Current surgical results with low-grade brain arteriovenous malformations

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  • 1 Departments of Neurological Surgery,
  • 2 Anesthesia and Perioperative Care, and the
  • 3 Center for Cerebrovascular Research, University of California, San Francisco, California
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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.

ABBREVIATIONSARUBA = A Randomized Trial of Unruptured Brain AVMs; AVM = arteriovenous malformation; mRS = modified Rankin Scale; OR = odds ratio.

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.

ABBREVIATIONSARUBA = A Randomized Trial of Unruptured Brain AVMs; AVM = arteriovenous malformation; mRS = modified Rankin Scale; OR = odds ratio.

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 or “gold standard” for many AVMs.4,24 Surgical results have improved over time with: 1) the creation of grading systems to select patients likely to experience optimal outcomes;5,11,18,19,42 2) the development of instruments such as bipolar forceps and AVM microclips to coagulate or occlude feeding arteries effectively; 3) the recognition of AVM subtypes that help decipher AVM anatomy;5,9,17,34,35 and 4) the refinement of surgical approaches, strategies, and dissection techniques that facilitate safe AVM resection.4,11,13,18,22,43 This impressive evolution of AVM surgery is at odds with the finding of “A Randomized Trial of Unruptured Brain AVMs” (ARUBA)23 that medical management alone was superior to interventional therapy for the prevention of death or stroke in patients with unruptured AVMs followed for 33 months. This finding is explained in part by the trial's 13% randomization rate, suggesting that many clinicians did not consider AVMs with low Spetzler-Martin grades (low treatment risk) to be in equipoise with medical management (high hemorrhage risk), or conversely, did not deem those with high grades (high treatment risk) to be in equipoise with medical management (low hemorrhage risk), and “selected treatment outside of the randomization process” in 177 patients, or 79% of included patients.23

Another important explanation for the ARUBA finding is the trial's surprising nonsurgical management of patients in the interventional group.23 Overall, 81% of patients were treated with embolization alone (32%), radiosurgery alone (33%), or combined embolization and radiosurgery (16%), and only 17 patients (18%) were treated surgically, with or without embolization. Therefore, the 3-fold increase in death or stroke in the interventional arm reflects current nonsurgical therapies and should not be interpreted as an indictment of AVM surgery.23 In the aftermath of ARUBA,23 it is i mportant to clarify t he safety, efficacy, and outcomes associated with AVM resection. Therefore, we reviewed our experience in managing Spetzler-Martin Grade I and II 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

Data Collection

This study was approved by the Institutional Review Board and conducted in compliance with Health Insurance Portability and Accountability Act regulations. The prospective registry of the University of California, San Francisco, Brain Arteriovenous Malformation Study Project was searched to identify patients with Spetzler-Martin Grade I and II AVMs who were treated with resection at our institution between 1997 and 2013. Operations were performed by the senior author (M.T.L.). The database as well as medical records, pre- and post-treatment radiological studies, and clinical follow-up evaluations were reviewed retrospectively.

Outcome Evaluation

The Spetzler-Martin grading system was used to establish AVM grade, and the Lawton-Young Supplementary grading system was used to augment surgical risk assessment.19,42 The primary outcome measure was functional outcome at last follow-up evaluation based on the modified Rankin Scale (mRS) score dichotomized to “good” (mRS score 0–1) or “poor” (mRS score 2–6). Long-term functional outcomes were only evaluated in patients with more than 30 days of follow-up. Neurological assessments were performed by a neurologist and/or a dedicated clinical research nurse, without involvement of treating neurosurgeons. The pretreatment functional status was obtained from pretreatment clinic visits or admission examinations, while follow-up information was obtained during posttreatment clinic visits, subsequent hospital admissions, or telephone interviews. The Social Security Death Index was searched for all patients with less than 30 days of follow-up to ensure that no early deaths were missed. Angiographic outcomes were determined by a neurointerventional radiologist.

Statistical Analysis

Statistical analysis was performed using the JMP program (version 11, SAS). Frequency distributions and summary statistics were calculated for all baseline characteristics and outcome measures. For all categorical variables (e.g., unruptured status), a cross-tabulation was generated and a Fisher's exact test (for 2 × 2 contingency tables) or Pearson chi-square test (for larger contingency tables) was used to compare distributions between groups of interest. Continuous variables were compared using an ANOVA. Statistical significance was defined as p < 0.05.

Results

Patients and AVM Characteristics

Between 1997 and 2013, 332 patients with Spetzler-Martin Grade I or II AVMs were managed at our institution and 234 (70%) of these were managed surgically. Two of these patients who underwent concomitant surgical treatment for other pathologies (orbital squamous-cell carcinoma resection in 1 and extracranial-to-intracranial bypass for moyamoya disease in the other) were excluded from this cohort. Nine patients who had aneurysms clipped concomitantly were included. Baseline characteristics for the 232 surgical patients are shown in Table 1. The mean age of the study population was 38 years with a slight female predominance (56%). The most common AVM location was the frontal lobe (34%). Over half of the patients (n = 120) presented with AVM rupture and 53% presented with an mRS score of 0 or 1. Spetzler-Martin grades were I in 33% and II in 67%. Patients presenting with AVM rupture differed from those presenting without rupture in AVM location (p = 0.0014), preoperative mRS score (p < 0.0001), and Lawton-Young supplementary AVM grade (p < 0.0001).

TABLE 1

Baseline characteristics of patients with low-grade AVMs

VariableUnruptured AVMRuptured AVMp Value*Total
Total no. of patients112120232
Mean age at surgery ± SD (yrs)39.4 ± 15.336.9 ± 18.40.1638.1 ± 17
Females (%)70 (63)61 (51)0.16131 (56)
Presentation (%)Not tested
 Hemorrhage0120 (100)120 (52)
 Seizure37 (33)037 (16)
 Headache40 (36)040 (17)
 Other35 (31)035 (15)
AVM location (%)0.0014
 Frontal49 (44)29 (24)78 (34)
 Parietooccipital27 (24)31 (26)58 (25)
 Temporal22 (20)22 (18)44 (19)
 Cerebellar7 (6)28 (23)35 (15)
 Ventricular2 (2)6 (5)8 (3)
 Deep3 (3)4 (3)7 (3)
 Brainstem1 (1)01 (<1)
 Mixed1 (1)01 (<1)
AVM side (%)0.07
 Rt59 (53)57 (48)116 (50)
 Lt52 (46)55 (46)107 (46)
 Midline1 (1)8 (7)9 (4)
Preop mRS score (%)<0.0001
 048 (43)14 (12)62 (27)
 145 (40)16 (13)61 (26)
 215 (13)20 (17)35 (15)
 34 (4)26 (22)30 (13)
 4022 (18)22 (9)
 5022 (18)22 (9)
Spetzler-Martin Grade (%)0.56
 I37 (33)39 (33)76 (33)
 II75 (67)81 (68)156 (67)
Supplementary AVM Grade (%)<0.0001
 1022 (18)22 (9)
 211 (10)35 (29)46 (20)
 337 (33)55 (46)92 (40)
 459 (53)8 (7)67 (29)
 55 (4)05 (2)
Prior treatments (%)61 (54)42 (35)103 (44)
 Preop embolization59 (53)40 (33)0.00599 (43)
 Remote embolization02 (2)0.52 (1)
 Radiosurgery3 (3)1 (1)0.14 (2)

Comparing unruptured and ruptured AVMs, an ANOVA was used for continuous variables, Fisher's exact test for 2 × 2 contingency tables, and Pearson chi-square test for larger contingency tables. Bold values are statistically significant.

Refers to an AVM involving both the temporal and parietooccipital regions.

Surgical Management

Overall, 99 patients (43%) underwent preoperative embolization, with unruptured AVMs embolized more often than ruptured AVMs (53% vs 33%, respectively; p = 0.005). Only 4 patients had been treated previously, 2 with stereotactic radiosurgery and 2 with both remote embolization and radiosurgery.

AVM resection was accomplished with a single stage in all but 5 patients. These 5 patients had unexpected residual AVMs noted on their postoperative angiograms and all were taken back to the operating room for complete resection. Postoperative angiograms were obtained in 218 patients (94%, Table 2). No residual AVM was noted in 213 of these 218 patients (98%). Repeat angiograms in the 5 patients with residual AVMs confirmed complete resection. Of the 14 patients with no postoperative angiography, 3 died during their postoperative hospitalization. The remaining 11 patients refused postoperative angiography, but had a mean follow-up duration of 1.6 years (range 25 days to 6.2 years).

TABLE 2

Surgical results with low-grade AVMs

VariableUnrupturedRupturedp ValueTotal
Total112120232
Angiographic outcome (%)0.46
 Complete106 (95)112 (93)218 (94)
 Residual0 (0)0 (0)0 (0)
 No study6 (5)8 (7)14 (6)
Patients w/ >30-day follow-up (%)100 (89)107 (89)Not tested207 (89)
Mean duration of follow-up ± SD (yrs)1.8 ± 2.11.6 ± 1.4Not tested1.7 ± 1.8
Median duration of last follow-up in yrs (range)1.2 (0.1–12.8)1.3 (0.1–6.3)Not tested1.2 (0.1–12.8)
Functional outcome (mRS score)*0.0008
 0–191 (91)70 (65)161 (78)
 26 (6)25 (23)31 (15)
 33 (3)5 (5)8 (4)
 40 (0)2 (2)2 (1)
 50 (0)4 (4)4 (2)
 60 (0)1 (1)1 (0)
Improved/unchanged96 (96)105 (98)0.43201 (97)
Worse4 (4)2 (2)6 (3)

Only available in 207 patients.

Significant intraoperative AVM rupture occurred in 1 patient. Postoperative hemorrhages due to surgical site bleeding occurred in 3 patients, all of which required evacuation of the hematoma. Two patients were noted to have postoperative infarcts, 1 involving a lenticulostriate artery and 1 a middle cerebral artery. Finally, 2 patients had wound infections requiring surgical debridement.

Of note, an 8-year-old patient who underwent complete resection of a left temporal Grade II AVM with a negative postoperative angiogram was found to have recurrent AVM in that same location on a 5-year follow-up angiogram. He underwent a repeat resection without complication and had no residual AVM noted on either the postoperative or a repeat 5-year follow-up angiogram.

Functional Outcomes

Four patients died within 30 days of AVM resection; all of these patients had ruptured AVMs. Three patients presented with devastating AVM hemorrhages (vermian, tonsillar, and temporal AVMs), underwent uncomplicated resection, and had pre- and postoperative mRS scores of 5; their families withdrew care. These deaths were attributed to severity of hemorrhage rather than surgery. One patient with a deep parietal AVM had a middle cerebral artery stroke related to AVM resection and died of resulting medical complications (surgical mortality rate = 0.4%). There were no deaths among patients with unruptured AVMs.

Long-term follow-up was available in 207 patients (89%; Table 2). Mean duration of follow-up was 1.7 years (median 1.2 years, range 2 weeks to 12.8 years). Four additional patients had died at late follow-up, all from causes unrelated to their AVM surgery: 1 patient died of cancer 3 years postoperatively (mRS score = 1), 1 patient died of renal failure 4 months postoperatively (mRS score = 0), and 2 patients died of unknown causes 1.9 years (mRS score = 1) and 5.7 years (mRS score = 1) postoperatively. The mRS score from the next-to-last clinical evaluation was used for the functional outcome analysis.

Overall, good outcomes (mRS score 0–1) were found in 78% of patients, with 97% improved or unchanged from their preoperative mRS scores (Table 2). As expected, patients with unruptured AVMs had better functional outcomes, with 91% having a good outcome at the time of the last follow-up evaluation compared with 65% in the ruptured AVM group (p = 0.0008). Relative outcomes were slightly better in patients with ruptured AVMs, with 98% improved or unchanged, compared with 96% in patients with unruptured AVMs.

Univariate analysis of factors associated with good (mRS score 0–1) compared with poor (mRS score ≥ 2) functional outcomes identified younger age (odds ratio [OR] 0.98 for each increasing year; p = 0.03, logistic regression), unruptured presentation (good outcomes in 88% of unruptured AVMs vs 65% of ruptured AVMs; p = 0.0001, 2-tailed Fisher's exact test), and preoperative mRS scores (good outcomes in 94% and 57% with preoperative mRS scores of 0–1 and ≥ 2, respectively; p < 0.0001, chi-square test). Of note, AVM location, Spetzler-Martin and Lawton-Young supplementary grades, preoperative embolization, and time to follow-up were not significantly associated with functional outcome. The 3 variables above were fit into a logistic regression model that confirmed that young age (OR 0.98 for each increasing year; p = 0.03) and low preoperative mRS score (OR 11.8 for mRS score 0–1 vs mRS score ≥ 2; p < 0.0001) remained significantly associated with good outcomes. The OR for hemorrhagic presentation in this model did not reach statistical significance (OR 0.97 for unruptured vs ruptured AVM; p = 0.95).

Discussion

Surgical Results With Low-Grade AVMs

This study exemplifies a surgical posture toward low-grade AVMs that regards curative resection as the first-line or “gold standard” therapy for the majority of lesions, utilizing embolization as a preoperative adjunct and reserving radiosurgery for risky AVMs in deep, inaccessible locations, in eloquent areas that might be associated with postoperative neurological deficits, and/or with diffuse nidus morphology that might complicate microdissection. Patients were carefully selected to optimize outcomes, with a mean age of 38 years, Lawton-Young supplementary grades of 3 or less in 69% of patients, and few (< 4%) in deep locations or brainstem. Conservative embolization minimized additional treatment risk, with only 43% of patients undergoing embolization and no patients experiencing endovascular complications. Surgical cures were confirmed in all patients who underwent postoperative angiography. Overall, 6 patients (3%) were worse neurologically after surgery, with 161 patients (78%) in total and 91 patients (91%) with unruptured AVMs experiencing good outcomes (mRS score 0–1). These surgical results are consistent with other reports in the literature (Table 3).4,11–13,24,32,37,38,40,42,43 In a review of 1235 patients with low-grade AVMs, the average surgical morbidity and mortality rates were 2.2% and 0.3%, respectively, with an average cure rate of 98.5% and a postoperative or delayed hemorrhage rate of 0.3% (Table 3).

TABLE 3

Summary of surgical results with low-grade AVMs

Authors & YearNo. of PatientsMorbidity (%)Mortality (%)Cure Rate (%)Hemorrhage (%)
Spetzler & Martin, 1986442.30NANA
Heros et al., 1990472.22.21000
Sundt et al., 1991842.201000
Sisti et al., 1993671.50940
Hamilton & Spetzler, 1994400.00100NA
Schaller & Schramm, 1997503.20982
Schaller et al., 1998810.00NANA
Pikus et al., 1998263.801000
Hartmann et al., 2000486.60NANA
Morgan et al., 20042200.90.51000
Davidson & Morgan, 20102960.7097NA
Lawton, 20142322.40.5980
Total12352.2 (mean)0.3 (mean)98.5 (mean)0.3 (mean)

NA = not available

Endovascular and Radiosurgical Results With Low-Grade AVMs

The management of AVMs in other parts of the world is diverging from the surgical approach described above. In Europe, for example, treatment is often limited only to ruptured AVMs, beginning with aggressive embolization, frequently adding radiosurgery for incompletely embolized AVMs,2,3,31,39 and rarely resorting to resection. Onyx (Covidien) is an important endovascular advancement because its high viscosity allows for slow intranidal injection, its prolonged solidification promotes deep penetration to the venous side of the AVM, and its nonadherence reduces catheter retention (J. Moret, presentation to the AANS Annual Meeting, 2014).31 Onyx has improved the efficacy of endovascular therapy with better cure rates than N-butyl cyanoacrylate glue, but cure rates are still low and curative attempts are associated with increased complications, occlusion of critical draining veins, and adverse imaging findings in as many as 40% of patients.1,10,15,20,25,27–30,36,41,45–47 In a review of 1297 patients with mostly low-grade AVMs, the average endovascular morbidity and mortality rates were 6.2% and 1.6%, respectively, with an average cure rate of 29% and a postoperative or delayed hemorrhage rate of 8.0% (Table 4).1,10,15,20,25,27–30,36,41,45–47 Therefore, aggressive endovascular therapy has higher procedural risks, significantly lower cure rates, and increased hemorrhage risks compared with surgery.

TABLE 4

Summary of endovascular results with Onyx for mostly low-grade AVMs

Authors & YearNo. of PatientsMorbidity (%)Mortality (%)Cure Rate (%)Hemorrhage (%)
Pérez-Higueras et al., 20054515.52.0228.9
Song et al., 20055010.00.0206.0
van Rooij et al., 2007444.62.3166.8
Weber et al., 2007935.40.020NA
Mounayer et al., 2007944.33.2288.5
Katsaridis et al., 20081018.03.0285.9
Pierot et al., 2009508.02.088.0
Panagiotopoulos et al., 2009827.32.42012.2
Gao et al., 20091152.60.9262.6
Maimon et al., 2010432.30.03713.9
Xu et al., 2011863.51.2197.0
Saatci et al., 20113504.31.4514.0
Abud et al., 2011175.90.09411.7
Pierot et al., 20131275.14.3248.5
Total12976.2 (mean)1.6 (mean)29.5 (mean)8.0 (mean)

NA = not available.

A similar comparison can be made with radiosurgery for low-grade AVMs. Although these lesions are ideal for radiosurgery because of their lower target volumes and higher obliteration rates, the 2- to 3-year latency period between treatment and obliteration opens a time window for AVM hemorrhage and associated complications. Radiation-induced complications are low, but in a review of 1051 patients with low-grade AVMs, 7.2% of patients hemorrhaged after treatment, resulting in morbidity and mortality rates of 6.5% and 1.2%, respectively (Table 5).6–8,14,16,21,26,33,48 T he 75.2% r adiosurgical c ure r ate w as substantially better than the endovascular cure rate, but still less than surgery. Therefore, 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. Surgery cannot compete with the minimally invasive appeal of these other modalities, but this issue remains secondary to functional outcome.

TABLE 5

Summary of radiosurgical results with low-grade AVMs

Authors & YearNo. of PatientsMorbidity (%)Mortality (%)Cure Rate (%)Hemorrhage (%)
Pollock et al., 1994655.03.086.07.7
Yamamoto et al., 199619NA0.063.22.5
Meder et al., 199757NANA65.0NA
Friedman et al., 2003107NANA66.410.4
Nataf et al., 200727NA0.077.810.0
Kano et al., 20122173.22.893.06.0
Fokas et al., 201324NANA61.06.0
Koltz et al., 20133312.10.088.09.1
Ding et al., 20145025.6NA76.15.6
Total10516.5 (mean)1.2 (mean)75.2 (mean)7.2 (mean)

NA = not available

The results of our analysis are consistent with other systematic meta-analyses of AVM therapy not limited to low-grade AVMs. In a recent meta-analysis of 13,698 patients by van Beijnum et al.,44 the complication rates and case fatality rates were 6.6% and 0.96% for embolization, 5.1% and 0.5% for radiosurgery, and 7.4% and 1.1% for surgery, respectively, with the increased surgical risks reflecting the inclusion of intermediate and high-grade AVMs. However, AVM obliteration rates were 13%, 38%, and 96% for embolization, radiosurgery, and surgery, respectively.44 Estimates of hemorrhage risk after surgery were 1.7%, 1.7%, and 0.2% for embolization, radiosurgery, and surgery, respectively.44

Critique of ARUBA

How do we interpret the ARUBA findings in the context of our study? First, based on the surgical experience described above, a significant number of neurosurgical investigators in ARUBA did not consider low-grade AVMs to be in equipoise with medical management and “selected treatment outside of the randomization process” in 177 patients, or close to the number of included patients.23 Conversely, intermediate (31.8%) and high-grade AVMs (10.3%) that are generally considered to have a more benign natural history and are at high risk for any treatment were included in the trial, diminishing the interventional results.23

As a participating site in the ARUBA trial, we screened 473 patients, identified 87 who were eligible, and enrolled only 4. Of the 74 ARUBA-eligible patients with sufficient follow-up for analysis, 61 were treated (including 36 with low-grade AVMs) and 13 were observed. Most treated patients underwent resection with or without preoperative embolization (43/61, 70.5%). Stroke and death, the primary end points by ARUBA definitions, were observed in 10 patients, including 1 in the observation group (8%), 5 in the surgical group (11%), and 4 in the radiosurgical group (27%). There was no significant difference in stroke/death rates (hazard ratio 1.34, 95% confidence interval 0.12–14.53; p = 0.807) or clinical impairment (p = 0.68, Fisher's exact test) between observed and treated patients. Therefore, our results in ARUBA-eligible patients were better than those reported in ARUBA, leading to an entirely different conclusion about AVM intervention. This difference was due to utilizing surgery as the primary therapy, selecting surgical patients judiciously with established outcome predictors, and developing surgical expertise through high AVM case volume.

Second, ARUBA was unusually biased toward nonsurgical therapy, with 81% of patients treated with endovascular embolization alone (32%), radiosurgery alone (33%), or combined embolization and radiosurgery (16%).23 The 18% of ARUBA patients treated surgically contrasts sharply with the 71% of ARUBA-eligible patients treated surgically at our site. Data on cure rates were not published with ARUBA,23 but the number of incompletely obliterated AVMs was likely significant and resulted in ongoing ruptures. Therefore, the event rates observed in Kaplan-Meier estimates of “as-treated” patients reflected the procedural morbidity of endovascular therapy in addition to the delayed morbidity of latent hemorrhage associated with radiosurgery.23 The outcome of such a group could never exceed that of an observational group whose only morbidity was the risk of AVM rupture.

Third, the shortage of surgical expertise in the ARUBA trial is apparent. Two-thirds of patients in the interventional group had low-grade surgical AVMs and yet only 18% underwent surgery, which is well below expectation for the gold standard therapy.23 The rates of stroke and death in this trial do not match reported surgical outcomes (Table 3). Therefore, the overall management of AVMs in ARUBA reflects a nonsurgical posture consistent with the fact that 38 of 65 total ARUBA sites were in Europe, Australia, and Brazil.22 Centers were required to manage 10 patients with AVMs per year, but there were no minimum requirements for neurosurgeons. AVM resection is among the most challenging neurosurgical procedures, and the best AVM surgeons typically perform three times ARUBA's minimum requirement annually. In a review of AVM outcome data from the National Inpatient Sample, we found that mortality rates were lowest and discharges to home were highest among neurosurgeons with the highest case volume, defined as the top decile with 30 or more AVM resections per year. Had the ARUBA trial been embraced by the neurosurgical community, the application of surgical therapy would have been higher, the interventional outcomes would have been better, and the benefits of intervention would have been obvious. Had ARUBA been more surgical with complete resections and no delayed hemorrhage in nearly all patients as described above, the event rates observed in Kaplan-Meier estimates of “as-treated” patients would have plateaued and the benefits of intervention would have been realized in much less than 10 years. Although this time interval is reasonable in a population of young patients (mean age 45 years) with long life expectancy, the trial was stopped long before reaching this crossover point (median follow-up duration of 33 months).23

Another Randomized Trial: BARBADOS

The ARUBA trial has had significant impact because it was a randomized, controlled trial. Our results with low-grade AVMs were derived from a larger cohort of patients than ARUBA (232 vs 223) and more than twice the number of treated patients (232 vs 98), but the impact of our results is limited by study design. Although the University of California, San Francisco AVM database is prospectively maintained by statisticians with input from multiple disciplines, including functional outcomes from dedicated clinical research nurses and neurologists (not treating neurosurgeons), and angiographic outcomes from neurointerventional radiologists, this case series is influenced by referral biases, institutional biases, and selection biases. Patients are selected according to established outcome predictors embodied in the Spetzler-Martin and Lawton-Young Supplementary grading systems. Furthermore, our site is a high-volume center with dedicated experts who have collaborated as a team for decades, which might set a high surgical benchmark but lower the generalizability of our results. As important as these surgical results are in ARUBA's aftermath, another trial is needed to reestablish the role of surgery in AVM management, this time conducted and embraced by the neurosurgical community.

We propose BARBADOS: Beyond ARUBA—Randomized low-grade Brain AVM stuDy: Observation versus Surgery. The elements of the trial are obvious from the name, and efforts are ongoing to organize, fund, and initiate it. There is now urgency among neurosurgeons to respond to ARUBA, which we expect to increase the acceptance of such a trial. In the meantime, the management of ruptured AVMs should remain unaffected by ARUBA and surgery should remain a dominant therapy because of its ability to evacuate hematomas, relieve intracranial pressure, and work through hematoma cavities.

Conclusions

Surgery should be regarded as the first-line or 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 both ruptured and unruptured patients support a dominant surgical posture, with radiosurgery reserved for risky AVMs in deep, inaccessible, and highly eloquent locations. In the aftermath of ARUBA, additional randomized trials are needed to validate the role of resection.

Author Contributions

Conception and design: Lawton, Potts, Young. Acquisition of data: all authors. Analysis and interpretation of data: all authors. Drafting the article: Lawton, Potts, Kim. Critically revising the article: Lawton, Potts, Kim. Reviewed submitted version of manuscript: Lawton, Potts, Lau, Kim. Approved the final version of the manuscript on behalf of all authors: Lawton. Statistical analysis: Lawton, Potts, Lau, Abla, Kim. Administrative/technical/material support: all authors. Study supervision: Lawton, Potts, Kim, Young.

References

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    Abud DG, , Riva R, , Nakiri GS, , Padovani F, , Khawaldeh M, & Mounayer C: Treatment of brain arteriovenous malformations by double arterial catheterization with simultaneous injection of Onyx: retrospective series of 17 patients. AJNR Am J Neuroradiol 32:152158, 2011

    • Search Google Scholar
    • Export Citation
  • 2

    Blackburn SL, , Ashley WW Jr, , Rich KM, , Simpson JR, , Drzymala RE, & Ray WZ, : Combined endovascular embolization and stereotactic radiosurgery in the treatment of large arteriovenous malformations. J Neurosurg 114:17581767, 2011

    • Search Google Scholar
    • Export Citation
  • 3

    Dalyai R, , Theofanis T, , Starke RM, , Chalouhi N, , Ghobrial G, & Jabbour P, : Stereotactic radiosurgery with neoadjuvant embolization of larger arteriovenous malformations: an institutional experience. Biomed Res Int 2014:306518, 2014

    • Search Google Scholar
    • Export Citation
  • 4

    Davidson AS, & Morgan MK: How safe is arteriovenous malformation surgery? A prospective, observational study of surgery as first-line treatment for brain arteriovenous malformations. Neurosurgery 66:498505, 2010

    • Search Google Scholar
    • Export Citation
  • 5

    Davies JM, , Kim H, , Young WL, & Lawton MT: Classification schemes for arteriovenous malformations. Neurosurg Clin N Am 23:4353, 2012

  • 6

    Ding D, , Yen CP, , Xu Z, , Starke RM, & Sheehan JP: Radiosurgery for low-grade intracranial arteriovenous malformations. J Neurosurg 121:457467, 2014

    • Search Google Scholar
    • Export Citation
  • 7

    Fokas E, , Henzel M, , Wittig A, , Grund S, & Engenhart-Cabillic R: Stereotactic radiosurgery of cerebral arteriovenous malformations: long-term follow-up in 164 patients of a single institution. J Neurol 260:21562162, 2013

    • Search Google Scholar
    • Export Citation
  • 8

    Friedman WA, , Bova FJ, , Bollampally S, & Bradshaw P: Analysis of factors predictive of success or complications in arteriovenous malformation radiosurgery. Neurosurgery 52:296308, 2003

    • Search Google Scholar
    • Export Citation
  • 9

    Gabarrós Canals A, , Rodríguez-Hernández A, , Young WL, & Lawton MT: Temporal lobe arteriovenous malformations: anatomical subtypes, surgical strategy, and outcomes. J Neurosurg 119:616628, 2013

    • Search Google Scholar
    • Export Citation
  • 10

    Gao K, , Yang XJ, , Mu SQ, , Li YX, , Zhang YP, & M, : Embolization of brain arteriovenous malformations with ethylene vinyl alcohol copolymer: technical aspects. Chin Med J (Engl) 122:18511856, 2009

    • Search Google Scholar
    • Export Citation
  • 11

    Hamilton MG, & Spetzler RF: The prospective application of a grading system for arteriovenous malformations. Neurosurgery 34:27, 1994

  • 12

    Hartmann A, , Stapf C, , Hofmeister C, , Mohr JP, , Sciacca RR, & Stein BM, : Determinants of neurological outcome after surgery for brain arteriovenous malformation. Stroke 31:23612364, 2000

    • Search Google Scholar
    • Export Citation
  • 13

    Heros RC, , Korosue K, & Diebold PM: Surgical excision of cerebral arteriovenous malformations: late results. Neurosurgery 26:570578, 1990

    • Search Google Scholar
    • Export Citation
  • 14

    Kano H, , Lunsford LD, , Flickinger JC, , Yang HC, , Flannery TJ, & Awan NR, : Stereotactic radiosurgery for arteriovenous malformations, Part 1: management of Spetzler-Martin Grade I and II arteriovenous malformations. J Neurosurg 116:1120, 2012

    • Search Google Scholar
    • Export Citation
  • 15

    Katsaridis V, , Papagiannaki C, & Aimar E: Curative embolization of cerebral arteriovenous malformations (AVMs) with Onyx in 101 patients. Neuroradiology 50:589597, 2008

    • Search Google Scholar
    • Export Citation
  • 16

    Koltz MT, , Polifka AJ, , Saltos A, , Slawson RG, , Kwok Y, & Aldrich EF, : Long-term outcome of Gamma Knife stereotactic radiosurgery for arteriovenous malformations graded by the Spetzler-Martin classification. J Neurosurg 118:7483, 2013

    • Search Google Scholar
    • Export Citation
  • 17

    Lawton MT: Seven AVMs: Tenets and Techniques for Resection New York, Thieme, 2014

  • 18

    Lawton MT: Spetzler-Martin Grade III arteriovenous malformations: surgical results and a modification of the grading scale. Neurosurgery 52:740749, 2003

    • Search Google Scholar
    • Export Citation
  • 19

    Lawton MT, , Kim H, , McCulloch CE, , Mikhak B, & Young WL: A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery 66:702713, 2010

    • Search Google Scholar
    • Export Citation
  • 20

    Maimon S, , Strauss I, , Frolov V, , Margalit N, & Ram Z: Brain arteriovenous malformation treatment using a combination of Onyx and a new detachable tip microcatheter, SONIC: short-term results. AJNR Am J Neuroradiol 31:947954, 2010

    • Search Google Scholar
    • Export Citation
  • 21

    Meder JF, , Oppenheim C, , Blustajn J, , Nataf F, , Merienne L, & Lefkoupolos D, : Cerebral arteriovenous malformations: the value of radiologic parameters in predicting response to radiosurgery. AJNR Am J Neuroradiol 18:14731483, 1997

    • Search Google Scholar
    • Export Citation
  • 22

    Mohr JP, , Moskowitz AJ, , Stapf C, , Hartmann A, , Lord K, & Marshall SM, : The ARUBA trial: current status, future hopes. Stroke 41:e537e540, 2010

    • Search Google Scholar
    • Export Citation
  • 23

    Mohr JP, , Parides MK, , Stapf C, , Moquete E, , Moy CS, & Overbey JR, : Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 383:614621, 2014

    • Search Google Scholar
    • Export Citation
  • 24

    Morgan MK, , Rochford AM, , Tsahtsarlis A, , Little N, & Faulder KC: Surgical risks associated with the management of Grade I and II brain arteriovenous malformations. Neurosurgery 54:832839, 2004

    • Search Google Scholar
    • Export Citation
  • 25

    Mounayer C, , Hammami N, , Piotin M, , Spelle L, , Benndorf G, & Kessler I, : Nidal embolization of brain arteriovenous malformations using Onyx in 94 patients. AJNR Am J Neuroradiol 28:518523, 2007

    • Search Google Scholar
    • Export Citation
  • 26

    Nataf F, , Schlienger M, , Bayram M, , Ghossoub M, , George B, & Roux FX: Microsurgery or radiosurgery for cerebral arteriovenous malformations? A study of two paired series. Neurosurgery 61:3950, 2007

    • Search Google Scholar
    • Export Citation
  • 27

    Panagiotopoulos V, , Gizewski E, , Asgari S, , Regel J, , Forsting M, & Wanke I: Embolization of intracranial arteriovenous malformations with ethylene-vinyl alcohol copolymer (Onyx). AJNR Am J Neuroradiol 30:99106, 2009

    • Search Google Scholar
    • Export Citation
  • 28

    Pérez-Higueras A, , López RR, & Tapia DQ: Endovascular treatment of cerebral AVM: our experience with onyx. Interv Neuroradiol 11:Suppl 1 141157, 2005

    • Search Google Scholar
    • Export Citation
  • 29

    Pierot L, , Cognard C, , Herbreteau D, , Fransen H, , van Rooij WJ, & Boccardi E, : Endovascular treatment of brain arteriovenous malformations using a liquid embolic agent: results of a prospective, multicentre study (BRAVO). Eur Radiol 23:28382845, 2013

    • Search Google Scholar
    • Export Citation
  • 30

    Pierot L, , Januel AC, , Herbreteau D, , Barreau X, , Drouineau J, & Berge J, : Endovascular treatment of brain arteriovenous malformations using onyx: results of a prospective, multicenter study. J Neuroradiol 36:147152, 2009

    • Search Google Scholar
    • Export Citation
  • 31

    Pierot L, , Kadziolka K, , Litré F, & Rousseaux P: Combined treatment of brain AVMs with use of Onyx embolization followed by radiosurgery. AJNR Am J Neuroradiol 34:13951400, 2013

    • Search Google Scholar
    • Export Citation
  • 32

    Pikus HJ, , Beach ML, & Harbaugh RE: Microsurgical treatment of arteriovenous malformations: analysis and comparison with stereotactic radiosurgery. J Neurosurg 88:641646, 1998

    • Search Google Scholar
    • Export Citation
  • 33

    Pollock BE, , Lunsford LD, , Kondziolka D, , Maitz A, & Flickinger JC: Patient outcomes after stereotactic radiosurgery for “operable” arteriovenous malformations. Neurosurgery 35:18, 1994

    • Search Google Scholar
    • Export Citation
  • 34

    Potts MB, , Young WL, & Lawton MT: Deep arteriovenous malformations in the basal ganglia, thalamus, and insula: microsurgical management, techniques, and results. Neurosurgery 73:417429, 2013

    • Search Google Scholar
    • Export Citation
  • 35

    Rodríguez-Hernández A, , Kim H, , Pourmohamad T, , Young WL, & Lawton MT: Cerebellar arteriovenous malformations: anatomic subtypes, surgical results, and increased predictive accuracy of the supplementary grading system. Neurosurgery 71:11111124, 2012

    • Search Google Scholar
    • Export Citation
  • 36

    Saatci I, , Geyik S, , Yavuz K, & Cekirge HS: Endovascular treatment of brain arteriovenous malformations with prolonged intranidal Onyx injection technique: long-term results in 350 consecutive patients with completed endovascular treatment course. J Neurosurg 115:7888, 2011

    • Search Google Scholar
    • Export Citation
  • 37

    Schaller C, & Schramm J: Microsurgical results for small arteriovenous malformations accessible for radiosurgical or embolization treatment. Neurosurgery 40:664674, 1997

    • Search Google Scholar
    • Export Citation
  • 38

    Schaller C, , Schramm J, & Haun D: Significance of factors contributing to surgical complications and to late outcome after elective surgery of cerebral arteriovenous malformations. J Neurol Neurosurg Psychiatry 65:547554, 1998

    • Search Google Scholar
    • Export Citation
  • 39

    Schwyzer L, , Yen CP, , Evans A, , Zavoian S, & Steiner L: Long-term results of gamma knife surgery for partially embolized arteriovenous malformations. Neurosurgery 71:11391148, 2012

    • Search Google Scholar
    • Export Citation
  • 40

    Sisti MB, , Kader A, & Stein BM: Microsurgery for 67 intracranial arteriovenous malformations less than 3 cm in diameter. J Neurosurg 79:653660, 1993

    • Search Google Scholar
    • Export Citation
  • 41

    Song D, , Leng B, , Gu Y, , Zhu W, , Xu B, & Chen X, : Clinical analysis of 50 cases of BAVM embolization with Onyx, a novel liquid embolic agent. Interv Neuroradiol 11:Suppl 1 179184, 2005

    • Search Google Scholar
    • Export Citation
  • 42

    Spetzler RF, & Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 65:476483, 1986

  • 43

    Sundt TM Jr, , Piepgras DG, & Stevens LN: Surgery for supratentorial arteriovenous malformations. Clin Neurosurg 37:49115, 1991

  • 44

    van Beijnum J, , van der Worp HB, , Buis DR, , Al-Shahi Salman R, , Kappelle LJ, & Rinkel GJ, : Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA 306:20112019, 2011

    • Search Google Scholar
    • Export Citation
  • 45

    van Rooij WJ, , Sluzewski M, & Beute GN: Brain AVM embolization with Onyx. AJNR Am J Neuroradiol 28:172178, 2007

  • 46

    Weber W, , Kis B, , Siekmann R, & Kuehne D: Endovascular treatment of intracranial arteriovenous malformations with onyx: technical aspects. AJNR Am J Neuroradiol 28:371377, 2007

    • Search Google Scholar
    • Export Citation
  • 47

    Xu F, , Ni W, , Liao Y, , Gu Y, , Xu B, & Leng B, : Onyx embolization for the treatment of brain arteriovenous malformations. Acta Neurochir (Wien) 153:869878, 2011

    • Search Google Scholar
    • Export Citation
  • 48

    Yamamoto M, , Jimbo M, , Hara M, , Saito I, & Mori K: Gamma knife radiosurgery for arteriovenous malformations: long-term follow-up results focusing on complications occurring more than 5 years after irradiation. Neurosurgery 38:906914, 1996

    • Search Google Scholar
    • Export Citation

If the inline PDF is not rendering correctly, you can download the PDF file here.

Contributor Notes

Correspondence Michael T. Lawton, Department of Neurological Surgery, University of California, San Francisco, 505 Parnassus Ave., M780, Box 0112, San Francisco, CA 94143-0112. email: michael.lawton@ucsf.edu.

INCLUDE WHEN CITING Published online February 6, 2015; DOI: 10.3171/2014.12.JNS14938.

DISCLOSURE This research was funded in part by NIH grants R01 NS034949 (to Dr. Young) and P01 NS044155 (to the Center for Cerebrovascular Research).

  • 1

    Abud DG, , Riva R, , Nakiri GS, , Padovani F, , Khawaldeh M, & Mounayer C: Treatment of brain arteriovenous malformations by double arterial catheterization with simultaneous injection of Onyx: retrospective series of 17 patients. AJNR Am J Neuroradiol 32:152158, 2011

    • Search Google Scholar
    • Export Citation
  • 2

    Blackburn SL, , Ashley WW Jr, , Rich KM, , Simpson JR, , Drzymala RE, & Ray WZ, : Combined endovascular embolization and stereotactic radiosurgery in the treatment of large arteriovenous malformations. J Neurosurg 114:17581767, 2011

    • Search Google Scholar
    • Export Citation
  • 3

    Dalyai R, , Theofanis T, , Starke RM, , Chalouhi N, , Ghobrial G, & Jabbour P, : Stereotactic radiosurgery with neoadjuvant embolization of larger arteriovenous malformations: an institutional experience. Biomed Res Int 2014:306518, 2014

    • Search Google Scholar
    • Export Citation
  • 4

    Davidson AS, & Morgan MK: How safe is arteriovenous malformation surgery? A prospective, observational study of surgery as first-line treatment for brain arteriovenous malformations. Neurosurgery 66:498505, 2010

    • Search Google Scholar
    • Export Citation
  • 5

    Davies JM, , Kim H, , Young WL, & Lawton MT: Classification schemes for arteriovenous malformations. Neurosurg Clin N Am 23:4353, 2012

  • 6

    Ding D, , Yen CP, , Xu Z, , Starke RM, & Sheehan JP: Radiosurgery for low-grade intracranial arteriovenous malformations. J Neurosurg 121:457467, 2014

    • Search Google Scholar
    • Export Citation
  • 7

    Fokas E, , Henzel M, , Wittig A, , Grund S, & Engenhart-Cabillic R: Stereotactic radiosurgery of cerebral arteriovenous malformations: long-term follow-up in 164 patients of a single institution. J Neurol 260:21562162, 2013

    • Search Google Scholar
    • Export Citation
  • 8

    Friedman WA, , Bova FJ, , Bollampally S, & Bradshaw P: Analysis of factors predictive of success or complications in arteriovenous malformation radiosurgery. Neurosurgery 52:296308, 2003

    • Search Google Scholar
    • Export Citation
  • 9

    Gabarrós Canals A, , Rodríguez-Hernández A, , Young WL, & Lawton MT: Temporal lobe arteriovenous malformations: anatomical subtypes, surgical strategy, and outcomes. J Neurosurg 119:616628, 2013

    • Search Google Scholar
    • Export Citation
  • 10

    Gao K, , Yang XJ, , Mu SQ, , Li YX, , Zhang YP, & M, : Embolization of brain arteriovenous malformations with ethylene vinyl alcohol copolymer: technical aspects. Chin Med J (Engl) 122:18511856, 2009

    • Search Google Scholar
    • Export Citation
  • 11

    Hamilton MG, & Spetzler RF: The prospective application of a grading system for arteriovenous malformations. Neurosurgery 34:27, 1994

  • 12

    Hartmann A, , Stapf C, , Hofmeister C, , Mohr JP, , Sciacca RR, & Stein BM, : Determinants of neurological outcome after surgery for brain arteriovenous malformation. Stroke 31:23612364, 2000

    • Search Google Scholar
    • Export Citation
  • 13

    Heros RC, , Korosue K, & Diebold PM: Surgical excision of cerebral arteriovenous malformations: late results. Neurosurgery 26:570578, 1990

    • Search Google Scholar
    • Export Citation
  • 14

    Kano H, , Lunsford LD, , Flickinger JC, , Yang HC, , Flannery TJ, & Awan NR, : Stereotactic radiosurgery for arteriovenous malformations, Part 1: management of Spetzler-Martin Grade I and II arteriovenous malformations. J Neurosurg 116:1120, 2012

    • Search Google Scholar
    • Export Citation
  • 15

    Katsaridis V, , Papagiannaki C, & Aimar E: Curative embolization of cerebral arteriovenous malformations (AVMs) with Onyx in 101 patients. Neuroradiology 50:589597, 2008

    • Search Google Scholar
    • Export Citation
  • 16

    Koltz MT, , Polifka AJ, , Saltos A, , Slawson RG, , Kwok Y, & Aldrich EF, : Long-term outcome of Gamma Knife stereotactic radiosurgery for arteriovenous malformations graded by the Spetzler-Martin classification. J Neurosurg 118:7483, 2013

    • Search Google Scholar
    • Export Citation
  • 17

    Lawton MT: Seven AVMs: Tenets and Techniques for Resection New York, Thieme, 2014

  • 18

    Lawton MT: Spetzler-Martin Grade III arteriovenous malformations: surgical results and a modification of the grading scale. Neurosurgery 52:740749, 2003

    • Search Google Scholar
    • Export Citation
  • 19

    Lawton MT, , Kim H, , McCulloch CE, , Mikhak B, & Young WL: A supplementary grading scale for selecting patients with brain arteriovenous malformations for surgery. Neurosurgery 66:702713, 2010

    • Search Google Scholar
    • Export Citation
  • 20

    Maimon S, , Strauss I, , Frolov V, , Margalit N, & Ram Z: Brain arteriovenous malformation treatment using a combination of Onyx and a new detachable tip microcatheter, SONIC: short-term results. AJNR Am J Neuroradiol 31:947954, 2010

    • Search Google Scholar
    • Export Citation
  • 21

    Meder JF, , Oppenheim C, , Blustajn J, , Nataf F, , Merienne L, & Lefkoupolos D, : Cerebral arteriovenous malformations: the value of radiologic parameters in predicting response to radiosurgery. AJNR Am J Neuroradiol 18:14731483, 1997

    • Search Google Scholar
    • Export Citation
  • 22

    Mohr JP, , Moskowitz AJ, , Stapf C, , Hartmann A, , Lord K, & Marshall SM, : The ARUBA trial: current status, future hopes. Stroke 41:e537e540, 2010

    • Search Google Scholar
    • Export Citation
  • 23

    Mohr JP, , Parides MK, , Stapf C, , Moquete E, , Moy CS, & Overbey JR, : Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA): a multicentre, non-blinded, randomised trial. Lancet 383:614621, 2014

    • Search Google Scholar
    • Export Citation
  • 24

    Morgan MK, , Rochford AM, , Tsahtsarlis A, , Little N, & Faulder KC: Surgical risks associated with the management of Grade I and II brain arteriovenous malformations. Neurosurgery 54:832839, 2004

    • Search Google Scholar
    • Export Citation
  • 25

    Mounayer C, , Hammami N, , Piotin M, , Spelle L, , Benndorf G, & Kessler I, : Nidal embolization of brain arteriovenous malformations using Onyx in 94 patients. AJNR Am J Neuroradiol 28:518523, 2007

    • Search Google Scholar
    • Export Citation
  • 26

    Nataf F, , Schlienger M, , Bayram M, , Ghossoub M, , George B, & Roux FX: Microsurgery or radiosurgery for cerebral arteriovenous malformations? A study of two paired series. Neurosurgery 61:3950, 2007

    • Search Google Scholar
    • Export Citation
  • 27

    Panagiotopoulos V, , Gizewski E, , Asgari S, , Regel J, , Forsting M, & Wanke I: Embolization of intracranial arteriovenous malformations with ethylene-vinyl alcohol copolymer (Onyx). AJNR Am J Neuroradiol 30:99106, 2009

    • Search Google Scholar
    • Export Citation
  • 28

    Pérez-Higueras A, , López RR, & Tapia DQ: Endovascular treatment of cerebral AVM: our experience with onyx. Interv Neuroradiol 11:Suppl 1 141157, 2005

    • Search Google Scholar
    • Export Citation
  • 29

    Pierot L, , Cognard C, , Herbreteau D, , Fransen H, , van Rooij WJ, & Boccardi E, : Endovascular treatment of brain arteriovenous malformations using a liquid embolic agent: results of a prospective, multicentre study (BRAVO). Eur Radiol 23:28382845, 2013

    • Search Google Scholar
    • Export Citation
  • 30

    Pierot L, , Januel AC, , Herbreteau D, , Barreau X, , Drouineau J, & Berge J, : Endovascular treatment of brain arteriovenous malformations using onyx: results of a prospective, multicenter study. J Neuroradiol 36:147152, 2009

    • Search Google Scholar
    • Export Citation
  • 31

    Pierot L, , Kadziolka K, , Litré F, & Rousseaux P: Combined treatment of brain AVMs with use of Onyx embolization followed by radiosurgery. AJNR Am J Neuroradiol 34:13951400, 2013

    • Search Google Scholar
    • Export Citation
  • 32

    Pikus HJ, , Beach ML, & Harbaugh RE: Microsurgical treatment of arteriovenous malformations: analysis and comparison with stereotactic radiosurgery. J Neurosurg 88:641646, 1998

    • Search Google Scholar
    • Export Citation
  • 33

    Pollock BE, , Lunsford LD, , Kondziolka D, , Maitz A, & Flickinger JC: Patient outcomes after stereotactic radiosurgery for “operable” arteriovenous malformations. Neurosurgery 35:18, 1994

    • Search Google Scholar
    • Export Citation
  • 34

    Potts MB, , Young WL, & Lawton MT: Deep arteriovenous malformations in the basal ganglia, thalamus, and insula: microsurgical management, techniques, and results. Neurosurgery 73:417429, 2013

    • Search Google Scholar
    • Export Citation
  • 35

    Rodríguez-Hernández A, , Kim H, , Pourmohamad T, , Young WL, & Lawton MT: Cerebellar arteriovenous malformations: anatomic subtypes, surgical results, and increased predictive accuracy of the supplementary grading system. Neurosurgery 71:11111124, 2012

    • Search Google Scholar
    • Export Citation
  • 36

    Saatci I, , Geyik S, , Yavuz K, & Cekirge HS: Endovascular treatment of brain arteriovenous malformations with prolonged intranidal Onyx injection technique: long-term results in 350 consecutive patients with completed endovascular treatment course. J Neurosurg 115:7888, 2011

    • Search Google Scholar
    • Export Citation
  • 37

    Schaller C, & Schramm J: Microsurgical results for small arteriovenous malformations accessible for radiosurgical or embolization treatment. Neurosurgery 40:664674, 1997

    • Search Google Scholar
    • Export Citation
  • 38

    Schaller C, , Schramm J, & Haun D: Significance of factors contributing to surgical complications and to late outcome after elective surgery of cerebral arteriovenous malformations. J Neurol Neurosurg Psychiatry 65:547554, 1998

    • Search Google Scholar
    • Export Citation
  • 39

    Schwyzer L, , Yen CP, , Evans A, , Zavoian S, & Steiner L: Long-term results of gamma knife surgery for partially embolized arteriovenous malformations. Neurosurgery 71:11391148, 2012

    • Search Google Scholar
    • Export Citation
  • 40

    Sisti MB, , Kader A, & Stein BM: Microsurgery for 67 intracranial arteriovenous malformations less than 3 cm in diameter. J Neurosurg 79:653660, 1993

    • Search Google Scholar
    • Export Citation
  • 41

    Song D, , Leng B, , Gu Y, , Zhu W, , Xu B, & Chen X, : Clinical analysis of 50 cases of BAVM embolization with Onyx, a novel liquid embolic agent. Interv Neuroradiol 11:Suppl 1 179184, 2005

    • Search Google Scholar
    • Export Citation
  • 42

    Spetzler RF, & Martin NA: A proposed grading system for arteriovenous malformations. J Neurosurg 65:476483, 1986

  • 43

    Sundt TM Jr, , Piepgras DG, & Stevens LN: Surgery for supratentorial arteriovenous malformations. Clin Neurosurg 37:49115, 1991

  • 44

    van Beijnum J, , van der Worp HB, , Buis DR, , Al-Shahi Salman R, , Kappelle LJ, & Rinkel GJ, : Treatment of brain arteriovenous malformations: a systematic review and meta-analysis. JAMA 306:20112019, 2011

    • Search Google Scholar
    • Export Citation
  • 45

    van Rooij WJ, , Sluzewski M, & Beute GN: Brain AVM embolization with Onyx. AJNR Am J Neuroradiol 28:172178, 2007

  • 46

    Weber W, , Kis B, , Siekmann R, & Kuehne D: Endovascular treatment of intracranial arteriovenous malformations with onyx: technical aspects. AJNR Am J Neuroradiol 28:371377, 2007

    • Search Google Scholar
    • Export Citation
  • 47

    Xu F, , Ni W, , Liao Y, , Gu Y, , Xu B, & Leng B, : Onyx embolization for the treatment of brain arteriovenous malformations. Acta Neurochir (Wien) 153:869878, 2011

    • Search Google Scholar
    • Export Citation
  • 48

    Yamamoto M, , Jimbo M, , Hara M, , Saito I, & Mori K: Gamma knife radiosurgery for arteriovenous malformations: long-term follow-up results focusing on complications occurring more than 5 years after irradiation. Neurosurgery 38:906914, 1996

    • Search Google Scholar
    • Export Citation

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