Disponible sur: http://www.who.int/tb/
publications/global_report/en/.
[2] Thwaites GE, van Toorn R, Schoeman J. Tuberculous
meningitis: more questions, still too few answers. Lancet
Neurol 2013;12(10):999–1010.
[3] Cecchini D, Ambrosioni J, Brezzo C, Corti M, Rybko A, Perez
M, et al. Tuberculous meningitis in HIV-infected and non-
infected patients: comparison of cerebrospinal fluid
findings. Int J Tuberc Lung Dis Off J Int Union Tuberc Lung
Dis 2009;13(2):269–71.
[4] Thwaites GE, Duc Bang N, Huy Dung N, Thi Quy H, Thi
Tuong Oanh D, Thi Cam Thoa N, et al. The influence of HIV
infection on clinical presentation, response to treatment,
and outcome in adults with Tuberculous meningitis. J
Infect Dis 2005;192(12):2134–41.
[5] Soria J, Metcalf T, Mori N, Newby RE, Montano SM, Huaroto
L, et al. Mortality in hospitalized patients with tuberculous
meningitis. BMC Infect Dis [Internet] 2019;19. [cité 8 juill
2019]https://www.ncbi.nlm.nih.gov/pmc/articles/PMC688/
6321.
[6] Wilkinson RJ, Rohlwink U, Misra UK, van Crevel R, Mai NTH,
Dooley KE, et al. Tuberculous meningitis. Nat Rev Neurol
2017;13(10):581–98.
[7] Mai NTH, Thwaites GE. Recent advances in the diagnosis
and management of tuberculous meningitis. Curr Opin
Infect Dis 2017;30(1):123–8.
[8] Marais S, Thwaites G, Schoeman JF, Török ME, Misra UK,
Prasad K, et al. Tuberculous meningitis: a uniform case
definition for use in clinical research. Lancet Infect Dis
2010;10(11):803–12.
[9] Botha H, Ackerman C, Candy S, Carr JA, Griffith-Richards S,
Bateman KJ. Reliability and diagnostic performance of CT
imaging criteria in the diagnosis of tuberculous meningitis.
PloS One 2012;7(6):e38982.
[10] Bahr NC, Marais S, Caws M, van Crevel R, Wilkinson RJ,
Tyagi JS, et al. GeneXpert MTB/Rif to Diagnose Tuberculous
Meningitis: Perhaps the First Test but not the Last. Clin
Infect Dis Off Publ Infect Dis Soc Am 2016;62(9):1133–5.
Please cite this article in press as: Méchaı̈ F, Bouchaud F. Tuberculous meningitis: Challenges in diagnosis and management. Revue
neurologique (2019), https://doi.org/10.1016/j.neurol.2019.07.007
[11] Nhu NTQ, Heemskerk D, Thu DDA, Chau TTH, Mai NTH,
Nghia HDT, et al. Evaluation of GeneXpert MTB/RIF for
diagnosis of tuberculous meningitis. J Clin Microbiol
2014;52(1):226–33.
[12] WHO | Xpert MTB/RIF assay for the diagnosis of pulmonary
and extrapulmonary TB in adults and children [Internet].
WHO. [cité 10 juill 2019]. Disponible sur: https://
www.who.int/tb/publications/xpert-mtb-rif-assay-
diagnosis-policy-update/en/.
[13] 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(10):e5361001.
[14] 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 for
tuberculous meningitis. J Clin Microbiol 2019;57(6).
[15] Heemskerk AD, Donovan J, Thu DDA, Marais S, Chaidir L,
Dung VTM, et al. Improving the microbiological diagnosis
of tuberculous meningitis: a prospective, international,
multicentre comparison of conventional and modified
Ziehl–Neelsen stain, GeneXpert, and culture of
cerebrospinal fluid. J Infect 2018;77(6):509–15.
[16] Chin JH, Musubire AK, Morgan N, Pellinen J, Grossman S,
Bhatt JM, et al. Xpert MTB/RIF Ultra for Detection of
Mycobacterium tuberculosis in Cerebrospinal Fluid. J Clin
Microbiol 2019;57(6):e00249–319.
[17] Bahr NC, Nuwagira E, Evans EE, Cresswell FV, Bystrom PV,
Byamukama A, et al. Diagnostic accuracy of Xpert MTB/
RIF Ultra for tuberculous meningitis in HIV-infected
adults: a prospective cohort study. Lancet Infect Dis
2018;18(1):68–75.
[18] Pormohammad A, Riahi S-M, Nasiri MJ, Fallah F,
Aghazadeh M, Doustdar F, et al. Diagnostic test accuracy of
adenosine deaminase for tuberculous meningitis: a
systematic review and meta-analysis. J Infect
2017;74(6):545–54.
[19] Lewinsohn DM, Leonard MK, LoBue PA, Cohn DL, Daley
CL, Desmond E, et al. Official American Thoracic Society/
Infectious Diseases Society of America/Centers for
Disease Control and Prevention Clinical Practice
Guidelines: Diagnosis of Tuberculosis in Adults and
Children. Clin Infect Dis Off Publ Infect Dis Soc Am
2017;64(2):111–5.
[20] Recommendations, | Tuberculosis | Guidance | NICE
[Internet] [cité 5 juillet 2019]. Disponible sur: https://
www.nice.org.uk/guidance/ng33/chapter/
recommendations
[21] Heemskerk AD, Bang ND, Mai NTH, Chau TTH, Phu NH,
Loc PP, et al. Intensified antituberculosis therapy in
adults with tuberculous meningitis. N Engl J Med
2016;374(2):124–34.
[22] 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(1):27–35.
[23] Thwaites GE, Bhavnani SM, Chau TTH, Hammel JP, Török
ME, Van Wart SA, et al. Randomized pharmacokinetic and
pharmacodynamic comparison of fluoroquinolones for
tuberculous meningitis. Antimicrob Agents Chemother
2011;55(7):3244–53.
[24] Cresswell FV, Ssebambulidde K, Grint D, Te Brake L,
Musabire A, Atherton RR, et al. High dose oral and
intravenous rifampicin for improved survival from adult
tuberculous meningitis: a phase II open-label randomised
controlled trial (the RifT study). Wellcome Open Res
2018;3:83.
NEUROL-2102; No. of Pages 7

revue neurologique xxx (2019) xxx–xxx 7

[25] Prasad K, Singh MB, Ryan H. Corticosteroids for managing
tuberculous meningitis. Cochrane Database Syst Rev 2016;4
[CD002244].
[26] Donovan J, Phu NH, Mai NTH, Dung LT, Imran D, Burhan E,
et al. Adjunctive dexamethasone for the treatment of HIV-
infected adults with tuberculous meningitis (ACT HIV):
Study protocol for a randomised controlled trial. Wellcome
Open Res 2018;3:31.
[27] Donovan J, Figaji A, Imran D, Phu NH, Rohlwink U, Thwaites
GE. The neurocritical care of tuberculous meningitis. Lancet
Neurol [Internet] 2019 [cité 1 juillet 2019]http://www.
sciencedirect.com/science/article/pii/S1474442219301541.
[28] Thwaites GE, Nguyen DB, Nguyen HD, Hoang TQ, Do TTO,
Nguyen TCT, et al. Dexamethasone for the treatment of
tuberculous meningitis in adolescents and adults. N Engl J
Med 2004;351(17):1741–51.

Please cite this article in press as: Méchaı̈ F, Bouchaud F. Tuberculous meningitis: Challenges in diagnosis and management. Revue
neurologique (2019), https://doi.org/10.1016/j.neurol.2019.07.007