Murat Gunel and colleagues report a genome-wide association study for intracranial aneurysm and identify risk variants near RBBP8, CNNM and STARD13. Saccular intracranial aneurysms are balloon-like dilations of the intracranial arterial wall; their hemorrhage commonly results in severe neurologic impairment and death. We report a second genome-wide association study with discovery and replication cohorts from Europe and Japan comprising 5,891 cases and 14,181 controls with ∼832,000 genotyped and imputed SNPs across discovery cohorts. We identified three new loci showing strong evidence for association with intracranial aneurysms in the combined dataset, including intervals near RBBP8 on 18q11.2 (odds ratio (OR) = 1.22, P = 1.1 × 10−12), STARD13-KL on 13q13.1 (OR = 1.20, P = 2.5 × 10−9) and a gene-rich region on 10q24.32 (OR = 1.29, P = 1.2 × 10−9). We also confirmed prior associations near SOX17 (8q11.23–q12.1; OR = 1.28, P = 1.3 × 10−12) and CDKN2A-CDKN2B (9p21.3; OR = 1.31, P = 1.5 × 10−22). It is noteworthy that several putative risk genes play a role in cell-cycle progression, potentially affecting the proliferation and senescence of progenitor-cell populations that are responsible for vascular formation and repair.

Background and Purpose—: The aim of this study is to assess whether the PHASES score allows to (1) match decisions taken by multidisciplinary team whether to observe or intervene, (2) classify patients being diagnosed with a ruptured versus unruptured intracranial aneurysm (UIA), and (3) discriminate patients at low risk of rupture from the population of patients diagnosed with intracranial aneurysm. Methods—: Population-based prospective and consecutive data were collected between 2006 and 2014. Patients (n=841) were stratified into 4 groups: stable UIA; growing observed UIA; immediately treated UIA; and aneurysmal subarachnoid hemorrhage (aSAH). All patients initially observed were pooled in a follow-up UIA group; patients from growing observed UIA, immediately treated UIA, and aSAH were pooled in a high risk of rupture group. Results are expressed as median [quartile 1, quartile 3]. Results—: PHASES scores of immediately treated UIA patients were significantly higher than follow-up UIA group (5 [3, 7] versus 2 [1, 4]). Patients diagnosed with UIA and PHASES score of >3 were more likely to be treated, and the score ≤3 was predictive for observation (areas under these curves=0.74). Odds of being diagnosed with an aSAH were associated with PHASES score of >3 (UIA, 4 [2, 6]; aSAH, 5 [4, 8]; areas under these curves=0.66). Scores of stable UIA patients were significantly lower than high risk of rupture group (2 [1, 4] versus 5 [4, 7]; stable UIA outcome prediction by PHASES score of ≤3: areas under these curves=0.76). Conclusions—: There is a progression of PHASES score between stable UIA, growing observed UIA, immediately treated UIA, and aSAH groups. PHASES score of ≤3 is associated with a low but not negligible likelihood of aneurysm rupture, and specificity of the classifier is low.

Blood blister-like aneurysms (BBAs) are a controversial entity. They arise from non-branching sites on the supraclinoid internal carotid artery (ICA) and are suspected to originate from a dissection. Our aim is to describe the BBA cases seen in our center and to present a systematic review of the literature on BBAs. We analyzed the eleven cases of BBA admitted to our center from 2003 to 2012. We assessed the medical history, treatment modality (endovascular and/or surgery), complications and clinical outcome. The cohort included 8 women and 4 men with a mean age of 53.16 years. Treatment of the BBA consisted of stenting and coiling in 5 patients, stenting only in 4 patients, coiling and clipping in 1 patient, clipping only in 1 patient, and conservative treatment in 1 patient. A good outcome was found in 10 patients, as defined by a modified Rankin Scale (mRS) less than or equal to two at three months. A systematic review of the literature was performed, and 314 reported patients were found: 221 patients were treated with a primarily surgical approach, and 87 patients were treated with a primarily endovascular approach. A rescue or second treatment was required in 46 patients (21%). The overall estimated treatment morbidity rate was 17%, and the mortality rate was 15%. BBAs exhibit more aggressive behavior compared to saccular aneurysms, and more intra-operative complications occur with BBAs, independent of the treatment type offered. They are also significantly more likely to relapse and rebleed after treatment. Endovascular treatment offers a lower morbidity-mortality compared with surgical approaches. Multilayer flow-diverting stents appear to be a promising strategy.

Background and Purpose—: According to the International Study of Unruptured Intracranial Aneurysms (ISUIA), anterior circulation (AC) aneurysms of <7 mm in diameter have a minimal risk of rupture. It is general experience, however, that anterior communicating artery (AcoA) aneurysms are frequent and mostly rupture at <7 mm. The aim of the study was to assess whether AcoA aneurysms behave differently from other AC aneurysms. Methods—: Information about 932 patients newly diagnosed with intracranial aneurysms between November 1, 2006, and March 31, 2012, including aneurysm status at diagnosis, its location, size, and risk factors, was collected during the multicenter @neurIST project. For each location or location and size subgroup, the odds ratio (OR) of aneurysms being ruptured at diagnosis was calculated. Results—: The OR for aneurysms to be discovered ruptured was significantly higher for AcoA (OR, 3.5 [95% confidence interval, 2.6–4.5]) and posterior circulation (OR, 2.6 [95% confidence interval, 2.1–3.3]) than for AC excluding AcoA (OR, 0.5 [95% confidence interval, 0.4–0.6]). Although a threshold of 7 mm has been suggested by ISUIA as a threshold for aggressive treatment, AcoA aneurysms <7 mm were more frequently found ruptured (OR, 2.0 [95% confidence interval, 1.3–3.0]) than AC aneurysms of 7 to 12 mm diameter as defined in ISUIA. Conclusions—: We found that AC aneurysms are not a homogenous group. Aneurysms between 4 and 7 mm located in AcoA or distal anterior cerebral artery present similar rupture odds to posterior circulation aneurysms. Intervention should be recommended for this high-risk lesion group.

The pathogenesis of intracranial aneurysm (IA) formation and rupture is complex, with significant contribution from genetic factors. We previously reported genome-wide association studies based on European discovery and Japanese replication cohorts of 5,891 cases and 14,181 controls that identified five disease-related loci. These studies were based on testing replication of genomic regions that contained SNPs with posterior probability of association (PPA) greater than 0.5 in the discovery cohort. To identify additional IA risk loci, we pursued 14 loci with PPAs in the discovery cohort between 0.1 and 0.5. Twenty-five SNPs from these loci were genotyped using two independent Japanese cohorts, and the results from discovery and replication cohorts were combined by meta-analysis. The results demonstrated significant association of IA with rs6841581 on chromosome 4q31.23, immediately 5′ of the endothelin receptor type A with P = 2.2 × 10 ⁻⁸ [odds ratio (OR) = 1.22, PPA = 0.986]. We also observed substantially increased evidence of association for two other regions on chromosomes 12q22 (OR = 1.16, P = 1.1 × 10 ⁻⁷ , PPA = 0.934) and 20p12.1 (OR = 1.20, P = 6.9 × 10 ⁻⁷ , PPA = 0.728). Although endothelin signaling has been hypothesized to play a role in various cardiovascular disorders for over two decades, our results are unique in providing genetic evidence for a significant association with IA and suggest that manipulation of the endothelin pathway may have important implications for the prevention and treatment of IA.