Sex Hormones and Risk of Aneurysmal Subarachnoid Hemorrhage: A Mendelian Randomization Study.

BACKGROUND: The risk of aneurysmal subarachnoid hemorrhage (aSAH) is increased in postmenopausal women compared with men of similar age, suggesting a role for sex hormones. We aimed to explore whether sex hormones, and age at menarche/menopause have a causal effect on aSAH risk by conducting a 2-sample MR study (Mendelian randomization). METHODS: We obtained sex-specific genetic instruments for serum estradiol, bioavailable testosterone (BioT), SHBG (sex hormone-binding globulin), and age at menarche/menopause from genome-wide association studies. The associated sex-specific aSAH risk was estimated with inverse-variance weighted MR analyses with various statistical sensitivity analyses. Multivariable and cluster MR analyses were performed for BioT and SHBG to account for a genetic and phenotypic correlation between the 2 exposures. The clusters represented (1) single-nucleotide polymorphisms primarily increasing SHBG, with secondary decreasing effects on BioT, and (2) single-nucleotide polymorphisms affecting BioT without affecting SHBG. RESULTS: Univariable MR analyses showed an 18% increased aSAH risk among women per 1-SD increase in genetically determined SHBG levels (odds ratio, 1.18 [95% CI, 1.05-1.34]; P=0.007). Suggestive evidence was identified for a 27% decreased risk of aSAH among women per 1-SD increase in BioT (odds ratio, 0.73 [95% CI, 0.55-0.95]; P=0.02). The latter association disappeared in cluster analysis when only using SHBG-independent variants. MR analyses with variants from the cluster with primary SHBG effects and secondary (opposite) BioT-effects yielded a statistically significant association (odds ratio, 1.21 [95% CI, 1.05-1.40]; P=0.008). No other causal associations were identified. CONCLUSIONS: Genetic predisposition to elevated serum levels of SHBG, with secondary lower serum BioT levels, is associated with an increased aSAH risk among women, suggesting that SHBG and BioT causally elevate aSAH risk. Further studies are required to elucidate the underlying mechanisms and their potential as an interventional target to lower aSAH incidence.

Sex Difference and Rupture Rate of Intracranial Aneurysms: An Individual Patient Data Meta-Analysis.

BACKGROUND AND PURPOSE: In previous studies, women had a higher risk of rupture of intracranial aneurysms than men, but female sex was not an independent risk factor. This may be explained by a higher prevalence of patient- or aneurysm-related risk factors for rupture in women than in men or by insufficient power of previous studies. We assessed sex differences in rupture rate taking into account other patient- and aneurysm-related risk factors for aneurysmal rupture. METHODS: We searched Embase and Pubmed for articles published until December 1, 2020. Cohorts with available individual patient data were included in our meta-analysis. We compared rupture rates of women versus men using a Cox proportional hazard regression model adjusted for the PHASES score (Population, Hypertension, Age, Size of Aneurysm, Earlier Subarachnoid Hemorrhage From Another Aneurysm, Site of Aneurysm), smoking, and a positive family history of aneurysmal subarachnoid hemorrhage. RESULTS: We pooled individual patient data from 9 cohorts totaling 9940 patients (6555 women, 66%) with 12 193 unruptured intracranial aneurysms, and 24 357 person-years follow-up. Rupture occurred in 163 women (rupture rate 1.04%/person-years [95% CI, 0.89-1.21]) and 63 men (rupture rate 0.74%/person-years [95% CI, 0.58-0.94]). Women were older (61.9 versus 59.5 years), were less often smokers (20% versus 44%), more often had internal carotid artery aneurysms (24% versus 17%), and larger sized aneurysms (≥7 mm, 24% versus 23%) than men. The unadjusted women-to-men hazard ratio was 1.43 (95% CI, 1.07-1.93) and the adjusted women/men ratio was 1.39 (95% CI, 1.02-1.90). CONCLUSIONS: Women have a higher risk of aneurysmal rupture than men and this sex difference is not explained by differences in patient- and aneurysm-related risk factors for aneurysmal rupture. Future studies should focus on the factors explaining the higher risk of aneurysmal rupture in women.

Intracranial aneurysm wall enhancement as an indicator of instability: a systematic review and meta-analysis.

BACKGROUND AND PURPOSE: Aneurysm wall enhancement (AWE) of intracranial aneurysms on magnetic resonance imaging has been described in previous studies as a surrogate marker of instability. With this study, an updated literature overview and summary risk estimates of the association between AWE and different specific outcomes (i.e., rupture, growth or symptomatic presentation) for both cross-sectional and longitudinal studies are provided. METHODS: The PRISMA guideline was followed and a search was performed of PubMed and Embase to 1 January 2021 for studies that reported on AWE and aneurysm instability. In cross-sectional studies, AWE was compared between patients with stable and unstable aneurysms. In longitudinal studies, AWE of stable aneurysms was assessed at baseline after which patients were followed longitudinally. Risk ratios were calculated for longitudinal studies, prevalence ratios for cross-sectional studies and then the ratios were pooled in a random-effects meta-analysis. Also, the performance of AWE to differentiate between stable and unstable aneurysms was evaluated. RESULTS: Twelve studies were included with a total of 1761 aneurysms. In cross-sectional studies, AWE was positively associated with rupture (prevalence ratio 11.47, 95% confidence interval [CI] 4.05-32.46) and growth or symptomatic presentation (prevalence ratio 4.62, 95% CI 2.85-7.49). Longitudinal studies demonstrated a positive association between AWE and growth or rupture (risk ratio 8.00, 95% CI 2.14-29.88). Assessment of the performance of AWE showed high sensitivities, mixed specificities, low positive predictive values and high negative predictive values. CONCLUSIONS: Although AWE is positively associated with aneurysm instability, current evidence mostly supports the use of its absence as a surrogate marker of aneurysm stability.

The Unruptured Intracranial Aneurysm Treatment Score as a predictor of aneurysm growth or rupture.

BACKGROUND AND PURPOSE: The Unruptured Intracranial Aneurysm Treatment Score (UIATS) was built to harmonize the treatment decision making on unruptured intracranial aneurysms. Therefore, it may also function as a predictor of aneurysm progression. In this study, we aimed to assess the validity of the UIATS model to identify aneurysms at risk of growth or rupture during follow-up. METHODS: We calculated the UIATS for a consecutive series of conservatively treated unruptured intracranial aneurysms, included in our prospectively kept neurovascular database. Computed tomography angiography and/or magnetic resonance angiography imaging at baseline and during follow-up was analyzed to detect aneurysm growth. We defined rupture as a cerebrospinal fluid or computed tomography-proven subarachnoid hemorrhage. We calculated the area under the receiver operator curve, sensitivity, and specificity, to determine the performance of the UIATS model. RESULTS: We included 214 consecutive patients with 277 unruptured intracranial aneurysms. Aneurysms were followed for a median period of 1.3 years (range 0.3-11.7 years). During follow-up, 17 aneurysms enlarged (6.1%), and two aneurysms ruptured (0.7%). The UIATS model showed a sensitivity of 80% and a specificity of 44%. The area under the receiver operator curve was 0.62 (95% confidence interval 0.46-0.79). CONCLUSIONS: Our observational study involving consecutive patients with an unruptured intracranial aneurysm showed poor performance of the UIATS model to predict aneurysm growth or rupture during follow-up.

Clinical relevance of short-term follow-up of unruptured intracranial aneurysms.

OBJECTIVE: Unruptured intracranial aneurysms are common incidental findings on brain imaging. Short-term follow-up for conservatively treated aneurysms is routinely performed in most cerebrovascular centers, although its clinical relevance remains unclear. In this study, the authors assessed the extent of growth as well as the rupture risk during short-term follow-up of conservatively treated unruptured intracranial aneurysms. In addition, the influence of patient-specific and aneurysm-specific factors on growth and rupture risk was investigated. METHODS: The authors queried their prospective institutional neurovascular registry to identify patients with unruptured intracranial aneurysms and short-term follow-up imaging, defined as follow-up MRA and/or CTA within 3 months to 2 years after initial diagnosis. Medical records and questionnaires were used to acquire baseline information. The authors measured aneurysm size at baseline and at follow-up to detect growth. Rupture was defined as a CT scan-proven and/or CSF-proven subarachnoid hemorrhage (SAH). RESULTS: A total of 206 consecutive patients with 267 conservatively managed unruptured aneurysms underwent short-term follow-up at the authors' center. Seven aneurysms (2.6%) enlarged during a median follow-up duration of 1 year (range 0.3-2.0 years). One aneurysm (0.4%) ruptured 10 months after initial discovery. Statistically significant risk factors for growth or rupture were autosomal-dominant polycystic kidney disease (RR 8.3, 95% CI 2.0-34.7), aspect ratio > 1.6 or size ratio > 3 (RR 10.8, 95% CI 2.2-52.2), and initial size ≥ 7 mm (RR 10.7, 95% CI 2.7-42.8). CONCLUSIONS: Significant growth of unruptured intracranial aneurysms may occur in a small proportion of patients during short-term follow-up. As aneurysm growth is associated with an increased risk of rupture, the authors advocate that short-term follow-up is clinically relevant and has an important role in reducing the risk of a potential SAH.

The Role of Hemodynamics through the Circle of Willis in the Development of Intracranial Aneurysm: A Systematic Review of Numerical Models.

Background: The role of regional hemodynamics in the intracranial aneurysmal formation, growth, and rupture has been widely discussed based on numerical models over the past decades. Variation of the circle of Willis (CoW), which results in hemodynamic changes, is associated with the aneurysmal formation and rupture. However, such correlation has not been further clarified yet. The aim of this systematic review is to investigate whether simulated hemodynamic indices of the CoW are relevant to the formation, growth, or rupture of intracranial aneurysm. Methods: We conducted a review of MEDLINE, Web of Science, and EMBASE for studies on the correlation between hemodynamics indices of the CoW derived from numerical models and intracranial aneurysm up to December 2020 in compliance with PRISMA guidelines. Results: Three case reports out of 1046 publications met our inclusion and exclusion criteria, reporting 13 aneurysms in six patients. Eleven aneurysms were unruptured, and the state of the other two aneurysms was unknown. Wall shear stress, oscillatory shear index, von-Mises tension, flow velocity, and flow rate were reported as hemodynamic indices. Due to limited cases and significant heterogeneity between study settings, meta-analysis could not be performed. Conclusion: Numerical models can provide comprehensive information on the cerebral blood flow as well as local flow characteristics in the intracranial aneurysm. Based on only three case reports, no firm conclusion can be drawn regarding the correlation between hemodynamic parameters in the CoW derived from numerical models and aneurysmal formation or rupture. Due to the inherent nature of numerical models, more sensitive analysis and rigorous validations are required to determine its measurement error and thus extend their application into clinical practice for personalized management. Prospero registration number: CRD42021125169.

Difference in Rupture Risk Between Familial and Sporadic Intracranial Aneurysms: An Individual Patient Data Meta-analysis.

BACKGROUND AND OBJECTIVES: We combined individual patient data (IPD) from prospective cohorts of patients with unruptured intracranial aneurysms (UIAs) to assess to what extent patients with familial UIA have a higher rupture risk than those with sporadic UIA. METHODS: For this IPD meta-analysis, we performed an Embase and PubMed search for studies published up to December 1, 2020. We included studies that (1) had a prospective study design; (2) included 50 or more patients with UIA; (3) studied the natural course of UIA and risk factors for aneurysm rupture including family history for aneurysmal subarachnoid haemorrhage and UIA; and (4) had aneurysm rupture as an outcome. Cohorts with available IPD were included. All studies included patients with newly diagnosed UIA visiting one of the study centers. The primary outcome was aneurysmal rupture. Patients with polycystic kidney disease and moyamoya disease were excluded. We compared rupture rates of familial vs sporadic UIA using a Cox proportional hazard regression model adjusted for PHASES score and smoking. We performed 2 analyses: (1) only studies defining first-degree relatives as parents, children, and siblings and (2) all studies, including those in which first-degree relatives are defined as only parents and children, but not siblings. RESULTS: We pooled IPD from 8 cohorts with a low and moderate risk of bias. First-degree relatives were defined as parents, siblings, and children in 6 cohorts (29% Dutch, 55% Finnish, 15% Japanese), totaling 2,297 patients (17% familial, 399 patients) with 3,089 UIAs and 7,301 person-years follow-up. Rupture occurred in 10 familial cases (rupture rate: 0.89%/person-year; 95% confidence interval [CI] 0.45-1.59) and 41 sporadic cases (0.66%/person-year; 95% CI 0.48-0.89); adjusted hazard ratio (HR) for familial cases 2.56 (95% CI 1.18-5.56). After adding the 2 cohorts excluding siblings as first-degree relatives, resulting in 9,511 patients, the adjusted HR was 1.44 (95% CI 0.86-2.40). DISCUSSION: The risk of rupture of UIA is 2.5 times higher, with a range from a 1.2 to 5 times higher risk, in familial than in sporadic UIA. When assessing the risk of rupture in UIA, family history should be taken into account.

The Odom Criteria: Validated at Last: A Clinimetric Evaluation in Cervical Spine Surgery.

BACKGROUND: The Odom criteria, established in 1958, are a widely used, 4-point rating scale for assessing the clinical outcome after cervical spine surgery. Surprisingly, the Odom criteria have never been validated, to our knowledge. The aim of this study was to investigate the reliability and validity of the Odom criteria for the evaluation of surgical procedures of the cervical spine. METHODS: Patients with degenerative cervical spine disease were included in the study and divided into 2 subgroups on the basis of their most predominant symptom: myelopathy or radiculopathy. Reliability was assessed with interrater and test-retest design using quadratic weighted kappa coefficients. Construct validity was assessed by means of hypotheses testing. To evaluate whether the Odom criteria could act as a global perceived effect (GPE) scale, we assessed concurrent validity by comparing area under the curve (AUC) values of receiver operating characteristic (ROC) curves for the set of questionnaires. RESULTS: A total of 110 patients were included in the study; 19 were excluded, leaving 91 in our analysis. Reliability assessments showed κ = 0.77 for overall interrater reliability and κ = 0.93 for overall test-retest reliability. Interrater reliability was κ = 0.81 for the radiculopathy subgroup and κ = 0.68 for the myelopathy subgroup. At least 75% of the hypotheses were met. The AUCs showed similar characteristics between the Odom criteria and GPE scale. CONCLUSIONS: The Odom criteria met the predefined criteria for reliability and validity. Therefore, the Odom criteria may be used to assess surgical outcome after a cervical spine procedure, specifically for patients presenting with radicular symptoms. The results of previous studies that have been deemed less trustworthy because of the use of the Odom criteria should be reconsidered.