7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Official reprint from UpToDate www.uptodate.com 2023 UpToDate, Inc. and/or its affiliates. All Rights Reserved. Unruptured intracranial aneurysms : Robert J Singer, MD, Christopher S Ogilvy, MD, Guy Rordorf, MD : Jos Biller, MD, FACP, FAAN, FAHA : Janet L Wilterdink, MD All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: Jun 2023. This topic last updated: Feb 11, 2020. INTRODUCTION Most subarachnoid hemorrhages (SAHs) are caused by ruptured intracranial saccular (berry) aneurysms [1-5]. The epidemiology and pathogenesis of intracranial aneurysms and the management of unruptured aneurysms are discussed here. The epidemiology, etiology, clinical manifestations, diagnosis, and treatment of SAH, and issues related to screening for aneurysms, are discussed separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis" and "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis" and "Screening for intracranial aneurysm".) EPIDEMIOLOGY The prevalence of intracranial saccular aneurysms by radiographic and autopsy series is estimated to be 3.2 percent in a population without comorbidity, a mean age of 50 years, and a 1:1 gender ratio [1,6,7]. Of patients with cerebral aneurysms, 20 to 30 percent have multiple aneurysms [8]. Aneurysmal subarachnoid hemorrhage (SAH) occurs at an estimated rate of 6 to 16 per 100,000 population [9]. In North America, this translates into approximately 30,000 affected persons per year. Thus, most aneurysms, particularly small aneurysms, do not rupture. (See 'Risk factors for aneurysm rupture' below.) Rupture of an intracranial aneurysm is believed to account for 0.4 to 0.6 percent of all deaths. Approximately 10 percent of patients die prior to reaching the hospital, and only one-third have https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 1/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate a "good result" after treatment. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) Most intracranial aneurysms (approximately 85 percent) are located in the anterior circulation, predominantly on the circle of Willis. Common sites include the junction of the anterior communicating artery with the anterior cerebral artery, the junction of the posterior communicating artery with the internal carotid artery, and the bifurcation of the middle cerebral artery. Posterior circulation sites often include the top of the basilar artery, the junction of the basilar artery and the superior or anterior inferior cerebellar arteries, and the junction of the vertebral artery and the posterior inferior cerebellar artery [10]. There is a female preponderance for aneurysms ranging from 54 to 61 percent [7,9]. In populations older than 50 years, the increased prevalence in women may approach a 2:1 ratio or greater. RISK FACTORS FOR ANEURYSM FORMATION Genetic factors The role for genetic factors in the pathogenesis of intracranial aneurysm formation is supported by studies that have found an increased risk in patients with some known hereditary syndromes and by the occurrence of aneurysms in families. A systematic review and meta-analysis confirmed a substantial genetic contribution to the occurrence of intracranial aneurysms that involve multiple pathophysiologic pathways, while noting that large- scale replication studies in a full spectrum of populations are needed with investigation on how specific genetic factors relate to aneurysm size, location, and risk of rupture [11]. Hereditary syndromes A known hereditary syndrome is often present when aneurysms are diagnosed in more than one family member. Heritable disorders associated with the presence of intracranial aneurysm include: Connective tissue diseases such as Ehlers-Danlos syndrome and pseudoxanthoma elasticum are associated with intracranial aneurysms [12,13], but probably not Marfan syndrome [14]. The mechanism by which connective tissue diseases predispose to aneurysm formation presumably involves an inherent weakness of the arterial wall exposed to the nonlaminar flow pattern of blood, which is then exposed to shear stresses. Aneurysm formation in glucocorticoid-remediable hyperaldosteronism may result in part from congenital hypertension during the early stages of cerebrovascular development [15]. Concurrent hypertension also may contribute in polycystic kidney disease (PKD), although the precise mechanism is unclear. It is uncertain whether patients with these disorders should undergo routine screening for intracranial https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 2/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate aneurysm. (See "Screening for intracranial aneurysm", section on 'Other hereditary disorders'.) Autosomal dominant PKD is associated with a 6.9 times higher risk of intracranial aneurysm [7]. Autosomal recessive PKD may also be a risk factor [16]. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".) The role of aneurysm screening in patients with PKD is discussed separately. (See "Screening for intracranial aneurysm", section on 'Autosomal dominant polycystic kidney disease'.) Glucocorticoid-remediable aldosteronism (familial aldosteronism type I). (See "Familial hyperaldosteronism".) Screening in these patients is described separately. (See "Screening for intracranial aneurysm", section on 'Other hereditary disorders'.) Moyamoya syndrome is also associated with an increased frequency of intracranial aneurysms. Although most cases of moyamoya are sporadic, there is probably a genetic susceptibility underlying the disease, and familial occurrence is known to occur. (See "Moyamoya disease and moyamoya syndrome: Etiology, clinical features, and diagnosis".) Familial aneurysms Family members of patients with intracranial aneurysms are at increased risk of having an aneurysm, even in the absence of a known hereditary syndrome. In one study, for example, the age-adjusted prevalence of incidental aneurysms in first-degree relatives of patients with an aneurysm was 9 percent, a number significantly higher than the general population [17]. Only a small proportion of these families had an identifiable hereditary syndrome known to be associated with aneurysms. In a second report of patients with mostly sporadic subarachnoid hemorrhage (SAH), intracranial aneurysms were found in 4 percent of first-degree relatives (approximately twice that of the general population) [18]. Other studies have estimated that a family history of aneurysm or SAH confers a 3.6 times greater risk [7]. The mode of inheritance is variable, with autosomal dominant, recessive, and multifactorial transmission evident in different families [19,20]. Familial aneurysms have been linked to multiple chromosomal loci [11,20-26]. Familial aneurysms tend to rupture at a smaller size and younger age than sporadic aneurysms [17,27,28]. Siblings often experience rupture in the same decade of life [27]. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 3/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Aneurysms tend to occur at similar locations within families, suggesting that a specific anatomic vulnerability may be inherited [29]. Other factors Because intracranial aneurysms are the major etiology of SAH, risk factors for SAH may also be risk factors for intracranial aneurysms. Risk factors for SAH include hypertension, cigarette smoking, and alcohol consumption [30-32]. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Hypercholesterolemia and regular physical exercise appear to decrease the risk of aneurysm formation [33]. Known and possible risk factors for aneurysm formation include: Cigarette smoking The importance of cigarette smoking was illustrated in a case-control analysis of 45 men and 70 women with SAH between the ages of 35 and 64 [34]. Cigarette smokers had a significantly increased risk of SAH compared with a control population; the relative risk for men and women was 3.0 and 4.7, respectively, and the risk increased with the number of cigarettes smoked. Those who both smoked and had hypertension had an almost 15-fold increase in risk of SAH compared with normotensive nonsmokers; this additive effect of hypertension and smoking on aneurysm formation has been noticed in other studies as well [33]. In a study of familial intracranial aneurysms, the risk of intracranial aneurysm within affected families was increased by cigarette smoking [24]. The mechanism by which cigarette smoking predisposes to aneurysm formation may involve decreasing the effectiveness of alpha-1 antitrypsin, an important inhibitor of proteases such as elastase [10]. Support for this hypothesis is derived from studies, which suggest that patients with alpha-1 antitrypsin deficiency are at increased risk of aneurysm formation [27]. Hypertension The association between hypertension and aneurysm formation and rupture has been controversial, although the balance of evidence suggests that hypertension is a risk factor [33]. One report, for example, compared 113 patients with SAH and angiographically verified aneurysms with 63 patients with SAH but no aneurysm [35]. Blood pressure greater than 160/95 was present in 62 percent of patients with aneurysms compared with 37 percent without. In another study in which over 20,000 Medicare patients were followed, there was an increased prevalence of hypertension in patients with aneurysms compared with a control population (43 versus 35 percent) [36]. Estrogen deficiency There is a female preponderance for aneurysms ranging from 54 to 61 percent [9]. The estrogen deficiency of menopause causes a reduction in the collagen https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 4/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate content of tissues. (See "Clinical manifestations and diagnosis of menopause".) This collagen wasting may contribute to aneurysm development in postmenopausal women, analogous to the situation in patients with connective tissue diseases. In one case- control study, premenopausal women without a history of smoking or hypertension were at reduced risk of SAH compared with age-matched postmenopausal women (odds ratio 0.24) [37]. Furthermore, the use of estrogen replacement therapy was associated with a reduced risk of SAH in postmenopausal women (odds ratio 0.47). This protective effect of estrogen replacement therapy has been seen in other studies as well [38]. Coarctation of the aorta Patients with coarctation of the aorta are at increased risk for aneurysm formation [39-41]. This may result from secondary hypertension or from shared morphologic or genetic risk factors. (See "Clinical manifestations and diagnosis of coarctation of the aorta".) PATHOGENESIS Aneurysm formation Saccular aneurysms are responsible for most subarachnoid hemorrhages (SAHs), although fusiform and mycotic aneurysms can be identified in selected patients. Saccular aneurysms are thin-walled protrusions from the intracranial arteries that are composed of a very thin or absent tunica media, and an absent or severely fragmented internal elastic lamina [42]. Fusiform aneurysms consist of enlargement or dilatation of the entire circumference of the involved vessel that may in part be formed due to atherosclerosis. Mycotic aneurysms usually result from infected emboli due to infective endocarditis [43]. Intracranial saccular aneurysms are acquired lesions, not congenital. The pathogenesis of saccular aneurysm formation is multifactorial [44]. Hemodynamic stress causes excessive wear and tear and breakdown of the internal elastic lamina. Turbulent blood flow produces vibrations that may coincide with the resonant frequency of the vessel wall, resulting in structural fatigue. Patients with hyperdynamic flow patterns as a result of anomalous collateral pathways or other high-flow states are predisposed to accelerated degenerative changes in the vessel wall and subsequent aneurysm development. Hypertension, cigarette smoking, and connective tissue disease probably play a contributory rather than causal role in this process (see 'Other factors' https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 5/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate above). There is some evidence that inflammation plays a role in the pathogenesis and growth of intracranial aneurysms [45-48]. In a study that examined 66 saccular aneurysm samples (42 ruptured and 24 unruptured), four histologic types of aneurysm walls were identified that may reflect consecutive stages of degeneration leading to rupture [49]: Endothelialized wall with linearly organized smooth muscle cells (Type A); 7 of 17 (41 percent) ruptured. Thickened wall with disorganized smooth muscle cells (Type B); 11 of 20 (55 percent) ruptured. Hypocellular wall with either intimal hyperplasia or organizing luminal thrombosis (Type C); 9 of 14 (64 percent) ruptured. Extremely thin thrombosis-lined hypocellular wall (Type D); all 15 (100 percent) ruptured. Lack of elastic lamina was a common feature of both ruptured and unruptured aneurysms. Ruptured aneurysm walls were more likely to have complete absence of endothelial lining and evidence of inflammation, characterized by T cell and macrophage infiltration, compared with unruptured walls. Subsequent pathologic studies identified odontogenic bacterial DNA in the walls of both ruptured and unruptured aneurysms, suggesting that infection may play a role in the formation or rupture of saccular aneurysms [50,51]. Aneurysm growth and rupture It is believed that most intracranial aneurysms develop over a short period of hours, days, or weeks, attaining a size allowed by the elasticity limits of the aneurysmal wall; at this point, the aneurysm either ruptures or undergoes stabilization and hardening [44,52,53]. Those aneurysms that do not rupture gain significant tensile strength due to compensatory hardening with formation of excessive collagen. Therefore, the likelihood of rupture decreases unless the size of the aneurysm is fairly large at the time of initial stabilization. Aneurysms 1 cm or larger at initial stabilization are considerably more likely to undergo subsequent growth and rupture because wall stress increases with the square of the diameter (Laplace's law). (See 'Size' below.) This theory of aneurysm growth and rupture is believed to explain the apparent discrepancy between data that show a low rate of rupture for aneurysms 7 to 10 mm and smaller [52,54-56] and the observation that a large percentage of patients that present with SAH appear to have had rupture of aneurysms that were smaller than 10 mm in diameter [57], and a majority appear smaller than 7 mm in diameter [58]. Thus, the critical size for aneurysmal rupture is smaller for aneurysms that rupture soon after formation, as would appear to be true for the vast majority of https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 6/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate small aneurysms that rupture [44,53]. This hypothesis is based on data derived from patients with unruptured aneurysms and no history of prior SAH, and may not be applicable to patients who have an unruptured aneurysm and prior SAH from another aneurysm. CLINICAL MANIFESTATIONS Most intracranial aneurysms are asymptomatic unless they rupture, and so they are usually found either incidentally or when a patient presents with subarachnoid hemorrhage (SAH). (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".) Some unruptured aneurysms can become symptomatic [59,60]. Symptoms include headache (which may be severe and comparable to the headache of SAH [59]), visual acuity loss, cranial neuropathies (particularly third nerve palsy), pyramidal tract dysfunction, and facial pain; they are felt to be due to the mass effect of the aneurysm. (See "Third cranial nerve (oculomotor nerve) palsy in adults".) Ischemia can occur as a result of emboli originating from within an aneurysm. Treatment of the aneurysm may lead to resolution of symptoms [60]. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".) DIAGNOSIS Most intracranial aneurysms present as subarachnoid hemorrhage (SAH) or are found incidentally or on screening. (See "Screening for intracranial aneurysm".) Because symptomatic unruptured aneurysms are unusual, there are few data on the best diagnostic strategy in the presence of symptoms that could be due to an aneurysm. One exception is the clinical setting of a non-pupil sparing third nerve palsy, the evaluation of which is discussed separately. (See "Third cranial nerve (oculomotor nerve) palsy in adults", section on 'Evaluation for intracranial aneurysm'.) Magnetic resonance angiography (MRA) and computed tomography angiography (CTA) appear to be able to detect aneurysms 5 mm or larger; smaller aneurysms (down to 2 mm) are less reliably detected or may be seen in retrospect when compared with cerebral angiography ( image 1) [61-64]. A systematic review of studies of CTA concluded that the sensitivity of CTA ranged from 53 percent for 2 mm aneurysms to 95 percent for 7 mm aneurysms, and that specificity was also higher for larger aneurysms ( figure 1A-B) [64]. As technology improves, the sensitivity and specificity of noninvasive imaging is also likely to improve. A 2011 meta- https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 7/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate analysis of CTA diagnosis of intracranial aneurysms found that, compared with single-detector CTA, use of multidetector CTA was associated with an overall improved sensitivity and specificity for aneurysm detection (both >97 percent) as well as improved detection of smaller aneurysms 4 mm in diameter [65]. Another study examining 307 aneurysm in 246 patients found that three-dimensional time-of-flight MRA with volume rendering at 3.0 Tesla had a sensitivity and specificity of 99 and 97 percent, respectively, that was irrespective of aneurysm size (range <3 to >10 mm) [66]. Pretest probability should affect the interpretations of CTA results: in the presence of SAH, an aneurysm is likely, and a positive CTA finding of any size can generally be trusted, while a negative result should lead to further testing; in the absence of SAH, a CTA finding of a large aneurysm (>7 mm) can be trusted, but findings of small or medium aneurysms have a higher likelihood of being false positives and may require confirmation, if felt to be clinically important [64]. Angiography is a more invasive test that is associated with a higher risk of complications, and it should only be performed if there is a high clinical suspicion for an aneurysm despite negative noninvasive studies. Very small aneurysms (below the practical limit of detection of MRA and CTA) can occasionally present with symptoms such as third nerve palsy [60]. RISK FACTORS FOR ANEURYSM RUPTURE Two large prospective studies have reported on the natural history of unruptured intracranial aneurysms, the International Study of Unruptured Intracranial Aneurysms (ISUIA), which prospectively assessed 1692 patients with 2686 unruptured, untreated aneurysms (6544 patient- years) in the United States, Canada, and Europe [54], and the Unruptured Cerebral Aneurysms Study (UCAS), a Japanese cohort that followed 6697 aneurysms in 5720 patients (11,660 aneurysm-years) [67]. Both of these studies noted that aneurysm size and location were associated with the risk of rupture. The PHASES score, developed from the pooled analysis of six prospective cohort studies, incorporates age, hypertension, the maximum diameter of the aneurysm, a previous history of subarachnoid hemorrhage (SAH), and the site of the aneurysm as the main predictors of rupture [68] and provides a useful summary for individualization of management decisions [69]. Size The ISUIA and UCAS confirmed results from previous studies showing that the rates of aneurysmal rupture were lower in smaller aneurysms [52,54-56,67]. The size cutpoint in both studies for defining low risk of rupture was 7 mm [54,67]. With increasing size over 7 mm, the risk of aneurysmal SAH increases correspondingly. In the ISUIA, for anterior circulation https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 8/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate aneurysms, five-year rates of rupture for those 7 to 12 mm was 2.6 percent; for those 13 to 24 mm, 14.5 percent; and for those >25 mm, 40 percent. Another prospective cohort study followed 374 patients with 448 aneurysms that were <5 mm in size; the average annual rupture rate was 0.54 percent overall, 0.34 percent for single aneurysms, and 0.95 percent for multiple aneurysms [70]. In this group, aneurysm rupture risk was also somewhat higher in those <50 years of age and those with aneurysms >4 mm in size. Hazard ratios reported in the UCAS, using aneurysms 3 to 4 mm as the reference, were 3.3 for aneurysms 7 to 9 mm, 9.1 for aneurysms 10 to 24 mm, and 76.3 for aneurysms 25 mm [67]. Aneurysm growth is more likely to occur in larger than smaller aneurysm [71,72]. Among 165 patients with 191 unruptured aneurysms, the frequency of enlargement over 47 months was 7, 25, and 83 percent for aneurysms <8 mm, 8 to 12 mm, and >13 mm, respectively [72]. One study also found that internal carotid and basilar artery aneurysms were more likely to grow than those located in other regions [71]. The results of one study suggest that risks of rupture in smaller, <5 mm aneurysms can be further stratified by the aneurysm-to-vessel size ratio; a ratio of 3.1 was the threshold identified for a higher risk of rupture (odds ratio 9.10) [73,74]. This finding requires independent verification. Aneurysm growth Based in part upon the theory of aneurysm growth and rupture discussed above as well as the data that associated aneurysm size and risk of rupture, it is believed that aneurysms that grow in size are also at high risk of rupture and that untreated aneurysms should be monitored for growth. (See 'Monitoring' below.) The data supporting this are expectedly somewhat limited. One study followed 165 patients with 258 unruptured aneurysms with serial computed tomography angiography (CTA) [75]. Eighteen percent of aneurysms were observed to grow larger and were associated with a higher rate of rupture than those that did not grow (2.4 versus 0.2 percent per year). Site Both the ISUIA and the UCAS, as well as other studies, have found that the risk of aneurysm rupture varied according to its location [54,67,76]. In the ISUIA, three aneurysm site groupings were associated with different rates of rupture [54]. The three groupings of aneurysm site were based on the parent artery: Cavernous carotid artery aneurysms had the lowest rates of rupture. Anterior circulation aneurysms, involving the anterior communicating, anterior cerebral, or internal carotid arteries, had intermediate rates of rupture. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 9/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Posterior circulation aneurysms, involving the vertebrobasilar, posterior cerebral arterial system, or posterior communicating arteries, had the highest rates of rupture. The cumulative five-year rate of rupture according to aneurysm site and size at diagnosis were as follows: For 7 to 12 mm aneurysms, rupture rates for cavernous carotid, anterior circulation, and posterior circulation aneurysms were 0, 2.6, and 14.5 percent. For 13 to 24 mm aneurysms, rupture rates for cavernous carotid, anterior circulation, and posterior circulation aneurysms were 3.0, 14.5, and 18.4 percent. For 25 mm or larger aneurysms, rupture rates for cavernous carotid, anterior circulation, and posterior circulation aneurysms were 6.4, 40, and 50 percent. In the UCAS, aneurysms in the anterior and posterior communicating arteries were more likely to rupture than those in the middle cerebral artery [67]. Using the latter group as a reference, the hazard ratios associated with rupture in the posterior and anterior communicating arteries were 1.9 and 2.0, respectively. Racial differences It is unclear whether racial or genetic background has a substantial impact upon the natural history of unruptured intracranial aneurysms. The prospective ISUIA data were obtained primarily from white populations in North America and Europe, but no similar large prospective study has been published in other populations. However, predisposition to aneurysm formation is clearly influenced by genetic makeup (see 'Genetic factors' above), and there is epidemiologic evidence of wide variations in the rate of SAH worldwide [77]. Although not directly comparable, data from a systematic review of 13 retrospective studies of unruptured intracranial aneurysms in Japan [78] found a much higher overall rupture rate than that reported in the ISUIA study [54]. Similar to the ISUIA data, the risk of rupture in Japan was significantly increased for large, posterior circulation and symptomatic aneurysms [78]. Most of the studies in the Japanese review included a mix of patients with and without prior SAH, populations that appear to have different risks in the prospective ISUIA study. Prospective studies underway in Japan may address these issues [79,80]. Precipitating events An acute trigger event such as physical exertion appears to occur in some cases of aneurysm rupture but not all. Emotionally stressful life events have not been convincingly shown to be a trigger for aneurysm rupture. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis", section on 'Pathogenesis'.) https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 10/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Prior hemorrhage If an individual has had a previous aneurysmal SAH, the risk of rupture of a separate aneurysm is probably higher than if the individual did not have that history. In the ISUIA, unruptured aneurysms less than 7 mm in a patient with a history of aneurysmal SAH ruptured at a rate of 0.5 percent per year compared with 0.1 percent per year in those with no prior aneurysmal SAH [54]. A higher risk for those with prior SAH was not noted for larger aneurysm categories in the ISUIA, but the number of patients with large unruptured aneurysms and prior SAH was relatively small. Family history Familial aneurysms tend to rupture at a smaller size and younger age than sporadic aneurysms [17,27,28]. In one study, the observed rupture rate of 1.2 percent per year was almost 17 times higher than the rupture rate of aneurysms matched for size and location in the ISUIA [28]. Others In the UCAS, the presence of a daughter sac (an irregular protrusion of the aneurysm wall) was associated with an increased risk of rupture (hazard ratio = 1.6), while the presence of thrombus or calcification did not appear to influence the risk of rupture [67]. One study found that multiple aneurysms were more likely to grow than single lesions [76]. Studies of advanced imaging techniques hold the promise that new technologies will be able to identify other characteristics of aneurysms at high risk of rupture, such as inflammation within the aneurysm wall [81]. In both the ISUIA and UCAS, the effect of patient's age, gender, hypertension, and tobacco smoking were not significant predictors of SAH in a multivariate analysis [54,67]. By contrast, a case-control study comparing patients with ruptured and unruptured cerebral aneurysm found that smoking and a migraine history appeared to increase the risk of rupture, while hypercholesterolemia (or possibly its treatment with statins) appeared to be protective [82]. In this study, the prevalence of hypertension, age, and gender was not different between the groups. Other prospective follow-up studies in patients with unruptured aneurysms have found that aneurysm rupture was associated with cigarette smoking and younger patient age [75,83]. MANAGEMENT The management of unruptured intracranial aneurysms is controversial [84]. There are no randomized trials on which to base recommendations. Decisions about therapy need to weigh the natural history of the aneurysm, the risks of intervention, and patient preferences. Risk of intervention A systematic review and meta-analysis of the available observational studies included 60 studies, 9845 patients, and 10,845 aneurysms. The overall mortality https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 11/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate associated with surgical clipping of unruptured aneurysms was 1.7 percent; unfavorable outcomes occurred in 6.7 percent [85]. Observational studies that compared the risks of surgical versus endovascular repair in general found lower rates of poor outcomes in patients treated with endovascular repair. In the International Study of Unruptured Intracranial Aneurysms (ISUIA), rates of poor neurologic outcome at one year were 12.6 and 9.8 percent for those treated surgically and endovascularly, respectively [54]. In another cohort study, endovascular repair was associated with lower mortality (0.6 versus 1.6 percent) and lower rates of stroke (4.3 versus 9.0 percent) [86]. Risk factors for poor outcomes include advanced age, larger aneurysm size, and location in the posterior circulation; these are more consistently observed in surgically rather than endovascularly treated patients [54,87]. Age is a crucial element in deciding whether to treat an unruptured aneurysm [44]. Morbidity and mortality are increased with open surgery in patients 50 years and older and with endovascular procedures in patients 70 years and older. However, age has relatively little effect on the natural history of unruptured aneurysms. Benefit of intervention The ISUIA investigators concluded that in patients without a history of previous subarachnoid hemorrhage (SAH), it is unlikely that any therapy would be able to improve upon the untreated natural history of aneurysms that are smaller than 7 mm, and they also suggested that in patients with larger asymptomatic unruptured aneurysms, patient preference for immediate risk versus risk over time might determine the appropriate course of action. The investigators also point to specific groups from their data that appear to have the largest benefit from intervention, such as open surgery for patients younger than 50 years with aneurysms of the posterior communicating artery that are 7 to 24 mm. Although it may be appropriate to take these subgroup data into account when making recommendations for individual patients, it is important to recognize that such subgroup analyses are vulnerable to statistical problems and need to be confirmed prospectively. The management of unruptured intracranial aneurysms has also been evaluated by studies performing cost-effectiveness analyses. One such study, published prior to the prospective 2003 ISUIA report [54], found that treatment of asymptomatic aneurysms <10 mm in diameter in patients with no history of SAH from another aneurysm worsened clinical outcomes; treatment of unruptured aneurysms that were larger, symptomatic, or in patients with a history of SAH was cost effective [88]. Aneurysm location was not considered in this analysis. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 12/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate A later decision and cost-effectiveness analysis used the 2003 ISUIA data and compared surgical or endovascular treatment with no treatment for unruptured intracranial aneurysms [89]. The following observations were reported: For 50-year-old patients, treatment was ineffective or not cost effective for aneurysms with the following characteristics: Small (<7 mm), due to the low risk of rupture Located in the cavernous carotid artery Large (>25 mm) and located in the posterior circulation, due to the high risk of complications from treatment For 40-year-old patients, treatment was ineffective or not cost effective for aneurysms with the following characteristics: Small (<12 mm) or large (>25 mm) and located in the cavernous carotid artery Small (<7 mm) and located in the anterior circulation Indications for intervention The available studies emphasize the need to examine each case individually, considering factors such as comorbid medical illness, patient age, aneurysm size and location, and risks of treatment. The sum of these data supports expectant management of very small saccular aneurysms, particularly when such aneurysms are located in the anterior circulation or when they are detected in older patients. A task force of the Stroke Council of the American Heart Association published recommendations (also prior to the 2003 ISUIA data) for the management of patients with an unruptured intracranial aneurysm that are similar to the above recommendations [90]: The treatment of small incidental intracavernous internal carotid artery aneurysms is generally not indicated. For large symptomatic intracavernous aneurysms, treatment decisions should be individualized on the basis of patient age, severity and progression of symptoms, and treatment alternatives. The higher risk of treatment and shorter life expectancy in older individuals must be considered in all patients, and it favors observation in older patients with asymptomatic aneurysms. Symptomatic intradural aneurysms of all sizes should be considered for treatment with relative urgency. https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 13/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate Coexisting or remaining aneurysms of all sizes in patients with an SAH due to another treated aneurysm warrant consideration for treatment. Aneurysms located at the basilar apex carry a relatively high risk of rupture. Treatment decisions must take into account the patient's age, existing medical and neurologic condition, and relative risks of repair. If a decision is made for observation, reevaluation on a periodic basis with computed tomography angiography (CTA)/magnetic resonance angiography (MRA) or selective contrast angiography should be considered, with changes in aneurysmal size sought, although careful attention to technical factors will be required to optimize the reliability of these measures. Given the apparent low risk of hemorrhage from incidental, small (<7 mm) aneurysms in patients without previous SAH, observation rather than intervention is generally advocated. However, special consideration for treatment should be given to young (<50 years) patients in this group. Asymptomatic aneurysms 7 to 10 mm in diameter warrant strong consideration for treatment, taking into account patient age, existing medical and neurologic conditions, and relative risks for treatment [91]. Choice of procedure Surgical treatment of unruptured aneurysms has been the most common procedure used in patients who undergo definitive therapy. In clinical studies, which are typically in centers with high case volumes, endovascular techniques appear to be associated with lower morbidity and mortality than surgical clipping and are playing an increasing role in the treatment of unruptured aneurysms [92-96]. (See "Treatment of cerebral aneurysms", section on 'Patients with unruptured aneurysms'.) New technologies, such as flow diversion, may advance the safety of endovascular treatment and allow aneurysms, previously considered to be inaccessible or technologically difficult for such treatment, to undergo treatment [97]. Special situations With AVM Rare patients have an intracranial aneurysm associated with an intracranial arteriovenous malformation (AVM). These aneurysms are more likely to be associated with growth and rupture than aneurysms in general [98]. Therefore, repairing the aneurysm prior to treating the AVM is recommended. Carotid stenosis One study found that intracranial aneurysms appeared to be more common than expected in a population of patients with symptomatic carotid artery disease, perhaps because of shared risk factors [99]. Aneurysms distal to a symptomatic cervical internal https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 14/28 7/7/23, 11:37 AM Unruptured intracranial aneurysms - UpToDate carotid artery stenosis may be susceptible to sudden hemodynamic changes with carotid endarterectomy (CEA) that could lead to aneurysmal rupture [44]. On the other hand, surgical clipping of an aneurysm distal to a severe internal carotid stenosis may increase the risk of ischemic stroke. Unfortunately, data for this situation are too sparse to allow firm conclusions as to which problem should be tackled first. However, caution is advised if CEA is performed in this setting, especially if the unruptured ipsilateral aneurysm is 7 mm or larger in diameter or if there is a history of SAH from another aneurysm. Use of antithrombotic therapy Patients with intracranial aneurysms may require antithrombotic therapy for the management of other conditions such as atrial fibrillation. The available data are limited, somewhat conflicting, and not sufficient to determine whether anticoagulant (eg, warfarin) or antiplatelet therapy increases the risk of aneurysm rupture. [100]. Anticoagulant therapy does appear to increase the severity of rupture should it occur. The available data regarding the risks of antithrombotic therapy in patients with unruptured aneurysm are discussed in detail separately. (See "Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm".) Monitoring For patients with unruptured intracranial aneurysms that are not treated with open surgery or endovascular methods, the following recommendations are made for monitoring [44]: We suggest that unruptured intracranial aneurysms be monitored with CTA or MRA annually for two to three years, and every two to five years thereafter if the aneurysm is clinically and radiographically stable [44]. However, it is not unreasonable to obtain the first reimaging study of newly detected small aneurysms at six months, since there is evidence that newly formed small aneurysms may be at higher risk of rupture than older, more stable aneurysms (see 'Aneurysm growth and rupture' above). Longer reimaging intervals are certainly appropriate if the six-month study shows no significant change. Patients should be instructed to avoid smoking, heavy alcohol consumption, stimulant medications, illicit drugs, and excessive straining and Valsalva maneuvers. Patients whose aneurysm is treated are at risk for recurrent aneurysm formation and require monitoring. This is discussed in detail separately. (See "Late recurrence of subarachnoid hemorrhage and intracranial aneurysms".) https://www.uptodate.com/contents/unruptured-intracranial-aneurysms/print 15/28 7/7/23, 11:37 AM