Skip to main content
NCBI home page
UKPMC Funders Author Manuscripts logoLink to UKPMC Funders Author Manuscripts
. Author manuscript; available in PMC: 2026 Jun 9.
Published in final edited form as: Curr Opin Infect Dis. 2026 Apr 8;39(3):179–188. doi: 10.1097/QCO.0000000000001194

Ischaemia in tuberculous meningitis: Update on pathophysiology, clinical predictors and management

Georgia Lamb 1,*, Reinout van Crevel 2,3, Graeme Meintjes 2,4,5, Angharad Davis 2,4,6
PMCID: PMC7619132  EMSID: EMS214124  PMID: 42041120

Abstract

Purpose of review

Tuberculous meningitis (TBM) is a severe manifestation of Mycobacterium tuberculosis infection, associated with high mortality and long-term neurological disability. Cerebral ischaemia and infarction are major contributors to poor outcomes, yet the underlying mechanisms remain incompletely understood. This review summarises current understanding of the pathophysiology, predictors, and emerging therapies for TBM-associated ischaemia, highlighting critical research priorities.

Recent findings

Stroke in TBM reflects a complex interplay of neuroinflammation, immunothrombosis, and raised intracranial pressure (ICP). Key emerging mediators include neutrophil extracellular traps, matrix metalloproteinases, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), platelet hyperactivation, and dysregulated tryptophan metabolism. Advanced neuroimaging, particularly vessel wall imaging, may improve infarction risk prediction and patient stratification, potentially supported by machine learning approaches. Large trials of adjunctive antiplatelet therapy show limited or inconsistent benefit, while small studies suggest anti-TNF therapy may be beneficial.

Summary

Despite progress in characterizing inflammation, thrombosis, and vascular injury in TBM, significant gaps remain in understanding mechanisms and timing of stroke. Improved mechanistic insight, integrated translational research, and trials of novel host-directed therapies are needed to prevent stroke and improve neurological outcomes. In parallel, efforts should focus on optimising existing strategies, particularly defining effective approaches to management of raised ICP.

Keywords: Tuberculous meningitis, stroke, neuroinflammation, host-directed therapy, intracranial pressure

Introduction

Tuberculous meningitis (TBM) is the most severe manifestation of Mycobacterium tuberculosis (M.tb) infection, associated with high mortality and long-term neurological morbidity. An estimated 10.7 million cases of tuberculosis occurred in 2024 [1]; TBM accounts for 1.3-6.8% of all tuberculosis cases, whilst the prevalence of TBM amongst people living with HIV reaches 13.6% [2,3]. Adult mortality ranges from 27-48%, with higher case-fatality rates in children and HIV co-infection, and 30-50% of survivors experience long-term neurological sequelae [2–5].

Cerebral ischaemia and infarction (stroke) are among the most devastating TBM complications, occurring in 15-57% of patients and conferring a threefold increase in mortality [5, 6]. Despite this burden, the mechanisms underlying TBM-associated ischaemia remain incompletely defined, and effective preventive strategies are lacking. Early identification of patients at high risk of stroke and development of targeted host-directed therapies represent major unmet needs.

TBM pathology is largely immune-mediated, prompting interest in adjuvant host-directed therapies including antiplatelet and immunomodulatory agents. However, evidence supporting these interventions for managing TBM-associated stroke is inconsistent or lacking [8]. International guidelines conclude there is insufficient evidence to recommend aspirin, thalidomide, or infliximab as adjunctive therapies in TBM [9]. Corticosteroids are the only host-directed therapy proven to reduce mortality, yet they do not reduce stroke incidence [10].

In this review, we synthesise current evidence on the pathophysiology of TBM-associated ischaemia from clinical, neuroimaging, and ex vivo studies, examine targeted therapeutic strategies, and highlight priorities for future research.

Part 1: Pathophysiology of inflammation and ischaemia in TBM

Ischaemia in TBM is driven by several pathogenic processes. Basal inflammatory exudate can surround and inflame arterial walls, causing large and perforator vessel thrombotic occlusion, while diffuse inflammatory vasculopathy causes luminal narrowing and reduced cerebral perfusion [5, 7]. Despite advances in characterising TBM neuroinflammation, mechanisms linking inflammation to cerebrovascular injury remain incompletely defined. Here, we review recent evidence for pathways connecting inflammation and ischaemia.

Vascular endothelial-derived growth factor (VEGF)

VEGF is released from endothelial cells in response to hypoxia and regulates endovascular permeability. In cerebral ischaemia, VEGF has protective and pathogenic roles, promoting angiogenesis but also blood-brain barrier (BBB) dysfunction, which implicates it in early TBM pathology [11]. A 2025 study found higher CSF VEGF levels in 222 TBM patients compared to controls, and VEGF predicted mortality, although this only reached statsitical signicifance in a discovery cohort and not in the validation cohort[12*]. A prior smaller study reported no overall increase in CSF or serum VEGF in TBM; whilst serum VEGF correlated with basal exudates on MRI, it was not independently associated with stroke [13*].

Intra-vitreal anti-VEGF therapy bevacuzimab improves outcomes in ocular TB and TB-immune reconstitution inflammatory syndrome (IRIS), where VEGF-driven angiogenesis promotes vasculitis and endovascular leakage [14, 15]. Experimental models suggest complex roles for VEGF signalling: IQGAP1, a scaffolding protein upregulated in Mycobacteria marinum-infected macrophages, promotes VEGF production, granuloma formation, and mycobacterial survival whilst suppressing TNF signalling. Pharmacological inhibition of IQGAP1 reduced VEGF production and tissue damage in ex-vivo models, identifying a potential therapeutic target [16*]. Although VEGF is linked to neuroinflammation and mortality in TBM, its role in TBM-associated infarction remains uncharacterised.

Neutrophils, Neutrophil extracellular traps and Matrix metalloproteinases

Neutrophils are central to innate immunity in TBM. Phagocytosis of M.tb-infected neutrophils and subsequent necrosis drive tissue damage, while peripheral neutrophils secrete pro-inflammatory cytokines including TNF-α and interleukin (IL)-1β [11]. Neutrophil extracellular traps (NETs) are web-like structures released by activated neutrophils, designed to capture and kill bacteria. NETs amplify macrophage activation and cytokine release (IL-6, TNF, IL-1β, IL-10), [17] and enhance thrombosis by activating platelets, inhibiting fibrinolysis, and providing a scaffold for clot formation. Activated platelets further drive NET formation, creating a self-reinforcing immunothrombotic cycle [18]. Higher pre-treatment CSF neutrophil counts correlate with mortality and stroke [19, 20]; this likely reflects disease severity, and whether neutrophil-driven thrombosis is causal remains unclear.

Matrix metalloproteinases (MMPs), secreted by astrocytes, microglia and neutrophils, degrade extracellular matrix and BBB components, facilitating leukocyte recruitment and vascular injury [11]. In vitro, astrocytes and microglia exposed to M.tb-infected monocytes secrete MMP-1, -3 and -9, with downregulated MMP-2, driven by pro-inflammatory cytokines including TNF-α [21]. In a cohort of 222 adult TBM patients, elevated CSF MMP-10 predicted mortality and genetic traits linked to CSF MMP-10 levels predicted mortality in a second group of 218 TBM patients, supporting a causal role for MMP-10 [12*].

Paediatric TBM studies are heterogenous. Rohlwink et al. demonstrated elevated CSF MMP-2 and -9 correlated with severity and neurological complications [22], while Manyelo et al. observed reduced CSF MMP-1 in children with stroke [23]. Transcriptomic analysis showed higher systemic MMP-8 expression in children with cerebral infarction compared to those without, with no differences in TNF-α, IL-1β, IL-10, IFN-γ, or VEGF [24*]. Poh et al identified marked CSF upregulation of MMP-1, -3, -7, -9 and -10 and NETs in TBM compared with controls, associated with leptomeningeal enhancement on neuroimaging, and high CSF MMP-7 and -10 predicted death or disability [25**]. In a murine TBM model, addition of doxycycline (an MMP inhibitor) to anti-tuberculosis therapy (ATT) improved survival, reduced CSF bacillary load and preserved intracranial vasculature, supporting MMP inhibition as a therapeutic strategy.

Platelet activation and thrombosis

M.tb infection induces clinical thrombocytosis, and plasma markers of platelet activation are upregulated in patients with TB [26, 27]. Activated platelets interact with neutrophils and monocytes to promote NET formation and MMP expression, promoting a pro-inflammatory, matrix-degrading phenotype [27, 28]. Transcriptomic analyses identified an upregulated haemostasis and platelet activation gene module correlating with disease severity, but not mortality, alongside marked neutrophil activation [29*].

Indices of platelet activation and heterogeneity (mean platelet volume, platelet distribution width, platelet-large cell ratio, platelet aggregometry) are associated with cerebral infarction in TBM, whereas conventional coagulation parameters (INR, clotting time) are not [30*]. These data support immunothrombosis (aberrant clot formation driven by innate immune responses) rather than classical hypercoagulability as the major driver of stroke.

Pro-inflammatory cytokines

Pro-inflammatory cytokines are essential for mycobacterial control but excessive production drives pathological neuroinflammation. TNF-α promotes granuloma formation yet increases BBB permeability and meningeal inflammation [11,31], providing a rationale for TNF-targeted therapies. IFN-γ activates macrophages, but elevated CSF levels are associated with poor outcomes, including stroke: meta-analyses demonstrate elevated CSF IFN-γ in TBM [32], and higher CSF IFN-γ, TNF-α, and IL-6 were observed in those who developed stroke in a cohort of 129 TBM patients [33*]. Although CSF IL-1β is elevated in TBM patients compared with controls, it does not predict mortality or disease severity, suggesting that IL-1-targeted strategies may have limited impact [32, 34].

Tryptophan

Tryptophan metabolism via the kynurenine pathway has been implicated in TBM pathogenesis (Figure 1). IFN-γ, IL-1β, IL-6 and TNF-α upregulate indoleamine 2,3-dioxygenase (IDO1), shunting tryptophan into the kynurenine pathway and generating neuroactive metabolites including quinolinic acid, an NMDA receptor agonist implicated in excitotoxic neuronal injury and stroke [11, 35].

Figure 1. Tryptophan pathway in Tuberculous Meningitis.

Figure 1

Open in a new tab

Tryptophan, an essential amino acid, can be metabolised by both the kynurenine and serotonin pathways. Pro-inflammatory cytokines released in response to Mycobacterium tuberculosis infection stimulate IDO-1, and preferential activation of the kynurenine-tryptophan pathway. Accumulation of quinolinic acid results in increased NMDA receptor activation, associated excitotoxic neuronal injury and stroke. Abbreviations: IFN-γ – interferon gamma; IL-6 – interleukin-6; TNF-α – tumour necrosis factor alpha; IDO-1 - indoleamine 2,3-dioxygenase; TPH – tryptophan hydroxylase; 5-HTP – 5-hydroxytryptophan

Created in BioRender. Lamb, G. (2026) https://BioRender.com/ref9bxc

In patients with TBM, higher baseline CSF tryptophan level is associated with increased mortality [36, 37*]. In >1000 TBM patients, CSF tryptophan independently predicted death and was inversely associated with IFN-γ, a key inducer of IDO1, whilst downstream metabolites of the kynurenine pathway correlated with CSF inflammation but not mortality [37*]. Plaatjie et al. showed greater CSF quinolinic acid accumulation in TBM compared to other CNS infections, with reduced CSF 5-hydroxytryptophan (5-HTP) indicating preferential activation of the tryptophan-kynurenine pathway [38**]. Quinolinic acid was associated with basal meningeal enhancement and hydrocephalus on MRI – key predictors of stroke [38**, 39]. Tryptophan-kynurenine pathway metabolites are linked with neuro-inflammation, supporting investigation of IDO1 inhibition, but additional unrecognised factors mediate the link between tryptophan and mortality.

Broader metabolic dysregulation may contribute to TBM pathology. Thuong et al confirmed that higher baseline CSF tryptophan levels predicted mortality in TBM, but found a stronger association between mortality and increased CSF 3-hydroxyoctanoate, part of a cluster of hydroxylated fatty acids that correlated with inflammatory markers [40*]. Whether altered tryptophan or fatty-acid metabolism directly influences stroke risk warrants further study.

Part 2: Clinical and radiological predictors of infarction in TBM

Early identification of patients at high stroke risk could aid prognostication and guide targeted host-directed therapies. Previous studies have linked radiological markers of inflammation (basal exudates, meningeal enhancement), and inflammatory biomarkers (raised C-reactive protein, elevated CSF protein and low CSF glucose) with stroke in TBM, supporting a relationship between inflammation, vasculopathy and ischaemia [39, 41*].

In one of the largest studies to date, Guo et al. reported a 20.4% incidence of new stroke within 30 days of ATT initiation among 1,353 TBM patients [42**]. Independent predictors of stroke included age >35 years (OR 1.49), hypertension (OR 3.56), diabetes (OR 1.78), smoking (OR 2.88), TBM severity (OR 2.11 for MRC grade ≥II), meningeal enhancement (OR 1.66) and hydrocephalus (OR 2.98). Although stroke strongly predicted 90-day disability, it mediated less than 20% of the association between neuroimaging markers of inflammation and disability, suggesting additional mechanisms such as diffuse cerebral ischaemia and hypoperfusion without overt stroke.

In contrast, Aggrohia et al. found no association between basal exudates or meningeal enhancement and infarction in a younger cohort with few vascular risk factors [43**]. In this study, 43% of patients had MRI-confirmed infarction, yet vasculitis was detected in fewer than half of those undergoing magnetic resonance angiography (MRA), suggesting thrombosis in absence of vessel wall inflammation visible on MRA. Infarction was most strongly associated with hydrocephalus, hypertension at presentation, reduced Glasgow Coma Scale (GCS) score and shorter symptom duration. Hydrocephalus likely promotes ischaemia through raised intracranial pressure (ICP) resulting in impaired cerebral perfusion. Vomiting, a clinical marker of raised ICP, independently predicts stroke in TBM [41*] as does systemic hypertension, which may reflect compensatory attempts to maintain cerebral perfusion [42**].

Subgroup analysis from Guo et al. showed that conventional vascular risk factors potentiated the effect of meningeal enhancement, but not hydrocephalus, on stroke risk [42**]. Patients with pre-existing endovascular dysfunction may be more susceptible to TB-related vasculitis and thrombosis, whereas raised ICP may predominate in those without vascular comorbidity. This is supported by paediatric data: children rarely have vascular risk factors, yet experience higher rates of hydrocephalus, infarction, and neurological sequelae exceeding 50% [44]. Among TBM patients without vascular comorbidity, disease severity remains the strongest predictor of stroke, although inflammatory biomarkers also retain prognostic value [45].

Collectively, these findings suggest that both neuroinflammation and raised ICP contribute to TBM-associated ischaemia, with their relative importance varying by age and comorbidity (Figure 2). Non-invasive ICP monitoring strategies, such as blood pressure and optic nerve sheath diameter measurement, may offer affordable tools for early risk stratification [46]. Future research should clarify the temporal interaction between inflammation and ICP, how this impacts on stroke risk, and determine whether more aggressive management of hydrocephalus reduces stroke risk.

Figure 2. Schematic to describe contributing processes in the development of ischaemia in TBM.

Figure 2

Open in a new tab

The dysregulated immune response leads to inflammatory exudate in the basal cisterns which causes direct arterial wall inflammatory changes in vessels in close proximity to the inflamed meninges. Inflammatory vasculopathy and vasospasm occurs more widely leading to reduced vessel calibre in small arteries of the brain. Simultaneously reduced CSF flow, vasogenic and cytotoxic oedema lead to raised pressures within the CNS. These processes contribute to reduced cerebral blood flow and subsequent ischemic changes in the brain.

Part 3: Advances in radiological characterisation of CNS ischaemia and infarction

Cerebral infarction in TBM was historically believed to occur predominantly within the ‘tubercular zone’, comprising the head of the caudate nucleus, internal capsule, and anteromedial thalamus, attributed to basal exudates and arteritis of vessels at the base of the brain. [47]. However, contemporary MRI-based studies, which are more sensitive than CT for detecting meningeal enhancement and stroke, challenge this paradigm [48]. In a cohort of 90 TBM patients, although 57.7% patients developed infarcts on MRI, only 13% occurred in the ‘tubercular zone’ [49]. Subsequent studies have demonstrated frequent involvement of cortical and cerebellar regions, with the middle cerebral artery (MCA) and its perforators most commonly affected [43**, 50]. Perforating and terminal cortical branches may be particularly vulnerable to raised ICP, reinforcing the link between, basal meningitis, hydrocephalus and ischaemia. In paediatric TBM, MRI-detected infarction rates exceed those in adults, with the cerebral hemispheres (59%), basal ganglia (53%) and thalamus (26%) most frequently involved [24*]. An autopsy study of 51 TBM patients identified macroscopic infarction in 72%, significantly higher than clinically or radiologically detected infarction, predominantly in the MCA territory supporting classification of TBM-related infarcts by vascular territory rather than zonal anatomy [51]. Microscopic infarction and necrotising injury of terminal arteries were nearly universal, consistent with diffuse inflammation-driven ischaemia.

Advances in vessel wall imaging (VWI) have enhanced detection of cerebral vasculitis in TBM. Arterial wall enhancement correlates with infarction in corresponding territories and may precede luminal changes detectable on MRA [52]. Choudhary et al. identified infarction in 48.5% of 101 adults with TBM, while vessel wall enhancement was seen in 66.3%; vessel involvement on VWI was associated with disease severity [53]. In a paediatric cohort, MRA-proven arteriopathy was detected in 65% of children with TBM-associated stroke, and was associated with recurrent stroke, cortical involvement and mortality, supporting a role for arterial inflammation in ongoing ischaemic injury while on ATT [54*].

Machine learning approaches may further refine imaging-based risk prediction in TBM [8]. Canas et al. developed a prognostic model, integrating imaging and clinical data to predict disease progression and outcomes, demonstrating better accuracy in HIV-negative patients and severe disease [55*]. Similar models could be adapted to stratify stroke risk at diagnosis, enabling earlier identification of patients most likely to benefit from targeted host-directed or ICP-focused interventions.

Part 4: Treatments targeting ischaemia in TBM

Given the immune-mediated nature of TBM pathology, host-directed therapies have been explored as adjuncts to ATT to reduce inflammation-driven thrombosis and ischaemia.

Antiplatelet therapy

Aspirin has been proposed as adjunctive treatment due to its antithrombotic and anti-inflammatory effects through irreversible inhibition of cyclo-oxygenase pathways and prostanoid production [56]. A 2021 meta-analysis suggested a reduction in new-onset stroke (hazard ratio 0.51; number needed to treat 10) but no clear mortality benefit with adjunctive aspirin [57]. Additional studies have since reported mixed findings (Table 1).

Table 1. Randomized and Planned Trials of Aspirin in Tuberculous Meningitis.
Trial Population (N) Sites Aspirin dosing Comparator Key outcomes Stroke-specific outcomes
Misra et al. 2010 Adults with TBM (n=118) India - single centre Aspirin 150mg/day for 3 months Placebo + ATT Significant reduction in 3-month mortality; aspirin well tolerated MRI-proven stroke at 3 months: 24.2% aspirin vs 43.3% placebo; not statistically significant
Schoeman et al. 2011 Children with TBM (n=146) South Africa - single centre Low dose (Aspirin 75mg/day) vs high dose (Aspirin 100mg/kg/day) regimens Placebo + ATT No significant difference in mortality or neurological disability; acceptable safety Not prespecified focused endpoint; no specific stroke outcome reported
Mai et al. 2018 (NCT02237365) HIV-uninfected adults with TBM (n=120) Vietnam – single centre Aspirin 81mg/day or 1000mg/day for 60 days Placebo + ATT Aspirin safe with standard ATT + dexamethasone; trend toward better outcomes in microbiologically confirmed TBM subgroup Composite: new brain infarction on MRI or death by day 60: Placebo 28.9%; Aspirin 81 mg 22.2%; Aspirin 1000 mg 15.8% (p=0.40 overall). Subgroup confirmed TBM: 34.4% events (placebo) vs 14.8% (81 mg) vs 10.7% (1000 mg) (p 0.06 trend toward benefit)
LASER-TBM trial, 2023 (NCT03927313) HIV-positive adults with TBM (n=52) South Africa - 4 hospitals Aspirin 1000 mg/day (with intensified regimen) SOC ± intensified ATT Safety study; primary AESI/death outcomes; efficacy not demonstrated No dedicated stroke endpoint reported; functional outcomes similar and no clear infarct data
ACT-TBM trial, 2025 Adults with TBM (n=237) India – multi-center Aspirin 75 mg/day Standard ATT alone No difference in mortality or functional outcome at 3 months Clinical stroke + imaging infarction composite: At 1 month: 9.1% (aspirin) vs 14.3% (standard) — not statistically significant; at 3 months: 6.7% vs 5.1% — no benefit
ISURE trial, 2025 Children with TBM (n=369) Asia – India, Vietnam; Africa – Uganda, Zambia, Zimbabwe Aspirin 20 mg/kg daily for first 8 weeks Placebo No significant difference in mortality with nonsignificant trend towards harm (22% severe disability/ death in aspirin group vs 15% in placebo group) No stroke-specific outcomes yet published
INTENSE-TBM (ongoing) (NCT04145258) Adults and adolescents with TBM (planned n~768) Africa - Côte d’Ivoire, Madagascar, South Africa, Uganda Aspirin 200mg/day (first 8 weeks), alongside intensified ATT Placebo Not yet published Stroke / cerebral infarction is included as a secondary outcome
Open in a new tab

Abbreviations: ATT – antituberculosis therapy; SOC – standard of care; MRI – magnetic resonance imaging; TBM – tuberculous meningitis.

The 2025 ACT-TBM trial evaluated aspirin and clopidogrel for prevention of clinical stroke, imaging-confirmed infarction and mortality and found neither agent significantly reduced stroke or death compared with placebo [58*]. High baseline disease severity and a substantial prevalence of stroke at enrolment may have limited the ability to demonstrate benefit, reflecting the late presentation typical of TBM in routine practice.

Low-dose aspirin (75mg daily) was used in ACT-TBM, but higher doses (>150mg) are required for anti-inflammatory effects. Earlier high-dose trials were inconclusive: Mai et al. reported reduced infarction and death with 1000mg daily [59], whereas the LASER-TBM trial showed no mortality advantage of high dose aspirin in HIV-associated TBM (although underpowered for efficacy endpoints) [60*]. Importantly, no trial has demonstrated significant bleeding risk with adjunctive aspirin [57–60]. The 2025 SURE trial in children with TBM found no benefit of high-dose aspirin, with a non-significant trend toward increased harm (22% vs 15% combined death/severe disability in aspirin vs placebo groups) [61*]. The ongoing phase 3 ITENSE-TBM trial in sub-Saharan Africa is assessing whether intensified ATT or aspirin 200 mg daily reduces mortality [62].

Corticosteroids

To date, corticosteroids are the only host-directed therapy shown to reduce mortality in TBM, but they have little effect on stroke incidence or disability [10, 63]. Despite two decades of routine use, there is little evidence steroids prevent cerebral ischaemia, and their benefit appears largely unrelated to vascular complications [9].

Anti-TNF therapies

TNF-α has emerged as a key cytokine associated with neuroinflammation and infarction, prompting interest in anti-TNF strategies.

Thalidomide

Thalidomide was the first agent with anti-TNF activity studied in TBM after animal models demonstrated reduced neuroinflammation and improved survival [64]. Systematic reviews suggest potential benefit in paradoxical reactions, and that low doses (3-5mg/kg/day) appear relatively safe [65]. A 2025 case series of four patients with HIV-associated TBM-IRIS (two with hydrocephalus, one with infarcts) reported rapid clinical and radiological improvement with thalidomide [66*]. Evidence remains limited to small series, and routine use cannot be recommended.

Infliximab

Off-label use of infliximab has been described in refractory TBM and TBM-IRIS. A retrospective Indian cohort reported improved disability-free survival in severe TBM, including patients with infarction, with infliximab compared with matched controls managed with ATT and steroids alone [67**]. A subsequent case series of 18 TBM patients treated with infliximab following clinical deterioration showed encouraging outcomes: at initiation, one-third had infarcts and one-third vasculitis, with a median modified Rankin Scale (mRS) score of 3.5 [68**]. After one month, 38% improved by ≥1 mRS point and 71% had radiological improvement; at one year, survival was 94% and disability-free survival 71%. While promising, these uncontrolled data require confirmation in prospective randomised controlled trials.

Other experimental treatments

Isolated reports describe successful use of IL-1 inhibitor anakinra for TBM paradoxical reactions, though without specific evaluation of stroke [69]. Recognition of MMPs in TBM pathogenesis has prompted interest in MMP inhibition as a therapeutic strategy [70]; the phase 2 DIRECT trial is underway to determine whether adjunctive doxycycline, an MMP inhibitor, reduces mortality or severe neurological deficit in TBM [71].

Conclusion

Cerebral ischaemia and infarction in TBM arise from a complex interaction between neuroinflammation, vascular injury and raised ICP. Despite decades of research, current adjunctive therapies provide limited protection against infarction, underscoring the need for earlier identification of high-risk patients and mechanism-guided intervention. Future research should prioritise integrated approaches that examine the link between inflammation, immunothrombosis, and raised ICP, harnessing advanced neuro-imaging and systems immunology approaches, alongside well-designed clinical trials evaluating host-directed strategies. In parallel, efforts should focus on optimising existing management strategies, particularly defining the most effective management of raised ICP.

Key points

  • Understanding of the pathophysiology of inflammation in TBM aids our understanding of ischaemia, which is linked to several key inflammatory pathways including platelet and neutrophil activation and excess of pro-inflammatory cytokines TNF-α, IFN-γ and IL-6.

  • NETs and MMPs may play a key role in pathogenesis of stroke in TBM and the role of MMP inhibitors as adjunctive therapy in TBM merits further research.

  • Features of neuroinflammation on MRI (leptomeningeal enhancement and basal exudates), and hydrocephalus are independent predictors of stroke in TBM, and early use of MRA or VWI could help to predict those at greatest risk of stroke.

  • Raised ICP likely drives ischaemia in TBM, particularly in those without underlying vascular risk factors and particularly in children; clinical studies to determine the optimum management of ICP in TBM are needed.

  • Clinical trials to determine the benefit of adjuvant aspirin in reducing stroke are inconclusive, and suggest no mortality benefit. Results of ongoing large phase 3 trials are awaited, but other possible targets to reduce immunothrombosis in TBM should be considered.

Acknowledgements

None

Financial support and sponsorship: no funding was obtained to support this review. AGD is funded by a Barts Charity grant via the Queen Mary and Barts Health TB Centre. RvC is supported for TBM research by the National Institutes of Health (R01AI165721)

Footnotes

Conflicts of interest: all authors declare no conflicts of interest

References

  • 1.World Health Organisation. Global tuberculosis report. 2025.
  • 2.Dodd PJ, Osman M, Cresswell FV, et al. The global burden of tuberculous meningitis in adults: A modelling study. PLOS Glob Public Health. 2021;1(12):e0000069. doi: 10.1371/journal.pgph.0000069. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.Chen X, Wei J, Zhang M, et al. Prevalence, incidence, and case fatality of tuberculous meningitis in adults living with HIV: a systematic review and meta-analysis. BMC Public Health. 2024 Aug 7;24(1):2145. doi: 10.1186/s12889-024-19683-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Du Preez K, Jenkins HE, Martinez L, et al. Global burden of tuberculous meningitis in children aged 0–14 years in 2019: a mathematical modelling study. Lancet Global Health. 2020;13(1):e59–e68. doi: 10.1016/S2214-109X(24)00383-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Misra UK, Kalita J, Maurya PK. Stroke in tuberculous meningitis. Journal of the Neurological Sciences. 303(1):22–30. doi: 10.1016/j.jns.2010.12.015. [DOI] [PubMed] [Google Scholar]
  • 6.Sy MC, Espiritu AI, Pascual JL. Global frequency and clinical features of stroke in patients with tuberculous meningitis: a systematic review. JAMA Netw Open. 2022;5:e2229282. doi: 10.1001/jamanetworkopen.2022.29282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Davis AG, Rohlwink UK, Proust A, et al. The pathogenesis of tuberculous meningitis. J Leukoc Biol. 2019;105:267–80. doi: 10.1002/JLB.MR0318-102R. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.Huynh J, Donovan J, Phu NH, et al. Tuberculous meningitis: progress and remaining questions. Lancet Neurol. 2022;21:450–464. doi: 10.1016/S1474-4422(21)00435-X. [DOI] [PubMed] [Google Scholar]
  • 9.Donovan J, Cresswell FV, Tucker EW, et al. A clinical practice guideline for tuberculous meningitis. Lancet Infect Dis. 2025 Aug 18;:S1473-3099(25)00364-0. doi: 10.1016/S1473-3099(25)00364-0. Epub ahead of print. Erratum in: Lancet Infect Dis. 2025 Dec;25(12):e684. doi: 10.1016/S1473-3099(25)00660-7. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Thwaites GE, Nguyen DB, Nguyen HD, et al. Dexamethasone for the treatment of tuberculous meningitis in adolescents and adults. N Engl J Med. 2004;351:1741–1751. doi: 10.1056/NEJMoa040573. [DOI] [PubMed] [Google Scholar]
  • 11.Barnacle JR, Davis AG, Wilkinson RJ. Recent advances in understanding the human host immune response in tuberculous meningitis. Front Immunol. 2024;14:1326651. doi: 10.3389/fimmu.2023.1326651. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.* Dian S, Koeken VACM, Ardiansyah E, et al. Inflammatory markers in the cerebrospinal fluid linked to mortality in tuberculous meningitis. Brain Commun. 2025 Jul 16;7(4):fcaf273. doi: 10.1093/braincomms/fcaf273. [• This prospective case control study identifies CSF VEGF and MMP-10 levels as predictors of 180-day mortality in 222 TBM patients, with only MMP-10 confirmed as prognostic in a validation cohort. This study supports a role for MMP-10 in TBM pathogenesis and disease severity.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.* Kumar D, Singh D, Modi T, et al. Role of vascular endothelial growth factor in tuberculous meningitis: a prospective study from a tertiary care center in North India. Indian J Pharmacol. 2023 Jul-Aug;55(4):216–222. doi: 10.4103/ijp.ijp_743_22. [• This small prospective study evaluates the role of CSF and serum VEGF in TBM, with a particular focus on association of VEGF with cerebral infarction. This study did not find a significant association between CSF or serum VEGF and incidence of TBM, or in the severity of disease or incidence of stroke, which contrasts with previous studies.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Agrawal M, Shyamsundar K, Raghu K, Raman R, et al. Intraocular Tuberculosis: Current Insights and Emerging Therapeutic Paradigms. Semin Ophthalmol. 2025 Nov 28;:1–17. doi: 10.1080/08820538.2025.2596385. Epub ahead of print. [DOI] [PubMed] [Google Scholar]
  • 15.Jain S, Bajgai P, Tigari B, et al. Bevacizumab for paradoxical worsening treatment adjunct in HIV patient with choroidal tuberculoma. J Ophthalmic Inflamm Infect. 2016 Dec;6(1):42. doi: 10.1186/s12348-016-0112-1. Epub 2016 Nov 8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 16.* Wen X, Li D, Wang H, et al. IQGAP1 domesticates macrophages to favor mycobacteria survival via modulating NF-κB signal and augmenting VEGF secretion. Int Immunopharmacol. 2024 Sep 10;138:112549. doi: 10.1016/j.intimp.2024.112549. Epub 2024 Jun 29. [• Ex vivo study that provides improved understanding of the mechanism of VEGF-mediated tissue damage in mycobacterial infection, and identifies a potential new therapeutic target in the signalling pathways of mycobacterial-infected macrophages.] [DOI] [PubMed] [Google Scholar]
  • 17.Braian C, Hogea V, Stendahl O. Mycobacterium tuberculosis-induced neutrophil extracellular traps activate human macrophages. J Innate Immun. 2013;5(6):591–602. doi: 10.1159/000348676. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 18.Zhou Y, Xu Z, Liu Z. Impact of Neutrophil Extracellular Traps on Thrombosis Formation: New Findings and Future Perspective. Front Cell Infect Microbiol. 2022 May 31;12:910908. doi: 10.3389/fcimb.2022.910908. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 19.van Laarhoven A, Dian S, Ruesen C, et al. Clinical Parameters, Routine Inflammatory Markers, and LTA4H Genotype as Predictors of Mortality Among 608 Patients With Tuberculous Meningitis in Indonesia. J Infect Dis. 2017 Apr 1;215(7):1029–1039. doi: 10.1093/infdis/jix051. [DOI] [PubMed] [Google Scholar]
  • 20.Thuong NTT, Vinh DN, Hai HT, et al. Pretreatment cerebrospinal fluid bacterial load correlates with inflammatory response and predicts neurological events during tuberculous meningitis treatment. J Infect Dis. 2019;219(6):986. doi: 10.1093/infdis/jiy588. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 21.Green JA, Dholakia S, Janczar K, et al. Mycobacterium tuberculosis-infected human monocytes down-regulate microglial MMP-2 secretion in CNS tuberculosis via TNFa, NFkB, p38 and caspase 8 dependent pathways. J Neuroinflamm. 2011;8(1):46. doi: 10.1186/1742-2094-8-46. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22.Rohlwink UK, Figaji A, Wilkinson KA, et al. Tuberculous meningitis in children is characterized by compartmentalized immune responses and neural excitotoxicity. Nat Commun. 2019;10(1) doi: 10.1038/s41467-019-11783-9. 3767. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Manyelo CM, Chegou NN, Seddon JA, et al. Serum and cerebrospinal fluid host proteins indicate stroke in children with tuberculous meningitis. PLoS One. 2021 Apr 30;16(4):e0250944. doi: 10.1371/journal.pone.0250944. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.* Huynh J, Pretorius PM, Jan W, et al. Brain Imaging and Whole Blood Targeted Transcriptomic Analyses to Characterize Cerebral Infarctions in Children With Tuberculous Meningitis. J Infect Dis. 2025 Oct 15;232(4):e676–e681. doi: 10.1093/infdis/jiaf399. [• Prospective cohort study including 55 children, using brain imaging and blood transcriptomic analysis to compare clinical, CSF, and brain MRI features of TBM between children with and without infarcts.] [• Identifies MMP-9 as a CSF marker particularly associated with stroke in TBM.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.** Poh XY, Loh FK, Bai C, et al. MMPs and NETs are detrimental in CNS-tuberculosis with MMP Inhibition in CNS-tuberculosis mice improving survival. J Neuroinflammation. 2025 Oct 11;22(1):230. doi: 10.1186/s12974-025-03548-7. [• This study provides both clinical and mechanistic evidence for the roles of MMPs and NETs in TBM.] [• It includes a prospective cohort study of 72 paediatric patients with TBM and non-TBM CNS infection, comparing CSF MMP gene expression, NETs production and clinical outcomes, and analysis of MMP expression in murine models of TBM.] [• It provides additional ex vivo evidence that MMPs and NETs are important in pathophysiology of TBM, drive a pro-inflammatory, matrix-degrading phenotype, and are particularly associated with worse outcomes including neurological deficit.] [• Identifies doxycycline, an MMP inhibitor, as a potential therapeutic target due to improved survival and reduced CSF bacillary load when doxycycline is added to standard ATT in murine TBM models, providing the mechanistic basis for the upcoming DIRECT randomised clinical trial.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 26.Kirwan DE, Chong DLW, Friedland JS. Platelet Activation and the Immune Response to Tuberculosis. Front Immunol. 2021 May 19;12:631696. doi: 10.3389/fimmu.2021.631696. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 27.Fox KA, Kirwan DE, Whittington AM, et al. Platelets Regulate Pulmonary Inflammation and Tissue Destruction in Tuberculosis. Am J Respir Crit Care Med. 2018 Jul 15;198(2):245–255. doi: 10.1164/rccm.201710-2102OC. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 28.Zucoloto AZ, Jenne CN. Platelet-Neutrophil Interplay: Insights Into Neutrophil Extracellular Trap (NET)-Driven Coagulation in Infection. Front Cardiovasc Med. 2019 Jun 20;6:85. doi: 10.3389/fcvm.2019.00085. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29.* Hai HT, Thanh Hoang Nhat L, Tram TTB, et al. Whole blood transcriptional profiles and the pathogenesis of tuberculous meningitis. Elife. 2024 Oct 30;13:RP92344. doi: 10.7554/eLife.92344. [• Large observational study including 281 adult patients with TBM, compared to patients with pulmonary TB and healthy controls. The key finding was that mortality was strongly associated with increased acute inflammation and neutrophil activation, and decreased adaptive immunity and T and B cell activation.] [• Supports an important role for over activation of neutrophil-mediated inflammatory responses in TBM pathogenesis, and heightened platelet activation associated with increased disease severity.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Verma R, Mahapatro S, Kumar A, et al. Platelet dysfunction and coagulation assessment in patients of tuberculous meningitis. Neurol Sci. 2020 Aug;41(8):2103–2110. doi: 10.1007/s10072-020-04299-4. Epub 2020 Feb 29. [DOI] [PubMed] [Google Scholar]
  • 31.Francisco NM, Hsu NJ, Keeton R, et al. TNF- dependent regulation and activation of innate immune cells are essential for host protection against cerebral tuberculosis. J Neuroinflamm. 2015;12(1):125. doi: 10.1186/s12974-015-0345-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Saghazadeh A, Rezaei N. Central inflammatory cytokines in tuberculous meningitis: A systematic review and meta-analysis. J Interferon Cytokine Res. 2022;42(3):95–107. doi: 10.1089/jir.2021.0176. [DOI] [PubMed] [Google Scholar]
  • 33.* Bhasin A, Kuthiala N, Sharma S, et al. Predictors of Infarction in Tuberculous Meningitis in Indian Patients. J Stroke Cerebrovasc Dis. 2021 Nov;30(11):106088. doi: 10.1016/j.jstrokecerebrovasdis.2021.106088. [• This prospective study of 129 adult patients identifies CSF cytokines TNF-α, IFN-γ and IL-6 as predictors of stroke in a cohort of patients with late-onset TBM, supporting the association between inflammation and cerebral infarction.] [DOI] [PubMed] [Google Scholar]
  • 34.Koeken VACM, Ganiem AR, Dian S, et al. Cerebrospinal fluid IL-1β is elevated in tuberculous meningitis patients but not associated with mortality. Tuberculosis (Edinb) 2021 Jan;126:102019. doi: 10.1016/j.tube.2020.102019. Epub 2020 Nov 11. [DOI] [PubMed] [Google Scholar]
  • 35.Wu QJ, Tymianski M. Targeting NMDA receptors in stroke: new hope in neuroprotection. Mol Brain. 2018;11(1):15. doi: 10.1186/s13041-018-0357-8. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 36.Van Laarhoven A, Dian S, Aguirre-Gamboa R, et al. Cerebral tryptophan metabolism and outcome of tuberculous meningitis: an observational cohort study. The Lancet Infectious Diseases. 2018;18:526–535. doi: 10.1016/S1473-3099(18)30053-7. [DOI] [PubMed] [Google Scholar]
  • 37.* Ardiansyah E, Avila-Pacheco J, Nhat LTH, et al. Tryptophan metabolism determines outcome in tuberculous meningitis: a targeted metabolomic analysis. Elife. 2023 May 9;12:e85307. doi: 10.7554/eLife.85307. [• This is the largest study to date looking at tryptophan metabolism in the pathogenesis of TBM and outcomes, in both HIV infected and non-infected individuals, and demonstrates that higher baseline CSF tryptophan predicts mortality.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 38.** Plaatjie ON, van Furth AMT, Solomons R, et al. Characterization of CSF tryptophan metabolites in South African children with tuberculous meningitis. Int J Infect Dis. 2026 Jan;162:108219. doi: 10.1016/j.ijid.2025.108219. Epub 2025 Nov 17. [• This is the first study evaluating tryptophan metabolism in children with TBM, and provides a mechanistic insight into the link between high CSF tryptophan and mortality in TBM.] [• It investigates the role and impact of downstream metabolites in the tryptophan kyrunenite pathway more closely, with revealing observations about the role of excess quinolinic acid production in driving neuroinflammation in TBM. This may link to stroke, given the known effect of quinolinic acid and subsequent NMDA receptor agonism on risk of ischaemic stroke.] [DOI] [PubMed] [Google Scholar]
  • 39.Kalita J, Misra UK, Nair PP. Predictors of stroke and its significance in the outcome of tuberculous meningitis. J Stroke Cerebrovasc Dis. 2009;18:251–8. doi: 10.1016/j.jstrokecerebrovasdis.2008.11.007. [DOI] [PubMed] [Google Scholar]
  • 40.* Le THN, van Abeelen KCJ, Ardiansyah E, et al. Pre-treatment untargeted cerebrospinal fluid metabolomic profiling in tuberculous meningitis uncovers pathways associated with mortality. Med. 2025 Sep 12;6(9):100703. doi: 10.1016/j.medj.2025.100703. Epub 2025 May 23. [• This study identifies fatty acid metabolism as a potential new metabolic pathway important in TBM pathogenesis and mortality.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 41.* Tomidy J, Satriadinatha GBY, Liwang FK, et al. Prognostic identifier of cerebrovascular complications in tuberculous meningitis: Meta-analysis. J Stroke Cerebrovasc Dis. 2023 Nov;32(11):107371. doi: 10.1016/j.jstrokecerebrovasdis.2023.107371. Epub 2023 Sep 20. [• This systematic review and meta-analysis identifies clinical and radiological predictors of stroke in TBM with high odds ratios for hypertension, and hydrocephalus and basal exudates on MRI, with low heterogeneity. It’s a large meta-analysis, involving 1535 TBM patients, and is internationally representative with centres in India, Pakistan, Taiwan, China, and New Zealand.] [DOI] [PubMed] [Google Scholar]
  • 42.** Guo Y-J, Gan X-L, Zhang R-Y, et al. Acute ischemic stroke in tuberculous meningitis. Front Public Health. 2024;12:1362465. doi: 10.3389/fpubh.2024.1362465. [• This is a large, multi-site cohort analysis of >1300 patients with TBM, investigating the predictors of acute ischaemic stroke in TBM and whether acute stroke mediates the relationship between neuroimaging inflammation markers and functional disability.] [• It is one of the first studies to specifically assess the role of inflammation in TBM-associated stroke and subsequent neurodisability, and considers the underlying impact of vascular risk factors on risk of stroke.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 43.** Aggrohia A, Bhatia V, Saroch A, Kumar Pannu A. Predicting cerebral infarction in tuberculous meningitis and its prognostic significance. Biomarkers in Medicine. 2024;18(8):407–417. doi: 10.1080/17520363.2024.2347194. [• This study characterises clinical and neuro-imaging predictors of stroke, and is one of the only studies to include vessel-wall imaging (MRA) for a high proportion ofincluded patients. It supports that baseline parameters of raised intracranial pressure predict cerebral infarction in TBM.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 44.* Lourens R, Singh G, Arendse T, et al. Tuberculous Meningitis Across the Lifespan. J Infect Dis. 2025 Jun 2;231(5):1101–1111. doi: 10.1093/infdis/jiaf181. [• This is the only review to directly compare the evidence for pathophysiology of ischaemia in TBM in children compared to adults.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 45.Tang S, Liu L, Xie Z, et al. Acute Ischemic Stroke in Tubercular Meningitis Patients Without Conventional Vascular Risk Factors: A Retrospective Case Control Study. J Inflamm Res. 2022 Dec 7;15:6617–6627. doi: 10.2147/JIR.S392040. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 46.Donovan J, Oanh PKN, Dobbs N, et al. Vietnam ICU Translational Applications Laboratory (VITAL) Investigators Optic Nerve Sheath Ultrasound for the Detection and Monitoring of Raised Intracranial Pressure in Tuberculous Meningitis. Clin Infect Dis. 2021 Nov 2;73(9):e3536–e3544. doi: 10.1093/cid/ciaa1823. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 47.Hsieh FY, Chia LG, Shen WC. Locations of cerebral infarctions in tuberculous meningitis. Neuroradiology. 1992;34:197–9. doi: 10.1007/BF00596334. [DOI] [PubMed] [Google Scholar]
  • 48.Chen X, Chen F, Liang C, et al. MRI advances in the imaging diagnosis of tuberculous meningitis: opportunities and innovations. Fron t Microbiol. 2023;14:1308149. doi: 10.3389/fmicb.2023.1308149. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 49.Soni N, Kumar S, Shimle A, et al. Cerebrovascular complications in tuberculous meningitis-a magnetic resonance imaging study in 90 patients from a tertiary care hospital. Neuroradiol J. 2020;33:3–16. doi: 10.1177/1971400919881188. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 50.Sy MC, Espiritu AI, Pascual JL. Global frequency and clinical features of stroke in patients with tuberculous meningitis: A systematic review. JAMA Netw Open. 2022;5:e2229282. doi: 10.1001/jamanetworkopen.2022.29282. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 51.Chatterjee D, Radotra BD, Vasishta RK, Sharma K. Vascular complications of tuberculous meningitis: An autopsy study. Neurol India. 2015 Nov-Dec;63(6):926–32. doi: 10.4103/0028-3886.170086. [DOI] [PubMed] [Google Scholar]
  • 52.Wang Y, Li Q, Zhen X, et al. Immunologic cerebral vasculitis and extrapulmonary tuberculosis: an uncommon association. J Clin Diagn Res. 2015;9:OD03–05. doi: 10.7860/JCDR/2015/13885.6497. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 53.Choudhary N, Vyas S, Modi M, Raj S, Kumar A, Sankhyan N, et al. MR vessel wall imaging in tubercular meningitis. Neuroradiology. 2021;63:1627–1634. doi: 10.1007/s00234-021-02678-y. [DOI] [PubMed] [Google Scholar]
  • 54.* Das S, Ray BK, Nandi M, Mondal G, Paul DK. The Spectrum of Intracranial Arteriopathies and Ischemic Strokes in Pediatric Tubercular Meningitis: A Tricentric Study From Eastern India. Pediatr Neurol. 2024 Aug;157:57–69. doi: 10.1016/j.pediatrneurol.2024.04.026. Epub 2024 May 6. [• This is the first prospective study of children with TBM using MRA imaging to characterise arteriopathy, supporting a role for arterial inflammation in ischaemic injury.] [DOI] [PubMed] [Google Scholar]
  • 55.* Canas LS, Dong THK, Beasley D, et al. Computer-aided prognosis of tuberculous meningitis combining imaging and non-imaging data. Sci Rep. 2024;14:17581. doi: 10.1038/s41598-024-68308-8. [• This is the first study to use machine learning to model disease progression and prognosis in TBM, and leverages the ability of new AI tools to extract imaging features without clinical assumptions that could bias relevant brain morphological changes associated with TBM severity and progression.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 56.Botting RM. Vane’s discovery of the mechanism of action of aspirin changed our understanding of its clinical pharmacology. Pharmacological Reports. 2010;62:518–525. doi: 10.1016/s1734-1140(10)70308-x. [DOI] [PubMed] [Google Scholar]
  • 57.Rohilla R, Shafiq N, Malhotra S. Efficacy and safety of aspirin as an adjunctive therapy in tubercular meningitis: a systematic review and meta-analysis. eClinicalMedicine. 2021;34:100819. doi: 10.1016/j.eclinm.2021.100819. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 58.** Bhatia R, Shree R, Modi M, et al. A randomised trial to assess the efficacy of add on therapy with aspirin or clopidogrel to the standard medical therapy alone in patients with tubercular meningitis: ACT TBM. Lancet Reg Health Southeast Asia. 2025 May 30;37:100604. doi: 10.1016/j.lansea.2025.100604. [• This is the first randomised controlled trial to assess antiplatelet therapy other than aspirin: it investigates whether adjunctive clopidogrel or aspirin is safe and effective in reducing clinical stroke and/or cerebral infarction on imaging in patients with TBM] [• It’s the largest trial to date, with the outcome that adjunctive antiplatelets had no effect on incidence of stroke, mortality, or safety outcomes in TBM, which is contrasting to previous smaller trials.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 59.Mai NT, Dobbs N, Phu NH, et al. A randomised double blind placebo controlled phase 2 trial of adjunctive aspirin for tuberculous meningitis in HIV-uninfected adults. Elife. 2018;7:e33478. doi: 10.7554/eLife.33478. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 60.* Davis A, Wasserman S, Stek C, et al. A phase 2A trial of the safety and tolerability of increased dose rifampicin and adjunctive linezolid, with or without aspirin, for human immunodeficiency virus–associated tuberculous meningitis: the LASER-TBM trial. Clinical Infectious Diseases. 2023;76(8):1412–22. doi: 10.1093/cid/ciac932. [• This is the first RCT looking at high-dose aspirin in HIV-associated TBM, mostly examining safety. No deaths were attributed to significant bleeding events, which is a reassuring result to support larger trials investigating high dose aspirin in HIV-TBM co-infection.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 61.* Gibb DM, the SURE Trial Team Shortened intensive anti-TB treatment and aspirin for African and Asian children with TB meningitis: The 48-week results from the phase-3 factorial randomised SURE trial. Abstract published at The Union World Conference on Lung Health; 2025. accessed at https://unionconf2025.abstractserver.com/programme/#/details/presentations/1796. [• This abstract provides an overview of the results of the recent phase 3 RCT of aspirin in children with TBM (SURE trial). It reveals that the trial found no evidence that adding high-dose aspirin for the first two months of treatment had any benefit in children with TB meningitis, and showed a non-significant trend towards harm.] [Google Scholar]
  • 62.Maitre T, Bonnet M, Calmy A, et al. Intensified tuberculosis treatment to reduce the mortality of HIV-infected and uninfected patients with tuberculosis meningitis (INTENSE-TBM): study protocol for a phase III randomized controlled trial. Trials. 2022 Nov 8;23(1):928. doi: 10.1186/s13063-022-06772-1. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 63.Prasad K, Singh MB, Ryan H. Corticosteroids for managing tuberculous meningitis. Cochrane Database Syst Rev. 2016;4:CD002244. doi: 10.1002/14651858.CD002244.pub4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 64.Kumar R, Kolloli A, Singh P, et al. Thalidomide and phosphodiesterase 4 inhibitors as host directed therapeutics for tuberculous meningitis: insights from the rabbit model. Front Cell Infect Microbiol. 2020;9:450. doi: 10.3389/fcimb.2019.00450. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 65.Panda PK, Panda P, Dawman L, et al. Efficacy and Safety of Thalidomide in Patients with Complicated Central Nervous System Tuberculosis: A Systematic Review and Meta-Analysis. Am J Trop Med Hyg. 2021 Jul 27;105(4):1024–1030. doi: 10.4269/ajtmh.21-0108. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 66.* Lee-Jones S, Rebe K, Marais S, et al. Thalidomide as an Adjunctive Therapy for HIV-Tuberculosis-Associated Immune Reconstitution Inflammatory Syndrome: A Case Series. Open Forum Infect Dis. 2025 Oct 1;12(11):ofaf617. doi: 10.1093/ofid/ofaf617. [• This case small case series provides some more recent evidence that low dose thalidomide is safe, and can result in favourable outcomes in patients with TBM IRIS unresponsive to steroids.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 67.** Manesh A, Gautam P, Kumar DSS, et al. Effectiveness of Adjunctive High-Dose Infliximab Therapy to Improve Disability-Free Survival Among Patients With Severe Central Nervous System Tuberculosis: A Matched Retrospective Cohort Study. Clin Infect Dis. 2023 Nov 17;77(10):1460–1467. doi: 10.1093/cid/ciad401. [• This is the first study to attempt a matched cohort comparison, although retrospective, of patients with severe TBM who receive infliximab compared to those who receive ATT and steroids alone (previous published studies have been case reports and descriptive studies).] [• This study also includes the largest cohort of patients treated with infliximab to date, and demonstrates a reduction in mortality and neurodsiability with adjunctive infliximab, providing promising supportive data for prospective clinical trials.] [DOI] [PubMed] [Google Scholar]
  • 68.** Benhard J, Monsel G, Dubée V, et al. Standardized Infliximab Regimen to Treat Severe Central Nervous System Tuberculosis: A Case Series of 18 Patients. Open Forum Infect Dis. 2025 Aug 12;12(8):ofaf450. doi: 10.1093/ofid/ofaf450. [• This case series of TBM patients managed with infliximab is one of the largest infliximab case series published to date, and the first from a European setting. It is the first case series to specifically focus on the incidence of vasculitis and outcomes of stroke following infliximab in TBM.] [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 69.Kanat A, Toker AK, Özer Şimşek Z, et al. Tuberculous Meningitis With Paradoxical Reaction in an Immunocompetent Young Male Treated by Interleukin-1 Receptor Antagonist. Case Rep Infect Dis. 2025 Nov 3;2025:8891508. doi: 10.1155/crdi/8891508. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 70.Jhilta A, Jadhav K, Singh R, et al. Breaking the Cycle: Matrix Metalloproteinase Inhibitors as an Alternative Approach in Managing Tuberculosis Pathogenesis and Progression. ACS Infect Dis. 2024 Aug 9;10(8):2567–2583. doi: 10.1021/acsinfecdis.4c00385. Epub 2024 Jul 22. [DOI] [PubMed] [Google Scholar]
  • 71.Adjunctive Doxycycline for Central Nervous System Tuberculosis (DIRECT) [Accessed February 2026]. https://clinicaltrials.gov/study/NCT06446245#study-overview .

RESOURCES