Risk Factors for Delayed Cerebral Ischemia in Good-Grade Patients With Aneurysmal Subarachnoid Hemorrhage.

Background A subset of good-grade patients with aneurysmal subarachnoid hemorrhage (aSAH) develop delayed cerebral ischemia (DCI) that may cause permanent disabilities after aSAH. However, little is known about the risk factors of DCI among this specific patient group. Methods and Results We obtained a multinational cohort of good-grade (Glasgow Coma Scale 13-15 on admission) patients with aSAH by pooling patient data from 4 clinical trials and 2 prospective cohort studies. We collected baseline data on lifestyle-related factors and the clinical characteristics of aSAHs. By calculating fully adjusted risk estimates for DCI and DCI-related poor outcome, we identified the most high-risk patient groups. The pooled study cohort included 1918 good-grade patients with aSAH (median age, 51 years; 64% women), of whom 21% and 7% experienced DCI and DCI-related poor outcome, respectively. Among men, patients with obesity and (body mass index ≥30 kg/m2) thick aSAH experienced most commonly DCI (33%) and DCI-related poor outcome (20%), whereas none of the normotensive or young (aged <50 years) men with low body mass index (body mass index <22.5 kg/m2) had DCI-related poor outcome. In women, the highest prevalence of DCI (28%) and DCI-related poor outcome (13%) was found in patients with preadmission hypertension and thick aSAH. Conversely, the lowest rates (11% and 2%, respectively) were observed in normotensive women with a thin aSAH. Conclusions Increasing age, thick aSAH, obesity, and preadmission hypertension are risk factors for DCI in good-grade patients with aSAH. These findings may help clinicians to consider which good-grade patients with aSAH should be monitored carefully in the intensive care unit.

Body Mass Index and the Risk of Poor Outcome in Surgically Treated Patients With Good-Grade Aneurysmal Subarachnoid Hemorrhage.

BACKGROUND: Heterogeneity among study populations and treatment procedures has led to conflicting results on outcome predictors for patients with aneurysmal subarachnoid hemorrhage (aSAH). One such conflicting predictor is body mass index (BMI). OBJECTIVE: To clarify whether high BMI values protect patients from poor outcome after aSAH, as previously suggested. METHODS: We surveyed 6 prospective studies conducted in 14 different countries (93 healthcare units) between 1985 and 2016 and pooled the data on surgically treated patients with good-grade (Glasgow Coma Scale 13-15 on admission) aSAH. We calculated BMI for each patient and created 4 balanced categories based on the BMI quartiles of each cohort. We calculated adjusted odds ratios (ORs) with 95% CIs for the 3-month poor outcome (Glasgow Outcome Scale 1-3) by BMI. RESULTS: The pooled study cohort included 1692 patients with good-grade aSAH (mean age 51 years; 64% female). At 3 months, 288 (17%) had poor outcomes. The risk for poor outcomes increased with increasing BMI values (OR = 1.15 [1.02-1.31] per each standard deviation increase of BMI). The risk for poor outcome was over 1.6 times higher (OR = 1.66 [1.13-2.43]) in the highest BMI category (range 27.1-69.2) compared with the lowest BMI category (range 14.4-23.8). These associations were found in each of the 6 study cohorts in both men and women, regardless of age. CONCLUSION: Because higher BMI values seem to associate with poor outcomes in surgically treated patients with good-grade aSAH, it seems unlikely that obesity protects patients with aSAH from poor outcomes.

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.

Cerebrovascular disease at young age is related to mother's health during the pregnancy-The Northern Finland Birth Cohort 1966 study.

BACKGROUND AND PURPOSE: For prevention of cerebrovascular diseases at younger age, it is important to understand the risk factors occurring early in life. We investigated the relationship between mothers' general health during pregnancy and the offspring's risk of cerebrovascular disease in age of 15 to 52 years. METHODS: Within the population-based prospective Northern Finland Birth Cohort 1966, 11,926 persons were followed from antenatal period to 52 years of age. Information on their mother's ill health conditions, i.e., hospitalizations, chronic diseases, medications, vitamin or iron supplement, fever, anemia, mood, and smoking was collected from 24th gestational week onwards. Ischemic and hemorrhagic cerebrovascular diseases of the offspring were identified from national registers in Finland. Cox proportional hazard models were used to estimate the association of mother's health conditions with incidence of cerebrovascular disease in the offspring, with adjustments for potential confounders. RESULTS: During 565,585 person-years of follow-up, 449 (2.8%) of the offspring had a cerebrovascular disease. Hospitalization during pregnancy was associated with an increased risk of cerebrovascular disease in the offspring (hazard ratio (HR) = 1.49; 95% confidence interval (CI) 1.06-2.08) after adjustment for confounders, as was having more than three ill health conditions (HR = 1.89; CI 1.14-3.11). Not using vitamin or iron supplement was associated with increased risk for cerebrovascular disease in the offspring (HR = 1.39; CI 1.01-1.89). CONCLUSIONS: The results suggest that the risk of cerebrovascular disease may start as early as during the antenatal period, and the health characteristics of mothers during pregnancy may play a role in cerebrovascular disease risk of the offspring.

PHASES score and treatment scoring with cigarette smoking in the long-term prediction of rupturing of unruptured intracranial aneurysms.

OBJECTIVE: Treatment indications in unruptured intracranial aneurysms (UIAs) are challenging because of the lack of prospective natural history studies without treatment selection and the decreasing incidence of aneurysm rupture. The purpose of this study was to test whether the population, hypertension, age, size of aneurysm, earlier aneurysm rupture, site of aneurysm (PHASES) score obtained from an individual-based meta-analysis could predict the long-term rupture risk of UIAs. METHODS: The series included 142 patients of working age with UIAs diagnosed before 1979, when these were not treated but were followed up until the first rupture, death, or the last contact. PHASES scores were recorded for all patients by using the baseline variables and compared with the new treatment score obtained from a recent cohort, consisting of age, smoking status, and aneurysm size and location. RESULTS: Of the 142 patients, 34 had an aneurysm rupture during a total follow-up of 3064 person-years. The median time between diagnosis and an aneurysm rupture was 10.6 years. The PHASES score at baseline was higher in those with an aneurysm rupture than in the others (5.3 ± 2.3 vs 4.2 ± 2.2, p = 0.012), and the difference relative to the new treatment score was 5.3 ± 2.4 versus 3.0 ± 2.2 (p < 0.001). The receiver operating characteristic curve of the PHASES score for predicting rupture showed a fair area under the curve (0.674, 95% CI 0.558-0.790) where the optimal cutoff point was obtained at ≥ 6 versus < 6 points for sensitivity (0.500) and specificity (0.811). The area under the curve of the new score was 0.755 (95% CI 0.657-0.853), with the optimal cutoff point at ≥ 5 versus < 5 points for sensitivity (0.607) and specificity (0.789). CONCLUSIONS: The PHASES and the new scores predicted the long-term aneurysm rupture risk moderately well, with the latter, which also included smoking, being slightly better and easier in clinical practice. The findings suggest that treatment decisions about UIAs in patients of working age can be done with an improved cost-effectiveness.

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.

Long-term survival after primary intracerebral hemorrhage: A population-based case-control study spanning a quarter of a century.

BACKGROUND AND PURPOSE: The aim of this study was to determine the differences in life expectancy and causes of death after primary intracerebral hemorrhage (ICH) relative to general population controls. METHODS: In a population-based setting, 963 patients from Northern Ostrobothnia who had their first-ever ICH between 1993 and 2008 were compared with a cohort of 2884 sex- and age-matched controls in terms of dates and causes of death as extracted from the Causes of Death Register kept by Statistics Finland and valid up to the end of 2017. RESULTS: Of our 963 patients, 781 died during the follow-up time (mortality 81.1%). Cerebrovascular disease was the most common cause of death for these patients, 37.3% compared with 8.2% amongst the controls. The most common reasons for cerebrovascular mortality in the ICH patients were late sequelae of ICH in 12.8% (controls 0%) and new bleeding in 10.6% (controls 1.0%). The long-term survivors had a smaller ICH volume (median 12 ml) than those patients who died within 3 months (median 39 ml). The mortality rate of ICH patients during a follow-up between 12 and 24 years was still higher than that of their controls (hazard ratio 2.08, 95% confidence interval 1.58-2.74, p < 0.001). CONCLUSIONS: Very long-term ICH survivors have a constant excess mortality relative to controls even 10 years after the index event. A significantly larger proportion of patients died of cerebrovascular causes and fewer because of cancer relative to the controls.

Outcome of Patients with Multiple Intracranial Aneurysms after Subarachnoid Hemorrhage and Future Risk of Rupture of Unruptured Aneurysm.

The purpose was to study the risk of rupture of unruptured intracranial aneurysms (UIAs) of patients with multiple intracranial aneurysms after subarachnoid hemorrhage (SAH), in a long-term follow-up study, from variables known at baseline. Future rupture risk was compared in relation to outcome after SAH. The series consists of 131 patients with 166 UIAs and 2854 person-years of follow-up between diagnosis of UIA and its rupture, death or the last follow-up contact. These were diagnosed before 1979, when UIAs were not treated in our country. Those patients with a moderate or severe disability after SAH, according to the Glasgow Outcome Scale, had lower rupture rates of UIA than those with a good recovery or minimal disability (4/37 or 11%, annual UIA rupture rate of 0.5% (95% confidence interval (CI) 0.1-1.3%) during 769 follow-up years vs. 27/94 or 29%, 1.3% (95% CI 0.9-1.9%) during 2085 years). Those with a moderate or severe disability differed from others by their older age. Those with a moderate or severe disability tended to have a decreased cumulative rate of aneurysm rupture (log rank test, p = 0.066) and lower relative risk of UIA rupture (hazard ratio 0.39, 95% CI 0.14-1.11, p = 0.077). Multivariable hazard ratios showed at least similar results, suggesting that confounding factors did not have a significant effect on the results. The results of this study without treatment selection of UIAs suggest that patients with a moderate or severe disability after SAH have a relatively low risk of rupture of UIAs. Their lower treatment indication may also be supported by their known higher treatment risks.

Increased mortality after post-stroke epilepsy following primary intracerebral hemorrhage.

OBJECTIVES: This study aimed to determine whether post-stroke epilepsy (PSE) predicts mortality, and to describe the most prominent causes of death (COD) in a long-term follow-up after primary intracerebral hemorrhage (ICH). METHODS: We followed 3-month survivors of a population-based cohort of primary ICH patients in Northern Ostrobothnia, Finland, for a median of 8.8 years. Mortality and CODs were compared between those who developed PSE and those who did not. PSE was defined according to the ILAE guidelines. CODs were extracted from death certificates (Statistics Finland). RESULTS: Of 961 patients, 611 survived for 3 months. 409 (66.9%) had died by the end of the follow-up. Pneumonia was the only COD that was significantly more common among the patients with PSE (56% vs. 37% of deaths). In the multivariable models, PSE (hazard ratio [HR] 1.41, 95% confidence interval [CI] 1.06-1.87), age (HR 1.07, 95% CI 1.06-1.08), male sex (HR 1.35, 95% CI 1.09-1.67), dependency at 3 months (HR 1.52, 95% CI 1.24-1.88), non-subcortical ICH location (subcortical location HR 0.78, 95% CI 0.61-0.99), diabetes (HR 1.43, 95% CI 1.07-1.90) and cancer (HR 1.45, 95% CI 1.06-1.98) predicted death in the long-term follow-up. CONCLUSION: PSE independently predicted higher late morality of ICH in our cohort. Pneumonia-related deaths were more common among the patients with PSE.

Scoring of Growth of Unruptured Intracranial Aneurysms.

The purpose was to obtain a reliable scoring for growth of unruptured intracranial aneurysms (UIAs) in a long-term follow-up study from variables known at baseline and to compare it with the ELAPSS (Earlier subarachnoid hemorrhage, Location of the aneurysm, Age > 60 years, Population, Size of the aneurysm, and Shape of the aneurysm) score obtained from an individual-based meta-analysis. The series consists of 87 patients with 111 UIAs and 1669 person-years of follow-up between aneurysm size measurements (median follow-up time per patient 21.7, range 1.2 to 51.0 years). These were initially diagnosed between 1956 and 1978, when UIAs were not treated in our country. ELAPSS scores at baseline did not differ between those with and those without aneurysm growth. The area under the curve (AUC) for the receiver operating curve (ROC) of the ELAPSS score for predicting long-term growth was fail (0.474, 95% CI 0.345-0.603), and the optimal cut-off point was obtained at ≥7 vs. <7 points for sensitivity (0.829) and specificity (0.217). In the present series UIA growth was best predicted by female sex (4 points), smoking at baseline (3 points), and age <40 years (2 points). The AUC for the ROC of the new scoring was fair (0.662, 95% CI 0.546-0.779), which was significantly better than that of ELAPSS score (p < 0.05). The optimal cut-off point was obtained at ≥4 vs. <4 points for sensitivity (0.971) and specificity (0.304). A new simple scoring consisting of only female sex, cigarette smoking and age <40 years predicted growth of an intracranial aneurysm in long-term follow-up, significantly better than the ELAPSS score.

Treatment Scoring of Unruptured Intracranial Aneurysms.

Background and Purpose- The purpose was to obtain a reliable treatment score for unruptured intracranial aneurysms (UIAs) from variables known at baseline. Methods- The series included 142 patients with UIAs diagnosed between 1956 and 1978 when UIAs were not treated and were followed up until the first aneurysm rupture, death, or the last contact. Previously published UIA treatment score was recorded, and finally, a new treatment score was constructed. Results- The median follow-up time was 21.0 years (interquartile range, 10.4-31.8 years). A total of 34 patients had an aneurysm rupture during 3064 person-years of follow-up. The UIA treatment score differed slightly between those with and without an aneurysm rupture (9.4±2.8 versus 8.3±3.1, P=0.082). The receiver operating characteristics curve of the UIA treatment score for predicting rupture showed a modest area under the curve (AUC; 0.618, 95% CI, 0.502-0.733; P=0.059). The best new treatment score consisted of 4 variables: age <40 years (2 points), current smoking (2 points), UIA size ≥7 mm (3 points), and location (anterior communicating artery, 5 points; internal carotid bifurcation, 4 points; and posterior communicating artery, 2 points). Scores of 5 to 12 points were associated with high cumulative UIA rupture rates (16%-60% at 10 years and 49%-80% at 30 years), favoring UIA treatment. Scores of 1 to 4 points (3% at 10 years and 18% at 30 years) favored conservative treatment and needed additional indications for treatment. Patients with a score of 0 points should not be treated (no ruptures during 513 follow-up years). The area under the curve for this scoring was 0.755 (95% CI, 0.657-0.853; P<0.001) and was better than that of the UIA treatment score (P=0.02). Conclusions- This new simple and rapid scoring system is reliable for evaluating treatment indications with regard to the lifelong prevention of aneurysm rupture.

Definition and Prioritization of Data Elements for Cohort Studies and Clinical Trials on Patients with Unruptured Intracranial Aneurysms: Proposal of a Multidisciplinary Research Group.

INTRODUCTION: Variability in usage and definition of data characteristics in previous cohort studies on unruptured intracranial aneurysms (UIA) complicated pooling and proper interpretation of these data. The aim of the National Institute of Health/National Institute of Neurological Disorders and Stroke UIA and Subarachnoid Hemorrhage (SAH) Common Data Elements (CDE) Project was to provide a common structure for data collection in future research on UIA and SAH. METHODS: This paper describes the development and summarization of the recommendations of the working groups (WGs) on UIAs, which consisted of an international and multidisciplinary panel of cerebrovascular specialists on research and treatment of UIAs. Consensus recommendations were developed by review of previously published CDEs for other neurological diseases and the literature on UIAs. Recommendations for CDEs were classified by priority into 'Core,' 'Supplemental-Highly Recommended,' 'Supplemental,' and 'Exploratory.' RESULTS: Ninety-one CDEs were compiled; 69 were newly created and 22 were existing CDEs. The CDEs were assigned to eight subcategories and were classified as Core (8), Supplemental-Highly Recommended (23), Supplemental (25), and Exploratory (35) elements. Additionally, the WG developed and agreed on a classification for aneurysm morphology. CONCLUSION: The proposed CDEs have been distilled from a broad pool of characteristics, measures, or outcomes. The usage of these CDEs will facilitate pooling of data from cohort studies or clinical trials on patients with UIAs.

Growth and rupture of unruptured intracranial aneurysms.

OBJECTIVE: Risk factors for growth of unruptured intracranial aneurysms (UIAs) during a lifelong follow-up in relation to subsequent rupture are unknown. The author's aim in this study was to investigate whether risk factors for UIA growth are different for those that lead to rupture than for those that do not. METHODS: The series consists of 87 patients with 111 UIAs diagnosed before 1979, when UIAs were not treated. A total follow-up time of the patients was 2648 person-years for all-cause death and 2182 years when patients were monitored until the first rupture, death due to unrelated causes, or the last contact (annual incidence of aneurysm rupture, 1.2%). The follow-up time between aneurysm measurements was 1669 person-years. Risk factors for UIA growth were analyzed in relation to subsequent rupture. RESULTS: The median follow-up time between aneurysm measurements was 21.7 years (range 1.2-51.0 years). In 40 of the 87 patients (46%), the UIAs increased in size ≥ 1 mm, and in 31 patients (36%) ≥ 3 mm. All ruptured aneurysms in 27 patients grew during the follow-up of 324 person-years (mean growth rates 6.1 mm, 0.92 mm/year, and 37%/year), while growth without rupture occurred in 13 patients during 302 follow-up years (3.9 mm, 0.18 mm/year, and 4%/year) and no growth occurred in 47 patients during 1043 follow-up years. None of the 60 patients without aneurysm rupture experienced one during the subsequent 639 follow-up years after the last aneurysm measurement. Independent risk factors for UIA growth (≥ 1 mm) in all patients were female sex (adjusted OR 3.08, 95% CI 1.04-9.13) and smoking throughout the follow-up time (adjusted OR 3.16, 95% CI 1.10-9.10), while only smoking (adjusted OR 4.36, 95% CI 1.27-14.99) was associated with growth resulting in aneurysm rupture. Smoking was the only independent risk factor for UIA growth ≥ 3 mm resulting in aneurysm rupture (adjusted OR 4.03, 95% CI 1.08-15.07). Cigarette smoking at baseline predicted subsequent UIA growth, while smoking at the end of the follow-up was associated with growth resulting in aneurysm rupture. CONCLUSIONS: Cigarette smoking is an important risk factor for UIA growth, particularly for growth resulting in rupture. Cessation of smoking may reduce the risk of devastating aneurysm growth.

Poststroke epilepsy in long-term survivors of primary intracerebral hemorrhage.

OBJECTIVE: To identify the incidence and predisposing factors for development of poststroke epilepsy (PSE) after primary intracerebral hemorrhage (PICH) during a long-term follow-up. METHODS: We performed a retrospective study of patients who had had their first-ever PICH between January 1993 and January 2008 in Northern Ostrobothnia, Finland, and who survived for at least 3 months. These patients were followed up for PSE. The associations between PSE occurrence and sex, age, Glasgow Coma Scale (GCS) score on admission, hematoma location and volume, early seizures, and other possible risk factors for PSE were assessed using the Cox proportional hazards regression model. RESULTS: Of the 615 PICH patients who survived for longer than 3 months, 83 (13.5%) developed PSE. The risk of new-onset PSE was highest during the first year after PICH with cumulative incidence of 6.8%. In univariable analysis, the risk factors for PSE were early seizures, subcortical hematoma location, larger hematoma volume, hematoma evacuation, and a lower GCS score on admission, whereas patients with infratentorial hematoma location or hypertension were less likely to develop PSE (all variables p < 0.05). In multivariable analysis, we found subcortical location (hazard ratio [HR] 2.27, 95% confidence interval [CI] 1.35-3.81, p < 0.01) and early seizures (HR 3.63, 95% CI 1.99-6.64, p < 0.01) to be independent risk factors, but patients with hypertension had a lower risk of PSE (HR 0.54, 0.35-0.84, p < 0.01). CONCLUSIONS: Subcortical hematoma location and early seizures increased the risk of PSE after PICH in long-term survivors, while hypertension seemed to reduce the risk.