Unruptured Intracranial Aneurysms.

Unruptured intracranial aneurysms are currently left untreated if the presumed complication risk of preventive endovascular or neurosurgical intervention is higher than the risk of rupture. Aneurysm wall inflammation and blood pressure are attractive modifiable risk factors of aneurysm rupture and growth. To investigate in patients with an unruptured intracranial aneurysm who do not qualify for preventive endovascular or neurosurgical intervention whether a treatment strategy of acetylsalicylic acid 100 mg/day plus intensive blood pressure treatment (targeted systolic blood pressure < 120 mmHg, monitored with a home blood pressure measuring device) reduces the risk of aneurysm rupture or growth compared with care as usual (no acetylsalicylic acid, targeted office systolic blood pressure < 140 mmHg, no home blood pressure measuring device). We aim to randomize 776 patients 1:1 to the intervention arm or care as usual. Bi-national (Germany and the Netherlands) multicenter, prospective, randomized, open-label phase III trial with blinded outcome assessment. The primary outcome is aneurysm rupture or growth (increase in any aneurysm diameter by ≥ 1 mm) on repeated MR or CT angiography within 36 ± 6 months after randomization. The Prospective Randomized Open-label Trial to Evaluate risk faCTor management in patients with Unruptured intracranial aneurysms (PROTECT-U) is the first randomized trial to investigate if a medical strategy reduces the risk of rupture or growth of intracranial aneurysms in patients not undergoing preventive endovascular or neurosurgical aneurysm treatment. Clinical trial Registration: NCT03063541.

The Natural Course of Unruptured Cerebral Aneurysms

Treatment of small, unruptured intracranial aneurysms is controversial, and the decision of whether to intervene is a difficult one. While a very small subset of unruptured aneurysms go on to rupture, the vast majority remain quiescent for years. Different factors (related to patient, aneurysm, and surgeon/technique) are taken into consideration to guide the decision-making process. The development of 3D imaging techniques has triggered an expanding number of reports on the predictive role of various geometric and hemodynamic measurements on the formation, growth, and rupture of intracranial aneurysms. While estimation of the putative role of these measurements is appealing and sophisticated, most of the studies suffer from a major methodological flaw: unruptured aneurysms are compared with ruptured aneurysms. As most surgeons who have operated on patients with ruptured and unruptured aneurysms are well aware, the 2 entities are often completely different. In their article, Lin and coworkers1 analyze a relatively large cohort of middle cerebral artery (MCA) aneurysms and compare unruptured and ruptured aneurysms with respect to various geometric measurements calculated on 3D CT angiography reconstructions. The authors conclude that aspect ratio, flow angle, and parentdaughter angle were more common in the ruptured rather than in the unruptured cohort. The authors of this study make an attempt to consider a homogeneous group of aneurysms by selecting only patients with MCA aneurysms. However, the 2 groups under consideration are still quite different, and the study is not devoid of the significant methodological flaws of similar studies. I suspect that composition and strength of the aneurysm wall and time elapsed from aneurysm formation to its detection are much more important differences between ruptured and unruptured aneurysms than are geometric differences. Most aneurysms that go on to rupture most likely do so shortly after their formation at a time when the aneurysm wall is more vulnerable to hemodynamic stress.2,3 It is possible that aneurysm geometry plays a role in this early stage of vulnerability, hence the differences between ruptured and unruptured aneurysms. While the growing body of literature on fluid dynamics and aneurysm geometry has had important repercussions in designing newer treatments for intracranial aneurysms (such as flow diverters), the ever-increasing list of complex geometric factors associated with “rupture” has done little to change our decision making in patients with unruptured aneurysms or our understanding of the formation, growth, and rupture of intracranial aneurysms. A prospective study of conservatively treated unruptured aneurysms with analysis of geometric factors associated with rupture risk may provide useful information, but even such a study could be inconclusive because of the small number of end points (that is, ruptures) and the interaction with other important variables (aneurysm size, patient age, aneurysm location, and correctable risk factors for aneurysm rupture). Despite the growing body of literature on aneurysm/parent artery geometry and computational fluid analysis, the decision making in treating unruptured intracranial aneurysms continues to be based on art rather than science. (http://thejns.org/doi/abs/10.3171/2012.3.JNS112260)

Background The UK Small Aneurysm Trial has shown that ultrasonographic surveillance is a safe management option for patients with small abdominal aortic aneurysms (4·0–5·5 cm in diameter), with an annual rupture rate of 1 per cent. In this study risk factors associated with aneurysm rupture have been investigated using both patients randomized into the UK Small Aneurysm Trial and those monitored for aneurysm growth in the associated study. Methods The cohort of patients included 1090 from the trial and 1167 from the associated study. In this cohort of 2257 patients (79 per cent men), aged 59–77 years, 103 instances of abdominal aortic aneurysm rupture were identified during the 7-year follow-up (1991–1998). The relationship between rupture and ten prespecified risk factors (including age, sex, aneurysm diameter, smoking status, plasma cholesterol, lung function and ankle: brachial pressure index) was investigated using Kaplan–Meier survival and Cox regression analysis. Results Almost all patients (98 per cent) had initial aneurysm diameters in the range 3–6 cm and the majority of ruptures (76 per cent) occurred in patients with aneurysms known to be larger than 5 cm in diameter. Kaplan–Meier survival and Cox regression analysis were used to identify baseline risk factors associated with aneurysm rupture. After 3 years, the annual rate of aneurysm rupture was 2·2 (95 per cent confidence interval 1·7–2·8) per cent. The risk of rupture was independently and significantly associated with female sex (P &amp;lt; 0·001), larger initial aneurysm diameter (P &amp;lt; 0·001), lower FEV1 (P = 0·004), current smoking (P = 0·01) and higher mean blood pressure (P = 0·01). Age, body mass index, serum cholesterol concentration and ankle: brachial pressure index were not associated with an increased risk of aneurysm rupture. Conclusion Within this cohort of patients women had a threefold higher risk of aneurysm rupture than men. Effective control of blood pressure and cessation of smoking are likely to diminish the risk of rupture.

Object. The authors conducted a study to investigate the long-term natural history of unruptured intracranial aneurysms and the predictive risk factors determining subsequent rupture in a patient population in which surgical selection of cases was not performed. Methods. One hundred forty-two patients with 181 unruptured aneurysms were followed from the 1950s until death or the occurrence of subarachnoid hemorrhage or until the years 1997 to 1998. The annual and cumulative incidence of aneurysm rupture as well as several potential risk factors predictive of rupture were studied using life-table analyses and Cox's proportional hazards regression models including time-dependent covariates. The median follow-up time was 19.7 years (range 0.8–38.9 years). During 2575 person-years of follow up, there were 33 first-time episodes of hemorrhage from previously unruptured aneurysms, for an average annual incidence of 1.3%. In 17 patients, hemorrhage led to death. The cumulative rate of bleeding was 10.5% at 10 years, 23% at 20 years, and 30.3% at 30 years after diagnosis. The diameter of the unruptured aneurysm (relative risk [RR] 1.11 per mm in diameter, 95% confidence interval [CI] 1–1.23, p = 0.05) and patient age at diagnosis inversely (RR 0.97 per year, 95% CI 0.93–1, p = 0.05) were significant independent predictors for a subsequent aneurysm rupture after adjustment for sex, hypertension, and aneurysm group. Active smoking status at the time of diagnosis was a significant risk factor for aneurysm rupture (RR 1.46, 95% CI 1.04–2.06, p = 0.033) after adjustment for size of the aneurysm, patient age, sex, presence of hypertension, and aneurysm group. Active smoking status as a time-dependent covariate was an even more significant risk factor for aneurysm rupture (adjusted RR 3.04, 95% CI 1.21–7.66, p = 0.02). Conclusions. Cigarette smoking, size of the unruptured intracranial aneurysm, and age, inversely, are important factors determining risk for subsequent aneurysm rupture. The authors conclude that such unruptured aneurysms should be surgically treated regardless of their size and of a patient's smoking status, especially in young and middle-aged adults, if this is technically possible and if the patient's concurrent diseases are not contraindications. Cessation of smoking may also be a good alternative to surgery in older patients with small-sized aneurysms.

The authors conducted a study to investigate the long-term natural history of unruptured intracranial aneurysms and the predictive risk factors determining subsequent rupture in a patient population in which surgical selection of cases was not performed. One hundred forty-two patients with 181 unruptured aneurysms were followed from the 1950s until death or the occurrence of subarachnoid hemorrhage or until the years 1997 to 1998. The annual and cumulative incidence of aneurysm rupture as well as several potential risk factors predictive of rupture were studied using lifetable analyses and Cox's proportional hazards regression models including time-dependent covariates. The median follow-up time was 19.7 years (range 0.8-38.9 years). During 2575 person-years of follow up, there were 33 first-time episodes of hemorrhage from previously unruptured aneurysms, for an average annual incidence of 1.3%. In 17 patients, hemorrhage led to death. The cumulative rate of bleeding was 10.5% at 10 years, 23% at 20 years, and 30.3% at 30 years after diagnosis. The diameter of the unruptured aneurysm (relative risk [RR] 1.11 per mm in diameter, 95% confidence interval [CI] 1-1.23, p = 0.05) and patient age at diagnosis inversely (RR 0.97 per year, 95% CI 0.93-1, p = 0.05) were significant independent predictors for a subsequent aneurysm rupture after adjustment for sex, hypertension, and aneurysm group. Active smoking status at the time of diagnosis was a significant risk factor for aneurysm rupture (RR 1.46, 95% CI 1.04-2.06, p = 0.033) after adjustment for size of the aneurysm, patient age, sex, presence of hypertension, and aneurysm group. Active smoking status as a time-dependent covariate was an even more significant risk factor for aneurysm rupture (adjusted RR 3.04, 95% CI 1.21-7.66, p = 0.02). Cigarette smoking, size of the unruptured intracranial aneurysm, and age, inversely, are important factors determining risk for subsequent aneurysm rupture. The authors conclude that such unruptured aneurysms should be surgically treated regardless of their size and of a patient's smoking status, especially in young and middle-aged adults, if this is technically possible and if the patient's concurrent diseases are not contraindications. Cessation of smoking may also be a good alternative to surgery in older patients with small-sized aneurysms.

Inflammation plays an integral role in the formation, growth, and progression to rupture of unruptured intracranial aneurysms. Aneurysm wall enhancement (AWE) in high-resolution magnetic resonance imaging (HR-MRI) has emerged as a surrogate biomarker of vessel wall inflammation and unruptured intracranial aneurysm instability. We investigated the correlation between anti-inflammatory drug use and three-dimensional AWE of fusiform intracranial aneurysms (FIAs). We retrospectively analyzed consecutive patients with FIAs in our database who underwent 3T HR-MRI at three Chinese centers. FIAs were classified as fusiform-type, dolichoectatic-type, or transitional-type. AWE was objectively defined using the aneurysm-to-pituitary stalk contrast ratio in three-dimensional space by determining the contrast ratio of the average signal intensity in the aneurysmal wall and pituitary stalk on post-contrast T1-weighted images. Data on aneurysm size, morphology, and location, as well as patient demographics and comorbidities, were collected. Univariate and multivariate logistic regression analyses were performed to determine factors independently associated with AWE of FIAs on HR-MRI. In total, 127 FIAs were included. In multivariate analysis, statin use (β = -0.236, P = 0.007) was the only independent factor significantly associated with decreased AWE. In the analysis of three FIA subtypes, the fusiform and transitional types were significantly associated with statin use (rs = -0.230, P = 0.035; and rs = -0.551, P = 0.010; respectively). It establishes an incidental correlation between the use of statins daily for ≥ 6 months and decreased AWE of FIAs. The findings also indicate that the pathophysiology may differ among the three FIA subtypes.

The prevalence of intracranial aneurysms is estimated to be around 3% in the general population. Although these are often incidental findings, they potentially carry the risk of rupture, with all of the devastating consequences of SAH. Several risk factors of aneurysm rupture have been identified, including aneurysm size, irregular shape, and location. Although it is widely accepted that the risk of rupture increases with size, small aneurysms remain the cause of a significant percentage of aneurysmal SAH. Up to 30% of patients with acute aneurysmal SAH have multiple aneurysms. Determining the site of rupture in these patients can be challenging, given that the results of imaging studies and clinical symptoms are sometimes inconclusive. It would be extremely useful to identify new imaging biomarkers of aneurysm instability which could have an impact on patient management and qualification for treatment. High-resolution vessel wall magnetic resonance imaging (HR-VW MRI) opens up new possibilities for improved characterisation of intracranial vasculature. One of the most promising clinical applications of this new imaging tool is the evaluation of intracranial aneurysms. Aneurysm wall enhancement (AWE) on HR-VW MRI is believed to be a marker for wall inflammation and, potentially, for aneurysm instability. In this article, we summarise the published literature on AWE with special emphasis on its use in determining the site of rupture in the setting of acute SAH in patients with multiple aneurysms, as well as its role in identifying unruptured aneurysms which are at the greatest risk of rupture. More and larger studies are needed to definitively establish the role of AWE on HR-VW MRI in the diagnostic workup of patients with intracranial aneurysms.

Concomitant unruptured intracranial aneurysms (UIAs) in patients with craniopharyngioma (CP) pose a challenge for surgical management. This study presents the largest known single-institution case series to investigate the incidence of UIA in CP patients, with the aim of exploring the potential risk factors for the occurrence of UIA in CP patients and proposing treatment strategies. The authors retrospectively reviewed the records of 289 adult CP patients treated in their department between January 2020 and August 2022. Routine CT angiography (CTA) was performed preoperatively in all cases. Logistic regression analysis was used to identify the risk factors for the occurrence of aneurysms. Aneurysms with the following characteristics were considered to have a high risk of intraoperative rupture and required treatment before tumor resection: 1) preliminary assessment of a high inherent risk of rupture (risk of rupture in their natural progression); and 2) location close to the tumor, irregular shape, and/or growth toward the tumor, even if the preliminary assessment indicated a low inherent risk of rupture. Twenty-three of 289 CP patients (7.96%, 95% CI 5.36-11.6) were diagnosed with both CP and UIA (CP-UIA). Hypertension (OR 4.148, 95% CI 1.654-10.398; p = 0.002), estrogen deficiency (OR 3.097, 95% CI 1.241-7.731; p = 0.015), and suprasellar tumor (OR 4.316, 95% CI 1.596-11.67; p = 0.004) were independent risk factors for intracranial aneurysms (IAs) in CP patients. Among the 23 CP-UIA patients, 6 (26.1%) with a high risk of aneurysm rupture underwent endovascular treatment (EVT) before tumor resection. Seventeen (73.9%) patients with a low risk of rupture underwent tumor resection only. The incidence rate of IA in patients with CP was higher than that in the general population. Routine preoperative CTA is advised for adult CP patients. Patients with papillary CP exhibited a higher proportion of CP-UIAs. Older age, hypertension, estrogen deficiency, and suprasellar tumor were independent risk factors for the occurrence of IAs in CP patients. IAs in CP patients are predominantly located in the C6 and C7 segments of the internal carotid artery and are often suitable for EVT. When treating CP-UIAs, tumor-related symptoms, risk of aneurysm rupture, the spatial relationship between the tumor and IA, and the approach for tumor resection should be considered.

ObjectiveAneurysm wall enhancement (AWE) is a potential biomarker of inflammation within the aneurysm wall that has been correlated with a higher risk of rupture. Aspirin (ASA) may decrease AWE due to its anti-inflammatory properties. We aimed to assess the effect of ASA on AWE in an animal model and a cohort of patients with unruptured intracranial aneurysms (UIAs).MethodsThree rabbits with elastase-induced aneurysms were exposed to ASA for 8 weeks and three rabbits were used as controls. 3 T high-resolution magnetic resonance imaging (HR-MRI) was performed at 7 days and 8 weeks to evaluate changes in AWE through histological and immunohistological analyses. Additionally, we evaluated AWE in patients who underwent imaging with a 3 T HR-MRI protocol. ASA exposure was defined as daily intake of 81 mg for at least six months prior to HR-MRI. AWE was quantified using three-dimensional AWE maps and histograms.ResultsAmong rabbits exposed to ASA, the mean AWE was lower at 8 weeks compared to the controls (2.11 vs 2.15, p = 0.13). Immunostaining of the aneurysm wall in rabbits that received ASA revealed a reduced expression of CD68 + or cyclooxygenase-2 + cells, compared to the controls. A total of 99 patients with 120 UIAs were included in the HR-MRI analysis of UIAs. UIAs exposed to ASA (22/120) had significantly lower median AWE than those that were not exposed (0.60 vs 0.72, p = 0.032).ConclusionASA therapy is associated with an objective reduction in AWE, suggesting a potential role in lowering the risk of aneurysm rupture.

Morphological changes in unruptured intracranial aneurysms (UIAs) are an imaging marker of aneurysm instability. Recent studies have indicated the ability of MR vessel wall imaging (VWI) to stratify unstable UIAs based on a correlation with histopathological aneurysm wall inflammation. In the present study the authors investigated the relationships between aneurysm growth patterns and the segmentation of aneurysm wall enhancement (AWE) in VWI. A total of 120 aneurysms with serial angiography from a follow-up period of at least 2 years (mean 65 months, range 24-215 months) were assessed by VWI. Two readers independently evaluated the patterns of morphological changes (stable, whole sac expansion, and secondary aneurysm formation) and the segmentation of AWE (no, focal, and circumferential AWE). The contrast enhancement ratio of the aneurysm wall versus the pituitary stalk (CRstalk) was calculated for the quantitative assessment of AWE. Statistical analyses were performed to investigate the relationships between AWE patterns and patient baseline profiles, aneurysm characteristics, and morphological modifications. Forty-one of 120 UIAs (34%) exhibited aneurysm growth (whole sac expansion in 19 and secondary aneurysm formation in 22). AWE was detected in 35 of 120 UIAs (focal AWE in 25 and circumferential AWE in 10). The maximum diameter of, irregularities in, and morphological modifications in aneurysms were associated with the segmentation of AWE. Focal AWE correlated with secondary aneurysm formation, and circumferential AWE correlated with whole sac expansion. In focal AWE, CRstalk was significantly higher in secondary aneurysm formation than in stable UIAs. UIAs without AWE (categorized as no AWE) correlated with aneurysm stability. The segmentation of AWE was associated with aneurysm growth scenarios and may provide a novel insight into the evaluation of unstable UIAs.

Risk factors for growth of unruptured intracranial aneurysms (UIAs) during a lifelong follow-up in relation to subsequent rupture are unknown. The author's aim in this study was to investigate whether risk factors for UIA growth are different for those that lead to rupture than for those that do not. The series consists of 87 patients with 111 UIAs diagnosed before 1979, when UIAs were not treated. A total follow-up time of the patients was 2648 person-years for all-cause death and 2182 years when patients were monitored until the first rupture, death due to unrelated causes, or the last contact (annual incidence of aneurysm rupture, 1.2%). The follow-up time between aneurysm measurements was 1669 person-years. Risk factors for UIA growth were analyzed in relation to subsequent rupture. The median follow-up time between aneurysm measurements was 21.7 years (range 1.2-51.0 years). In 40 of the 87 patients (46%), the UIAs increased in size ≥ 1 mm, and in 31 patients (36%) ≥ 3 mm. All ruptured aneurysms in 27 patients grew during the follow-up of 324 person-years (mean growth rates 6.1 mm, 0.92 mm/year, and 37%/year), while growth without rupture occurred in 13 patients during 302 follow-up years (3.9 mm, 0.18 mm/year, and 4%/year) and no growth occurred in 47 patients during 1043 follow-up years. None of the 60 patients without aneurysm rupture experienced one during the subsequent 639 follow-up years after the last aneurysm measurement. Independent risk factors for UIA growth (≥ 1 mm) in all patients were female sex (adjusted OR 3.08, 95% CI 1.04-9.13) and smoking throughout the follow-up time (adjusted OR 3.16, 95% CI 1.10-9.10), while only smoking (adjusted OR 4.36, 95% CI 1.27-14.99) was associated with growth resulting in aneurysm rupture. Smoking was the only independent risk factor for UIA growth ≥ 3 mm resulting in aneurysm rupture (adjusted OR 4.03, 95% CI 1.08-15.07). Cigarette smoking at baseline predicted subsequent UIA growth, while smoking at the end of the follow-up was associated with growth resulting in aneurysm rupture. Cigarette smoking is an important risk factor for UIA growth, particularly for growth resulting in rupture. Cessation of smoking may reduce the risk of devastating aneurysm growth.

BackgroundRuptured aneurysms, the commonest cause of nontraumatic subarachnoid hemorrhage, can be catastrophic; the mortality and morbidity of affected patients being very high. Some risk factors, such as smoking, hypertension and female sex have been identified, whereas others, such as hemodynamics, imaging, and genomics, remain unclear. Currently, no accurate model that includes all factors for predicting such rupture is available. We plan to use data from a large cohort of Chinese individuals to set up a multidimensional model for predicting risk of rupture of unruptured intracranial aneurysms (UIAs).MethodsThe China Intracranial Aneurysm Project-2 (CIAP-2) will comprise screening of a cohort of 500 patients with UIA (From CIAP-1) and focus on hemodynamic factors, high resolution magnetic resonance imaging (HRMRI) findings, genetic factors, and biomarkers. Possible risk factors for rupture of UIA, including genetic factors, biomarkers, HRMRI, and hemodynamic factors, will be analyzed. The first project of the China Intracranial Aneurysm Project (CIAP-1; chaired by the Department of Neurosurgery, Tangdu Hospital, Fourth Military Medical University, Xi’an, Shaanxi, China) will prospectively collect a cohort of 5000 patients with UIA from 20 centers in China, and collect baseline information for each patient. Multidimensional data will be acquired in follow-up assessments. Statistically significant clinical features in the UIA cohort will also be analyzed and integrated into the model for predicting risk of UIA rupture. After the model has been set up, the resultant evidence-based prediction will provide a preliminary theoretical basis for treating aneurysms at high risk of rupture.DiscussionThis study will explore the risk of rupture of aneurysms and develop a scientific multidimensional model for predicting rupture of unruptured intracranial aneurysms.Clinical Trials registration A Study on a Multidimensional Prediction Model for Rupture Risk of Unruptured Intracranial Aneurysms (CIAP-2), NCT03133624. Registered: 16 April 2017. https://clinicaltrials.gov/ct2/show/NCT03133624

BackgroundIntracranial aneurysms (IAs) are common in the population and current imaging-based rupture risk assessment needs to be refined. We aimed to use four-dimensional CT angiography (4D-CTA) to investigate the associations...

Abdominal Aortic Calcification Volume Is Associated with Wall Enhancement of Unruptured Intracranial Aneurysm