Review

A clinical practice guideline for tuberculous meningitis

Joseph Donovan*, Fiona V Cresswell*, Elizabeth W Tucker*, Angharad G Davis*, Ursula K Rohlwink*, Julie Huynh*, Regan Solomons*,
James A Seddon*, Nathan C Bahr, Arjan van Laarhoven, Suzanne T Anderson, Sanjay K Jain, Felicia C Chow, Sophie Pattison, James E Scriven,
Gabriela Singh, Rob E Aarnoutse, Jan-Willem C Alffenaar, Sofiati Dian, Abi Manesh, Robin Basu Roy, Varinder Singh, Ronald van Toorn,
Caryn M Upton, Reinout van Crevel, Kelly E Dooley, Diana Gibb, David Meya, Robert J Wilkinson, Ewelina Rogozińska, Usha K Misra,
Anthony Figaji, Guy E Thwaites

Tuberculous meningitis is the most severe form of tuberculosis, causing death or disability in around half of those Lancet Infect Dis 2025
affected. There are no up-to-date international guidelines defining its optimal management. Therefore, the Published Online
Tuberculous Meningitis International Research Consortium conducted a systematic review of available evidence to August 18, 2025
https://doi.org/10.1016/
address key management questions and to develop practice guidance. The consortium includes representatives from
S1473-3099(25)00364-0
India, Indonesia, South Africa, Uganda, Viet Nam, Australia, the Netherlands, the UK, and the USA. Questions were
*Contributed equally
developed using the Population, Intervention, Comparator, Outcome (PICO) format for tuberculous meningitis
Oxford University Clinical
diagnosis, anti-tuberculosis chemotherapy, adjunctive anti-inflammatory therapy, and neurocritical and neurosurgical Research Unit, Ho Chi Minh
care. A Grading of Recommendations, Assessment, Development and Evaluations approach was used to assess the City, Viet Nam (J Donovan PhD,
certainty (or quality) of evidence and establish the direction and strength of recommendations for each PICO-based J Huynh PhD,
question. We provide evidence-based recommendations for the optimal treatment and diagnosis of tuberculous Prof G E Thwaites PhD);
Department of Clinical
meningitis, alongside expert opinion. We expose substantial knowledge and evidence gaps, thereby highlighting Research, London School of
current research priorities. Hygiene & Tropical Medicine,
London, UK (J Donovan,
Introduction We provide guidance for the diagnosis and management F V Cresswell PhD); Global
Health and Infection, Brighton
An estimated 10·8 million people develop tuberculosis of tuberculous meningitis in children and adults, including and Sussex Medical School,
globally each year,1 of whom 2–5% have tuberculous people living with HIV. We provide some review of other Brighton, UK (F V Cresswell);
meningitis.2–4 Young children and people who are CNS tuberculous complications, including isolated brain Medical Research Council
Uganda Virus Research
immunosuppressed, including those living with HIV, are tuberculomas, spinal cord tuberculosis, and tuberculous
Institute and London School of
at a particularly high risk of the disease and the associated brain abscesses. We sought to make recommendations Hygiene & Tropical Medicine
poor outcomes.5 using the best available evidence, providing an assessment Uganda Research Unit,
Tuberculous meningitis develops following dissem­ Nakiwogo Road, Entebbe,
Uganda (F V Cresswell);
ination of Mycobacterium tuberculosis from the lungs to
Department of Anesthesiology
the brain and has a clinical course that is usually Key messages
and Critical Care Medicine,
insidious, with typical features of headache, neck • Diagnosing tuberculous meningitis is difficult; no single Division of Pediatric
stiffness, and fever, that develops in days to weeks. In test excludes tuberculous meningitis and anti-
Anesthesiology and Critical
Care Medicine (E W Tucker MD),
untreated cases, neurological deficits develop, tuberculosis treatment is often needed based on Center for Tuberculosis
consciousness declines, which results in death.5 Even compatible clinical features alone Research (E W Tucker,
with the best available treatment, 20–50% of patients • Xpert Ultra or Xpert PCR tests, in addition to Prof S K Jain MD), Center for
die.6–10 Early diagnosis and treatment, before the onset of Infection and Inflammation
mycobacterial culture, are strongly recommended as Imaging Research (E W Tucker,
coma, substantially reduces death and disability,11 yet the diagnostic tests for tuberculous meningitis Prof S K Jain), and Department
best diagnostics and most effective treatments are not • There is insufficient evidence to recommend greater than of Pediatrics (Prof S K Jain), John
well defined. Therefore, we conducted a systematic a dose of 10 mg/kg per day of rifampicin in adults at Hopkins University School of
review of the available evidence to address a series of Medicine, Baltimore, MD, USA;
present; however, limited data suggest a dose greater The Francis Crick Institute,
predefined, crucial clinical questions, to produce than 20 mg/kg per day is safe, and the results of on-going London, UK (A G Davis MD PhD,
authoritative international practice guidelines for the phase 3 trials investigating greater doses (35 mg/kg per Prof R J Wilkinson FMedSci);
management of tuberculous meningitis. day) are awaited Wellcome Discovery Research
No international clinical practice guideline exists for Platforms in Infection, Centre
• Corticosteroids reduce mortality in tuberculous for Infectious Diseases
tuberculous meningitis. Previous national guidelines by meningitis without HIV co-infection, and are strongly Research in Africa, Institute of
the United Kingdom British Infection Society for CNS recommended as an adjunctive therapy Infectious Disease and
tuberculosis in adults and children, published in 2009, • In the absence of an effective alternative adjunctive Molecular Medicine (A G Davis,
have not been updated.12 Tuberculosis treatment guidelines Prof R J Wilkinson) and Division
therapy for HIV-associated tuberculous meningitis and of Neurosurgery, Department
from WHO13–15 and jointly from the American Thoracic given their safety and potential effectiveness, of Surgery, Neuroscience
Society (ATS), Centers for Disease Control and corticosteroids are recommended for use in HIV- Institute (U K Rohlwink PhD,
Prevention (CDC), and Infectious Diseases Society of associated tuberculous meningitis on a case-by-case basis
G Singh MSc, Prof A Figaji PhD),
America (IDSA)16,17 include limited recommendations on University of Cape Town,
• Tuberculous meningitis leads to critical illness with Observatory, South Africa;
CNS tuberculosis management. Up-to-date, evidence- unique neurocritical and neurosurgical considerations, Queen Mary and Barts
based practice guidelines are required to help physicians yet there is little evidence guiding management Tuberculosis Centre, Queen
globally provide the best care to adults and children with strategies for these complications
Mary University London,
tuberculous meningitis.

www.thelancet.com/infection Published online August 18, 2025 https://doi.org/10.1016/S1473-3099(25)00364-0 1

 Review

London, UK (A G Davis, of the strength and certainty of our recommendations. International Research Consortium Meetings (Oxford,
R Basu Roy PhD); Centre for However, the recommendations are to guide and do not UK in September, 2023, and Bali, Indonesia in
Tropical Medicine and Global
Health, Nuffield Department of
mandate treatment approaches. Clinicians should November, 2024). An evaluation of patient values and
Medicine, Oxford University, continue to exercise their own judgment based upon the preferences was not performed.
Oxford, UK (J Huynh, individual characteristics of their patients. Recognising the need to provide practical guidance,
Prof R van Crevel PhD, The guideline is written for health-care workers even when evidence is scarce or absent, we also provide
Prof G E Thwaites); Desmond
Tutu TB Centre
responsible for tuberculous meningitis management expert-opinion-based good practice points and figures
(Prof J A Seddon PhD), anywhere in the world. We recognise that not all (figures 1 and 2) summarising suggested diagnostic and
Department of Paediatrics and diagnostic tests, treatments, and management strategies therapeutic approaches.
Child Health are available in all settings, and decisions should be
(Prof R Solomons PhD,
Prof R van Toorn PhD), Faculty
individualised by the treating clinician according to PICO questions for the diagnosis of tuberculous
of Medicine and Health available resources. meningitis
Sciences, Stellenbosch Recommendations are shown in panel 1, with evidence
University, Cape Town, Methods synthesis in the appendix (pp 3–13). A uniform case
South Africa; Department of
Infectious Diseases, Imperial
The Tuberculous Meningitis International Research definition was created in 2010 as a research tool for
College London, London, UK Consortium identified the need for tuberculous tuberculous meningitis classification, defining definite,
(Prof J A Seddon, meningitis practice guidelines in October, 2020. A probable, possible, and not having tuberculous menin­
Prof R J Wilkinson); Division of
writing group was convened from within the gitis.24 Developed as a standardised approach to classifying
Infectious Diseases and
International Medicine, multidisciplinary and global consortium to define its tuberculous meningitis diagnosis in research, it is now
Department of Medicine, scope, target audience, and methods. used as a standard against which diagnostic tests are
University of Minnesota, Four working groups addressed key questions assessed.
Minneapolis, MN, USA
concerning diagnosis, anti-tuberculosis chemotherapy,
(N C Bahr MD); Department of
Internal Medicine adjunctive therapy, and neurocritical and neurosurgical How accurate are CSF microscopy and biochemistry for
(A van Laarhoven MD PhD, care. Individuals were assigned to working groups (four to diagnosing tuberculous meningitis?
Prof R van Crevel) and six members per group) based on expertise and experience, We found no studies directly addressing this question.
Department of Pharmacy
ensuring adult and paediatric expertise within each group. The tuberculous meningitis lumbar cerebrospinal
(Prof R E Aarnoutse),
Radboudumc, Nijmegen, A Guideline Steering Group provided oversight. Working fluid (CSF) profile typically includes a moderate
Netherlands; Meta-Analysis groups were supported by a librarian and methodologist. lymphocytic pleocytosis, elevated protein, low glucose
Group (E Rogozińska PhD), MRC The key questions were developed using the (<50% plasma concentration), and moderately elevated
Clinical Trials Unit
Population, Intervention, Comparator, Outcome (PICO) lactate (5–10 mmol/L).25 However, none of these param­
(S T Anderson PhD,
Prof D Gibb MD), University format. Final questions, with recommendations, are eters is specific enough individually, or in combination,
College London, London, UK; given in panels 1–4. A GRADE18 approach was used to for definitive diagnosis. Nevertheless, CSF analysis is
Department of Neurology and assess certainty (or quality) of evidence and establish an essential part of the tuberculous meningitis diag­
Department of Infectious
Diseases, University of
the direction and strength of recommendations. Data nostic workup, providing supporting evidence for
California, San Francisco, CA, for PICO questions were summarised and presented in tuberculous meningitis diagnosis26 and an opportunity to
USA (F C Chow MD MAS); UCL the appendix (pp 3–18, 19–25). The following domains detect M tuberculosis or identify other causes of
Library Services, Library, were assessed: risk of bias (using a standard approach meningoencephalitis.
Culture, Collections and Open
Science (LCCOS), University
to applying signalling questions), indirectness, incon­
College London, London, UK sistency, imprecision, and other considerations How accurate are microbiological and molecular tests
(S Pattison MSc); Department (eg, publication bias). Risk of bias assessment was for diagnosing tuberculous meningitis?
of Microbes, Infection & performed using the appropriate tools—eg, Quality The challenge in detecting M tuberculosis within CSF is
Microbiomes, School of
Infection, Inflammation and
Assessment of Diagnostic Accuracy Studies 2 for the very low bacterial numbers, limiting the sensitivity of
Immunology, College of diagnostic studies and revised Cochrane risk-of-bias all currently available tests. Technician skill, large CSF
Medicine and Health, tool for randomised controlled trials (RCTs).19,20 volumes, and optimal processing can improve diagnostic
University of Birmingham, Certainty assessment was performed by one individual yields.27–29
Birmingham, UK
(J E Scriven PhD); Institute for
from the respective working group, with certainty In most settings, CSF Ziehl–Neelsen (ZN) smear testing
Infectious Diseases and Sydney downgrading or upgrading conducted in line with the is insensitive (<30%), and provides little advantage
Pharmacy School, Faculty of GRADE approach.21 compared with GeneXpert Xpert MTB/RIF (Xpert) or
Medicine and Health, For each PICO question, the certainty of evidence Xpert MTB/RIF Ultra (Ultra) tests (GeneXpert, Cepheid
University of Sydney, Sydney,
NSW, Australia
(high, moderate, weak, or very weak) and the strength of Sunnyvale, CA USA; appendix pp 3–4).29 Xpert and Ultra
(Prof J-W C Alffenaar PhD); recom­mendation (strong or weak, and for or against) are PCR-based tests that provide rapid results and detect
Westmead Hospital, were stated.18 Justifications for recommendation mutations associated with rifampicin resistance. Ultra
Department of Pharmacy,
strengths are given in the accompanying narrative. Draft PCR’s lower limit of detection enhances its sensitivity,
Westmead, NSW, Australia
(Prof J-W C Alffenaar); recom­ mendations were developed and approved in making it the test of choice, when available.26 Both Xpert
Department of Neurology and guideline group meetings. Wider consultations with and Ultra PCR tests showed high specificity (appendix
Research Center for Care and global tuberculous meningitis experts (approximately pp 5–8), although neither test can rule out tuberculous
Control of Infectious Disease,
120 people) occurred during Tuberculous Meningitis meningitis. These tests should, when possible, be

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Faculty of Medicine,
Panel 1: Population, Intervention, Comparator, Outcome (PICO) questions for the diagnosis of tuberculous meningitis Universitas Padjadjaran and
Hasan Sadikin Hospital,
How accurate are CSF microscopy and biochemistry for • Mycobacterial culture: moderate certainty of evidence, Bandung, Indonesia
diagnosing tuberculous meningitis? strong recommendation for use in diagnosis of (S Dian MD PhD); Department
• Population: all individuals in hospital being evaluated for tuberculous meningitis, ideally in combination with Xpert of Infectious Diseases, Christian
Medical College, Vellore, India
tuberculous meningitis or Xpert Ultra PCR (A Manesh DM); National
• Intervention: CSF cell microscopy, biochemistry, and lactate • AlereLAM: insufficient evidence to recommend for or Center for Excellence in
• Comparators: (1) definite or probable tuberculous meningitis, against use Pediatric Tuberculosis,
and (2) positive CSF mycobacterial culture Department of Pediatrics, Lady
How accurate is adenosine deaminase (ADA) for diagnosing Hardinge Medical College and
• Outcome: true positive, false positive, true negative, and false Kalawati Saran Children’s
tuberculous meningitis?
negative Hospital, Bangla Sahib Marg,
• Population: all individuals in hospital being evaluated for
• Conclusion: insufficient evidence to recommend for or against New Delhi, India (V Singh MD);
tuberculous meningitis TASK Clinical Research Centre,
use
• Intervention: ADA Cape Town, South Africa
How accurate are microbiological and molecular tests for • Comparators: (1) definite or probable tuberculous meningitis, (C M Upton MD); Department
of Medicine, Vanderbilt
diagnosing tuberculous meningitis? and (2) positive CSF mycobacterial culture
University Medical Center,
• Population: all individuals in hospital being evaluated for • Outcome: true positive, false positive, true negative, and false Nashville, TN, USA
tuberculous meningitis negative (Prof K E Dooley); Infectious
• Intervention: each of Ziehl–Neelsen smear microscopy, • Conclusion: very low certainty of evidence for test accuracy, Diseases Institute, College of
Health Sciences, Makerere
Xpert or Xpert Ultra PCR test, mycobacterial weak recommendation for use in the diagnosis of University, Kampala, Uganda
culture (eg, mycobacteria growth indicator tube, tuberculous meningitis (D Meya PhD); TS Misra Medical
Lowenstein–Jensen, or microscopic observation drug College, Apollo Medics Super
How accurate is neuroimaging for diagnosing tuberculous Specialty Hospital and
susceptibility assay), and Alere–Lipoarabinomannan
meningitis? Vivekanand Polyclinic and
(AlereLAM)
• Population: all individuals in hospital being evaluated for Institute of Medical Sciences,
• Comparators: (1) definite or probable tuberculous meningitis, Lucknow, India
tuberculous meningitis or other CNS tuberculosis (eg, spinal
and (2) positive CSF mycobacterial culture (Prof U K Misra DM)
tuberculosis and tuberculomas)
• Outcome: true positive, false positive, true negative, and false Correspondence to:
• Intervention: CT or MRI brain (with or without contrast) Joseph Donovan, Oxford
negative
• Comparators: (1) definite or probable tuberculous meningitis, University Clinical Research Unit,
• Conclusions:
and (2) positive CSF mycobacterial culture Ho Chi Minh City,
• Ziehl–Neelsen smear microscopy: low certainty of 764 Vo Van Kiet, Viet Nam
• Outcome: true positive, false positive, true negative, and false
evidence for test accuracy, weak recommendation for use jdonovan@oucru.org
negative
in diagnosis of tuberculous meningitis See Online for appendix
• Conclusion: insufficient evidence to recommend for or against
• Xpert PCR: high certainty of evidence for test accuracy,
neuroimaging use as a diagnostic tool for tuberculous
strong recommendation for use in diagnosis of
meningitis, but neuroimaging might demonstrate features
tuberculous meningitis, in addition to mycobacterial
that increase the likelihood of a diagnosis of tuberculous
culture
meningitis; neuroimaging has an important role in
• Xpert Ultra PCR: moderate certainty of evidence for test
identifying intracerebral mass lesions and ensuring lumbar
accuracy, strong recommendation for use in diagnosis of
puncture safety (see figure 1); baseline neuroimaging is
tuberculous meningitis, in addition to mycobacterial
recommended
culture

combined with mycobacterial culture, enabling subsequent test cutoffs, and lack of gold standard comparators
extended drug susceptibility tests (appendix p 9). The (appendix pp 12–13). Elevated CSF ADA
accuracy of Xpert and Ultra PCR tests for detecting concentrations are not specific for tuberculous
rifampicin resistance is reduced when bacterial numbers meningitis. While evidence certainty is very low,
are very low.30 The Alere-Lipoarabinomannan (AlereLAM) ADA measurement is relatively inexpensive,
test (Abbott Determine TB-LAM antigen, Lake Bluff, IL, and elevated concentrations might prompt use of
USA) identifies M tuberculosis cell wall components by better tests (eg, Ultra PCR). Measurement of CSF
lateral flow. There is insufficient evidence to recommend ADA should not replace Xpert or Ultra PCR tests or
for or against using the AlereLAM test on CSF (appendix culture.
pp 10–11).
How accurate is neuroimaging for diagnosing
How accurate is ADA for diagnosing tuberculous tuberculous meningitis?
meningitis? We found no studies directly assessing this question.
Adenosine deaminase (ADA) accuracy assessment However, brain imaging, with CT or MRI, enables
is limited by variable assays with uncertain positive assessment of the incidence and evolution of

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Panel 2: Population, Intervention, Comparator, Outcome (PICO) questions for anti-tuberculosis chemotherapy
Does increasing the rifampicin dose reduce mortality in • Comparators: standard anti-tuberculosis chemotherapy
adults with tuberculous meningitis versus a standard • Outcome: mortality
10 mg/kg per day dose? • Conclusion: insufficient evidence to make recommendation,
• Population: adults in hospital requiring treatment for for or against use of linezolid
tuberculous meningitis
Does higher dosing, or alternative administration routes, of
• Intervention: rifampicin dose greater than 10 mg/kg per
other tuberculosis drugs reduce mortality in adults caused
day, given orally or parenterally
by tuberculous meningitis?
• Comparators: rifampicin dose of 10 mg/kg per day, given
• Population: adults in hospital requiring treatment for
orally or parenterally
tuberculous meningitis
• Outcome: mortality
• Intervention: change in dose and route of administration, or
• Conclusion: moderate quality of evidence, does not support
addition or substitution of any other tuberculosis drugs
increased dose of rifampicin at 15 mg/kg per day and
• Comparators: standard anti-tuberculosis chemotherapy
higher*
• Outcome: mortality
Does rifampicin dose greater than 20 mg/kg per day reduce • Conclusion: insufficient evidence to make recommendation,
mortality in adults with tuberculous meningitis versus a for or against higher dosing or alternative administration
standard 10 mg/kg per day dose? routes, or other tuberculosis drugs
• Population: adults in hospital requiring treatment for
Is treatment duration less than 12 months effective against
tuberculous meningitis
tuberculous meningitis in adults?
• Intervention: rifampicin dose of greater than 20 mg/kg per
• Population: adults in hospital requiring treatment for
day, given orally or parenterally
tuberculous meningitis
• Comparators: rifampicin dose of 10 mg/kg per day, given
• Intervention: anti-tuberculosis chemotherapy duration of
orally or parenterally
less than 12 months
• Outcome: mortality
• Comparators: standard anti-tuberculosis chemotherapy
• Conclusion: insufficient evidence to recommend for or
duration of 12 months
against rifampicin dose of 20 mg/kg per day and higher*
• Outcome: mortality
Does an adjunctive fluoroquinolone reduce mortality from • Conclusion: insufficient evidence to make a
tuberculous meningitis in adults versus no fluoroquinolone? recommendation, for or against less than 12 months of
• Population: adults in hospital requiring treatment for anti-tuberculosis chemotherapy
tuberculous meningitis
What is the optimal treatment for childhood tuberculous
• Intervention: adjunctive fluoroquinolone
meningitis?
• Comparators: standard anti-tuberculosis chemotherapy
• Population: children in hospital requiring treatment for
• Outcome: mortality
tuberculous meningitis
• Conclusions: high quality of evidence; in adults with fully
• Intervention: 6 months of high-dose isoniazid, high-dose
drug-susceptible Mycobacterium tuberculosis, strong
rifampicin, pyrazinamide, and ethionamide
recommendation against adding a fluoroquinolone to the
(6H15–20R20–30Z40Eto20)
tuberculosis regimen or using a fluoroquinolone in place of
• Comparators: standard anti-tuberculosis chemotherapy
another drug in the regimen; for individuals with a high
• Outcome: mortality
probability of tuberculous meningitis caused by isoniazid-
• Conclusion: insufficient evidence to make a
resistant bacteria, strong recommendation for adding a
recommendation for or against the shorter regimen; either
fluoroquinolone to the regimen or using a fluoroquinolone
the 6-month 6H15–20R20–30Z40Eto20 intensive regimen or the
in place of isoniazid
standard 12-month regimen can be used†
Does adjunctive linezolid reduce mortality from tuberculous
*Trial results from HARVEST (ISRCTN15668391, reporting in 2025) and INTENSE-TBM
meningitis in adults versus no linezolid? (NCT04145258, reporting in 2026) should provide definitive data. †Standard antibiotic
• Population: adults in hospital requiring treatment for dosing achieves subtherapeutic levels in children; please see narrative under the PICO
questions for anti-tuberculosis chemotherapy recommendations.
tuberculous meningitis
• Intervention: adjunctive linezolid

common tuberculous meningitis complications Good practice points

(eg, hydrocephalus, tuberculomas, and infarctions) CSF volume
before and after the start of tuberculous meningitis We recommend sampling 6 mL or more of CSF for
treatment.31 For these purposes, baseline brain imaging dedicated M tuberculosis testing.27 Larger CSF volumes
is recommended. are a strong predictor of positive ZN stain, M tuberculosis

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culture, and Xpert PCR.28,32 CSF should be centrifuged at

3000 g for 20 min, with the cell pellet used for Panel 3: Population, Intervention, Comparator, Outcome
mycobacterial tests.27,32,33 (PICO) questions for adjunctive therapy
Should corticosteroids be used as an adjunctive therapy in
Children and adults living with HIV patients with tuberculous meningitis?
Our recommendations apply to all age groups and people • Population: adults and children with tuberculous
living with HIV. Only one study evaluated Ultra PCR meningitis
tests in children, reporting 50% sensitivity,34 lower than • Intervention: anti-tuberculosis chemotherapy with
adult studies (approximately 65%), probably reflecting adjunctive corticosteroids
lower CSF volumes from children. ZN staining, • Comparators: anti-tuberculosis chemotherapy without
mycobacterial culture, and Xpert and Ultra PCR tests adjunctive corticosteroids
have higher sensitivity in people living with HIV, possibly • Outcome: mortality and morbidity
due to higher bacillary loads.35–37 • Conclusions: high certainty of evidence, strong
recommendation for use in individuals without HIV;
Diagnostic approach and empirical therapy high certainty of evidence, weak recommendation for use
No single negative test can rule out tuberculous in people living with HIV so the decision to use should be
meningitis. Combining CSF ZN smear, Xpert or Ultra made on a case-by-case basis
PCR, and mycobacterial culture might increase
diagnostic yields.35,37 Repeated testing of CSF can increase What is the optimal timing of antiretroviral therapy for
diagnostic yields. Consistent neuroimaging features— CNS tuberculosis?
eg, hydrocephalus, basal exudates, infarcts, or • Population: adults and children with tuberculous
tuberculomas—increases the probability of a diagnosis meningitis
of tuberculous meningitis,31,38,39 as does M tuberculosis • Intervention: immediate antiretroviral therapy (within
identification outside of the CNS. Testing of sputum for 7 days of commencing anti-tuberculosis treatment)
M tuberculosis is recommended given that pulmonary • Comparators: deferred antiretroviral therapy initiation
tuberculosis is present in around 50% of cases of (after 2 months of anti-tuberculosis treatment)
tuberculous meningitis.9,10 Nevertheless, given the • Outcome: mortality and morbidity
limited sensitivity of available tests and the fatal • Conclusion: high certainty of evidence, weak
consequences of delayed treatment, many patients recommendation to defer initiating antiretroviral therapy
(30–50%) must start treatment empirically,6,9,10,40 based on 4–8 weeks after starting anti-tuberculosis treatment
clinical suspicion alone. A diagnostic approach to What other adjunctive therapies can be considered for the
tuberculous meningitis, based on evidence and expert management of tuberculous meningitis?
opinion, is presented in figure 1. • Population: adults and children with tuberculous
meningitis
PICO questions for anti-tuberculosis • Intervention: adjunctive aspirin, thalidomide, infliximab,
chemotherapy cyclophosphamide, anakinra, or interferon-γ
Recommendations are shown in panel 2, with evidence • Comparators: anti-tuberculosis chemotherapy without
synthesis in the appendix (pp 14–18). Anti-tuberculosis the aforementioned adjunctive agents
drug regimens for tuberculous meningitis treatment are • Outcome: mortality and morbidity
based on those developed for pulmonary tuberculosis • Conclusion: insufficient evidence to make a
and do not account for the need to achieve therapeutic recommendation for or against adjunctive aspirin,
concentrations within the CNS.41 Tuberculous meningitis thalidomide, infliximab, cyclophosphamide, anakinra, or
caused by bacteria resistant to first-line drugs (rifampicin interferon-γ; decision to initiate these treatments should
and isoniazid) is an increasing therapeutic challenge, be made on a case-by-case basis considering factors
with few data describing the CNS activity and effective­ discussed in the guideline
ness of drugs recently approved and highly effective for
multidrug resistant pulmonary tuberculosis treat­
ment.42–45 Recent animal and clinical studies using PET was undetectable in CSF in two-thirds of patients with
imaging with radio-labelled antibiotics have provided tuberculous meningitis as reported in two studies that
insights on CSF and brain distribution, and the activity used the standard dose.7,51 Higher rifampicin doses or
of these drugs.46–49 exposures increase bacterial killing in pulmonary
tuberculosis,52 and 35 mg/kg per day has been safely
Does increasing the rifampicin dose reduce mortality in used in adults and children with pulmonary tuberculosis
adults with tuberculous meningitis versus a standard and tuberculous meningitis.53–56
10 mg/kg per day dose? Four phase 2 trials and one phase 3 trial have investigated
Standard 10 mg/kg per day rifampicin dosing results in higher rifampicin doses for tuberculous meningitis
very low CSF concentrations or exposures.9,50 Rifampicin (appendix pp 14–15). Across these five studies, three studies

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Panel 4: Population, Intervention, Comparator, Outcome (PICO) questions for neurocritical and neurosurgical care
Should active management (medical or surgical) or standard • Conclusion: insufficient evidence to make a
of care be used in individuals with tuberculous meningitis recommendation for or against surgical management of
with hydrocephalus or raised intracranial pressure? tuberculomas at diagnosis or after medical treatment failure
• Population: adults or children (with or without HIV) in
Should surgical management of tuberculous abscesses with
hospital with tuberculous meningitis and hydrocephalus or
or without tuberculous meningitis occur at time of
raised intracranial pressure
diagnosis or after medical treatment failure?
• Intervention: active medical (repeated lumbar punctures
• Population: adults or children (with or without HIV) in
with diuretics) or surgical management (or a combination)
hospital with tuberculous abscesses (with or without
• Comparators: standard WHO therapy (ie, the current
tuberculous meningitis)
treatment regimen of isoniazid, rifampicin, pyrazinamide,
• Intervention: surgical management of tuberculous
and ethambutol given daily for the first 2 months, followed
abscesses at diagnosis
by isoniazid and rifampicin given daily for an additional
• Comparators: surgical management after failure of standard
10 months, that was established in 1995 and excludes
WHO therapies
streptomycin as first-line therapy)
• Outcome: mortality, morbidity, radiological outcome, and
• Outcome: mortality and morbidity, radiological outcome,
complications (including treatment failure)
and complications (including treatment failure)
• Conclusion: insufficient evidence to make a
• Conclusion: insufficient evidence to make a
recommendation for or against surgical management of
recommendation, for or against active medical or surgical
tuberculous abscesses at diagnosis or after medical
management of hydrocephalus or raised intracranial pressure
treatment failure
Should a ventriculoperitoneal shunt or endoscopic third
Should the management of hyponatremia in patients with
ventriculostomy be used for the surgical management of
tuberculous meningitis be based on aetiology?
hydrocephalus in patients with tuberculous meningitis?
• Population: adults or children (with or without HIV) in
• Population: adults or children (with or without HIV) in
hospital with tuberculous meningitis and hyponatraemia
hospital with tuberculous meningitis and hydrocephalus or
• Intervention: treatment of hyponatremia tailored by
raised intracranial pressure
aetiology (cerebral salt-wasting syndrome or syndrome of
• Intervention: surgical management of hydrocephalus by
inappropriate antidiuretic hormone secretion)
ventriculoperitoneal shunt
• Comparators: treatment of hyponatremia not tailored by
• Comparators: surgical management of hydrocephalus by
aetiology (cerebral salt-wasting syndrome or syndrome of
endoscopic third ventriculostomy
inappropriate antidiuretic hormone secretion)
• Outcome: mortality, morbidity, radiological outcome, and
• Outcome: mortality, morbidity, and complications
complications (including treatment failure)
(including treatment failure)
• Conclusion: insufficient evidence to recommend
• Conclusion: insufficient evidence to make a
ventriculoperitoneal shunt over endoscopic third
recommendation for or against treatment of hyponatremia
ventriculostomy if surgical intervention is required;
tailored by aetiology
discretion of the treating clinician is required
Should all patients with tuberculous meningitis be assessed
Should surgical management of tuberculomas with or
for clinical and subclinical seizures?
without tuberculous meningitis occur at time of diagnosis
• Population: adults or children (with or without HIV) in
or after medical treatment failure?
hospital with tuberculous meningitis
• Population: adults or children (with or without HIV) in
• Intervention: assessed for clinical and subclinical seizures
hospital with tuberculomas (with or without tuberculous
by electroencephalogram
meningitis)
• Comparators: not assessed for clinical and subclinical
• Intervention: surgical management of tuberculomas at
seizures by electroencephalogram
diagnosis
• Outcome: mortality and morbidity
• Comparators: surgical management after failure of standard
• Conclusion: insufficient evidence to make a
WHO therapies
recommendation for or against assessment for clinical and
• Outcome: mortality, morbidity, radiological outcome, and
subclinical seizures
complications (including treatment failure)

did not have mortality as their primary outcomes or used tuberculous meningitis mortality (odds ratio 0·91,
high-dose rifampicin with other interventions (eg, 95% CI 0·56–1·46). However, these data are dominated by
linezolid and aspirin).43,51,57 The duration (2–8 weeks) and a large (817 adults) phase 3 trial investigating 15 mg/kg
doses (15–35 mg/kg per day) of rifampicin varied, but per day rifampicin, which might not have resulted in
higher rifampicin doses were not associated with reduced sufficiently high CSF exposures.9,50 We therefore examined

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 Review

the benefit of rifampicin doses higher than 20 mg/kg recent proponents,63,64 although there are no comparative
per day, including lower dose intravenous administration trials and data are insufficient to make a recommendation.
that achieved equivalent exposures. Data were limited and
a mortality benefit was not observed, although a dose Is treatment duration less than 12 months effective
higher than 20 mg/kg per day was safe. against tuberculous meningitis in adults?
Two active phase 3 trials are investigating 35 mg/kg There were no trials comparing anti-tuberculosis
per day of rifampicin in adults with tuberculous chemotherapy for less than 12 months versus 12 months
meningitis. Later in 2025, the HARVEST trial or longer. In 2016, a meta-analysis of 19 observational
(ISRCTN15668391) will report results, followed by the studies concluded that in all cohorts, most deaths
INTENSE-TBM trial (NCT04145258) that will report occurred in the first 6 months and that relapse was
results in 2026. The results of these trials might provide uncommon in all participants irrespective of the
definitive data to address this particular PICO question. regimen. No inferences regarding optimal treatment
duration could be made.65 WHO currently recommends
Does an adjunctive fluoroquinolone or linezolid reduce treating adult tuberculous meningitis with 12 months of
mortality in adults caused by tuberculous meningitis? anti-tuberculosis drugs; there is no evidence supporting
Five RCTs have evaluated the addition of fluoroquinolones a different recommendation. Additionally, there is no
to standard rifampicin-based regimens for tuberculous substantive evidence to support longer durations of anti-
meningitis (appendix p 16). Three studied levofloxacin, tuberculosis chemotherapy for tuberculous meningitis
one moxifloxacin, and one levofloxacin, ciprofloxacin, and (than for pulmonary tuberculosis) in terms of better
gatifloxacin together. Taken together, the addition of a outcomes.
fluoroquinolone to the regimen was not associated with
significantly reduced mortality (odds ratio 0·86, What is the optimal treatment for childhood
95% CI 0·51–1·45). However, post-hoc analysis of the tuberculous meningitis?
2016 Viet Nam trial9 found that rifampicin at 15 mg/kg Due to the non-linear effect of weight on clearance, young
per day with levofloxacin (as the fifth drug) reduced children, particularly those younger than 2 years, have
mortality in adults with tuberculous meningitis caused by lower drug exposures when given the same dose (mg/kg)
isoniazid-resistant bacteria (hazard ratio 0·34, 95% CI as older children, adolescents, and adults.66 Rifampicin up
0·15–0·76, p=0·01).58 to 35 mg/kg per day is safe in children, and in one study,
WHO endorsed linezolid for multidrug-resistant doses of up to 65–70 mg/kg rifampicin were needed to
pulmonary tuberculosis treatment in 2019.14 Data reach the target exposure.54 Additionally, a small phase 2
investigating linezolid use for tuberculous meningitis RCT of children with tuberculous meningitis reported
treatment are limited to three small phase 2 trials better neurocognitive outcomes in those receiving
(appendix p 17),42,43,59 which did not establish its benefit in regimens containing high-dose (30 mg/kg per day)
presumed drug-sensitive tuberculous meningitis. rifampicin.67 For more than 30 years, children with
Linezolid might, however, have a role in treating tuberculous meningitis in South Africa have been treated
multidrug-resistant tuberculous meningitis, given its with 6 months of higher doses of RHZ and ethionamide,
favourable CNS pharmacokinetic and bactericidal activity.60 with excellent outcomes.68 A recent systematic review
informed the 2022 WHO child and adolescent tuberculosis
Does higher dosing, or alternative administration guidelines;69 no clinical trials were identified but
routes, of other tuberculosis drugs reduce mortality in seven observational studies provided evidence that were
adults caused by tuberculous meningitis? graded as low quality. For children and adolescents aged
Only one study has addressed this question: a phase 2 19 years or younger with drug-susceptible tuberculous
trial of higher-dose intravenous isoniazid (500 mg meningitis, WHO recently recommended that a 6-month
per day) and ethambutol (2 g per day) with rifampicin regimen (isoniazid 15–20 mg/kg per day, rifampicin
and pyrazinamide in 54 adults (appendix p 18).61 22·5–30 mg/kg per day, and pyrazinamide 35–45 mg/kg
Pharmacokinetic analysis of the 2016 Viet Nam trial per day, and the substitution of ethambutol with
found a strong association between high CSF isoniazid ethionamide at 17·5–22·5 mg/kg per day) can be used
concentrations, slow acetylator status, and reduced case instead of the 12-month standard regimen.70
fatality.50 A 6-month regimen with high doses of Results of the SURE trial (ISRCTN40829906),71 an RCT
rifampicin, isoniazid, pyrazinamide (RHZ), and comparing a 6-month intensive regimen to the 12-month
ethionamide has produced excellent outcomes in standard for childhood tuberculous meningitis, should
South African children (see question 5), but has not been be available by the end of 2025.
studied in adults.
Intrathecal administration, usually of aminoglycosides, Good practice points
were used in the early years of anti-tuberculosis Drug-resistant tuberculous meningitis
chemotherapy,62 but became uncommon once RHZ Mortality from tuberculous meningitis caused by
became available. Intrathecal administration has some bacteria resistant to rifampicin and isoniazid

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 Review

Clinically suspected CNS infection

Yes
Investigate for cryptococcal Is there HIV co-infection?
meningitis

No

Cryptococcal meningitis excluded Box 1: Suspect tuberculous

meningitis*
(further investigation)

Box 2:
Neuroimaging†
CSF tests
Evaluate for tuberculosis elsewhere

Any one of the neuroimaging Typical CSF commonly shows: Atypical CSF findings can occur Evaluate for tuberculosis elsewhere
features: • White blood cells 10–500 cells/μl • Acellular in people living with • Chest x-ray and respiratory
• Basal enhancement • Lymphocytic predominance HIV or AIDS, those who are samples (essential)
• Hydrocephalus • Protein >1 g/L immunocompromised, and Other sites on case-by-case basis:
• Infarcts • Glucose <2·2 mmol/L OR children • Lymph node, hepatosplenic
• Tuberculomas CSF:blood <0·5 • Neutrophil predominance lesions, sampling
• Soft tissue and bone MRI
• CT of the abdomen, with or
without endoscopy and biopsy

Direct tuberculosis testing

AFB smear, Xpert or Ultra PCR, mycobacterial
culture (prioritise Xpert or Ultra PCR if limited
CSF volume)

POSITIVE Xpert or Ultra PCR OR POSITIVE AFB NEGATIVE Xpert or Ultra PCR AND NEGATIVE
smear OR neuroimaging consistent with AFB smear; neuroimaging not consistent
tuberculous meningitis with tuberculous meningitis

Start tuberculous meningitis Yes Other causes reasonably excluded, clinical

treatment signs and symptoms consistent with
tuberculous meningitis

No
Yes Not critically ill Critically ill
Reconsider boxes 1–2; are two or more features Consider alternative diagnoses, repeat lumbar Consider starting empirical therapy for
present? puncture (if safe) and expand search for tuberculous meningitis‡
tuberculosis at other body sites

No
Repeat lumbar puncture if safe to do so

Unexplained meningitis AND low glucose AND CSF has tuberculous meningitis Investigations for other causes Alternative non-tuberculous
focal neurology OR falling GCS pattern OR positive Xpert or and for Mycobacterium meningitis cause identified
Ultra PCR or AFB OR evidence of tuberculosis all negative
tuberculosis elsewhere

No
Continue investigation; low Continue tuberculous meningitis Case-by-case clinical judgement Stop tuberculous meningitis
threshold for starting tuberculous treatment on ongoing anti-tuberculosis treatment
meningitis treatment treatment factoring in pre-test
probability and risk–benefit profile
of treatment

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 Review

(multidrug-resistant tuberculous meningitis) exceeds although CSF concentrations of some drugs do not
70%.58,72 Poor outcomes are driven by delayed detection correlate well with brain concentrations. For example,
of resistance and initiation of second-line anti- rifampicin, delamanid, pretomanid, and bedaquiline
tuberculosis treatment, compounded by the uncertain achieve much higher concentrations in the brain than
effectiveness of second-line drugs in tuberculous CSF.46–48,73 Employing therapeutic drug monitoring to
meningitis. Currently, there are no RCTs informing address low exposure in plasma or serum could help to
guidance. optimise CNS concentration.74
Early rifampicin resistance detection is crucial for The bedaquiline, pretomanid, and linezolid (BPaL)
outcomes. Therefore, Xpert or Ultra PCR testing of CSF regimen is highly effective for multidrug-resistant
and other specimens, if extra-neural tuberculosis is pulmonary tuberculosis,75 but has not been evaluated in
suspected, are strongly encouraged in all patients with patients with multidrug-resistant tuberculous meningitis.
tuberculous meningitis. Clinical deterioration after the In animal models of tuberculous meningitis, the BPaL
start of anti-tuberculosis treatment is an unreliable regimen is inferior to the standard tuberculosis regimen,46
indicator of multidrug-resistant tuberculous meningitis with no additive effective of bedaquiline.49 Excellent
as it is more commonly caused by hydrocephalus, infarcts, activity was however noted in animal studies with
or other inflammatory complications (eg, tuberculomas). PaZ-based regimens.49 Whether bedaquiline achieves
Without trials, the selection of second-line drugs is based sufficient CNS exposure to be effective is uncertain;
upon their predicted activity within the CNS (appendix however, more than 50% of patients with tuberculous
p 19). CSF pharmacokinetic data assist drug selection, meningitis have concurrent pulmonary tuberculosis,9 for
which bedaquiline will be highly effective.

Figure 1: Diagnostic approach for suspected tuberculous meningitis in Adverse drug effects
children and adults Pyrazinamide, isoniazid, and rifampicin can all cause
Boxes shaded in blue represent evidence-based recommendations. Boxes without
shading represent consensus recommendations drawn from collective expert
drug-induced liver injury, the most common reason for
opinion and expertise. In people living with HIV or AIDS, cryptococcal meningitis treatment interruption and drug substitution. However,
can present similarly to tuberculous meningitis and should be excluded in the first unlike in pulmonary tuberculosis, stopping anti-
instance as cryptococcal antigen testing is highly sensitive.22 Large volumes of CSF tuberculosis drugs is an independent risk factor for death
are recommended. Diagnostic tests performed will depend on local availability;
however, multiple tuberculosis testing where available should be performed.
from tuberculous meningitis.76–78 Therefore, clinicians
Where rapid diagnostic testing or neuroimaging is consistent, anti-tuberculosis should weigh carefully the risks of discontinuing of anti-
therapy for tuberculous meningitis should be commenced. While mycobacterial tuberculosis therapy with the severity of drug-induced
culture does not return rapid results, it remains an important diagnostic test to liver injury.
perform. When rapid diagnostic testing is negative and neuroimaging is not
suggestive of tuberculous meningitis, a decision to start treatment should be made
Little evidence exists to guide clinicians, although the
on degree of clinical suspicion, repeated evaluations, neurological deterioration, ACT HIV10,78 and LAST ACT77 (NCT03100786) tuberculous
and active exclusion of other possible causes. For box 1, suspected tuberculous meningitis trials randomly assigned participants who
meningitis* refers to risk factors, symptoms, and signs that are suggestive. developed drug-induced liver injury to three strategies:
Compatible symptoms and signs include more than 5 days of fever with any of:
headache, vomiting, neck stiffness, poor appetite or poor weight gain (young
replace RHZ with a fluoroquinolone and an
children), cough, or cranial nerve palsy. In the absence of HIV co-infection, a aminoglycoside, withdraw pyrazinamide and monitor
potential diagnosis of cryptococcal meningitis should still be considered. For box 2, aminotransferases, or continue all drugs unless amino­
mass lesions and raised intracranial pressure can develop as part of CNS transferases rise by more than ten times the upper limit of
tuberculosis (tuberculoma or tuberculous abscess) or from an alternative diagnosis
(eg, brain tumour or bacterial abscess); as such, in patients being evaluated for normal. Results are anticipated by the end of 2025.
tuberculous meningitis there may be contraindications to lumbar puncture due to Reintroduction of first-line drugs can be considered
the risk of cerebral herniation. Obtaining neuroimaging before lumbar puncture once liver function normalises, either stepwise or all at
can delay treatment initiation;23 therefore, clinical discretion should be used on a once, at a full dose, or an escalating dose. There is
case-by-case basis. Modality of neuroimaging† depends on availability. CT is often
accessible and, using contrast, can detect hydrocephalus, basal exudates, large insufficient evidence to support one approach instead of
infarcts, and tuberculomas. MRI is more sensitive at detecting small and evolving another, or the order of the drugs to be reintroduced.79
infarcts, particularly in the brainstem. Strongly consider starting empirical therapy Drug–drug interactions are an essential consideration
in conjunction with treatment for alternative causes in patients who are critically
for the treatment of tuberculosis. Rifampicin induces
unwell. Repeating CSF analysis with tuberculosis testing can provide valuable
guidance when deciding between tuberculous meningitis or other CNS infections. the hepatic metabolism of various drugs, including
In the absence of a perfect test to diagnose tuberculous meningitis, clinical antiretroviral therapies. The most up-to-date information
judgement on whether to initiate or continue anti-tuberculosis treatment should on drug interactions are listed on the HIV Drug For the HIV Drug Interactions
consider all aspects of the case, including epidemiological, clinical, laboratory, and tracker see https://www.hiv-
Interactions tracker.
imaging features where available. Specialist input should be also sought. AFB=acid- druginteractions.org/checker
fast bacilli. CSF=cerebrospinal fluid. GCS=Glasgow Coma Scale. *Risk factors other
than HIV include immunosuppression, malnutrition, travel or residence in a PICO questions for adjunctive therapy
tuberculosis-endemic region, young age, and contact with infectious tuberculosis Recommendations are given in panel 3, with evidence
in the last 1–2 years. †Neuroimaging should be performed before lumbar puncture
synthesis in the appendix (pp 21–24). Outcomes from
(to exclude the risk of herniation) if this is possible, and lumbar puncture should
only be performed when it is safe to do so. ‡Differentiating tuberculous meningitis tuberculous meningitis are strongly associated with
from other meningitides in high incidence tuberculosis settings can be challenging. dysregulated inflammatory responses.80 However, these

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 Review

HIV-positive Initiate anti-tuberculosis therapy HIV-negative

Adults: RHZE with quinolone if at high risk of
isoniazid resistance; children: RHZE or
Corticosteroids Cape Town regimen* Corticosteroids
Consider balance of benefits and risks Adults: dexamethasone 0·3–0·4 mg/kg per day
No evidence of harm, and small benefit weaned over 6–8 weeks unless clinical
observed in people living with HIV Supportive care as appropriate contraindication; children: dexamethasone
Oxygen, fluid balance, temperature, blood 0·3–0·6 mg/kg per day, or prednisone 2 mg/kg
pressure; nutrition: swallow assesment and per day (maximum 60 mg/day), for 4 weeks,
oral or nasogastric feed; mobility: pressure- followed by a 2–4 week tapering period, unless
relieving mattress, thromboembolism clinical contraindication
Clinical deterioration prevention
Repeat brain imaging

Pyridoxine (B6) supplementation

Hydrocephalus Stroke Mass lesion

Check for drug interactions between Drug-induced liver injury
Consult neurologist Oxygen, fluid Consider differential
medications† Consider risk and benefits of treatment
or neurosurgeon as resuscitation, diagnosis;
available regarding aspirin per local tuberculoma: interruption based on degree of liver
management: guidelines treat 9–12 months dysfunction, certainty of diagnosis, stage of
regular lumbar Clinical monitoring treatment; consider use of alternative
puncture, diuretics, Symptoms, vital signs, conscious level, focal antimicrobials during interruption
EVD, ETV, VPS neurology, seizures (eg, quinolone, linezolid, cycloserine,
ethionamide, prothionamide, and
aminoglycoside); reinitiate first-line therapy as
soon as liver function normalises; initiation of
ART treatment with four agents together or
If not already on ART initiate at week 4–8 unless there stepwise acceptable
is a clinical need for earlier initiation (eg, other Monitor electrolytes and liver function as
opportunistic illness); if CD4 count more than 50 then locally available
consider ART at 2 weeks
Hyponatraemia
Predictor of worse outcome; CSW is more
Complete 9–12 months of anti-tuberculosis common than SIADH, but differentiating
Immune reconstitution inflammatory therapy aetiology is complex; adequately rehydrate
syndrome or paradoxical reaction Step down to rifampicin and isoniazid after first and fluid balance monitoring is important;
Increase or prolong corticosteroids; in refractory 2 months; duration as per local guidelines, avoid fluid restriction in the presence of active
cases consider other immunomodulating agents considering resistance pattern and any infection; caution warranted with hypertonic
(eg, anti-TNF, thalidomide, or anakinra) treatment interruptions; if using Cape Town saline; rapid correction of chronic
regimen*, duration is 6 months hyponatraemia can cause harm

Figure 2: Summary of the treatment and follow-up of adults and children, with or without HIV, with tuberculous meningitis
Boxes shaded in blue represent evidence-based recommendations while boxes without shading represent consensus recommendations drawn from collective expert opinion and expertise.
ART=antiretroviral therapy. CSW=cerebral salt-wasting syndrome. EVD=external ventricular drain. ETV=endoscopic third ventriculostomy. RHZE=rifampicin and isoniazid and pyrazinamide with
ethambutol. SIADH=syndrome of inappropriate antidiuretic hormone secretion. TNF=tumour necrosis factor. VPS=ventriculoperitoneal shunt. *The Cape Town regimen is also recommended by WHO
for the treatment of drug-susceptible tuberculous meningitis in children and is of 6-months duration, with elevated doses of isoniazid (15–20 mg/kg per day), rifampicin (22·5–30 mg/kg per day), and
pyrazinamide (35–45 mg/kg per day), and the substitution of ethambutol with ethionamide (17·5–22·5 mg/kg per day). †Drug interactions can be seen in the HIV Drug Interactions tracker and the
Medscape Drug Interaction Checker.

For more on the Medscape Drug responses vary substantially between individuals. For regardless of severity.16,83 The results of two large (n=1065)
Interaction Checker see https:// example, people living with HIV and tuberculous and seven smaller (n=585) RCTs support these and our
reference.medscape.com/drug-
interactionchecker
meningitis have higher concentrations of inflammatory recommendations (appendix pp 21–22). Corticosteroids
markers but lower numbers of leucocytes, compared reduced case fatality, especially in children and adults
with patients with tuberculous meningitis without without HIV.84 There is no signal for a change in
HIV.40,81 disability among survivors in these groups. In people
Adjunctive corticosteroids have been given to control living with HIV and tuberculous meningitis, the
tuberculous meningitis-associated inflammation ever since benefits of corticosteroids are uncertain. One large RCT,
anti-tuberculosis drugs became available to treat tuberculous published 3 months after the updated literature
meningitis.82 The challenge, however, has been recognising search (July 23, 2023), was included given its relevance.10
the heterogeneity in inflammatory responses and identifying 520 adults with HIV-associated tuberculous men­
patients who benefit most from corticosteroids or, more ingitis were enrolled; dexamethasone was associated
recently, better targeted adjunctive therapies. with a non-significant survival benefit (hazard
ratio 0·85, 95% CI 0·66–1·10). Disability and the inci­
Should corticosteroids be used as an adjunctive therapy dence of immune reconstitution inflammatory
in patients with tuberculous meningitis? syndrome (IRIS) were not reduced by dexamethasone.
Corticosteroids are recommended by WHO and ATS/ Despite most participants being pro­foundly immune
CDC/IDSA for everyone with tuberculous meningitis, suppressed (52% with CD4 <50 cells/mm³),

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dexamethasone did not increase the number of adverse Case series have suggested that biological agents
events. targeting TNF (eg, infliximab or adalimumab) can help
In the absence of an effective alternative adjunctive treat tuberculomas and optochiasmatic arachnoiditis.97,98
therapy for HIV-associated tuberculous meningitis, and A retrospective cohort study in India reported
the safety and potential effectiveness of corticosteroids, adjunctive infliximab (10 mg/kg for one to three doses,
we recommend their use on a case-by-case basis in 4 weeks apart) was safe and effective in treating
people living with HIV. severe inflammatory complications of tuberculous
meningitis.99 The active TIMPANI trial (NCT05590455)
What is the optimal timing of antiretroviral therapy for is investigating adjunctive adalimumab in adults with
CNS tuberculosis? tuberculous meningitis and HIV.
Clinical trials for people living with HIV with pulmonary
tuberculosis have shown clear mortality benefits for Good practice points
patients with CD4 counts lower than 50 cells per mm³ Paradoxical reactions and IRIS
who initiate antiretroviral therapy within 2 weeks of Adjunctive anti-inflammatory therapies (eg, cortico­
starting anti-tuberculosis treatment, albeit with increased steroids) are usually given with anti-tuberculosis drugs
risk of IRIS.85–87 One RCT was conducted for people living at the start of treatment. However, in around 20% of
with HIV with tuberculous meningitis (median CD4 patients with tuberculous meningitis (>30% of people
count 41 cells per mm³) comparing antiretroviral therapy living with HIV), inflammatory intracerebral compli­
initiation within 7 days of anti-tuberculosis treatment or cations occur. These complications typically arise
at 2 months. No difference in 9-month survival between after 20–60 days of treatment, but can occur
the groups was found (appendix p 23).88 This finding was many months later. Often called ‘paradoxical reactions’,
similar for all CD4 counts. More grade 4 laboratory they can occur despite effective anti-tuberculosis
events were observed in the immediate antiretroviral treatment. In the context of people living with
therapy group, but there was no increase in neurological HIV starting antiretroviral therapy, they can meet
events. the criteria for IRIS,100 although the clinical and
These limited data inform our weak recommendation imaging characteristic are similar, regardless of HIV
to defer antiretroviral therapy for 4–8 weeks after starting status.
tuberculosis treatment, which is in agreement with The management of these inflammatory com­
WHO and other guidelines.89–92 A range of time to start plications has not been subject to trials. Expert opinion
antiretroviral therapy has been given based on expert recommends using high-dose corticosteroids initially
opinion and clinicians should decide to start therapy (eg, dexamethasone at 0·4 mg/kg per day), tapering
based on individual patient factors considering CD4 slowly according to symptom resolution. If cortico­
count (if available), other opportunistic infections, steroids do not control symptoms, then small
neuroimaging, and tuberculous meningitis-IRIS risk case-series and case reports have described the use of
factors (eg, CSF ZN or culture positivity or CSF anti-TNF biologicals (eg, infliximab),99 thalidomide,101 or
neutrophil pleocytosis).93 anakinra.102,103
Adjuvant interferon-γ treatment has been described in
What other adjunctive therapies can be considered for refractory CNS tuberculosis,104 and cyclophosphamide
the management of tuberculous meningitis? treatment described in CNS vasculitis.105,106 Data are too
Several small phase 2 studies in adults and children limited to make recommendations concerning their use
suggest aspirin, added to corticosteroids, can reduce the (appendix p 35).
incidence of brain infarcts and death (appendix p 24).
However, the trials are too small and heterogeneous to be PICO questions for the neurocritical and
definitive and a recommendation to use aspirin routinely neurosurgical care
cannot be given. The SURE (ISRCTN40829906) and Recommendations are shown in panel 4, with evidence
INTENSE-TBM (NCT04145258) trials, investigating synthesis in the appendix (p 25). Tuberculous
adjunctive aspirin in children and adults, respectively, will meningitis causes critical illness with unique
provide high-quality data from the end of 2025. neurocritical and neurosurgical considerations. Raised
Observational studies in South African children have intracranial pressure can fatally compress brain tissue
suggested that adjunctive thalidomide (2–5 mg/kg and cause ischaemia. Cerebral infarction is common
per day) was safe and effective in treating tuberculous (>65%) and predictive of poor outcomes.107 Key
mass lesions and optochiasmatic arachnoiditis.94,95 A management concerns relate to controlling raised
trial of higher dose thalidomide (24 mg/kg per day) was intracranial pressure, whether from oedema,
terminated early due to adverse effects and mortality in hydrocephalus, or mass lesions (eg, tuberculomas or
the thalidomide group.96 No additional trials have been tuberculous abscess), and ameliorating cerebral
reported. Teratogenicity and other adverse events have ischaemia from raised intracranial pressure and
restricted thalidomide’s use as an adjunctive agent. vasculitis.108

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 Review

Should active management (medical or surgical) or case-by-case basis; recommending one procedure
standard of care be used in individuals with tuberculous instead of the other cannot be made based on the
meningitis with hydrocephalus or raised intracranial available data.
pressure?
Hydrocephalus occurs in 50–90% of patients. Should surgical management of tuberculomas with or
Management varies from monitoring without without tuberculous meningitis occur at time of
intervention, to medical (regular lumbar punctures or diagnosis or after medical treatment failure; and should
diuretics) and neurosurgical (lumbar or external surgical management of tuberculous abscesses with or
ventricular drain, endoscopic third ventriculostomy, without tuberculous meningitis occur at time of
or ventriculoperitoneal shunt) inter­ ventions;107,109–112 diagnosis or after medical treatment failure?
however, no studies have directly compared these No studies directly address these two PICO questions.
approaches. A lack of standardised definitions and Surgery can be necessary, but no studies have compared
management approaches preclude evidence-based the timing of surgery for tuberculomas or tuberculous
recommendations. abscesses. There was heterogeneity in diagnosis,
surgical techniques (eg, biopsy vs debulking vs full
Should a ventriculoperitoneal shunt or endoscopic third resection), lesion location, duration of follow-up,
ventriculostomy be used for the surgical management and assessment of resolution or treatment failure.
of hydrocephalus in patients with tuberculous Evidence-based recom­ mendations cannot be made.
meningitis? Consortium members have reviewed the manage­
Two single-centre RCTs have compared ment of intracranial tuberculous mass lesions
ventriculoperitoneal shunt with endoscopic third elsewhere.115
ventriculostomy,113,114 and although both studies showed
the benefit of surgery, mortality and success rates were Should the management of hyponatremia in patients
similar between the interventions (appendix p 25). with tuberculous meningitis be based on aetiology?
These procedures should be considered on a Hyponatremia can cause cerebral oedema, raised
intracranial pressure, and infarction.108,116–118 Studies
suggest that hyponatremia is more commonly caused
Search strategy and selection criteria by cerebral salt-wasting syndrome than syndrome of
Literature searches were conducted for each Population, Intervention, Comparator, inappropriate antidiuretic hormone secretion, although
Outcome (PICO) question using keywords and controlled vocabulary. OVID MEDLINE, their discrimination is difficult and diagnostic criteria
Embase, Cochrane CENTRAL, Global Health, and Global Index Medicus were searched vary.118,119 Whether outcomes are improved by manage­
from inception until July 24, 2023, followed by a final screening for new literature on ment tailored to the cause of hyponatremia is uncertain.
March 11, 2025 (appendix p 34). Search strategies for MEDLINE are provided in the There are insufficient data to make recommendations
appendix (pp 26–32). A total of 35 143 records were retrieved, with 7380 records concerning optimal management of tuberculous
screened for relevance after duplicate removal. Non-English language articles and meningitis-associated hyponatraemia.
conference abstracts were excluded. For diagnostic questions, we only included test
accuracy studies. For anti-tuberculosis chemotherapy, only data from phase 2 and 3 Should all patients with tuberculous meningitis be
randomised controlled trials using standard WHO recommended therapy as the assessed for clinical and subclinical seizures?
comparator were considered for adults. Pharmacokinetic studies not reporting a Seizures can occur due to raised intracranial pressure,
mortality endpoint were excluded. An up-to-date systematic review and meta-analysis tuberculomas, and ischaemia, and can increase cerebral
of anti-tuberculosis chemotherapy in children directly informed recommendations; a oxygen consumption to increasing the risk of a metabolic
literature review was not repeated. For optimal antiretroviral therapy timing, only crisis and infarction.120,121 The pooled incidence of
randomised controlled trials were included. For neurocritical and neurosurgical care, a electroencephalogram-confirmed seizures was 25% from
standard WHO therapy comparator included only studies after 1995, when five descriptive studies, with seizures more common in
streptomycin was phased out as a first-line drug (ensuring recommendations were children than adults.122–126 Seizures are associated with
relevant to current treatment). For all questions, abstracts were independently increased mortality and morbidity.121,123 We found no
assessed by two reviewers from working groups and relevant abstracts were shortlisted studies directly addressing the PICO question; therefore,
for full text review. When the reviewers did not agree on abstract inclusion, consensus we were unable to provide recommendations.
was reached after discussion. Full texts of included studies were retrieved and
independently assessed for eligibility by two reviewers. Data extracted from eligible Good practice points
studies was tabulated and quality assessed. Full text data extraction was performed by Supportive care and checklists
one group member, with data from a random sample of 10% of studies cross-checked A comprehensive assessment proforma and an
by another group member. Only English language articles were included; studies from accompanying priorities checklist for patients with
high-burden countries not published in English were not included. Quality assessment tuberculous meningitis were proposed in 2019, by
was performed by an individual researcher from each working group (rather than two consortium members.127 The proforma outlines what
independent researchers). should be asked, checked, or tested at initial evaluation,
and daily inpatient reviews are conducted to assist

12 www.thelancet.com/infection Published online August 18, 2025 https://doi.org/10.1016/S1473-3099(25)00364-0

 Review

supportive clinical care for patients. The checklist offers randomised controlled trials on tuberculous meningitis (no payments
a useful and easy reminder of important issues to review received). SKJ received an institutional grant from the US NIH.
The other authors declare no competing interests.
during a time-critical period of acute patient deterioration.
A global survey showed that many centres (>90%) have Acknowledgments
We thank Hung Tran Thai (biostatistics, Oxford University Clinical
the resources to apply these approaches.127,128 Figure 2 Research Unit, Ho Chi Minh City, Viet Nam) who provided statistical
provides an evidence-based and expert opinion overview support for PICO question 2 of the diagnostics section. We thank the
of tuberculous meningitis treatment. Tuberculous Meningitis International Research Consortium for their
contribution to the development of the recommendations reported in
this Review.
Conclusion
In conclusion, we present a clinical practice guideline References
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