Prevalence of pre-eclampsia in 265 patients with an intracranial aneurysm, 393 female relatives versus a control cohort: A case-control study.

BACKGROUND AND OBJECTIVES: There is emerging evidence on the connection between pre-eclampsia and saccular intracranial aneurysms (sIAs). Our aim was to study the prevalence of pre-eclampsia in sIA patients, their female relatives, and matched controls, and to examine familial sIA disease and familial pre-eclampsia in sIA patients' families. METHODS: We included all female sIA patients in the Kuopio Intracranial Aneurysm Patient and Family Database from 1995 to 2018. First, we identified the sIA patients, their female relatives, and matched population controls with the first birth in 1987 or later and studied the prevalence of pre-eclampsia. Second, all female sIA patients and all female relatives were analyzed for familial sIA disease and familial pre-eclampsia. Using the Finnish nationwide health registries, we obtained data on drug purchases, hospital diagnoses, and causes of death. RESULTS: In total, 265 sIA patients, 57 daughters, 167 sisters, 169 nieces, and 546 matched controls had the first birth in 1987 or later. Among them, 29 (11%) sIA patients, 5 (9%) daughters, 10 (6%) sisters, 10 (6%) nieces, and 32 (6%) controls had pre-eclampsia. Of all the 1895 female sIA patients and 12,141 female relatives, 68 sIA patients and 375 relatives had pre-eclampsia, including 32 families with familial pre-eclampsia. CONCLUSIONS: Pre-eclampsia was significantly more common in the sIA patients than in their matched controls. Familial sIA disease and familial pre-eclampsia co-occurred in seven families. Further studies of the mechanisms by which pre-eclampsia could affect the walls of brain arteries and increase the rupture risk in sIA disease are indicated.

Acute evacuation of 54 intracerebral hematomas (aICH) during the microsurgical clipping of a ruptured middle cerebral artery bifurcation aneurysm-illustration of the individual clinical courses and outcomes with a serial brain CT/MRI panel until 12 months.

PURPOSE: In aneurysmal intracerebral hemorrhage (aICH), our review showed the lack of the patient's individual (i) timeline panels and (ii) serial brain CT/MRI slice panels through the aICH evacuation and neurointensive care until the final brain tissue outcome. METHODS: Our retrospective cohort consists of 54 consecutive aICH patients from a defined population who acutely underwent the clipping of a middle cerebral artery bifurcation saccular aneurysm (Mbif sIA) with the aICH evacuation at Kuopio University Hospital (KUH) from 2010 to 2019. We constructed the patient's individual timeline panels since the emergency call and serial brain CT/MRI slice panels through the aICH evacuation and neurointensive care until the final brain tissue outcome. The patients were indicated by numbers (1.-54.) in the pseudonymized panels, tables, results, and discussion. RESULTS: The aICH volumes on KUH admission (median 46 cm3) plotted against the time from the emergency call to the evacuation (median 8 hours) associated significantly with the rebleeds (n=25) and the deaths (n=12). The serial CT/MRI slice panels illustrated the aICHs, intraventricular hemorrhages (aIVHs), residuals after the aICH evacuations, perihematomal edema (PHE), delayed cerebral injury (DCI), and in the 42 survivors, the clinical outcome (mRS) and the brain tissue outcome. CONCLUSIONS: Regarding aICH evacuations, serial brain CT/MRI panels present more information than words, figures, and graphs. Re-bleeds associated with larger aICH volumes and worse outcomes. Swift logistics until the sIA occlusion with aICH evacuation is required, also in duty hours and weekends. Intraoperative CT is needed to illustrate the degree of aICH evacuation. PHE may evoke uncontrollable intracranial pressure (ICP) in spite of the acute aICH volume reduction.

Should individual timeline and serial CT/MRI panels of all patients be presented in acute brain insult cohorts? A pilot study of 45 patients with decompressive craniectomy after aneurysmal subarachnoid hemorrhage.

PURPOSE: Our review of acute brain insult articles indicated that the patients' individual (i) timeline panels with the defined time points since the emergency call and (ii) serial brain CT/MRI slice panels through the neurointensive care until death or final brain tissue outcome at 12 months or later are not presented. METHODS: We retrospectively constructed such panels for the 45 aneurysmal subarachnoid hemorrhage (aSAH) patients with a secondary decompressive craniectomy (DC) after the acute admission to neurointensive care at Kuopio University Hospital (KUH) from a defined population from 2005 to 2018. The patients were indicated by numbers (1.-45.) in the pseudonymized panels, tables, results, and discussion. The timelines contained up to ten defined time points on a logarithmic time axis until death ([Formula: see text]; 56%) or 3 years ([Formula: see text]; 44%). The brain CT/MRI panels contained a representative slice from the following time points: SAH diagnosis, after aneurysm closure, after DC, at about 12 months (20 survivors). RESULTS: The timelines indicated re-bleeds and allowed to compare the times elapsed between any two time points, in terms of workflow swiftness. The serial CT/MRI slices illustrated the presence and course of intracerebral hemorrhage (ICH), perihematomal edema, intraventricular hemorrhage (IVH), hydrocephalus, delayed brain injury, and, in the 20 (44%) survivors, the brain tissue outcome. CONCLUSIONS: The pseudonymized timeline panels and serial brain imaging panels, indicating the patients by numbers, allowed the presentation and comparison of individual clinical courses. An obvious application would be the quality control in acute or elective medicine for timely and equal access to clinical care.

Risk factor management matters more than pharmaceutical cyclooxygenase-2 inhibition in the prevention of de novo intracranial aneurysms.

BACKGROUND AND PURPOSE: Pathophysiological studies of saccular intracranial aneurysm (sIA) disease have shown that inflammation plays a crucial role in sIA development. Pharmaceutical inhibition of COX-2-PGE2-NF-κB signaling (COX-2, cyclooxygenase-2; PGE2, prostaglandin E2; NF-κB, nuclear factor κB) has been shown in animal models to inhibit sIA formation and progression suggesting that use of medication inhibiting COX-2 could reduce intracranial aneurysm formation also in patients. METHODS: The impact of COX-2 inhibition on de novo sIA formation was studied in two cohorts: in a previously described angiographically followed cohort of 1419 sIA patients and in a cohort of 117 sIA patients treated with stenting or stent-assisted embolization. Patients were identified from our population-based Kuopio Intracranial Aneurysm Database. Data on the use of anti-inflammatory medications and hospital diagnoses were obtained from national registries. Risk factors were identified by univariate and multivariate analyses. RESULTS: De novo sIA patients were younger and more often smokers. Use of COX-2 selective inhibitors or nonsteroidal anti-inflammatory drugs did not significantly reduce de novo sIA formation, but the percentage of patients with de novo sIA formation was smaller in patients with prescribed regular acetylsalicylic acid medication (1.1% vs. 3.6%). In the multivariate analysis, however, neither acetylsalicylic acid use nor other type of pharmaceutical inhibition of COX-2 reduced the formation of de novo sIAs. The risk was mostly affected by age, smoking history and irregular usage of antihypertensive medication regardless of used COX-2 inhibition level. CONCLUSION: For the prevention of de novo sIA formation, risk factor management with focus on cessation of smoking and treating hypertension adequately seems more important than pharmaceutical COX-2 inhibition.

Use of antihypertensive medication and formation of de novo intracranial aneurysms.

BACKGROUND AND PURPOSE: Hypertension is a risk factor for subarachnoid hemorrhage and is also considered a risk factor for saccular intracranial aneurysm (sIA) formation. However, there is little direct evidence that antihypertensive medication will reduce sIA formation. METHODS: The impact of antihypertensive medication on de novo sIA formation was studied in an angiographically followed cohort of 1419 patients. Patients were identified from our population-based Kuopio Intracranial Aneurysm Database, and data on the purchases of antihypertensive medication were obtained from a national registry. Univariate and multivariate analyses were used to investigate the risk factors. RESULTS: Of the 966 sIA patients who were prescribed with antihypertensive medication, 841 patients used the medication regularly; 20 of them had de novo sIA. One hundred and twenty-five patients used the medication irregularly and 12 of them developed de novo sIAs. Four hundred and fifty-three patients did not use antihypertensive medication even though 27 of them had a diagnosis of hypertension, and 10 of them developed de novo sIAs. In the multivariate analysis antihypertensive medication did not significantly reduce de novo sIA formation (hazard ratio [HR] 1.60, 95% confidence interval [CI] 0.84-3.06). Age at primary diagnosis (HR: 0.95, 95%: CI 0.93-0.98) and smoking history (HR: 5.53, 95% CI: 2.77-11.05) were significant risk factors for de novo sIA formation. Also, irregular usage of antihypertensive medication was a significant risk factor (HR: 3.84, 95% CI: 1.59-9.29) for de novo sIA formation. CONCLUSIONS: Antihypertensive agents were not associated with a reduction of de novo sIA formation, but irregular use of antihypertensive agents was associated with an increased risk of de novo sIA formation.

Pre-eclampsia, gestational diabetes and hypertensive disorders in patients with intracranial aneurysms: A case-control study.

BACKGROUND AND PURPOSE: The aim of this study was to define the prevalence of pre-eclampsia, gestational hypertension (HT), chronic HT, and gestational diabetes during pregnancy in a defined population of patients with saccular intracranial aneurysms (sIAs). METHODS: We included all patients with sIA, first admitted to the Neurosurgery Department of Kuopio University Hospital from its defined catchment population between 1990 and 2015, who had given birth for the first time in 1990 or later. The patients' medical records were reviewed, and clinical data were linked with prescription drug usage, hospital diagnoses and causes of death, obtained from nationwide registries. The prevalences of pre-eclampsia, other hypertensive disorders and gestational diabetes in patients were compared with a matched control population (n = 324). In addition, the characteristics of sIA disease in patients with pre-eclampsia were compared to those of sIA patients without pre-eclampsia. RESULTS: A total of 169 patients with sIA fulfilled the inclusion criteria. Of these, 22 (13%) had pre-eclampsia and 32 (19%) had other hypertensive disorders during pregnancy. In 324 matched controls who had given birth, the prevalence of pre-eclampsia was 5% (n = 15) and other hypertensive disorders were diagnosed in 10% (n = 34). There was no significant difference in prevalence of gestational diabetes (12% vs. 11%). Patients with sIA with pre-eclampsia more frequently had irregularly shaped aneurysms (p = 0·003). CONCLUSIONS: Pre-eclampsia was significantly more frequent in patients with sIA than in their population controls. Irregularly shaped aneurysms were more frequent in sIA patients with pre-eclampsia. Further studies are required to determine whether history of pre-eclampsia may indicate an elevated risk for sIA formation or rupture.

Shunt performance in 349 patients with hydrocephalus after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Shunt-dependent hydrocephalus after aneurysmal subarachnoid hemorrhage (aSAH) is a common sequelae leading to poorer neurological outcomes and predisposing to various complications. METHODS: A total of 2191 consecutive patients with aSAH were acutely admitted to the Neurointensive Care at the Kuopio University Hospital between 1990 and 2018 from a defined population. A total of 349 (16%) aSAH patients received a ventriculoperitoneal shunt, 101 with an adjustable valve (2012-2018), 232 with a fixed pressure valve (1990-2011), and 16 a valveless shunt (2010-2013). Clinical timelines were reconstructed from the hospital records and nationwide registries until death (n = 120) or June 2019. RESULTS: Comparing the adjustable valves vs. the fixed pressure valves vs. the valveless shunts, intraventricular hemorrhage was present in 61%, 44% and 100%, respectively. The median times to the shunt were 7 days vs. 38 days vs. 10 days. The rates of the first revision were 25% vs. 32% vs. 69%. The causes included infection in 11% vs. 7% vs. 25% and overdrainage in 1% vs. 4% vs. 31%. The valveless shunt was the only independent risk factor (HR 2.9) for revision. After the first revision, more revisions were required in 48% vs. 52% vs. 45%. CONCLUSIONS: The protocol to shunt evolved over time to favor earlier shunt. In post-aSAH hydrocephalus, adjustable valve shunts, without anti-siphon device, can be installed at an early phase after aSAH, in spite of intraventricular blood, with a modest risk (25%) of revision. Valveless shunts are not recommendable due to high risk of revisions.

Clinical condition of 120 patients alive at 3 years after poor-grade aneurysmal subarachnoid hemorrhage.

BACKGROUND: To study the clinical condition of poor-grade aneurysmal subarachnoid hemorrhage (aSAH) patients alive at 3 years after neurointensive care. METHODS: Of the 769 consecutive aSAH patients from a defined population (2005-2015), 269 (35%) were in poor condition on admission: 145 (54%) with H&H 4 and 124 (46%) with H&H 5. Their clinical lifelines were re-constructed from the Kuopio Intracranial Aneurysm Database and Finnish nationwide registries. Of the 269 patients, 155 (58%) were alive at 14 days, 125 (46%) at 12 months, and 120 (45%) at 3 years. RESULTS: The 120 H&H 4-5 patients alive at 3 years form the final study population. On admission, 73% had H&H 4 but only 27% H&H 5, 59% intracerebral hematoma (ICH; median 22 cm3), and 26% intraventricular blood clot (IVH). The outcome was favorable (mRS 0-1) in 45% (54 patients: ICH 44%; IVH clot 31%; shunt 46%), moderate (mRS 2-3) in 30% (36 patients: ICH 64%; IVH clot 19%; shunt 42%), and unfavorable (mRS 4-5) in 25% (30 patients: ICH 80%; IVH clot 23%; shunt 50%). A total of 46% carried a ventriculoperitoneal shunt. ICH volume was a significant predictor of mRS at 3 years. CONCLUSIONS: Of poor-grade aSAH patients, 45% were alive at 3 years, even 27% of those extending to pain (H&H 5). Of the survivors, 75% were at least in moderate condition, while only 2.6% ended in hospice care. Consequently, we propose non-selected admission to neurointensive care (1) for a possibility of moderate outcome, and (2), in case of brain death, possibly improved organ donation rates.

Higher Preimplantation Opioid Doses Associated With Long-Term Spinal Cord Stimulation Failure in 211 Patients With Failed Back Surgery Syndrome.

OBJECTIVE: Spinal cord stimulation (SCS) is an effective treatment in failed back surgery syndrome (FBSS). We studied the effect of preimplantation opioid use on SCS outcome and the effect of SCS on opioid use during a two-year follow-up period. MATERIALS AND METHODS: The study cohort included 211 consecutive FBSS patients who underwent an SCS trial from January 1997 to March 2014. Participants were divided into groups, which were as follows: 1) SCS trial only (n = 47), 2) successful SCS (implanted and in use throughout the two-year follow-up period, n = 131), and 3) unsuccessful SCS (implanted but later explanted or revised due to inadequate pain relief, n = 29). Patients who underwent explantation for other reasons (n = 4) were excluded. Opioid purchase data from January 1995 to March 2016 were retrieved from national registries. RESULTS: Higher preimplantation opioid doses associated with unsuccessful SCS (ROC: AUC = 0.66, p = 0.009), with 35 morphine milligram equivalents (MME)/day as the optimal cutoff value. All opioids were discontinued in 23% of patients with successful SCS, but in none of the patients with unsuccessful SCS (p = 0.004). Strong opioids were discontinued in 39% of patients with successful SCS, but in none of the patients with unsuccessful SCS (p = 0.04). Mean opioid dose escalated from 18 ± 4 MME/day to 36 ± 6 MME/day with successful SCS and from 22 ± 8 MME/day to 82 ± 21 MME/day with unsuccessful SCS (p < 0.001). CONCLUSIONS: Higher preimplantation opioid doses were associated with SCS failure, suggesting the need for opioid tapering before implantation. With continuous SCS therapy and no explantation or revision due to inadequate pain relief, 39% of FBSS patients discontinued strong opioids, and 23% discontinued all opioids. This indicates that SCS should be considered before detrimental dose escalation.

Benzodiazepine Use Is Associated With Poorer Spinal Cord Stimulation Outcome in 373 Neuropathic Pain Patients.

OBJECTIVES: The aim of the study is to investigate whether benzodiazepine use differs between patients with favorable and unfavorable spinal cord stimulation (SCS) treatment outcome. We hypothesize that the patients with unfavorable SCS outcome would exhibit a higher level of benzodiazepine use. MATERIALS AND METHODS: Using a case-control study setting, we examined benzodiazepine use in SCS patients and in matched population controls as a potential risk factor poor SCS outcome. A total of 373 consecutive SCS patients treated in Kuopio University Hospital between 1997 and 2014 and their 1117 matched population controls were followed until patient death or the end of March 2016. RESULTS: Benzodiazepines were used during the 24-month period before or after SCS implantation by 42.3% of the SCS patients who had the device explanted, 39.5% who had an unsuccessful trial stimulation, 28.0% who still had the device at the end of the follow-up period, and 8.0% of the controls. Diazepam use before SCS increased the odds for explanting of SCS by 2.4-fold (95% Cl: 1.0-5.4). Starting clonazepam use after SCS was associated with a 5.2-fold (95% CI: 1.5-18.9) increase in the odds of unsuccessful trial stimulation. CONCLUSION: The benzodiazepine use in patients with poor SCS outcome illustrates the role of anxiety in SCS outcomes and the need for multidisciplinary treatment of pain.

Antipsychotic Use Among 1144 Patients After Aneurysmal Subarachnoid Hemorrhage.

Background and Purpose- At acute phase and neurointensive care, patients with aneurysmal subarachnoid hemorrhage (aSAH) may become agitated or delirious. We found no previous studies on psychotic disorders or antipsychotic drug (APD) use by long-term aSAH survivors. We defined the APD use and its risk factors among 12-month survivors of aSAH in an Eastern Finnish population-based cohort with long-term follow-up. Methods- We analyzed APD use in 1144 consecutive patients with aSAH alive at 12 months of the Kuopio intracranial aneurysm patient and family database and their age, sex, and birth municipality matched controls (3:1; n=3432) from 1995 to 2013 and median follow-up of 9 years. Using the Finish nationwide health registries, we obtained drug purchase and hospital discharge data. Results- In total, 140 (12%) of the 1144 patients started APD use first time after aSAH (index date), in contrast to 145 (4%) of the 3432 matched population controls. The cumulative rate of starting APD was 6% at 1 year and 9% at 5 years, in contrast to 1% and 2% in the controls, respectively. The rates at 1 and 5 years were only 1% and 2% in the 489 patients with a good condition (modified Rankin Scale score, 0 or 1 at 12 months; no shunt, intracerebral hemorrhage, or intraventricular hemorrhage). Instead, the highest rate of APD use, 23% at 5 years was among the 192 patients shunted for hydrocephalus after aSAH. Eighty-eight (63%) of the 140 aSAH patients with APD use had also concomitant antidepressant or antiepileptic drug use. Conclusions- The 12-month survivors of aSAH were significantly more likely to be started on APD after aSAH than their matched population controls. These patients often used antidepressant and antiepileptic drugs concomitantly. The use of APDs strongly correlated with signs of brain injury after aSAH, with low use if no signs of significant brain injury were present.

Saccular Intracranial Aneurysms in Children When Both Parents Are Sporadic or Familial Carriers of Saccular Intracranial Aneurysms.

BACKGROUND AND PURPOSE: To study the penetrance of saccular intracranial aneurysm (IA) disease in children when both parents carry the disease. PATIENTS AND METHODS: The Kuopio IA Patient and Family Database includes all 4,411 IA patients admitted to the Kuopio University Hospital from its defined Eastern Finnish catchment population since 1980. We fused IA database with hospital diagnoses for IA patients and their 46,021 relatives from a national registry to identify couples concordant for IA disease. Penetrance of IA disease and hypertension were studied in these families. RESULTS: A total of 3,659 IA patients had 1 or more children. In total, 18 couples concordant for the IA disease with a total of 48 children, all born healthy, were identified. Hypertension was diagnosed in 23 (64%) of the 36 parents, and 7 of the 12 sporadic-sporadic couples were concordant for hypertension. Six sporadic-sporadic couples were concordant for subarachnoid haemorrhage (SAH). None of the 24 children to the 12 sporadic-sporadic couples had been diagnosed with SAH or IA disease. Instead, 11 (46%) of the 24 children to the 6 familial-sporadic couples had a diagnosed with SAH or IA disease. CONCLUSIONS: Couples concordant for IA disease are uncommon but not exceedingly rare. Biparental sporadic exposure does not seem to increase the risk of a clinically diagnosed IA disease or SAH in the offspring. IAs were common in the children with biparental sporadic-familial exposure.

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.

High risk population isolate reveals low frequency variants predisposing to intracranial aneurysms.

3% of the population develops saccular intracranial aneurysms (sIAs), a complex trait, with a sporadic and a familial form. Subarachnoid hemorrhage from sIA (sIA-SAH) is a devastating form of stroke. Certain rare genetic variants are enriched in the Finns, a population isolate with a small founder population and bottleneck events. As the sIA-SAH incidence in Finland is >2× increased, such variants may associate with sIA in the Finnish population. We tested 9.4 million variants for association in 760 Finnish sIA patients (enriched for familial sIA), and in 2,513 matched controls with case-control status and with the number of sIAs. The most promising loci (p<5E-6) were replicated in 858 Finnish sIA patients and 4,048 controls. The frequencies and effect sizes of the replicated variants were compared to a continental European population using 717 Dutch cases and 3,004 controls. We discovered four new high-risk loci with low frequency lead variants. Three were associated with the case-control status: 2q23.3 (MAF 2.1%, OR 1.89, p 1.42×10-9); 5q31.3 (MAF 2.7%, OR 1.66, p 3.17×10-8); 6q24.2 (MAF 2.6%, OR 1.87, p 1.87×10-11) and one with the number of sIAs: 7p22.1 (MAF 3.3%, RR 1.59, p 6.08×-9). Two of the associations (5q31.3, 6q24.2) replicated in the Dutch sample. The 7p22.1 locus was strongly differentiated; the lead variant was more frequent in Finland (4.6%) than in the Netherlands (0.3%). Additionally, we replicated a previously inconclusive locus on 2q33.1 in all samples tested (OR 1.27, p 1.87×10-12). The five loci explain 2.1% of the sIA heritability in Finland, and may relate to, but not explain, the increased incidence of sIA-SAH in Finland. This study illustrates the utility of population isolates, familial enrichment, dense genotype imputation and alternate phenotyping in search for variants associated with complex diseases.

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.

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.

MicroRNA-Attenuated Clone of Virulent Semliki Forest Virus Overcomes Antiviral Type I Interferon in Resistant Mouse CT-2A Glioma.

UNLABELLED: Glioblastoma is a terminal disease with no effective treatment currently available. Among the new therapy candidates are oncolytic viruses capable of selectively replicating in cancer cells, causing tumor lysis and inducing adaptive immune responses against the tumor. However, tumor antiviral responses, primarily mediated by type I interferon (IFN-I), remain a key problem that severely restricts viral replication and oncolysis. We show here that the Semliki Forest virus (SFV) strain SFV4, which causes lethal encephalitis in mice, is able to infect and replicate independent of the IFN-I defense in mouse glioblastoma cells and cell lines originating from primary human glioblastoma patient samples. The ability to tolerate IFN-I was retained in SFV4-miRT124 cells, a derivative cell line of strain SFV4 with a restricted capacity to replicate in neurons due to insertion of target sites for neuronal microRNA 124. The IFN-I tolerance was associated with the viral nsp3-nsp4 gene region and distinct from the genetic loci responsible for SFV neurovirulence. In contrast to the naturally attenuated strain SFV A7(74) and its derivatives, SFV4-miRT124 displayed increased oncolytic potency in CT-2A murine astrocytoma cells and in the human glioblastoma cell lines pretreated with IFN-I. Following a single intraperitoneal injection of SFV4-miRT124 into C57BL/6 mice bearing CT-2A orthotopic gliomas, the virus homed to the brain and was amplified in the tumor, resulting in significant tumor growth inhibition and improved survival. IMPORTANCE: Although progress has been made in development of replicative oncolytic viruses, information regarding their overall therapeutic potency in a clinical setting is still lacking. This could be at least partially dependent on the IFN-I sensitivity of the viruses used. Here, we show that the conditionally replicating SFV4-miRT124 virus shares the IFN-I tolerance of the pathogenic wild-type SFV, thereby allowing efficient targeting of a glioma that is refractory to naturally attenuated therapy vector strains sensitive to IFN-I. This is the first evidence of orthotopic syngeneic mouse glioma eradication following peripheral alphavirus administration. Our findings indicate a clear benefit in harnessing the wild-type virus replicative potency in development of next-generation oncolytic alphaviruses.

Intracranial aneurysm risk locus 5q23.2 is associated with elevated systolic blood pressure.

Although genome-wide association studies (GWAS) have identified hundreds of complex trait loci, the pathomechanisms of most remain elusive. Studying the genetics of risk factors predisposing to disease is an attractive approach to identify targets for functional studies. Intracranial aneurysms (IA) are rupture-prone pouches at cerebral artery branching sites. IA is a complex disease for which GWAS have identified five loci with strong association and a further 14 loci with suggestive association. To decipher potential underlying disease mechanisms, we tested whether there are IA loci that convey their effect through elevating blood pressure (BP), a strong risk factor of IA. We performed a meta-analysis of four population-based Finnish cohorts (n(FIN)  =  11 266) not selected for IA, to assess the association of previously identified IA candidate loci (n  =  19) with BP. We defined systolic BP (SBP), diastolic BP, mean arterial pressure, and pulse pressure as quantitative outcome variables. The most significant result was further tested for association in the ICBP-GWAS cohort of 200 000 individuals. We found that the suggestive IA locus at 5q23.2 in PRDM6 was significantly associated with SBP in individuals of European descent (p(FIN)  =  3.01E-05, p(ICBP-GWAS)  =  0.0007, p(ALL)  =  8.13E-07). The risk allele of IA was associated with higher SBP. PRDM6 encodes a protein predominantly expressed in vascular smooth muscle cells. Our study connects a complex disease (IA) locus with a common risk factor for the disease (SBP). We hypothesize that common variants in PRDM6 can contribute to altered vascular wall structure, hence increasing SBP and predisposing to IA. True positive associations often fail to reach genome-wide significance in GWAS. Our findings show that analysis of traditional risk factors as intermediate phenotypes is an effective tool for deciphering hidden heritability. Further, we demonstrate that common disease loci identified in a population isolate may bear wider significance.

Genome-wide association study of intracranial aneurysm identifies a new association on chromosome 7.

BACKGROUND AND PURPOSE: Common variants have been identified using genome-wide association studies which contribute to intracranial aneurysms (IA) susceptibility. However, it is clear that the variants identified to date do not account for the estimated genetic contribution to disease risk. METHODS: Initial analysis was performed in a discovery sample of 2617 IA cases and 2548 controls of white ancestry. Novel chromosomal regions meeting genome-wide significance were further tested for association in 2 independent replication samples: Dutch (717 cases; 3004 controls) and Finnish (799 cases; 2317 controls). A meta-analysis was performed to combine the results from the 3 studies for key chromosomal regions of interest. RESULTS: Genome-wide evidence of association was detected in the discovery sample on chromosome 9 (CDKN2BAS; rs10733376: P<1.0×10(-11)), in a gene previously associated with IA. A novel region on chromosome 7, near HDAC9, was associated with IA (rs10230207; P=4.14×10(-8)). This association replicated in the Dutch sample (P=0.01) but failed to show association in the Finnish sample (P=0.25). Meta-analysis results of the 3 cohorts reached statistical significant (P=9.91×10(-10)). CONCLUSIONS: We detected a novel region associated with IA susceptibility that was replicated in an independent Dutch sample. This region on chromosome 7 has been previously associated with ischemic stroke and the large vessel stroke occlusive subtype (including HDAC9), suggesting a possible genetic link between this stroke subtype and IA.