Gabriel J. E. Rinkel

Aneurysmal subarachnoid haemorrhage (aSAH) results from the rupture of an intracranial aneurysm. The case-fatality after aSAH is approximately 40% and those who survive often have functional, cognitive or emotional sequelae. We prepared guidelines according to Grading of Recommendations, Assessment, Development and Evaluations (GRADE) methodology, using data from meta-analyses, randomised trials, prospective observational and case–control studies, prospective registries with external validation and single-arm cohort studies with > 50 patients with aSAH. Based on high levels of evidence, we recommend oral administration of nimodipine and regular coiling over clipping if both aneurysm treatment options are equally suitable in patients who are in good clinical condition, and recommend against the routine use of antifibrinolytic drugs prior to aneurysm treatment and against the use of tirilazad, statins, magnesium sulphate or endothelin receptor antagonists. Because of lower levels of evidence, no evidence-based recommendations can be made for the prophylactic use of antiplatelet drugs or external lumbar drainage, hypertension induction, treatment of the ruptured aneurysm with endovascular devices other than coils or endovascular treatment of vasospasm. We formulated 37 expert-consensus statements, which include, among others, the suggestions to treat aSAH patients in a dedicated neuro-ICU or high care unit in a centre that treats at least 70 patients with aSAH per year or at least 35 patients with aSAH per year in geographically remote areas, and to treat the ruptured aneurysm within 24 h after ictus provided that the most dedicated team of experts is available. These guidelines present up-to-date recommendations and expert-consensus statements on key aspects in the management of aSAH patients.

Introduction: Flow-diverting (FD) stents are increasingly used to treat small, unruptured intracranial aneurysms (UIA), but high-quality, unbiased data on initial complications and clinical outcomes were limited in previous literature reviews. We updated the literature review to assess quality, potential bias, complications and short-term outcomes in studies on FD-stents for UIAs. Patients and methods: We systematically searched PubMed, Embase and Cochrane Library until January 9, 2025 for studies on FD-stents for UIAs. We assessed methodological quality using the methodological index for non-randomised studies (poor: 0–9, moderate: 10–13, good: 14–16), and financial conflicts of interest. The primary outcome was neurological outcome according to a validated outcome scale at 1–3 months after treatment. Secondary outcomes were clinical worsening and complications. Results: We included 13 studies with 743 patients and 806 UIAs, of which 88.4% (95% CI: 85.7%–91.2%) were <10 mm. All studies were uncontrolled. The methodological quality was poor in six and moderate in seven studies. Financial conflicts of interest were reported in six studies. At 1–3 months after treatment, the proportion of patients were for mRS ⩾1 13.3% (95% CI: 10.0%–16.6%), mRS ⩾2 5.3% (95% CI: 3.2%–7.5%), mRS ⩾3 2.4% (95% CI: 0.1%–3.9%) and neurological worsening 3.1% (95% CI: 1.5%–4.6%). Complications within 3 months occurred in 12.7% (95% CI: 10.3%–15.0%). Discussion and conclusion: The literature on FD-stents is methodologically weak and potentially biased by financial interests but still shows relevant proportions of complications and post-treatment morbidity. Currently, there are no good data supporting the use of FD-stents for UIAs where standard treatment options are available. Randomised-controlled trials are needed to compare safety, efficacy and durability between FD-stents and coiling or clipping.

Objective: Aneurysm wall enhancement (AWE) may predict aneurysm growth and rupture in the short‐term, but there is a lack of long‐term follow‐up studies. We aimed to determine whether unruptured intracranial aneurysms (UIAs) with AWE have a higher probability of aneurysm instability during long‐term follow‐up compared with those without AWE. Methods: For this longitudinal cohort study, we obtained individual patient data from two international cohorts. We included patients with ≥ 1 untreated UIA who underwent gadolinium‐enhanced aneurysm wall imaging and magnetic resonance angiography (MRA) between 2012 and 2016, and had follow‐up imaging and/or had a rupture during follow‐up. The outcome was aneurysm instability, defined as time to growth, morphological change, or rupture during follow‐up. We calculated the 7.5‐year probability of aneurysm instability with 95% confidence interval (CI) with the Kaplan–Meier estimator. We used Cox regression survival analysis to calculate the crude hazard ratio (HR) with corresponding 95% CI of AWE for aneurysm instability, and the HR adjusted for age and aneurysm size at baseline. Results: We included 198 patients (median age = 58 years, interquartile range = 50–68, 139 women, 70%) with 224 aneurysms. Aneurysm instability was observed in 15 of 72 aneurysms (21%) with AWE and 13 of 152 aneurysms (9%) without AWE during a median follow‐up duration of 6.8 years (IQR = 3.3–7.9). The 7.5‐year probability of instability was 29.2% (95% CI = 14.5%–41.3%) in aneurysms with AWE and 9.3% (95% CI = 2.9%–15.3%) in aneurysms without AWE (crude HR = 4.29, 95% CI = 1.90–9.72, adjusted HR = 5.06, 95% CI = 2.13–12.02). Interpretation: UIAs with AWE have a higher probability of 7.5‐year aneurysm instability compared with those without AWE. ANN NEUROL 2026;99:863–870

BACKGROUND AND PURPOSE: Aneurysm wall enhancement on MRI after administration of gadolinium is associated with aneurysm growth or rupture. Aneurysm wall enhancement has mostly been studied at baseline. The change in the presence or absence of aneurysm wall enhancement with time is largely unknown but can provide a better understanding of the pathophysiological processes occurring within the aneurysm wall. Therefore, we aimed to determine the proportion of aneurysm wall enhancement appearance or disappearance. MATERIALS AND METHODS: In this multicenter cohort study, we analyzed individual patient data from 11 international cohorts. Patients 18 years of age or older with at least 1 untreated saccular unruptured intracranial aneurysm were included if they had 2 consecutive MRIs with aneurysm wall imaging. A Wilson score interval was used to calculate confidence intervals for the proportion of aneurysms with aneurysm wall enhancement changes, defined as appearance or disappearance between the 2 MRIs. RESULTS: We included 305 patients with 387 unruptured intracranial aneurysms. Aneurysm wall enhancement was present at baseline in 142 (37%) aneurysms in 122 patients. Aneurysm wall enhancement appeared or disappeared in 20/387 aneurysms (5.2% [95% CI, 3.4–7.8]) after a median follow-up of 12 months (interquartile range, 5–13). Of the 245 aneurysms without enhancement at baseline, 13 (5.3% [95% CI, 3.1–8.9]) had the appearance of wall enhancement at the second MR aneurysm wall imaging. Of the 142 aneurysms with aneurysm wall enhancement at baseline, 7 aneurysms (4.9% [95% CI, 2.4–9.8]) had the disappearance of aneurysm wall enhancement. CONCLUSIONS: Most unruptured intracranial aneurysms have persistent presence or absence of aneurysm wall enhancement during a median 1-year follow-up period. This finding suggests that underlying pathophysiological processes in the aneurysm wall are long-lasting. Graphical Abstract

Introduction: Flow-diverting (FD) stents are increasingly used to treat small, unruptured intracranial aneurysms (UIA), but high-quality, unbiased data on initial complications and clinical outcomes were limited in previous literature reviews. We updated the literature review to assess quality, potential bias, complications and short-term outcomes in studies on FD-stents for UIAs. Patients and methods: We systematically searched PubMed, Embase and Cochrane Library until January 9, 2025 for studies on FD-stents for UIAs. We assessed methodological quality using the methodological index for non-randomised studies (poor: 0–9, moderate: 10–13, good: 14–16), and financial conflicts of interest. The primary outcome was neurological outcome according to a validated outcome scale at 1–3 months after treatment. Secondary outcomes were clinical worsening and complications. Results: We included 13 studies with 743 patients and 806 UIAs, of which 88.4% (95% CI: 85.7%–91.2%) were <10 mm. All studies were uncontrolled. The methodological quality was poor in six and moderate in seven studies. Financial conflicts of interest were reported in six studies. At 1–3 months after treatment, the proportion of patients were for mRS ⩾1 13.3% (95% CI: 10.0%–16.6%), mRS ⩾2 5.3% (95% CI: 3.2%–7.5%), mRS ⩾3 2.4% (95% CI: 0.1%–3.9%) and neurological worsening 3.1% (95% CI: 1.5%–4.6%). Complications within 3 months occurred in 12.7% (95% CI: 10.3%–15.0%). Discussion and conclusion: The literature on FD-stents is methodologically weak and potentially biased by financial interests but still shows relevant proportions of complications and post-treatment morbidity. Currently, there are no good data supporting the use of FD-stents for UIAs where standard treatment options are available. Randomised-controlled trials are needed to compare safety, efficacy and durability between FD-stents and coiling or clipping.

MRI markers of cerebral small vessel disease (cSVD) in patients with spontaneous intracerebral hemorrhage (sICH) have provided insight in the underlying vascular pathology. Cortical cerebral microinfarcts (CMIs) are a relatively novel marker of cSVD. We aimed to assess presence and location within the cortex of CMIs in patients with sICH on 3T and 7T MRI, and to determine their association with hematoma location and other neuroimaging markers of cSVD. From a multicenter prospective observational cohort study, we included consecutive adult patients who underwent 3T and/or 7T MRI within 3 months after sICH. We determined presence and location of CMIs within the cortex (superficial or deeper layers; on 7T MRI) and assessed associations between presence of cortical CMIs and vascular risk factors, hematoma location, and other MRI markers of cSVD with multiple regression analyses. We included 135 patients (mean age 63 years; 30% female). On 3T MRIs, we found 100 cortical CMIs in 57 patients (42%, median number 2, interquartile range [IQR] 1-3; lobar ICH 24 of 58 patients [41%]; non-lobar ICH 33 of 77 patients [43%]). On 7T MRI images, we found 59 cortical CMIs in 28 of 40 patients (70%; median number of 2, IQR 1-3; lobar ICH 8 of 12 patients [67%]; non-lobar ICH 20 of 28 patients [71%]). Presence of cortical CMIs was associated with history of TIA/ischemic stroke (relative risk [RR] 2.7, 95% CI 1.1-6.4), but not with other vascular risk factors or any of the MRI markers of cSVD. On 7T MRI, CMIs were located in the superficial part of the cortex in 30% of patients with lobar vs 5% of patients with non-lobar ICH (RR 2.7, 95% CI 1.5-5.0). Cortical CMIs are a common finding in patients with sICH on both 3T and 7T MRIs with a similar frequency in patients with lobar and non-lobar sICH. Patients with lobar sICH, more often have CMIs in the superficial part of the cortex than those with non-lobar sICH. Location of CMIs within the cortex might provide insight into the underlying type of small vessel disease in sICH.

BACKGROUND AND PURPOSE: Previous studies showed that intracranial aneurysm wall enhancement (AWE) is associated with aneurysm growth or rupture. These studies assessed growth with manual 2D measurements or eyeballing, both of which are prone to interobserver variability. To minimize this variability, we assessed the association between AWE and semi-automatically quantified 3D morphological changes in aneurysms during long-term follow-up. MATERIALS AND METHODS: We included patients with an unruptured intracranial aneurysm who had baseline MR aneurysm wall imaging and were followed with MR or CT angiography for ≥1 year. We used in-house-developed software to measure six 3D morphological parameters on paired baseline and follow-up scans and determined changes over time. We compared the proportion of aneurysms showing morphological change (modified Z-score <-3.5 or >+3.5) between aneurysms with and without AWE. The risk difference with 95% CI was calculated for each morphological parameter. For parameters with a statistically significant change difference between aneurysms with and without AWE, we calculated ORs with 95% CI in a univariable logistic regression model, and adjusted for aneurysm size in a bivariable model. RESULTS: Sixty-two patients with 72 unruptured intracranial aneurysms met inclusion criteria. Twenty aneurysms (28%) in 18 patients showed AWE at baseline. Median follow-up was 5.8 years (IQR 4.6–6.6). For the parameter curvedness, the proportion of aneurysms showing an increase was higher in aneurysms with AWE (6 of 20, 30%) than aneurysms without AWE (2 of 52, 4%), with a risk difference of 26% (95%CI 9–49%). For the other five morphological parameters, the proportion of aneurysms with morphological change was comparable between aneurysms with and without AWE. In logistic regression analysis, AWE was associated with curvedness increase (crude OR 10.7 [95%CI 2.2–78.9], adjusted OR 6.1 [95%CI 1.01–50.3]). CONCLUSIONS: AWE was associated with aneurysm shape change during long-term follow-up, with an increase in 3D quantified curvedness that was independent of aneurysm size. This reinforces previous findings that AWE is associated with aneurysm instability, in particular curvedness increase, and suggests that curvedness could be a suitable parameter to capture aneurysm instability. Future studies need to investigate whether an increase in this parameter predicts aneurysmal rupture. ABBREVIATIONS: AWE = aneurysm wall enhancement; AWI = aneurysm wall imaging; IBSI = imaging biomarker standardization initiative; UIA = unruptured intracranial aneurysm.

A 2005 review identified smoking, hypertension, and excessive alcohol intake as the most important risk factors of aneurysmal subarachnoid hemorrhage (aSAH), but data on other factors remained inconclusive. While aSAH is more prevalent in female participants, evidence on sex differences and female-specific factors remains limited. Comprehensive identification of all risk factors, including potential sex differences and female-specific factors, is essential for improving prevention and accurately assessing aSAH risk. We aimed to determine whether there is now greater certainty around previously inconclusive risk factors, identify any new emerging factors, and explore sex differences in both established and emerging risk factors. We conducted a systematic review and meta-analysis of cohort and case-control studies on prevalent lifestyle exposures, following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. These exposures included smoking, hypertension, alcohol abuse, oral contraception, hormone replacement therapy, hypercholesterolemia, rigorous physical activity, lean body mass index, and diabetes. We calculated pooled sex-specific relative risks (RRs) and odds ratios (ORs) with 95% CIs for overall risk and female-to-male ratios of RRs (RRRs) and ORs (RORs) for sex comparisons. We included 67 studies (34 cohort [8 with sex-specific data], 33 case-control [6 with sex-specific data]; n = 5,743,262; 57% female). A sex-specific association was found for current smoking (RRR 1.53, 95% CI 1.05-2.23), but not for hypertension (RRR 1.50, 95% CI 0.78-2.89) or excessive alcohol intake (RRR 0.46, 95% CI 0.13-1.63). Regular rigorous exercise (RR 0.74, 95% CI 0.53-1.04; OR 0.69, 95% CI 0.57-0.83) and diabetes (RR 0.75, 95% CI 0.55-1.02; OR 0.52, 95% CI 0.41-0.65) were associated with reduced risk, without sex-specific associations. Data on hypercholesterolemia (RR 1.24, 95% CI 0.97-1.58; OR 0.52, 95% CI 0.37-0.74) and lean BMI (RR 1.31, 95% CI 1.15-1.50; OR 1.39, 95% CI 0.74-2.60) were inconsistent and showed no sex-specific associations. Hormone replacement therapy (RR 1.03, 95% CI 0.72-1.48) and oral contraceptive use (RR 5.40, 95% CI 0.68-42.57) were limited to female patients, with current users compared with never users. Most studies contained potential sources of bias. Current smoking, but not hypertension or excessive alcohol, has a stronger association with aSAH in female patients than in male patients. Regular exercise and diabetes are associated with a reduced risk, with no sex-specific associations. Data on female-specific factors remain inconsistent. Targeted smoking prevention may particularly benefit female patients. Large-scale studies are needed to clarify the role of female-specific factors in explaining the higher incidence of aSAH in female patients.

BACKGROUND AND PURPOSE: The performance of current prediction models for intracranial aneurysm growth and rupture is suboptimal, and new markers are needed to improve prediction. There is a strong need for longitudinal studies that use standardized morphological parameters. In this longitudinal study, we aimed to identify standardized three-dimensional (3D) quantified morphological parameters as predictors of aneurysm growth or rupture during long-term follow-up. MATERIALS AND METHODS: We used a database of consecutive patients with saccular unruptured intracranial aneurysms diagnosed between 2008–2018. Employing a retrospective case-cohort design, we included a computer-generated random sample of aneurysms from the full cohort and aneurysms with growth or rupture during follow-up outside the random sample. The case-cohort design is efficient for low-incidence outcomes while maintaining the temporal association between exposure and outcome. Aneurysms were annotated on baseline CTA or MRA images, and 3D morphological parameters were quantified. Univariable and multivariable Cox proportional hazards models were used to identify 3D morphological predictors of either aneurysm growth or aneurysm rupture. An inverse sampling probability weight was applied to obtain unbiased estimates of the hazard ratios. RESULTS: We included 278 patients (median age, 59 years [IQR50-66]; 209 women) with 327 aneurysms, of which 239 aneurysms were stable during follow-up (73%), 68 grew without subsequent rupture (21%), 7 grew with subsequent rupture (2%), and 13 ruptured without preceding growth (4%). In the multivariable model for growth prediction (median follow-up 4.1 years [IQR1.9–7.1]), 2 parameters were retained: major axis (HR 1.16, 95%CI: 0.84–1.61) and shape index (HR 1.53, 95%CI: 0.76–3.08), with a c-statistic of 0.56 (95%CI: 0.49–0.63). The same parameters were retained in the multivariable model for prediction of rupture (median follow-up 4.5 years [IQR2.1–7.3]): major axis (HR 2.27, 95%CI: 1.36–3.80) and shape index (HR 3.33, 95%CI: 0.95–11.62), with a c-statistic of 0.85 (95%CI: 0.77–0.94). CONCLUSIONS: We identified major axis and shape index as candidate 3D quantified morphological predictors of both aneurysm growth and rupture, but only for rupture these had good discriminative power in our cohort. These parameters will need external validation and should be integrated with existing clinical prediction models. ABBREVIATIONS: ELAPSS = Earlier subarachnoid hemorrhage, Location of the aneurysm, Age, Population, Size of the aneurysm, and Shape of the aneurysm; IBSI = imaging biomarker standardization initiative; PHASES = Population, Hypertension, Age, Size of aneurysm, Earlier SAH from another aneurysm, and Site of aneurysm; UIA = unruptured intracranial aneurysm.

BACKGROUND: Spontaneous intracerebral hemorrhage (ICH) in the cerebellum has a poor short-term prognosis, whereas data on the long-term case fatality and recurrent vascular events are sparse. Herewith, we aimed to assess the long-term case fatality and recurrence rate of vascular events after a first cerebellar ICH. METHODS: In this international cohort study, we included patients from 10 hospitals (the United States and Europe from 1997 to 2017) aged ≥18 years with a first spontaneous cerebellar ICH who were discharged alive. Data on long-term case fatality and recurrence of vascular events (recurrent ICH [supratentoria or infratentorial], ischemic stroke, myocardial infarction, or major vascular surgery) were collected for survival analysis and absolute event rate calculation. RESULTS: We included 405 patients with cerebellar ICH (mean age [SD], 72 [13] years, 49% female). The median survival time was 67 months (interquartile range, 23–100 months), with a cumulative survival rate of 34% at 10-year follow-up (median follow-up time per center ranged: 15–80 months). In the 347 patients with data on vascular events 92 events occurred in 78 patients, after initial cerebellar ICH: 31 (8.9%) patients had a recurrent ICH (absolute event rate, 1.8 per 100 patient-years [95% CI, 1.2–2.6]), 39 (11%) had an ischemic stroke (absolute event rate, 2.3 [95% CI, 1.6–3.2]), 13 (3.7%) had a myocardial infarction (absolute event rate, 0.8 [95% CI, 0.4–1.3]), and 5 (1.4%) underwent major vascular surgery (absolute event rate, 0.3 [95% CI, 0.1–0.7]). The median time to a first vascular event during follow-up was 27 months (interquartile range, 8.7–50 months), with a cumulative hazard of 47% at 10 years. CONCLUSIONS: The long-term prognosis of patients who survive a first spontaneous cerebellar ICH is poor and comparable to that of patients who survive a first supratentorial ICH. Further identification of patients at high risk of vascular events following the initial cerebellar ICH is needed. Including patients with cerebellar ICH in randomized controlled trials on secondary prevention of patients with ICH is warranted.