Terhi Huttunen

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.

OBJECTIVEFinnish 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. METHODSEastern Finland, which is particularly isolated genetically, is served by Kuopio University Hospitals 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. RESULTSThe 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. CONCLUSIONThe 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.

Long-term excess mortality of 244 familial and 1502 sporadic one-year survivors of aneurysmal subarachnoid hemorrhage compared with a matched Eastern Finnish catchment population.

BACKGROUND:Saccular intracranial aneurysms (sIAs) develop in 2% of the population. Rupture of the sIA wall causes almost all cases of aneurysmal subarachnoid hemorrhage (aSAH). OBJECTIVE:We analyzed the long-term excess mortality of 244 familial and 1502 sporadic 1-year survivors of aSAH from sIA compared with a matched Eastern Finnish catchment population. METHODS:The Kuopio Neurosurgery Database contains 1746 one-year survivors of aSAH (1980-2007) from a defined population. The median follow-up time, until death (n = 494) or the end of 2008, was 12 years. Relative survival ratios were calculated compared with the matched (sex, age, calendar time) catchment population. Relative excess risk of death (RER) was estimated for variables known on admission for aSAH as well as Glasgow Outcome Scale score at 12 months. RESULTS:There was 12% excess mortality at 15 years (cumulative relative survival ratio: 0.88; 95% confidence interval: 0.85-0.91). Independent risk factors were male sex (RER: 1.6), age older than 64 years (RER: 2.9), ruptured basilar tip sIA (RER: 4.5), severe hydrocephalus on admission (RER: 3.6), no occlusive therapy (RER: 6.0), and Glasgow Outcome Scale scores of 2, 3, or 4 at 12 months (RER: 23, 4.1, 2.1, respectively), but not familial sIA disease. There were lethal rebleeds from 13 of the 1440 clipped sIAs, 2 of the 265 coiled sIAs, and 2 from the 17 nonoccluded sIAs, and 14 new lethal bleeds from other sIAs. CONCLUSION:The impact of both sporadic and familial aSAH and their sequelae in the central nervous and cardiovascular systems may cause long-term morbidity and mortality. The complex sIA disease may predispose to other vascular events later in life. The causes of the long-term excess mortality are heterogeneous, and more detailed analyses are required.

Risk Factors for Three Phases of 12-Month Mortality in 1657 Patients from a Defined Population After Acute Aneurysmal Subarachnoid Hemorrhage

OBJECTIVE To analyze the impact of factors known after admission on mortality attributable to aneurysmal subarachnoid hemorrhage (SAH) resulting from saccular intracranial aneurysm (IA). METHODS Data of 1657 consecutive patients admitted alive within 24 hours after aneurysmal SAH to Kuopio Neurosurgery during the years 1980-2007 from a defined population were analyzed. RESULTS Aneurysmal SAH caused excess mortality for 12 months, after which other causes of death became dominant. The 12-month mortality curve on a logarithmic time scale indicated acute (first 3 days), subacute (4-30 days), and delayed (1-12 months) mortality, with cumulative rates of 11% at 3 days, 22% at 30 days, and 27% at 12 months. The acute mortality was predicted by Hunt & Hess (H&H) grades IV-V, ruptured aneurysm ≥ 15 mm, and acute subdural hematoma. Age, gender, intracerebral hemorrhage (ICH), and time period of admission were not independent risk factors. Advanced age, H&H grades IV-V, intraventricular hemorrhage (IVH), giant ruptured saccular IA, ruptured saccular IA on the internal carotid artery or the basilar artery bifurcation, and severe hydrocephalus in different combinations predicted subacute and delayed mortality. Patients in good condition on admission had a mortality rate of only 3.5% at 12 months, regardless of age. CONCLUSIONS Sequelae of aneurysmal SAH were the leading cause of death for 12 months. Mortality analysis of this period displayed three phases with distinct independent risk factors. These data support the creation of prognosticators for prediction on admission of the everyday individual risk of death until 12 months after aneurysmal SAH.

Risk of Shunting After Aneurysmal Subarachnoid Hemorrhage: A Collaborative Study and Initiation of a Consortium.

Background and Purpose— Shunt dependent hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH) is a common sequela that may lead to poor neurological outcome and predisposes to various interventions, admissions, and complications. We reviewed post-aSAH shunt dependency in a population-based sample and tested the feasibility of a clinical risk score to identify subgroups of aSAH patients with increasing risk of shunting for hydrocephalus. Methods— A total of 1533 aSAH patients from the population-based Eastern Finland Saccular Intracranial Aneurysm Database (Kuopio, Finland) were used in a recursive partitioning analysis to identify risk factors for shunting after aSAH. The risk model was built and internally validated in random split cohorts. External validation was conducted on 946 aSAH patients from the Southwestern Tertiary Aneurysm Registry (Dallas, TX) and tested using receiver-operating characteristic curves. Results— Of all patients alive ≥14 days, 17.7% required permanent cerebrospinal fluid diversion. The recursive partitioning analysis defined 6 groups with successively increased risk for shunting. These groups also successively risk stratified functional outcome at 12 months, shunt complications, and time-to-shunt rates. The area under the curve–receiver-operating characteristic curve for the exploratory sample and internal validation sample was 0.82 and 0.78, respectively, with an external validation of 0.68. Conclusions— Shunt dependency after aSAH is associated with higher morbidity and mortality, and prediction modeling of shunt dependency is feasible with clinically useful yields. It is important to identify and understand the factors that increase risk for shunting and to eliminate or mitigate the reversible factors. The aSAH-PARAS Consortium (Aneurysmal Subarachnoid Hemorrhage Patients’ Risk Assessment for Shunting) has been initiated to pool the collective insights and resources to address key questions in post-aSAH shunt dependency to inform future aSAH treatment guidelines.

De Novo Aneurysm Formation in Carriers of Saccular Intracranial Aneurysm Disease in Eastern Finland

Background and Purpose— Formation of new (de novo) aneurysms in patients carrying saccular intracranial aneurysm (sIA) disease has been published, but data from population-based cohorts are scarce. Methods— Kuopio sIA database (http://www.uef.fi/ns) contains all unruptured and ruptured sIA patients admitted to Kuopio University Hospital from its Eastern Finnish catchment population. We studied the incidence and risk factors for de novo sIA formation in 1419 sIA patients with ≥5 years of angiographic follow-up, a total follow-up of 18 526 patient-years. Results— There were 42 patients with a total of 56 de novo sIAs, diagnosed in a median of 11.7 years after the first sIA diagnosis. The cumulative incidence of de novo sIAs was 0.23% per patient-year and that of subarachnoid hemorrhage from a ruptured de novo sIA 0.05% per patient-year. The risk of de novo sIA discovery per patient-year increased with younger age at the first sIA diagnosis: 2.2% in the patients aged <20 years and 0.46% in the patients aged between 20 and 39 years. In Cox regression analysis, smoking history and younger age at the first sIA diagnosis significantly associated with de novo sIA formation, but female sex, multiple sIAs, and sIA family did not. Conclusions— Patients aged < 40 years at the first sIA diagnosis are in a significant risk of developing de novo sIAs, and they should be scheduled for long-term angiographic follow-up. Smoking increases the risk of de novo sIA formation, suggesting long-term follow-up for smokers. Antismoking efforts are highly recommended for sIA patients.

Antidepressant Use After Aneurysmal Subarachnoid Hemorrhage: A Population-Based Case–Control Study

Background and Purpose— To elucidate the predictors of antidepressant use after subarachnoid hemorrhage from saccular intracranial aneurysm (sIA-SAH) in a population-based cohort with matched controls. Methods— The Kuopio sIA database includes all unruptured and ruptured sIA cases admitted to the Kuopio University Hospital from its defined catchment population in Eastern Finland, with 3 matched controls for each patient. The use of all prescribed medicines has been fused from the Finnish national registry of prescribed medicines. In the present study, 2 or more purchases of antidepressant medication indicated antidepressant use. The risk factors of the antidepressant use were analyzed in 940 patients alive 12 months after sIA-SAH, and the classification tree analysis was used to create a predicting model for antidepressant use after sIA-SAH. Results— The 940 12-month survivors of sIA-SAH had significantly more antidepressant use (odds ratio, 2.6; 95% confidence interval, 2.2–3.1) than their 2676 matched controls (29% versus 14%). Classification tree analysis, based on independent risk factors, was used for the best prediction model of antidepressant use after sIA-SAH. Modified Rankin Scale until 12 months was the most potent predictor, followed by condition (Hunt and Hess Scale) and age on admission for sIA-SAH. Conclusions— The sIA-SAH survivors use significantly more often antidepressants, indicative of depression, than their matched population controls. Even with a seemingly good recovery (modified Rankin Scale score, 0) at 12 months after sIA-SAH, there is a significant risk of depression requiring antidepressant medication.

Increased incidence of aneurysmal subarachnoid hemorrhage on Sundays and Mondays in 1,862 patients from Eastern Finland.

Background: Temporal patterns of aneurysmal subarachnoid hemorrhage (aSAH) from saccular intracranial aneurysm (sIA) were studied in a consecutive series of 1,862 patients. Methods: Neurosurgery of Kuopio University Hospital (KUH) solely serves a defined catchment population in Eastern Finland. Kuopio’s sIA database contains 1,596 sporadic and 266 familial patients admitted to KUH within 72 h from the onset of aSAH between 1980 and 2007. The distributions by the weekday of the onset of aSAH, admission to KUH, and occlusive therapy of the ruptured sIA were analyzed. Logistic regression was used to search for clinical variables (patients, sIA disease, clinical condition) that would independently correlate with each distribution. Results: The onset of aSAH occurred significantly most often (p < 0.001) on Sundays (n = 330) and Mondays (n = 309) and least frequently on Saturdays (n = 231). None of the clinical variables tested associated significantly and independently with the Sunday and Monday peaks. The admissions to KUH after aSAH were most frequent (p < 0.001) on Mondays (n = 331) and least frequent on Thursdays (n = 221) and Saturdays (n = 221). Overall, 1,655 patients underwent occlusive therapy, most frequently on Mondays (n = 318) and least frequently on Saturdays (n = 189) and Sundays (n = 197). Conclusions: Sundays and Mondays were the most frequent and Saturdays the least frequent days of aSAH in a defined Eastern Finnish population. We could not identify any etiology to this temporal pattern. Binge drinking is frequent in Finland, especially among young males, but age and gender did not correlate with the Sunday and Monday peaks.

Irregular Shape Identifies Ruptured Intracranial Aneurysm in Subarachnoid Hemorrhage Patients With Multiple Aneurysms

Background and Purpose— We investigated which aneurysm-related risk factors for rupture best discriminate ruptured versus unruptured saccular intracranial aneurysms (sIAs) in subarachnoid hemorrhage patients with multiple sIAs. Methods— We included 264 subarachnoid hemorrhage patients with a ruptured sIA and at least one additional unruptured sIA, from the Kuopio Intracranial Aneurysm database from 2003 to 2015. These patients had 268 ruptured and 445 unruptured sIAs. Angiograms of the 713 sIAs were reevaluated for multiple variables describing aneurysm shape. Multivariate generalized linear mixed models were used to calculate odds ratios with corresponding 95% confidence intervals for the independent risk factors for aneurysm rupture. Results— In the multivariate analysis, only sIA size (P<0.004) and irregular shape (P<0.000) independently associated with sIA rupture. As an independent risk factor, irregular shape showed the strongest association with rupture (odds ratio 90.3; 95% confidence interval, 47.0–173.5). The sIA location, flow angles, bottleneck factor, or aspect ratio were not significantly associated with rupture. Conclusions— Irregular shape may identify the ruptured sIA better than size in patients presenting with aSAH and multiple sIAs.

Epilepsy-associated long-term mortality after aneurysmal subarachnoid hemorrhage

Objective: To elucidate the epilepsy-associated causes of death and subsequent excess long-term mortality among 12-month survivors of subarachnoid hemorrhage from saccular intracranial aneurysm (SIA-SAH). Methods: The Kuopio SIA Database (kuopioneurosurgery.fi) includes all SIA-SAH patients admitted to the Kuopio University Hospital from its defined catchment population in Eastern Finland. The study cohort consists of 779 patients, admitted from 1995 to 2007, who were alive at 12 months after SIA-SAH. Their use of reimbursable antiepileptic drugs and the causes of death (ICD-10) were fused from the Finnish national registries from 1994 to 2014. Results: The 779 12-month survivors were followed up until death (n = 197) or December 31, 2014, a median of 12.0 years after SIA-SAH. Epilepsy had been diagnosed in 121 (15%) patients after SIA-SAH, and 34/121 (28%) had died at the end of follow-up, with epilepsy as the immediate cause of death in 7/34 (21%). In the 779 patients alive at 12 months after SIA-SAH, epilepsy was an independent risk factor for mortality (hazard ratio 1.8, 95% confidence interval 1.1–3.0). Conclusions: Comorbid epilepsy in 12-month survivors of SIA-SAH is associated with increased risk of death in long-term follow-up. Survivors of SIA-SAH require long-term dedicated follow-up, including identification and effective treatment of comorbid epilepsy to prevent avoidable deaths.

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.