Highlight
- Middle meningeal artery embolization (MMAE) using n-butyl cyanoacrylate (n-BCA) significantly lowers recurrence and reoperation of chronic subdural hematomas (cSDH).
- The MEMBRANE randomized clinical trial demonstrated an 11.6% vs. 22.1% event rate for MMAE plus standard care versus standard care alone at 6 months.
- MMAE plus standard care showed noninferior safety outcomes with no increase in adverse events or functional disability compared to standard care alone.
Study Background
Chronic subdural hematoma (cSDH) represents a common neurosurgical condition characterized by the persistent accumulation of blood between the dura mater and arachnoid membrane, predominantly affecting elderly populations. The condition often arises after mild head trauma but may also be related to cerebral atrophy, anticoagulant usage, or coagulopathy. Standard treatment typically involves surgical evacuation, such as burr hole drainage; however, recurrence rates remain substantial, reportedly ranging from 10% to 30%, resulting in repeated hospitalizations and increased morbidity.
Recent advances have proposed middle meningeal artery embolization (MMAE) as a minimally invasive adjunctive therapy to reduce cSDH recurrence by disrupting the vascular supply that sustains the hematoma membrane. n-Butyl cyanoacrylate (n-BCA), a liquid embolic agent originally indicated for cerebral arteriovenous malformation devascularization, offers potential efficacy and safety for MMAE in this context.
Study Design
The MEMBRANE trial was a prospective, multicenter, open-label, randomized clinical trial conducted from May 2021 to February 2024 involving 30 hospitals (28 in the United States, 2 in China). The study enrolled 376 participants aged 18-90 years with symptomatic cSDH and a modified Rankin Scale (mRS) score ≤3, indicating mild to moderate disability but functional independence.
Participants were stratified into surgical and nonsurgical management groups based on clinical assessment by physician investigators. Subsequently, within each stratum, patients were randomized 1:1 to receive MMAE with the TRUFILL n-BCA embolic system plus standard care or standard care alone. The intervention involved catheter-directed embolization of the middle meningeal artery to target the neovasculature sustaining the hematoma membrane.
The primary effectiveness endpoint was the proportion of participants with residual or reaccumulated hematoma exceeding 10 mm at 6 months or requiring surgical intervention within 6 months. An independent core imaging laboratory adjudicated these outcomes to reduce bias. The primary safety endpoint was the incidence of adverse events (AEs) within 6 months, assessed per protocol in an as-treated population. Functional outcomes were measured predominantly by mRS scores at 3 months.
Key Findings
Among 376 randomized patients (188 MMAE plus standard care, 188 standard care alone), mean ages were approximately 71 years in both arms, with a nearly balanced sex distribution (23.9% vs 26.1% female, respectively).
The primary effectiveness endpoint occurred in 11.6% (17/146) patients receiving MMAE plus standard care versus 22.1% (29/131) in the standard care alone group. Statistical analysis yielded a common odds ratio of 0.53 (90% CI, 0.31-0.91; P = .04), indicating a significant 47% relative risk reduction with adjunctive MMAE.
Adverse events were comparable between groups with 71.8% experiencing events in the MMAE group and 65.3% in controls, without significant increase attributable to the embolization procedure. Importantly, MMAE demonstrated noninferiority regarding good functional outcomes (mRS ≤3) at 3 months, supporting safety and tolerability.
| Outcome | MMAE + Standard Care (n=146) | Standard Care Alone (n=131) | Effect Size (OR, 90% CI) |
|---|---|---|---|
| Primary endpoint: Residual/Recurrent hematoma or reoperation | 11.6% | 22.1% | 0.53 (0.31–0.91); P = .04 |
| Adverse events through 6 months | 71.8% | 65.3% | NS |
| Good functional outcome (mRS ≤3) at 3 months | Noninferior | Reference | – |
Expert Commentary
The MEMBRANE trial provides robust randomized clinical evidence supporting the use of middle meningeal artery embolization with n-BCA as a safe and effective adjunct therapy to current management of chronic subdural hematoma. The substantial reduction in hematoma recurrence and reoperation is likely due to the targeted devascularization of the hematoma membrane, disrupting pathological neoangiogenesis that fuels ongoing bleeding and fluid exudation.
While prior studies have suggested the benefit of MMAE using various embolic agents including polyvinyl alcohol particles or Onyx, the choice of n-BCA in this trial appears advantageous given its rapid polymerization and durable vascular occlusion, potentially translating into longer-lasting therapeutic effects. The noninferiority in functional outcomes and lack of observed increased adverse events affirm procedural safety across a diverse cohort.
Limitations include the open-label design, possibly introducing some performance bias, although independent imaging adjudication mitigated assessment bias. Generalizability is strengthened by the trial’s large sample size and multicenter international enrollment. Future research might explore long-term outcomes beyond 6 months and cost-effectiveness analyses.
Conclusion
This landmark randomized clinical trial demonstrates that middle meningeal artery embolization with n-butyl cyanoacrylate significantly reduces the risk of chronic subdural hematoma recurrence and the need for reoperation when added to standard care. The treatment is safe, well-tolerated, and maintains functional outcomes, positioning MMAE as an emergent standard adjunctive therapy in the management paradigm for cSDH, particularly in elderly populations at high risk of recurrence.
Clinicians should consider incorporating MMAE in treatment algorithms, balancing institutional expertise and patient-specific factors. Further studies to optimize embolic agents and procedural protocols are warranted to enhance therapeutic efficacy.
Funding and Trial Registration
The MEMBRANE trial was supported by institutional and industry collaborations. The study is registered on ClinicalTrials.gov with identifier NCT04816591.
References
- Kellner CP, Rai AT, Shoirah H, et al. Middle Meningeal Artery Embolization With n-Butyl Cyanoacrylate in Patients With Chronic Subdural Hematoma: A Randomized Clinical Trial. JAMA Neurol. 2026; PMID:42295790.
- Bhaskar S, Tripathi M, Caldito G, et al. Middle meningeal artery embolization for chronic subdural hematoma: A review of the literature. Neurosurg Focus. 2022;52(4):E6.
- Almenawer SA, Farrokhyar F, Hong C, et al. Chronic subdural hematoma management: A systematic review and meta-analysis of surgical interventions. Neurosurgery. 2014;75(5):507-520.