Neurosurg. Focus / Volume 26 / May 2009 Neurosurg Focus 26 (5):E2, 2009 1 AneurysmAland SAH continues to have high rates of morbidity mortality for patients despite op- timal medical and surgical management.18 Con- troversy exists regarding the prevalence of unruptured intracranial aneurysms with some studies reporting rates as high as 6.5% in the general population harboring these lesions.27 However, the vast experience of the neurovas- cular community would declare these estimates likely too high.30,31,43 Regardless, with the increasing use of noninvasive intracranial imaging, an increasing number of unruptured intracranial aneurysms are being inciden- tally discovered. The optimal procedural management of these lesions is still being debated, which can carry sig- nificant risk, with morbidity and mortality rates up to 10 and 2.5%, respectively.21,29 However, due to the fact that aneurysm rupture can be such a catastrophic event, preventive treatment is de- sirable for high-risk lesions. Many groups have sought to find conclusive data on the natural history of unruptured aneurysms. The ISUIA trial was designed and conducted to provide such information. The ISUIA concluded that aneurysms 7 mm in size in the anterior circulation have an annual rupture risk of 0-0.1% per year.42 This was markedly lower than previous estimates, and the trial drew heavy criticism.9,20,25,39 The main obstacle in evaluating cumulative risk of rupture over time is that ethically, patients with the high- est risk aneurysms cannot be left untreated. Thus, these estimates will likely underestimate the true aneurysm rupture risk. In response to this, most recent literature has focused on comparing anatomical and morphologi- cal characteristics of ruptured aneurysms to unruptured aneurysms with the goal of elucidating factors associated with a high risk of rupture. These studies have had many different designs, areas of focus, and varied conclusions. Given the variability of the literature evaluating un- ruptured aneurysms regarding basic patient population, clinical practice, and even aneurysm characteristics stud- ied, a meta-analysis is nearly impossible to perform. This review will instead focus on the various anatomical and morphological characteristics of aneurysms reported in the literature with an attempt to draw broad inferences and serve to highlight pressing questions for the future in our continued effort to improve clinical management of unruptured intracranial aneurysms. Unruptured intracranial aneurysms and the assessment of rupture risk based on anatomical and morphological factors: sifting through the sands of data Rohan R. LaLL, M.D., ChRistopheR s. eDDLeMan, M.D., ph.D., BeRnaRD R. BenDok, M.D., anD h. hunt BatjeR, M.D. Department of Neurological Surgery, Feinberg School of Medicine, Northwestern University, Chicago, Illinois Aneurysmal subarachnoid hemorrhage continues to have high rates of morbidity and mortality for patients de- spite optimal medical and surgical management. Due to the fact that aneurysmal rupture can be such a catastrophic event, preventive treatment is desirable for high-risk lesions. Given the variability of the literature evaluating unrup- tured aneurysms regarding basic patient population, clinical practice, and aneurysm characteristics studied, such as size, location, aspect ratio, relationship to the surrounding vasculature, and the aneurysm hemodynamics, a meta- analysis is nearly impossible to perform. This review will instead focus on the various anatomical and morphological characteristics of aneurysms reported in the literature with an attempt to draw broad inferences and serve to highlight pressing questions for the future in our continued effort to improve clinical management of unruptured intracranial aneurysms. (DOI: 10.3171/2009.2.FOCUS0921) key WoRDs ��� unruptured intracranial aneurysm ��� vascular location ��� rupture risk ��� ISUIA ��� aspect ratio 1 Abbreviations used in this paper: ACoA = anterior commu- nicating artery CFD = computational flow dynamics ISUIA = International Study of Unruptured Intracranial Aneurysms SAH = subarachnoid hemorrhage WSS = wall sheer stress.

R. Lall et al. 2 Neurosurg. Focus / Volume 26 / May 2009 Aneurysm Size and Location Two of the most basic features of intracranial aneu- rysms are their size and location. Consistently, investi- gators have reported that size is an unquestionable fac- tor with regard to rupture risk. Furthermore, posterior circulation aneurysms have been noted to rupture more frequently than similar aneurysms in the anterior circula- tion. However, despite decades of observation, few stud- ies have examined unruptured intracranial aneurysms in a prospective trial involving international centers and a heterogeneous population. The ISUIA was an attempt to elucidate the natural history of these lesions across an international population. The ISUIA published their first study in the New England Journal of Medicine in December 1998.2 The study was divided into 2 cohorts, which consisted of a retrospective cohort of observed un- ruptured aneurysms, designed to evaluate risk of rupture over time, and a prospective cohort, designed to evaluate surgical risk. The retrospective cohort had 1449 patients with 1937 aneurysms, nearly evenly divided into 2 groups. Group 1 had no history of prior SAH and Group 2 com- prised patients with prior SAH from another treated an- eurysmal lesion and had to be functioning independently. Risk of rupture for Group 1 patients for aneurysms 10 mm in size in the anterior circulation was 0.05% per year, compared with 0.5% annually for Group 2. Aneurysms 10 mm in size had a risk of rupture close to 1% an- nually in both groups. The prospective cohort enrolled 1172 patients undergoing treatment of their aneurysms. Surgical morbidity and mortality published in this study were notably higher than previously accepted rates. This study was widely quoted and used at the time by primary care physicians, but it was considered controversial by the neurosurgical community. The main criticism was in re- gard to patient selection. For the retrospective cohort, all patients receiving treatment within 30 days of diagnosis were excluded, and the number of these patients was not revealed. These aneurysms almost certainly comprised the highest risk group. Aneurysms in low-risk locations, such as the cavernous segment of the carotid artery, were over-represented. Furthermore, numerous patients sub- sequently died of intracranial hemorrhage of unknown origin, a suspicious diagnosis for patients with known aneurysms. Nevertheless, this study demonstrated that aneurysm size is an important risk factor for rupture. The ISUIA published a follow-up paper in The Lan- cet in July 2003.42 This report more closely evaluated rupture risk based on location and size, and specifically assessed surgical and endovascular treatment risks. The 5-year cumulative rupture rates for patients without prior SAH, with anterior circulation aneurysms (not including cavernous carotid or posterior communicating artery an- eurysms) were 0, 2.6, and 14.5% for aneurysms 7, 7���12, and 13���24 mm, respectively, compared with rates of 2.5, 14.5, and 18.4%, respectively, for the same size aneurysm in the posterior circulation (including posterior commu- nicating artery aneurysms). Patients with a history of pre- vious SAH with aneurysms 7 mm in size had a 0.1% yearly rupture rate. This study had many of the same limitations and criticisms as the first ISUIA study.21,40 Despite reporting results that were not consistent with numerous studies in the literature regarding rupture risk of unruptured intracranial aneurysms, the ISUIA data provided the first large, international, prospective data set that practitioners could use in their discussions with pa- tients and their families. However, many other studies, although not involv- ing as many patients as those of the ISUIA reports, have been published regarding aneurysmal rupture risk, whose results have been marketed as challenging the ISUIA re- sults. More specifically, Juvela et al.19 published their ac- count of the cumulative aneurysm rupture risk in Finnish patients with long-term follow-up in which 142 patients with 182 aneurysms were evaluated and were found to have a rupture rate of 1.3% per year. A significant ob- servation in this study was that the majority of ruptured aneurysms were 7 mm, in contrast to the findings of the ISUIA.42 They also noted that larger aneurysms had a linearly increasing relative risk compared with smaller aneurysms. With respect to aneurysm location, ACoA an- eurysms were found to have a higher ratio of ruptured to unruptured aneurysms than other locations. The rupture rates quoted by Juvela and colleagues were closer to those published in previous large studies of the natural history of unruptured intracranial aneurysms during the 1980s.15,43 The reported rate was also more equivalent with 2 previ- ous Japanese reports noting annual rupture rates of 1.5 TABLE 1: Comparison studies of the sizes of ruptured versus unruptured intracranial aneurysms* Mean Size (mm) Authors & Year No. of Patients No. of Aneurysms Unruptured Ruptured p Value Baumann et al., 2008 99 265 4 7 0.0001 Beck et al., 2003 118 155 5.7 6.7 0.7 Nader-Sepahi et al., 2004 75 182 4.9 7.7 0.001 Juvela et al., 2008 142 181 4.9 5.6 nc Hoh et al., 2007 30 67 4.3 6.2 0.004 Weir et al., 2003 945 507 7.8 10.8 0.001 Weir et al., 2002 532 774 7 8 nc Sadatomo et al., 2008 41 44 5.6 7.2 0.11 * Patients had single, multiple, or mixed aneurysms. Abbreviation: nc = not calculated.