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Joseph H. Garcia, Ethan A. Winkler, Ramin A. Morshed, Alex Lu, Simon G. Ammanuel, Satvir Saggi, Elaina J. Wang, Steve Braunstein, Christine K. Fox, Heather J. Fullerton, Helen Kim, Daniel L. Cooke, Steven W. Hetts, Michael T. Lawton, Adib A. Abla, and Nalin Gupta

OBJECTIVE

Children with cerebral arteriovenous malformations (AVMs) can present with seizures, potentially increasing morbidity and impacting clinical management. However, the factors that lead to seizures as a presenting sign are not well defined. While AVM-related seizures have been described in case series, most studies have focused on adults and have included patients who developed seizures after an AVM rupture. To address this, the authors sought to analyze demographic and morphological characteristics of AVMs in a large cohort of children.

METHODS

The demographic, clinical, and AVM morphological characteristics of 189 pediatric patients from a single-center database were studied. Univariate and multivariate logistic regression models were used to test the effect of these characteristics on seizures as an initial presenting symptom in patients with unruptured brain AVMs.

RESULTS

Overall, 28 of 189 patients initially presented with seizures (14.8%). By univariate comparison, frontal lobe location (p = 0.02), larger AVM size (p = 0.003), older patient age (p = 0.04), and the Supplemented Spetzler-Martin (Supp-SM) grade (0.0006) were associated with seizure presentation. Multivariate analysis confirmed an independent effect of frontal lobe AVM location and higher Supp-SM grade. All patients presenting with seizures had AVMs in the cortex or subcortical white matter.

CONCLUSIONS

While children and adults share some risk factors for seizure presentation, their risk factor profiles do not entirely overlap. Pediatric patients with cortical AVMs in the frontal lobe were more likely to present with seizures. Additionally, the Supp-SM grade was highly associated with seizure presentation. Future clinical research should focus on the effect of therapeutic interventions targeting AVMs on seizure control in these patients.

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Sen Gao, Jeffrey Nelson, Shantel Weinsheimer, Ethan A. Winkler, Caleb Rutledge, Adib A. Abla, Nalin Gupta, Joseph T. Shieh, Daniel L. Cooke, Steven W. Hetts, Tarik Tihan, Christopher P. Hess, Nerissa Ko, Brian P. Walcott, Charles E. McCulloch, Michael T. Lawton, Hua Su, Ludmila Pawlikowska, and Helen Kim

OBJECTIVE

Sporadic brain arteriovenous malformation (BAVM) is a tangled vascular lesion characterized by direct artery-to-vein connections that can cause life-threatening intracerebral hemorrhage (ICH). Recently, somatic mutations in KRAS have been reported in sporadic BAVM, and mutations in other mitogen-activated protein kinase (MAPK) signaling pathway genes have been identified in other vascular malformations. The objectives of this study were to systematically evaluate somatic mutations in MAPK pathway genes in patients with sporadic BAVM lesions and to evaluate the association of somatic mutations with phenotypes of sporadic BAVM severity.

METHODS

The authors performed whole-exome sequencing on paired lesion and blood DNA samples from 14 patients with sporadic BAVM, and 295 genes in the MAPK signaling pathway were evaluated to identify genes with somatic mutations in multiple patients with BAVM. Digital droplet polymerase chain reaction was used to validate KRAS G12V and G12D mutations and to assay an additional 56 BAVM samples.

RESULTS

The authors identified a total of 24 candidate BAVM-associated somatic variants in 11 MAPK pathway genes. The previously identified KRAS G12V and G12D mutations were the only recurrent mutations. Overall, somatic KRAS G12V was present in 14.5% of BAVM lesions and G12D was present in 31.9%. The authors did not detect a significant association between the presence or allelic burden of KRAS mutation and three BAVM phenotypes: lesion size (maximum diameter), age at diagnosis, and age at ICH.

CONCLUSIONS

The authors confirmed the high prevalence of somatic KRAS mutations in sporadic BAVM lesions and identified several candidate somatic variants in other MAPK pathway genes. These somatic variants may contribute to understanding of the etiology of sporadic BAVM and the clinical characteristics of patients with this condition.

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Joshua S. Catapano, Fabio A. Frisoli, Candice L. Nguyen, Mohamed A. Labib, Tyler S. Cole, Jacob F. Baranoski, Helen Kim, Robert F. Spetzler, and Michael T. Lawton

OBJECTIVE

Supplemented Spetzler-Martin grading (Supp-SM), which is the combination of Spetzler-Martin and Lawton-Young grades, was validated as being more accurate than stand-alone Spetzler-Martin grading, but an operability cutoff was not established. In this study, the authors surgically treated intermediate-grade AVMs to provide prognostic factors for neurological outcomes and to define AVMs at the boundary of operability.

METHODS

Surgically treated Supp-SM intermediate-grade (5, 6, and 7) AVMs were analyzed from 2011 to 2018 at two medical centers. Worsened neurological outcomes were defined as increased modified Rankin Scale (mRS) scores on postoperative examinations. A second analysis of 2000–2011 data for Supp-SM grade 6 and 7 AVMs was performed to determine the subtypes with improved or unchanged outcomes. Patients were separated into three groups based on nidus size (S1: < 3 cm, S2: 3–6 cm, S3: > 6 cm) and age (A1: < 20 years, A2: 20–40 years, A3: > 40 years), followed by any combination of the combined supplemented grade: low risk (S1A1, S1A2, S2A1), intermediate risk (S2A2, S1A3, S3A1, or high risk (S3A3, S3A2, S2A3).

RESULTS

Two hundred forty-six patients had intermediate Supp-SM grade AVMs. Of these patients, 102 had Supp-SM grade 5 (41.5%), 99 had Supp-SM grade 6 (40.2%), and 45 had Supp-SM grade 7 (18.3%). Significant differences in the proportions of patients with worse mRS scores at follow-up were found between the groups, with 24.5% (25/102) of patients in Supp-SM grade 5, 29.3% (29/99) in Supp-SM grade 6, and 57.8% (26/45) in Supp-SM grade 7 (p < 0.001). Patients with Supp-SM grade 7 AVMs had significantly increased odds of worse postoperative mRS scores (p < 0.001; OR 3.7, 95% CI 1.9–7.3). In the expanded cohort of 349 Supp-SM grade 6 AVM patients, a significantly higher proportion of older patients with larger Supp-SM grade 6 AVMs (grade 6+, 38.6%) had neurological deterioration than the others with Supp-SM grade 6 AVMs (22.9%, p = 0.02). Conversely, in an expanded cohort of 197 Supp-SM grade 7 AVM patients, a significantly lower proportion of younger patients with smaller Supp-SM grade 7 AVMs (grade 7–, 19%) had neurological deterioration than the others with Supp-SM grade 7 AVMs (44.9%, p = 0.01).

CONCLUSIONS

Patients with Supp-SM grade 7 AVMs are at increased risk of worse postoperative neurological outcomes, making Supp-SM grade 6 an appropriate operability cutoff. However, young patients with small niduses in the low-risk Supp-SM grade 7 group (grade 7−) have favorable postoperative outcomes. Outcomes in Supp-SM grade 7 patients did not improve with surgeon experience, indicating that the operability boundary is a hard limit reflecting the complexity of high-grade AVMs.

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Ethan A. Winkler, Alex Lu, Ramin A. Morshed, John K. Yue, W. Caleb Rutledge, Jan-Karl Burkhardt, Arati B. Patel, Simon G. Ammanuel, Steve Braunstein, Christine K. Fox, Heather J. Fullerton, Helen Kim, Daniel Cooke, Steven W. Hetts, Michael T. Lawton, Adib A. Abla, and Nalin Gupta

OBJECTIVE

Brain arteriovenous malformations (AVMs) consist of dysplastic blood vessels with direct arteriovenous shunts that can hemorrhage spontaneously. In children, a higher lifetime hemorrhage risk must be balanced with treatment-related morbidity. The authors describe a collaborative, multimodal strategy resulting in effective and safe treatment of pediatric AVMs.

METHODS

A retrospective analysis of a prospectively maintained database was performed in children with treated and nontreated pediatric AVMs at the University of California, San Francisco, from 1998 to 2017. Inclusion criteria were age ≤ 18 years at time of diagnosis and an AVM confirmed by a catheter angiogram.

RESULTS

The authors evaluated 189 pediatric patients with AVMs over the study period, including 119 ruptured (63%) and 70 unruptured (37%) AVMs. The mean age at diagnosis was 11.6 ± 4.3 years. With respect to Spetzler-Martin (SM) grade, there were 38 (20.1%) grade I, 40 (21.2%) grade II, 62 (32.8%) grade III, 40 (21.2%) grade IV, and 9 (4.8%) grade V lesions. Six patients were managed conservatively, and 183 patients underwent treatment, including 120 resections, 82 stereotactic radiosurgery (SRS), and 37 endovascular embolizations. Forty-four of 49 (89.8%) high-grade AVMs (SM grade IV or V) were treated. Multiple treatment modalities were used in 29.5% of low-grade and 27.3% of high-grade AVMs. Complete angiographic obliteration was obtained in 73.4% of low-grade lesions (SM grade I–III) and in 45.2% of high-grade lesions. A periprocedural stroke occurred in a single patient (0.5%), and there was 1 treatment-related death. The mean clinical follow-up for the cohort was 4.1 ± 4.6 years, and 96.6% and 84.3% of patients neurologically improved or remained unchanged in the ruptured and unruptured AVM groups following treatment, respectively. There were 16 bleeding events following initiation of AVM treatment (annual rate: 0.02 events per person-year).

CONCLUSIONS

Coordinated multidisciplinary evaluation and individualized planning can result in safe and effective treatment of children with AVMs. In particular, it is possible to treat the majority of high-grade AVMs with an acceptable safety profile. Judicious use of multimodality therapy should be limited to appropriately selected patients after thorough team-based discussions to avoid additive morbidity. Future multicenter studies are required to better design predictive models to aid with patient selection for multimodal pediatric care, especially with high-grade AVMs.

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Grace F. Donzelli, Jeffrey Nelson, David McCoy, Charles E. McCulloch, Steven W. Hetts, Matthew R. Amans, Christopher F. Dowd, Van V. Halbach, Randall T. Higashida, Michael T. Lawton, Helen Kim, and Daniel L. Cooke

OBJECTIVE

Preoperative embolization of brain arteriovenous malformations (AVMs) is performed to facilitate resection, although its impact on surgical performance has not been clearly defined. The authors tested for associations between embolization and surgical performance metrics.

METHODS

The authors analyzed AVM cases resected by one neurosurgeon from 2006 to 2017. They tested whether cases with and without embolization differed from one another with respect to patient and AVM characteristics using t-tests for continuous variables and Fisher’s exact tests for categorical variables. They used simple and multivariable regression models to test whether surgical outcomes (blood loss, resection time, surgical clip usage, and modified Rankin Scale [mRS] score) were associated with embolization. Additional regression analyses integrated the peak arterial afferent contrast normalized for the size of the region of interest (Cmax/ROI) into models as an additional predictor.

RESULTS

The authors included 319 patients, of whom 151 (47%) had preoperative embolization. Embolized AVMs tended to be larger (38% with diameter > 3 cm vs 19%, p = 0.001), less likely to have hemorrhaged (48% vs 63%, p = 0.013), or be diffuse (19% vs 29%, p = 0.045). Embolized AVMs were more likely to have both superficial and deep venous drainage and less likely to have exclusively deep drainage (32% vs 17% and 12% vs 23%, respectively; p = 0.002). In multivariable analysis, embolization was not a significant predictor of blood loss or mRS score changes, but did predict longer operating times (+29 minutes, 95% CI 2–56 minutes; p = 0.034) and increased clip usage (OR 2.61, 95% CI 1.45–4.71; p = 0.001). Cmax/ROI was not a significant predictor, although cases with large Cmax/ROI tended to have longer procedure times (+25 minutes per doubling of Cmax/ROI, 95% CI 0–50 minutes; p = 0.051).

CONCLUSIONS

In this series, preoperative embolization was associated with longer median resection times and had no association with intraoperative blood loss or mRS score changes.

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Peyton L. Nisson, Salman A. Fard, Christina M. Walter, Cameron M. Johnstone, Michael A. Mooney, Ali Tayebi Meybodi, Michael Lang, Helen Kim, Heidi Jahnke, Denise J. Roe, Travis M. Dumont, G. Michael Lemole Jr., Robert F. Spetzler, and Michael T. Lawton

OBJECTIVE

The objective of this study was to evaluate the existing Spetzler-Martin (SM), Spetzler-Ponce (SP), and Lawton-Young (LY) grading systems for cerebellar arteriovenous malformations (AVMs) and to propose a new grading system to estimate the risks associated with these lesions.

METHODS

Data for patients with cerebellar AVMs treated microsurgically in two tertiary medical centers were retrospectively reviewed. Data from patients at institution 1 were collected from September 1999 to February 2013, and at institution 2 from October 2008 to October 2015. Patient outcomes were classified as favorable (modified Rankin Scale [mRS] score 0–2) or poor (mRS score 3–6) at the time of discharge. Using chi-square and logistic regression analysis, variables associated with poor outcomes were assigned risk points to design the proposed grading system. The proposed system included neurological status prior to treatment (poor, +2 points), emergency surgery (+1 point), age > 60 years (+1 point), and deep venous drainage (deep, +1 point). Risk point totals of 0–1 comprised grade 1, 2–3 grade 2, and 4–5 grade 3.

RESULTS

A total of 125 cerebellar AVMs of 1328 brain AVMs were reviewed in 125 patients, 120 of which were treated microsurgically and included in the study. With our proposed grading system, we found poor outcomes differed significantly between each grade (p < 0.001), while with the SM, SP, and LY grading systems they did not (p = 0.22, p = 0.25, and p = 1, respectively). Logistic regression revealed grade 2 had 3.3 times the risk of experiencing a poor outcome (p = 0.008), while grade 3 had 9.9 times the risk (p < 0.001). The proposed grading system demonstrated a superior level of predictive accuracy (area under the receiver operating characteristic curve [AUROC] of 0.72) compared with the SM, SP, and LY grading systems (AUROC of 0.61, 0.57, and 0.51, respectively).

CONCLUSIONS

The authors propose a novel grading system for cerebellar AVMs based on emergency surgery, venous drainage, preoperative neurological status, and age that provides a superior prognostication power than the formerly proposed SM, SP, and LY grading systems. This grading system is clinically predictive of patient outcomes and can be used to better guide vascular neurosurgeons in clinical decision-making.

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Justin R. Mascitelli, Seungwon Yoon, Tyler S. Cole, Helen Kim, and Michael T. Lawton

OBJECTIVE

Although numerous arteriovenous malformation (AVM) grading scales consider eloquence in risk assessment, none differentiate the types of eloquence. The purpose of this study was to determine if eloquence subtype affects clinical outcome.

METHODS

This is a retrospective review of a prospectively collected clinical database of brain AVMs treated with microsurgery in the period from 1997 to 2017. The only inclusion criterion for this study was the presence of eloquence as defined by the Spetzler-Martin grading scale. Eloquence was preoperatively categorized by radiologists. Poor outcome was defined as a modified Rankin Scale (mRS) score 3–6, and worsening clinical status was defined as an increase in the mRS score at follow-up. Logistic regression analyses were performed.

RESULTS

Two hundred forty-one patients (49.4% female; average age 33.9 years) with eloquent brain AVMs were included in this review. Of the AVMs (average size 2.7 cm), 54.4% presented with hemorrhage, 46.2% had deep venous drainage, and 17.0% were diffuse. The most common eloquence type was sensorimotor (46.1%), followed by visual (27.0%) and language (22.0%). Treatments included microsurgery alone (32.8%), microsurgery plus embolization (51.9%), microsurgery plus radiosurgery (7.9%), and all three modalities (7.5%). Motor mapping was used in 9% of sensorimotor AVM cases, and awake speech mapping was used in 13.2% of AVMs with language eloquence. Complications occurred in 24 patients (10%). At the last follow-up (average 24 months), 71.4% of the patients were unchanged or improved and 16.6% had a poor outcome. There was no statistically significant difference in the baseline patient and AVM characteristics among the different subtypes of eloquence. In a multivariate analysis, in comparison to visual eloquence, both sensorimotor (OR 7.4, p = 0.004) and language (OR 6.5, p = 0.015) eloquence were associated with poor outcomes. Additionally, older age (OR 1.31, p = 0.016) and larger AVM size (OR 1.37, p = 0.034) were associated with poor outcomes.

CONCLUSIONS

Unlike visual eloquence, sensorimotor and language eloquence were associated with worse clinical outcomes after the resection of eloquent AVMs. This nuance in AVM eloquence demands consideration before deciding on microsurgical intervention, especially when numerical grading systems produce a score near the borderline between operative and nonoperative management.

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Ethan A. Winkler, Harjus Birk, Jan-Karl Burkhardt, Xiaolin Chen, John K. Yue, Diana Guo, W. Caleb Rutledge, George F. Lasker, Carlene Partow, Tarik Tihan, Edward F. Chang, Hua Su, Helen Kim, Brian P. Walcott, and Michael T. Lawton

OBJECTIVE

Brain arteriovenous malformations (bAVMs) are rupture-prone tangles of blood vessels with direct shunting of blood flow between arterial and venous circulations. The molecular and/or cellular mechanisms contributing to bAVM pathogenesis and/or destabilization in sporadic lesions have remained elusive. Initial insights into AVM formation have been gained through models of genetic AVM syndromes. And while many studies have focused on endothelial cells, the contributions of other vascular cell types have yet to be systematically studied. Pericytes are multifunctional mural cells that regulate brain angiogenesis, blood-brain barrier integrity, and vascular stability. Here, the authors analyze the abundance of brain pericytes and their association with vascular changes in sporadic human AVMs.

METHODS

Tissues from bAVMs and from temporal lobe specimens from patients with medically intractable epilepsy (nonvascular lesion controls [NVLCs]) were resected. Immunofluorescent staining with confocal microscopy was performed to quantify pericytes (platelet-derived growth factor receptor–beta [PDGFRβ] and aminopeptidase N [CD13]) and extravascular hemoglobin. Iron-positive hemosiderin deposits were quantified with Prussian blue staining. Syngo iFlow post–image processing was used to measure nidal blood flow on preintervention angiograms.

RESULTS

Quantitative immunofluorescent analysis demonstrated a 68% reduction in the vascular pericyte number in bAVMs compared with the number in NVLCs (p < 0.01). Additional analysis demonstrated 52% and 50% reductions in the vascular surface area covered by CD13- and PDGFRβ-positive pericyte cell processes, respectively, in bAVMs (p < 0.01). Reductions in pericyte coverage were statistically significantly greater in bAVMs with prior rupture (p < 0.05). Unruptured bAVMs had increased microhemorrhage, as evidenced by a 15.5-fold increase in extravascular hemoglobin compared with levels in NVLCs (p < 0.01). Within unruptured bAVM specimens, extravascular hemoglobin correlated negatively with pericyte coverage (CD13: r = −0.93, p < 0.01; PDGFRβ: r = −0.87, p < 0.01). A similar negative correlation was observed with pericyte coverage and Prussian blue–positive hemosiderin deposits (CD13: r = −0.90, p < 0.01; PDGFRβ: r = −0.86, p < 0.01). Pericyte coverage positively correlated with the mean transit time of blood flow or the time that circulating blood spends within the bAVM nidus (CD13: r = 0.60, p < 0.05; PDGFRβ: r = 0.63, p < 0.05). A greater reduction in pericyte coverage is therefore associated with a reduced mean transit time or faster rate of blood flow through the bAVM nidus. No correlations were observed with time to peak flow within feeding arteries or draining veins.

CONCLUSIONS

Brain pericyte number and coverage are reduced in sporadic bAVMs and are lowest in cases with prior rupture. In unruptured bAVMs, pericyte reductions correlate with the severity of microhemorrhage. A loss of pericytes also correlates with a faster rate of blood flow through the bAVM nidus. This suggests that pericytes are associated with and may contribute to vascular fragility and hemodynamic changes in bAVMs. Future studies in animal models are needed to better characterize the role of pericytes in AVM pathogenesis.

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Jan-Karl Burkhardt, George F. Lasker, Ethan A. Winkler, Helen Kim, and Michael T. Lawton

OBJECTIVE

Few outcomes studies have been published on microsurgical resection of arteriovenous malformations (AVMs) in elderly patients, and most are limited by a small sample size and the heterogeneous application of treatment modalities. This study aimed to determine whether functional outcomes at last follow-up (LFU) in patients 60 years or older differed when stratified by age.

METHODS

Patients 60 years or older (n = 104) who had undergone microsurgical AVM resection (total, n = 72; 60–65 years, n = 35; and > 65 years, n = 37) or observation (n = 32) were identified from a prospective database. Age, sex, Spetzler-Martin (SM) grade, supplemented SM grade, clinical presentation, AVM location, AVM-associated aneurysms, and functional outcome measured using the modified Rankin Scale (mRS score 0–2 [favorable] vs mRS score > 2 [unfavorable]) at LFU were analyzed.

RESULTS

AVM patients undergoing microsurgical resection were younger, had lower AVM grades, and were more likely to present with rupture. Overall outcome in the surgical group was favorable in 71% of the patients and was statistically significantly better in patients 60–65 years old (p = 0.039). In patients older than 65 years, outcome was dependent on SM grade and level of preexisting functional dependence. Patients with supplemented SM grades of greater than 6 points had favorable outcomes that were age dependent (p = 0.029). This difference was not observed in patients with lower supplemented SM grades or in those with low or high preoperative SM grades (SM grade ≤ 2 and grade ≥ 4, respectively).

CONCLUSIONS

This study demonstrates that favorable outcomes can be achieved with microsurgical resection of AVMs in elderly patients, with careful patient selection. Outcomes in more elderly patients (> 65 years of age) are more dependent on preoperative SM and supplemented SM grading than those in younger cohorts.

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Matthew B. Potts, Darryl Lau, Adib A. Abla, Helen Kim, William L. Young, and Michael T. Lawton

OBJECT

Resection is an appealing therapy for brain arteriovenous malformations (AVMs) because of its high cure rate, low complication rate, and immediacy, and has become the first-line therapy for many AVMs. To clarify safety, efficacy, and outcomes associated with AVM resection in the aftermath of A Randomized Trial of Unruptured Brain AVMs (ARUBA), the authors reviewed their experience with low-grade AVMs—the most favorable AVMs for surgery and the ones most likely to have been selected for treatment outside of ARUBA's randomization process.

METHODS

A prospective AVM registry was searched to identify patients with Spetzler-Martin Grade I and II AVMs treated using resection during a 16-year period.

RESULTS

Of the 232 surgical patients included, 120 (52%) presented with hemorrhage, 33% had Spetzler-Martin Grade I, and 67% had Grade II AVMs. Overall, 99 patients (43%) underwent preoperative embolization, with unruptured AVMs embolized more often than ruptured AVMs. AVM resection was accomplished in all patients and confirmed angiographically in 218 patients (94%). There were no deaths among patients with unruptured AVMs. Good outcomes (modified Rankin Scale [mRS] score 0–1) were found in 78% of patients, with 97% improved or unchanged from their preoperative mRS scores. Patients with unruptured AVMs had better functional outcomes (91% good outcome vs 65% in the ruptured group, p = 0.0008), while relative outcomes were equivalent (98% improved/unchanged in patients with ruptured AVMs vs 96% in patients with unruptured AVMs).

CONCLUSIONS

Surgery should be regarded as the “gold standard” therapy for the majority of low-grade AVMs, utilizing conservative embolization as a preoperative adjunct. High surgical cure rates and excellent functional outcomes in patients with both ruptured and unruptured AVMs support a dominant surgical posture for low-grade AVMS, with radiosurgery reserved for risky AVMs in deep, inaccessible, and highly eloquent locations. Despite the technological advances in endovascular and radiosurgical therapy, surgery still offers the best cure rate, lowest risk profile, and greatest protection against hemorrhage for low-grade AVMs. ARUBA results are influenced by a low randomization rate, bias toward nonsurgical therapies, a shortage of surgical expertise, a lower rate of complete AVM obliteration, a higher rate of delayed hemorrhage, and short study duration. Another randomized trial is needed to reestablish the role of surgery in unruptured AVM management.