Small Cerebral Aneurysms: Can We Identify Patients at Risk for Rupture?

Although the prevalence of unruptured intracranial aneurysms (UIAs) is 1% to 3% in the general population, it exceeds 19% in high-risk groups (1, 2). These aneurysms may produce a devastating form of stroke by rupturing and producing subarachnoid hemorrhage. Although subarachnoid hemorrhage accounts for a small percentage of strokes, it represents nearly 25% of potential life-years lost through stroke because of its predilection for a relatively young population and the poor outcomes in these patients (2, 3). Because of imaging improvements and availability, small UIAs are increasingly diagnosed (4). Optimal management of these lesions remains unclear because of heterogeneity in patient and aneurysm risk factors. In their article, Malhotra and colleagues (5) review the literature to determine the risk for growth and rupture of small UIAs (7 mm). They included 26 studies in their final analysis and concluded that poor-quality evidence suggests that small UIAs have low growth and rupture rates and that very small UIAs have little or no risk for rupture. The authors should be commended for their detailed review and attempts to define the risks of UIAs. The question they aimed to answer is important, because most UIAs are smaller than 7 mm, but the poor quality of available data makes answering the question challenging. No data from randomized studies have compared outcomes of treated and untreated UIAs. The Trial on Endovascular Aneurysm Management, the first randomized controlled trial comparing treatment with natural history (6), was terminated early because of low patient enrollment and ethical concerns. Randomly assigning patients to treatment or observation seems infeasible; therefore, available evidence is limited to observational studies. Malhotra and colleagues (5) found that the annual growth rate for aneurysms 7 mm or smaller was less than 3% in all but 1 study. Previous studies found that aneurysms may have 3 natural patterns: no growth, slow growth, and rapid growth. Aneurysms entered into natural history studies are low risk for growth and rupture, high risk for intervention, or both. Aneurysms that are treated or that rupture are often removed from growth studies, further decreasing the observed growth rates to that of low-risk, preselected aneurysms. In the subset of UIAs smaller than 7 mm assessed by Wermer and colleagues, 37 of 403 aneurysms (9%) enlarged (7). Predictors of growth included size, dome-to-neck ratio greater than 1, posterior circulation location, and multilobularity. Across studies, assessing growth rates is challenging because of variable definitions of growth, which is even more difficult to determine in small aneurysms. In addition, studies used diverse imaging techniques (magnetic resonance, computed tomography, or cerebral angiography) and follow-up intervals. The American Heart Association/American Stroke Association's 2015 guidelines recommend a first follow-up study at 6 to 12 months after aneurysm discovery, with additional follow-up yearly or every other year (class IIb; level of evidence C) but offer no specific recommendations for small UIAs (2). Malhotra and colleagues (5) found the annual rupture rate for aneurysms 3 mm or smaller, 3 to 5 mm, and 5 to 7 mm to be 0%, less than 0.5%, and less than 1%, respectively. Determining the risk for aneurysm rupture is as challenging as determining growth rate. The Natural Course of Unruptured Cerebral Aneurysms study was one of the largest prospective observational studies to attempt to determine the natural history of UIAs (8). Again, patients deemed at high risk for rupture, low risk for treatment, or both were excluded. The study began with 6697 aneurysms, but 3050 were removed and treated, likely because of aneurysm progression or change in patient preference, leaving an even smaller cohort of low-risk patients in whom to determine the natural history. In addition, only 1969 aneurysms were still available for study at 3-year follow-up. Patients excluded because of intervention were younger and were more likely to have a history of smoking, hyperlipidemia, a personal or family history of subarachnoid hemorrhage, and symptoms of mass effect or embolic episodes. Treated aneurysms also differed substantially by size, location, and presence of a daughter sac. The annual rupture rate of 5- to 6-mm aneurysms was 1.1%. In addition, those that had a daughter sac and were located in the posterior or anterior communicating artery were more likely to rupture. Follow-up is another concern in the studies included in the review. Only 1 previous study included long-term follow-up (9). A total of 142 patients with 181 UIAs were followed prospectively until rupture or death, with a median interval of 21 years (range, 0.8 to 52.3 years). Mean size of ruptured aneurysms was 5.64. 8 mm. Of the 96 patients with small UIAs (<7 mm), 24 (25%) had an aneurysmal subarachnoid hemorrhage during follow-up. In addition, 4 patients had subarachnoid hemorrhage from an aneurysm that was not present originally, highlighting the risk for further aneurysm formation. In the International Study of Unruptured Intracranial Aneurysms, the observed risk for rupture of 3- to 7-mm aneurysms was 0% (10). However, the actual risk for rupture of aneurysms less than 7 mm is not 0%, because the vast majority of ruptured aneurysms in clinical practice are smaller than 7 mm. Again, an 80-year-old patient with a calcified ophthalmic artery aneurysm was more likely to be enrolled than a 20-year-old patient with a 5-mm aneurysm in the anterior communicating artery, a history of smoking, uncontrolled hypertension, and familial subarachnoid hemorrhage. One should not conclude from this study that small aneurysms have no risk for rupture but rather that experts are skilled at predicting which aneurysms are more likely to rupture. Thus, all patients with aneurysms should be evaluated by an expert who can review associated risk factors and determine both the optimal follow-up plan (if any) and the need for treatment. The consequences of observation (or no observation) may be serious, because the mortality rate is approximately 50% in patients with a ruptured aneurysm. Although ethical concerns likely will continue to preclude a randomized clinical trial, the review by Malhotra and colleagues (5) should prompt better prospective observational studies.