Irregular Shape of Intracranial Aneurysm Indicates Rupture Risk Irrespective of Size in a Population-Based Cohort.

BACKGROUND AND PURPOSE: Size and shape of saccular intracranial aneurysms (sIA) reflect the condition of the sIA wall and were risk factors for rupture in previous follow-up studies. We investigated how well size or shape identify rupture-prone sIAs. METHODS: In a population-based registry, we investigated the characteristics of ruptured sIAs treated in a single neurosurgical center (1980-2014). In addition to univariate analysis, logistic regression was used in multivariate analysis, and sensitivity and specificity of size or shape were calculated using receiver operating characteristic curves. RESULTS: Ruptured sIAs were on average larger than unruptured sIAs (median, 7 versus 4 mm; P<0.000), but location and patient background affected the size at rupture. Of the ruptured sIAs, 38% were smaller than 7 mm and 18% were smaller than 4 mm. Of those sIAs that had ruptured at a small (<7 mm) size, 87% had an irregular shape. In multivariate analysis, irregular shape had the strongest association with presentation as ruptured sIA (odds ratio, 7.1; 95% confidence interval, 6.0-8.3), with better sensitivity (91%) and specificity (76%), in contrast to smoking (odds ratio, 0.7; 95% confidence interval, 0.6-0.9; sensitivity, 28%; specificity 57%) and Population, Hypertension, Age, Size of sIA, Earlier SAH from another sIA, Site of sIA score (odds ratio, 1.5; 95% confidence interval, 1.4-1.6). CONCLUSIONS: Irregular or multilobular shape is strongly associated with rupture in sIAs of all sizes and independent of location and patient background. Especially sIAs with irregular shape should be considered as high rupture risk lesions, even if small in diameter and in nonsmoking patients with low PHASES scores.

Secondary hypertension in patients with saccular intracranial aneurysm disease: A population based study.

BACKGROUND: Secondary hypertension is a serious form of hypertension, involving 5% to 10% of all hypertension patients. Hypertension is a risk factor of the saccular intracranial aneurysm (sIA) disease and subarachnoid hemorrhage from ruptured sIA (aSAH), but the impact of secondary hypertension on sIA disease is poorly known. In a defined Eastern Finnish sIA population we studied the prevalence of secondary hypertension and its impact on sIA disease phenotype. METHODS: We included 2704 consecutive sIA patients first admitted to Kuopio University Hospital from 1995 to 2014. Their clinical data from Kuopio Intracranial Aneurysm patient and Family Database was fused with prescription drug usage data, hospital diagnoses and causes of death, retrieved from nationwide registries. Medical records of hypertensive sIA patients were reviewed to confirm or exclude secondary hypertension. Prevalence of secondary hypertension and associated diagnoses were calculated. Logistic regression was used to identify clinical characteristics of sIA disease that associated with secondary hypertension. RESULTS: We identified 2029 (75%) sIA patients with hypertension and 208 (10%) of them had secondary hypertension. Most frequent conditions associated with secondary hypertension were kidney and renovascular diseases (45%), sleep apnea (27%) and hypothyroidism (19%); 46 (22%) of the 208 patients had more than one such condition. In multivariate logistic regression analyses of 1561 aSAH patients, secondary hypertension significantly associated with the number of sIAs (p = 0.003; OR 1.32; 95% CI 1.10-1.58) and male gender (p = 0.034; OR 1.59; 95% CI 1.04-2.43). CONCLUSIONS: Secodary hypertension was relatively common (10%) among hypertensive sIA patients. Secondary causes for hypertension should be taken into account in hypertensive sIA patients, especially in aSAH patients with multiple intracranial aneurysms. Further research is indicated to evaluate the impact of secondary hypertension on the long-term rupture risk of unruptured sIA carriers and long-term outcome after aSAH.

Impact of Young Age on the Presentation of Saccular Intracranial Aneurysms: Population-Based Analysis of 4082 Patients.

BACKGROUND: Formation and rupture of saccular intracranial aneurysms (sIAs) may have different pathobiologies in patients with younger age at first diagnosis of sIA disease. OBJECTIVE: To study the phenotype of sIA disease and formation of new (de novo) sIAs in patients below 40 yr. METHODS: A population-based cohort study was conducted in 613 young (<40 yr) sIA patients with first diagnosis between 1980 and 2014 and total angiographic follow-up of 3768 yr. RESULTS: Of the 613 sIA patients <40 yr, 508 had aneurysmal subarachnoid hemorrhage (sIA-SAH) and 105 unruptured sIA(s) at first sIA diagnosis. Hypertension was 2 times less common among <40 than >40-yr-old patients (unruptured and ruptured). Smoking was very prevalent in <40-yr-old patients (33% in SAH, 68% unruptured). SAH patients <40 yr more often had family history of sIA, and lower PHASES scores (age omitted, P < .001). Ruptured sIAs were small (<7 mm) in 33% of 39 to 30 yr patients, in 44% of 29 to 20 yr patients, and 57% of <19 yr patients. Their shape was irregular in 90%, 94%, and 95%, respectively. Smoking history (hazard ratio [HR] 2.8, 95% confidence interval [CI] 1.2-7.0), family history for sIAs (HR 3.1, 95% CI 1.3-7.7), and age at presentation (HR .91 per year, 95% CI .85-.98) were risk factors for de novo sIA formation, diagnosed in 4% even after 20 yr (median 11.8 yr). CONCLUSION: Smoking and family history are risk factors for sIA formation and aneurysmal SAH at young age. Young aneurysmal SAH patients had lower PHASES scores and often rupture from a small sIA, suggesting need for more aggressive management.

Association of kallikrein gene polymorphisms with intracranial aneurysms.

BACKGROUND AND PURPOSE: Genomewide DNA linkage analysis identified a susceptibility locus for intracranial aneurysm (IA) on chromosome 19q13 in the Finnish population, a region including the kallikrein gene cluster. We investigated the association of single nucleotide polymorphisms (SNPs) in the kallikrein gene cluster with IA in the Finnish population. METHODS: We genotyped 18 haplotype-tagging SNPs spanning a 244 kbp region in the kallikrein gene cluster for 266 Finnish IA cases and 290 Finnish control subjects. In a second phase, we genotyped 2 SNPs (rs1722561 and rs1701946) in an additional set of 102 Finnish IA cases and 102 Finnish control subjects; and in a third phase, we genotyped these 2 SNPs in 156 Russian IA cases and 186 Russian control subjects. Both single-marker and haplotype-based tests of association were performed. RESULTS: In phase I, SNPs rs1722561 and rs1701946 were significantly associated with IA in the Finnish population for single locus models (rs1722561: P=0.0395; rs1701946: P=0.0253). A 2-SNP haplotype block (rs1722561-rs1701946) identified in phase I was also associated with IA in the expanded Finnish (phase II) data set (asymptotic P=0.012; empirical P=0.019). In the Finnish and Russian combined data set (phase III) with 524 cases and 578 control subjects, the same 2 SNPs (OR: 1.35, 95% CI: 1.14, 1.60; P=0.0005 for rs1722561 and OR: 1.32, 95% CI: 1.12, 1.57; P=0.0011 for rs1701946) were significantly associated with IA. These SNPs are located in the intronic region of KLK8, although linkage disequilibrium could extend from rs268912-rs2250066, a approximately 76-kbp region that includes KLK5-KLK10. CONCLUSIONS: Polymorphisms within the kallikrein gene cluster are associated with IA suggesting that the kallikreins are important candidate genes for IA.

Polycystic kidney disease among 4,436 intracranial aneurysm patients from a defined population.

OBJECTIVE: To define the association of autosomal dominant polycystic kidney disease (ADPKD) with the characteristics of aneurysmal subarachnoid hemorrhage (aSAH) and unruptured intracranial aneurysm (IA) disease. METHODS: We fused data from the Kuopio Intracranial Aneurysm database (n = 4,436 IA patients) and Finnish nationwide registries into a population-based series of 53 IA patients with ADPKD to compare the aneurysm- and patient-specific characteristics of IA disease in ADPKD and in the general IA population, and to identify risks for de novo IA formation. RESULTS: In total, there were 33 patients with ADPKD with aSAH and 20 patients with ADPKD with unruptured IAs. The median size of ruptured IAs in ADPKD was significantly smaller than in the general population (6.00 vs 8.00 mm) and the proportion of small ruptured IAs was significantly higher (31% vs 18%). Median age at aSAH was 42.8 years, 10 years younger than in the general IA population. Multiple IAs were present in 45% of patients with ADPKD compared to 28% in the general IA population. Cumulative risk of de novo IA formation was 1.3% per patient-year (vs 0.2% in the general IA population). Hazard for de novo aneurysm formation was significantly elevated in patients with ADPKD (Cox regression hazard ratio 7.7, 95% confidence interval 2.8-20; p < 0.0005). CONCLUSIONS: Subarachnoid hemorrhage occurs at younger age and from smaller IAs in patients with ADPKD and risk for de novo IAs is higher than in the general Eastern Finnish population. ADPKD should be considered as an indicator for long-term angiographic follow-up in patients with diagnosed IAs.

Neurofibromatosis type 1 is not associated with subarachnoid haemorrhage.

BACKGROUND: The prevalence of intracranial aneurysms (IAs) has been proposed to be elevated in the patients with neurofibromatosis type 1 (NF1). Our aims were to determine the prevalence of NF1 in a large Finnish population based cohort of IA patients and, on the other hand, the occurrences of subarachnoid haemorrhage and unruptured intracranial aneurysms in a nationwide population-based cohort of NF1 patients and its matched ten-fold control cohort. METHODS: The Kuopio IA Database (www.kuopioneurosurgery.fi) includes all ruptured and unruptured IA cases admitted to the Kuopio University Hospital (KUH) from its defined Eastern Finnish catchment population since 1980. In this registry-based study, we cross-linked the Kuopio IA database with the Finnish national registry covering all hospital diagnoses. The NF1 diagnoses of the 4543 patients with either saccular of fusiform IA were identified from 1969 to 2015 and verified from patient records. Our second approach was to analyze the occurrence of aneurysmal subarachnoid haemorrhage (aSAH) and unruptured IAs in a nationwide population-based database of 1410 NF1 patients and its ten-fold matched control cohort (n = 14030) using national registry of hospital diagnoses between 1987 and 2014. RESULTS: One NF1 patient was identified among the 4543 IA patients. Three verified IA cases (one unruptured IA and two aSAH cases) were identified in the cohort of 1410 NF1 patients, with similar occurrences in the control cohort. CONCLUSIONS: We found no evidence in our population-based cohorts to support the conception that NF1 is associated with IAs. Our results indicate that the incidence of aSAH is not elevated in patients with NF1. Further studies are required to confirm that there is no association between NF1 and unruptured IAs.

Familial intracranial aneurysms: an analysis of 346 multiplex Finnish families.

BACKGROUND AND PURPOSE: Genetic risk factors are considered important in the development, growth, and rupture of intracranial aneurysms; however, few have been identified. We analyzed intracranial aneurysm families with at least 2 affected persons and determined relationships between affected persons and assessed the inheritance patterns of aneurysms. METHODS: Families with > or =2 members with verified diagnoses of intracranial aneurysms were recruited from Kuopio and Helsinki, Finland. Families with a diagnosis of other heritable disorders that have associated intracranial aneurysms, such as autosomal dominant polycystic kidney disease, were excluded. RESULTS: We identified 346 Finnish multiplex families with 160 (46.2%) male and 186 (53.8%) female index cases. There were a total of 937 aneurysm cases, with an average of 2.7 cases per family. The majority of the families had only 2 affected relatives (n=206; 59.5%), although there were families with up to 6 (n=10), 7 (n=1), 8 (n=1), or 10 (n=2) affected persons. The affected relatives of the index cases included 108 sisters, 116 brothers, 105 parents, 30 children, 15 grandparents, 102 aunts or uncles, and 64 cousins. Of the 937 affected persons, 569 (60.7%) were alive and available for genetic analysis. Inheritance patterns consistent with autosomal recessiveness were observed in 198 (57.2%), autosomal dominance in 126 (36.4%), and autosomal dominance with incomplete penetrance in 19 (5.5%) of the families. CONCLUSIONS: The collection is the most extensive published to date and extends previous observations of familial aggregation that are consistent with a major gene effect.

Saccular intracranial aneurysm disease: distribution of site, size, and age suggests different etiologies for aneurysm formation and rupture in 316 familial and 1454 sporadic eastern Finnish patients.

OBJECTIVE: Finnish saccular intracranial aneurysm (sIA) disease associates to 2q33, 8q11, and 9p21 loci and links to 19q13, Xp22, and kallikrein cluster in sIA families. Detailed phenotyping of familial and sporadic sIA disease is required for fine mapping of the Finnish sIA disease. METHODS: Eastern Finland, which is particularly isolated genetically, is served by Kuopio University Hospital's Department of Neurosurgery. We studied the site and size distribution of unruptured and ruptured sIAs in correlation to age and sex in 316 familial and 1454 sporadic sIA patients on first admission from 1993 to 2007. RESULTS: The familial and sporadic aneurysmic subarachnoid hemorrhage patients had slightly different median ages (46 vs 51 years in men; 50 vs 57 years in women), different proportion of males (50% vs 42%), equal median diameter of ruptured sIAs (7 mm vs 7 mm) with no correlation to age, and equally unruptured sIAs (30% vs 28%). The unruptured sIAs were most frequent at the middle cerebral artery (MCA) bifurcation (44% vs 39%) and the anterior communicating artery (12% vs 13%), in contrast to the ruptured sIAs at the anterior communicating artery (37% vs 29%) and MCA bifurcation (29% vs 29%). The size of unruptured sIAs increased by age in the sporadic group. CONCLUSION: The MCA bifurcation was most prone to develop unruptured sIAs, suggesting that MCA branching during the embryonic period might be involved. The different site distribution of ruptured and unruptured sIAs suggests different etiologies for sIA formation and rupture. The lack of correlation of size and age at rupture (exposure to risk factors) suggests that the size at rupture is more dependent on hemodynamic stress.

Intracranial aneurysms in Finnish families: confirmation of linkage and refinement of the interval to chromosome 19q13.3.

We recently reported a two-stage genomewide screen of 48 sib pairs affected with intracranial aneurysms (IAs) that revealed suggestive linkage to chromosome 19q13, with a LOD score of 2.58. The region supporting linkage spanned approximately 22 cM. Here, we report a follow-up study of the locus at 19q13, with a sample size expanded to 139 affected sib pairs, along with 83 other affected relative pairs (222 affected relative pairs in total). Suggestive linkage was observed in both independent sample sets, and linkage was significant in the combined set at 70 cM (LOD score 3.50; P=.00006) and at 80 cM (LOD score 3.93; P=.00002). Linkage was highly significant at 70 cM (LOD score 5.70; P=.000001) and at 80 cM (LOD score 3.99; P=.00005) when a covariate measuring the number of affected individuals in the nuclear family was included. To evaluate further the contribution to the linkage signal from families with more than two affected relatives, we performed model-based linkage analysis with a recessive model and a range of penetrances, and we obtained maximum linkage at 70 cM (LOD score 3.16; P=.00007) with a penetrance of 0.3. We then estimated location by using GENEFINDER. The most likely location for a gene predisposing to IAs in the Finnish population is in a region with a 95% confidence interval of 11.6 cM (P=.00007) centered 2.0 cM proximal to D19S246.