Risk Prediction of New Intracranial Aneurysms at Follow-Up Screening in People With a Positive Family History.

BACKGROUND: In first-degree relatives of patients with aneurysmal subarachnoid hemorrhage (aSAH), the risk of an intracranial aneurysm can be predicted at initial screening but not at follow-up screening. We aimed to develop a model for predicting the probability of a new intracranial aneurysm after initial screening in people with a positive family history of aSAH. METHODS: In a prospective study, we obtained data from follow-up screening for aneurysms of 499 subjects with ≥2 affected first-degree relatives. Screening took place at the University Medical Center Utrecht, the Netherlands, and the University Hospital of Nantes, France. We studied associations between potential predictors and the presence of aneurysms using Cox regression analysis and the predictive performance at 5, 10, and 15 years after initial screening using C statistics and calibration plots, while correcting for overfitting. RESULTS: In 5050 person-years of follow-up, intracranial aneurysms were found in 52 subjects. The risk of aneurysm at 5 years was 2% to 12%, at 10 years, 4% to 28%, and at 15 years, 7% to 40%. Predictors were female sex, history of intracranial aneurysms/aneurysmal subarachnoid hemorrhage, and older age. The sex, previous history of intracranial aneurysm/aSAH, older age score had a C statistic of 0.70 (95% CI, 0.61-0.78) at 5 years, 0.71 (95% CI, 0.64-0.78) at 10 years, and 0.70 (95% CI, 0.63-0.76) at 15 years and showed good calibration. CONCLUSIONS: The sex, previous history of intracranial aneurysm/aSAH, older age score provides risk estimates for finding new intracranial aneurysms at 5, 10, and 15 years after initial screening, based on 3 easily retrievable predictors; this can help to define a personalized screening strategy after initial screening in people with a positive family history for aSAH.

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.

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.

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.

Venous Thrombosis in Children with Acute Lymphoblastic Leukemia Treated on DCOG ALL-9 and ALL-10 Protocols: The Effect of Fresh Frozen Plasma.

Background Venous thromboembolism (VTE) is an important complication for treatment of acute lymphoblastic leukemia (ALL) in children. Especially, ALL treatment, with therapeutics such as asparaginase and steroids, increases the thrombotic risk by reduction in procoagulant and anticoagulant proteins. Replacement of deficient natural anticoagulants by administration of fresh frozen plasma (FFP) may have a preventive effect on the occurrence of VTE. Methods We retrospectively analyzed all consecutive children (≤18 years) with ALL, treated on the Dutch Childhood Oncology Group (DCOG) ALL-9 and ALL-10 protocols at the Emma Children's Hospital Academic Medical Center between February 1997 and January 2012, to study the effect of FFP on VTE incidence, antithrombin and fibrinogen plasma levels, and VTE risk factors. Results In total, 18/205 patients developed VTE (8.8%; 95% confidence interval [CI]: 4.9-12.7%). In all patients, VTE occurred after asparaginase administration. In total, 82/205 patients (40%) received FFP. FFP supplementation did not prevent VTE or alter plasma levels of antithrombin or fibrinogen. In the multivariate analysis, VTE occurred significantly more frequently in children ≥12 years (odds ratio [OR]: 3.89; 95% CI: 1.29-11.73) and treated according to the ALL-10 protocol (OR: 3.71; 95% CI: 1.13-12.17). Conclusion FFP supplementation does not seem to be beneficial in the prevention of VTE in pediatric ALL patients. In addition, age ≥12 years and treatment according to the DCOG ALL-10 protocol with intensive and prolonged administration of asparaginase in combination with prednisone are risk factors. There is a need for effective preventive strategies in ALL patients at high risk for VTE.

Evaluation of the yield of 24-h close observation in patients with mild traumatic brain injury on anticoagulation therapy: a retrospective multicenter study and meta-analysis.

BACKGROUND/AIMS: Patients with mild traumatic brain injury (mTBI) on anticoagulants have an increased risk of intracranial hemorrhage (ICH). However, consensus is lacking on whether to admit them after normal initial cranial CT. We evaluated the yield of 24-h neurological observation. METHODS: Retrospective multicenter study including adult patients admitted over a 5-year period with mTBI on anticoagulation [therapeutic dose heparin, direct oral anticoagulant, or vitamin K antagonist (VKA) with international normalized ratio (INR) ≥ 1.7] and reportedly normal cranial CT obtained within 24 h after trauma. Primary endpoint was symptomatic ICH within 24 h of injury. Literature on delayed ICH in patients with mTBI and anticoagulation use was reviewed. RESULTS: Of 17.643 mTBI patients, 905 met the inclusion criteria (median age 82 years). 97% used VKA (median INR 2.9). None developed delayed ICH within 24 h. Nine patients deteriorated neurologically due to ICH, four within 24 h (0.4%, 95% CI 0.1-1.2) and five on day 2, 18, 22, 36 and 52, respectively. In six patients, including all four that developed symptoms within 24 h, ICH was found upon reevaluation of initial imaging. The meta-analysis comprised of 9 studies with data from 2885 patients. The estimated pooled proportion of symptomatic delayed ICH or delayed diagnosis of ICH within 24 h was 0.2% (95% CI 0.0-0.5). CONCLUSIONS: Delayed (diagnosis of) ICH within 24 h is very rare in mTBI patients on anticoagulants after reportedly normal initial CT. Routine hospitalization of these patients seems unwarranted when the initial cranial CT is scrupulously evaluated.