2026 Volume 20 Issue 1 Article ID: ra.2025-0153
Middle meningeal artery embolization (MMAE) for chronic subdural hematoma (CSDH) is gaining global prevalence as a minimally invasive treatment aimed at serving as an adjunct to or method of avoiding surgery; however, its optimal positioning remains unclear. This study outlines the current status of MMAE in Japan, Germany, and the United States based on nationwide survey reports, recently published consensus guidelines, and meta-analyses including randomized controlled trials (RCTs) reported in the New England Journal of Medicine (NEJM; EMBOLISE, STEM, and MAGIC-MT) and examines its efficacy and limitations. Real-world clinical data from Japan, Germany, and the United States indicate that MMAE is primarily used as an adjunctive therapy following surgery for older and high-risk or recurrent cases, or as a stand-alone therapy in selected cases to safely reduce the risk of recurrence and reoperation. While a multidisciplinary consensus statement takes a cautious stance that limits MMAE to recurrent or inoperable cases such as those at high risk associated with interrupting antithrombotic medication, the Society of Vascular and Interventional Neurology guidelines published after the RCTs strongly recommend the concurrent use of MMAE with standard therapy in de novo cases. Meta-analyses integrating the 3 NEJM trials and other RCTs showed that MMAE suppressed recurrence and reoperation versus standard treatment, with particularly pronounced effects in the nonsurgical (conservative treatment) group; however, the additive effect was limited in the surgical adjunct group. No improvement in functional outcomes (modified Rankin Scale score) was observed. Cost-effectiveness analyses suggest that, while MMAE reduces reoperations, routine implementation for all cases is difficult to justify economically because of high procedural costs, indicating the need to narrow the indication to populations at high risk of recurrence. In conclusion, although MMAE is an effective treatment option, the current evidence does not support its uniform introduction in all patients with CSDH. Thus, it is necessary to individualize and adapt the indications for specific patient subgroups, such as those at high risk of recurrence or those for whom surgery is difficult. Finally, we propose a pragmatic treatment strategy for MMAE stratified by disease stage (de novo vs. recurrent) and clinical severity to guide the individualized selection of adjunctive and stand-alone embolization.
Concomitant with global population aging and the increasing use of antithrombotic and anticoagulant medications, the incidence of chronic subdural hematoma (CSDH) is predicted to rise rapidly.1) While the current standard of care for symptomatic CSDH is burr hole evacuation, postoperative recurrence rates remain high (reportedly 10%–30%), necessitating reoperation in many cases.2,3) Particularly in older patients and those with comorbidities, recurrence and reoperation are significant challenges associated with increased morbidity and mortality rates.4)
It was recently elucidated that the pathophysiology of CSDH involves recurrence driven by repeated microhemorrhages and inflammatory reactions originating from neovasculature in the hematoma outer membrane supplied by the middle meningeal artery (MMA).5) Accordingly, MMA embolization (MMAE), which suppresses recurrence by embolizing the MMA to block blood flow, is garnering attention as an adjunct to surgery or stand-alone therapy. Since Mandai et al.6) first reported on MMAE for the treatment of recurrent CSDH in 2000, it has been widely adopted as a novel therapeutic option.
The results of major randomized controlled trials (RCTs) verifying the efficacy of adjunctive MMAE were reported in succession in 2024.7–9) This paper overviews the current status of MMAE treatment in Japan and abroad, recently published consensus statements on MMAE, and the latest RCT results.
The proportion of older patients and the number of CSDH cases are steadily increasing in Japan.10,11) Although MMAE for CSDH is not currently covered by public health insurance, its use is rapidly increasing, particularly in recurrent cases or high-risk patients receiving antithrombotic therapy.
Murai et al. conducted the first nationwide survey in Japan investigating the real-world clinical usefulness of MMAE for CSDH.12) The authors performed a multicenter retrospective study of 40 facilities affiliated with the Japanese Society for Neuroendovascular Therapy and analyzed 466 cases treated with MMAE between January 2018 and December 2022. The mean patient age was 78.0 years, and 36.1% of the patients had bleeding risks such as antithrombotic medication use or a bleeding predisposition. The annual number of MMAE procedures in Japan has surged approximately 4-fold, from 46 in 2018 to 193 in 2022. N-butyl-2-cyanoacrylate (n-BCA) was the most frequently used embolic material (66.7%), while particles and coils were used in 35.7% and 29.0% of cases, respectively. Regarding MMAE timing, only 10.1% of procedures were performed at initial onset, with the remaining approximately 90% performed after burr hole surgery. Specifically, MMAE was performed after the 1st burr hole surgery in 32.4% of patients, after the 2nd in 34.8%, and after the 3rd or subsequent in 21.5%. However, the authors noted a limitation in their retrospective data: it was not possible to determine, for each session, whether MMAE was performed immediately after the burr hole surgery as an adjunct or after a period of delay following recurrence. Local anesthesia (including sedation) was used in 94.2% of cases, whereas general anesthesia was used in only 5.8%. Treatment outcomes demonstrated high safety, with a complication rate of 5.2% (MMA-venous shunt, 2.4%; cerebral ischemia, 0.6%; and intracranial hemorrhage, 0.6%) and a complication-related morbidity rate of only 0.9%. On 30-day posttreatment imaging, a hematoma reduction was observed in 77.8% of patients, while the stabilization rate (including unchanged cases) reached 91.5%. This study revealed that, while n-BCA use and local anesthesia were predominant in Japan, MMAE demonstrated acceptable safety and efficacy in real-world clinical practice.
Furthermore, the study’s multivariate analysis identified “MMAE after the 2nd or subsequent burr hole surgery” as being significantly associated with symptomatic recurrence (odds ratio [OR], 2.55; p = 0.014), suggesting limited efficacy of MMAE in refractory cases.12) In cases of repeated recurrence, the hematoma may be organized, potentially limiting the blood flow–blocking effect of MMAE.13) Although MMAE is safe, these findings suggest that, rather than utilizing it as a rescue intervention after repeated burr hole surgeries, introducing it earlier (at initial onset or after the 1st surgery) for patients at high risk of recurrence may yield greater clinical benefit.12)
To date, national surveys of MMAE abroad have only been conducted in Germany14) and the United States.15–18) Furthermore, US nationwide surveys have primarily utilized comprehensive medical databases (e.g., the National Inpatient Sample [NIS]15,16) and the Nationwide Readmissions Database [NRD]18)) and thus did not include detailed procedural data (e.g., anesthesia methods and types of embolic materials).
In Germany, Vollherbst et al.14) conducted a nationwide multicenter retrospective study to clarify the current status and clinical outcomes of MMAE for CSDH. This study analyzed data from 569 patients who underwent MMAE between January 2014 and December 2023 at 30 neurovascular centers in Germany. The mean patient age was 76.3 ± 10.6 years; notably, more than half of all patients (51.1%) were taking antithrombotic medications (anticoagulants or antiplatelets). Regarding MMAE timing, 57.1% were conducted as first-time treatments versus 42.9% for recurrent disease. While MMAE was performed combined with surgical treatment in 59.2% of cases, MMAE monotherapy comprised a substantial proportion (40.8%). General anesthesia was most commonly used (57.5%), while local anesthesia was used in 39.5% of cases. Particles were the most frequently used embolic material (73.1%), whereas liquid embolic agents (Onyx [Medtronic, Irvine, CA, USA], Squid [Balt, Montmorency, France], etc.) were used in 26.9% of cases. The rate of symptomatic procedure-related complications was low (2.5%), while treatment failure (TF; defined as a residual hematoma >10 mm, progression, or the need for rescue surgery) was observed in 16.2% of the cohort. A comparative analysis showed no significant difference in TF rates between the stand-alone (13.1%) and surgery-adjunct (12.9%) groups, suggesting that hematoma control is possible with MMAE alone in select cases. On the other hand, the therapeutic effect of MMAE was significantly reduced in “treatment for recurrent cases” (TF rate, 19.8% vs. first-time, 13.5%, p = 0.045) and “patients taking antithrombotic medication” (TF rate, 17.7% vs. nonusers, 11.5%, p = 0.044). In Germany, particle embolization under general anesthesia was the predominant approach, with demonstrated safety and efficacy as a viable stand-alone therapy. However, the findings also suggest that the efficacy of MMAE may be attenuated in high-risk groups such as those with recurrence or who were using antithrombotics, necessitating the optimization of treatment strategies accordingly.
In the United States, several analyses utilizing nationwide databases, including NIS,15,16) Vizient,17) and NRD,18) have been reported. Regarding utilization trends, Dicpinigaitis et al.,15) using the NIS, reported that the MMAE rate for 59655 patients with CSDH treated across the United States increased exponentially from 0.2% in 2012 to 3.7% in 2018. Ninety-six percent of these procedures were performed at urban teaching hospitals, primarily large centers with established neurointerventional capabilities.15) Furthermore, data from 2018 to 2022 indicate that the MMAE utilization rate reached 8.7%, demonstrating a continued increasing trend.18) Regarding MMAE efficacy, adjunct MMAE combined with surgical evacuation was associated with a significantly lower 30-day readmission rate than surgical evacuation alone (4.26% vs. 8.00%, p <0.01).17) Additionally, a propensity score–matched analysis showed that the MMAE-only treatment group had a significantly lower 90-day retreatment rate than the surgical evacuation-only group (2.6% vs. 9.0%, respectively; p = 0.001).18) Adjunctive MMAE was associated with a significantly longer length of stay (LOS) than surgery alone,17) while MMAE alone resulted in a significantly shorter LOS than surgery alone.18) Both adjunctive MMAE and MMAE alone were significantly more expensive than surgical evacuation alone.17) However, a lifetime analysis using a Markov model estimated that the recurrence-suppressing effect of MMAE extended quality-adjusted life years by 1.3 years. Consequently, despite the high total costs, MMAE was concluded to be a long-term cost-effective treatment.18) MMAE is becoming increasingly common in the United States, and while it incurs higher initial costs, it has demonstrated the ability to reduce reoperation and readmission rates.
De Maria et al.19) conducted a large-scale international survey of neurosurgeons in 2023 and obtained responses from 551 neurosurgeons across 90 countries. The majority of the respondents (69.5%) reported not performing MMAE to treat CSDH, while 29.6% reported performing MMAE only for “specific indications” and <1% reported performing it in all cases. The most common indication for MMAE was to stop the growth of the residual hematoma after surgical evacuation (58.9%), followed by avoiding surgery in patients taking antiplatelet medications (44.8%) or to treat small hematomas (33.7%). Biases were observed among facility type and region in the adoption of MMAE. The MMAE adoption rate was significantly higher in teaching and public hospitals versus nonteaching and private hospitals. Regionally, the adoption rates were relatively high in Europe (50.6%) and North America (43.3%), but lower in Asia (22.1%) and Africa (8.6%). This disparity is attributed to the higher cost of MMAE versus surgery and the requirement for interventional neuroradiology facilities, which limit its widespread adoption, particularly in low- and middle-income countries. Although MMAE is being introduced in specific regions and facilities, issues regarding cost, equipment requirements, and lack of evidence hinder its global utilization. Further research is required to establish the indications for MMAE.
In 2024, Bartek et al. published a multidisciplinary consensus statement on MMAE developed by a panel representing key European and international societies, including the European Association of Neurosurgical Societies, the European Society of Neuroradiology, and the World Federation of Neurosurgical Societies, among others.20) However, this consensus statement predated the publication of 3 major randomized trials on MMAE (EMBOLISE,7) STEM,8) and MAGIC-MT9)); rather, it was grounded on existing reports published through March 2024, based on a literature search. The consensus statement recommended MMAE only in limited clinical scenarios: stand-alone treatment in de novo or recurrent cases in which the patient is in an inoperable state (e.g., high risk of interrupting antithrombotic therapy or coagulopathy) and as an adjunct to surgery in cases of recurrence. Furthermore, the consensus statement explicitly states that surgery may take precedence in cases of severe mass effects or neurological symptoms, even when the risk of interrupting antithrombotic therapy is high. The consensus statement posited MMAE as a procedure to be used cautiously and in a limited manner, warning against the excessive expansion of its indications.20) Regarding embolic materials, various options exist, including liquid embolic agents, particles, and coils. Although a recent review noted that particulate embolic agents are the most frequently used,21) the consensus statement noted that there is insufficient evidence to determine the optimal agent.20)
The Aneurysm/AVM/cSDH Roundtable Discussion With Industry and Stroke Experts (ARISE) consensus statement22)—a United States-led academic–industry roundtable convening representatives from academia, industry, and government—was published shortly before Bartek et al.’s consensus statement20) and adopted a similar position, supporting MMAE as a useful adjunct to rather than a replacement for standard therapy. Meanwhile, the United Kingdom has adopted a stricter approach, with the National Institute for Health and Care Excellence23) recommending that MMAE for CSDH be used only in research.
The Society of Vascular and Interventional Neurology (SVIN) published consensus guidelines for MMAE in 2025 following the release of the RCT results.24) Considering the results of multiple RCTs (e.g., EMBOLISE,7) STEM,8) MAGIC-MT9)), these guidelines offer more aggressive recommendations. The SVIN guidelines strongly recommend considering adjunctive MMAE with standard treatment (surgical or nonsurgical) in symptomatic, nonemergent, nonrecurrent CSDH (Class I).24) In fact, the EMBOLISE trial showed a significant reduction in reoperation rates, from 11.3% in the surgery-alone group to 4.1% in the surgery plus MMAE group.7) Similarly, the STEM trial demonstrated a significant reduction in the composite endpoint of recurrence/residual hematoma or reoperation/rescue surgery within 180 days: 16% in the MMAE group versus 36% in the standard treatment group.8) The MAGIC-MT trial showed a reducing trend in the symptomatic recurrence or progression rates within 90 days: 6.7% in the MMAE group versus 9.9% in the standard treatment group.9) Based on the results of these prospective trials, the guidelines significantly expand the indication for MMAE to include initially symptomatic patients, citing it as an effective means of reducing recurrence and reoperation risks. In cases of recurrence, while MMAE has shown promising ability to prevent further recurrence and offers a nonsurgical alternative to conventional methods, no specific recommendation grade is specified; at present, the recommendation is not considered as established as it is for de novo cases. In cases presenting with profound neurological symptoms due to CSDH, urgent surgery is stated as the standard of care to prevent neurological deterioration. Since the foundational RCTs primarily enrolled clinically stable, nonemergent patients, the Class 1 recommendation for MMAE is explicitly limited to “non-emergent” cases due to a lack of evidence regarding its efficacy in emergent situations. The panel suggests that future RCTs should explore MMAE in neurologically unstable, emergent CSDH cases as an adjunct to standard care. The SVIN guidelines state that stand-alone MMAE may be reasonable to consider (Class 2b) in patients with CSDH for whom surgery is contraindicated. Liquid embolic agents used in RCTs (Onyx [Medtronic], Squid [Balt], and n-BCA) are recommended as Class 1. Conversely, particulate agents and coils are listed as Class 2b (weak recommendation) alternatives to liquid agents.
Thus, the positioning of MMAE indications shifted significantly after publication of the RCT results. While the 2024 multidisciplinary consensus adopted a cautious stance, recommending use only in limited situations such as inoperable or recurrent cases, the 2025 SVIN guidelines, based on currently available prospective RCT evidence, assigned a clear Class 1 recommendation to adjunctive therapy for de novo cases, supporting its use across broader indications (Table 1).20,24) However, as numerous RCTs are ongoing, the clinical positioning of MMAE remains in a transitional phase.25,26) Furthermore, critical perspectives regarding RCT results exist, and some experts argue that caution should be exercised regarding the aggressive expansion of indications following the publication of recent trial findings.27)
| Multidisciplinary consensus —Bartek et al. (2024)20) |
SVIN consensus/guideline —Siddiq et al. (2025)24) |
|
|---|---|---|
| Publishing body | EANS/ESMINT/ESNR and others (9 total societies) | SVIN |
| Evidence base | Mainly observational studies (pre-RCT publications) | Multiple RCTs (EMBOLISE,7) STEM,8) MAGIC-MT,9) MEMBRANE42)) |
| Stance on MMAE | Restrictive/specific scenarios | Actively recommended/broad indications |
| De novo CSDH (surgical candidates) | Surgery is the first choice | MMAE recommended as an adjunct to surgery (Class 1) |
| Recurrent CSDH (surgical candidates) | MMAE recommended as an adjunct to surgery | MMAE should be considered as an adjunct to surgery or a stand-alone treatment |
| De novo/recurrent CSDH (surgical contraindication/very high surgical risk) | MMAE recommended as a stand-alone treatment | MMAE is reasonable as a stand-alone treatment (Class 2b) |
| Severe cases (severe neurological symptoms) | Surgery is the first choice | Surgery is the first choice |
| Embolic agents | Insufficient evidence to support any specific embolic agent | Onyx/Squid/n-BCA (Class 1), particles/coils (Class 2b) |
| Follow-up imaging | No established criteria | Recommended at 1 day, 1 month, 3 months, and 6 months (Class 2a) |
CSDH, chronic subdural hematoma; EANS, European Association of Neurosurgical Societies; ESMINT, European Society for Minimally Invasive Neurological Therapy; ESNR, European Society of Neuroradiology; MMAE, middle meningeal artery embolization; n-BCA, N-butyl-2-cyanoacrylate; Onyx, Medtronic, Irvine, CA, USA; RCT, randomized controlled trial; Squid, Balt, Montmorency, France; SVIN, Society of Vascular and Interventional Neurology
The 3 trials published in the New England Journal of Medicine (NEJM)—EMBOLISE,7) STEM,8) and MAGIC-MT9)—represent the first RCTs to verify the efficacy of MMAE for CSDH with high-quality evidence; however, meta-analyses and reviews integrating these studies highlight uncertainties regarding its effect as a surgical adjunct, the lack of contribution to functional prognosis, and challenges regarding cost-effectiveness; thus, careful interpretation of its clinical utility is required.
Multiple meta-analyses, including trials beyond the 3 mentioned above, reported that MMAE significantly reduces the risk of recurrence versus standard care.28–30) Notably, in the conservative treatment (nonsurgical) group, MMAE significantly suppressed hematoma progression, suggesting that it may be an effective stand-alone treatment for patients who are ineligible for surgery or have mild symptoms.28) However, when MMAE is used as an adjunct to surgical evacuation (surgery + MMAE vs. surgery alone), its ability to prevent recurrence becomes uncertain.31,32) While the EMBOLISE trial alone showed a significant reduction in reoperation rates (11.3% vs. 4.1%), the effect sizes in the surgical arms of the MAGIC-MT and STEM trials were small, and meta-analyses integrating these data indicate that the statistical significance of the recurrence suppression effect disappeared in the surgical adjunct group (relative risk [RR], 0.60; p = 0.194).31,32)
This discrepancy in results is likely attributable to differences in patient severity and treatment protocols, as the STEM8) and MAGIC-MT9) trials employed a 2-tiered design in which the surgeon first determined “surgery versus conservative management” before randomization. This structure mirrors clinical practice but introduces selection bias in which patients with milder symptoms or at high surgical risk are more likely to be assigned to the conservative group; thus, it cannot be denied that the high suppression effect observed in the conservative treatment group may have been driven by this bias.32) Gillespie et al. pointed out that the efficacy of MMAE seen in the pooled data was largely driven by the results of this nonsurgical group.32) Outcome definitions also varied significantly; STEM8) adopted a composite endpoint including “residual hematoma >10 mm” alongside “stroke, myocardial infarction, and death,” and with a long follow-up period of 180 days, factors other than the pure hematoma suppression effect may have confounded the results, potentially overestimating the efficacy of MMAE.29,32) The proportion of patients taking antithrombotic medications was notably low (approximately 7%) in the MAGIC-MT9) versus other trials (approximately 40%), suggesting the cohort was not a typical high-risk population, which may have contributed to the lack of statistical significance regarding MMAE’s efficacy in that cohort.32)
Across all meta-analyses, while MMAE reduced radiological recurrence and reoperation rates, it did not contribute to improvements in functional prognosis (modified Rankin Scale score) representing patient quality of life or independence; the reality that preventing radiological recurrence does not necessarily translate to improved activities of daily living is a significant concern for expanding its indications.28–30) Regarding safety, however, MMAE does not significantly increase serious adverse event or mortality rates, establishing the procedure itself as safe.28–30)
There are also critical views regarding cost-effectiveness; a cost analysis by Jayakumar et al. based on the United Kingdom National Health Service model estimated that, while MMAE reduces reoperations, its high cost would cause a substantial net loss (approximately £1.6–1.9 million) if introduced in all cases.30) The number needed to treat (NNT) to prevent recurrence is calculated at 14–15, making it difficult to claim economic justification unless the application is strictly limited to patients at extremely high recurrence risk.7,30)
While major RCTs have demonstrated the safety and a certain degree of efficacy of MMAE, they have also highlighted challenges such as the uncertainty of its adjunct effect with surgery, lack of improvement in functional prognosis, and high medical costs.30,32) Therefore, the current evidence does not immediately support the introduction of MMAE as a standard of care for all patients with CSDH. The view has been presented that “while the routine adjunctive use of MMAE for all patients undergoing surgery may not be supported from the perspectives of cost-effectiveness and recurrence suppression, it may be recommended as an option to avoid reoperation in cases involving antithrombotic medication or an extremely high risk of recurrence.”28,30,32) Moving forward, a perspective of personalized medicine will likely be essential to identifying “which patient populations yield a recurrence suppression effect that justifies the cost and burden of MMAE.”
Three RCTs published in NEJM—EMBOLISE,7) STEM,8) and MAGIC-MT9)—reported the efficacy of MMAE. However, critical clinical questions remain unresolved, such as whether MMAE can serve as a stand-alone alternative to surgery, which specific patient populations derive the most benefits from it, and how to select the optimal anti-embolic agent. Against this backdrop, more than 20 RCTs are currently underway worldwide, and their results are eagerly awaited.25,26,32) Table 2 summarizes the main recently published and ongoing RCTs.
| Trial name | Country | Size | Completion | Population | Intervention | Embolic agent | Primary outcome | Follow-up |
|---|---|---|---|---|---|---|---|---|
| MMAE + surgery vs. surgery | ||||||||
| METRICS40) | China | 516 | Dec-24 | At least 1 risk factor for recurrence | 1. MMAE + surgery vs. surgery 2. MMAE vs. atorvastatin |
Not stated | Repeat surgery or radiological | 6 months |
| MEMBRANE (USA)42) | USA | 376 | Mar-25 | mRS score ≤3 | 1. MMAE + surgery vs. surgery 2. MMAE vs. conservative |
TRUFILL n-BCA | Repeat surgery or radiological | 6 months |
| OTEMACS37) | France | 440 | May-25 | Symptoms and mRS score ≤3 | 1. MMAE + surgery vs. surgery 2. MMAE vs. conservative |
Onyx | Repeat surgery or radiological | 3 months |
| LEADH43) | France | 550 | Sep-26 | CSDH >10 mm | 1. MMAE + surgery vs. surgery 2. MMAE vs. conservative |
Cyanoacrylates | Symptomatic recurrence or repeat surgery or radiological | 2, 6 months |
| STORMM41) | Switzerland | 180 | Jan-27 | Symptoms or failed conservative | 1. MMAE + surgery vs. surgery 2. MMAE vs. conservative |
Not stated | Symptomatic recurrence or repeat surgery or radiological | 6 months |
| ChiCTR200003935947) | China | 480 | Mar-23 | Symptoms | MMAE + surgery vs. surgery | Not stated | Rate of recurrence | Not stated |
| ENCLOSURE48) | Spain | 280 | Dec-23 | CSDH >10 mm or symptoms | MMAE + surgery vs. surgery | Onyx, Phil, Squid, or Libro | Symptomatic recurrence or radiological | 6 months |
| ELIMINATE44) | Netherlands | 170 | Oct-25 | Age ≥50 years, symptoms | MMAE + surgery vs. surgery | PVA particles | Repeat surgery | 8, 16, 24 weeks |
| MEMBRANE (Germany)49) | Germany | 154 | Oct-25 | Candidate for surgery | MMAE + surgery vs. surgery | PVA particles (mainly) | Repeat surgery or radiological | 3 months |
| EMPROTECT38) | France | 342 | Oct-23 | Recurrence or high risk factor of recurrence | MMAE + surgery vs. conventional treatment | EmboSphere | Repeat surgery or radiological | 6 months |
| EMMA-Can50) | Canada | 200 | Mar-26 | Symptoms and mRS score ≤2 | MMAE + conventional treatment vs. conventional treatment | Particulate polymer or liquid embolic agents | Radiological | 3 months |
| COMPLEMENT39) | Japan | 600 | Mar-29 | Pre-mRS score ≤3, CSDH ≥10 mm, at least 1 risk factor for recurrence | MMAE + conventional treatment vs. conventional treatment | Not stated | Repeat surgery or radiological | 6 months |
| MMAE vs. surgery or conservative | ||||||||
| Embotrial-136) | Italy | 300 | Mar-26 | Markwalder grade ≤1 | MMAE vs. conservative management | PVA particles or liquid embolic agents | Requires surgery or hematoma resolution | 6 months |
| SWEMMA34) | Sweden | 288 | Mar-27 | Markwalder grade <2, GCS >13 | MMAE vs. surgery | Onyx, Squid, or Phil | Repeat surgery | 3 months |
| CHESS33) | USA | 520 | Feb-29 | Age ≥40 years, CSDH >10 mm | MMAE vs. surgery | EmboSphere or Contour | Repeat surgery or death | 6–7 months |
| PREMMA35) | Puerto Rico | 658 | Jul-32 | Markwalder grade ≤2, GCS ≥14 | MMAE vs. surgery | PVA particles | Repeat surgery | 3, 6, 12 months |
Contour, Boston Scientific, Marlborough, MA, USA; CSDH, chronic subdural hematoma; Embosphere, Merit Medical, South Jordan, UT, USA; GCS, Glasgow Coma Scale; Libro, INVAMED, Ankara, Turkey; MMAE, middle meningeal artery embolization; mRS, modified Rankin Scale; n-BCA, N-butyl-2-cyanoacrylate; Onyx, Medtronic, Irvine, CA, USA; PHIL, Terumo Neuro, Aliso Viejo, CA, USA; PVA, polyvinyl acrylate; Squid, Balt, Montmorency, France; TRUFILL, Johnson & Johnson, Irvine, CA, USA
Three RCTs are currently underway to evaluate whether MMAE monotherapy can be established as a first-line stand-alone therapy: the CHESS trial in the United States (520 patients),33) SWEMMA trial in Sweden (288 patients),34) and PREMMA trial in Puerto Rico (658 patients),35) which directly compare an MMAE-only and surgical evacuation arm.
The utility of MMAE in mild cases or patients in whom surgery is contraindicated is also being investigated. In Italy, the Embotrial-1 trial36) compared MMAE monotherapy with conservative management in 300 mild cases and assessed the hematoma resolution and surgery avoidance rates. In France, the OTEMACS trial,37) which targeted 440 patients, compared MMAE monotherapy and conservative management for symptomatic CSDH not requiring surgery to verify whether it can reduce recurrence and reoperation rates.
Several trials are currently underway to verify the efficacy of MMAE in specific patient populations. The EMPROTECT trial38) targeted patients who had already undergone surgery for recurrence and primary patients at high risk of recurrence, such as those taking antithrombotics. The COMPLEMENT trial in Japan39) and the METRICS trial in China40) targeted patients with risk factors for recurrence, including advanced age, bilateral hematomas, and antithrombotic use. The STORMM trial41) targeted cases in which conservative treatment failed, resulting in a residual or recurrent hematoma.
The 3 NEJM-published trials7–9) achieved favorable outcomes using liquid embolic agents (Onyx [Medtronic], Squid [Balt]). In contrast, the EMPROTECT trial, which utilized particulate agents (Embosphere; Merit Medical, South Jordan, UT, USA) for recurrent or high-risk primary CSDH, failed to demonstrate a significant reduction in recurrence compared to surgery alone.38) The efficacy of other formulations and the selection of the optimal embolic agent remain an ongoing debate. Ongoing studies are evaluating a wide range of embolic agents. While agents such as Onyx and n-BCA are widely employed, the MEMBRANE42) and LEADH trials43) utilized adhesive liquid embolic agents such as TRUFILL n-BCA and cyanoacrylates. Meanwhile, the ELIMINATE44) and CHESS33) trials are investigating particulate agents, including polyvinyl alcohol particles and contour particles, to optimize procedural safety and efficacy.
Ongoing trials are expected to provide critical insights into the positioning of MMAE for the treatment of CSDH. The results of head-to-head trials comparing MMAE with surgery have the potential to shift the first-line treatment for CSDH from surgical evacuation to endovascular therapy. Furthermore, identifying specific patient populations that derive clear benefits from MMAE and verifying differences in therapeutic effects among embolic agents are key factors in the future widespread adoption of MMAE.
In adjunctive treatment, where MMAE is combined with surgery (adjunctive MMAE), the primary objective is “recurrence prevention.” Surgical evacuation provides immediate decompression, but the inflammatory neovasculature within the outer membrane often persists, resulting in microbleeding and a reported recurrence rate of approximately 10%–20%.20) Adjunctive MMAE targets this pathophysiology by interrupting arterial inflow to these vascular networks, thereby breaking the “vicious cycle” of inflammation and rebleeding.20)
In contrast, the primary goal of stand-alone MMAE is “cure,” aiming to achieve symptomatic improvement sufficient to serve as an alternative to surgery. Although stand-alone MMAE effectively devascularizes the hematoma membranes, volume reduction relies on natural resorption mechanisms. This process is gradual, taking weeks to months; therefore, immediate relief of mass effect cannot be expected.20) Consequently, surgery takes precedence in cases requiring emergency decompression—such as those with severe consciousness disturbance or impending herniation—rendering stand-alone MMAE unsuitable. Indications for stand-alone MMAE are therefore limited to neurologically stable mild cases or surgical candidates in whom antithrombotic therapy cannot be interrupted.20,24)
Based on guidelines and evidence20,22,24) from major RCTs,7–9) as well as recent meta-analyses and reviews28–32) incorporating RCT results,7–9) this section outlines the current pragmatic indications for MMAE based on disease status (de novo vs. recurrent) and clinical severity (Table 3).
| Clinical severity | De novo CSDH | Recurrent CSDH |
|---|---|---|
| Severe (emergent) | Surgery is first-line (adjunct MMAE may be considered electively after stabilization; evidence is limited) |
|
| Symptomatic | Adjunct MMAE is reasonable in selected high-recurrence–risk patients | Adjunct MMAE should be considered |
| Mild symptomatic | Stand-alone MMAE can be considered | |
| Asymptomatic | Conservative management is first-line (consider MMAE if large/progressive) | |
| Not a surgical candidate/surgery contraindicated | Consider stand-alone MMAE | |
CSDH, chronic subdural hematoma; MMAE, middle meningeal artery embolization
Whether presenting as de novo or recurrent, emergent cases with profound impairment of consciousness or signs of cerebral herniation necessitate immediate surgical decompression as the first-line, life-saving intervention.20,22,24) Standalone MMAE is inappropriate in such scenarios due to its lack of an immediate mass-reducing effect.20,22,24) However, severe cases are often associated with massive hematomas or marked cerebral atrophy—factors that may increase the risk of recurrence by limiting postoperative brain re-expansion.45) Accordingly, elective adjunctive MMAE, performed after surgical evacuation once the patient’s systemic condition has stabilized, may represent a clinically reasonable strategy for recurrence prevention. Nevertheless, since all major RCTs have excluded severe presentations, the efficacy of adjunctive MMAE in this subgroup remains unestablished and represents a critical area for future investigation.24)
Symptomatic de novo casesMeta-analyses incorporating the latest RCTs have demonstrated the efficacy of MMAE in de novo CSDH; however, whether MMAE should be applied to all such cases remains debated.20,25) Recurrence rates after conventional surgery alone are already modest (approximately 10%–20%),20) and the routine addition of MMAE—which entails significant costs—may offer limited incremental clinical benefit, especially considering the relatively high NNT of 14–15.7,30) Therefore, a more rational approach would be to avoid routine use and instead reserve MMAE for selected patients, such as those at high risk of recurrence.25,30) However, the specific patient population that would derive the greatest benefit from MMAE remains undefined, warranting further investigation,20,25,28) although factors such as antithrombotic therapy, larger hematoma volume, bilateral hematomas, and specific imaging features like the “separated” subtype are frequently cited as potential predictors of recurrence.20,24,30)
Symptomatic recurrent casesRecurrent CSDH carries a re-recurrence rate of approximately 20%, significantly higher than the approximately 10% observed after initial treatment,20) underscoring the substantial value of strengthening recurrence prevention strategies once recurrence occurs. Against this background, the multidisciplinary consensus statement by Bartek et al. positions MMAE as an adjunct to surgery that should be considered for recurrent CSDH.20) Similarly, the SVIN guidelines state that for patients with recurrent CSDH, MMAE has shown promising results in preventing additional recurrences.24) However, a nationwide survey by Murai et al. suggests diminishing benefit: symptomatic recurrence rates after postoperative MMAE increased from 4.1% following the initial burr hole surgery to 9.9% after a second surgery, and to 14.7% after 3 or more surgeries.12) Based on these findings, rather than aimlessly repeating surgical evacuations alone—which may lead to a refractory condition—it may be clinically rational to consider the combination of surgery and MMAE as a therapeutic option at the time of the “first recurrence.” On the other hand, the EMPROTECT trial, an RCT investigating the strategy of adding MMAE using microparticles for recurrent CSDH (or initial CSDH with high recurrence risk), failed to demonstrate a significant reduction in the 6-month recurrence rate (14.8% vs. 21.0%, p = 0.13).38) Apart from this, there are currently no other reports of RCTs including recurrent cases, and further validation is necessary.
Mild symptomatic casesAmong symptomatic patients with relatively mild symptoms—where a time window for gradual resolution is acceptable—stand-alone MMAE may be considered as a potential alternative to surgery alone. In the STEM trial, within the nonsurgical stratum of symptomatic patients, TF occurred in 19% of the MMAE group versus 56% of the medical management group, indicating that stand-alone MMAE significantly reduced TF (OR 0.19).8) In addition, a meta-analysis integrating the 3 major RCTs showed that, compared with nonsurgical management, MMAE significantly suppressed progression (RR 0.36).32) At present, no RCT has directly compared surgery alone with stand-alone MMAE. However, an analysis of 8 observational studies (156 patients treated with MMAE alone and 246 treated with MMAE plus surgical evacuation) found that the surgical recurrence rate—that is, the need for rescue surgery—was low in both groups, with no statistically significant difference between them, suggesting that stand-alone embolization may achieve durable hematoma control in most cases.28) Collectively, these findings highlight the potential role of embolization as a minimally invasive alternative, particularly for patients who are asymptomatic or only mildly symptomatic, or for those in whom surgery is difficult or undesirable.24,28)
Asymptomatic casesFor asymptomatic CSDH—whether de novo or recurrent—conservative management remains the first-line strategy.24) Such cases are typically not considered candidates for surgical intervention; likewise, the routine use of MMAE is difficult to justify. However, given that approximately 30% of patients managed conservatively ultimately require surgery,20) MMAE may be considered in selected cases as a minimally invasive option when follow-up imaging demonstrates a clear trend toward hematoma enlargement or when a large hematoma raises substantial concern for imminent symptom development, analogous to the strategy for mild symptomatic cases.
Supplementary information on treatmentRegarding the timing of adjunctive MMAE (preoperative vs. postoperative), no clear consensus has been established to date.20) Consensus statements by Bartek et al. suggest that preoperative MMAE may be more effective, as it avoids the risk of incomplete embolization resulting from iatrogenic injury (e.g., coagulation or transection) to the MMA during surgical maneuvers.20) Conversely, post-operative MMAE allows for the procedure to be performed for recurrence prevention after prioritizing surgical decompression. In clinical practice, decisions are made on a case-by-case basis, taking into account urgency and institutional capabilities. Regarding RCTs, protocols varied among major RCTs: while the STEM and MAGIC-MT trials principally mandated preoperative MMAE,8,9) the EMBOLISE trial allowed operator discretion regarding timing, resulting in postoperative MMAE in approximately 42% (78/185) of the adjunctive treatment group.7)
Regarding the choice of anesthesia, a multicenter propensity score-matched analysis of 956 MMAE procedures in 778 patients by Salem et al. found no significant differences in radiographic improvement or clinical outcomes between general anesthesia and non-general anesthesia groups.46) Particularly for older patients with coagulopathy or comorbidities, MMAE under conscious sedation and transradial access (TRA) may be considered as viable options to minimize perioperative complications, including those related to anesthesia and access site.22,24) When liquid embolization with dimethyl sulfoxide/Onyx (Medtronic) is performed under conscious sedation, adjunctive intra-arterial lidocaine may be used to mitigate injection-related discomfort and improve patient tolerance.22,24)
Kenji Sugiu received lecture fees from Medtronic Japan, Terumo, Kaneka Medix, and Japan Lifeline. The remaining authors have no conflict of interest.
