Preventive screening for intracranial aneurysms

Background: Subarachnoid hemorrhage from rupture of an intracranial aneurysm (aneurysmal subarachnoid hemorrhage) is a devastating subset of stroke. Since brain damage from the initial hemorrhage is a major cause for the poor outcome after aneurysmal subarachnoid hemorrhage, prevention of aneurysmal subarachnoid hemorrhage has the highest potential to prevent poor outcome from aneurysmal subarachnoid hemorrhage. Aim: In this review, we describe the groups at high risk of aneurysmal subarachnoid hemorrhage who may benefit from preventive screening for unruptured intracranial aneurysms followed by preventive treatment of unruptured intracranial aneurysms found. Furthermore, we describe the advantages and disadvantages of screening and advise how to perform counseling on screening. Summary of review: Modeling studies show that persons with two or more affected first-degree relatives with aneurysmal subarachnoid hemorrhage and patients with autosomal dominant polycystic kidney disease (ADPKD) are candidates for screening for unruptured intracranial aneurysms. One modeling study also suggests that persons with only one affected first-degree relative with aneurysmal subarachnoid hemorrhage are also likely candidates for screening. Another group who may benefit from screening are persons ≥35 years who smoke(d) and are hypertensive, given their high lifetime risk of aneurysmal subarachnoid hemorrhage of up to 7%, but the prevalence of unruptured intracranial aneurysms in such persons and the efficiency and cost-effectiveness of screening in this group are not yet known. The ultimate goal of screening is to increase the number of quality years of life of the screening candidates, and therefore the benefits but also many downsides of screening –such as risk of incidental findings, very small unruptured intracranial aneurysms that require regular follow-up, preventive treatment with inherent risk of complications and anxiety – should be discussed with the candidate so that an informed decision can be made before intracranial vessels are imaged. Conclusions: Several groups of persons who may benefit from screening have been identified, but since these constitute only a minority of all aneurysmal subarachnoid hemorrhage patients, additional high-risk groups still need to be identified. Further research is also needed to identify persons at low or high risk of aneurysmal development and rupture within the groups identified thus far to improve the efficiency of screening. Moreover, if new medical treatment strategies that can reduce the risk of rupture of unruptured intracranial aneurysm become available, the groups of persons who may benefit from screening could increase considerably

Serial Quality of Life Assessment around Screening for Familial Intracranial Aneurysms: A Prospective Cohort Study

Introduction: Screening for intracranial aneurysms (IAs) is cost-effective in first-degree relatives of aneurysmal subarachnoid haemorrhage patients, but its psychosocial impact is largely unknown. Patients and Methods: A consecutive series of persons aged 20–70 years visiting the University Medical Centre Utrecht for first screening for familial IA was approached between 2017 and 2020. E-questionnaires were administered at six time points, consisting of the EQ-5D for health-related quality of life (QoL), HADS for emotional functioning, and USER-P for social participation. QoL outcomes were compared with the general population and between participants with a positive and negative screening for IA. Predictors of QoL outcomes were assessed with linear mixed effects models. Results: 105 participants from 75 families were included; in 10 (10%), an IA was found. During the first year after screening, we found no negative effect on QoL, except for a temporary decrease in QoL 6 months after screening in participants with a positive screen (EQ-5D −11.3 [95% CI: −21.7 to −0.8]). Factors associated with worse QoL were psychiatric disease (EQ-5D −10.3 [95% CI: −15.1 to −5.6]), physical complaints affecting mood (EQ-5D −8.1 [95% CI: −11.7 to −4.4]), and a passive coping style (EQ-5D decrease per point increase on the Utrecht Coping List −1.1 [95% CI: −1.5 to −0.6]). Discussion and Conclusion: We did not find a lasting negative effect on QoL during the first year after screening for familial IA. Predictors for a worse QoL were psychiatric disease, physical complaints affecting mood, and a passive coping style. This information can be used in counselling about familial IA screening

Devastating delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

BACKGROUND: We investigated the proportion of patients in an initial good clinical condition who developed devastating DCI, and aimed to characterize these patients by aneurysm location, blood pressure instability prior to DCI, and the extent of cerebral ischemia. METHODS: We included aSAH patients admitted between 2010 and 2021 with a Glasgow Coma Scale of 11 or higher 24 h after aneurysm treatment, who developed devastating DCI, defined as DCI leading to coma for at least 48 h with cerebral infarction on the subsequent scan. Blood pressure instability was defined as nimodipine-induced blood pressure drops, dosage adjustments, or the use of blood pressure drugs before onset of DCI. Descriptive statistics were used to summarize the data. RESULTS: Out of 1,211 consecutive aSAH patients, 617 patients had a good clinical condition after aneurysm treatment of whom 16 (3%) patients [14 (88%) women] were included in this study. Thirteen (81%) patients had an aneurysm in the anterior circulation. Thirteen patients (81%) had blood pressure instability: twelve (75%) had nimodipine-induced blood pressure drops, eleven (69%) received antihypertensive drugs, and 7 (44%) received hypertension induction before onset of DCI. Thirteen (81%) patients had bilateral ischemia, mainly in the anterior circulation (56%). CONCLUSIONS: The proportion of aSAH patients with a good clinical condition after aneurysm treatment who develop devastating DCI is small. The vast majority of these patients had blood pressure instability. Future studies are needed to investigate if a reduction in the number and extent of blood pressure fluctuations decreases the incidence of devastating DCI

Genome-wide linkage analysis combined with genome sequencing in large families with intracranial aneurysms

Rupture of an intracranial aneurysm (IA) leads to aneurysmal subarachnoid haemorrhage (ASAH), a severe type of stroke. Some rare variants that cause IA in families have been identified, but still, the majority of genetic causes, as well as the biological mechanisms of IA development and rupture, remain unknown. We aimed to identify rare, damaging variants for IA in three large Dutch families with multiple affected members with IA (N = 9, 11, and 6). By combining linkage analysis and genome sequencing (GS), we identified six rare and damaging variants for which all cases within one of the families were heterozygous. These variants were p.Tyr87Cys in SYCP1, p.Phe1077Leu in FMNL2, p.Thr754Lys in TBC1D2, p.Arg321His in ZNF782, p.Arg979Trp in CCDC180, and p.Val125Met in NCBP1. None of the variants showed association with IA status in a large cohort of 937 patients from the general IA patient population and 1046 controls. Gene expression in IA and cerebral artery tissue further prioritized FMNL2 and TBC1D2 as potential important players in IA pathophysiology. Further studies are needed to characterize the functional consequences of the identified variants and their role in the biological mechanisms of IA

Analysis of aneurysmal subarachnoid hemorrhage as a multistep process

Background and purpose: Aneurysmal subarachnoid hemorrhage (ASAH) is a complex disease with higher incidence in women compared to men and in Japan compared to other countries. It was hypothesized that ASAH is consistent with a multistep model of disease. The following assessments were made: (1) the number of steps needed for the disease to occur and (2) whether this number may be different in female versus male and in Japanese versus non-Japanese patients. Methods: Incidence data were generated from a meta-analysis on ASAH incidence until 2017, which was supplemented with a literature search from 2017 to April 2023. Age- and sex-adjusted incidences per 10-year age groups were calculated and the logarithm of age-specific incidence against the logarithm of age was regressed with least-squares regression. Results: In 2317 ASAH patients a linear relationship between logarithm of incidence and logarithm of age was found with a slope estimate of 3.13 (95% confidence interval 2.60–3.65), consistent with a four-step process. Similar estimates were found for female, male, Japanese and non-Japanese patients. Conclusions: Our results suggest that ASAH is a four-step process, also in subgroups with higher ASAH incidence. Elucidation of the exact nature of these steps can provide important clues for identification of disease mechanisms underlying ASAH

Aneurysm treatment within 6 h versus 6–24 h after rupture in patients with subarachnoid hemorrhage

Background: The risk of rebleeding after aneurysmal subarachnoid hemorrhage (aSAH) is the highest during the initial hours after rupture. Emergency aneurysm treatment may decrease this risk, but is a logistic challenge and economic burden. We aimed to investigate whether aneurysm treatment <6 h after rupture is associated with a decreased risk of poor functional outcome compared to aneurysm treatment 6–24 h after rupture. Methods: We used data of patients included in the ULTRA trial (NCT02684812). All patients in ULTRA were admitted within 24 h after aneurysm rupture. For the current study, we excluded patients in whom the aneurysm was not treated <24 h after rupture. We calculated crude and adjusted risk ratios (aRR) with 95% confidence intervals using Poisson regression analyses for poor functional outcome (death or dependency, assessed by the modified Rankin Scale) after aneurysm treatment <6 h versus 6–24 h after rupture. Adjustments were made for age, sex, clinical condition on admission (WFNS scale), amount of extravasated blood (Fisher score), aneurysm location, tranexamic acid treatment, and aneurysm treatment modality. Results: We included 497 patients. Poor outcome occurred in 63/110 (57%) patients treated within 6 h compared to 145/387 (37%) patients treated 6–24 h after rupture (crude RR: 1.53, 95% CI: 1.24–1.88; adjusted RR: 1.36, 95% CI: 1.11–1.66). Conclusion: Aneurysm treatment <6 h is not associated with better functional outcome than aneurysm treatment 6–24 h after rupture. Our results do not support a strategy aiming to treat every patient with a ruptured aneurysm <6 h after rupture

Number of Affected Relatives, Age, Smoking, and Hypertension Prediction Score for Intracranial Aneurysms in Persons with a Family History for Subarachnoid Hemorrhage

Background: Persons with a positive family history of aneurysmal subarachnoid hemorrhage are at increased risk of aneurysmal subarachnoid hemorrhage. Preventive screening for intracranial aneurysms (IAs) in these persons is cost-effective but not very efficient. We aimed to develop and externally validate a model for predicting the probability of an IA at first screening in persons with a positive family history of aneurysmal subarachnoid hemorrhage. Methods: For model development, we studied results from initial screening for IA in 660 prospectively collected persons with ≥2 affected first-degree relatives screened at the University Medical Center Utrecht. For validation, we studied results from 258 prospectively collected persons screened in the University Hospital of Nantes. We assessed potential predictors of IA presence in multivariable logistic regression analysis. Predictive performance was assessed with the C statistic and a calibration plot and corrected for overfitting. Results: IA were present in 79 (12%) persons in the development cohort. Predictors were number of affected relatives, age, smoking, and hypertension (NASH). The NASH score had a C statistic of 0.68 (95% CI, 0.62-0.74) and showed good calibration in the development data. Predicted probabilities of an IA at first screening varied from 5% in persons aged 20 to 30 years with two affected relatives, without hypertension who never smoked, up to 36% in persons aged 60 to 70 years with ≥3 affected relatives, who have hypertension and smoke(d). In the external validation data IA were present in 67 (26%) persons, the model had a C statistic of 0.64 (95% CI, 0.57-0.71) and slightly underestimated IAs risk. Conclusions: For persons with ≥2 affected first-degree relatives, the NASH score improves current predictions and provides risk estimates for an IA at first screening between 5% and 36% based on 4 easily retrievable predictors. With the information such persons can now make a better informed decision about whether or not to undergo preventive screening

Scanxiety and quality of life around follow-up imaging in patients with unruptured intracranial aneurysms: a prospective cohort study

Objectives: Patients with an unruptured intracranial aneurysm (UIA) may experience scanxiety around follow-up imaging. We studied the prevalence and temporal pattern of scanxiety, and compared quality of life (QoL) outcomes in patients with and without scanxiety. Methods: We performed a prospective cohort study in a tertiary referral center in the Netherlands between October 2021 and November 2022. We sent questionnaires to patients ≥ 18 years old undergoing UIA follow-up imaging 4 weeks before (T1), immediately after (T2), and 6 weeks after the scan (T3) to assess health-related QoL (HRQoL) and emotional functioning. At T3, we also assessed scanxiety with a purpose-designed questionnaire. We compared differences in QoL outcomes between respondents with and without scanxiety using mixed models. Results: Of 158 eligible patients, 106 (67%) participated (mean age 61 years ± 11 [standard deviation], 84 women). Sixty of the 91 respondents (66%) who completed the purpose-designed questionnaire experienced scanxiety. Of the 49 respondents who experienced scanxiety after the scan, it resolved in 22 (45%) within a day after receiving the radiology report. HRQoL did not differ between respondents with or without scanxiety. Emotional functioning was worse for respondents with scanxiety (mean Hospital Anxiety and Depression Scale sum score difference at T1, 3.6 [95% CI, 0.9–6.3]; T2, 4.1 [95% CI, 1.5–6.8]; and T3, 4.0 [95% CI, 1.5–6.5]). Conclusions: Two-thirds of the respondents experienced scanxiety around follow-up imaging, which often resolved within a day after receiving results. Patients with scanxiety had similar HRQoL but worse emotional functioning compared to patients without scanxiety. The time between the scan and receiving the results should be minimized to decrease the duration of scanxiety. Clinical relevance statement: We showed that scanxiety is common in UIA patients, and negatively associated with emotional functioning. Since scanxiety often disappears immediately after receiving the radiology report, it should be communicated to the patient as early as possible to alleviate patients’ distress. Key Points: • Many patients with an unruptured intracranial aneurysm experience emotional distress around follow-up imaging, termed “scanxiety.” • Patients with scanxiety had worse emotional functioning compared to patients without scanxiety. • Scanxiety often resolved within a day after receiving the radiology report

Complement C5 contributes to brain injury after subarachnoid hemorrhage

Previous studies showed that complement activation is associated with poor functional outcome after aneurysmal subarachnoid hemorrhage (SAH). We investigated whether complement activation is underlying brain injury after aneurysmal SAH (n = 7) and if it is an appropriate treatment target. We investigated complement expression in brain tissue of aneurysmal SAH patients (n = 930) and studied the role of common genetic variants in C3 and C5 genes in outcome. We analyzed plasma levels (n = 229) to identify the functionality of a single nucleotide polymorphism (SNP) associated with outcome. The time course of C5a levels was measured in plasma (n = 31) and CSF (n = 10). In an SAH mouse model, we studied the extent of microglia activation and cell death in wild-type mice, mice lacking the C5a receptor, and in mice treated with C5-specific antibodies (n = 15 per group). Brain sections from aneurysmal SAH patients showed increased presence of complement components C1q and C3/C3b/iC3B compared to controls. The complement component 5 (C5) SNP correlated with C5a plasma levels and poor disease outcome. Serial measurements in CSF revealed that C5a was > 1400-fold increased 1 day after aneurysmal SAH and then gradually decreased. C5a in plasma was 2-fold increased at days 3–10 after aneurysmal SAH. In the SAH mouse model, we observed a ≈ 40% reduction in both microglia activation and cell death in mice lacking the C5a receptor, and in mice treated with C5-specific antibodies. These data show that C5 contributes to brain injury after experimental SAH, and support further study of C5-specific antibodies as novel treatment option to reduce brain injury and improve prognosis after aneurysmal SAH