Unruptured intracranial aneurysms

INTRODUCTION — Subarachnoid hemorrhage (SAH) is often a devastating event. Approximately 20 to 25 percent of patients die prior to reaching the hospital and, of those who make it in time, only one-third will have a "good result" after treatment [1,2]. Most SAHs are caused by ruptured intracranial saccular (berry) aneurysms [3-7]. Most aneurysms come to medical attention in the setting of an SAH; however, unruptured aneurysms may be identified in the setting of other clinical symptoms or as an incidental finding on neuroimaging.

The epidemiology and pathogenesis of intracranial aneurysms and the management of unruptured aneurysms are discussed here. The recommendations provided are generally in agreement with those of the American Stroke Association as well as with those of the European Stroke Organization [8,9]. The epidemiology, etiology, clinical manifestations, diagnosis, and treatment of SAH, and issues related to screening for aneurysms, are discussed separately:

●(See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis".)

●(See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".)

●(See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".)

●(See "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 [3,10,11]. Aneurysms are uncommon under the age of 30 years; the prevalence rises with age, peaking in the sixth decade [8]. There is a female preponderance for aneurysms ranging from 54 to 61 percent [8,11-13].

Aneurysmal subarachnoid hemorrhage (SAH) occurs at an estimated rate of 6 to 16 per 100,000 population [12]. In North America, this translates into approximately 30,000 affected persons per year. Thus, most aneurysms, particularly small aneurysms, do not rupture. (See 'Aneurysm rupture' below.)

SAH is associated with a high early mortality rate; thus, rupture of an intracranial aneurysm is believed to account for 0.4 to 0.6 percent of all deaths. Approximately 20 percent of patients die prior to reaching the hospital, and only one-third have a "good result" after treatment [1,2]. (See "Aneurysmal subarachnoid hemorrhage: Treatment and prognosis".)

RISK FACTORS FOR ANEURYSM FORMATION

Genetic factors — The role of 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 [14].

●Hereditary syndromes – A known hereditary syndrome is often present when aneurysms are diagnosed in more than one family member. Screening in these patients is described separately. (See "Screening for intracranial aneurysm", section on 'Hereditary syndromes associated with aneurysm formation'.)

Heritable disorders associated with the presence of intracranial aneurysm include:

•Connective tissue diseases. Ehlers-Danlos syndrome and pseudoxanthoma elasticum [15,16], but probably not Marfan syndrome [17], are associated with intracranial aneurysms. 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.

•Polycystic kidney disease (PKD). Autosomal dominant PKD is associated with a 6.9 times higher risk of intracranial aneurysm [11]. Autosomal recessive PKD may also be a risk factor [18]. Concurrent hypertension may contribute to aneurysm formation in PKD, although the precise mechanism is unclear. (See "Autosomal dominant polycystic kidney disease (ADPKD): Extrarenal manifestations".)

•Glucocorticoid-remediable aldosteronism (familial aldosteronism type I). Aneurysm formation in glucocorticoid-remediable hyperaldosteronism may result in part from congenital hypertension during the early stages of cerebrovascular development [19]. (See "Familial hyperaldosteronism".)

•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 in the general population [20]. 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) [21]. Other studies have estimated that a family history of aneurysm or SAH confers a 3.6 times greater risk [11].

The mode of inheritance is variable, with autosomal dominant, recessive, and multifactorial transmission evident in different families [22,23]. Familial aneurysms have been linked to multiple chromosomal loci [14,23-29].

Familial aneurysms tend to rupture at a smaller size and younger age than sporadic aneurysms [20,30,31]. Siblings often experience rupture in the same decade of life [30]. Aneurysms tend to occur at similar locations within families, suggesting that a specific anatomic vulnerability may be inherited [32].

Screening in these patients is described separately. (See "Screening for intracranial aneurysm", section on 'Screening family members'.)

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 [33-35]. These are described separately. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis".)

Hypercholesterolemia and regular physical exercise appear to decrease the risk of aneurysm formation [36].

Known and possible risk factors for aneurysm formation include:

●Cigarette smoking – Cigarette smoking is an established risk factor for both unruptured aneurysm and aneurysmal SAH [8]. (See "Aneurysmal subarachnoid hemorrhage: Epidemiology, risk factors, and pathogenesis", section on 'Cigarette smoking'.)

In one case-control study, unruptured intracranial aneurysms were prevalent in 19 percent of females who smoked compared with 2 percent of females who didn't smoke [37]. A follow-up multicenter case-control study documented an almost fourfold greater risk of unruptured intracranial aneurysm in females who smoked (odds ratio [OR] 3.7, 95% CI 1.61-8.50) and a seven-times-higher risk if they smoked and had hypertension (OR 6.9, 95% CI 2.49-19.24) [38].

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 [39]. Support for this hypothesis is derived from studies that suggest that patients with alpha-1 antitrypsin deficiency are at increased risk of aneurysm formation [30].

●Hypertension – The association between hypertension and aneurysm formation has been controversial, although the balance of evidence suggests that hypertension is a risk factor [36]. One report, for example, compared 113 patients with SAH and angiographically verified aneurysms with 63 patients with SAH but no aneurysm [40]. 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) [41].

●Estrogen deficiency – There is a female preponderance for aneurysms ranging from 54 to 61 percent [12]. In populations older than 50 years, the increased prevalence in females may approach a 2:1 ratio or greater.

In one case-control study, premenopausal females without a history of smoking or hypertension were at reduced risk of SAH compared with age-matched postmenopausal females (OR 0.24) [42]. Furthermore, the use of estrogen replacement therapy was associated with a reduced risk of SAH in postmenopausal females (OR 0.47). This protective effect of estrogen replacement therapy has been seen in other studies as well [43].

The estrogen deficiency of menopause causes a reduction in the collagen content of tissues. This collagen wasting may contribute to aneurysm development in postmenopausal females, analogous to the situation in patients with connective tissue diseases. (See "Clinical manifestations and diagnosis of menopause".)

●Coarctation of the aorta – Patients with coarctation of the aorta are at increased risk for aneurysm formation [44-46]. This may result from secondary hypertension or from shared morphologic or genetic risk factors. (See "Clinical manifestations and diagnosis of coarctation of the aorta", section on 'Intracranial aneurysms'.)

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 [47].

•Fusiform aneurysms consist of enlargement or dilatation of the entire circumference of the involved vessel that may be formed in part due to atherosclerosis.

•Mycotic aneurysms usually result from infected emboli due to infective endocarditis [48].

Intracranial saccular aneurysms are acquired lesions, not congenital. The pathogenesis of saccular aneurysm formation is multifactorial [49]. 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' above). There is some evidence that inflammation plays a role in the pathogenesis and growth of intracranial aneurysms [50-53].

●Pathology – 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 [54]:

•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 deoxyribonucleic acid (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 [55,56].

●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 [49,57,58].

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 'Aneurysm 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 [57,59-61] 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 [62], and a majority appear smaller than 7 mm in diameter [63]. 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 small aneurysms that rupture [49,58].

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 PRESENTATION — 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 [64,65]. Symptoms include visual acuity loss (because of optic nerve compression), other cranial neuropathies (particularly third nerve palsy), pyramidal tract dysfunction, and facial pain. These symptoms are felt to be due to the mass effect of the aneurysm on adjacent brain or cranial nerve. (See "Third cranial nerve (oculomotor nerve) palsy in adults", section on 'Evaluation for intracranial aneurysm'.)

While headache is a common indication for the neuroimaging study that first identifies an aneurysm, in most cases, the aneurysm is not the cause of the headache, which does not improve with aneurysm management [8]. By contrast, a sudden, severe headache would be considered a sentinel headache in this setting; these are felt to identify aneurysms at imminent risk of rupture, although the exact mechanism of headache in this setting (warning leak, aneurysm growth, or dissection) is uncertain [64]. It has also been suggested that the association may be spurious due to recall bias. The first imperative in this setting is to exclude SAH with computed tomography (CT) and lumbar puncture. (See "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Clinical presentation' and "Overview of thunderclap headache", section on 'Sentinel headache'.)

Ischemia can occur as a result of emboli originating from thrombus within an aneurysm producing ischemic stroke or transient ischemic attack [65-67].

VASCULAR IMAGING FEATURES — Most unruptured intracranial aneurysms are first identified on computed tomography angiography (CTA) or magnetic resonance angiography (MRA) (image 1), whether performed for an unrelated indication, screening of a high-risk population, or because of the patient's presenting symptoms. (See 'Clinical presentation' above.)

While both CTA and MRA are accurate, sensitive tests for cerebral aneurysm, conventional (digital subtraction) angiography remains the gold standard and is superior for very small aneurysms (<5 mm). Conventional angiography is required for preoperative planning and for endovascular management [68]. However, because it is invasive and has attendant risks, CTA and MRA are generally relied upon for initial diagnosis and monitoring. (See "Screening for intracranial aneurysm", section on 'Choice of screening test' and "Third cranial nerve (oculomotor nerve) palsy in adults", section on 'Evaluation for intracranial aneurysm'.)

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 [39].

Of patients with cerebral aneurysms, 20 to 30 percent have multiple aneurysms [8,69].

ANEURYSM RUPTURE

Incidence — The vast majority of cerebral aneurysms do not rupture. One analysis estimated that the overall rate of aneurysm rupture is 0.25 percent per year [8].

Risk factors

Aneurysm size — Aneurysm size is a risk factor for aneurysm growth and rupture.

●Rupture. The International Study of Unruptured Intracranial Aneurysms (ISUIA) and Unruptured Cerebral Aneurysm Study (UCAS) confirmed results from previous studies showing that the rates of aneurysmal rupture were lower in smaller aneurysms [57,59-61,70]. The size cutpoint in both studies for defining low risk of rupture was 7 mm [59,70]. With increasing size over 7 mm, the risk of aneurysmal subarachnoid hemorrhage (SAH) increases correspondingly. In the ISUIA, for anterior circulation aneurysms, five-year rates of rupture for those 7 to 12 mm was 2.6 percent, for those 13 to 24 mm was 14.5 percent, and for those ≥25 mm was 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 [71]. 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 [70].

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 [OR] 9.10) [72,73]. This finding requires independent verification.

●Growth. Aneurysm growth is more likely to occur in larger than in smaller aneurysms [74,75]. 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 [75].

Aneurysm location — Both the ISUIA and the UCAS, as well as other studies, have found that the risk of aneurysm rupture varied according to its location [59,70,76].

In the ISUIA, three aneurysm site groupings were associated with different rates of rupture [59]. 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.

●Posterior circulation aneurysms, involving the vertebrobasilar, posterior cerebral arterial system, or posterior communicating arteries, had the highest rates of rupture.

The cumulative five-year rates 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, respectively.

●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, respectively.

●For 25 mm or larger aneurysms, rupture rates for cavernous carotid, anterior circulation, and posterior circulation aneurysms were 6.4, 40, and 50 percent, respectively.

Other studies have found that anterior and posterior communicating arteries are approximately twice as likely to rupture than those in the middle cerebral artery [70].

Other factors

●Family history – Familial aneurysms tend to rupture at a smaller size and younger age than sporadic aneurysms [20,30,31]. 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 [31].

●Prior SAH – 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 [59]. 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.

●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 'Neurovascular 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) [77]. 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). Another case series reported an even higher annual risk of rupture (18.5 percent) in aneurysms that enlarged or developed a bleb [78].

●Multiple versus single aneurysms – One study found that multiple aneurysms were more likely to grow than single lesions [76].

●Aneurysm morphology – Predicting aneurysm rupture on the basis of morphology has been challenging. 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 [70]. 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 [79].

●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'.)

●Vascular risk factors – In both the ISUIA and UCAS, the effect of patient's age, sex, hypertension, and tobacco smoking were not significant predictors of SAH in a multivariate analysis [59,70]. 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 [80]. In this study, the prevalence of hypertension, age, and sex 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 [77,81].

●Racial, ethnic, and geographic 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 [82,83].

Although not directly comparable, data from a systematic review of 13 retrospective studies of unruptured intracranial aneurysms in Japan [84] found a much higher overall rupture rate than that reported in the ISUIA study [59]. Similar to the ISUIA data, the risk of rupture in Japan was significantly increased for large, posterior circulation and symptomatic aneurysms [84]. 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 [85,86].

Similarly, high aneurysm rupture rates were reported in a study in Finland [8]. While more recent data are not available, this higher rupture rate observed in Finland is mirrored by the higher-than-average incidence of aneurysmal SAH that is reported in that country [83,87].

MANAGEMENT RECOMMENDATIONS — The management of unruptured intracranial aneurysms is controversial [9,88]. There are no randomized trials with long-term follow-up on which to base recommendations [89]. Decisions about therapy need to weigh the risk of aneurysm rupture without intervention, the risks of intervention, and patient preferences.

Symptomatic aneurysms

●Cranial nerve palsy and other neurologic deficits – For patients who present with neurologic deficits attributed to mass effect from the aneurysm, intervention is generally advised. Because the presence of symptoms suggests recent expansion of the aneurysm with a risk for rupture in the short term, it is generally advised that intervention proceed promptly. Limited data suggest that for patients with third nerve palsy, outcomes may be improved with surgical clipping rather than endovascular occlusion [90-92]. However, in this and other settings, either clipping or endovascular occlusion are effective [93,94], and the choice of treatment is based on other factors. (See "Treatment of cerebral aneurysms", section on 'Techniques' and 'Surgical and endovascular interventions' below.)

Conservative treatment alone is thought not to be an option for these patients because the risk of aneurysm rupture is perceived to be high, although high-quality data to quantify this risk and support intervention are lacking.

●Cerebral ischemia – The role of interventions in patients with unruptured aneurysms who present with ischemic events is uncertain. Only small case series inform this treatment decision, with some emphasizing the benign course with or without surgical treatment, although some patients present with ischemic stroke in the postoperative setting [8,67].

Other aspects of secondary stroke prevention are generally advised in this setting, including treatment with aspirin, which does not appear to increase the risk of aneurysm rupture [95]. (See "Overview of secondary prevention of ischemic stroke" and "Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm", section on 'Effect of antiplatelet therapy'.)

●Headache – Most headaches that lead to a diagnosis of unruptured aneurysm are unrelated to the aneurysm; such patients should not be considered to have a symptomatic aneurysm.

An exception may be the patient who presents with sudden-onset, severe headache. The first imperative in this setting is to exclude aneurysmal subarachnoid hemorrhage (SAH) with a cranial CT and lumbar puncture. If these are negative, other causes of thunderclap headache should be considered, and decisions regarding aneurysm treatment should be made as for asymptomatic patients. (See "Overview of thunderclap headache", section on 'Sentinel headache' and "Aneurysmal subarachnoid hemorrhage: Clinical manifestations and diagnosis", section on 'Evaluation and diagnosis'.)

Asymptomatic aneurysms — In the absence of high-quality randomized trials comparing conservative and interventional treatment of asymptomatic unruptured aneurysms, management decisions for individual patients are based upon what is known regarding the risk of aneurysm rupture and the risk of intervention. Thus, aneurysm size and location and other risk factors guide management decisions.

Thus, for patients with small (<7.0 mm) asymptomatic aneurysms and no risk factors, we suggest conservative management (see 'Conservative management' below). The risk of aneurysm rupture in such patients is very low; none of the patients in the International Study of Unruptured Intracranial Aneurysms (ISUIA) with these characteristics experienced an aneurysm rupture over five years of follow-up [59]; thus, the risks of intervention likely exceed potential benefits.

For patients with larger aneurysms and those with risk factors, interventions may be considered along with shared decision-making.

A number of risk scores have been developed to aid in clinical decision-making:

●PHASES – 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 SAH, and the site of the aneurysm as the main predictors of rupture [96] and may provide a useful summary for individualization of management decisions [97]:

•Japanese – 3 points

•Finnish – 5 points

•Hypertension – 1 point

•Age ≥70 years – 1 point

•Aneurysm size 7.0 to 9.9 mm – 3 points

•Aneurysm size 10.0 to 19.9 mm – 6 points

•Aneurysm size ≥20 mm – 10 points

•SAH history – 1 point

•Middle cerebral artery aneurysm – 2 points

•Anterior communicating, posterior communicating, or posterior circulation aneurysm – 4 points

Risk scores of 5 or lower were associated with a low five-year risk of aneurysm rupture of 0.4 to 1.3 percent [96]. Risk scores of 12 or higher were associated with a high 17.8 percent five-year risk of aneurysm rupture, while intermediate scores were associated with intermediate five-year risks: as examples, 6 points associated with 1.7 percent, 8 points with 3.2 percent, and 10 points with 5.3 percent.

The PHASES score has not been prospectively validated; retrospective applications have provided mixed results [98,99]. In one study in which the score was retrospectively applied to populations who presented with SAH versus those who presented with unruptured aneurysms, the score was deemed to underperform in patients with small aneurysms [99]. A limitation to this study is that aneurysm size may have been affected by the aneurysm rupture.

●UIATS – The Unruptured Intracranial Aneurysm Treatment Score (UIATS) was developed by Delphi consensus among a multispecialty group of experts. More complicated than the PHASES score, it incorporates risks for aneurysm rupture as well as risks for intervention and considers age, comorbidities, and aneurysm-specific features [100]. In a prospective validation study, the sensitivity and specificity were 80 and 44 percent, respectively [101]. In another small cohort study, UIATS had lower discriminatory power to distinguish between low and high rupture risk compared with the PHASES score [102].

●UCAS – A prediction model was derived from prospective Japanese cohorts and externally validated in a Japanese population [103]. Similar to PHASES, it considers relatively few risk factors (age, sex, hypertension, aneurysm size, location, presence of a daughter sac) and is thus relatively easy to apply. It has good discrimination and calibration properties. It has not been validated in a population outside of Japan.

Age can be an important factor in deciding whether to treat an unruptured aneurysm [49]. Morbidity and mortality are increased with open surgery in patients 50 years and older and with endovascular procedures in patients 70 years and older. While age has relatively little effect on the natural history of unruptured aneurysms, older patients are likely to have lower cumulative rates of aneurysm rupture due to their shortened life expectancy. Patients with limited life expectancy for reasons other than age may also elect conservative management.

Special situations

With AVM — Patients can have an intracranial aneurysm associated with an intracranial arteriovenous malformation (AVM) [104-107]. These can be disparate from the AVM or on feeding vessels to the AVM ("flow-related aneurysms"). These aneurysms may be more likely to be associated with growth and rupture than aneurysms in general, although they can also regress with treatment of the AVM [108]. Repairing the aneurysm prior to treating the AVM may be recommended in some cases. (See "Brain arteriovenous malformations", section on 'Associated aneurysm'.)

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 [109]. Aneurysms distal to a symptomatic cervical internal carotid artery stenosis may be susceptible to sudden hemodynamic changes with carotid endarterectomy (CEA) that could lead to aneurysmal rupture [49]. 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. In these patients, aneurysm treatment soon after carotid treatment is advised. For patients where the aneurysm is symptomatic and the carotid disease incidental, treatment of aneurysm first is preferred if anatomically possible.

COMPONENTS OF MANAGEMENT

Conservative management — All patients with unruptured intracranial aneurysms are eligible for and should receive conservative management.

Education and risk factor management

●Education regarding risk of aneurysm subarachnoid hemorrhage (SAH) – Patients should understand what their approximate risk of aneurysm rupture is based upon their specific characteristics. Patients should be counseled to seek immediate medical attention in the event of a sudden-onset severe headache.

●Hypertension management – Patients with hypertension should be treated with antihypertensive drugs as is appropriate for their other risk factors and comorbidities. (See "Overview of hypertension in adults".)

●Counseling and interventions regarding smoking cessation – The evidence linking tobacco smoking and aneurysm formation is limited; similarly, there are no data demonstrating a benefit of smoking cessation on the risk of aneurysm rupture. However, smoking cessation is likely to achieve other health benefits.

●Other activities to avoid – Patients should also avoid things associated with precipitating aneurysm rupture such as heavy alcohol consumption, stimulant medications, illicit drugs, and excessive straining and Valsalva maneuvers, even if the evidence is anecdotal.

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 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".)

While an analysis of untreated patients in the International Study of Unruptured Intracranial Aneurysms (ISUIA) suggested that aneurysm rupture was lower in aspirin-treated patients, these data do not support the use of aspirin in patients with unruptured aneurysms who do not have another indication for such treatment. (See "Anticoagulant and antiplatelet therapy in patients with an unruptured intracranial aneurysm", section on 'Effect of antiplatelet therapy'.)

Neurovascular monitoring

●Untreated aneurysms – For patients with unruptured intracranial aneurysms that are not treated with open surgery or endovascular methods, we suggest that they be monitored with computed tomography angiography (CTA) or magnetic resonance angiography (MRA) annually for two to three years, and every two to five years thereafter if the aneurysm is clinically and radiographically stable [49,110]. However, it is reasonable 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 [110]. Longer reimaging intervals are certainly appropriate if the six-month study shows no significant change.

The ELAPSS score was developed from review of 10 cohorts of patients with unruptured aneurysms to identify those patients at risk for aneurysm growth; a prior history of SAH, location of the aneurysm, age >60 years, population (Finland or Japan), increasing size, and irregular shape of the aneurysm were found to be predictors of aneurysmal growth [111]. The score has been externally validated [112,113]. While a subsequent study found that the ELAPSS score did identify patients at higher risk, they also found that current smoking (not included in ELAPSS) was an important risk factor for aneurysm growth in their population and that age, aneurysm location, and prior SAH (all included in ELAPSS) were not associated with aneurysm growth [112].

●Treated aneurysms – Patients whose aneurysm is treated are also at risk for recurrent and de novo aneurysm formation and require monitoring. This is discussed in detail separately. (See "Late recurrence of subarachnoid hemorrhage and intracranial aneurysms".)

Surgical and endovascular interventions

Techniques — Surgical and endovascular techniques are available for aneurysm treatment. In surgical management, a clip is placed across the neck of the aneurysm. Endovascular techniques occlude the aneurysm using platinum coils or other embolic material. These interventions are described separately. (See "Treatment of cerebral aneurysms", section on 'Techniques'.)

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 [114].

Comparative efficacy, adverse events, treatment selection — Both surgical and endovascular techniques are safe and effective. In many cases, anatomic considerations, such as size and location, along with other morphologic features determine which treatment is most appropriate for the patient. Available expertise also influences the choice of intervention.

The available evidence suggests that surgical clipping may be more effective and reduce the risk of aneurysm recurrence. Endovascular occlusion appears to be associated with fewer adverse events [115-123].

In an unblinded, seven-center, randomized trial of 291 patients with 3 to 25 mm unruptured intracranial aneurysms, surgical clipping was associated with higher rates of aneurysm occlusion assessed by angiography at one year (80 versus 57 percent) [123]. However, surgery was also associated with longer hospitalization (6.7 versus 3.8 days) and a higher rate of postoperative neurologic deficits (22 versus 12 percent). One-year rates of mortality and disability (assessed by modified Rankin score >2) were low (2 percent) and similar in both treatment groups.

Previously published observational studies have come to similar conclusions [59,115,116,124]. In one study that pooled data across 114 studies, the following pooled adverse outcomes were reported [124]:

●Surgical clipping – Complication rate was 8.3 percent; case fatality rate was 0.1 percent. Risk factors for complications included advanced age, female sex, aneurysm location in the posterior circulation, aneurysm calcification, coagulopathy or anticoagulant treatment, smoking, hypertension, diabetes, and congestive heart failure.

●Endovascular treatment – Complication rate was 5.0 percent; case fatality rate was 0.3 percent. Risk factors for complications included wide aneurysm neck, posterior circulation location, female sex, diabetes, and cardiac comorbidity.

SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Stroke in adults".)

INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5^th to 6^th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10^th to 12^th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.

Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)

●Basics topic (see "Patient education: Brain aneurysm (The Basics)")

SUMMARY AND RECOMMENDATIONS

●Epidemiology and risk factors – In the general population, the prevalence of unruptured intracranial aneurysms is estimated to be approximately 3 percent.

A higher risk of intracranial aneurysm formation occurs in certain genetic syndromes including Ehlers-Danlos syndrome, polycystic kidney disease (PKD), and others. Apart from these genetic syndromes, a family history of intracranial aneurysm is also a risk factor.

Nongenetic risk factors include hypertension and cigarette smoking. (See 'Epidemiology' above and 'Risk factors for aneurysm formation' above.)

●Clinical presentation – Most unruptured aneurysms present as an incidental finding on a neuroimaging study or in screening. Occasionally, aneurysms can produce compressive symptoms such as a third cranial nerve palsy. (See 'Clinical presentation' above.)

●Neurovascular imaging – Most unruptured aneurysms are discovered by magnetic resonance angiography (MRA) and computed tomography angiography (CTA), which can detect aneurysms 5 mm or larger. Conventional angiography is more sensitive but carries procedural risks.

Most intracranial aneurysms (approximately 85 percent) are located in the anterior circulation, predominantly on the circle of Willis. Approximately 20 to 30 percent of cerebral aneurysms are multiple. (See 'Vascular imaging features' above.)

●Risk of aneurysm rupture – Cerebral aneurysms have differing rates of rupture depending on the aneurysm size, location, and other characteristics. (See 'Aneurysm rupture' above.)

●Interventional management – The most common interventions for aneurysms are surgical clipping and endovascular coiling.

Indications for intervention take into account the risk of aneurysm rupture:

•For patients with symptomatic intracranial aneurysm (eg, third cranial nerve palsy), we recommend prompt surgical or endovascular intervention (Grade 1C). The presence of symptoms suggests recent expansion of the aneurysm with a risk for rupture in the short term.

•For patients with small (<7.0 mm), asymptomatic aneurysms and no risk factors, we suggest conservative management (Grade 2C). Such aneurysms have a low risk of rupture, which is outweighed by the potential risks of intervention.

•For patients with larger asymptomatic aneurysms and those with risk factors, we engage in shared decision-making, considering the risk of aneurysm rupture based on specific risk factors as well as the procedural risk and individual patient circumstances and preferences. For example, patients with larger aneurysms (>10 to 20 mm) and aneurysms located in the posterior circulation are more likely to benefit from intervention, while those with smaller aneurysms (<10 mm) and aneurysms located in the cavernous carotid or middle cerebral artery have a lower risk of rupture.

The choice of intervention between surgical clipping and endovascular occlusion is individualized, considering the anatomic features of the aneurysm and the available expertise. Both interventions are effective; studies suggest that surgical clipping may be somewhat more effective but is associated with a higher complication rate.

●Conservative management and monitoring – Noninterventional management, appropriate for all patients, includes management of hypertension, smoking cessation, and instruction to avoid heavy alcohol consumption, stimulant medications, illicit drugs, and excessive straining. (See 'Conservative management' above.)

Patients with an unruptured intracranial aneurysm should be monitored with MRA or CTA for aneurysm growth, aneurysm recurrence, and new aneurysm formation. Such examinations may occur annually at first and then can occur less frequently. (See 'Neurovascular monitoring' above and "Late recurrence of subarachnoid hemorrhage and intracranial aneurysms", section on 'Follow-up evaluations'.)