Introduction

Saccular aneurysms, also known as berry aneurysms, are the most common type of intracranial aneurysm (IA). These arterial wall outpouchings commonly occur at proximal arterial bifurcations in the Circle of Willis. The prevalence of unruptured intracranial aneurysms (UIAs) in the general population has been estimated to be anywhere from 1 to 10 % [1, 2] with most studies suggesting a frequency of about 2–3 % for unruptured intracranial aneurysms [1]. UIAs are typically discovered as an incidental finding on head imaging performed for unrelated reasons [3]. While most UIAs are asymptomatic, some present with symptoms including headache, seizure, focal deficit, or cranial nerve palsy from mass effect and rarely with ischemic stroke from emboli distal to the aneurysm [4–6]. Intracranial aneurysms can also present with subarachnoid hemorrhage (SAH), with associated potentially significant morbidity and mortality [7, 8]. In order to optimally manage UIAs, it is important to identify factors associated with the presence of a UIA and predictors of rupture once detected and carefully compare these risks of rupture to the risks of interventional management.

Risk Factors

There are several non-modifiable risk factors associated with the presence of IA including the female gender (3:1 prevalence), older age (>50 years), family history of IA or SAH, and hereditary diseases associated with intracranial aneurysms such as autosomal dominant polycystic kidney disease (ADPKD). Ethnicity has also been shown to be a risk factor, as individuals of Finnish or Japanese descent appear to have both an increased prevalence and rate of rupture when compared to North American and other European populations (3.6 and 2.8×, respectively) [9, 10••].

Screening

Current studies and guidelines typically recommend screening individuals with a family history of two or more first-degree relatives with UIA or SAH, as the prevalence of aneurysms in these populations is 8–10 % [11••]. There is a 4 % risk of UIA in those with one affected relative, and although not typically recommended, it would not be inappropriate to consider screening in those individuals, particularly if there are other risk factors present. The role of screening in patients with only affected second-degree relatives is less certain.

Screening for IA is also advised in patients with hereditary or congenital diseases that predispose to intracranial aneurysms. These diseases include ADPKD, Ehlers Danlos-vascular type IV, microcephalic osteodysplastic primordial dwarfism, coarctation of the aorta, and bicuspid aortic valve [11••]. In population-based studies of patients with ADPKD, approximately 10 % had UIA and the prevalence rose to 20 % if there was a family history of IA [1, 12], leading to the recommendation to strongly consider screening of those family members affected with ADPKD, especially if there is a family history of UIA or SAH.

Radiographic screening is recommended with either a magnetic resonance angiography (MRA) or a computer-tomography angiography (CTA). Screening is generally recommended to begin in the fourth decade for high-risk patients (i.e., ADPKD or a strong family history), as aneurysm occurrence typically increases with age [13]. However, studies show that de novo aneurysm formation can occur in up to 7 % of cases following a negative initial screening study [14]. For this reason, high-risk patients with a negative initial screen are advised to undergo repeat screening every 5 years.

Natural History

There are seven large prospective UIA natural history studies to date, which estimate the overall annual rupture risk of UIA to be 0.5–1.4 %/year [15–21]. The International Study of Unruptured Intracranial Aneurysms (ISUIA) is a North American prospective study that followed 1692 patients with UIA and found that larger aneurysm size, location of the aneurysm (posterior circulation and posterior communicating artery (PCOM)), and previous subarachnoid hemorrhage are the strongest predictors of rupture. The largest prospective cohort published to date is the Unruptured Cerebral Aneurysm Study (UCAS) from Japan which followed 6697 patients and found that along with aneurysm size (>7 mm), factors associated with increased risk of rupture were aneurysm location (anterior and posterior communicating arteries) and the presence of a daughter sac, defined as an irregular protrusion of the aneurysm wall [19].

Several of the other prospective studies have also suggested that larger size and posterior circulation location are associated with risk of rupture. Other factors that have been reported to be associated with rupture of a UIA include previous history of SAH [15, 16, 21], presence of daughter sac [19, 21] multiple aneurysms [17], hypertension, cigarette smoking, and heavy alcohol consumption [20]. Two smaller prospective studies from Finland and Japan have shown that age <50 years was associated with risk of rupture [17, 20].

Pooled data from large prospective series on the natural history of UIAs have been essential to developing predictive models for aneurysm growth and rupture. In a recent study, investigators from six large prospective natural history studies pooled data on 8382 patients to develop a prognostication scoring system called PHASES [10••, 22]. The PHASES scoring system individualizes the 5-year UIA rupture risk based on six risk factors: (1) population, (2) hypertension, (3) age, (4) size of aneurysm, (5) earlier SAH from another aneurysm, and (6) site of aneurysm. A summary of the PHASES scoring system is provided in Table 1. Population-based risk factors include Japanese or Finnish ancestry. Site-based risk factors include middle cerebral artery (MCA) bifurcation location and anterior cerebral artery (ACA)/posterior communicating artery (PCom)/posterior circulation location. Scoring systems such as PHASES can only be used as a guide since there are several aspects that should be considered that are not included in this scoring system including aneurysm sac and neck morphology, hemodynamics, history of growth on sequential angiographic studies, history of smoking, medical co-morbidities that would affect surgical/endovascular treatments, family history of subarachnoid hemorrhage, and a history of connective tissue disease.

Table 1 Summary of PHASES score
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Aneurysm growth on serial imaging is a risk factor for UIA aneurysm rupture. The definition of aneurysm enlargement is variably defined, but an increase of ≥1 mm would be considered as enlargement for small aneurysms, ≤5 mm in diameter, and an increase of ≥2 mm for aneurysms ≥5 mm in diameter. Aneurysms that demonstrate growth on long-term follow-up (∼4 years) have rupture rates of about 3 % per year compared to about 0.1 % per year for aneurysms that demonstrate stability on follow-up [23]. Growth of an aneurysm on follow-up imaging will often trigger endovascular or surgical intervention due to the higher rate of rupture. The PHASES score has been shown to be predictive of aneurysm growth as well as rupture [10••, 22]. Other factors that have been shown to be associated with aneurysm growth in one recently published meta-analysis include age (>50 years), female sex, smoking history, shape (non-saccular, lobulated, or daughter sac), location, and size >10 mm [23].

Management

Once an incidental and asymptomatic unruptured intracranial aneurysm is detected, an individualized assessment of the balance of risk of rupture versus risk of intervening should be performed in order to determine the best management option for each patient (Table 2). If an incidental asymptomatic IA is deemed to have a low risk of rupture, then conservative management is warranted. This includes optimizing modifiable risk factors such as smoking cessation and blood pressure control in conjunction with radiographic monitoring for growth by serial CTA or MRA as growing aneurysms are associated with a high risk of rupture [23, 24••]. There are no guidelines regarding the optimal interval in which to serially image these patients. However, annual MRA or CTA for at least 3–5 years with reduction in imaging frequency once stability is established is reasonable.

Table 2 Summary of considerations for management of unruptured aneurysms
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In addition to aneurysm growth during follow-up, new neurological symptoms caused by compressive or ischemic phenomena from a UIA would lead to a recommendation for treatment. It is generally thought that these symptoms are due to aneurysm growth and therefore portend a higher risk of rupture. Furthermore, compressive and ischemic symptoms from an aneurysm can be debilitating, and it is possible that treatment of the UIA could mitigate these symptoms.

In addition to predictive models of rupture risk and close monitoring of brain aneurysm patients, clinicians have other tools that they can rely on to decide whether or not to treat an aneurysm. There is a new treatment risk model named the Unruptured Intracranial Aneurysm Treatment Score (UIATS), which has been developed based on consensus of multidisciplinary experts in the field and indirect data from natural history and intervention studies. This model is an attempt to individualize the comparison of risks of intervention compared to conservative management [24••]. The UIATS model accounts for 29 factors in UIA management, including demographic factors, symptoms, life expectancy, aneurysm size and morphology, and treatment-related factors.

Once a decision is made to take an interventional approach to the UIA; the type of intervention depends on several characteristics, including patient’s age, co-morbidities, aneurysm location, morphology, size, and procedure-related risk factors. The most common approaches are craniotomy with clipping or endovascular therapies such as coiling alone, device-assisted coiling (i.e., stent or balloon angioplasty), and flow-diverting stenting.

In general, aneurysms with a narrow neck may be considered for coiling of the sac, as opposed to those with a wide neck. If endovascular therapies are pursued for wide-necked aneurysms, these may include stent-assisted coiling to keep the coils within the aneurysm sac or flow diversion; these aneurysms may also be treated with surgical clipping. Over the past several years, flow diversion has emerged as the method of choice for treating large and wide-necked unruptured aneurysms of the internal carotid artery (ICA) with high cure rates and low complication rates [25, 26]. Meanwhile, coiling is preferred for treating narrow-necked ICA aneurysms as well as aneurysms of the posterior circulation aneurysms and ACA/anterior communicating artery complex [26]. Patients who are treated with simple coiling (i.e., without stent placement) do not require dual antiplatelet therapy while patients who are treated with stent-assisted coiling or flow diversion require dual antiplatelet therapy for at least 5 days prior to the procedure and then 3–6 months following treatment. After 3–6 months, these patients are kept on aspirin for life.

Contemporary endovascular management of UIAs is generally considered to be associated with a periprocedural morbidity and mortality rate of 2 and 0.5 % for coiling and 3 and 1 % for flow diversion, respectively [26, 27]. The primary causes of morbidity from endovascular procedures are perioperative infarction and intraoperative rupture. Rates of perioperative morbidity and mortality depend on a variety of risk factors including aneurysm size (giant aneurysms and tiny aneurysms are often associated with higher complication rates), location (posterior circulation is associated with higher complication rates), and morphology [26]. Close post-operative follow-up is recommended for all endovascular-treated patients as recurrence rates range from 5 to 15 % [26]. Catheter angiography is the preferred imaging modality for follow-up of these patients in the short term. Contrast-enhanced MRA is also useful [28]. Modern endovascular implants are MRI compatible.

There are some situations in which surgical clipping is favored over endovascular treatment. In general, clipping is often considered for MCA bifurcation aneurysms [27, 29]. Furthermore, clipping is a reasonable option for very small aneurysms as these aneurysms are harder to treat with endovascular techniques [30]. Complex aneurysm morphologies may also favor clipping, especially aneurysms with branches arising from the sac/neck or those with a wide neck. Surgical clipping requires an open craniotomy to visualize and clip the aneurysm. The clip is typically made of platinum metal and placed at the neck of the aneurysm. Surgical clipping is effective in eliminating the aneurysm, and recurrence risks are generally very low. There are two randomized controlled trials comparing outcomes of clipping compared to coiling in ruptured aneurysms, but none comparing these outcomes in unruptured aneurysms [31, 32]. There is, however, a trial underway called The Canadian Unruptured Endovascular Versus Surgery Trial. Outcomes for this trial include treatment success, overall morbidity and mortality, perioperative morbidity and mortality, hospital length of stay, and angiographic outcomes [33]. A meta-analysis comparing clipping and endovascular treatment of unruptured aneurysms demonstrated that in general, coiling is associated with lower short-term complications and morbidity as compared to clipping [27]. However, treatment decisions need to be made on a case-by-case basis, carefully weighing the risks and benefits of all potential management options [34].

Medical Management

Antithrombotics are not contraindicated in the setting of unruptured intracranial aneurysms. It is generally recommended that antiplatelet and anticoagulation medications be used if there is a specific indication for treatment (i.e., atrial fibrillation, cardiac stenting, DVT prophylaxis, etc). While there have been a few case-control studies that suggest an increased association with dipyramidole and non-traumatic subarachnoid hemorrhage [35] and worsened outcomes in patients with subarachnoid hemorrhage on anticoagulation; there are no studies demonstrating an association between aneurysm rupture and anticoagulant or antiplatelet use [36, 37].

There is some experimental evidence suggesting that aspirin therapy could potentially reduce aneurysm wall inflammation and thus risk of rupture [38, 39]. In an analysis of the ISUIA cohort, the UIA rupture risk was somewhat lower in patients who were taking aspirin most frequently, but the data are not definitive in terms of leading to a change in clinical practice [40]. In one small randomized controlled trial including 11 patients randomized to daily aspirin therapy or placebo, Hasan et al found that patients on aspirin therapy had decreased macrophage activity and aneurysm wall inflammation when compared to those on placebo. Ultimately, further randomized controlled trials are needed to validate these findings [41].

For hypertension management, there is no level 1 evidence supporting the use of one antihypertensive over another. The best treatment strategy is to find an antihypertensive that is effective and well tolerated. There is some experimental evidence that suggests that angiotensin-converting enzyme (ACE)-inhibitors and angiotensin receptor blockers are effective in reducing aneurysm rupture in animal models; however, no human studies to date have validated these findings [42]. These agents are thought to prevent aneurysm rupture by decreasing elastin degradation.

Statin therapy is recommended for aneurysm patients only if a specific separate indication exists (i.e., hypercholesterolemia, coronary artery disease, and cerebrovascular disease). In general, large studies have demonstrated no association between statin therapy and aneurysm growth or rupture [43]. One large study of 1200 patients found no association between statin use and incidence of intracranial aneurysm formation [44]. These findings contrast those of animal models which indicated that statin therapy is associated with a reduced incidence of aneurysm formation through pleiotropic effects including inhibition of inflammation and improved endothelial function [45].

Conclusions/Main Points

Over the last two decades, natural history studies have clarified factors that may predict a higher risk of rupture in certain saccular aneurysms. Aneurysms with low rupture risk can be monitored for growth with serial radiographic imaging. Those with a predicted risk of rupture that is greater than management risks should be considered for intervention such as craniotomy with clipping or endovascular therapies (i.e., coiling, assisted coiling, flow diversion stent, or flow disruption). Aneurysm screening should be considered for patients with a high risk of aneurysm detection (i.e., >2 affected first degree relatives with UIA or SAH, ADPKD, other disorders associated with a high frequency of UIA detection) who would be candidates for intervention. Antithrombotics have not been shown to increase rupture risk in patients with unruptured intracranial aneurysms and may be used for a specific indication. Aspirin may actually lower the risk of rupture in UIAs, but this issue requires further study before aspirin would be recommended for all patients with a UIA. However, despite the evolving available data, the optimal management of all UIAs is uncertain. Additional study is needed to clarify many of the key clinical questions that occur when managing a patient with a UIA. Clarification of the optimal imaging interval and frequency for those managed conservatively is important. Data regarding specific surgical or endovascular outcomes based on particular aneurysmal morphology, size, and location are important. Lastly, medical strategies aimed at reducing the risk of UIA rupture, and studies aimed at determining the influence of genetic factors on outcomes are essential.