Review

Tuberculous meningitis: progress and remaining questions

Julie Huynh*, Joseph Donovan*, Nguyen Hoan Phu, Ho Dang Trung Nghia, Nguyen Thuy Thuong Thuong, Guy E Thwaites

Lancet Neurol 2022; 21: 450–64 Tuberculous meningitis is a devastating brain infection that is caused by Mycobacterium tuberculosis and is
*Contributed equally notoriously difficult to diagnose and treat. New technologies characterising the transcriptome, proteome, and
Centre for Tropical Medicine metabolome have identified new molecules and pathways associated with tuberculous meningitis severity and
and Global Health, Nuffield poor outcomes that could offer novel diagnostic and therapeutic targets. The next-generation GeneXpert MTB/RIF
Department of Medicine,
Ultra assay, when used on CSF, offers diagnostic sensitivity for tuberculous meningitis of approximately 70%,
Oxford University, Oxford, UK
(J Huynh MD, J Donovan PhD, although it is not widely available and a negative result cannot rule out tuberculous meningitis. Small trials indicate
N H Phu PhD, N T T Thuong PhD, that clinical outcomes might be improved with increased doses of rifampicin, the addition of linezolid or
Prof G E Thwaites FMedSci); fluoroquinolones to standard antituberculosis therapy, or treatment with adjunctive aspirin combined with
Oxford University Clinical
corticosteroids. Large phase 3 clinical trials are underway worldwide to address these and other questions
Research Unit, Centre for
Tropical Medicine, Ho Chi Minh concerning the optimal management of tuberculous meningitis; these studies also form a platform for studying
City, Vietnam (J Huynh, pathogenesis and identifying novel diagnostic and treatment strategies, by allowing the implementation of new
J Donovan, N T T Thuong, genomic, transcriptomic, proteomic, and metabolomic technologies in nested substudies.
Prof G E Thwaites); Vietnam
National University School of
Medicine, Ho Chi Minh City, Introduction Pathogenesis
Vietnam (N H Phu); Hospital for Tuberculosis affects 10 million people globally each Brain injury and death
Tropical Diseases, Ho Chi Minh year,1 of which an estimated 2–5% have tuberculous Inflammation and damage of brain tissue (ie,
City, Vietnam
meningitis.2 The true incidence of tuberculous menin­ encephalitis) and the meninges (ie, meningitis) in
(H D T Nghia PhD); Pham Ngoc
Thach University of Medicine, gitis is unknown; however, tuberculous meningitis is patients with tuberculous meningitis is predominantly
Ho Chi Minh City, Vietnam the leading cause of bacterial brain infections in driven by an aberrant host-immune response, triggered
(H D T Nghia) settings with a high tuberculosis burden, dis­ by Mycobacterium tuberculosis (M tuberculosis) invading
Correspondence to: proportionately affecting young children and the CNS. Although M tuberculosis causes direct damage
Prof Guy Thwaites, Oxford
individuals with HIV.3 Here, we review advances made to microglia, neurons, and astrocytes through antigen
University Clinical Research Unit,
Centre for Tropical Medicine, Ho in the past 7 years concerning the pathogenesis, recognition,8 the host-immune response ultimately
Chi Minh City, Vietnam diagnosis, and treatment of tuberculous meningitis, determines the nature of disease.
gthwaites@oucru.org emphasising areas of uncertainty and updating Reviews Investigations of biomarkers of neuronal excitotoxicity
published in The Lancet Neurology in 2005 and 2013.4,5 and cerebral damage have advanced understanding of
This Review focuses mainly on adult tuberculous brain injury associated with tuberculous meningitis.
meningitis and briefly emphasises novel research Concentrations of S100B, ENO2, and GFAP were
advances in paediatric tuberculous meningitis, significantly higher in the ventri­cular CSF of 23 children
including important clinical trials on its management. with tuberculous meningitis-associated hydrocephalus
Management recom­mendations and research published compared with in 11 healthy controls.9 In seven children
before July 1, 2015, are discussed elsewhere and are not with tuberculous meningitis-associated hydro­ cephalus
included.6 who died, markers of cerebral injury increased over time,
whereas inflam­matory markers decreased,9 suggesting
Global burden of tuberculous meningitis that brain injury mechanisms might be independent
In retrospective region-specific studies, 0·3–4·9% of all from inflammation.
people with tuberculosis have tuberculous meningitis Other molecules might play a role in pathogenesis.
See Online for appendix (appendix p 1). Applying these proportions to the WHO Specialised proresolving mediators counter-regulate the
global estimate of 10 million tuberculosis cases suggests production of proinflammatory mediators to promote
that 30 000–490 000 people are diagnosed with tuber­ repair and regeneration of damaged tissues.10 Increased
culous meningitis each year. The variable geographical concentrations of specialised proresolving mediators in
distri­
bution of key tuberculous meningitis risk the CSF have been associated with reduced severity of
factors—eg, prevalence of pulmonary tuberculosis, age, disease and improved chance of survival from
and HIV infection—probably contributes to regional tuberculous meningitis.11 These molecules might
variation in incidence of the disease. Furthermore, represent a novel therapeutic target: a phase 2 trial of
global shortages in Bacillus Calmette-Guérin vaccine, adjunctive aspirin in adults with tuberculous meningitis
which reduces the risk of tuberculous meningitis in reported upregulation of specialised pro­ resolving
young children, have been linked to rising tuberculous mediators in CSF and improved survival for patients
meningitis cases in settings with a high tuberculosis taking aspirin and dexamethasone compared with
burden.7 Tuberculous meningitis is likely to be placebo and dexamethasone.11,12
substantially under-reported, given the difficulties Immune-mediated tissue destruction in patients with
confirming microbiological diagnosis and inadequate tuberculous meningitis is characterised by a disequi­
surveillance. librium of proinflammatory and anti-inflammatory

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 Review

cytokines.13 Neurological events in adults with tuber­ South Africa, peripheral blood transcriptional responses
culous meningitis have been associated with high in 33 people with tuberculous meningitis who were HIV-
pretreatment CSF neutrophil counts, cytokine con­ positive19 showed more abundant neutrophil-associated
centrations, and mycobacterial load.14 A study of transcripts in the 16 people who had immune
692 Vietnamese adults with tuberculous meningitis reconstitution inflammatory syndrome (IRIS) than in
reported that death was associated with an attenuated those who did not. The inflammatory signal preceded
inflammatory response at the start of treatment when antituberculosis therapy and the onset of tuberculous
compared with survivors,14,15 which challenges the dogma meningitis-associated IRIS by several weeks, raising the
that only excessive inflammation is associated with death possibility of identifying people at highest risk of IRIS at
or long-term disability in patients with tuberculous the start of treatment and providing pre-emptive anti-
meningitis.14,15 inflammatory therapy.
Heterogeneity of intracerebral inflammatory response Similarly, transcriptional responses by use of RNA
can be partly explained by the LTA4H gene, which encodes sequencing showed distinct immune responses between
an enzyme that balances the activities of proinflammatory different CNS compartments in 15 children with
and anti-inflammatory eicosanoids.14,15 A prospective tuberculous meningitis compared with 24 healthy
study of 764 Vietnamese adults with tuberculous controls who had similar immune responses between
meningitis who were HIV-negative and treated with dexa­ compartments.20 Whole blood analysis showed an
methasone reported that presence of inflammatory increase in inflammasome activation and decreased T-cell
markers in CSF and fatality rates were predicted by activation, whereas ventricular CSF transcripts suggested
LTA4H genotype (fatality in 3 [7%] of 42 patients with TT neuronal excitotoxicity and cerebral damage, and lumbar
genotype [ie, high inflammatory variant], 40 [21%] of CSF transcripts suggested protein translation and
187 patients with CT genotype [ie, intermediate cytokine signalling in children with tuberculous
inflammatory variant], and 39 [19%] of 209 patients with meingitis.
CC genotype [ie, low inflammatory variant]).15 These Different pathological states occur simultaneously in
findings support the possibility of personalising the same host, exemplified in dynamic [¹¹C]-rifampicin
adjunctive dexamethasone treatment on the basis of PET imaging of rabbits with experimentally induced
LTA4H genotype. However, in a study of 427 Indonesian tuberculous meningitis.21 Radiolabelled imaging allows
adults with tuberculous meningitis, LTA4H variants were visual representation of drug tissue penetration, an
not associated with mortality.16 Addressing these important consideration when drugs need to cross the
conflicting findings, a Bayesian analysis of both datasets blood–brain and blood–CSF barrier. [¹¹C]-rifampicin PET
suggested that the TT genotype confers survival benefit in exposures were spatially heterogeneous and variable
both Vietnamese and Indonesian populations, but the within brain lesions, and temporal changes in drug
effect might be modified in patients with severe disease, exposures occurred over the duration of treatment for
in whom other factors, such as HIV co-infection and tuberculous meningitis, suggesting that this imaging
Glasgow Coma Scale score, might have a greater influence method could be used to assess and optimise the drug
on outcome than in patients with less severe disease.17 therapy of tuberculosis brain lesions.21 Drug-labelled PET
Whether LTA4H genotype could be used clinically to imaging has allowed nuanced characterisation of
define adjunctive treatment in patients with tuberculous neuropathological features in tuberculous meningitis in
meningitis will depend on the results of an ongoing large humans.21
randomised controlled trial (NCT03100786) of adjunctive CSF metabolome analysis on 33 Indonesian adults with
dexamethasone stratified by LTA4H genotype.18 tuberculous meningitis who were HIV-negative identified
Other factors can modulate the intracerebral inflam­ that high tryptophan concentrations in CSF were
matory response. Data suggest that co-infection with the associated with significantly higher mortality.22 11 genetic
widely distributed helminth Strongyloides stercoralis loci were identified that predicted both tryptophan
(S stercoralis) can result in reduced concen­ trations of concentrations in CSF and survival. These findings need
proinflammatory cytokines in the CSF before treatment validation in a different population but might offer new
and reduced neurological complications by 3 months in therapeutic targets for host-directed therapy.
adults with tuberculous meningitis.8 Mechanisms of
immunomodulation are uncertain, but S stercoralis- Diagnosis
induced T-helper-2-cell immune responses could inhibit Diagnostic tests for tuberculous meningitis
proinflammatory T-helper-1-cell responses. Confirming a diagnosis of tuberculous meningitis is
challenging because it requires detection of M tuberculosis
Advancing understanding of pathogenesis with new in CSF (table 1). CSF Ziehl-Neelsen staining and
technology microscopy is rapid, inexpensive, and can be performed
The era of omics (eg, genomics, transcriptomics, proteo­ in many laboratories with few resources. However, a
mics, and metabolomics8,19) has allowed new insights into study of 618 individuals with tuberculous meningitis in
the pathophysiology of tuberculous meningitis. In Vietnam, South Africa, and Indonesia reported that its

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 Review

Confirms Principle Strengths Limitations Sensitivity for

tuberculous tuberculous meningitis
meningitis?* diagnosis*
Ziehl-Neelsen smear Yes† M tuberculosis cell-wall Quick—performed in approximately 30 min; Poor sensitivity; requires laboratory Approximately 10–50%,23
microscopy staining widely available; little equipment required experience to conduct and interpret rarely exceeds 50%24,25
GeneXpert MTB/RIF Yes M tuberculosis DNA Quick—performed in approximately 2 h; Cannot exclude tuberculous meningitis Approximately 20–60%23–28
identification offers rifampicin susceptibility if positive when negative
GeneXpert MTB/RIF Yes M tuberculosis DNA Higher sensitivity than GeneXpert MTB/RIF Insufficient sensitivity to exclude 44–77% (against individual
Ultra identification tuberculous meningitis when negative; centre standards of
not widely available worldwide tuberculous
meningitis)24,26,27,29–31
Loop-mediated Yes M tuberculosis DNA Quick—performed in <1 h; can be read by the Cannot identify rifampicin resistance 76% (95% CI 56–89;
isothermal identification naked eye pooled estimate from
amplification a meta-analysis of
four studies)32
Truenat‡ Yes M tuberculosis DNA Preliminary data suggested similar diagnostic Single study describing use in patients 79–86%33
identification accuracy to GeneXpert MTB/RIF for sputum with tuberculous meningitis
and suspected pulmonary tuberculosis;33
first study for tuberculous meningitis
diagnosis published in 2021 suggested
that sensitivity was similar to GeneXpert
MTB/RIF Ultra33
Metagenomic next Yes M tuberculosis DNA Huge potential if technical and analytical Challenging interpretation; expensive; 78–84%34,35
generation identification challenges can be overcome scarce availability
sequencing
Lipoarabinomannan Yes M tuberculosis cell-wall CSF or urine testing is possible; future Low sensitivity 22–33%36,37
identification generations of this test might show improved
performance
MGIT Yes M tuberculosis culture Allows drug-susceptibility testing Expensive and slow; requires specialised Approximately 25–70%23–28
laboratory facilities
Microscopic Yes M tuberculosis culture Allows drug susceptibility testing Labour intensive; faster than MGIT but Diagnostically equivalent
observation drug still too slow to define tuberculous to MGIT38
susceptibility testing meningitis therapy
Interferon-γ release No Immune response to Based on host response, so overcomes Cannot confirm tuberculous meningitis; 77% (95% CI 69–84; pooled
assay M tuberculosis challenges of detecting low bacterial can be false negative in active disease; estimate for meta-analysis
concentrations in CSF can be indeterminate in of six studies);39
immunosuppression; not 76% (95% CI 72–80; pooled
confirmatory—88% specific in meta- estimate for meta-analysis
analysis of six studies39 and 88% specific for T-SPOT)40
in meta-analysis of 16 studies for
T-SPOT.TB40
Adenosine No Enzyme elevated in Relatively cheap to measure, although variable Adenosine deaminase cutoff values 89% (95% CI 84–92;
deaminase patients with assays and diagnostic cutoff values uncertain; not confirmatory— pooled estimate from
tuberculosis and other 91% pooled specificity (95% CI 87–93; meta-analysis of
diseases meta-analysis of 20 studies);41 study had 20 studies)41
substantial heterogeneity and variable
cutoff values (cutoff values ranging
6–16 IU/L, 14 of 20 studies used a low
cutoff of ≤10 IU/L)
MGIT=mycobacteria growth indicator tube. M tuberculosis=Mycobacterium tuberculosis. *Diagnostic sensitivities vary by reference standard used, and individual studies should be reviewed for a full range.
Comparison of an index test (eg, GeneXpert MTB/RIF) against more accurate reference standards (eg, against a mycobacterial culture standard [ie, confirmed tuberculous meningitis] rather than against clinical
standard [ie, probable tuberculous meningitis]) increases index-test sensitivity, probably through selection of a reference standard with higher bacillary load, in which the index test is more likely to return a
positive result than with a lower bacillary load. Specificities of confirmatory tests generally approach 100%, although accurate assessment of specificity of such tests is challenging given that a positive
confirmatory test result can rarely be considered a false positive when no other gold-standard comparator test exists. *A confirmatory test detects the presence of M tuberculosis in CSF or brain tissue and thus
confirms the diagnosis of tuberculous meningitis. †Although non-tuberculous mycobacteria and other bacteria can identify as positive by Ziehl-Neelsen smear microscopy, the presence of these organisms in CSF
is sufficiently low to justify calling this test confirmatory. ‡Truenat MTB and Truenat MTB Plus are semi-automated chip-based molecular assays.42 All confirmatory tests are expected to be highly specific
(approaching 100%), although true values are uncertain as a positive test is unlikely to be classified as false positive.

Table 1: Diagnostic tests for tuberculous meningitis

sensitivity was generally poor (ie, approximately 30%) and resistance. Although these tests are useful when positive,
was not improved by adaptations to enhance staining of the negative predictive values of GeneXpert MTB/RIF
intracellular bacteria.23 and GeneXpert MTB/RIF Ultra are insufficient to rule
PCR-based tests, such as GeneXpert MTB/RIF and out tuberculous meningitis.24 Many other diagnostic
GeneXpert MTB/RIF Ultra (Cepheid, Sunnyvale, CA, tests for tuberculous meningitis exist (table 1), but most
USA), are rapid and offer identification of rifampicin research activity in the past 5 years has focused on

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 Review

GeneXpert MTB/RIF. Large-volume CSF sampling and identified 85 [79%] patients with tuberculous meningitis,
meticulous processing steps are essential to optimise whereas GeneXpert MTB/RIF Ultra identified 73 [68%]
the performance of smear, culture, and nucleic acid patients with tuberculous meningitis; p=0·059).33
amplification tests. Searching for M tuberculosis outside
of the CNS (eg, in respiratory samples, such as Tests for detecting drug-resistant M tuberculosis
bronchoalveolar lavage) in people who have relevant The ability of GeneXpert MTB/RIF and GeneXpert
neurological symptoms (eg, headache with fever) can MTB/RIF Ultra to simultaneously detect M tuberculosis
also aid diagnosis of tuberculous meningitis.43 and rifampicin resistance enables the identification of
GeneXpert MTB/RIF Ultra is recommended by WHO patients with tuberculous meningitis that is likely to be
as the initial test for extrapulmonary tuberculosis in multidrug resistant (ie, resistant to at least isoniazid and
adults and children,44 although it is still not widely rifampicin) and the start of life-saving, second-line,
available in low-income and middle-income countries. antituberculosis drugs. Before these tests, multidrug-
The performance of GeneXpert MTB/RIF Ultra resistant tuberculous meningitis was almost always fatal,
for diagnosis of patients with tuberculous menin­gitis because the diagnosis came too late through culture and
has been assessed in two large17,24 and many phenotypic drug-susceptibility testing to prompt timely
smaller27,29–31 studies. A prospective randomised study of changes to the antituberculosis regimen. Other assays
205 Vietnamese adults with meningitis (31 are available (table 1), but all (including GeneXpert
[15%] HIV-positive) found that the diagnostic sensitivity MTB/RIF Ultra48) have decreased sensitivity when
of GeneXpert MTB/RIF Ultra was 47·2% (95% CI bacterial numbers are low.
34·4–60·3; 25 of 53 patients with M tuberculosis were Compared with rifampicin resistance, the mechanisms
correctly identified) and that of GeneXpert MTB/RIF for resistance to other tuberculosis drugs, such as
was 39·6% (27·6–53·1; 21 of 53 patients with isoniazid, are more complex and not fully understood. As
M tuberculosis were correctly identified; p=0·56 for the such, the rapid detection of resistance to isoniazid,
comparison of sensitivity between tests), compared fluoroquinolone, and aminoglycoside by molecular
against a reference standard of definite, probable, or methods is difficult and an important research priority.
possible tuberculous meningitis.24 A study of Line-probe assays (eg, genotype MTBDR [Hain Life-
204 Ugandan adults (196 [96%] of patients were HIV- Science, Nehren, Germany]) can detect both rifampicin
positive) with meningitis reported that the sensitivity of and isoniazid resistance, but sensitivity is low from
GeneXpert MTB/RIF Ultra was 76·5% (95% CI clinical specimens with small numbers of bacteria
62·5–87·2; 39 of 51 patients with M tuberculosis correctly (table 2).45 The new GeneXpert MTB/XDR assay detects
identified) and that of GeneXpert MTB/RIF was 55·6% resistance to isoniazid, fluoroquinolones, and amino­
(44·0–70·4; 25 of 45 patients with M tuberculosis correctly glycosides,42 but has yet to be evaluated for patients with
identified; p=0·001 for the comparison of sensitivity tuberculous meningitis. A novel CSF diagnostic tool for
between tests), compared against a reference standard of antimicrobial resistance, combining metagenomic next-
definite or probable tuberculous meningitis.26 generation sequencing with finding low-abundance
CSF-sampling volume and processing, host and bacillary sequences by hybridisation enrichment, offers promise
factors, and variable reference standards could explain for detecting multidrug-resistant tuberculous meningitis
the different findings.28 by identifying multiple antimicrobial resistance muta­
Alternative diagnostic platforms to GeneXpert MTB/RIF tions, although further clinical data are required to
are emerging (table 2), such as loop-mediated isothermal establish its performance.46
amplification (LAMP), a test-tube-based DNA amplification
technique (TB-LAMP; Eiken Chemical Company, Tokyo, Future role for novel diagnostic tests
Japan).47 A meta-analysis of LAMP performance for The detection of urinary tuberculosis lipoarabinomannan
diagnosis of patients with extra­ pulmonary tuberculosis (ie, a cell-wall component of M tuberculosis)49 offers
reported pooled sensitivity of 76% (95% CI 68–85) and promise as an inexpensive and convenient point-of-care
specificity of 99% (96–100) for the identification of test. When performed on CSF from 59 adults with HIV
M tuberculosis in CSF against a composite reference and suspected tuberculous meningitis, the first
standard (four studies, with a total of 727 patients from generation lipoarabinomannan test performed poorly on
China and India).32 Importantly, however, LAMP tests do sensi­tivity (24%, 95% CI 7–50; 4 of 17 patients with
not identify rifampicin resistance. tuberculous meningitis correctly identified) and
In a study of 108 individuals with definite or probable specificity (95%, 84–99; 40 of 42 patients without tuber­
tuberculous meningitis in India, the semiautomated culous meningitis correctly identified) when compared
chip-based PCR assay Truenat MTB (TruPlus, Molbio with the definite or probable tuberculous meningitis
Diagnostics, Goa, India) showed similar performance to reference standard.36 In a study of 550 patients with
GeneXpert MTB/RIF Ultra for the diagnosis of patients suspected tuberculous meningitis from Zambia,
with tuberculous meningitis against a reference standard 474 (86%) of whom were HIV-positive, sensitivity to detect
of definite or probable tuberculous meningitis. Truplus CSF lipoarabinomannan was 22% and specificity was

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 Review

Principle Drug resistance detected Strengths Limitations Sensitivity for drug resistance
in tuberculous meningitis
(phenotypic drug-
susceptibility testing as
reference standard)
GeneXpert MTB/RIF Genotypic: single-copy Rifampicin Quick—performed in 2 h Detects rifampicin resistance only; 92–97%24,26,27
gene mutation does not detect isoniazid
resistance
GeneXpert Genotypic: single-copy Rifampicin Quick—performed in 2 h; able to Detects rifampicin resistance only; 92–97%24,26,27
MTB/RIF Ultra gene mutation detect trace results in CSF (ie, true does not detect isoniazid
positives) resistance
GeneXpert MTB/XDR Genotypic: multiple- Fluoroquinolone; isoniazid; Quick—performed in 2 h; detects Requires upgrade of GeneXpert Unknown
copy gene mutations amikacin, kanamycin multidrug-resistant tuberculous module; no published data on
meningitis or extensively drug- performance in patients with
resistant tuberculous meningitis tuberculous meningitis
when used as follow-on from
GeneXpert MTB/RIF
Line probe assay Genotypic: multiple- GenoType MTBDRplus: rifampicin Quick and accurate when used on Low yield on direct CSF; limited to Few data; 55%45
copy gene mutations and isoniazid; GenoType cultured bacteria—results in prominent target DNA sequences
MTBDRsl: fluoroquinolone and 1 day; detect resistance to associated with resistance
amikacin; Genoscholar second-line agents; detect low-
NTM+MDRTB II: rifampicin and level and high-level isoniazid
isoniazid resistance
Genome sequencing Genotypic: full genome All current first-line and second- Complete drug-susceptibility Expensive—expertise and Unknown34,46
line drugs profile within 1–2 days extensive training required; DNA
sequences associated with
resistance not yet known for new
and repurposed drugs; performed
from cultures, not yet directly
from CSF
Mycobacteria growth Phenotypic: culture All drugs, including new and Gold standard for resistance Slow (ie, 2–6 weeks) to result; 100% (eg, bedaquiline,
indicator tube based repurposed drugs testing; initial test for new and labour intensive; requires skilled delamanid, pretomanid,
repurposed drugs staff and laboratory linezolid, clofazimine)

Table 2: Diagnostic tests for drug-resistant tuberculous meningitis

94% compared with a diagnosis made with CSF culture.37 38 of 45 patients with M tuberculosis correctly identified)
The next-generation SILVAMP TB lipoarabinomannan and specificity of 100% (52–100, 6 of 6 patients without
assay (FujiLAM, Fujifilm, Tokyo, Japan) detects M tuberculosis correctly identified).35 These preliminary
concentrations 30 times lower than the conventional results are encouraging, but costs and insufficient
lipoarabinomannan assay and is 35% more sensitive in availability reduce the applicability of this technique.
detecting tuberculosis in adults with HIV.50 One In a South African study of 47 children diagnosed with
prospective cohort study of 101 Ugandan adults (of whom tuberculous meningitis, a biosignature of three markers
95 participants were HIV-positive) showed that the (adipsin, amyloid β42, and IL10) gave 83% (95% CI
sensitivity of FujiLAM on CSF was similar to GeneXpert 61–95) diagnostic sensitivity and 75% (53–90) diagnostic
MTB/RIF Ultra (52%, 95% CI 38–65, 30 of 58 participants specificity.52 A Chinese study reported 28 differentially
with tuberculous meningitis correctly identified vs 55%, expressed microRNAs in patients with tuberculous
42–68, 32 of 58 participants correctly identified) against a meningitis compared with patients who had viral
reference standard of definite or probable tuberculous meningitis, suggesting possible diagnostic use.53
meningitis.51 Whether FujiLAM has sufficient sensitivity Emerging technologies to characterise the transcriptome,
to assist in the diagnosis of patients with tuberculous metabolome, and proteome of patients with tuberculous
meningitis is uncertain. meningitis are likely to identify new molecules and
Metagenomic next-generation sequencing offers a pathways that might become novel diagnostic and
novel option for untargeted pathogen detection in CSF. A therapeutic targets.
retrospective study of 23 patients from China with
definite, probable, or possible tuberculous meningitis Predictors of tuberculous meningitis outcomes
reported that Torrent NGS platform (BGISEQ, BGI, The accurate and early identification of patients at
Tianjin, China) detected M tuberculosis DNA sequences highest risk of complications and death from tuberculous
in 18 (78%) of these individuals.34 Another study of meningitis can help to target resources and treatment to
45 individuals with definite, probable, or possible those most in need. The three Medical Research Council
tuberculous meningitis, reported metagenomic next- grades have been used to categorise tuberculous
generation sequencing sensitivity of 84% (95% CI 70–93; meningitis severity for nearly 75 years, and the system

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 Review

strongly predicts death (appendix p 2). Investigators from tuberculous meningitis generally include four drugs
India suggested creating a new fourth grade, which (ie, rifampicin, isoniazid, pyrazinamide, and ethambutol)
would define patients at the highest risk of death by deep at standard doses for at least 2 months, followed by
coma and need for mechanical ventilation.54 A new rifampicin and isoniazid for a further 10 months.61,65 In
prognostic model, developed from studies of August, 2021, WHO issued a rapid communication
1699 Vietnamese adults with tuberculous meningitis, suggesting that a 6-month intensified regimen for
predicted outcome more accurately than did the Medical patients with tuberculous meningitis could be used as an
Research Council grade or Glasgow Coma Scale score.55 alternative to the standard 12 months in children and
Accuracy of predictions of poor prognosis and death adolescents,67 although supporting evidence for this
were improved by a subsequent dynamic prediction statement from randomised controlled trials is scarce.
model, which was developed from pretreatment and Although 2010 WHO tuberculosis treatment guidelines65
post-treatment data (ie, Glasgow Coma Scale score and recommended that streptomycin should replace
serial plasma sodium concentration) from ethambutol for treatment of patients with tuberculous
1048 Vietnamese adults with tuberculous meningitis.56 meningitis, in practice the side-effects of streptomycin
These models could be used as clinical tools to identify and drug resistance have reduced its use.
people with tuberculous meningitis who require critical Rifampicin is considered a crucial drug in patients
illness care. with tuberculous meningitis, yet its poor CNS penetration
Quantitative measurements of bacillary loads, by use of and multiple drug interactions present challenges.
cycle threshold values, have been shown to predict Heemskerk and colleagues compared an intensified
outcomes. High CSF bacillary load, measured with antituberculosis regimen containing higher dose
GeneXpert MTB/RIF, was associated with disease severity rifampicin (15 mg/kg per day) and levofloxacin
and new neurological events in 692 Vietnamese adults (20 mg/kg per day) for the first 8 weeks of treatment with
with tuberculous meningitis who were HIV-negative.14 a standard regimen (10 mg/kg per day rifampicin) in
Cycle threshold values for GeneXpert MTB/RIF Ultra in 817 Vietnamese adults with tuberculous meningitis.68
102 Ugandan adults with tuberculous meningitis who The group receiving intensified treatment did not have
were HIV-positive predicted mortality: low cycle threshold reduced mortality at 9 months.68
values (ie, high bacillary loads) were associated with a A phase 2 study of 60 adults with tuberculous
two-fold increase in mortality (57%) compared with high meningitis in Indonesia showed that, compared with
cycle threshold values (ie, low bacillary load; 25%) cycle 10 mg/kg rifampicin per day, 30 mg/kg per day increased
threshold values.57 These results raise the possibility of plasma and CSF rifampicin concentrations without
using GeneXpert MTB/RIF cycle threshold values to increasing adverse events.69 Pharmacokinetic analyses of
identify patients at greatest risk of death and who would rifampicin use in 133 Indonesian adults suggested that
benefit from additional supportive care. high rifampicin exposure reduced the risk of death and
Little is known about neurocognitive outcomes in the predicted that doses higher than 30 mg/kg per day might
long term following tuberculous meningitis. A study further improve survival.70 A phase 2, open-label trial
reported worse neurocognitive outcomes in people with of Ugandan adults with suspected tuber­culous menin­
HIV-associated tuberculous meningitis than in controls gitis showed that high-dose intravenous rifampicin
who were HIV-negative,58 emphasising the potential (20 mg/kg/day; geometric mean CSF concentrations
value of targeted neurorehabilitation in management of 1·74 mg/L) and oral rifampicin (35 mg/kg/day; geometric
tuberculous meningitis. mean CSF concentrations 2·17 mg/L) were safe and
resulted in 6-fold and 8-fold higher CSF concentrations
Management than the standard dose (10 mg/kg/day; geometric mean
International guidelines CSF concentrations 0·27 mg/L), which resulted in
WHO guidelines for the treatment of drug-susceptible subtherapeutic CSF concentrations for 16 (89%) of
tuberculosis were updated in 2017.59 They, and other 18 patients with tuberculous meningitis.71 Pharma­
current guidelines, largely focus on pulmonary cokinetic studies in the same population showed that
tuberculosis and recommend similar antituberculosis rifampicin concentrations in plasma were higher when
drug regimens for tuberculous meningitis treatment, patients were dosed orally at 35 mg/kg per day than
albeit with longer durations (table 3).59,65 British Infection when dosed intravenously at 20 mg/kg per day,
Society guidelines for the diagnosis and treatment of CNS supporting further evaluation of high-dose oral rifam­
tuberculosis in adults and children were published in 2009 picin.72 Phase 3 trials of high-dose (ie, 30–35 mg/kg)
and have not been updated.66 rifampicin are ongoing (ISRCTN15668391, NCT02958709,
The evidence base supporting recommended anti­ NCT04021121, NCT04145258, ISRCTN40829906,
tuberculosis chemotherapy regimens (ie, drugs, doses, NCT03927313; table 3).
and durations) for patients with tuberculous meningitis Metabolism of isoniazid includes acetylation by NAT2,
is weak due to scarcity of evidence. Recommendations with polymorphism in the NAT2 gene resulting in fast or
for the treatment of patients with drug-susceptible slow acetylator phenotypes.73 Fast acetylation reduces

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 Review

blood and CSF isoniazid exposures and can impair (NCT04145258, NCT02958709, NCT04021121,
treatment responses. In a subgroup of participants with NCT03537495, NCT04145258, NCT03927313).
tuberculous meningitis (n=237) from Heemskerk and Treatment adherence is an important consideration in
colleagues’ intensified antituberculosis treatment trial,68 management of tuberculosis and is more likely to be an
low isoniazid exposure predicted death and was linked issue with the long regimens used for patients with
to the fast acetylator phenotype (ie, 28 of 38 deaths were tuberculous meningitis. Adherence has not been
in fast acetylators).74 A NAT2-stratified trial of higher comprehensively studied, but the SURE trial
isoniazid doses (ie, 600 mg per day vs 300 mg per day) (ISRCTN40829906) evaluating shortened, intensified
in patients with tuberculous meningitis is being anti­
tuberculosis and anti-inflammatory therapy will
conducted in China (NCT03787940). address this gap (table 4).
The fluoroquinolones, particularly levofloxacin and
moxifloxacin, achieve high CSF exposures after Tuberculous meningitis caused by drug-resistant
standard oral doses and might improve outcomes. bacteria
However, aside from the benefit of levofloxacin in Drug-resistant tuberculous meningitis is difficult to
people with isoniazid-resistant tuberculous meningitis,68 diagnose and optimal therapy is unknown. Isoniazid
there are no clinical trial data to indicate that resistance is common (ie, 20–30% of cases in some
fluoroquinolones improve survival in people with drug- settings) and impairs treatment responses in patients
sensitive tuberculous meningitis.75 Similarly, linezolid with tuberculous meningitis, especially in individuals
penetrates the CNS well (although co-administration with HIV.78 Trials comparing different regimens for
with rifampicin can reduce exposure76) and rapidly,77 yet isoniazid-resistant tuberculous meningitis have not
clinical trial data are scarce. Randomised controlled been conducted, but Heemskerk and colleagues’ trial
trials evaluating levofloxacin and linezolid for treatment comparing the standard antituberculosis regimen with
of patients with tuberculous meningitis are ongoing an intensified regimen of 15 mg/kg rifampicin and

Guideline focus Anti-tuberculosis chemotherapy for patients Adjunctive therapy or antiretroviral

with tuberculous meningitis: main therapy: main recommendations
recommendations
WHO (2020)60 WHO-consolidated Long duration regimens for multidrug- No information
guidelines on drug-resistant resistant tuberculosis also apply to
tuberculosis treatment extrapulmonary disease; treatment of
multidrug-resistant tuberculous meningitis is
guided by drug-susceptibility testing of the
infecting strain; treatment of multidrug-
resistant tuberculous meningitis is guided by
knowledge of which drugs cross the blood–
brain barrier; CNS penetration of individuals
agents is discussed
American Thoracic Society, Treatment of drug-resistant Use of prothionamide and ethionamide in Optimal approach to starting antiretroviral
US Centers for Disease tuberculosis treatment of patients with tuberculous therapy in patients with tuberculous
Control and Prevention, meningitis meningitis is uncertain62
European Respiratory
Society, Infectious Diseases
Society of America (2019)61
WHO (2017)59 Guidelines for treatment of In patients with tuberculous meningitis, an Immediate antiretroviral therapy was
drug-susceptible tuberculosis initial adjuvant corticosteroid therapy with significantly associated with more severe
and patient care—2017 dexamethasone or prednisolone tapered over adverse events than was initiation of
update 6–8 weeks should be used antiretroviral therapy 2 months after the start
of tuberculosis treatment62
American Thoracic Society, Clinical practice guidelines: Initial therapy is rifampicin, isoniazid, Adjunctive corticosteroid therapy with
US Centers for Disease treatment of drug- pyrazinamide, and ethambutol—after 2 months dexamethasone or prednisolone is
Control and Prevention, susceptible tuberculosis of these four drugs, if Mycobacterium recommended, tapered over 6–8 weeks
Infectious Diseases Society tuberculosis strain is known or presumed to be
of America (2016)63 susceptible, continue just rifampicin and
isoniazid for an additional 7–10 months;
optimal duration of chemotherapy is not
defined; repeat lumbar punctures should be
considered to monitor changes in CSF
parameters
British Infection Society guidelines for the diagnosis and management of tuberculous meningitis were published in 2009.64 The guidelines listed include the management of
patients with tuberculous meningitis, published in the past 5 years. The guidelines are listed in date order, with the most recent first.

Table 3: International guidelines published since 2015 containing recommendations for the management of patients with tuberculous meningitis,
by supporting organisation

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 Review

Registry number Study population with Trial type Setting Planned

clinical tuberculous sample size
meningitis
Anti-tuberculosis chemotherapy
Optimizing NCT03787940 Aged 18–65 years NAT2-stratified, randomised, parallel China 676
antituberculosis therapy group trial of high-dose isoniazid
in adults with tuberculous
meningitis
HARVEST ISRCTN15668391 Aged ≥18 years Randomised, double-blind, placebo- Indonesia, South 500
controlled, phase 3 trial of high-dose Africa, and Uganda
rifampicin
TBM-KIDS NCT02958709 Aged ≥6 months to Randomised, open-label, phase 2 trial of India and Malawi 120
<12 years and weight high-dose rifampicin and levofloxacin
>6 kg
ALTER NCT04021121 Aged >18 years Randomised, open-label, phase 2 trial of Uganda 60
high-dose rifampicin and linezolid
SIMPLE NCT03537495 Aged ≥18 years Randomised, open-label, phase 2 trial of Indonesia 36
high-dose rifampicin and linezolid
Adjunctive therapy
LAST ACT NCT03100786 Aged ≥18 years without LTA4H-stratified, randomised, double- Vietnam 720
HIV infection blind, placebo-controlled, phase 3 trial
of adjunctive dexamethasone
ACT HIV NCT03092817 Aged ≥18 years with HIV Randomised, double-blind, placebo- Vietnam and 520
co-infection controlled, phase 3 trial of adjunctive Indonesia
dexamethasone
A study for evaluation of CTRI/2018/02/011722 Any age without HIV Randomised, open-label trial of India 300
utility of indomethacin in infection standard of care plus indomethacin
tuberculous meningitis in versus standard of care
patients
Anti-tuberculosis chemotherapy plus adjunctive therapy
INTENSE-TBM NCT04145258 Aged ≥15 years Randomised, placebo-controlled, Ivory Coast, 768
phase 3, 2 × 2 factorial trial of high-dose Madagascar, South
rifampicin, linezolid, and aspirin Africa, and Uganda
SURE ISRCTN40829906 Aged >28 days and Factorial, randomised, phase 3 trial of India, Uganda, 400
<15 years and weight 6-month intensified tuberculosis-drug Vietnam, Zambia,
≥3 kg regimen and aspirin and Zimbabwe
LASER-TBM NCT03927313 Aged ≥18 years with HIV Randomised, parallel group, multiarm, South Africa 100
co-infection phase 2a trial of high-dose rifampicin,
linezolid, and aspirin
We searched ClinicalTrials.gov, the ISRCTN registry, and the WHO International Clinical Trials Registry platform for clinical trials in patients with tuberculous meningitis that
have either started recruitment or are registered but have not yet started recruitment. Trials are listed in three subsections, then by trial sample size with the largest first. Data
correct to Nov 1, 2021. People with and without HIV were included in the population unless otherwise specified.

Table 4: Planned or ongoing clinical trials evaluating anti-tuberculosis drug regimens and adjunctive therapies

20 mg/kg levofloxacin for the first 2 months in Vietnam Similarly, in rats, pretomanid showed early drug
reported that the intensified regimen benefited only penetration into the rat brain compared with penetration
participants with isoniazid-resistant tuberculous into the lung.81,82 Little is known about the role of
meningitis (n=86).78 bedaquiline, a highly protein-bound drug, in the treat­
Multidrug resistant-tuberculous meningitis is still ment of patients with multidrug resistant-tuberculous
associated with unacceptably high mortality78 owing to meningitis.83 Undetectable CSF concen­ trations were
the absence of a standardised treatment approach and reported in one human study with tuberculous
few drug options that adequately penetrate the blood– meningitis,83 although these findings are complicated
brain barrier.79 CNS pharmacokinetic data on the new by the propensity for bedaquiline to adsorb to plastic
antituberculosis drugs delamanid, bedaquiline, and during CSF collection and assaying.84
pretomanid are scarce. Studies on experimentally Improved understanding of the role of new
induced tuberculous meningitis in rabbits showed that, tuberculosis drugs in patients with multidrug resistant-
although delamanid concentrations were markedly tuberculous meningitis could be provided through
lower in CSF than in plasma, they were five-fold higher non-invasive dynamic PET imaging and animal
in brain tissue (9 h after drug administration, mean models.21 Studies using whole-body PET, as seen first
plasma delamanid concentrations of 96·4 ng/mL vs with rifampicin, have shown detectable concentrations
mean brain tissue concentrations of 549·0 ng/mL).80 of bedaquiline and linezolid in brains of mice infected

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 Review

with M tuberculosis.85,86 In the absence of clinical trials, Infliximab, a selective TNF inhibitor, has been used
dynamic PET imaging with radiolabelled drugs and in adults and children with tuberculous meningitis.
through preclinical models could guide future Case series have reported that infliximab used as a
tuberculous meningitis studies87 and optimal drug so-called rescue adjuvant therapy for refractory
regimens for patients with multidrug-resistant paradoxical reactions, or tuberculous meningitis-
tuberculous meningitis. associated vasculo­pathy, improved clinical outcomes.93,94
Anakinra (an interleukin-1 inhibitor) has also been
Host-directed anti-inflammatory drugs used to control tuberculous meningitis-associated
A systematic review of nine randomised controlled trials, paradoxical inflam­mation.95 Clinical trials are required
including 1337 participants, reported that adjunctive to investigate how and when biological agents should
corticosteroids reduced deaths from tuber­ culous be used in the treatment of patients with tuberculous
meningitis by almost a quarter (risk ratio 0·75, 95% CI meningitis, while carefully monitoring for aggravation
0·65–0·87)88 but had no effect on disabling neurological of disease.
deficits. The mechanism by which corticosteroids confer
benefit, and their optimum starting dose or tapering HIV co-infection
regimen, are still unknown. Whether their beneficial Initiation of antiretroviral therapy (ART) in patients
therapeutic effect depends on LTA4H genotype and HIV with tuberculous meningitis is guided by studies
status are important unanswered questions and are the published around 10 years ago.62,96 Drug interactions
focus of two ongoing trials (NCT03100786, NCT03092817; with rifampicin complicate choice and dose of ART,64,97
table 4). and the timing of ART initiation in individuals with
Aspirin acts by irreversibly inhibiting the cyclo- tuberculous meningitis who are ART naive is a
oxygenase pathways of arachidonic acid metabolism and challenging clinical issue. The primary risk of early
the production of prostanoids involved in inflammation ART initiation is intracerebral IRIS, which occurs after
and thrombosis.12 Anti-inflammatory effects occur at the start of ART in up to 50% of those with tuberculous
high doses by inhibition of proinflammatory prosta­ meningitis and incurs substantial morbidity and
glandins and by triggering the production of specialised mortality.96 A trial indicated that prednisone given with
proresolving mediators. A phase 2, placebo-controlled ART could prevent tuberculosis-associated IRIS,98
trial of adjunctive aspirin in 120 adults with tuberculous although people with tuberculous meningitis were
meningitis who were HIV-negative suggested that excluded. Whether cortico­ steroids prevent and treat
aspirin could reduce brain infarcts and death, especially tuberculous meningitis-associated IRIS is an important
at a high dose (ie, 1000 mg/day).12 Aspirin was associated unanswered question.
with dose-dependent inhibition of prostanoids and Only one trial has examined whether to start ART
upregulation of specialised proresolving mediators in immediately after initiation of antituberculosis drugs
CSF.11 Phase 3 trials are now being conducted in during treatment of patients with tuberculous
adults (NCT04145258, NCT03927313) and children meningitis or to defer for up to 2 months.62 Immediate
(ISRCTN40829906) to define the role of aspirin in the commence­ ment of ART was associated with more
treatment of patients with tuberculous meningitis. grade 4 adverse events than was ART given after
Immunomodulatory treatment with thalidomide (a 2 months, but there was no overall benefit associated
TNF inhibitor) has been studied in animals and humans with either strategy when compared with each other.62 A
with tuberculous meningitis, with contrasting results.89 pharmacokinetic substudy in 85 participants reported
Although thalidomide reduced neuroinflammation and that ART did not influence tuberculosis drug
dramatically improved survival in rabbit models of pharmacokinetics.99
tuberculous meningitis, high dose (ie, 24 mg/kg/day)
was associated with increased mortality in the only trial Critical illness
in children with tuberculous meningitis.90 No further The neurocritical care of patients with tuberculous
clinical trials of thalidomide have been conducted, but meningitis and management of the common compli­
case series have renewed interest in the drug. cations (figure) has been reviewed by Donovan and
Thalidomide has been prescribed safely at much lower colleagues.104 A subsequent inter­national survey from
doses (ie, 3–5mg/kg/day) in 38 South African children 43 countries (with 222 responses) showed substantial
with CNS tuberculosis-related complications.91 variation in supportive care and scarcity of available
Thalidomide appeared to cause clinical and radiological data to guide the management of critical illness caused
improvement in 16 South African children with by tuberculous meningitis.105 Attempts to improve care
progressive tuberculosis cerebral pseudo­abscesses92 and of patients with tuberculous meningitis have included
five English adults who had favourable outcomes.93 the development of checklists that provide
Further clinical trials are required to define the role of comprehensive tailored proformas for inpatient and
adjuvant thalidomide in the treatment of patients with critical care assessments, with an additional checklist
tuberculous meningitis. for acutely deteriorating patients.106 Studies are required

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 Review

Early phase Late phase Management

No clinical trials, but corticosteroids are often used. Case series suggest
Tuberculomas (caused by paradoxical reactions or IRIS)
thalidomide might be useful in selected patients.90

Cerebral infarcts (often affecting the basal ganglia, thalamus, or brainstem) No large clinical trials, but small trials indicate aspirin might prevent
infarcts. Await phase 3 trial results.

One trial of fludrocortisone showed no benefit.100 Mechanisms and

Hyponatraemia (often caused by cerebral salt wasting or SIADH)
optimal treatment are uncertain.

No clinical trials. Optic nerve sheath diameter measurement might

Raised intracranial pressure (multifactorial causes)
help assessments.101

Treatment options include diuretics or surgery (eg,

Hydrocephalus (communicating or non-communicating) ventriculoperitoneal shunt or endoscopic third ventriculostomy).102
Selection for surgery is unclear.

Seizures (associated with meningeal irritation, cerebral oedema, hydrocephalus, infarcts, No clinical trials. Best management is uncertain.
or tuberculomas)

Alterations to antituberculosis drug regimen early in treatment is

Adverse reactions to antituberculosis drugs associated with poor outcome.103 Preserve antibacterial activity with
alternative drugs whenever possible.
No completed clinical trials; one trial of different antituberculosis
Drug-induced liver injury strategies underway. Preserve antibacterial activity with alternative
drugs whenever possible.
0 3 6 9 12
Months from diagnosis of tuberculous meningitis

Most common Least common

Figure: Timeline of complications in patients with tuberculous meningitis and evidence for their management
Early complications occur while the patient is in critical care and during the first 3 months from diagnosis, when most tuberculous meningitis deaths occur;
late complications are defined as occurring beyond 3 months. Tuberculous meningitis complications can present at diagnosis and most occur in the early phase.
Management of these complications is varied with scarce supporting evidence. In the past 5 years, few clinical trials have been designed to address these areas.
IRIS=immune reconstitution inflammatory syndrome. SIADH=syndrome of inappropriate antidiuretic hormone.

to show whether checklists improve clinical outcomes required to define how optic nerve sheath diameter
in patients with tuberculous meningitis. measurements can be used to improve clinical outcomes.
Hydrocephalus is a common complication of tuber­
culous meningitis, and ventriculoperitoneal shunt Conclusions and future directions
insertion and endoscopic third ventriculostomy are often Major advances in management of patients with
considered. A systematic review and meta-analysis of tuberculous meningitis are anticipated following the
ventriculoperitoneal shunt insertion in adults with HIV completion of trials evaluating antituberculosis drugs
(including three studies and 75 patients) reported and adjunctive therapy (table 4). Within 5 years,
12-month survival of only 33·3%.107 A systematic review evidence should suggest whether survival from
and meta-analysis of endoscopic third ventriculostomy in tuberculous meningitis is improved by high doses of
patients with tuberculous meningitis (including eight rifampicin (ie, 30–35mg/kg) or the addition of
studies and 174 patients) estimated that endoscopic third levofloxacin or linezolid to treatment regimens. New
ventriculostomy had a 59% pooled success rate and a data should also show whether adjunctive dexa­
15% complication rate.102 How patients should be selected methasone should be used only in people with specific
for either procedure, the precise timing, and the benefit LTA4H genotypes, and whether dexamethasone
of surgical shunting are uncertain. improves outcomes in adults with tuberculous menin­
Ultrasound measurement of diameter of the optic gitis who are HIV-positive. Uncertainty concerning the
nerve sheath, which distends under the influence of use of adjunctive aspirin should be resolved by
raised intracranial pressure, might have a role in the completion of trials in adults and children. New
management of patients with tuberculous meningitis. upcoming treatment options for both drug-susceptible
Optic nerve sheath diameter was measured 267 times and drug-resistant tuberculosis are expected, with an
during the treatment of 107 Vietnamese adults with increasing number of drugs in the clinical development
tuberculous meningitis; higher pretreatment optic nerve phase.108 However, studies are limited to patients with
sheath diameter was associated with more severe disease pulmonary tuberculosis and yet to include patients with
and abnormal brain imaging.101 Further studies are tuberculous meningitis.

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 Review

Panel: Important unanswered questions in tuberculous meningitis

Burden of disease • What second-line drug combination (ie, dose and duration)
• How many adults and children have tuberculous meningitis improves outcome in patients with drug-resistant
globally? tuberculous meningitis?*
• What are the mortality rates of tuberculous meningitis in
Adjuvant therapy
adults and children in low-income and middle income
• Should dexamethasone use be stratified by HIV status and
settings and high-income settings?
LTA4H ?
Understanding pathogenesis • Does high-dose aspirin have a role in improving mortality
• What are the underlying mechanisms of cerebral infarctions, and neurodisability?*
tuberculomas, and hydrocephalus? • Do thalidomide and biological agents improve outcomes
• How is intracerebral inflammation regulated and controlled and CNS complications?
by corticosteroids? • What is the optimal dose and duration of corticosteroid
• How is pathogenesis different between people with or therapy and weaning?
without HIV?*
Complications
• What are the mechanisms of brain injury and their relation to
• Can blood biomarkers be used clinically to predict the
neuroinflammation?*
development of immune reconstitution inflammatory
Diagnosis syndrome or paradoxical reactions?
• How can we improve sensitivity of pathogen-based testing to • What is the best treatment regimen for managing immune
improve diagnosis of patients with tuberculous meningitis? reconstitution inflammatory syndrome or paradoxical
• Does host response-based testing (eg, biomarkers) have a reactions?
role in diagnosis?* • How can raised intracranial pressure be detected and
• What is the role of new point-of-care testing monitored in low-resource settings?
(eg, lipoarabinomannan) in diagnosis?* • What is the optimum management of patients with
• How can we improve detection of drug-resistant tuberculous hydrocephalus (eg, ventricular shunting vs diuretic
meningitis, including isoniazid-resistant tuberculous therapy)?
meningitis? • Does aspirin reduce the development of cerebral infarcts in
• Which diagnostic test could be used to monitor treatment patients with tuberculous meningitis?
response in patients with tuberculous meningitis with or • What causes tuberculous meningitis-associated
without brain abscesses?* hyponatraemia and how is it best managed?
• Should patients with brain abscesses and CNS tuberculomas
Drug therapy
be managed differently to patients with tuberculous
• What is the optimal dose of rifampicin in the treatment of
meningitis?*
patients with tuberculous meningitis?
Outcomes
Antimicrobial therapy
• Can advanced technology (eg, artificial intelligence or
• Should fast metabolisers of isoniazid receive higher doses of
machine learning) be used as a tool to improve prediction of
isoniazid than slow or intermediate metabolisers?*
treatment responses and outcomes?*
• Should linezolid or fluoroquinolones be used as alternative
fourth antituberculosis drugs to ethambutol? *New questions since the 2013 Lancet Neurology Review.5 Other questions were posed in
the previous review but remain unanswered.
• Can duration of tuberculous meningitis therapy be
shortened?

Many of the ongoing trials provide a platform for Brain MRI features that predict future outcome and
substudies on pathogenesis and diagnostics. Nested treatment response are poorly defined. Tools based on
multi-omic studies will increase understanding of the artificial intelligence and machine learning are being
immunopathology of tuberculous meningitis, its developed to enable an unbiased and automated
regulation by host genotype, and novel host-directed assessment of brain images and provide guidance to
therapies that target brain injury and specific inflam­ clinicians on treatment response and outcomes.
matory mediators. The next 5 years are likely to include Artificial intelligence and machine learning, particularly
the exploration and validation of new signatures and when applied to digital brain imaging, have been
biomarkers in blood and CSF and the generation of new implemented to devise diagnostic, complication
diagnostic tests. Their potential role, in combination prediction, and outcome prediction systems for neuro­
with current pathogen-based tests, is likely to be an degenerative disorders, demyelinating disorders of the
important future contribution to improving survival brain, and acute ischaemic strokes.109,110 Machine
from tuberculous meningitis. learning in tuberculous meningitis is likely to assist in

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 Review

4 Thwaites GE, Tran TH. Tuberculous meningitis: many questions,

Search strategy and selection criteria too few answers. Lancet Neurol 2005; 4: 160–70.
5 Thwaites GE, van Toorn R, Schoeman J. Tuberculous meningitis:
We searched PubMed using each of the search terms more questions, still too few answers. Lancet Neurol 2013;
“tuberculous meningitis”, “TB meningitis”, “TBM”, 12: 999–1010.
”Tuberculosis”, and “meningeal”, with each of “prevention”, 6 Wilkinson RJ, Rohlwink U, Misra UK, et al. Tuberculous
meningitis. Nat Rev Neurol 2017; 13: 581–98.
“pathology”, “pathophysiology”, “diagnosis”, “treatment”, 7 du Preez K, Seddon JA, Schaaf HS, et al. Global shortages of BCG
“management, “drug-resistant”, “multidrug-resistant”, vaccine and tuberculous meningitis in children. Lancet Glob Health
“bedaquiline”, “delamanid”, and “pretomanid”, for articles 2019; 7: e28–29.
8 Cresswell FV, Davis AG, Sharma K, et al. Recent developments in
published between July 1, 2015, and Nov 1, 2021. tuberculous meningitis pathogenesis and diagnostics.
We identified additional articles through relevant references Wellcome Open Res 2021; 4: 164.
of selected papers. Only publications in English were 9 Rohlwink UK, Mauff K, Wilkinson KA, et al. Biomarkers of cerebral
injury and inflammation in pediatric tuberculous meningitis.
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Curr Opin Immunol 2018; 50: 48–54.
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the future. outcome in adults with tuberculous meningitis. FASEB J 2019;
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imaging has been used to successfully track antibiotic 12 Mai NT, Dobbs N, Phu NH, et al. A randomised double blind
placebo controlled phase 2 trial of adjunctive aspirin for
penetration into and concentrations in infected brain tuberculous meningitis in HIV-uninfected adults. eLife 2018;
lesions of rabbits with experimentally induced 7: e33478.
tuber­­culous meningitis.21 If this technique can be applied 13 Visser DH, Solomons RS, Ronacher K, et al. Host immune
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treatment or those who require optimised or prolonged fluid bacterial load correlates with inflammatory response and
predicts neurological events during tuberculous meningitis
antituberculosis therapy. treatment. J Infect Dis 2019; 219: 986–95.
Substantial progress had been made in the past 5 years, 15 Thuong NTT, Heemskerk D, Tram TTB, et al. Leukotriene A4
with better molecular diagnostic tests than previously hydrolase genotype and HIV infection influence intracerebral
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available, and better understanding of disease mech­ 2017; 215: 1020–28.
anisms and how antituberculosis drugs and anti- 16 van Laarhoven A, Dian S, Ruesen C, et al. Clinical parameters,
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important questions exist concerning the optimal Indonesia. J Infect Dis 2017; 215: 1029–39.
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18 Donovan J, Phu NH, Thao LTP, et al. Adjunctive dexamethasone for
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Contributors 19 Marais S, Lai RPJ, Wilkinson KA, Meintjes G, O’Garra A,
GET, JH, and JD conceptualised the manuscript. JH and JD conducted Wilkinson RJ. Inflammasome activation underlying central nervous
the literature search and wrote the first draft of the manuscript, which system deterioration in HIV-associated tuberculosis. J Infect Dis
was subsequently reviewed and revised by all authors before submission 2017; 215: 677–86.
for publication. 20 Rohlwink UK, Figaji A, Wilkinson KA, et al. Tuberculous
meningitis in children is characterized by compartmentalized
Declaration of interests immune responses and neural excitotoxicity. Nat Commun 2019;
We declare no competing interests. 10: 3767.
Acknowledgments 21 Tucker EW, Guglieri-Lopez B, Ordonez AA, et al. Noninvasive
JH, JD, NTTT, NHP, and GET are supported by the Wellcome Trust, UK. ¹¹C-rifampin positron emission tomography reveals drug
Wellcome had no role in the study design, data collection, data analysis, biodistribution in tuberculous meningitis. Sci Transl Med 2018;
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