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Commentary: Unruptured Brain Arteriovenous Malformations: What a Tangled Web They Weave In this report, the authors outline results from the Scottish Intracranial Vascular Malformations Study (SIVMS), a populationbased cohort study collecting information prospectively from a National Health Service database of adult (age .16 years) patients diagnosed with an unruptured brain arteriovenous malformation (AVM) in 2 epochs, 1999 to 2003 and 2006 to 2010.1 The authors aim to compare intervention (using any treatment modality alone or in combination) with conservative management. Some methodological weaknesses in this observational study are noteworthy. Assessment of clinical outcome events was performed independently by 2 investigators, but does not appear to have been blinded to intervention or conservative therapy, as is typically routine to avoid assessment bias. Ascertainment of disability, based on the Oxford Handicap Scale (OHS), was performed based on review of records, rather than in-person assessment, reducing reliability. Furthermore, an OHS score of 2 (defined as “some restriction to lifestyle, but the patient can look after themselves”) was included as a poor outcome in this analysis, representing a higher than usual threshold for favorable outcome. Given the observational nature of the study, patients were selected for treatment or conservative therapy based on unknown and uncontrolled factors; in this scenario the selection bias would typically be towards choosing conservative therapy for patients clinically perceived at low risk from observation. The significantly lower proportion of symptomatic patients in the observed cohort would tend to support the existence of this form of bias. In assessing outcome, OHS score of 2 to 6, including death, was used as the primary outcome. This was only considered the outcome if sustained for .2 years, although the OHS on presentation was not taken into account, which is notable since only about 2/3 of patients were enrolled with scores of 0 to 1. The secondary outcome of nonfatal symptomatic stroke included any neurological deficit attributable to the AVM or treatment lasting more than 24 hours. Included in the analysis were 204 patients: 103 with intervention, 101 undergoing observation. The treated cohort was noted to be, on average, younger (41 vs 53 years old), more frequently presenting with seizure, and less frequently with very large AVMs. Spetzler-Martin grade was only specified for 46 of the observed cases; the remaining observed patients did not undergo catheter angiography, which raises some concern regarding accuracy of diagnosis, and the possibility of more benign malformations such as developmental venous anomalies or cavernomas included in the observation cohort. This is potentially highlighted by 2 of the 101 patients in the conservative cohort being described as having “spontaneous AVM resolution,” an otherwise decidedly rare phenomenon amongst true AVMs.

NEUROSURGERY

COMMENTARY

The follow-up period was a median of 6.9 years. Although the authors emphasize up to 12 years as the follow-up interval, only a small proportion of patients actually achieved prolonged followup, thereby limiting the power of statistical analysis at the long-term outcome. This is particularly important, as the primary outcome is reported as developing less frequently in the observation group in the first 4 years (just reaching significance with an adjusted hazard ratio (HR) of 0.59 and 95% confidence interval [CI] of 0.35 to 0.99). By the last 4 years of follow-up, the adjusted HR is actually far in favor of intervention at 4.7, but with a lack of power to achieve significance due to small sample size. Furthermore, the number of definite and possible AVM-related deaths was appreciably higher in the observation group at 11/101 vs 4/103 (P ¼ .06). In reviewing the survival curve globally, progression to primary outcome occurred more frequently in the first years of follow-up, but the curves cross at about 6 years and actually diverge by year 12 in favor of intervention. This would be very much in line with expected course of most interventions, namely, an “up front” risk in order to gain a long-term benefit. Although the secondary outcome was more frequent in the intervention group, this was primarily due to the most insubstantial component of the outcome, defined as “any neurological deficit lasting more than 24 hours,” rather than actual hemorrhages and infarction. Ultimately, the short-term results of this observational study and the randomized ARUBA trial (A Randomized Trial of Unruptured Brain Arteriovenous Malformations)2 concur in their conclusions, but are similarly “barking up the wrong tree.” Both studies are posing the question “Should unruptured AVMs be treated?” by looking at a heterogeneous group of AVMs treated with a mixture of differing therapies, and focused on proximate rather than lifetime outcomes. In this study in particular, the intended goal of intervention is not discernable—partial treatments to palliate symptoms vs intended obliteration cannot be differentiated, and would impact outcome very differently. Rather, the more relevant and meaningful question of “Which unruptured AVM should be treated, and with which modality?” is ignored. If appropriately planned and analyzed, a careful observational study could help uncover lesion and intervention features, which would inform AVM management in a more meaningful way, rather than posit blanket conclusions against intervention. Disclosure The authors have no personal, financial, or institutional interest in any of the drugs, materials, or devices described in this article.

Sepideh Amin-Hanjani, MD Chicago, Illinois Felipe C. Albuquerque, MD Phoenix, Arizona Gavin Britz, MD, MPH Houston, Texas

VOLUME 75 | NUMBER 2 | AUGUST 2014 | 195

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COMMENTARY

E. Sander Connolly, MD New York, New York Murat Gunel, MD New Haven, Connecticut Sean D. Lavine, MD New York, New York Michael T. Lawton, MD San Francisco, California Joel MacDonald, MD Salt Lake City, Utah Christopher S. Ogilvy, MD Boston, Massachusetts

196 | VOLUME 75 | NUMBER 2 | AUGUST 2014

Charles J. Prestigiacomo, MD Newark, New Jersey

1. Al-Shahi Salman R, White PM, Counsell CE, et al. Outcome after conservative management or intervention for unruptured brain arteriovenous malformations. JAMA. 2014;311(16):1661-1669. 2. Mohr JP, 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. Lancet. 2014;383(9917):614-621. 10.1227/NEU.0000000000000418

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Commentary: unruptured brain arteriovenous malformations: what a tangled web they weave.

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