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Surgery Editorial Management of Unruptured Brain Arteriovenous Malformations Andrew F Ducruet, MD 1 and Robert M Friedlander, MD, MA 2 1. Assistant Professor of Neurological Surgery; 2. Chairman and Walter E Dandy Professor of Neurological Surgery, Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, Philadelphia, US Abstract Brain arteriovenous malformations (bAVMs) portent a lifelong risk of hemorrhage but the treatment of these lesions may also be associated with significant morbidity. Two recent high-profile studies have suggested that patients undergoing treatment of bAVMs may suffer a worse outcome than patients managed conservatively. However, both of these studies suffer from significant limitations that limit the conclusions that can be drawn. Further work, including the establishment of a prospective registry, is necessary to definitively address this matter. Keywords Brain, arteriovenous, malformation, embolization, radiosurgery, resection, rupture Disclosure: Andrew F Ducruet, MD, and Robert M Friedlander, MD, MA, have no conflicts of interests to declare. No funding was received for the publication of this article. Received: September 15, 2014 Accepted: September 19, 2014 Citation: US Neurology, 2014;10(2):120–1 Correspondence: Robert M Friedlander, MD, MA, UPMC Presbyterian Hospital, 200 Lothrop Street, Suite B-400, Pittsburgh, PA 15213, USA. E: Brain arteriovenous malformations (bAVMs) are rare congenital lesions that confer a lifelong risk for hemorrhage. Treatment options for these lesions include microsurgical resection, embolization, and radiosurgery, alone or in combination. The goal of bAVM intervention is to eliminate the risk for future hemorrhage, which must mean complete obliteration of the lesion. However, treatment also poses a risk for morbidity and morbidity. Two recent high-profile studies compared outcomes between patients with bAVMs treated with multimodality therapy with those managed conservatively. 1,2 Although both studies on the surface demonstrate worse outcome following intervention, they both have significant limitations, which preclude the conclusion that conservative management is superior to intervention in patients with bAVMs. The primary results of the Medical management with or without interventional therapy for unruptured brain arteriovenous malformations (ARUBA) trial were recently published. 1 This multicentered international randomized trial compared interventional treatment to medical management for unruptured bAVMs. The primary endpoint of the study was symptomatic stroke or death, with a secondary outcome of death and disability measured by the modified Rankin scale (mRS). The trial was initially designed to include 800 patients, however, the target sample size was later reduced to 400 and the trial was halted after only 223 subjects were randomized. Of the 109 patients in the medical group, 10.1  % experienced the primary endpoint compared with 30.7  % in the interventional group (30.7 %). A significantly lower proportion of patients in the medical group (15 %) also demonstrated an mRS ≥2 versus 46 % in the interventional group. 120 Interpretation of these results is complicated by several limitations in trial design and execution. First, relatively slow patient enrollment engendered a significant selection bias. Of the 66 centers listed as participating, only 39 ultimately enrolled patients. Because of the low enrollment for each center, including some centers with large bAVM practices, many patients were treated outside the trial. A careful review of screening logs is thus required to understand how the patients that were treated outside the trial differed from those that were enrolled. It is likely that bAVMs with a perceived low treatment risk would be preferentially treated and ones with more benign natural history may have been randomized. These two would result in a preferential bias of randomizing bAVMs with perceived higher treatment risk as well as ones with a more benign natural history. Second, centers that treat as few as 10 bAVMs per year among all practitioners were allowed to participate in the trial without further rigorous accreditation. This is a critical limitation, as the relationship between volume and outcome has been repeatedly and convincingly demonstrated in cerebrovascular surgery. 3 Perhaps because of a relative lack of experience at the enrolling centers, no clear standardization in intervention was seen. In fact, only five patients underwent surgery alone, which is generally regarded as the gold standard treatment for low-grade bAVMs—perhaps because many centers may not have had access to a neurosurgeon to resect these lesions. A high number of patients were treated by standalone embolization (30 patients), which has been shown to yield a low rate of complete occlusion and potentially a high rate of complications. Finally, and perhaps most importantly, the trial was interrupted after only a short follow-up interval (mean of 33 months). Given the annual 2.2 % hemorrhage rate in the medical group, coupled with an average age of patients of 44 years in the interventional group, a © TOU C H ME D ICA L ME D IA 2014