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Objective:In counselling patients with an unruptured intracranial aneurysm (UIA), quality-of-life (QoL) outcomes are important for informed decision-making. We evaluated QoL outcomes in patients with and without preventive aneurysm occlusion at multiple time points during the first year after UIA diagnosis and studied predictors of QoL outcomes.Methods:We performed a prospective cohort study in patients ≥18 years old with a newly diagnosed UIA in two tertiary referral centers in the Netherlands between 2017 and 2019. Patients were sent QoL questionnaires at 7 (aneurysm occlusion) or 5 (no occlusion) moments during the first year after diagnosis. We collected baseline data on patient and aneurysm characteristics, passive coping style (Utrecht Coping List), occlusion modality, and neurological complications. We assessed health-related QoL (HRQoL) with the EuroQol 5-dimensions (EQ-5D), emotional functioning with the Hospital Anxiety and Depression Scale (HADS), and restrictions in daily activities with the Utrecht Scale for Evaluation of Rehabilitation-Participation (USER-P). We used a linear mixed effects model to assess the course of QoL over time and to explore predictors of QoL outcomes.Results:Of 153 eligible patients, 99 (65%) participated, of whom 30/99 (30%) underwent preventive occlusion. Patients undergoing occlusion reported higher baseline levels of passive coping, anxiety and depression, and restrictions than patients without occlusion. During recovery after occlusion, patients reported more restrictions compared to baseline (adjusted USER-P decrease one-month post-occlusion: -12.8 (95%CI:-23.8- -1.9). HRQoL and emotional functioning gradually improved after occlusion (EQ-5D increase at one-year: 8.6 (95%CI:0.1-17.0) and HADS decrease at one-year: -5.4 (95%CI:-9.4- -1.5)). In patients without occlusion, the largest HRQoL improvement occurred directly after visiting the outpatient aneurysm clinic (EQ-5D increase: 9.2 (95%CI:5.5-12.8)). At one-year, QoL outcomes were comparable in patients with and without occlusion. Factors associated with worse QoL outcomes were a passive coping style in all patients, complications in patients with occlusion and higher rupture risks in patients without occlusion.Conclusions:After UIA diagnosis, QoL improves gradually after preventive occlusion and directly after counselling at the outpatient clinic in patients without occlusion, resulting in comparable one-year QoL outcomes. A passive coping style is an important predictor of poor QoL outcomes in all UIA patients.

Objective:Preventive unruptured intracranial aneurysm occlusion can reduce the risk of subarachnoid hemorrhage, but both endovascular and microneurosurgical treatment carry a risk of serious complications. To improve individualized management decisions, we developed risk scores for complications of endovascular and microneurosurgical treatment based on easily retrievable patient, aneurysm, and treatment characteristics.Methods:For this multicenter cohort study, we combined individual patient data from unruptured intracranial aneurysm patients ≥18 years undergoing preventive endovascular treatment (standard, balloon-assisted or stent-assisted coiling, Woven EndoBridge-device, or flow-diverting stent) or microneurosurgical clipping at one of 10 participating centers from three continents between 2000-2018. The primary outcome was death from any cause or clinical deterioration from neurological complications ≤30 days. We selected predictors based on previous knowledge about relevant risk factors and predictor performance and studied the association between predictors and complications with logistic regression. We assessed model performance with calibration plots and concordance (c) statistics.Results:Of 1282 included patients, 94 (7.3%) had neurological symptoms that resolved c-statistic was 0.72 (95%CI:0.67-0.77) and the absolute complication risk ranged from 3.2% (95%CI:1.6%-14.9%;≤1 point) to 33.1% (95%CI:25.4%-41.5%;≥6 points). For microneurosurgical treatment (n=530), the c-statistic was 0.72 (95%CI:0.67-0.77) and the complication risk ranged from 4.9% (95%CI:1.5%-14.9%;≤1 point) to 49.9% (95%CI:39.4%-60.6%;≥6 points).Conclusions:The SAFETEA risk scores for endovascular and microneurosurgical treatment are based on seven easily retrievable risk factors to predict the absolute risk of procedural complications in patients with unruptured intracranial aneurysms. The scores need external validation before the predicted risks can be properly used to support decision making in clinical practice.

BACKGROUND: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months.METHODS: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812.FINDINGS: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups.INTERPRETATION: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale.FUNDING: Fonds NutsOhra.

Background: Whether certain activities can trigger spontaneous intracerebral hemorrhage (ICH) remains unknown. Insights into factors that trigger vessel rupture resulting in ICH improves knowledge on the pathophysiology of ICH. We assessed potential trigger factors and their risk for ICH onset. Methods: We included consecutive patients diagnosed with ICH between July 1, 2013, and December 31, 2019. We interviewed patients on their exposure to 12 potential trigger factors (eg, Valsalva maneuvers) in the (hazard) period soon before onset of ICH and their normal exposure to these trigger factors in the year before the ICH. We used the case-crossover design to calculate relative risks (RR) for potential trigger factors. Results: We interviewed 149 patients (mean age 64, 66% male) with ICH. Sixty-seven (45%) had a lobar hemorrhage, 60 (40%) had a deep hemorrhage, 19 (13%) had a cerebellar hemorrhage, and 3 (2%) had an intraventricular hemorrhage. For ICH in general, there was an increased risk within an hour after caffeine consumption (RR=2.5 [95% CI=1.8–3.6]), within an hour after coffee consumption alone (RR=4.8 [95% CI=3.3–6.9]), within an hour after lifting >25 kg (RR=6.6 [95% CI=2.2–19.9]), within an hour after minor head trauma (RR=10.1 [95% CI=1.7–60.2]), within an hour after sexual activity (RR=30.4 [95% CI=16.8–55.0]), within an hour after straining for defecation (RR=37.6 [95% CI=22.4–63.4]), and within an hour after vigorous exercise (RR=21.8 [95% CI=12.6–37.8]). Within 24 hours after flu-like disease or fever, the risk for ICH was also increased (RR=50.7 [95% CI=27.1–95.1]). Within an hour after Valsalva maneuvers, the RR for deep ICH was 3.5 (95% CI=1.7–6.9) and for lobar ICH the RR was 2.0 (95% CI=0.9–4.2). Conclusions: We identified one infection and several blood pressure related trigger factors for ICH onset, providing new insights into the pathophysiology of vessel rupture resulting in ICH.

Background and Purpose— Genome-wide association studies significantly link intracranial aneurysm (IA) to single-nucleotide polymorphisms (SNPs) in 6 genomic loci. To gain insight into the relevance of these IA-associated SNPs, we aimed to identify regulatory regions and analyze overall gene expression in the human circle of Willis (CoW), on which these aneurysms develop. Methods— We performed chromatin immunoprecipitation and sequencing for histone modifications H3K4me1 and H3K27ac to identify regulatory regions, including distal enhancers and active promoters, in postmortem specimens of the human CoW. These experiments were complemented with RNA sequencing on the same specimens. We determined whether these regulatory regions overlap with IA-associated SNPs, using computational methods. By combining our results with publicly available data, we investigated the effect of IA-associated SNPs on the newly identified regulatory regions and linked them to potential target genes. Results— We find that IA-associated SNPs are significantly enriched in CoW regulatory regions. Some of the IA-associated SNPs that overlap with a regulatory region are likely to alter transcription factor binding, and in proximity to these regulatory regions are 102 genes that are expressed in the CoW. In addition, gene expression in the CoW is enriched for genes related to cell adhesion and the extracellular matrix. Conclusions— CoW regulatory regions link IA-associated SNPs to genes with a potential role in the development of IAs. Our data refine previous predictions on SNPs associated with IA and provide a substantial resource from which candidates for follow-up studies can be prioritized.

Background and Purpose— We updated our previous review from 1996 on the risk of rupture of unruptured intracranial aneurysms, aiming to include the newly published articles. Methods— We reviewed all studies from our former meta-analysis and performed a Medline search for new studies published after 1996. We calculated overall risks of rupture for studies with a mean follow-up time of 10 years. Relative risks (RR) were calculated by comparing the risk of rupture in patients with and without potential risk factors. We aimed to perform multivariable analyses of the different risk factors with meta-regression analysis. Results— We included 19 studies (10 new) with 4705 patients and 6556 unruptured aneurysms (follow-up 26 122 patient-years). The overall rupture risks were 1.2% (follow-up 10 years). In the univariable analysis, statistically significant risk factors for rupture were age >60 years (RR 2.0; 95% confidence interval [CI], 1.1 to 3.7), female gender (RR 1.6; 95% CI, 1.1 to 2.4), Japanese or Finnish descent (RR 3.4; 95% CI, 2.6 to 4.4), size >5 mm (RR 2.3; 95% CI, 1.0 to 5.2), posterior circulation aneurysm (RR 2.5; 95% CI, 1.6 to 4.1), and symptomatic aneurysm (RR 4.4; 95% CI, 2.8 to 6.8). Meta-regression analysis yielded implausible results. Conclusions— Age, gender, population, size, site, and type of aneurysm should be considered in the decision whether to treat an unruptured aneurysm. Pooled multivariable analyses of individual data are needed to identify independent risk factors and to provide more reliable risk estimates for individual patients.

Intracranial aneurysm is probably a complex disease with both genetic and non-genetic or environmental risk factors contributing to the etiology of the disease. A disruption of the extracellular matrix (ECM) of the arterial wall is a likely factor in the pathogenesis of intracranial aneurysms. We analyzed 44 potential candidate genes involved in the maintenance of the integrity of the ECM in 382 Dutch Caucasian patients with intracranial aneurysms and 609 Dutch Caucasian controls for 384 tag single nucleotide polymorphisms (SNPs) using the GoldenGate assay on an Illumina BeadStation 500 GX. We identified SNPs that were associated with intracranial aneurysms (P< 0.01) in six of these 44 genes: serpinel (SERPINE1, P = 0.0008), transforming growth factor beta induced (TGFBI, P = 0.0026), perlecan (HSPG2, P = 0.0044), fibronectin (FN1, P = 0.0069), fibrillin 2 (FBN2, P = 0.0077) and alpha 1 type IV collagen (COL4A1, P = 0.0087). In a second independent cohort of 310 Dutch Caucasian intracranial aneurysm patients and 336 Dutch Caucasian controls, the association for the HSPG2 gene [combined odds ratio (OR) 1.33, 95% confidence interval (Cl) 1.13-1.57, P = 6 x 10 -4 ] was replicated. The population attributable risk (PAR) for this SNP is 19%. Combining the two cohorts still showed association for the SERPINE1 (combined OR 1.27, 95% Cl 1.07-1.50, P = 0.004, PAR 6%), FBN2 (combined OR 1.37, 95% Cl 1.07-1.75, P=0.01, PAR 3%) and COL4A1 (combined OR 1.22, 95% Cl 1.05-1.42, P = 0.007, PAR 7%) genes. These PARs are likely to be overestimates as they are calculated from the joint analyses combining stages 1 and 2 of our association study. Our findings indicate that variation in genes involved in the maintenance of the integrity of the ECM of the arterial wall plays a role in susceptibility to intracranial aneurysms. These findings further support our hypothesis that diminished maintenance of the ECM of the arterial wall is important in the development of intracranial aneurysms.

Background and Purpose— Patients with a history of subarachnoid hemorrhage (SAH) or familial intracranial aneurysms (FIA) are at increased risk for aneurysm formation and rupture. Small aneurysms detected at screening may be left untreated and followed over time. The yield of follow-up CT/MR angiography (CTA/MRA) 1 or 2 years after detection to evaluate growth of these aneurysms is unknown. Methods— We prospectively followed patients with small aneurysms detected at screening at a 1-year interval using CTA or MRA. We assessed size, site, and number of the aneurysms and risk factors such as smoking, alcohol use, and hypertension. We evaluated the short-term growth and rupture rate and possible risk factors for growth and rupture. Results— Ninety-three patients (67 with a history of SAH, 16 with FIA, and 10 with a history of both SAH and FIA) with 125 aneurysms underwent CTA/MRA follow-up. Sixty-five patients were followed up once, and 28 patients were followed up twice (median follow-up time, 1.3 years). In 3 of the 93 patients (3.2%), an aneurysm enlarged slightly (0.5 to 1.5 mm). Two patients (2.2%) had a SAH: 1 from an aneurysm at the clip-site from a previous operation that ruptured without enlargement and the other from a newly developed dissecting aneurysm. The only statistically significant risk factor for growth and rupture was a history of both SAH and FIA (relative risk, 10.1; 95% CI, 1.3 to 81.9). Conclusions— The yield of early follow-up of small aneurysms in patients with a history of SAH or FIA is small and does not eliminate the risk of rupture. Whether follow-up at intervals >1 year is useful requires further study.

Background and Purpose— Because intracranial aneurysms develop during life, patients with subarachnoid hemorrhage (SAH) and successfully occluded aneurysms are at risk for a recurrence. We studied the incidence of and risk factors for recurrent SAH in patients who regained independence after SAH and in whom all aneurysms were occluded by means of clipping. Methods— From a cohort of patients with SAH admitted between 1985 and 2001, we included those patients who were discharged home or to a rehabilitation facility. We interviewed these patients about new episodes of SAH. We retrieved all medical records and radiographs in case of reported recurrences. If patients had died, we retrieved the cause of death. We analyzed the incidence of and risk factors for recurrent SAH by Kaplan-Meier curves and Cox regression analysis. Results— Of 752 patients with 6016 follow-up years (mean follow up 8.0 years), 18 had a recurrence. In the first 10 years after the initial SAH, the cumulative incidence of recurrent SAH was 3.2% (95% confidence interval [CI], 1.5% to 4.9%) and the incidence rate 286 of 100 000 patient-years (95% CI, 160 to 472 per 100 000). Risk factors were smoking (hazard ratio [HR], 6.5; 95% CI, 1.7 to 24.0), age (HR, 0.5 per 10 years; 95% CI, 0.3 to 0.8) and multiple aneurysms at the time of the initial SAH (HR, 5.5; 95% CI, 2.2 to 14.1). Conclusions— After SAH, the incidence of a recurrence within the first 10 years is 22 (12 to 38) times higher than expected in populations with comparable age and sex. Whether this increased risk justifies screening for recurrent aneurysms in patients with a history of SAH requires further study.

Objective: Patients who have been successfully treated for subarachnoid hemorrhage (SAH) are at risk for new episodes. The authors studied the effect of screening with CT angiography (CTA) for new aneurysms. Methods: In a decision model, the authors compared the strategies “screening” and “no screening” after SAH. A literature review yielded the risks of aneurysm recurrence, complications of CTA, and re-treatment. The authors estimated the expected number of quality-adjusted life-years (QALYs), the number of SAH, and the mortality and disability rates for both strategies. They evaluated screening at intervals of 2, 5, and 10 years after SAH, using 10 years and remaining life expectancy as time horizon. Results: The expected number of QALYs 10 years after clipping was virtually the same for no screening (8.33), screening once after 5 years (8.28), and screening every 2 years (8.27). With screening every 2 years, the expected rate of new SAH decreased from 1.9 to 0.5%, and mortality decreased from 0.9 to 0.6%; however, the disability rate increased from 0.5 to 1.9%. Results were comparable with remaining life expectancy as time horizon and for screening after initial treatment with coils. The key estimates of the analyses were the incidence and rupture rate of new aneurysms, the risk of dying from recurrent SAH, the utility of disability, and the risk of complications from DSA and re-treatment. Conclusions: Presently, screening for new aneurysms after subarachnoid hemorrhage cannot be recommended. Screening may prevent new episodes of subarachnoid hemorrhage but with too high a cost in terms of complications from preventive treatment.

Background and Purpose— In families with ≥2 first-degree relatives with subarachnoid hemorrhage (SAH), screening for aneurysms is often recommended. The benefit of repeated screening and the interval at which screening should be performed are unknown. We studied patient compliance and the yield of repeated screening for familial intracranial aneurysms. Methods— Relatives with familial SAH screened between 1990 and 1997 were advised to return every 5 years for follow-up screening with MR angiography. If neurosurgical clipping had been performed in the past, screening was done with CT angiography. We analyzed the results for the group as a whole and for the subgroups of relatives with and without previous aneurysms. Results— Of 129 relatives who were advised to undergo further screening, 27 did not return, 74 had 1 repeated screening, and 28 had a second repeated screening. We detected 10 new aneurysms in 9 of the 102 screened relatives (9%), 3 of the 19 relatives with previous aneurysms (16%), and 6 of the 83 relatives without previous aneurysms (7%). One of the 9 subjects with a new aneurysm and 1 other relative had an SAH 3 years after a negative screening procedure. Conclusions— In persons with familial occurrence of aneurysms, the motivation for repeated screening every 5 years is high and the yield is considerable, particularly in relatives who have been treated for aneurysms in the past. The occurrence of SAH

Objective: We investigated whether risk alleles of single nucleotide polymorphisms associated with intracranial aneurysm (IA) are enriched in patients with familial IA, IA located at the middle cerebral artery (MCA), or IA rupture at a younger age. Methods: In this case-only study, we calculated genetic risk scores (GRS) for 973 Dutch and 718 Finnish patients with IA by summing effect size–weighted risk allele counts of 7 single nucleotide polymorphisms associated with IAs previously identified through genome-wide association studies. We tested the GRS for association with presence of familial IA or IA at the MCA using logistic regression, and with age at time of IA rupture using linear regression. We also calculated odds ratios with 95% confidence intervals for the proportion of patients with each characteristic in the highest compared with the lowest GRS tertile. Results: GRS were higher in IA at the MCA in the Dutch ( p = 2.5 × 10 −4 ), Finnish ( p = 0.039), and combined cohort ( p = 4.9 × 10 −5 ). GRS were not associated with familial IA in the Dutch ( p = 0.34), Finnish ( p = 0.45), and combined cohort ( p = 0.98), or with age at time of IA rupture in the Dutch ( p = 0.28), Finnish ( p = 0.86), and combined cohort ( p = 0.45). In the combined cohort, odds ratios were 0.89 (0.67–1.20) for familial IA, 1.03 (0.79–1.34) for lower age, and 1.54 (1.20–1.98) for MCA aneurysms. Conclusions: Our findings suggest that genetic risk factors have a larger role in the development of IA at the MCA than at other sites, and that genetic heterogeneity should be considered in future genetic studies.

Background and Purpose— Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. Methods— Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. Results— Genome-wide evidence of association was detected in the discovery sample on chromosome 9 ( CDKN2BAS ; rs10733376: P −11 ), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9 , was associated with IA (rs10230207; P =4.14×10 −8 ). This association replicated in the Dutch sample ( P =0.01) but failed to show association in the Finnish sample ( P =0.25). Meta-analysis results of the 3 cohorts reached statistical significant ( P =9.91×10 −10 ). Conclusions— We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9 ), suggesting a possible genetic link between this stroke subtype and IA.

3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2× increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p, Author Summary Genome-wide association studies (GWAS) have been extensively used to identify common genetic variants associated with complex diseases. As common genetic variants have explained only a small fraction of the heritability of most complex diseases, there is a growing interest in the role of how low frequency and rare variants contribute to the susceptibility. Low frequency variants are more often specific to populations of distinct ancestries. Saccular intracranial aneurysms (sIA) are balloon-like dilatations in the arteries on the surface of the brain. The rupture of sIA causes life-threatening intracranial bleeding. sIA is a complex disease, which is known to sometimes run in families. Here, we utilize the recent advancements in knowledge of genetic variation in different populations to examine the role of low-frequency variants in sIA disease in the isolated population of Finland where sIA related strokes are more common than in most other populations. By studying >8000 Finns we identify four low-frequency variants associated with the sIA disease. We also show that the association of two of the variants are seen in other European populations as well. Our findings demonstrate that multiple study designs are needed to uncover more comprehensively their genetic background, including population isolates.

Background and Purpose— In families with ≥2 relatives with intracranial aneurysms (IAs), screening for IAs in asymptomatic first-degree relatives is often recommended. We assessed the long-term psychosocial impact of such screening. Methods— We identified all persons with IA (screen-positives) and matched them for age and sex with 2 controls without IA (screen-negatives) from hospital-based registers of familial IA. Persons underwent telephone interviews using questionnaires that covered the areas of psychosocial impact of screening, health-related quality of life (HRQoL), and mood. Data were compared between screen-positives and screen-negatives, and with reference populations. Results— Overall, 105 persons from 33 families with IA were included, of whom 35 were screen-positive and 70 were screen-negative. Of the screen-positives, 12 (44%) had reduced their work and 23 (66%) had experienced changes in ≥1 area of independence, self-esteem, future outlook, or personal relationships. In contrast, only 1 (2%) screen-negative person had stopped working and 12 (17%) others had experienced changes in their self-esteem, future outlook, or relationships. Screen-positives had lower HRQoL compared with screen-negatives and the reference population, whereas both screen groups had higher mean depression scores than the reference population. Despite these effects, only 3 persons regretted participating in screening. Conclusion— Although screening for IA is an important preventative strategy in high-risk individuals, it is associated with considerable psychosocial effects, both positive and negative. Greater awareness of such outcomes, and appropriate intervention where necessary, would appear to be a necessary component of IA screening programs.