Gabriel J.E. Rinkel

Prevalence and Risk of Rupture of Intracranial Aneurysms A Systematic Review

BACKGROUND AND PURPOSE The estimates on the prevalence and the risk of rupture of intracranial saccular aneurysms vary widely between studies. We conducted a systematic review on prevalence and risk of rupture of intracranial aneurysms and classified the data according to study design, study population, and aneurysm characteristics. METHODS We searched for studies published between 1955 and 1996 by means of a MEDLINE search and a cumulative review of the reference lists of all relevant publications. Two authors independently assessed eligibility of all studies and extracted data on study design and on numbers and characteristics of patients and aneurysms. RESULTS For data on prevalence we found 23 studies, totalling 56,304 patients; 6685 (12%) of these patients were from 15 angiography studies. Prevalence was 0.4% (95% confidence interval, 0.4% to 0.5%) in retrospective autopsy studies, 3.6% (3.1 to 4.1) for prospective autopsy studies, 3.7% (3.0 to 4.4) in retrospective angiography studies, and 6.0% (5.3 to 6.8) in prospective angiography studies. For adults without specific risk factors, the prevalence was 2.3% (1.7 to 3.1); it tended to increase with age. The prevalence was higher in patients with autosomal dominant polycystic kidney disease (relative risk [RR], 4.4 [2.7 to 7.2]), a familial predisposition (RR, 4.0 [2.7 to 6.0]), or atherosclerosis (RR, 2.3 [1.7 to 3.1]). Only 8% (5 to 11) of the aneurysms were >10 mm. For the risk of rupture, we found nine studies, totalling 3907 patient-years. The overall risk per year was 1.9% (1.5 to 2.4); for aneurysms = 10 mm, the annual risk was 0.7% (0.5 to 1.0). The risk was higher in women (RR, 2.1[1.1 to 3.9]) and for aneurysms that were symptomatic (RR, 8.3 [4.0 to 17]), >10 mm (RR, 5.5 [3.3 to 9.4]), or in the posterior circulation (RR, 4.1 [1.5 to 11]). CONCLUSIONS Data on prevalence and risk of rupture vary considerably according to study design, study population, and aneurysm characteristics. If all available evidence with inherent overestimation and underestimation is taken together, for adults without risk factors for subarachnoid hemorrhage, aneurysms are found in approximately 2%. The vast majority of these aneurysms are small (=10 mm) and have an annual risk of rupture of approximately 0.7%.

Incidence, case fatality, and functional outcome of intracerebral haemorrhage over time, according to age, sex, and ethnic origin: a systematic review and meta-analysis

BACKGROUND Since the early 1980s, imaging techniques have enabled population-based studies of intracerebral haemorrhage. We aimed to assess the incidence, case fatality, and functional outcome of intracerebral haemorrhage in relation to age, sex, ethnic origin, and time period in studies published since 1980. METHODS From PubMed and Embase searches with predefined inclusion criteria, we identified population-based studies published between January, 1980, and November, 2008. We calculated incidence and case fatality. Incidences for multiple studies were pooled in a random-effects binomial meta-analysis. Time trends of case fatality were assessed with weighted linear-regression analysis. FINDINGS 36 eligible studies described 44 time periods (mid-year range 1983-2006). These studies included 8145 patients with intracerebral haemorrhage. Incidence did not decrease between 1980 and 2008. Overall incidence was 24.6 per 100 000 person-years (95% CI 19.7-30.7). Incidence was not significantly lower in women than in men (overall incidence ratio 0.85, 95% CI 0.61-1.18). Using the age group 45-54 years as reference, incidence ratios increased from 0.10 (95% CI 0.06-0.14) for people aged less than 45 years to 9.6 (6.6-13.9) for people older than 85 years. Median case fatality at 1 month was 40.4% (range 13.1-61.0) and did not decrease over time, and was lower in Japan (16.7%, 95% CI 15.0-18.5) than elsewhere (42.3%, 40.9-43.6). Six studies reported functional outcome, with independency rates of between 12% and 39%. Incidence of intracerebral haemorrhage per 100 000 person-years was 24.2 (95% CI 20.9-28.0) in white people, 22.9 (14.8-35.6) in black people, 19.6 (15.7-24.5) in Hispanic people, and 51.8 (38.8-69.3) in Asian people. INTERPRETATION Incidence of intracerebral haemorrhage increases with age and has not decreased between 1980 and 2006. Case fatality is lower in Japan than elsewhere, increases with age, and has not decreased over time. More data on functional outcome are needed. FUNDING Netherlands Heart Foundation.

The same sequence variant on 9p21 associates with myocardial infarction, abdominal aortic aneurysm and intracranial aneurysm

Recently, two common sequence variants on 9p21, tagged by rs10757278-G and rs10811661-T, were reported to be associated with coronary artery disease (CAD) and type 2 diabetes (T2D), respectively. We proceeded to further investigate the contributions of these variants to arterial diseases and T2D. Here we report that rs10757278-G is associated with, in addition to CAD, abdominal aortic aneurysm (AAA; odds ratio (OR) = 1.31, P = 1.2 × 10−12) and intracranial aneurysm (OR = 1.29, P = 2.5 × 10−6), but not with T2D. This variant is the first to be described that affects the risk of AAA and intracranial aneurysm in many populations. The association of rs10811661-T to T2D replicates in our samples, but the variant does not associate with any of the five arterial diseases examined. These findings extend our insight into the role of the sequence variant tagged by rs10757278-G and show that it is not confined to atherosclerotic diseases.

Incidence of Subarachnoid Haemorrhage: A systematic review with emphasis on region, age, gender and time trends

Background and aim: To update our 1996 review on the incidence of subarachnoid haemorrhage (SAH) and assess the relation of incidence with region, age, gender and time period. Methods: We searched for studies on the incidence of SAH published until October 2005. The overall incidences with corresponding 95% confidence intervals were calculated. We determined the relationship between the incidence of SAH and determinants by means of univariate Poisson regression. Results: We included 51 studies (33 new), describing 58 study populations in 21 countries, observing 45 821 896 person-years. Incidences per 100 000 person-years were 22.7 (95% CI 21.9 to 23.5) in Japan, 19.7 (18.1 to 21.3) in Finland, 4.2 (3.1 to 5.7) in South and Central America, and 9.1 (8.8 to 9.5) in the other regions. With age category 45–55 years as the reference, incidence ratios increased from 0.10 (0.08 to 0.14) for age groups younger than 25 years to 1.61 (1.24 to 2.07) for age groups older than 85 years. The incidence in women was 1.24 (1.09 to 1.42) times higher than in men; this gender difference started at age 55 years and increased thereafter. Between 1950 and 2005, the incidence decreased by 0.6% (1.3% decrease to 0.1% increase) per year. Conclusions: The overall incidence of SAH is approximately 9 per 100 000 person-years. Rates are higher in Japan and Finland and increase with age. The preponderance of women starts only in the sixth decade. The decline in incidence of SAH over the past 45 years is relatively moderate compared with that for stroke in general.

Risk factors for subarachnoid hemorrhage : An updated systematic review of epidemiological studies

Background and Purpose— After a 1996 review from our group on risk factors for subarachnoid hemorrhage (SAH), much new information has become available. This article provides an updated overview of risk factors for SAH. Methods— An overview of all longitudinal and case-control studies of risk factors for SAH published in English from 1966 through March 2005. We calculated pooled relative risks (RRs) for longitudinal studies and odds ratios (ORs) for case-control studies, both with corresponding 95% CIs. Results— We included 14 longitudinal (5 new) and 23 (12 new) case-control studies. Overall, the studies included 3936 patients with SAH (892 cases in 14 longitudinal studies and 3044 cases in 23 case-control studies) for analysis. Statistically significant risk factors in longitudinal and case-control studies were current smoking (RR, 2.2 [1.3 to 3.6]; OR, 3.1 [2.7 to 3.5]), hypertension (RR, 2.5 [2.0 to 3.1]; OR, 2.6 [2.0 to 3.1]), and excessive alcohol intake (RR, 2.1 [1.5 to 2.8]; OR, 1.5 [1.3 to 1.8]). Nonwhite ethnicity was a less robust risk factor (RR, 1.8 [0.8 to 4.2]; OR, 3.4 [1.0 to 11.9]). Oral contraceptives did not affect the risk (RR, 5.4 [0.7 to 43.5]; OR, 0.8 [0.5 to 1.3]). Risk reductions were found for hormone replacement therapy (RR, 0.6 [0.2 to 1.5]; OR, 0.6 [0.4 to 0.8]), hypercholesterolemia (RR, 0.8 [0.6 to 1.2]; OR, 0.6 [0.4 to 0.9]), and diabetes (RR, 0.3 [0 to 2.2]; OR, 0.7 [0.5 to 0.8]). Data were inconsistent for lean body mass index (RR, 0.3 [0.2 to 0.4]; OR, 1.4 [1.0 to 2.0]) and rigorous exercise (RR, 0.5 [0.3 to 1.0]; OR, 1.2 [1.0 to 1.6]). In the studies included in the review, no other risk factors were available for the meta-analysis. Conclusions— Smoking, hypertension, and excessive alcohol remain the most important risk factors for SAH. The seemingly protective effects of white ethnicity compared to nonwhite ethnicity, hormone replacement therapy, hypercholesterolemia, and diabetes in the etiology of SAH are uncertain.

Changes in case fatality of aneurysmal subarachnoid haemorrhage over time, according to age, sex, and region: a meta-analysis.

BACKGROUND In a systematic review, published in 1997, we found that the case fatality of aneurysmal subarachnoid haemorrhage (SAH) decreased during the period 1960-95. Because diagnostic and treatment strategies have improved and new studies from previously non-studied regions have been published since 1995, we did an updated meta-analysis to assess changes in case fatality and morbidity and differences according to age, sex, and region. METHODS A new search of PubMed with predefined inclusion criteria for case finding and diagnosis identified reports on prospective population-based studies published between January, 1995, and July, 2007. The studies included in the previous systematic review were reassessed with the new inclusion criteria. Changes in case fatality over time and the effect of age and sex were quantified with weighted linear regression. Regional differences were analysed with linear regression analysis, and the regions of interest were subsequently defined as reference regions and compared with the other regions. FINDINGS 33 studies (23 of which were published in 1995 or later) were included that described 39 study periods. These studies reported on 8739 patients, of whom 7659 [88%] were reported on after 1995. 11 of the studies that were included in the previous review did not meet the current, more stringent, inclusion criteria. The mean age of patients had increased in the period 1973 to 2002 from 52 to 62 years. Case fatality varied from 8.3% to 66.7% between studies and decreased 0.8% per year (95% CI 0.2 to 1.3). The decrease was unchanged after adjustment for sex, but the decrease per year was 0.4% (-0.5 to 1.2) after adjustment for age. Case fatality was 11.8% (3.8 to 19.9) lower in Japan than it was in Europe, the USA, Australia, and New Zealand. The unadjusted decrease in case fatality excluding the data for Japan was 0.6% per year (0.0 to 1.1), a 17% decrease over the three decades. Six studies reported data on case morbidity, but these were insufficient to assess changes over time. INTERPRETATION Despite an increase in the mean age of patients with SAH, case-fatality rates have decreased by 17% between 1973 and 2002 and show potentially important regional differences. This decrease coincides with the introduction of improved management strategies. FUNDING Netherlands Organisation for Scientific Research; ZonMw.

Treatment of Intracranial Aneurysms by Embolization with Coils A Systematic Review

BACKGROUND Embolization with coils is increasingly used for the treatment of intracranial aneurysms. To assess the percentage of complications, the percentage of aneurysm occlusion, and the short-term outcome, we performed a systematic review of studies on embolization with controlled detachable or pushable coils. SUMMARY OF REVIEW To find studies on embolization with coils, we performed a MEDLINE search from January 1990 to March 1997, checked all reference lists of the studies found, performed a Science Citation Index search on Guglielmi, and hand searched recent volumes of 25 journals. Two authors independently extracted data by means of a standardized data extraction form from 48 eligible studies totalling 1383 patients. Permanent complications of embolization with controlled detachable coils occurred in 46 of 1256 patients (3.7%; 95% CI, 2.7% to 4.9%); 400 of 744 aneurysms (54%; 95% CI, 50% to 57%) were completely occluded. By means of weighted linear regression, no relation between baseline characteristics and outcome measurements was found. The results in the prespecified subgroups of patients with a ruptured aneurysm, an unruptured aneurysm, or a basilar bifurcation aneurysm were essentially the same as the overall results. CONCLUSIONS Short-term results indicate that embolization with coils is a reasonably safe treatment for patients with an unruptured aneurysm and for patients with aneurysmal subarachnoid hemorrhage. The effectiveness in terms of complete occlusion of the aneurysm is moderate. Randomized trials are warranted to compare surgical clipping with embolization with coils.

Definition of Delayed Cerebral Ischemia After Aneurysmal Subarachnoid Hemorrhage as an Outcome Event in Clinical Trials and Observational Studies Proposal of a Multidisciplinary Research Group

Background and Purpose— In clinical trials and observational studies there is considerable inconsistency in the use of definitions to describe delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage. A major cause for this inconsistency is the combining of radiographic evidence of vasospasm with clinical features of cerebral ischemia, although multiple factors may contribute to DCI. The second issue is the variability and overlap of terms used to describe each phenomenon. This makes comparisons among studies difficult. Methods— An international ad hoc panel of experts involved in subarachnoid hemorrhage research developed and proposed a definition of DCI to be used as an outcome measure in clinical trials and observational studies. We used a consensus-building approach. Results— It is proposed that in observational studies and clinical trials aiming to investigate strategies to prevent DCI, the 2 main outcome measures should be: (1) cerebral infarction identified on CT or MRI or proven at autopsy, after exclusion of procedure-related infarctions; and (2) functional outcome. Secondary outcome measure should be clinical deterioration caused by DCI, after exclusion of other potential causes of clinical deterioration. Vasospasm on angiography or transcranial Doppler can also be used as an outcome measure to investigate proof of concept but should be interpreted in conjunction with DCI or functional outcome. Conclusion— The proposed measures reflect the most relevant morphological and clinical features of DCI without regard to pathogenesis to be used as an outcome measure in clinical trials and observational studies.

Risk Factors for Intracerebral Hemorrhage in the General Population: A Systematic Review

Background and Purpose— Although data on some risk factors for intracerebral hemorrhage (ICH) already are beyond doubt, for other factors, the evidence is less clear. We performed a systematic overview of case-control and cohort studies on risk factors for ICH. Methods— We searched MEDLINE, LILACS, EXTRAMED, and Pascal from 1966 to 2001 to identify studies. Studies were included if they met predefined methodological criteria. When possible, 2×2 tables were extracted and combined with the Mantel-Haenszel method. Summary odds ratios (ORs) were calculated for case-control studies, and summary relative risks (RRs) were found for cohort studies and for case-control and cohort studies combined. Results— Fourteen case-control and 11 cohort studies were identified. We could not always combine the results of case-control and cohort studies. In cohort studies, the crude RR for age (every 10-year increase) was 1.97 (95% confidence interval [CI], 1.79 to 2.16). In case-control studies, the crude OR for high alcohol intake was 3.36 (95% CI, 2.21 to 5.12) and for hypertension was 3.68 (95% CI, 2.52 to 5.38). Two cohort studies showed an increasing risk of ICH with increasing degree of hypertension. In cohort and case-control studies combined, the crude RR for sex (male versus female) was 3.73 (95% CI, 3.28 to 4.25); for current smoking, 1.31 (95% CI, 1.09 to 1.58); and for diabetes, 1.30 (95% CI, 1.02 to 1.67). Conclusions— Risk factors for ICH appeared to be age, male sex, hypertension, and high alcohol intake. High cholesterol tends to be associated with a lower risk of ICH. We could not assess whether these risk factors are independent.

Mortality and Morbidity of Surgery for Unruptured Intracranial Aneurysms A Meta-Analysis

BACKGROUND AND PURPOSE Greater availability and improvement of neuroradiological techniques have resulted in more frequent detection of unruptured aneurysms. Because prognosis of subarachnoid hemorrhage is still poor, preventive surgery is increasingly considered as a therapeutic option. Elective surgery requires reliable data on its risks. Therefore, we performed a meta-analysis on the mortality and morbidity of surgery for unruptured intracranial aneurysms. METHODS Through Medline and additional searches by hand, we retrieved studies on clipping of unruptured (additional, symptomatic, or incidental) aneurysms published from 1966 through June 1996. Two authors independently extracted data. We used weighted linear regression for data analysis. RESULTS We included 61 studies that involved 2460 patients (57% female; mean age, 50 years) and at least 2568 unruptured aneurysms (27% >25 mm, 30% located in the posterior circulation). Mortality was 2.6% (95% confidence interval [CI], 2.0% to 3.3%). Permanent morbidity occurred in 10.9% (95% CI, 9.6% to 12.2%) of patients. Postoperative mortality was significantly lower in more recent years for nongiant aneurysms and aneurysms with an anterior location; the last 2 characteristics were also associated with a significantly lower morbidity. CONCLUSIONS In studies published between 1966 and 1996 on clipping of unruptured aneurysms, mortality was 2.6% and morbidity was 10.9%. In calculating the pros and cons of preventive surgery, these proportions should be taken into account.