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Treatment of unruptured intracranial aneurysms-Current perspective
Correspondence Address: Source of Support: None, Conflict of Interest: None DOI: 10.4103/0028-3886.170101
Unruptured intracranial aneurysms (UIAs) present a unique challenge due to the lack of a clear understanding of their natural history and outcome. As the treatment of UIAs is aimed at preventing the possibility of rupture, the immediate risk of treatment must be weighed against the risk of rupture in the future. As such, no specific guidelines exist for a large proportion of UIAs, and treatment is currently individualized. It is also of paramount importance that the physicians be aware of the recent advances in the therapy of UIAs. The present article focuses on the recent advances in the understanding of UIAs. Keywords: Aneurysm; intracranial; natural history; pharmacology; subarachnoid hemorrhage; unruptured
The management of unruptured intracranial aneurysms (UIAs) remains one of the most controversial topics in cerebrovascular surgery. As a result, there have been a number of studies that have attempted to evaluate the natural history of UIAs. Recently, the focus has shifted to characterizing the risk of rupture based on morphological and hemodynamic characteristics of aneurysms. With the increasing safety features and expanding indications of neurosurgical and neurointerventional techniques, it is all the more relevant in today's world to be able to clearly define the rupture risk of an unruptured aneurysm, and also streamline the indications of treatment. Despite the advances in research, there is no clear consensus. While a small subset of aneurysms clearly falls in the category for observation or treatment, a large proportion of aneurysms are managed based on the treating physician's and patient's preferences and bias. Much of the earlier research depended on understanding the natural history and risk of rupture based on the patient characteristics and the basic aneurysmal morphology. In this article, we discuss the recent developments in the understanding of unruptured intracranial aneurysms and their management.
The prevalence of UIAs has been variously cited between 1% and 6% in the general population.[1],[2],[3],[4],[5],[6],[7] In a large systematic review of more than 56,000 patients, the authors found that the prevalence of UIAs in adults without specific risk factors was 2.3% and tended to increase with age. The prevalence was higher in patients with autosomal-dominant polycystic kidney disease (relative risk [RR], 4.4), familial predisposition (RR, 4.0), and atherosclerosis (RR, 2.3)[8] The International Study of Unruptured Intracranial Aneurysms (ISUIA) was a multicenter study of the natural history of UIAs. The study had two arms. In the retrospective arm, patients were divided into two groups, the first group consisting of patients without any history of subarachnoid hemorrhage (SAH; n = 727); and, the second group of patients with a history of SAH (n = 722). The mean follow-up duration was 8.3 years. For Group 1, the rate of SAH for aneurysms <10 mm in size was 0.05% per year, whereas for aneurysms ≥10 mm in size, it was approximately 1% per year. For Group 2, the SAH rate was 0.5% per year for aneurysms <10 mm in size and 1% per year for aneurysms ≥10 mm in size. Aneurysms in the posterior circulation and posterior communicating artery had a higher risk of rupture in Group 1, whereas increasing age and basilar bifurcation location were risk factors for a higher risk of rupture in Group 2.[9] In the prospective arm, the patients were divided into the same two groups. Group I consisted of 1077 patients without a previous SAH, and Group II had 615 patients with a history of SAH. All aneurysms were confirmed with angiography and followed for 14.1 years. The rates of rupture in the internal carotid artery (ICA), middle cerebral artery, anterior cerebral artery, and anterior communicating artery (anterior circulation) for aneurysms <7 mm, 7–12 mm, 13–24 mm, and ≥25 mm in size were noted to be 0%, 2.6%, 14.5%, and 40%, respectively. In contrast, the rates of rupture for aneurysms located in the posterior communicating artery and posterior circulation were noted to be 2.5%, 14.5%, 18.4%, and 50%, respectively.[10] One of the largest prospective studies on the natural history of UIAs comes from the Japanese cohort of 5720 subjects with 6697 aneurysms. The majority of aneurysms were either in the middle cerebral artery (36%) or the internal carotid artery (34%). The mean size of aneurysms was 5.7 ± 3.6 mm. During the follow-up period of 11,660 aneurysm-years, the authors reported an annual rupture rate of 0.95% (95% confidence interval [95% CI], 0.79–1.15). Aneurysms that were 5–6 mm in maximum diameter were not at higher risk of rupture than those with a maximum diameter of 3–4 mm, but the risk was increased for aneurysms that were ≥ 7 mm in diameter. The hazard ratios for size categories, compared with the aneurysms with a diameter of 3–4 mm, were as follows: 5–6 mm, 1.13 (95% CI, 0.58–2.22); 7–9 mm, 3.35 (1.87–6.00); 10–24 mm, 9.09 (5.25–15.74); and ≥ 25 mm, 76.26 (32.76–177.54). They also observed that aneurysms in the anterior and posterior communicating arteries were more likely to rupture when compared with those located in the middle cerebral artery.[11] A recent retrospective study followed 140 patients for 21 years and reported a rate of rupture of approximately 1.1% per year. Aneurysm diameter >7 mm (P = 0.028), current cigarette smoking (P = 0.024), and heavy alcohol consumption (P = 0.043) were significantly associated with a higher aneurysmal rupture rate.[12] [Table 1] lists the important studies describing the natural history of UIAs.
One of the most intriguing aspects of intracranial aneurysms is determining the rupture risk in patients diagnosed with unruptured aneurysms. While the rupture risk in a particular subset of patients may be very small and subjecting these patients to any treatment (surgical or endovascular) may put them at a higher risk of complications than would be with natural history, another subset of patients may be at a higher risk of aneurysmal rupture and intervention rather than watchful waiting may be warranted. Again, the rupture risk is known to differ depending on a number of clinical, morphological, hemodynamic, and genetic characteristics. In this section, we discuss the putative factors that have a role in influencing rupture risk of cerebral aneurysms and should be taken into consideration while individualizing therapy.
Race, age, gender, hypertension, smoking, history of subarachnoid hemorrhage (SAH), and number of aneurysms have all been proposed to influence the risk of rupture. It is well known that Finnish people have 3–6 times and the Japanese have 2–6 times increased risk of aneurysm rupture than people of North America and of European countries other than Finland.[16] This difference spans across aneurysms of all sizes. For example, in the International Study of Unruptured Intracranial Aneurysms (ISUIA), which involved predominantly Caucasian patients, the 5-year cumulative rupture risk in patients with anterior circulation aneurysms less than 7 mm in size and without a history of SAH was 0%,[10] whereas the annual rate of rupture in the Unruptured Cerebral Aneurysm Study (UCAS), which was performed in a Japanese cohort, was between 0.23% and 1% for anterior circulation aneurysms.[11] In the Small Unruptured Intracranial Aneurysm Verification Study (SUAVe), the annual rupture risk of single unruptured aneurysms <5 mm in diameter was 0.34% per year and that of multiple unruptured aneurysms was 0.95% per year, with an overall rate of 0.54% per year.[13] An increasing age increases the rupture risk in an unruptured aneurysm. In a cumulative analysis of 8382 patients with 10,272 unruptured aneurysms from six cohort studies from North America and Europe, only 12% of patients with ruptured, and 5% with unruptured aneurysms, were less than 40 years of age. The 5-year predicted absolute risk of rupture ranged from 0.25% in individuals younger than 70 years without vascular risk factors and with an internal carotid artery aneurysm <7 mm in size to approximately 15% in patients aged 70 years or more with hypertension, a history of SAH, and a >20-mm posterior circulation aneurysm.[16] In a meta-analysis, patients older than 60 years had a two time higher risk of rupture than those younger than 60 years.[14] More than two-thirds of all intracranial aneurysms occur in women. Among women, more than half of the aneurysms are located in the ICA (54%), while the anterior cerebral artery (ACA) is the most common location in men (29%). Women also tend to present later in life, with multiple aneurysms and with SAH.[17] The reason for most women presenting with ruptured aneurysms later in life may be linked to the protective effect of estrogen through the activation of estrogen receptor-β.[18] Hypertension and cigarette smoking have long been recognized as risk factors for aneurysmal rupture. Presence of hypertension alone increases the risk of rupture three-fold even in small aneurysms less than 7 mm in diameter.[19] It has been demonstrated that cigarette smoking increases wall shear stress at the site of aneurysm initiation. It also promotes aneurysm growth and increases the rupture risk simultaneously by acting as a catalyst in a complex interplay of hemodynamic stress, vascular inflammation, and cerebral aneurysm formation.[20] A history of SAH and the presence of multiple aneurysms have been shown to increase the risk of subsequent SAH in two Japanese studies. However, this effect has not been uniform across other studies, and their impact is uncertain.[13],[15]
A number of morphological indices have been proposed to correlate with and predict the rupture risk. The simplest parameter is aneurysm size. The ISUIA demonstrated that aneurysms less than 10 mm in size have a very low risk of rupture, and the 5-year cumulative rupture rate was 0%–2.5% for aneurysms <7 mm in size, 2.6%–14.5% for aneurysms 7–12 mm in size, 14.5%–18.4% for aneurysms 12–24 mm in size, and 40%–50% for aneurysms ≥25 mm size.[9],[10] Although ISUIA provided the first large, international, prospective data for decision making in the treatment of intracranial aneurysms, it had many limitations. Patients receiving treatment within 30 days of diagnosis were excluded in the retrospective cohort, leading to a selection bias. In addition, cavernous carotid aneurysms were over-represented, and patients who died of intracranial hemorrhage of unknown origin were not accounted for. However, the Finnish and Japanese studies revealed a 1.3%–2.3% risk of rupture even in patients with aneurysms <7 mm in size.[12],[21],[22] Location of the aneurysm also influences the predisposition to aneurysmal rupture. Posterior circulation aneurysms have been reported to rupture more often than anterior circulation aneurysms, and among the aneurysms located in the anterior circulation, those located at the anterior communicating artery and the origin of posterior communicating artery have a higher risk of rupture than elsewhere. Aneurysms with daughter sacs and wall irregularity have also been reported to have a higher rupture risk.[11],[23],[24],[25],[26] Aspect ratio (AR) is defined as the ratio of the maximum perpendicular height to the average neck diameter, where the average neck diameter is calculated as twice the average distance from the neck centroid to the edge of the neck.[27] Ruptured aneurysms have been reported to have a higher AR than unruptured aneurysms. Ujiie et al., noted that a significantly higher proportion of unruptured aneurysms had an AR <1.6.[28] Weir et al., reported that the mean AR of unruptured and ruptured aneurysms was 1.8 and 3.4, respectively.[29] Other authors have variously reported the mean AR in ruptured aneurysms to be 2.24 and 2.7.[26],[30] Size ratio (SR) refers to the ratio of the maximum aneurysm height to the average parent vessel diameter. The average parent vessel diameter is obtained by calculating the average of two vessel cross-sections upstream of the aneurysm. The maximum height is the maximum distance from the centroid of the aneurysm neck to any point on the aneurysm dome.[27] An SR of >2 has been associated with large areas of low wall shear stress (WSS) in the aneurysm that in turn predisposes to aneurysm growth and rupture.[31] Other parameters such as ellipticity index; nonsphericity index; undulation index; vessel angle; aneurysm (inclination) angle; relationship between the aneurysm neck, parent artery, and daughter branches; daughter artery ratio, and lateral angle ratio have been proposed to predict the risk of rupture in unruptured aneurysms.[26],[27],[32]
Blood flow hemodynamics play a pivotal role in the initiation, growth, and rupture of intracranial aneurysms. Hassan et al., demonstrated that a high WSS may be responsible for growth and rupture of high-flow intracranial aneurysms, whereas high intra-aneurysmal pressure and flow stasis are responsible for rupture in low-flow aneurysms.[33] WSS is a dynamic frictional force induced by blood moving along the vessel wall. Low WSS can affect vascular remodeling and induce apoptosis of endothelial cells, resulting in vessel wall degeneration and aneurysmal growth and rupture.[33],[34],[35],[36] In contrast, high WSS has been proposed to induce degradation of the internal elastic lamina, resulting in aneurysm formation.[37] In another study, WSS and oscillatory shear index (OSI) were the only independent hemodynamic parameters that were significantly different in ruptured and unruptured aneurysms. OSI measures the directional change of WSS during a cardiac cycle.[38] Other proposed hemodynamic parameters that might have a role in aneurysmal growth and rupture include maximal intra-aneurysmal WSS (MWSS), low WSS area, WSS gradient (WSSG), number of vortices (NV), and relative resistance time (RRT).[38] [Table 2] lists the factors affecting rupture of intracranial aneurysms
Management of UIAs is challenging. The various issues in decision making in the management of unruptured brain aneurysms (UBAs) include (1) observation versus treatment, (2) surgical clipping versus endovascular therapy (EVT), and (3) management of aneurysmal remnants.
With the increasing use of high-resolution neuroimaging techniques, more people with UIAs will be diagnosed each year, and a clear understanding of the current literature is paramount to optimize treatment. Treatment of UIAs is indicated when the risk of rupture from natural history is higher than the risk of treatment and follow-up. Not only does this imply that despite guidelines, therapy should be individualized, but also that the expertise of the individual center should be taken into consideration. The risk of treatment at a center varies depending on the expertise of the neurosurgeon, the neurointerventionist, and the support staff. Also, while there is a fair consensus across all populations regarding the treatment of aneurysms with known high-rupture-risk features such as female sex, young age, maximum size of ≥7 mm, anterior communicating artery, posterior communicating artery, or basilar bifurcation location, a history of subarachnoid hemorrhage, Finnish and Japanese descent, smoking, and hypertension, management of small aneurysms remain a matter of debate. While natural history studies provide some information on the rupture risk of UIAs, they have certain limitations such as selection bias and not being applicable to the entire population across the world. The PHASES score was developed to estimate the risk of aneurysm rupture based on a pooled analysis of six studies.[16] It uses Population (North American or European, Japanese or Finnish descent), Hypertension, Age (<70 or ≥ 70 years), Size (<7 mm, 7–9.9 mm, 10–19.9 mm, and ≥20 mm), Earlier SAH, and Site of aneurysm to predict the risk of rupture. The 5-year absolute aneurysm rupture risk ranges from 0.25% in North American or European population other than those from Finland and in individuals younger than 70 years without vascular risk factors and with a small-sized (<7 mm) internal carotid artery aneurysm to >15% in patients aged ≥70 years with hypertension, a history of SAH, and a large (>20 mm) posterior circulation aneurysm. However, sex, smoking status, and presence of multiple aneurysms were not found to have a significant effect on the risk of rupture. More recently, the PHASES score has been correlated with aneurysm growth as well.[39]
Very few areas in cerebrovascular medicine have created as much differences in opinion as the treatment of UBAs. With the rapid refinement of endovascular techniques and the introduction of flow diversion devices, EVT has become the first-line treatment of most UIAs. There has been no randomized trial of surgical clipping versus EVT for UIAs; however, numerous meta-analyses and systematic reviews have demonstrated the efficacy of EVT over clipping. In a systematic review, clipping resulted in significantly higher disability using the Modified Rankin Scale (odds ratio [OR], 2.83; 95% CI, 1.42–5.63) when compared with coiling. ORs for complications were also higher with clipping (ORs for neurological and cardiac complications were 1.94 and 2.51, respectively). Clipping resulted in significantly greater disability in the short term (≤6 months), but not in the long term (>6 months).[40] The TEAM trial (Trial on Endovascular Aneurysm Management) was an international, randomized, multicenter, controlled trial comparing endovascular treatment and conservative management of UIAs. However, the study was suspended due to logistic reasons. The Canadian Unruptured Endovascular versus Surgery Trial (CURES) is a two-phase trial: the pilot Canadian phase intends to examine the incidence of treatment failure by 1 year, using a composite primary end point that includes anatomic outcomes,[41] and the second international phase aims to compare the clinical efficacy and safety of a surgical or endovascular management strategy at 1 and 5 years. The primary outcome measure is treatment failure, and the secondary outcome measures are morbidity and mortality, hospitalization >5 days, and discharge other than to home. The study is currently recruiting participants (https://www.clinicaltrials.gov/ct2/show/NCT01139892?term = NCT01139892 and rank = 1). [Table 3] lists the studies describing the outcome of surgical and EVT.
Management of aneurysm remnant and recanalization after surgical clipping or EVT are other issues for debate. Re-treatment is a major event in that, in addition to being costly, places the patient at some risk, although much lower than that incurred during the primary treatment. In the long-term follow-up of patients in the International Subarachnoid Aneurysm Trial (ISAT), patients in the endovascular group were more likely to be alive and independent at 10 years than those in the neurosurgery group. The cumulative risk of a rebleed from the target aneurysm was 0.0216 for patients in the endovascular group and 0.0064 for patients in the neurosurgery group. Although the rebleed risk was small, the probability of disability-free survival was significantly greater in the endovascular group than in the neurosurgical group at 10 years.[54] It is not known whether the recurrent hemorrhages occurred only in patients with residual aneurysm filling or recanalized aneurysms. There is no such data available after treatment of UIAs. The term 'target aneurysm recurrence (TAR)' refers to the occurrence of more than one of the following events: (1) target aneurysm rupture, (2) sudden unexplained death, and (3) target aneurysm re-treatment. It is not yet known which aneurysm recurrences or residuals need to be treated to prevent delayed rehemorrhage. Until then, the decision to treat aneurysm recurrence or recanalization depends on individual patient and surgeon preference.
The initial prospective data on 798 patients, who underwent clipping in the ISUIA study, showed a mortality of 2.3% at 1 month and 3% at 1 year, which was slightly higher than that mentioned in previous studies. The combined morbidity (which included substantial functional disability or cognitive impairment) was approximately 13% in patients with a history of previous hemorrhage from another aneurysm as compared with 17.5% in those with no history of an aneurysm. The morbidity noted in ISUIA was higher than that seen in previous studies, primarily owing to the addition of cognitive impairment as a measure of morbidity, as this aspect was largely ignored in previous studies.[9] In a larger prospective cohort from ISUIA consisting of 1917 subjects, the morbidity and mortality rates at 1 year in patients who underwent open surgical repair were 12·6% for subjects with no history of SAH as compared with 10·1% for those with a history of SAH from other aneurysms. In both of these studies, a large size, location in posterior circulation, and advanced age were noted to be predictors of bad outcome.[9],[10] King et al., performed a meta-analysis of mortality and morbidity of elective surgery for asymptomatic aneurysms, which included 28 studies with more than 700 patients, and demonstrated a morbidity rate of 4.1% (95% CI, 2.8–5.8) and a mortality rate of 1.0% (95% CI, 0.4–2.0).[55] In a larger meta-analysis consisting of more than 2400 patients undergoing surgical treatment, a mortality rate of 2.6% and a morbidity rate of 10.9% were reported. The authors also reported that aneurysm location in the anterior circulation and its small size are associated with lower mortality and morbidity as compared with aneurysms in the posterior location and having a large size.[56] Currently, with advancements in angiographic techniques, endovascular approach is rapidly becoming the standard of treatment, unless indicated otherwise. Johnston et al., observed that in-hospital death or discharge to a nursing home or rehabilitation hospital occurred in 10% of the patients treated with EVT compared with 25% of those treated surgically.[57] Prospective data from 498 patients treated with EVT in the ISUIA showed mortality and morbidity rates of 9.1% and 9.5% at 30 days and 1 year, respectively. An advanced age was not a predictor of bad outcome in subgroup analysis, suggesting that EVT might be more suitable for older patients.[10]
Recent data show that a number of morphological and hemodynamic changes and the perianeurysmal environment affect the rupture risk of intracranial aneurysms directly or indirectly. Given the uncertainty in the determination of rupture risk of a large proportion of unruptured intracranial aneurysms, we recommend that therapy should be individualized based on the outcomes at the treating center and patient preference. Financial support and sponsorship Nil. Conflicts of interest There are no conflicts of interest.
[Table 1], [Table 2], [Table 3]
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