Comparative Effectiveness Of Treatment Modalities For Unruptured Brain Arteriovenous Malformations: A Systematic Review And Meta-Analysis Of 6,124 Patients

Comparative Effectiveness Of Treatment Modalities For Unruptured Brain Arteriovenous Malformations: A Systematic Review And Meta-Analysis Of 6,124 Patients | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Research Article Comparative Effectiveness Of Treatment Modalities For Unruptured Brain Arteriovenous Malformations: A Systematic Review And Meta-Analysis Of 6,124 Patients Donald E Ogolo, Okwunodulu Okwuoma, Kelechi Ndukuba, Obioma Akwada, and 4 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7169115/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Background The optimal management of unruptured brain arteriovenous malformations (AVMs) remains controversial, with conflicting evidence regarding conservative versus interventional approaches, especially in the light of the ARUBA trials. This meta-analysis aims to provide comprehensive, grade-specific outcomes across treatment modalities to guide clinical decision-making. Methods We conducted a PRISMA-compliant meta-analysis of 16 studies (n = 6,124 patients) comparing conservative management, microsurgery, stereotactic radiosurgery (SRS), embolization, and hybrid therapy. Databases searched included MEDLINE (PubMed), Embase (Ovid), Cochrane Central Register, and Web of Science (2000–2025). Risk of bias was assessed using the Cochrane Risk of Bias Tool 2.0 for RCTs and Newcastle-Ottawa Scale for cohort studies. Data were synthesized using random-effects models (DerSimonian-Laird method), with heterogeneity quantified via the I² statistic. Primary outcomes were hemorrhage risk and obliteration rates; secondary outcomes included functional status (mRS ≥ 2), new-onset seizures, and mortality. Results Microsurgery achieved the highest obliteration rates (99% for Spetzler-Martin [SM] I-II, 86% for SM III) and lowest hemorrhage risk (0.6%/yr for SM I-II, 1.3%/yr for SM III), with superior functional outcomes (8% disability [95% CI 5–11%] vs. 11% for conservative management; p = 0.04). SRS showed moderate efficacy (76% obliteration for SM I-II, 47% for SM III-IV) with higher latency-period hemorrhage risk (1.1–2.1%/yr) and disability rates comparable to conservative management (13% [95% CI 10–16%]; p = 0.18). New-onset seizures occurred in 9.1% of microsurgery and 4.9% of SRS cases. Mortality was low across treatments (1–2%), with conservative management at 1.1% and SRS at 1.6%. Conservative management had a 1.9–2.6%/yr hemorrhage risk without procedural morbidity. Conclusions Microsurgery is preferred for operable SM I-II AVMs due to superior obliteration, hemorrhage protection, and functional outcomes, despite higher seizure risk. SRS is suitable for inoperable cases, while conservative management remains reasonable for high-grade AVMs unless high-risk features exist. unruptured arteriovenous malformation conservative microsurgery embolization stereotactic radiosurgery hybrid treatment intervention Figures Figure 1 Figure 2 INTRODUCTION Cerebral arteriovenous malformations (AVMs) remains one of the most multifaceted and controversial challenges in modern cerebrovascular neurosurgery. These congenital vascular lesions are characterized by abnormal connections between arteries and veins without intervening capillaries, and they carry a lifetime risk of rupture estimated at 2–4% annually. 1, 2 While the management approach of urgent intervention for ruptured AVMs is well established, due to their high associated morbidity (30–50% permanent neurological deficits) and mortality (10–15% per hemorrhage), 3 the optimal management strategy of unruptured AVMs remains one of the most debated topics in contemporary vascular neurosurgical practice. The benefit of intervention for patients with unruptured AVM has long been a subject of debate. This stems from three fundamental uncertainties based on the natural history of AVMs and treatment outcomes which are usually interpreted to favour conservative approach. First, the annual hemorrhage risk of unruptured AVMs (1–3%) is substantially lower than their ruptured counterparts (4–39%), 4–10 making the risk-benefit calculation for preventive intervention more individualized. Second, the morbidity associated with AVM treatment modalities, including microsurgical resection, stereotactic radiosurgery (SRS), and endovascular embolization, can be significant, particularly for complex lesions in eloquent areas. These might ultimately be higher than those for ruptured AVMs following conservative management. Third, the long-term durability of treatment success versus the cumulative lifetime risk of conservative management remains incompletely understood, especially for younger patients who may face over 30–40% lifetime bleeding risks. 11 This clinical balance was brought into focus by the landmark ARUBA trial (A Randomized Trial of Unruptured Brain AVMs), which in 2014 reported superior short-term outcomes with conservative management compared to intervention (medical management alone vs. medical management with interventional therapy). 12 However, ARUBA’s conclusions have been strongly criticized due to several methodological limitations, including relatively short follow-up duration (mean follow-up of 33 months and 50.4 months in the extended trials) that may not capture the long-term benefits of intervention or risks of conservative management, heterogeneity in treatment protocols and operator experience across participating centres, exclusion of many ideal surgical candidates with low-grade AVMs and high crossover rates from conservative to interventional arms during extended follow-up. 13 , 14 Subsequent studies, including the TOBAS trial (Treatment of Brain AVMs Study), the NASSAU study and multiple large retrospective series, challenged ARUBA’s findings, particularly for low-grade (Spetzler-Martin I-II) AVMs where microsurgical resection and SRS have demonstrated excellent outcomes with minimal morbidity in experienced centres. 15 – 18 Similarly, refinements in SRS techniques, including dose planning and repeat treatments, have improved outcomes for hitherto inoperable lesions. 18 , 19 Additionally, the current landscape of AVM management is further complicated by the emergence of hybrid treatment strategies that combine multiple modalities. These approaches, while theoretically appealing, require systematic evaluation to determine their appropriate role in neurosurgical practice. Moreover, advances in microsurgical techniques, neuroanesthesia, and postoperative care have improved surgical outcomes beyond those reported in ARUBA-era studies. 20 These developments suggest that ARUBA-era outcomes may no longer reflect contemporary treatment realities. Several critical knowledge gaps persist in the literature. First, most studies report outcomes by treatment modality rather than comparative effectiveness. Also, limited data exists on long-term (> 10 year) outcomes across all approaches. Furthermore, grade-specific outcomes, particularly for Spetzler-Martin (SM) III AVMs, remain poorly characterized. Lastly, the role of emerging hybrid therapies requires systematic evaluation. This meta-analysis attempts to directly addresses these gaps. Our study provides several unique contributions to the field. First, we present the most comprehensive comparative analysis to date of hemorrhage risk reduction and obliteration rates across treatment modalities, stratified by SM grade. Second, we evaluate long-term durability where available, including extended follow-up data from ARUBA and TOBAS that better reflect the cumulative risks of conservative management. Third, we systematically analyze functional outcomes and quality of life measures across treatments, evaluating outcomes beyond simple obliteration rates. The clinical imperative for this work is underscored by the young age at which many AVMs are diagnosed (median 30–40 years), 21 – 25 making long-term outcome data particularly crucial. This meta-analysis further aims to resolve key controversies in unruptured AVM management and establish an evidence-based framework for clinical decision-making in the post-ARUBA era. METHODOLOGY Study Design and Registration This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. To ensure transparency and minimize reporting bias, the study protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO). Literature Search Strategy A comprehensive search strategy was developed in collaboration with a medical librarian specializing in systematic reviews. Electronic databases, including MEDLINE via PubMed, Embase via Ovid, the Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection, were searched from January 2000 to March 2025. The search strategy incorporated Medical Subject Headings (MeSH) terms and free-text keywords related to “arteriovenous malformations,” “unruptured,” “conservative,” “microsurgery,” “embolization,” “stereotactic radiosurgery” and “treatment outcomes.” Additional studies were identified through manual searches of reference lists from included articles and relevant review papers, consultation with content experts, and exploration of clinical trial registries (ClinicalTrials.gov and WHO ICTRP). Eligibility Criteria Studies were selected based on the PICOS (Population, Intervention, Comparison, Outcome, Study design) framework. The population of interest comprised adults (≥ 18 years) with radiologically confirmed unruptured brain arteriovenous malformations (AVMs) who had not undergone prior treatment for the index AVM and had a minimum follow-up of 12 months. Interventions of interest included conservative management (observation), microsurgical resection, stereotactic radiosurgery (SRS), endovascular embolization, and multimodal or hybrid approaches. Comparisons were made between conservative and interventional management, as well as head-to-head comparisons of different treatment modalities. Primary outcomes included annual hemorrhage rate and complete angiographic obliteration rate (confirmed by imaging). Secondary outcomes encompassed functional status (assessed via the modified Rankin Scale [mRS] ≥ 2), treatment-related mortality, and procedure-related complications. Eligible study designs consisted of randomized controlled trials, prospective cohort studies, retrospective cohort studies with at least 50 patients, and registry studies with clearly defined outcomes. Exclusion criteria comprised studies with > 20% ruptured AVMs without separate outcome data, case reports, reviews, paediatric populations (< 18 years), previously treated AVMs, follow-up < 12 months, non-English studies without available translations, duplicate publications, and studies with incomplete outcome reporting. Study Selection Process Two independent reviewers screened all titles and abstracts using Rayyan QCRI software. Full-text articles of potentially eligible studies were obtained and independently assessed against the inclusion criteria. Discrepancies were resolved through discussion or consultation with a third reviewer. The study selection process followed the PRISMA flowchart structure (Fig. 1 ). Phase 1: Identification Records identified through database searching – 2,347 (PubMed: 872, Embase: 1,102, Cochrane: 228, Other sources: 145) Duplicates removed: 487 Phase 2: Screening Titles/abstracts screened: 1,860 Records excluded: 1,715 Irrelevant population: 892 No outcomes of interest: 623 Non-English/no translation: 200 Phase 3: Eligibility Full-text articles assessed: 145 Studies excluded: 122 Mixed rupture status (no subgroup data): 68 Insufficient follow-up: 27 Small sample size (< 50): 19 Duplicate cohorts: 8 Phase 4: Included Studies in qualitative synthesis: 23 Studies in quantitative meta-analysis: 16 Conservative: 4 studies (n = 604) Microsurgery: 3 studies (n = 395) SRS: 6 studies (n = 4671) Embolization: 1 study (n = 288) Hybrid: 1 study (n = 61) Mixed interventions: 1 study (n = 105) Hybrid therapy were those treatments done as a single-staged combined procedure, such as embolization followed by microsurgery in one operative session. Mixed interventions were those done as staged multi-modality treatments such as embolization done weeks before a separate SRS procedure. Data Extraction and Management Data were extracted using a standardized, piloted form that captured study characteristics (author, year, design, sample size), patient demographics (age, sex, Spetzler-Martin [SM] grade distribution), AVM characteristics (size, location, venous drainage), treatment details (modality, technical parameters), outcome measures (as specified above), and follow-up duration and completeness. In cases of overlapping cohorts, the most comprehensive or recent report was included to avoid duplication. Risk of Bias Assessment Study quality was evaluated using the Cochrane Risk of Bias Tool 2.0 for randomized controlled trials, the Newcastle-Ottawa Scale for cohort studies, and a modified Joanna Briggs Institute checklist for case series. Key domains assessed included selection bias (patient recruitment, group comparability), performance bias (intervention standardization), detection bias (outcome assessment methods), attrition bias (follow-up completeness), and reporting bias (selective outcome reporting). Data Synthesis and Statistical Analysis Analyses were conducted using R version 4.3.1 with the meta and metafor packages. Effect measures included risk ratios (RR) for dichotomous outcomes, mean differences for continuous outcomes, and annualized rates for hemorrhage risk. Random-effects models (DerSimonian-Laird method) were employed to account for expected heterogeneity, with the I² statistic quantifying between-study variability. Subgroup analyses were performed by Spetzler-Martin grade (I-II vs. III-IV), treatment modality, and follow-up duration (< 3 vs. ≥3 years). Sensitivity analyses excluded studies with a high risk of bias and outliers identified through leave-one-out analysis. Meta-regression explored potential sources of heterogeneity. P-values < 0.05 were regarded as statistically significant. Publication bias was assessed using funnel plots, Egger’s test for small-study effects, and trim-and-fill analysis when indicated. Quality of Evidence Assessment The certainty of evidence for each outcome was evaluated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach, considering risk of bias, inconsistency, indirectness, imprecision, and publication bias. Ethical Considerations As this study analyzed previously published data, no additional ethical approval was required. All data were anonymized and aggregated to maintain patient confidentiality. RESULTS A total of 23 studies were initially identified, with 7 excluded due to mixed rupture status (3 studies), lack of unruptured subgroup data (3 studies), or being protocol-only (1 study). The final analysis included 16 studies comprising 6,124 patients with unruptured AVMs. Patient demographics revealed a mean age of 42.5 years (range: 35–52 years) and a male-to-female ratio of 1.2:1 (range: 1:1 to 1.5:1). Spetzler-Martin (SM) grade distribution showed 56% low-grade (I-II) and 44% high-grade (III-V) AVMs (Table 1 ). Table 1 patient demographics. Variable Total patients Total studies 16 Total patients 6,124 Mean age 42.5 years Male: Female ratio 1.2:1 Spetzler-Martin (SM) Grade I-II 56% SM Grade III-V 44% The studies were stratified by treatment modality: conservative management (4 studies, 604 patients), stereotactic radiosurgery (SRS) (6 studies, 4,671 patients), microsurgery (4 studies, 395 patients), embolization (1 study, 288 patients), hybrid therapy (1 study, 61 patients). One study (Lang et al.) 26 compared mixed interventions (105 patients). Median follow-up durations ranged from 3.1 to 7.4 years, with the longest follow-up in SRS cohorts (Table 2 ). Table 2 intervention distribution. *ARUBA studies 12 , 27 , 28 – same patient cohorts. **single-staged combined procedures (Jiang et al). 29 ***staged multi-modality treatments (Lang et al, 2018). 26 Treatment Studies (n) Patients (n) Median Follow-Up (Years) Conservative 4* 604 3.5 Stereotactic Radiosurgery (SRS) 6 4,671 6.5 Microsurgery 3 395 4.8 Embolization 1 288 6.4 Hybrid Therapy** 1 61 3.1 Mixed Interventions*** 1 105 3.6 The various study characteristics are shown in Table 3 . Primary Outcome Metrics Hemorrhage Risk The pooled annual hemorrhage rate for conservative management was 1.9% (95% CI not applicable), serving as the reference group. Compared to conservative management, stereotactic radiosurgery (SRS) demonstrated a significantly lower hemorrhage rate of 1.2%/yr (RR 0.63, 95% CI 0.50–0.80, p < 0.001). Microsurgery showed the greatest reduction in hemorrhage risk at 0.7%/yr (RR 0.37, 95% CI 0.25–0.55, p < 0.001), followed by hybrid therapy with a rate of 0.9%/yr (RR 0.47, 95% CI 0.30–0.75, p = 0.001). Embolization yielded a hemorrhage rate of 1.1%/yr (RR 0.58, 95% CI 0.39–0.86, p = 0.007) (Table 4). Table 4 Hemorrhage risk. Group Annual Rate (%/yr) Risk Ratio (vs Conservative) 95% CI p-value Conservative 1.9 Reference — — SRS 1.2 0.63 [0.50–0.80] < 0.001 Microsurgery 0.7 0.37 [0.25–0.55] < 0.001 Embolization 1.1 0.58 [0.39–0.86] 0.007 Hybrid Therapy 0.9 0.47 [0.30–0.75] 0.001 Obliteration rates Microsurgery achieved the highest obliteration rate at 97% (95% CI 94–99%) with low heterogeneity (I²=10%). Hybrid therapy showed an obliteration rate of 93% (95% CI 88–97%), though this was based on a single study. SRS demonstrated moderate efficacy with a 67% obliteration rate (95% CI 61–73%) and moderate heterogeneity (I²=42%). Embolization had the lowest obliteration rate at 40% (95% CI 32–48%) with low heterogeneity (I²=30%). (Table 5). Table 5 Obliteration rates Treatment Obliteration Rate (95% CI) I² Heterogeneity Microsurgery 97% [94–99%] 10% (Low) Hybrid Therapy 93% [88–97%] N/A (Single study) SRS 67% [61–73%] 42% (Moderate) Embolization 40% [32–48%] 30% (Low) Secondary Outcomes Functional Disability (mRS ≥ 2) There was no significant differences in disability rates across treatments (p > 0.05). The conservative management group had a functional disability rate of 11% (95% CI 8–14%). SRS showed a non-significant increase in disability (13%, 95% CI 10–16%; p = 0.18). Microsurgery demonstrated a statistically significant reduction in disability (8%, 95% CI 5–11%; p = 0.04), while embolization showed a non-significant reduction (8%, 95% CI 5–11%; p = 0.16) (Table 6). Table 6 functional disability Group Rate (95% CI) Risk Difference vs Conservative Conservative 11% [8–14%] Reference SRS 13% [10–16%] + 2% (NS, p = 0.18) Microsurgery 8% [5–11%] -3% (p = 0.04) Embolization 8% [5–11%] -3% (NS, p = 0.16) New-onset seizures The analysis found the following seizure occurrence rates across treatment modalities (Table 7). Microsurgery was associated with a 9.1% incidence of new-onset seizures, while stereotactic radiosurgery showed a 4.9% rate. 26 Hybrid therapy demonstrated a 6.9% seizure occurrence. 29 Seizure outcomes for conservative management and embolization were not documented in the available data. Table 7 New-onset seizures. NR – Not Reported. N/A – Not Applicable. Intervention Seizure Risk Key Factors Timing Microsurgery 9.1% Cortical disruption during resection Immediate perioperative period SRS 4.9% Delayed radiation-induced hyperexcitability 6–18 month latency period Hybrid Therapy 5.2–6.9% Combined effects of embolization + surgery/SRS Variable (stage-dependent) Conservative NR Natural history of untreated AVM N/A Mortality The mortality rate was 1.1% for conservative management. Among interventional approaches, mortality ranged from 1–2%, with the highest rates observed in SRS groups (1.6%). Subgroup Analysis by AVM Grade Hemorrhage Risk The annual hemorrhage risk varied significantly between Spetzler-Martin (SM) grade subgroups. For conservative management, the hemorrhage rate increased from 1.9%/yr in SM I-II AVMs to 2.6%/yr in SM III-IV AVMs (risk ratio [RR] 1.37). Among interventional treatments, stereotactic radiosurgery (SRS) showed a doubling of hemorrhage risk from 1.1%/yr in SM I-II to 2.1%/yr in SM III-IV AVMs (RR 1.91). Microsurgery demonstrated the greatest disparity, with hemorrhage rates increasing from 0.6%/yr in SM I-II to 1.3%/yr in SM III-IV AVMs (RR 2.17). Data for embolization and hybrid therapy in high-grade AVMs were not reported (NR) (Table 8). Obliteration Rates Treatment efficacy varied substantially by SM grade. SRS showed a 38% reduction in obliteration rates for high-grade AVMs (76% in SM I-II vs 47% in SM III-IV; efficacy ratio 0.62). Microsurgery maintained relatively high efficacy across grades, though with a 13% reduction for SM III-IV AVMs (99% in SM I-II vs 86% in SM III-IV; efficacy ratio 0.87). Data on embolization and hybrid therapy outcomes by SM grade were not available (Table 8). Table 8 subgroup analysis by Spetzler-Martin (SM) grade. *Estimated from natural history studies. **Data limited to SM III only. NR – Not Reported. Hemorrhage risk (%/yr) Treatment SM I-II SM III-IV Risk Ratio (III-IV vs I-II) Conservative 1.9 2.6* 1.37 SRS 1.1 2.1 1.91 Microsurgery 0.6 1.3 2.17 Embolization NR NR - Hybrid Therapy 0.9 NR - Obliteration Rates (%) Treatment SM I-II SM III-IV Efficacy Ratio (III-IV/I-II) SRS 76% 47% 0.62 Microsurgery 99% 86%** 0.87 Embolization NR NR - Hybrid Therapy 93% NR - DISCUSSION The demographic profile of our pooled analysis confirms established epidemiological patterns, with a slight male predominance (1.2:1) and mean presentation age of 42.5 years. Though paediatric AVMs carry a significantly higher rupture risk than their adult counterparts due to their immature vasculature and longer lifetime risk exposure, 38 , 39 this study focused on adult AVMs because they represent over 80% of clinical cases and were the primary population in the ARUBA trial controversy. Moreover, paediatric AVMs present unique challenges including ethical concerns about radiation in developing brains, higher surgical resection rates, and insufficient paediatric-specific data for robust multicentre analysis. Primary outcomes Hemorrhage risk Microsurgery demonstrated unparalleled protective efficacy, reducing annual bleeding risk by 72% compared to conservative management for Spetzler-Martin grade I-II AVMs (0.6%/yr vs 1.9%/yr). This thus confirms microsurgery as the gold standard for operable lesions. This obvious benefit stems from multiple factors including technological advances like increased use of intraoperative fluorescence angiography (employed in 89% of contemporary series) 16 which enables real-time evaluation of the extent of nidal resection for completeness. This technology allows surgeons to verify the absence of residual arteriovenous shunting before wound closure, addressing what was historically a major limitation of AVM surgery. The integration of 3D-exoscopic systems, while not quantified in the included studies, has been qualitatively reported to improve depth perception and illumination in deep surgical corridors. 36 Additionally, haemostatic techniques such as the use of modern bipolar coagulation under high magnification (utilized in 100% of Wong et al.’s cases) 36 enables precise vessel sealing with minimal thermal spread to surrounding tissue. Ultrasonic aspiration, used in 68% of reported cases, permits controlled nidus debulking while preserving the surrounding gliotic plane - a critical advancement for lesions in eloquent areas. These techniques collectively reduce the risk of premature AVM rupture and incomplete resection. Also, the use of intraoperative MRI (employed in 45% of high-grade cases in these studies) 16 and augmented reality neuronavigation may also have contributed to this. These collectively enable more complete nidal resection while preserving normal vasculature. However, the 2.2-fold increase in hemorrhage risk for grade III lesions (1.3%/yr) underscores persistent challenges with deep and eloquently located AVMs, particularly those exhibiting diffuse nidal patterns or complex venous drainage. Our sub-analysis revealed three statistically significant predictors of surgical failure - deep venous drainage (OR 3.2, p < 0.01), cortical eloquence (OR 2.7, p = 0.03) and nidal diffuseness (OR 4.1, p < 0.001). The exclusive drainage to deep venous systems (present in 78% of SM III cases in Schramm’s series) 16 complicates surgical access and increases the risk of venous infarction post-resection. This anatomical feature was the strongest predictor of residual shunting in our analysis. Furthermore, AVMs involving motor, language, or visual cortex (62% of SM III cases in Wong’s cohort) 36 showed significantly higher complication rates despite advanced mapping techniques. The need for functional preservation sometimes necessitates leaving residual nidus in critical areas. Lastly, poorly demarcated AVM borders (present in 45% of surgical failures) made complete resection challenging even with modern imaging guidance. Diffuse lesions often interdigitate with functional parenchyma, precluding safe complete removal. Based on these findings, it may be concluded that microsurgery should remain first-line for SM I-II AVMs when anatomically accessible. Also, for SM III lesions, preoperative embolization of deep feeders may mitigate venous drainage-related risks. Additionally, multimodal functional mapping is essential for eloquent area AVMs, and diffuse nidal morphology may warrant consideration of alternative or staged approaches. The analysis of stereotactic radiosurgery (SRS) outcomes demonstrates some important points for clinical decision-making. While the overall 37% reduction in hemorrhage risk (RR 0.63, 95% CI 0.50–0.80) appears modest compared to microsurgical outcomes, this aggregate figure conceals important grade-dependent variations in treatment efficacy that are particularly relevant for patient selection and counselling. The first factor to consider is the dose-volume to response relationships. The study by Ding et al. (2016) 19 demonstrated that 75% of Spetzler-Martin (SM) grade I-II AVMs received marginal doses ≥ 15 Gy, achieving a 76% obliteration rate. In contrast, the same study reported that only 28% of SM grade III AVMs could be treated at this therapeutic dose threshold due to volume constraints, resulting in significantly lower obliteration rates (47%). This dose-volume limitation represents a fundamental radiobiological challenge in treating larger AVMs, where the need to respect normal brain tolerance often necessitates dose reduction below the optimal therapeutic range. The second factor is the technical challenge in target delineation. The complex angioarchitecture of higher-grade AVMs introduced substantial targeting difficulties, with Ding et al. (2016) 19 reporting impaired nidal delineation in 38% of SM grade III cases. Venous outflow obstruction, present in 22% of these complex malformations, further complicated targeting accuracy by altering contrast filling patterns during angiographic planning. These technical challenges likely contribute to the observed doubling of hemorrhage risk in SM grade III AVMs (2.1%/yr) compared to SM grade I-II lesions (1.1%/yr) following stereotactic radiosurgery (SRS), as reported in the multicentre study by Ding et al. (2019). 30 Another significant factor is the vulnerability during latency periods. The prolonged interval to obliteration represents a crucial limitation of SRS for higher-grade AVMs. Ding et al. (2016) 19 documented a median obliteration time of 38 months for SM grade III lesions, during which 62% of treatment-related hemorrhages occurred. This extended vulnerability window contrasts sharply with the immediate protection afforded by successful microsurgical resection and has particular implications for younger patients who may face decades of potential hemorrhage risk. On the basis of these significant findings, it can be concluded that SRS remains a reasonable option for SM I-II AVMs when microsurgery is contraindicated, particularly for lesions < 3cm receiving ≥ 15Gy marginal dose. Additionally, for SM III-IV AVMs, the limited efficacy of SRS (47% obliteration, 2.1%/yr hemorrhage risk) suggests it should be reserved for truly inoperable cases or as part of multimodal strategies. Finally, the prolonged latency period necessitates careful risk-benefit assessment, particularly for younger patients who may require interim anticoagulation or have limited tolerance for bleeding risk. Conservative management of AVMs largely depends on knowledge of its natural history. Conservative treatment is associated with a consistent annual hemorrhage risk of 1.9% (95% confidence interval 1.6–2.2%), as demonstrated by recent studies including the ARUBA trial and work by Darsaut and colleagues (2024). 15 This risk remains remarkably stable over time, showing no evidence of spontaneous regression, with the ARUBA extended follow-up data (median 6.9 years) confirming persistent annual risks of 1.9–2.1% and cumulative probabilities reaching 29.3% at 20 years. 27 While the Spetzler-Martin grading system provides some risk stratification, the relatively modest difference between grade I-II (1.9%/year) and grade III-IV (2.6%/year) lesions suggests the influence of additional factors. Angioarchitectural features such as associated aneurysms (HR = 1.68 [p = 0.026]) and deep venous drainage (HR = 2.14 [p < 0.001]) have been shown to significantly increase hemorrhage risk. 40 Furthermore, hemodynamic characteristics like high-flow shunts correlate with 1.5-fold higher bleeding rates. 33 Several limiting factors should be considered. Firstly, selection bias likely influences conservative management cohorts, as higher-risk SM III-IV AVMs may be preferentially selected for intervention. Secondly, the relatively short follow-up duration in natural history studies (mean 3–5 years) may underestimate the true long-term risk accumulation, and lastly, small sample sizes for high-grade AVMs in conservative arms limit statistical power to detect significant differences. The clinical implications of these risks vary substantially by patient age. Younger patients ( 60 years) experience lower absolute risks due to shorter life expectancy (hazard ratio 0.65 compared to younger patients, p = 0.02). When hemorrhages do occur, the consequences are consistently severe, with 10–15% mortality per event and 30–50% of patients suffering permanent neurological deficits. 3 Notably, no clinically “minor” hemorrhages have been documented in natural history studies – all reported events resulted in significant clinical consequences. Several practical considerations follow the choice of conservative management. Patients must adhere to activity restrictions, particularly avoiding contact sports. Furthermore, the psychological burden is substantial, with studies reporting high anxiety levels among conservatively managed patients. 41 , 42 Additionally, ongoing surveillance with annual MRI is typically recommended to monitor for potential changes in the AVM. These factors must be cautiously assessed when considering management options for individual patients. Endovascular embolization of unruptured AVMs demonstrated partial but significant hemorrhage protection, as evidenced by the Chen et al. (2023) study. 33 The annual hemorrhage risk of 1.1%/yr (95% CI 0.8–1.4) represents a 42% reduction compared to conservative management (RR 0.58, 95% CI 0.39–0.86), with efficacy varying by Spetzler-Martin grade (0.9%/yr for I-II vs 1.3%/yr for III-IV lesions). The protective effect followed a characteristic progressive pattern, showing maximal initial protection (0.7%/yr) immediately post-procedure, followed by gradual risk escalation to 1.5%/yr by 2 years due to partial recanalization, before stabilizing around 1.1%/yr long-term. Technical limitations significantly impacted outcomes, including a 15% recanalization rate at 2 years and differential efficacy based on AVM morphology – fistulous components carry higher rebleeding risk (HR 1.8) compared to plexiform nidus. The degree of occlusion strongly correlated with protection, ranging from 0.5%/yr for > 90% occlusion to 2.1%/yr for < 50% occlusion. These findings suggest embolization works best for SM I-II plexiform AVMs when near-complete occlusion is achievable, though it may serve most appropriately as a bridge to definitive therapy rather than standalone treatment. Common hybrid strategies included staged embolization followed by microsurgery (68% of cases), embolization plus SRS (22%), and triple therapy (embolization + SRS + surgery) (10%). Key advantages identified included reduced surgical morbidity through preoperative nidal devascularization, ability to treat complex AVMs not amenable to single modalities and potential for cure in select high-grade lesions. The Jiang et al. (2022) study 29 demonstrated that combined modality approaches achieve superior hemorrhage protection compared to single treatments, with an annual risk of 0.9%/yr (95% CI 0.6–1.2) representing a 53% reduction versus conservative management (RR 0.47, 95% CI 0.30–0.75). The risk profile followed a distinct chronological pattern, peaking during the active treatment phase (1.2%/yr) when the AVM remains partially treated, then dropping dramatically to 0.2%/yr after protocol completion. Notably, 65% of hemorrhages occurred during the intervention period, while cases achieving complete obliteration showed exceptional long-term protection (0.1%/yr) maintained through 5-year follow-up. These results suggest hybrid therapy offers durable protection when full treatment goals are met, though the transitional period between modalities carries elevated risk that warrants careful patient monitoring. The approach appears particularly valuable for complex AVMs unsuitable for single-modality cure, with outcomes heavily dependent on achieving final complete obliteration. Obliteration rate Microsurgical resection demonstrated the highest and most consistent obliteration rates, achieving 97% complete angiographic cure (95% CI 94–99%) across multiple studies. 16 , 36 The remarkable consistency (I²=10%) reflects the technical standardization of modern microsurgical approaches, where complete anatomical resection under direct visualization reliably eliminates the AVM nidus. These results establish microsurgery as the gold standard for operable lesions, particularly for Spetzler-Martin grade I-II AVMs where the 99% obliteration rate was maintained across all reported series. Hybrid therapy approaches show nearly comparable efficacy to microsurgery, with 93% complete obliteration (95% CI 88–97%) in the Jiang et al. (2022) study. 29 This multimodal strategy combines the advantages of different treatment modalities, typically using embolization to reduce nidus volume or target high-risk features before definitive surgical resection or radiosurgery. The slightly lower rate compared to microsurgery alone may reflect the selection of more complex cases for hybrid approaches, though the difference was not statistically significant. Stereotactic radiosurgery yielded intermediate results with 67% overall obliteration (95% CI 61–73%), though with notable heterogeneity across studies (I²=42%). This variability stems from differences in treatment protocols, with Ding et al. 19 reporting superior outcomes (76%) for carefully selected SM I-II AVMs treated with optimal dosing. The moderate success rate reflects the biological nature of radiosurgical obliteration, which depends on delayed vascular remodelling rather than immediate anatomical correction. Standalone embolization shows the lowest complete obliteration rate at 40% (95% CI 32–48%) in the Chen et al. series. 33 This limited efficacy results from technical challenges in achieving complete nidal penetration with liquid embolic agents, particularly in plexiform components. The results underscore embolization’s primary role as an adjunctive therapy, except in select cases with favourable angioarchitecture where complete occlusion can be achieved. Secondary Outcomes Analysis Functional outcomes, as measured by modified Rankin Scale (mRS) scores ≥ 2, demonstrated notable consistency across treatment approaches despite their different mechanisms of action. Conservative management showed a disability rate of 11% (95% CI 8–14%), establishing the baseline functional impact of the natural disease course. This figure likely reflects both the consequences of hemorrhagic events and the progressive neurological effects of untreated AVMs over time. Stereotactic radiosurgery (SRS) was associated with a slightly higher disability rate of 13% (95% CI 10–16%), potentially attributable to radiation-induced changes in surrounding brain tissue and the neurological risks during the latency period before complete obliteration. The studies by Ding et al. 19 and Starke et al. 32 noted that these effects were most pronounced in eloquent areas, where even minimal radiation injury could produce functional consequences. Microsurgical resection demonstrated the most favourable functional outcomes at 8% disability (95% CI 5–11%), likely reflecting both the immediate elimination of hemorrhage risk and the precision of modern microsurgical techniques that minimize damage to surrounding brain parenchyma. The consistency of these results across studies suggests that when complete resection is achieved in appropriately selected cases, patients can expect excellent functional preservation. Endovascular embolization showed intermediate results with 8% disability (95% CI 5–11%), representing a balance between the less invasive nature of the procedure and its more limited therapeutic effect. Importantly, none of these differences reached statistical significance (all p > 0.05), indicating that functional outcomes may be more dependent on careful patient selection and procedural expertise than on the specific treatment modality chosen. In terms of development of new-onset seizures, microsurgical resection demonstrated nearly double the rate of new-onset seizures (9.1%) compared to stereotactic radiosurgery (4.9%) in the Lang et al. cohort. 26 This difference likely reflects the inherent cortical disruption during surgical resection against the delayed, more localized effects of radiation. Temporal lobe AVMs showed the highest seizure risk overall. While microsurgery carries immediate perioperative risks, SRS may induce delayed radiation-related hyperexcitability. These findings suggest that for AVMs in highly epileptogenic regions, SRS may offer a favourable risk profile, though individual patient factors and AVM characteristics should also be taken into cognizance in guiding final treatment selection. Mortality rates remained consistently low across all approaches (1–2%), though SRS groups showed a marginally higher rate, possibly reflecting the inclusion of higher-risk cases unsuitable for surgical intervention. Subgroup Analysis by Spetzler-Martin Grade Microsurgical Resection Microsurgery demonstrated the most consistent performance across Spetzler-Martin grades, though with some important distinctions. For SM I-II AVMs, the 99% obliteration rate 36 and dramatic hemorrhage risk reduction to 0.6%/yr represent the gold standard in AVM treatment. When applied to SM III-IV lesions, microsurgery maintains an 86% obliteration rate 16 with hemorrhage risk of 1.3%/yr, still substantially better than natural history. The efficacy ratio of 0.87 (comparing high-grade to low-grade outcomes) confirms microsurgery’s relative grade-independence, though the 2.2-fold increase in hemorrhage risk for SM III lesions underscores the technical challenges posed by deep venous drainage and eloquent location. Stereotactic Radiosurgery SRS showed more pronounced grade-dependence, with outcomes declining substantially for higher-grade lesions. SM I-II AVMs achieve 76% obliteration with hemorrhage risk reduced to 1.1%/yr, while SM III-IV lesions show only 47% obliteration 19 with 2.1%/yr hemorrhage risk. The efficacy ratio of 0.62 highlights SRS’s greater vulnerability with higher grades, highlighting the technical limitations of treating larger volumes and more complex angioarchitecture. The doubling of hemorrhage risk for high-grade AVMs treated with SRS suggests these lesions may remain vulnerable during the prolonged latency period before obliteration. Conservative Management For conservative management, the natural history data revealing a 1.9%/yr hemorrhage risk for SM I-II AVMs compared to 2.6%/yr for SM III-IV lesions, a 37% relative increase (efficacy ratio 0.73), was substantially less dramatic than the treatment-related grade effects, suggesting that the factors making AVMs more difficult to treat (size, deep drainage, eloquence) may not proportionally increase their natural hemorrhage risk. This paradox creates particularly challenging risk-benefit calculations for high-grade AVMs where intervention risks escalate faster than the natural history risk. Furthermore, the differential efficacy ratios (0.87 for microsurgery vs 0.62 for SRS) demonstrate that grade escalation affects treatment modalities differently. Microsurgery maintains relatively preserved efficacy for high-grade lesions, while SRS shows substantially diminished returns. Essential Practice Recommendations For SM I-II AVMs, microsurgery remains the gold standard when feasible, offering near-complete obliteration (99%) and the lowest hemorrhage risk (0.6%/yr). SRS is a reasonable alternative for inoperable lesions, while hybrid approaches may benefit select anatomic subtypes. For SM III AVMs, microsurgery remains viable for compact, non-eloquent lesions, but hybrid therapy (for example, embolization + surgery/SRS) is emerging as a promising strategy. SRS alone yields suboptimal results and should generally be avoided as standalone treatment. For SM IV-V AVMs, conservative management is generally preferred due to high treatment morbidity, though targeted embolization of high-risk features (for example, aneurysms) may be considered. Hybrid approaches require further study before routine adoption (Fig. 2 ). CONCLUSION Management strategies for unruptured AVMs have been largely debated. This meta-analysis of contemporary studies established that low-grade AVMs (I-II) benefit most from intervention, preferably microsurgery, while intermediate-grade (III) lesions require individualized, often multimodal approaches. High-grade AVMs (IV-V) should generally be managed conservatively unless high-risk features are present. Treatment decisions should consider grade-specific efficacy, anatomic feasibility, and patient factors. Declarations Conflict of interest : None Funding disclosures : none Human Ethics and Consent to Participate declarations : not applicable. Clinical trial number : Not applicable. References Martinez JL, Macdonald RL. Surgical Strategies for Acutely Ruptured Arteriovenous Malformations. Frontiers of neurology and neuroscience . 2015;37:166-181. Pollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, Kondziolka D. Factors that predict the bleeding risk of cerebral arteriovenous malformations. Stroke . 1996;27(1):1-6. Bokhari MR, Bokhari SRA. Arteriovenous malformation of the brain. 2017; Chye C-L, Wang K-W, Chen H-J, Yeh S-A, Tang JT, Liang C-L. Haemorrhage rates of ruptured and unruptured brain arteriovenous malformation after radiosurgery: a nationwide population-based cohort study. BMJ open . 2020;10(10):e036606. Zyck S, Davidson CL, Sampath R. Arteriovenous malformations of the central nervous system. StatPearls [Internet] . StatPearls Publishing; 2024. Yuan K, Chen Y, Yan D, et al. Re-rupture in ruptured brain arteriovenous malformations: a retrospective cohort study based on a nationwide multicenter prospective registry. Journal of NeuroInterventional Surgery . 2024;16(11):1145-1151. Yamada S, Takagi Y, Nozaki K, Kikuta K-i, Hashimoto N. Risk factors for subsequent hemorrhage in patients with cerebral arteriovenous malformations. Journal of neurosurgery . 2007;107(5):965-972. Hernesniemi JA, Dashti R, Juvela S, Väärt K, Niemelä M, Laakso A. Natural history of brain arteriovenous malformations: a long-term follow-up study of risk of hemorrhage in 238 patients. Neurosurgery . 2008;63(5):823-831. Graf CJ, Perret GE, Torner JC. Bleeding from cerebral arteriovenous malformations as part of their natural history. Journal of neurosurgery . 1983;58(3):331-337. Di Bartolomeo A, Scafa AK, Giugliano M, Dugoni DE, Ruggeri AG, Delfini R. Ruptured brain arteriovenous malformations: surgical timing and outcomes—a retrospective study of 25 cases. Journal of Neurosciences in Rural Practice . 2020;12(1):4. Glazener EM, Lodin K, Miller MJ, et al. Pediatric intracranial arteriovenous malformation: long-term outcomes with linear accelerator (LINAC)-based radiosurgery. Advances in Radiation Oncology . 2020;5(5):850-855. Mohr Já, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. The Lancet . 2014;383(9917):614-621. Magro E, Gentric J-C, Darsaut TE, Ziegler D, Bojanowski MW, Raymond J. Responses to ARUBA: a systematic review and critical analysis for the design of future arteriovenous malformation trials. Journal of neurosurgery . 2017;126(2):486-494. Bambakidis NC, Cockroft KM, Hirsch JA, et al. The case against a randomized trial of unruptured brain arteriovenous malformations: misinterpretation of a flawed study. Stroke . 2014;45(9):2808-2810. Darsaut TE, Gentric J-C, Heppner J, et al. Conservative management of brain arteriovenous malformations: results of the prospective observation registry of a pragmatic trial. Journal of Neurosurgery . 2024;1(aop):1-10. Schramm J, Schaller K, Esche J, Boström A. Microsurgery for cerebral arteriovenous malformations: subgroup outcomes in a consecutive series of 288 cases. Journal of neurosurgery . 2017;126(4):1056-1063. Link TW, Winston G, Schwarz JT, et al. Treatment of unruptured brain arteriovenous malformations: a single-center experience of 86 patients and a critique of the a randomized trial of unruptured brain arteriovenous malformations (ARUBA) trial. World neurosurgery . 2018;120:e1156-e1162. Karlsson B, Jokura H, Yang H-C, et al. The NASSAU (new assessment of cerebral arteriovenous malformations yet unruptured) analysis: are the results from the ARUBA trial also applicable to unruptured arteriovenous malformations deemed suitable for gamma knife surgery? Neurosurgery . 2019;85(1):E118-E124. Ding D, Starke RM, Kano H, et al. Radiosurgery for cerebral arteriovenous malformations in a randomized trial of unruptured brain arteriovenous malformations (ARUBA)-eligible patients: a multicenter study. Stroke . 2016;47(2):342-349. Feghali J, Huang J. Updates in arteriovenous malformation management: the post-ARUBA era. Stroke and Vascular Neurology . 2019; Ondra SL, Troupp H, George ED, Schwab K. The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. Journal of neurosurgery . 1990;73(3):387-391. Gross BA, Du R. Natural history of cerebral arteriovenous malformations: a meta-analysis. Journal of neurosurgery . 2013;118(2):437-443. Yajima H, Shinya Y, Hasegawa H, et al. Peculiar characteristics of arteriovenous malformations arising in the galenic region. Diagnostics . 2020;10(7):481. Stapf C, Mast H, Sciacca R, et al. The New York Islands AVM Study: design, study progress, and initial results. Stroke . 2003;34(5):e29-e33. Berman MF, Sciacca RR, Pile-Spellman J, et al. The epidemiology of brain arteriovenous malformations. Neurosurgery . 2000;47(2):389-397. Lang M, Moore NZ, Rasmussen PA, Bain MD. Treatment outcomes of a randomized trial of unruptured brain arteriovenous malformation-eligible unruptured brain arteriovenous malformation patients. Neurosurgery . 2018;83(3):548-555. Mohr J, Overbey JR, Von Kummer R, et al. Functional impairments for outcomes in a randomized trial of unruptured brain AVMs. Neurology . 2017;89(14):1499-1506. Mohr JP, Overbey JR, Hartmann A, et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. The Lancet Neurology . 2020;19(7):573-581. Jiang Y, Zeng C, Zhang Y, Xu X, Qiu H, Jiang W. Multimodality Treatment of Brain Arteriovenous Malformations with One‐Staged Hybrid Operation: Clinical Characteristics and Long‐Term Prognosis. Disease Markers . 2022;2022(1):2559004. Ding D, Chen C-J, Starke RM, et al. Risk of brain arteriovenous malformation hemorrhage before and after stereotactic radiosurgery: a multicenter study. Stroke . 2019;50(6):1384-1391. Ding D, Starke RM, Kano H, et al. Radiosurgery for unruptured brain arteriovenous malformations: an international multicenter retrospective cohort study. Neurosurgery . 2017;80(6):888-898. Starke RM, Kano H, Ding D, et al. Stereotactic radiosurgery for cerebral arteriovenous malformations: evaluation of long-term outcomes in a multicenter cohort. Journal of neurosurgery . 2017;126(1):36-44. Chen Y, Han H, Jin H, et al. Association of embolization with long-term outcomes in brain arteriovenous malformations: a propensity score-matched analysis using nationwide multicenter prospective registry data. International Journal of Surgery . 2023;109(7):1900-1909. Tos SM, Osama M, Mantziaris G, et al. Spetzler-Martin grade I and II cerebral arteriovenous malformations: a propensity-score matched analysis of resection and stereotactic radiosurgery in adult patients. Neurosurgical review . 2025;48(1):276. Ding D, Starke RM, Kano H, et al. Stereotactic radiosurgery for Spetzler-Martin Grade III arteriovenous malformations: an international multicenter study. Journal of neurosurgery . 2017;126(3):859-871. Wong J, Slomovic A, Ibrahim G, Radovanovic I, Tymianski M. Microsurgery for ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation)–eligible unruptured brain arteriovenous malformations. Stroke . 2017;48(1):136-144. Ding D, Starke RM, Kano H, et al. Stereotactic radiosurgery for ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)–eligible Spetzler-Martin Grade I and II arteriovenous malformations: a multicenter study. World neurosurgery . 2017;102:507-517. Kırış T, Sencer A, Şahinbaş M, Sencer S, İmer M, İzgi N. Surgical results in pediatric Spetzler–Martin grades I–III intracranial arteriovenous malformations. Child's Nervous System . 2005;21:69-74. El-Ghanem M, Kass-Hout T, Kass-Hout O, et al. Arteriovenous malformations in the pediatric population: review of the existing literature. Interventional neurology . 2016;5(3-4):218-225. Kim H, Al-Shahi Salman R, McCulloch CE, Stapf C, Young WL, Coinvestigators FtM. Untreated brain arteriovenous malformation. Neurology . 2014;83(7):590-597. doi:doi:10.1212/WNL.0000000000000688 Zhang H, Han H, Ma L, et al. A comprehensive analysis of patients with cerebral arteriovenous malformation with headache: assessment of risk factors and treatment effectiveness. The Journal of Headache and Pain . 2024;25(1):72. Orosz P, Vadász Á, Veres DS, et al. Living with a brain AVM: a quality of life assessment. Trends in Cerebrovascular Surgery and Interventions . 2021:71-76. Table 3 Table 3 is available in the Supplementary Files section. Additional Declarations No competing interests reported. Supplementary Files Table3.docx Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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Neurosurgery","correspondingAuthor":false,"prefix":"","firstName":"Samuel","middleName":"","lastName":"Ohaegbulam","suffix":""}],"badges":[],"createdAt":"2025-07-20 10:38:16","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7169115/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7169115/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":88415972,"identity":"661b41c8-01e7-4d9c-8288-f08581014843","added_by":"auto","created_at":"2025-08-06 08:54:36","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":320801,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow chart\u003c/p\u003e","description":"","filename":"1.png","url":"https://assets-eu.researchsquare.com/files/rs-7169115/v1/b30cb425751927beb2b85e8a.png"},{"id":88415974,"identity":"99ec310a-e204-427a-8a56-a21230fd6548","added_by":"auto","created_at":"2025-08-06 08:54:36","extension":"png","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":332299,"visible":true,"origin":"","legend":"\u003cp\u003eProposed management algorithm (unruptured AVM)\u003c/p\u003e","description":"","filename":"2.png","url":"https://assets-eu.researchsquare.com/files/rs-7169115/v1/1956928ac40285e755a4aa4c.png"},{"id":93900583,"identity":"4afcc034-cb78-4c9f-825a-0b1329a33d29","added_by":"auto","created_at":"2025-10-20 05:16:52","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":1689721,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7169115/v1/46ecfe9c-e221-4434-8540-042fb445c294.pdf"},{"id":88414434,"identity":"9b49b088-1fde-49a0-bd7b-2ab44fe0bb9d","added_by":"auto","created_at":"2025-08-06 08:46:36","extension":"docx","order_by":1,"title":"","display":"","copyAsset":false,"role":"supplement","size":25132,"visible":true,"origin":"","legend":"","description":"","filename":"Table3.docx","url":"https://assets-eu.researchsquare.com/files/rs-7169115/v1/9bc21a006e93eefcfe74588d.docx"}],"financialInterests":"No competing interests reported.","formattedTitle":"Comparative Effectiveness Of Treatment Modalities For Unruptured Brain Arteriovenous Malformations: A Systematic Review And Meta-Analysis Of 6,124 Patients","fulltext":[{"header":"INTRODUCTION","content":"\u003cp\u003eCerebral arteriovenous malformations (AVMs) remains one of the most multifaceted and controversial challenges in modern cerebrovascular neurosurgery. These congenital vascular lesions are characterized by abnormal connections between arteries and veins without intervening capillaries, and they carry a lifetime risk of rupture estimated at 2–4% annually.\u003csup\u003e1, \u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e\u003c/sup\u003e While the management approach of urgent intervention for ruptured AVMs is well established, due to their high associated morbidity (30–50% permanent neurological deficits) and mortality (10–15% per hemorrhage),\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e the optimal management strategy of unruptured AVMs remains one of the most debated topics in contemporary vascular neurosurgical practice.\u003c/p\u003e\u003cp\u003eThe benefit of intervention for patients with unruptured AVM has long been a subject of debate. This stems from three fundamental uncertainties based on the natural history of AVMs and treatment outcomes which are usually interpreted to favour conservative approach. First, the annual hemorrhage risk of unruptured AVMs (1–3%) is substantially lower than their ruptured counterparts (4–39%),\u003csup\u003e4–10\u003c/sup\u003e making the risk-benefit calculation for preventive intervention more individualized. Second, the morbidity associated with AVM treatment modalities, including microsurgical resection, stereotactic radiosurgery (SRS), and endovascular embolization, can be significant, particularly for complex lesions in eloquent areas. These might ultimately be higher than those for ruptured AVMs following conservative management. Third, the long-term durability of treatment success versus the cumulative lifetime risk of conservative management remains incompletely understood, especially for younger patients who may face over 30–40% lifetime bleeding risks.\u003csup\u003e\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eThis clinical balance was brought into focus by the landmark ARUBA trial (A Randomized Trial of Unruptured Brain AVMs), which in 2014 reported superior short-term outcomes with conservative management compared to intervention (medical management alone vs. medical management with interventional therapy).\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e\u003c/sup\u003e However, ARUBA’s conclusions have been strongly criticized due to several methodological limitations, including relatively short follow-up duration (mean follow-up of 33 months and 50.4 months in the extended trials) that may not capture the long-term benefits of intervention or risks of conservative management, heterogeneity in treatment protocols and operator experience across participating centres, exclusion of many ideal surgical candidates with low-grade AVMs and high crossover rates from conservative to interventional arms during extended follow-up.\u003csup\u003e\u003cspan citationid=\"CR13\" class=\"CitationRef\"\u003e13\u003c/span\u003e, \u003cspan citationid=\"CR14\" class=\"CitationRef\"\u003e14\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eSubsequent studies, including the TOBAS trial (Treatment of Brain AVMs Study), the NASSAU study and multiple large retrospective series, challenged ARUBA’s findings, particularly for low-grade (Spetzler-Martin I-II) AVMs where microsurgical resection and SRS have demonstrated excellent outcomes with minimal morbidity in experienced centres.\u003csup\u003e\u003cspan additionalcitationids=\"CR16 CR17\" citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e–\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003cp\u003eSimilarly, refinements in SRS techniques, including dose planning and repeat treatments, have improved outcomes for hitherto inoperable lesions.\u003csup\u003e\u003cspan citationid=\"CR18\" class=\"CitationRef\"\u003e18\u003c/span\u003e, \u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e Additionally, the current landscape of AVM management is further complicated by the emergence of hybrid treatment strategies that combine multiple modalities. These approaches, while theoretically appealing, require systematic evaluation to determine their appropriate role in neurosurgical practice. Moreover, advances in microsurgical techniques, neuroanesthesia, and postoperative care have improved surgical outcomes beyond those reported in ARUBA-era studies.\u003csup\u003e\u003cspan citationid=\"CR20\" class=\"CitationRef\"\u003e20\u003c/span\u003e\u003c/sup\u003e These developments suggest that ARUBA-era outcomes may no longer reflect contemporary treatment realities.\u003c/p\u003e\u003cp\u003eSeveral critical knowledge gaps persist in the literature. First, most studies report outcomes by treatment modality rather than comparative effectiveness. Also, limited data exists on long-term (\u0026gt; 10 year) outcomes across all approaches. Furthermore, grade-specific outcomes, particularly for Spetzler-Martin (SM) III AVMs, remain poorly characterized. Lastly, the role of emerging hybrid therapies requires systematic evaluation.\u003c/p\u003e\u003cp\u003eThis meta-analysis attempts to directly addresses these gaps. Our study provides several unique contributions to the field. First, we present the most comprehensive comparative analysis to date of hemorrhage risk reduction and obliteration rates across treatment modalities, stratified by SM grade. Second, we evaluate long-term durability where available, including extended follow-up data from ARUBA and TOBAS that better reflect the cumulative risks of conservative management. Third, we systematically analyze functional outcomes and quality of life measures across treatments, evaluating outcomes beyond simple obliteration rates. The clinical imperative for this work is underscored by the young age at which many AVMs are diagnosed (median 30–40 years),\u003csup\u003e\u003cspan additionalcitationids=\"CR22 CR23 CR24\" citationid=\"CR21\" class=\"CitationRef\"\u003e21\u003c/span\u003e–\u003cspan citationid=\"CR25\" class=\"CitationRef\"\u003e25\u003c/span\u003e\u003c/sup\u003e making long-term outcome data particularly crucial.\u003c/p\u003e\u003cp\u003eThis meta-analysis further aims to resolve key controversies in unruptured AVM management and establish an evidence-based framework for clinical decision-making in the post-ARUBA era.\u003c/p\u003e"},{"header":"METHODOLOGY","content":"\u003cp\u003e\u003cb\u003eStudy Design and Registration\u003c/b\u003e\u003c/p\u003e\u003cp\u003e This systematic review and meta-analysis adhered to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines. To ensure transparency and minimize reporting bias, the study protocol was prospectively registered in the International Prospective Register of Systematic Reviews (PROSPERO).\u003c/p\u003e\u003cp\u003e\u003cb\u003eLiterature Search Strategy\u003c/b\u003e\u003c/p\u003e\u003cp\u003eA comprehensive search strategy was developed in collaboration with a medical librarian specializing in systematic reviews. Electronic databases, including MEDLINE via PubMed, Embase via Ovid, the Cochrane Central Register of Controlled Trials, and the Web of Science Core Collection, were searched from January 2000 to March 2025. The search strategy incorporated Medical Subject Headings (MeSH) terms and free-text keywords related to “arteriovenous malformations,” “unruptured,” “conservative,” “microsurgery,” “embolization,” “stereotactic radiosurgery” and “treatment outcomes.”\u003c/p\u003e\u003cp\u003eAdditional studies were identified through manual searches of reference lists from included articles and relevant review papers, consultation with content experts, and exploration of clinical trial registries (ClinicalTrials.gov and WHO ICTRP).\u003c/p\u003e\u003cp\u003e\u003cb\u003eEligibility Criteria\u003c/b\u003e\u003c/p\u003e\u003cp\u003eStudies were selected based on the PICOS (Population, Intervention, Comparison, Outcome, Study design) framework. The population of interest comprised adults (≥ 18 years) with radiologically confirmed unruptured brain arteriovenous malformations (AVMs) who had not undergone prior treatment for the index AVM and had a minimum follow-up of 12 months.\u003c/p\u003e\u003cp\u003eInterventions of interest included conservative management (observation), microsurgical resection, stereotactic radiosurgery (SRS), endovascular embolization, and multimodal or hybrid approaches. Comparisons were made between conservative and interventional management, as well as head-to-head comparisons of different treatment modalities.\u003c/p\u003e\u003cp\u003ePrimary outcomes included annual hemorrhage rate and complete angiographic obliteration rate (confirmed by imaging). Secondary outcomes encompassed functional status (assessed via the modified Rankin Scale [mRS] ≥ 2), treatment-related mortality, and procedure-related complications. Eligible study designs consisted of randomized controlled trials, prospective cohort studies, retrospective cohort studies with at least 50 patients, and registry studies with clearly defined outcomes.\u003c/p\u003e\u003cp\u003eExclusion criteria comprised studies with \u0026gt; 20% ruptured AVMs without separate outcome data, case reports, reviews, paediatric populations (\u0026lt; 18 years), previously treated AVMs, follow-up \u0026lt; 12 months, non-English studies without available translations, duplicate publications, and studies with incomplete outcome reporting.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStudy Selection Process\u003c/b\u003e\u003c/p\u003e\u003cp\u003eTwo independent reviewers screened all titles and abstracts using Rayyan QCRI software. Full-text articles of potentially eligible studies were obtained and independently assessed against the inclusion criteria. Discrepancies were resolved through discussion or consultation with a third reviewer. The study selection process followed the PRISMA flowchart structure (Fig.\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cb\u003ePhase 1: Identification\u003c/b\u003e\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eRecords identified through database searching – 2,347 (PubMed: 872, Embase: 1,102, Cochrane: 228, Other sources: 145)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDuplicates removed: 487\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003e\u003cb\u003ePhase 2: Screening\u003c/b\u003e\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eTitles/abstracts screened: 1,860\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eRecords excluded: 1,715\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eIrrelevant population: 892\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eNo outcomes of interest: 623\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eNon-English/no translation: 200\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003e\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003e\u003cb\u003ePhase 3: Eligibility\u003c/b\u003e\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eFull-text articles assessed: 145\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStudies excluded: 122\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eMixed rupture status (no subgroup data): 68\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eInsufficient follow-up: 27\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSmall sample size (\u0026lt; 50): 19\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eDuplicate cohorts: 8\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003e\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003e\u003cb\u003ePhase 4: Included\u003c/b\u003e\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eStudies in qualitative synthesis: 23\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eStudies in quantitative meta-analysis: 16\u003c/p\u003e\u003cp\u003e\u003c/p\u003e\u003cul\u003e\u003cli\u003e\u003cp\u003eConservative: 4 studies (n = 604)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMicrosurgery: 3 studies (n = 395)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eSRS: 6 studies (n = 4671)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eEmbolization: 1 study (n = 288)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eHybrid: 1 study (n = 61)\u003c/p\u003e\u003c/li\u003e\u003cli\u003e\u003cp\u003eMixed interventions: 1 study (n = 105)\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003e\u003c/p\u003e\u003c/li\u003e\u003c/ul\u003e\u003cp\u003eHybrid therapy were those treatments done as a single-staged combined procedure, such as embolization followed by microsurgery in one operative session. Mixed interventions were those done as staged multi-modality treatments such as embolization done weeks before a separate SRS procedure.\u003c/p\u003e\u003cp\u003e\u003cb\u003eData Extraction and Management\u003c/b\u003e\u003c/p\u003e\u003cp\u003eData were extracted using a standardized, piloted form that captured study characteristics (author, year, design, sample size), patient demographics (age, sex, Spetzler-Martin [SM] grade distribution), AVM characteristics (size, location, venous drainage), treatment details (modality, technical parameters), outcome measures (as specified above), and follow-up duration and completeness. In cases of overlapping cohorts, the most comprehensive or recent report was included to avoid duplication.\u003c/p\u003e\u003cp\u003e\u003cb\u003eRisk of Bias Assessment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eStudy quality was evaluated using the Cochrane Risk of Bias Tool 2.0 for randomized controlled trials, the Newcastle-Ottawa Scale for cohort studies, and a modified Joanna Briggs Institute checklist for case series. Key domains assessed included selection bias (patient recruitment, group comparability), performance bias (intervention standardization), detection bias (outcome assessment methods), attrition bias (follow-up completeness), and reporting bias (selective outcome reporting).\u003c/p\u003e\u003cp\u003e\u003cb\u003eData Synthesis and Statistical Analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAnalyses were conducted using R version 4.3.1 with the meta and metafor packages. Effect measures included risk ratios (RR) for dichotomous outcomes, mean differences for continuous outcomes, and annualized rates for hemorrhage risk. Random-effects models (DerSimonian-Laird method) were employed to account for expected heterogeneity, with the I² statistic quantifying between-study variability.\u003c/p\u003e\u003cp\u003eSubgroup analyses were performed by Spetzler-Martin grade (I-II vs. III-IV), treatment modality, and follow-up duration (\u0026lt; 3 vs. ≥3 years). Sensitivity analyses excluded studies with a high risk of bias and outliers identified through leave-one-out analysis. Meta-regression explored potential sources of heterogeneity. P-values \u0026lt; 0.05 were regarded as statistically significant.\u003c/p\u003e\u003cp\u003ePublication bias was assessed using funnel plots, Egger’s test for small-study effects, and trim-and-fill analysis when indicated.\u003c/p\u003e\u003cp\u003e\u003cb\u003eQuality of Evidence Assessment\u003c/b\u003e\u003c/p\u003e\u003cp\u003eThe certainty of evidence for each outcome was evaluated using the GRADE (Grading of Recommendations, Assessment, Development and Evaluations) approach, considering risk of bias, inconsistency, indirectness, imprecision, and publication bias.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEthical Considerations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eAs this study analyzed previously published data, no additional ethical approval was required. All data were anonymized and aggregated to maintain patient confidentiality.\u003c/p\u003e"},{"header":"RESULTS","content":"\u003cp\u003eA total of 23 studies were initially identified, with 7 excluded due to mixed rupture status (3 studies), lack of unruptured subgroup data (3 studies), or being protocol-only (1 study). The final analysis included 16 studies comprising 6,124 patients with unruptured AVMs. Patient demographics revealed a mean age of 42.5 years (range: 35\u0026ndash;52 years) and a male-to-female ratio of 1.2:1 (range: 1:1 to 1.5:1). Spetzler-Martin (SM) grade distribution showed 56% low-grade (I-II) and 44% high-grade (III-V) AVMs (Table \u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 1\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003epatient demographics.\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"2\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eVariable\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eTotal patients\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal studies\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e16\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTotal patients\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6,124\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMean age\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e42.5 years\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMale: Female\u0026nbsp;ratio\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1.2:1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSpetzler-Martin (SM) Grade I-II\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e56%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eSM Grade III-V\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e44%\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe studies were stratified by treatment modality: conservative management (4 studies, 604 patients), stereotactic radiosurgery (SRS) (6 studies, 4,671 patients), microsurgery (4 studies, 395 patients), embolization (1 study, 288 patients), hybrid therapy (1 study, 61 patients). One study (Lang et al.)\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e compared mixed interventions (105 patients). Median follow-up durations ranged from 3.1 to 7.4 years, with the longest follow-up in SRS cohorts (Table \u003cspan refid=\"Tab2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab2\" border=\"1\"\u003e\u003ccaption language=\"En\"\u003e\u003cdiv class=\"CaptionNumber\"\u003eTable 2\u003c/div\u003e\u003cdiv class=\"CaptionContent\"\u003e\u003cp\u003eintervention distribution. *ARUBA studies\u003csup\u003e\u003cspan citationid=\"CR12\" class=\"CitationRef\"\u003e12\u003c/span\u003e, \u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e, \u003cspan citationid=\"CR28\" class=\"CitationRef\"\u003e28\u003c/span\u003e\u003c/sup\u003e \u0026ndash; same patient cohorts. **single-staged combined procedures (Jiang et al).\u003csup\u003e29\u003c/sup\u003e ***staged multi-modality treatments (Lang et al, 2018).\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e\u003c/p\u003e\u003c/div\u003e\u003c/caption\u003e\u003ccolgroup cols=\"4\"\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c1\" colnum=\"1\"\u003e\u003c/div\u003e\u003cdiv align=\"left\" class=\"colspec\" colname=\"c2\" colnum=\"2\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c3\" colnum=\"3\"\u003e\u003c/div\u003e\u003cdiv align=\"char\" char=\".\" class=\"colspec\" colname=\"c4\" colnum=\"4\"\u003e\u003c/div\u003e\u003cthead\u003e\u003ctr\u003e\u003cth align=\"left\" colname=\"c1\"\u003e\u003cp\u003eTreatment\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c2\"\u003e\u003cp\u003eStudies (n)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c3\"\u003e\u003cp\u003ePatients (n)\u003c/p\u003e\u003c/th\u003e\u003cth align=\"left\" colname=\"c4\"\u003e\u003cp\u003eMedian Follow-Up (Years)\u003c/p\u003e\u003c/th\u003e\u003c/tr\u003e\u003c/thead\u003e\u003ctbody\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eConservative\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e4*\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e604\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eStereotactic Radiosurgery (SRS)\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e6\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e4,671\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.5\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMicrosurgery\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e3\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e395\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e4.8\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eEmbolization\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e288\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e6.4\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eHybrid Therapy**\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e61\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.1\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003ctr\u003e\u003ctd align=\"left\" colname=\"c1\"\u003e\u003cp\u003eMixed Interventions***\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"left\" colname=\"c2\"\u003e\u003cp\u003e1\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c3\"\u003e\u003cp\u003e105\u003c/p\u003e\u003c/td\u003e\u003ctd align=\"char\" char=\".\" colname=\"c4\"\u003e\u003cp\u003e3.6\u003c/p\u003e\u003c/td\u003e\u003c/tr\u003e\u003c/tbody\u003e\u003c/colgroup\u003e\u003c/table\u003e\u003c/div\u003e\u003c/p\u003e\u003cp\u003eThe various study characteristics are shown in Table \u003cspan refid=\"Tab3\" class=\"InternalRef\"\u003e3\u003c/span\u003e.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003ePrimary Outcome Metrics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHemorrhage Risk\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe pooled annual hemorrhage rate for conservative management was 1.9% (95% CI not applicable), serving as the reference group. Compared to conservative management, stereotactic radiosurgery (SRS) demonstrated a significantly lower hemorrhage rate of 1.2%/yr (RR 0.63, 95% CI 0.50–0.80, p \u0026lt; 0.001). Microsurgery showed the greatest reduction in hemorrhage risk at 0.7%/yr (RR 0.37, 95% CI 0.25–0.55, p \u0026lt; 0.001), followed by hybrid therapy with a rate of 0.9%/yr (RR 0.47, 95% CI 0.30–0.75, p = 0.001). Embolization yielded a hemorrhage rate of 1.1%/yr (RR 0.58, 95% CI 0.39–0.86, p = 0.007) (Table 4).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab4\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 4\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eHemorrhage risk.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eAnnual Rate (%/yr)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRisk Ratio (vs Conservative)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003e95% CI\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003ep-value\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConservative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e—\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e—\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.2\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.63\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e[0.50–0.80]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMicrosurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.7\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.37\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e[0.25–0.55]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u0026lt; 0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmbolization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.58\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e[0.39–0.86]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.007\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHybrid Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"char\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.47\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e[0.30–0.75]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.001\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eObliteration rates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMicrosurgery achieved the highest obliteration rate at 97% (95% CI 94–99%) with low heterogeneity (I²=10%). Hybrid therapy showed an obliteration rate of 93% (95% CI 88–97%), though this was based on a single study. SRS demonstrated moderate efficacy with a 67% obliteration rate (95% CI 61–73%) and moderate heterogeneity (I²=42%). Embolization had the lowest obliteration rate at 40% (95% CI 32–48%) with low heterogeneity (I²=30%). (Table 5).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab5\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 5\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eObliteration rates\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eObliteration Rate (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eI² Heterogeneity\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMicrosurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e97% [94–99%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e10% (Low)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHybrid Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e93% [88–97%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A (Single study)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e67% [61–73%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e42% (Moderate)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmbolization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e40% [32–48%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e30% (Low)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eSecondary Outcomes \u003c/strong\u003e\u003cp\u003eFunctional Disability (mRS ≥ 2)\u003c/p\u003eThere was no significant differences in disability rates across treatments (p \u0026gt; 0.05). The conservative management group had a functional disability rate of 11% (95% CI 8–14%). SRS showed a non-significant increase in disability (13%, 95% CI 10–16%; p = 0.18). Microsurgery demonstrated a statistically significant reduction in disability (8%, 95% CI 5–11%; p = 0.04), while embolization showed a non-significant reduction (8%, 95% CI 5–11%; p = 0.16) (Table 6).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab6\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 6\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003efunctional disability\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eGroup\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRate (95% CI)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eRisk Difference vs Conservative\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConservative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e11% [8–14%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eReference\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e13% [10–16%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e+ 2% (NS, p = 0.18)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMicrosurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8% [5–11%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3% (p = 0.04)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmbolization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e8% [5–11%]\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-3% (NS, p = 0.16)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eNew-onset seizures\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe analysis found the following seizure occurrence rates across treatment modalities (Table 7). Microsurgery was associated with a 9.1% incidence of new-onset seizures, while stereotactic radiosurgery showed a 4.9% rate.\u003csup\u003e26\u003c/sup\u003e Hybrid therapy demonstrated a 6.9% seizure occurrence.\u003csup\u003e29\u003c/sup\u003e Seizure outcomes for conservative management and embolization were not documented in the available data.\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab7\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 7\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003eNew-onset seizures. NR – Not Reported. N/A – Not Applicable.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eIntervention\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eSeizure Risk\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eKey Factors\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\n \u003cp\u003eTiming\u003c/p\u003e\n \u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eMicrosurgery\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e9.1%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCortical disruption during resection\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eImmediate perioperative period\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSRS\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e4.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eDelayed radiation-induced hyperexcitability\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e6–18 month latency period\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eHybrid Therapy\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e5.2–6.9%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eCombined effects of embolization + surgery/SRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eVariable (stage-dependent)\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eConservative\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNatural history of untreated AVM\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eN/A\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e\n\u003cp\u003e\u003cstrong\u003eMortality\u003c/strong\u003e \u003cp\u003eThe mortality rate was 1.1% for conservative management. Among interventional approaches, mortality ranged from 1–2%, with the highest rates observed in SRS groups (1.6%).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSubgroup Analysis by AVM Grade\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHemorrhage Risk\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe annual hemorrhage risk varied significantly between Spetzler-Martin (SM) grade subgroups. For conservative management, the hemorrhage rate increased from 1.9%/yr in SM I-II AVMs to 2.6%/yr in SM III-IV AVMs (risk ratio [RR] 1.37). Among interventional treatments, stereotactic radiosurgery (SRS) showed a doubling of hemorrhage risk from 1.1%/yr in SM I-II to 2.1%/yr in SM III-IV AVMs (RR 1.91). Microsurgery demonstrated the greatest disparity, with hemorrhage rates increasing from 0.6%/yr in SM I-II to 1.3%/yr in SM III-IV AVMs (RR 2.17). Data for embolization and hybrid therapy in high-grade AVMs were not reported (NR) (Table 8).\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eObliteration Rates\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eTreatment efficacy varied substantially by SM grade. SRS showed a 38% reduction in obliteration rates for high-grade AVMs (76% in SM I-II vs 47% in SM III-IV; efficacy ratio 0.62). Microsurgery maintained relatively high efficacy across grades, though with a 13% reduction for SM III-IV AVMs (99% in SM I-II vs 86% in SM III-IV; efficacy ratio 0.87). Data on embolization and hybrid therapy outcomes by SM grade were not available (Table 8).\u003c/p\u003e\n\u003cdiv\u003e\n \u003ctable id=\"Tab8\" border=\"1\"\u003e\n \u003ccaption language=\"En\"\u003e\n \u003cdiv\u003eTable 8\u003c/div\u003e\n \u003cdiv\u003e\n \u003cp\u003esubgroup analysis by Spetzler-Martin (SM) grade. *Estimated from natural history studies. **Data limited to SM III only. NR – Not Reported.\u003c/p\u003e\n \u003c/div\u003e\n \u003c/caption\u003e\n \u003cthead\u003e\n \u003ctr\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003cth align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003eHemorrhage risk (%/yr)\u003c/p\u003e\n \u003c/th\u003e\n \u003cth align=\"left\"\u003e\u0026nbsp;\u003c/th\u003e\n \u003c/tr\u003e\n \u003c/thead\u003e\n \u003ctbody\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSM I-II\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSM III-IV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eRisk Ratio (III-IV vs I-II)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eConservative\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.6*\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.37\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.1\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.91\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMicrosurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.6\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e1.3\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e2.17\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmbolization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHybrid Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.9\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003ctd align=\"left\" colspan=\"2\"\u003e\n \u003cp\u003e\u003cstrong\u003eObliteration Rates (%)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\u0026nbsp;\u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eTreatment\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSM I-II\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eSM III-IV\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e\u003cstrong\u003eEfficacy Ratio (III-IV/I-II)\u003c/strong\u003e\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eSRS\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e76%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e47%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.62\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eMicrosurgery\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e99%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e86%**\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e0.87\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eEmbolization\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003ctr\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eHybrid Therapy\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e93%\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003eNR\u003c/p\u003e\n \u003c/td\u003e\n \u003ctd align=\"left\"\u003e\n \u003cp\u003e-\u003c/p\u003e\n \u003c/td\u003e\n \u003c/tr\u003e\n \u003c/tbody\u003e\n \u003c/table\u003e\n\u003c/div\u003e"},{"header":"DISCUSSION","content":"\u003cp\u003eThe demographic profile of our pooled analysis confirms established epidemiological patterns, with a slight male predominance (1.2:1) and mean presentation age of 42.5 years. Though paediatric AVMs carry a significantly higher rupture risk than their adult counterparts due to their immature vasculature and longer lifetime risk exposure,\u003csup\u003e\u003cspan citationid=\"CR38\" class=\"CitationRef\"\u003e38\u003c/span\u003e, \u003cspan citationid=\"CR39\" class=\"CitationRef\"\u003e39\u003c/span\u003e\u003c/sup\u003e this study focused on adult AVMs because they represent over 80% of clinical cases and were the primary population in the ARUBA trial controversy. Moreover, paediatric AVMs present unique challenges including ethical concerns about radiation in developing brains, higher surgical resection rates, and insufficient paediatric-specific data for robust multicentre analysis.\u003c/p\u003e\u003cp\u003e\u003cb\u003ePrimary outcomes\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eHemorrhage risk\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMicrosurgery demonstrated unparalleled protective efficacy, reducing annual bleeding risk by 72% compared to conservative management for Spetzler-Martin grade I-II AVMs (0.6%/yr vs 1.9%/yr). This thus confirms microsurgery as the gold standard for operable lesions. This obvious benefit stems from multiple factors including technological advances like increased use of intraoperative fluorescence angiography (employed in 89% of contemporary series)\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e which enables real-time evaluation of the extent of nidal resection for completeness. This technology allows surgeons to verify the absence of residual arteriovenous shunting before wound closure, addressing what was historically a major limitation of AVM surgery. The integration of 3D-exoscopic systems, while not quantified in the included studies, has been qualitatively reported to improve depth perception and illumination in deep surgical corridors.\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e Additionally, haemostatic techniques such as the use of modern bipolar coagulation under high magnification (utilized in 100% of Wong et al.\u0026rsquo;s cases)\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e enables precise vessel sealing with minimal thermal spread to surrounding tissue. Ultrasonic aspiration, used in 68% of reported cases, permits controlled nidus debulking while preserving the surrounding gliotic plane - a critical advancement for lesions in eloquent areas. These techniques collectively reduce the risk of premature AVM rupture and incomplete resection. Also, the use of intraoperative MRI (employed in 45% of high-grade cases in these studies)\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e and augmented reality neuronavigation may also have contributed to this. These collectively enable more complete nidal resection while preserving normal vasculature. However, the 2.2-fold increase in hemorrhage risk for grade III lesions (1.3%/yr) underscores persistent challenges with deep and eloquently located AVMs, particularly those exhibiting diffuse nidal patterns or complex venous drainage. Our sub-analysis revealed three statistically significant predictors of surgical failure - deep venous drainage (OR 3.2, p\u0026thinsp;\u0026lt;\u0026thinsp;0.01), cortical eloquence (OR 2.7, p\u0026thinsp;=\u0026thinsp;0.03) and nidal diffuseness (OR 4.1, p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The exclusive drainage to deep venous systems (present in 78% of SM III cases in Schramm\u0026rsquo;s series)\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e complicates surgical access and increases the risk of venous infarction post-resection. This anatomical feature was the strongest predictor of residual shunting in our analysis. Furthermore, AVMs involving motor, language, or visual cortex (62% of SM III cases in Wong\u0026rsquo;s cohort)\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e showed significantly higher complication rates despite advanced mapping techniques. The need for functional preservation sometimes necessitates leaving residual nidus in critical areas. Lastly, poorly demarcated AVM borders (present in 45% of surgical failures) made complete resection challenging even with modern imaging guidance. Diffuse lesions often interdigitate with functional parenchyma, precluding safe complete removal. Based on these findings, it may be concluded that microsurgery should remain first-line for SM I-II AVMs when anatomically accessible. Also, for SM III lesions, preoperative embolization of deep feeders may mitigate venous drainage-related risks. Additionally, multimodal functional mapping is essential for eloquent area AVMs, and diffuse nidal morphology may warrant consideration of alternative or staged approaches.\u003c/p\u003e\u003cp\u003eThe analysis of stereotactic radiosurgery (SRS) outcomes demonstrates some important points for clinical decision-making. While the overall 37% reduction in hemorrhage risk (RR 0.63, 95% CI 0.50\u0026ndash;0.80) appears modest compared to microsurgical outcomes, this aggregate figure conceals important grade-dependent variations in treatment efficacy that are particularly relevant for patient selection and counselling. The first factor to consider is the dose-volume to response relationships. The study by Ding et al. (2016)\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e demonstrated that 75% of Spetzler-Martin (SM) grade I-II AVMs received marginal doses\u0026thinsp;\u0026ge;\u0026thinsp;15 Gy, achieving a 76% obliteration rate. In contrast, the same study reported that only 28% of SM grade III AVMs could be treated at this therapeutic dose threshold due to volume constraints, resulting in significantly lower obliteration rates (47%). This dose-volume limitation represents a fundamental radiobiological challenge in treating larger AVMs, where the need to respect normal brain tolerance often necessitates dose reduction below the optimal therapeutic range. The second factor is the technical challenge in target delineation. The complex angioarchitecture of higher-grade AVMs introduced substantial targeting difficulties, with Ding et al. (2016)\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e reporting impaired nidal delineation in 38% of SM grade III cases. Venous outflow obstruction, present in 22% of these complex malformations, further complicated targeting accuracy by altering contrast filling patterns during angiographic planning. These technical challenges likely contribute to the observed doubling of hemorrhage risk in SM grade III AVMs (2.1%/yr) compared to SM grade I-II lesions (1.1%/yr) following stereotactic radiosurgery (SRS), as reported in the multicentre study by Ding et al. (2019).\u003csup\u003e\u003cspan citationid=\"CR30\" class=\"CitationRef\"\u003e30\u003c/span\u003e\u003c/sup\u003e Another significant factor is the vulnerability during latency periods. The prolonged interval to obliteration represents a crucial limitation of SRS for higher-grade AVMs. Ding et al. (2016)\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e documented a median obliteration time of 38 months for SM grade III lesions, during which 62% of treatment-related hemorrhages occurred. This extended vulnerability window contrasts sharply with the immediate protection afforded by successful microsurgical resection and has particular implications for younger patients who may face decades of potential hemorrhage risk. On the basis of these significant findings, it can be concluded that SRS remains a reasonable option for SM I-II AVMs when microsurgery is contraindicated, particularly for lesions\u0026thinsp;\u0026lt;\u0026thinsp;3cm receiving\u0026thinsp;\u0026ge;\u0026thinsp;15Gy marginal dose. Additionally, for SM III-IV AVMs, the limited efficacy of SRS (47% obliteration, 2.1%/yr hemorrhage risk) suggests it should be reserved for truly inoperable cases or as part of multimodal strategies. Finally, the prolonged latency period necessitates careful risk-benefit assessment, particularly for younger patients who may require interim anticoagulation or have limited tolerance for bleeding risk.\u003c/p\u003e\u003cp\u003eConservative management of AVMs largely depends on knowledge of its natural history. Conservative treatment is associated with a consistent annual hemorrhage risk of 1.9% (95% confidence interval 1.6\u0026ndash;2.2%), as demonstrated by recent studies including the ARUBA trial and work by Darsaut and colleagues (2024).\u003csup\u003e\u003cspan citationid=\"CR15\" class=\"CitationRef\"\u003e15\u003c/span\u003e\u003c/sup\u003e This risk remains remarkably stable over time, showing no evidence of spontaneous regression, with the ARUBA extended follow-up data (median 6.9 years) confirming persistent annual risks of 1.9\u0026ndash;2.1% and cumulative probabilities reaching 29.3% at 20 years.\u003csup\u003e\u003cspan citationid=\"CR27\" class=\"CitationRef\"\u003e27\u003c/span\u003e\u003c/sup\u003e While the Spetzler-Martin grading system provides some risk stratification, the relatively modest difference between grade I-II (1.9%/year) and grade III-IV (2.6%/year) lesions suggests the influence of additional factors. Angioarchitectural features such as associated aneurysms (HR\u0026thinsp;=\u0026thinsp;1.68 [p\u0026thinsp;=\u0026thinsp;0.026]) and deep venous drainage (HR\u0026thinsp;=\u0026thinsp;2.14 [p\u0026thinsp;\u0026lt;\u0026thinsp;0.001]) have been shown to significantly increase hemorrhage risk.\u003csup\u003e\u003cspan citationid=\"CR40\" class=\"CitationRef\"\u003e40\u003c/span\u003e\u003c/sup\u003e Furthermore, hemodynamic characteristics like high-flow shunts correlate with 1.5-fold higher bleeding rates.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e Several limiting factors should be considered. Firstly, selection bias likely influences conservative management cohorts, as higher-risk SM III-IV AVMs may be preferentially selected for intervention. Secondly, the relatively short follow-up duration in natural history studies (mean 3\u0026ndash;5 years) may underestimate the true long-term risk accumulation, and lastly, small sample sizes for high-grade AVMs in conservative arms limit statistical power to detect significant differences. The clinical implications of these risks vary substantially by patient age. Younger patients (\u0026lt;\u0026thinsp;40 years) face substantial cumulative risks of 30% over 20 years (25\u0026ndash;35%) and 45% over 30 years (39\u0026ndash;51%). In contrast, older patients (\u0026gt;\u0026thinsp;60 years) experience lower absolute risks due to shorter life expectancy (hazard ratio 0.65 compared to younger patients, p\u0026thinsp;=\u0026thinsp;0.02). When hemorrhages do occur, the consequences are consistently severe, with 10\u0026ndash;15% mortality per event and 30\u0026ndash;50% of patients suffering permanent neurological deficits.\u003csup\u003e\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e\u003c/sup\u003e Notably, no clinically \u0026ldquo;minor\u0026rdquo; hemorrhages have been documented in natural history studies \u0026ndash; all reported events resulted in significant clinical consequences. Several practical considerations follow the choice of conservative management. Patients must adhere to activity restrictions, particularly avoiding contact sports. Furthermore, the psychological burden is substantial, with studies reporting high anxiety levels among conservatively managed patients.\u003csup\u003e\u003cspan citationid=\"CR41\" class=\"CitationRef\"\u003e41\u003c/span\u003e, \u003cspan citationid=\"CR42\" class=\"CitationRef\"\u003e42\u003c/span\u003e\u003c/sup\u003e Additionally, ongoing surveillance with annual MRI is typically recommended to monitor for potential changes in the AVM. These factors must be cautiously assessed when considering management options for individual patients.\u003c/p\u003e\u003cp\u003eEndovascular embolization of unruptured AVMs demonstrated partial but significant hemorrhage protection, as evidenced by the Chen et al. (2023) study.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e The annual hemorrhage risk of 1.1%/yr (95% CI 0.8\u0026ndash;1.4) represents a 42% reduction compared to conservative management (RR 0.58, 95% CI 0.39\u0026ndash;0.86), with efficacy varying by Spetzler-Martin grade (0.9%/yr for I-II vs 1.3%/yr for III-IV lesions). The protective effect followed a characteristic progressive pattern, showing maximal initial protection (0.7%/yr) immediately post-procedure, followed by gradual risk escalation to 1.5%/yr by 2 years due to partial recanalization, before stabilizing around 1.1%/yr long-term. Technical limitations significantly impacted outcomes, including a 15% recanalization rate at 2 years and differential efficacy based on AVM morphology \u0026ndash; fistulous components carry higher rebleeding risk (HR 1.8) compared to plexiform nidus. The degree of occlusion strongly correlated with protection, ranging from 0.5%/yr for \u0026gt;\u0026thinsp;90% occlusion to 2.1%/yr for \u0026lt;\u0026thinsp;50% occlusion. These findings suggest embolization works best for SM I-II plexiform AVMs when near-complete occlusion is achievable, though it may serve most appropriately as a bridge to definitive therapy rather than standalone treatment.\u003c/p\u003e\u003cp\u003eCommon hybrid strategies included staged embolization followed by microsurgery (68% of cases), embolization plus SRS (22%), and triple therapy (embolization\u0026thinsp;+\u0026thinsp;SRS\u0026thinsp;+\u0026thinsp;surgery) (10%). Key advantages identified included reduced surgical morbidity through preoperative nidal devascularization, ability to treat complex AVMs not amenable to single modalities and potential for cure in select high-grade lesions. The Jiang et al. (2022) study\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e demonstrated that combined modality approaches achieve superior hemorrhage protection compared to single treatments, with an annual risk of 0.9%/yr (95% CI 0.6\u0026ndash;1.2) representing a 53% reduction versus conservative management (RR 0.47, 95% CI 0.30\u0026ndash;0.75). The risk profile followed a distinct chronological pattern, peaking during the active treatment phase (1.2%/yr) when the AVM remains partially treated, then dropping dramatically to 0.2%/yr after protocol completion. Notably, 65% of hemorrhages occurred during the intervention period, while cases achieving complete obliteration showed exceptional long-term protection (0.1%/yr) maintained through 5-year follow-up. These results suggest hybrid therapy offers durable protection when full treatment goals are met, though the transitional period between modalities carries elevated risk that warrants careful patient monitoring. The approach appears particularly valuable for complex AVMs unsuitable for single-modality cure, with outcomes heavily dependent on achieving final complete obliteration.\u003c/p\u003e\u003cp\u003e\u003cb\u003eObliteration rate\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMicrosurgical resection demonstrated the highest and most consistent obliteration rates, achieving 97% complete angiographic cure (95% CI 94\u0026ndash;99%) across multiple studies.\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e, \u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e The remarkable consistency (I\u0026sup2;=10%) reflects the technical standardization of modern microsurgical approaches, where complete anatomical resection under direct visualization reliably eliminates the AVM nidus. These results establish microsurgery as the gold standard for operable lesions, particularly for Spetzler-Martin grade I-II AVMs where the 99% obliteration rate was maintained across all reported series.\u003c/p\u003e\u003cp\u003eHybrid therapy approaches show nearly comparable efficacy to microsurgery, with 93% complete obliteration (95% CI 88\u0026ndash;97%) in the Jiang et al. (2022) study.\u003csup\u003e\u003cspan citationid=\"CR29\" class=\"CitationRef\"\u003e29\u003c/span\u003e\u003c/sup\u003e This multimodal strategy combines the advantages of different treatment modalities, typically using embolization to reduce nidus volume or target high-risk features before definitive surgical resection or radiosurgery. The slightly lower rate compared to microsurgery alone may reflect the selection of more complex cases for hybrid approaches, though the difference was not statistically significant.\u003c/p\u003e\u003cp\u003eStereotactic radiosurgery yielded intermediate results with 67% overall obliteration (95% CI 61\u0026ndash;73%), though with notable heterogeneity across studies (I\u0026sup2;=42%). This variability stems from differences in treatment protocols, with Ding et al.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e reporting superior outcomes (76%) for carefully selected SM I-II AVMs treated with optimal dosing. The moderate success rate reflects the biological nature of radiosurgical obliteration, which depends on delayed vascular remodelling rather than immediate anatomical correction.\u003c/p\u003e\u003cp\u003eStandalone embolization shows the lowest complete obliteration rate at 40% (95% CI 32\u0026ndash;48%) in the Chen et al. series.\u003csup\u003e\u003cspan citationid=\"CR33\" class=\"CitationRef\"\u003e33\u003c/span\u003e\u003c/sup\u003e This limited efficacy results from technical challenges in achieving complete nidal penetration with liquid embolic agents, particularly in plexiform components. The results underscore embolization\u0026rsquo;s primary role as an adjunctive therapy, except in select cases with favourable angioarchitecture where complete occlusion can be achieved.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSecondary Outcomes Analysis\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFunctional outcomes, as measured by modified Rankin Scale (mRS) scores\u0026thinsp;\u0026ge;\u0026thinsp;2, demonstrated notable consistency across treatment approaches despite their different mechanisms of action. Conservative management showed a disability rate of 11% (95% CI 8\u0026ndash;14%), establishing the baseline functional impact of the natural disease course. This figure likely reflects both the consequences of hemorrhagic events and the progressive neurological effects of untreated AVMs over time.\u003c/p\u003e\u003cp\u003eStereotactic radiosurgery (SRS) was associated with a slightly higher disability rate of 13% (95% CI 10\u0026ndash;16%), potentially attributable to radiation-induced changes in surrounding brain tissue and the neurological risks during the latency period before complete obliteration. The studies by Ding et al.\u003csup\u003e\u003cspan citationid=\"CR19\" class=\"CitationRef\"\u003e19\u003c/span\u003e\u003c/sup\u003e and Starke et al.\u003csup\u003e\u003cspan citationid=\"CR32\" class=\"CitationRef\"\u003e32\u003c/span\u003e\u003c/sup\u003e noted that these effects were most pronounced in eloquent areas, where even minimal radiation injury could produce functional consequences.\u003c/p\u003e\u003cp\u003eMicrosurgical resection demonstrated the most favourable functional outcomes at 8% disability (95% CI 5\u0026ndash;11%), likely reflecting both the immediate elimination of hemorrhage risk and the precision of modern microsurgical techniques that minimize damage to surrounding brain parenchyma. The consistency of these results across studies suggests that when complete resection is achieved in appropriately selected cases, patients can expect excellent functional preservation.\u003c/p\u003e\u003cp\u003eEndovascular embolization showed intermediate results with 8% disability (95% CI 5\u0026ndash;11%), representing a balance between the less invasive nature of the procedure and its more limited therapeutic effect. Importantly, none of these differences reached statistical significance (all p\u0026thinsp;\u0026gt;\u0026thinsp;0.05), indicating that functional outcomes may be more dependent on careful patient selection and procedural expertise than on the specific treatment modality chosen.\u003c/p\u003e\u003cp\u003eIn terms of development of new-onset seizures, microsurgical resection demonstrated nearly double the rate of new-onset seizures (9.1%) compared to stereotactic radiosurgery (4.9%) in the Lang et al. cohort.\u003csup\u003e\u003cspan citationid=\"CR26\" class=\"CitationRef\"\u003e26\u003c/span\u003e\u003c/sup\u003e This difference likely reflects the inherent cortical disruption during surgical resection against the delayed, more localized effects of radiation. Temporal lobe AVMs showed the highest seizure risk overall. While microsurgery carries immediate perioperative risks, SRS may induce delayed radiation-related hyperexcitability. These findings suggest that for AVMs in highly epileptogenic regions, SRS may offer a favourable risk profile, though individual patient factors and AVM characteristics should also be taken into cognizance in guiding final treatment selection.\u003c/p\u003e\u003cp\u003eMortality rates remained consistently low across all approaches (1\u0026ndash;2%), though SRS groups showed a marginally higher rate, possibly reflecting the inclusion of higher-risk cases unsuitable for surgical intervention.\u003c/p\u003e\u003cp\u003e\u003cb\u003eSubgroup Analysis by Spetzler-Martin Grade\u003c/b\u003e\u003c/p\u003e\u003cp\u003e\u003cb\u003eMicrosurgical Resection\u003c/b\u003e\u003c/p\u003e\u003cp\u003eMicrosurgery demonstrated the most consistent performance across Spetzler-Martin grades, though with some important distinctions. For SM I-II AVMs, the 99% obliteration rate\u003csup\u003e\u003cspan citationid=\"CR36\" class=\"CitationRef\"\u003e36\u003c/span\u003e\u003c/sup\u003e and dramatic hemorrhage risk reduction to 0.6%/yr represent the gold standard in AVM treatment. When applied to SM III-IV lesions, microsurgery maintains an 86% obliteration rate\u003csup\u003e\u003cspan citationid=\"CR16\" class=\"CitationRef\"\u003e16\u003c/span\u003e\u003c/sup\u003e with hemorrhage risk of 1.3%/yr, still substantially better than natural history. The efficacy ratio of 0.87 (comparing high-grade to low-grade outcomes) confirms microsurgery\u0026rsquo;s relative grade-independence, though the 2.2-fold increase in hemorrhage risk for SM III lesions underscores the technical challenges posed by deep venous drainage and eloquent location.\u003c/p\u003e\u003cp\u003e\u003cb\u003eStereotactic Radiosurgery\u003c/b\u003e\u003c/p\u003e\u003cp\u003eSRS showed more pronounced grade-dependence, with outcomes declining substantially for higher-grade lesions. SM I-II AVMs achieve 76% obliteration with hemorrhage risk reduced to 1.1%/yr, while SM III-IV lesions show only 47% obliteration\u003csup\u003e19\u003c/sup\u003e with 2.1%/yr hemorrhage risk. The efficacy ratio of 0.62 highlights SRS\u0026rsquo;s greater vulnerability with higher grades, highlighting the technical limitations of treating larger volumes and more complex angioarchitecture. The doubling of hemorrhage risk for high-grade AVMs treated with SRS suggests these lesions may remain vulnerable during the prolonged latency period before obliteration.\u003c/p\u003e\u003cp\u003e\u003cb\u003eConservative Management\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFor conservative management, the natural history data revealing a 1.9%/yr hemorrhage risk for SM I-II AVMs compared to 2.6%/yr for SM III-IV lesions, a 37% relative increase (efficacy ratio 0.73), was substantially less dramatic than the treatment-related grade effects, suggesting that the factors making AVMs more difficult to treat (size, deep drainage, eloquence) may not proportionally increase their natural hemorrhage risk. This paradox creates particularly challenging risk-benefit calculations for high-grade AVMs where intervention risks escalate faster than the natural history risk.\u003c/p\u003e\u003cp\u003eFurthermore, the differential efficacy ratios (0.87 for microsurgery vs 0.62 for SRS) demonstrate that grade escalation affects treatment modalities differently. Microsurgery maintains relatively preserved efficacy for high-grade lesions, while SRS shows substantially diminished returns.\u003c/p\u003e\u003cp\u003e\u003cb\u003eEssential Practice Recommendations\u003c/b\u003e\u003c/p\u003e\u003cp\u003eFor SM I-II AVMs, microsurgery remains the gold standard when feasible, offering near-complete obliteration (99%) and the lowest hemorrhage risk (0.6%/yr). SRS is a reasonable alternative for inoperable lesions, while hybrid approaches may benefit select anatomic subtypes. For SM III AVMs, microsurgery remains viable for compact, non-eloquent lesions, but hybrid therapy (for example, embolization\u0026thinsp;+\u0026thinsp;surgery/SRS) is emerging as a promising strategy. SRS alone yields suboptimal results and should generally be avoided as standalone treatment. For SM IV-V AVMs, conservative management is generally preferred due to high treatment morbidity, though targeted embolization of high-risk features (for example, aneurysms) may be considered. Hybrid approaches require further study before routine adoption (Fig.\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e).\u003c/p\u003e\u003cp\u003e\u003c/p\u003e"},{"header":"CONCLUSION","content":"\u003cp\u003eManagement strategies for unruptured AVMs have been largely debated. This meta-analysis of contemporary studies established that low-grade AVMs (I-II) benefit most from intervention, preferably microsurgery, while intermediate-grade (III) lesions require individualized, often multimodal approaches. High-grade AVMs (IV-V) should generally be managed conservatively unless high-risk features are present. Treatment decisions should consider grade-specific efficacy, anatomic feasibility, and patient factors.\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eConflict of interest\u003c/strong\u003e: None\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding disclosures\u003c/strong\u003e: none\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHuman Ethics and Consent to Participate declarations\u003c/strong\u003e: not applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eClinical trial number\u003c/strong\u003e: Not applicable.\u003c/p\u003e\n"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMartinez JL, Macdonald RL. Surgical Strategies for Acutely Ruptured Arteriovenous Malformations. \u003cem\u003eFrontiers of neurology and neuroscience\u003c/em\u003e. 2015;37:166-181. \u003c/li\u003e\n\u003cli\u003ePollock BE, Flickinger JC, Lunsford LD, Bissonette DJ, Kondziolka D. Factors that predict the bleeding risk of cerebral arteriovenous malformations. \u003cem\u003eStroke\u003c/em\u003e. 1996;27(1):1-6. \u003c/li\u003e\n\u003cli\u003eBokhari MR, Bokhari SRA. Arteriovenous malformation of the brain. 2017;\u003c/li\u003e\n\u003cli\u003eChye C-L, Wang K-W, Chen H-J, Yeh S-A, Tang JT, Liang C-L. Haemorrhage rates of ruptured and unruptured brain arteriovenous malformation after radiosurgery: a nationwide population-based cohort study. \u003cem\u003eBMJ open\u003c/em\u003e. 2020;10(10):e036606. \u003c/li\u003e\n\u003cli\u003eZyck S, Davidson CL, Sampath R. Arteriovenous malformations of the central nervous system. \u003cem\u003eStatPearls [Internet]\u003c/em\u003e. StatPearls Publishing; 2024.\u003c/li\u003e\n\u003cli\u003eYuan K, Chen Y, Yan D, et al. Re-rupture in ruptured brain arteriovenous malformations: a retrospective cohort study based on a nationwide multicenter prospective registry. \u003cem\u003eJournal of NeuroInterventional Surgery\u003c/em\u003e. 2024;16(11):1145-1151. \u003c/li\u003e\n\u003cli\u003eYamada S, Takagi Y, Nozaki K, Kikuta K-i, Hashimoto N. Risk factors for subsequent hemorrhage in patients with cerebral arteriovenous malformations. \u003cem\u003eJournal of neurosurgery\u003c/em\u003e. 2007;107(5):965-972. \u003c/li\u003e\n\u003cli\u003eHernesniemi JA, Dashti R, Juvela S, V\u0026auml;\u0026auml;rt K, Niemel\u0026auml; M, Laakso A. Natural history of brain arteriovenous malformations: a long-term follow-up study of risk of hemorrhage in 238 patients. \u003cem\u003eNeurosurgery\u003c/em\u003e. 2008;63(5):823-831. \u003c/li\u003e\n\u003cli\u003eGraf CJ, Perret GE, Torner JC. Bleeding from cerebral arteriovenous malformations as part of their natural history. \u003cem\u003eJournal of neurosurgery\u003c/em\u003e. 1983;58(3):331-337. \u003c/li\u003e\n\u003cli\u003eDi Bartolomeo A, Scafa AK, Giugliano M, Dugoni DE, Ruggeri AG, Delfini R. Ruptured brain arteriovenous malformations: surgical timing and outcomes\u0026mdash;a retrospective study of 25 cases. \u003cem\u003eJournal of Neurosciences in Rural Practice\u003c/em\u003e. 2020;12(1):4. \u003c/li\u003e\n\u003cli\u003eGlazener EM, Lodin K, Miller MJ, et al. Pediatric intracranial arteriovenous malformation: long-term outcomes with linear accelerator (LINAC)-based radiosurgery. \u003cem\u003eAdvances in Radiation Oncology\u003c/em\u003e. 2020;5(5):850-855. \u003c/li\u003e\n\u003cli\u003eMohr J\u0026aacute;, Parides MK, Stapf C, et al. Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. \u003cem\u003eThe Lancet\u003c/em\u003e. 2014;383(9917):614-621. \u003c/li\u003e\n\u003cli\u003eMagro E, Gentric J-C, Darsaut TE, Ziegler D, Bojanowski MW, Raymond J. Responses to ARUBA: a systematic review and critical analysis for the design of future arteriovenous malformation trials. \u003cem\u003eJournal of neurosurgery\u003c/em\u003e. 2017;126(2):486-494. \u003c/li\u003e\n\u003cli\u003eBambakidis NC, Cockroft KM, Hirsch JA, et al. The case against a randomized trial of unruptured brain arteriovenous malformations: misinterpretation of a flawed study. \u003cem\u003eStroke\u003c/em\u003e. 2014;45(9):2808-2810. \u003c/li\u003e\n\u003cli\u003eDarsaut TE, Gentric J-C, Heppner J, et al. Conservative management of brain arteriovenous malformations: results of the prospective observation registry of a pragmatic trial. \u003cem\u003eJournal of Neurosurgery\u003c/em\u003e. 2024;1(aop):1-10. \u003c/li\u003e\n\u003cli\u003eSchramm J, Schaller K, Esche J, Bostr\u0026ouml;m A. Microsurgery for cerebral arteriovenous malformations: subgroup outcomes in a consecutive series of 288 cases. \u003cem\u003eJournal of neurosurgery\u003c/em\u003e. 2017;126(4):1056-1063. \u003c/li\u003e\n\u003cli\u003eLink TW, Winston G, Schwarz JT, et al. Treatment of unruptured brain arteriovenous malformations: a single-center experience of 86 patients and a critique of the a randomized trial of unruptured brain arteriovenous malformations (ARUBA) trial. \u003cem\u003eWorld neurosurgery\u003c/em\u003e. 2018;120:e1156-e1162. \u003c/li\u003e\n\u003cli\u003eKarlsson B, Jokura H, Yang H-C, et al. The NASSAU (new assessment of cerebral arteriovenous malformations yet unruptured) analysis: are the results from the ARUBA trial also applicable to unruptured arteriovenous malformations deemed suitable for gamma knife surgery? \u003cem\u003eNeurosurgery\u003c/em\u003e. 2019;85(1):E118-E124. \u003c/li\u003e\n\u003cli\u003eDing D, Starke RM, Kano H, et al. Radiosurgery for cerebral arteriovenous malformations in a randomized trial of unruptured brain arteriovenous malformations (ARUBA)-eligible patients: a multicenter study. \u003cem\u003eStroke\u003c/em\u003e. 2016;47(2):342-349. \u003c/li\u003e\n\u003cli\u003eFeghali J, Huang J. Updates in arteriovenous malformation management: the post-ARUBA era. \u003cem\u003eStroke and Vascular Neurology\u003c/em\u003e. 2019;\u003c/li\u003e\n\u003cli\u003eOndra SL, Troupp H, George ED, Schwab K. The natural history of symptomatic arteriovenous malformations of the brain: a 24-year follow-up assessment. \u003cem\u003eJournal of neurosurgery\u003c/em\u003e. 1990;73(3):387-391. \u003c/li\u003e\n\u003cli\u003eGross BA, Du R. Natural history of cerebral arteriovenous malformations: a meta-analysis. \u003cem\u003eJournal of neurosurgery\u003c/em\u003e. 2013;118(2):437-443. \u003c/li\u003e\n\u003cli\u003eYajima H, Shinya Y, Hasegawa H, et al. Peculiar characteristics of arteriovenous malformations arising in the galenic region. \u003cem\u003eDiagnostics\u003c/em\u003e. 2020;10(7):481. \u003c/li\u003e\n\u003cli\u003eStapf C, Mast H, Sciacca R, et al. The New York Islands AVM Study: design, study progress, and initial results. \u003cem\u003eStroke\u003c/em\u003e. 2003;34(5):e29-e33. \u003c/li\u003e\n\u003cli\u003eBerman MF, Sciacca RR, Pile-Spellman J, et al. The epidemiology of brain arteriovenous malformations. \u003cem\u003eNeurosurgery\u003c/em\u003e. 2000;47(2):389-397. \u003c/li\u003e\n\u003cli\u003eLang M, Moore NZ, Rasmussen PA, Bain MD. Treatment outcomes of a randomized trial of unruptured brain arteriovenous malformation-eligible unruptured brain arteriovenous malformation patients. \u003cem\u003eNeurosurgery\u003c/em\u003e. 2018;83(3):548-555. \u003c/li\u003e\n\u003cli\u003eMohr J, Overbey JR, Von Kummer R, et al. Functional impairments for outcomes in a randomized trial of unruptured brain AVMs. \u003cem\u003eNeurology\u003c/em\u003e. 2017;89(14):1499-1506. \u003c/li\u003e\n\u003cli\u003eMohr JP, Overbey JR, Hartmann A, et al. Medical management with interventional therapy versus medical management alone for unruptured brain arteriovenous malformations (ARUBA): final follow-up of a multicentre, non-blinded, randomised controlled trial. \u003cem\u003eThe Lancet Neurology\u003c/em\u003e. 2020;19(7):573-581. \u003c/li\u003e\n\u003cli\u003eJiang Y, Zeng C, Zhang Y, Xu X, Qiu H, Jiang W. Multimodality Treatment of Brain Arteriovenous Malformations with One‐Staged Hybrid Operation: Clinical Characteristics and Long‐Term Prognosis. \u003cem\u003eDisease Markers\u003c/em\u003e. 2022;2022(1):2559004. \u003c/li\u003e\n\u003cli\u003eDing D, Chen C-J, Starke RM, et al. Risk of brain arteriovenous malformation hemorrhage before and after stereotactic radiosurgery: a multicenter study. \u003cem\u003eStroke\u003c/em\u003e. 2019;50(6):1384-1391. \u003c/li\u003e\n\u003cli\u003eDing D, Starke RM, Kano H, et al. Radiosurgery for unruptured brain arteriovenous malformations: an international multicenter retrospective cohort study. \u003cem\u003eNeurosurgery\u003c/em\u003e. 2017;80(6):888-898. \u003c/li\u003e\n\u003cli\u003eStarke RM, Kano H, Ding D, et al. Stereotactic radiosurgery for cerebral arteriovenous malformations: evaluation of long-term outcomes in a multicenter cohort. \u003cem\u003eJournal of neurosurgery\u003c/em\u003e. 2017;126(1):36-44. \u003c/li\u003e\n\u003cli\u003eChen Y, Han H, Jin H, et al. Association of embolization with long-term outcomes in brain arteriovenous malformations: a propensity score-matched analysis using nationwide multicenter prospective registry data. \u003cem\u003eInternational Journal of Surgery\u003c/em\u003e. 2023;109(7):1900-1909. \u003c/li\u003e\n\u003cli\u003eTos SM, Osama M, Mantziaris G, et al. Spetzler-Martin grade I and II cerebral arteriovenous malformations: a propensity-score matched analysis of resection and stereotactic radiosurgery in adult patients. \u003cem\u003eNeurosurgical review\u003c/em\u003e. 2025;48(1):276. \u003c/li\u003e\n\u003cli\u003eDing D, Starke RM, Kano H, et al. Stereotactic radiosurgery for Spetzler-Martin Grade III arteriovenous malformations: an international multicenter study. \u003cem\u003eJournal of neurosurgery\u003c/em\u003e. 2017;126(3):859-871. \u003c/li\u003e\n\u003cli\u003eWong J, Slomovic A, Ibrahim G, Radovanovic I, Tymianski M. Microsurgery for ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformation)\u0026ndash;eligible unruptured brain arteriovenous malformations. \u003cem\u003eStroke\u003c/em\u003e. 2017;48(1):136-144. \u003c/li\u003e\n\u003cli\u003eDing D, Starke RM, Kano H, et al. Stereotactic radiosurgery for ARUBA (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)\u0026ndash;eligible Spetzler-Martin Grade I and II arteriovenous malformations: a multicenter study. \u003cem\u003eWorld neurosurgery\u003c/em\u003e. 2017;102:507-517. \u003c/li\u003e\n\u003cli\u003eKırış T, Sencer A, Şahinbaş M, Sencer S, İmer M, İzgi N. Surgical results in pediatric Spetzler\u0026ndash;Martin grades I\u0026ndash;III intracranial arteriovenous malformations. \u003cem\u003eChild\u0026apos;s Nervous System\u003c/em\u003e. 2005;21:69-74. \u003c/li\u003e\n\u003cli\u003eEl-Ghanem M, Kass-Hout T, Kass-Hout O, et al. Arteriovenous malformations in the pediatric population: review of the existing literature. \u003cem\u003eInterventional neurology\u003c/em\u003e. 2016;5(3-4):218-225. \u003c/li\u003e\n\u003cli\u003eKim H, Al-Shahi Salman R, McCulloch CE, Stapf C, Young WL, Coinvestigators FtM. Untreated brain arteriovenous malformation. \u003cem\u003eNeurology\u003c/em\u003e. 2014;83(7):590-597. doi:doi:10.1212/WNL.0000000000000688\u003c/li\u003e\n\u003cli\u003eZhang H, Han H, Ma L, et al. A comprehensive analysis of patients with cerebral arteriovenous malformation with headache: assessment of risk factors and treatment effectiveness. \u003cem\u003eThe Journal of Headache and Pain\u003c/em\u003e. 2024;25(1):72. \u003c/li\u003e\n\u003cli\u003eOrosz P, Vad\u0026aacute;sz \u0026Aacute;, Veres DS, et al. Living with a brain AVM: a quality of life assessment. \u003cem\u003eTrends in Cerebrovascular Surgery and Interventions\u003c/em\u003e. 2021:71-76. \u003c/li\u003e\n\u003c/ol\u003e"},{"header":"Table 3","content":"\u003cp\u003eTable 3 is available in the Supplementary Files section.\u003c/p\u003e\n"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"unruptured arteriovenous malformation, conservative, microsurgery, embolization, stereotactic radiosurgery, hybrid treatment, intervention","lastPublishedDoi":"10.21203/rs.3.rs-7169115/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7169115/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003ch2\u003eBackground\u003c/h2\u003e\u003cp\u003eThe optimal management of unruptured brain arteriovenous malformations (AVMs) remains controversial, with conflicting evidence regarding conservative versus interventional approaches, especially in the light of the ARUBA trials. This meta-analysis aims to provide comprehensive, grade-specific outcomes across treatment modalities to guide clinical decision-making.\u003c/p\u003e\u003ch2\u003eMethods\u003c/h2\u003e\u003cp\u003eWe conducted a PRISMA-compliant meta-analysis of 16 studies (n\u0026thinsp;=\u0026thinsp;6,124 patients) comparing conservative management, microsurgery, stereotactic radiosurgery (SRS), embolization, and hybrid therapy. Databases searched included MEDLINE (PubMed), Embase (Ovid), Cochrane Central Register, and Web of Science (2000\u0026ndash;2025). Risk of bias was assessed using the Cochrane Risk of Bias Tool 2.0 for RCTs and Newcastle-Ottawa Scale for cohort studies. Data were synthesized using random-effects models (DerSimonian-Laird method), with heterogeneity quantified via the I\u0026sup2; statistic. Primary outcomes were hemorrhage risk and obliteration rates; secondary outcomes included functional status (mRS\u0026thinsp;\u0026ge;\u0026thinsp;2), new-onset seizures, and mortality.\u003c/p\u003e\u003ch2\u003eResults\u003c/h2\u003e\u003cp\u003eMicrosurgery achieved the highest obliteration rates (99% for Spetzler-Martin [SM] I-II, 86% for SM III) and lowest hemorrhage risk (0.6%/yr for SM I-II, 1.3%/yr for SM III), with superior functional outcomes (8% disability [95% CI 5\u0026ndash;11%] vs. 11% for conservative management; p\u0026thinsp;=\u0026thinsp;0.04). SRS showed moderate efficacy (76% obliteration for SM I-II, 47% for SM III-IV) with higher latency-period hemorrhage risk (1.1\u0026ndash;2.1%/yr) and disability rates comparable to conservative management (13% [95% CI 10\u0026ndash;16%]; p\u0026thinsp;=\u0026thinsp;0.18). New-onset seizures occurred in 9.1% of microsurgery and 4.9% of SRS cases. Mortality was low across treatments (1\u0026ndash;2%), with conservative management at 1.1% and SRS at 1.6%. Conservative management had a 1.9\u0026ndash;2.6%/yr hemorrhage risk without procedural morbidity.\u003c/p\u003e\u003ch2\u003eConclusions\u003c/h2\u003e\u003cp\u003eMicrosurgery is preferred for operable SM I-II AVMs due to superior obliteration, hemorrhage protection, and functional outcomes, despite higher seizure risk. SRS is suitable for inoperable cases, while conservative management remains reasonable for high-grade AVMs unless high-risk features exist.\u003c/p\u003e","manuscriptTitle":"Comparative Effectiveness Of Treatment Modalities For Unruptured Brain Arteriovenous Malformations: A Systematic Review And Meta-Analysis Of 6,124 Patients","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-08-06 08:46:31","doi":"10.21203/rs.3.rs-7169115/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"e3fbfa04-4da8-4b6d-aa33-2e33ec76958e","owner":[],"postedDate":"August 6th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[],"tags":[],"updatedAt":"2025-10-20T05:08:36+00:00","versionOfRecord":[],"versionCreatedAt":"2025-08-06 08:46:31","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7169115","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7169115","identity":"rs-7169115","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}