There are no data from randomized studies comparing treatment outcome with the natural history of unruptured intracranial aneurysms (UIAs). The rates of hemorrhage in UIAs are controversial and limited by the complexity of patient and aneurysm characteristics as well as the significant bias associated with the available literature. The Trial on Endovascular Aneurysm Management (TEAM) was the first prospective randomized, controlled trial to compare endovascular treatment of UIs with the natural history.1 The primary outcome suggested was morbidity and mortality from rupture intervention. Secondary endpoints included hemorrhage, morbidity, complication rates, and overall outcome and quality of life. The study was ultimately terminated due to low patient enrollment and ethical concerns. Randomization of patients to treatment and observation may not be possible and available literature is limited to observational studies. The point of equipoise between risks of treatment and risk of rupture is commonly confounded by the high incidence of rupture of small intracranial aneurysms in clinical practice and studies on subarachnoid hemorrhage (SAH) despite the low rate of rupture found in observational studies of UIAs.
Early observational studies by Juvela et al found an average annual risk of rupture of 1.3% with cigarette smoke, aneurysm size, and younger age at diagnosis as important predictors of rupture.2 In this cohort, 131 of 142 patients had a previously treated aneurysm following SAH; an additional unruptured aneurysm was followed over time. Thus even early observational studies that sought to assess rates of rupture, primarily assessed patients deemed to be at lower risk of hemorrhage.
In the International Study of Unruptured Intracranial Aneurysm (ISUIA) centers from USA, Canada, and Europe enrolled patients for prospective evaluation of hemorrhage and morbidity and mortality in treated patients.3,4 In 2003, 5-year follow up was reported for the 1692 patients observed, 1917 patients treated with open microsurgery, and 451 patients treated with endovascular procedures. Five-year cumulative rates of hemorrhage in patients without history of prior SAH for aneurysms located in internal carotid artery, anterior communicating or anterior cerebral artery, or middle cerebral artery were 0%, 2.6%, 14.5%, and 40% for aneurysms less than 7 mm, 7 mm to 12 mm, 13 mm to 24 mm, and 25 mm or greater, respectively, compared with rates of 2.5%, 14.5%, 18.4%, and 50%, respectively, for the same size categories involving posterior circulation and posterior communicating artery aneurysms. Patients' age and aneurysm size and location were strong predictors of outcome. Despite the large number of patients included, a larger sample size would be necessary to allow for assessment of rupture risk according to specific aneurysm location.
Recently, results of the natural history of Unruptured Cerebral Aneurysms Study (UCAS) in Japan were published.5 The study followed a similar overall design as the ISUIA. From 2001 to 2004 information was collected on 5720 patients 20 years of age or older (mean age, 62.5 years; 68% women) who had saccular aneurysms that were 3 mm or more in the largest dimension and who initially presented with no more than a slight disability. The projected study was powered according to the hypothesis that unruptured cerebral aneurysms of 5 mm or more rupture at an annual rate of more than 0.5%. To reject the null hypothesis the authors estimated that an enrollment period of 3 years with 3 years of follow up would be necessary.
Of the 6697 aneurysms studied, 91% were discovered incidentally. The mean (±SD) size of the aneurysms was 5.7 ± 3.6 mm, and the majority of aneurysms were located in the middle cerebral artery (36%) and internal carotid artery (34%). During the follow up period rupture occurred at an annual rate of 0.95% for the entire cohort. The annual rupture rate by location for those locations with at least 500 aneurysm-year observation was 0.26% for paraclinoid, 0.67% for MCA, 1.31% for Acom, 1.72% for Pcom and 1.90% for BA, all irrespective of size. The annual rupture rate by size for those with at least 500 aneurysm-year observation was 0.36% for 3 mm to 4 mm, 0.50% for 5 mm to 6 mm, 1.67% for 7 mm to 9 mm and 4.37% for 10 mm to 24 mm. Giant aneurysms were rare in the study (n = 34) with only 24 aneurysm-years of observation but the annual rupture risk was 33.40% (95% CI: 16.07-66.79%). Aneurysms that were partially thrombosed, calcified or had daughter sacs appeared to be at greater risk of rupture, as were those presenting with symptoms.
The authors should be commended for their impressive study and follow up. The larger sample size in this study allowed assessment of rupture rates amongst specific aneurysm locations. They confirmed prior notions that posterior and anterior communicating arteries aneurysm are more likely to rupture as compared to middle cerebral artery aneurysms, and aneurysms with a daughter sac were 1.6 times more likely to rupture. Additionally, the rate of rupture for small aneurysms was significantly higher than found by the ISUIA. This supports daily practice whereby most ruptured aneurysms are <10 mm, and prior trials where a majority of ruptured aneurysms were ≤5 mm.6
The authors also found that aneurysms were larger in older patients. This supports evidence that similar appearing aneurysms may have different natural histories. Some small aneurysms likely rupture soon after formation, while others reach period of slow growth or latency.
An alternative explanation is that larger aneurysms in younger patients were more likely to receive intervention. During the follow up period, 2722 patients with 3050 aneurysms underwent surgical repair before rupture of the aneurysm. Patient data was censored at time of repair and those receiving surgery significantly differed in nearly every patient and aneurysm attribute. As in the ISUIA and studies by Juvella et al, rates of rupture were assessed from untreated aneurysms deemed low risk. Thus the actual rates of rupture may be underestimated. Interpretation of these data also need to take into account the racial makeup of the patient population as studies of subarachnoid hemorrhage suggest racial and ethnic differences in the incidence of bleeding.7
Ultimately, it remains difficult to assess the external validity of the data as it relates to patients evaluated on a daily basis. Simple data on the risk of an asymptomatic 11 mm basilar apex aneurysm with a daughter sac even in this well done study are not available, as each characteristic reduces the overall number of observation years so significantly that the authors don't even bother reporting the confidence intervals. Information from observational studies supplies the rates of rupture in untreated patients that are deemed low risk of rupture and/or high risk for treatment. Despite large observational studies and advances in treatment of UIAs, the incidence of SAH has remained relatively unchanged in the last 20 years,8 in part, due to the small number of patients deemed at risk. The consequences of observation may be serious as the mortality rate is approximately 50% in patients with a ruptured aneurysm. A randomized clinical trial or comparative effectiveness review may be the only means to fully assess the risks of rupture of untreated UIAs, but patients and physicians are unlikely to tolerate a trial or come to an acceptable definition of equipoise.
1. Raymond J, Roy D, Weill A, et al.. Unruptured intracranial aneurysms and the Trial on Endovascular Aneurysm Management (TEAM): the principles behind the protocol. J Vasc Interv Neurol. 2008;1(1):22–26.
2. Juvela S, Porras M, Poussa K. Natural history of unruptured intracranial aneurysms: probability and risk factors for aneurysm rupture. Neurosurg Focus. 2000;8(5):Preview 1.
3. Unruptured intracranial aneurysms-risk of rupture and risks of surgical intervention. International Study of Unruptured Intracranial Aneurysms Investigators. N Engl J Med. 1998;339(24):1725–1733.
4. Wiebers DO, Whisnant JP, Huston J III, et al.. Unruptured intracranial aneurysms: natural history, clinical outcome, and risks of surgical and endovascular treatment. Lancet. 2003;362(9378):103–110.
5. Morita A, Kirino T, Hashi K, et al.. The natural course of unruptured cerebral aneurysms in a Japanese cohort. N Engl J Med. 2012;366(26):2474–2482.
6. Molyneux A, Kerr R, Stratton I, et al.. International Subarachnoid Aneurysm Trial (ISAT) of neurosurgical clipping versus endovascular coiling in 2143 patients with ruptured intracranial aneurysms: a randomised trial. Lancet. 2002;360(9342):1267–1274.
7. Vlak MH, Algra A, Brandenburg R, Rinkel GJ. Prevalence of unruptured intracranial aneurysms, with emphasis on sex, age, comorbidity, country, and time period: a systematic review and meta-analysis. Lancet Neurol. 2011;10(7):626–636.
8. Andaluz N, Zuccarello M. Recent trends in the treatment of cerebral aneurysms: analysis of a nationwide inpatient database. J Neurosurg. 2008;108(6):1163–1169.