Impact of time to start of tranexamic acid treatment on rebleed risk and outcome in aneurysmal subarachnoid hemorrhage.

INTRODUCTION: The ULTRA-trial investigated effectiveness of ultra-early administration of tranexamic acid (TXA) in subarachnoid hemorrhage (SAH) and showed that TXA reduces the risk of rebleeding without concurrent improvement in clinical outcome. Previous trials in bleeding conditions, distinct from SAH, have shown that time to start of antifibrinolytic treatment influences outcome. This post-hoc analysis of the ULTRA-trial investigates whether the interval between hemorrhage and start of TXA impacts the effect of TXA on rebleeding and functional outcome following aneurysmal SAH. PATIENTS AND METHODS: A post-hoc comparative analysis was conducted between aneurysmal SAH patients of the ULTRA-trial, receiving TXA and usual care to those receiving usual care only. We assessed confounders, hazard ratio (HR) of rebleeding and odds ratio (OR) of good outcome (modified Rankin Scale 0-3) at 6 months, and investigated the impact of time between hemorrhage and start of TXA on the treatment effect, stratified into time categories (0-3, 3-6 and >6 h). RESULTS: Sixty-four of 394 patients (16.2%) in the TXA group experienced a rebleeding, compared to 83 of 413 patients (19.9%) with usual care only (HR 0.86, 95% confidence interval (CI): 0.62-1.19). Time to start of TXA modifies the effect of TXA on rebleeding rate (p < 0.001), with a clinically non-relevant reduction observed only when TXA was initiated after 6 h (absolute rate reduction 1.4%). Tranexamic acid treatment showed no effect on good outcome (OR 0.96, 95% CI: 0.72-1.27) with no evidence of effect modification on the time to start of TXA (p = 0.53). DISCUSSION AND CONCLUSIONS: This study suggests that the effect of TXA on rebleeding is modified by time to treatment, providing a protective, albeit clinically non-relevant, effect only when started after 6 h. No difference in functional outcome was seen. Routine TXA treatment in the aneurysmal SAH population, even within a specified time frame, is not recommended to improve functional outcome.

Case fatality and functional outcome after spontaneous subarachnoid haemorrhage: A systematic review and meta-analysis of time trends and regional variations in population-based studies.

INTRODUCTION: A previous systematic review of population-based studies from 1973 to 2002 found a decrease in case fatality for spontaneous subarachnoid haemorrhage, but could not find a sufficient number of studies to assess changes in functional outcome. Since then, treatment has advanced distinctly. We assessed whether case fatality has decreased further and whether functional outcome has improved. PATIENTS AND METHODS: We searched PubMed and Web of Science for new population-based studies using the same criteria as in our previous systematic review. We assessed changes in case fatality and functional outcome over time using linear regression. RESULTS: We included 24 new studies with 827 patients and analysed 9542 patients described in 62 study periods between 1973 and 2017. Case fatality decreased by 0.3% (95% CI: -0.7 to 0.1) per year. In a sensitivity analysis excluding studies that did not provide 1-month outcome and outliers, the age and sex-adjusted decrease was 0.1% per year (95% CI: -0.9 to 0.6). The mean case fatality rate decreased from 47% (95% CI: 31-63) in the 1970s to 35% (95% CI: 30-39) in the 1990s, and remained stable in the 2000s (34%; 95% CI: 27-41) and 2010s (38%; 95% CI: 15-60). In 15 studies, the mean proportion of patients living independently increased by 0.2% per year (95%CI: -0.7 to 1.1) and the mean was 45% (95% CI: 39-50) in six studies that reported outcome after 12 months. DISCUSSION AND CONCLUSION: From 1973 to 2017, the case-fatality rate of spontaneous subarachnoid haemorrhage declined overall by 13.5%, but remained stable over the last two decades. The data on time trends in functional outcome were inconclusive.

Serial quality of life assessment around screening for familial intracranial aneurysms: a prospective cohort study.

INTRODUCTION: Screening for intracranial aneurysms (IAs) is cost-effective in first-degree relatives of aneurysmal subarachnoid haemorrhage (aSAH) patients, but its psychosocial impact is largely unknown. PATIENTS AND METHODS: A consecutive series of persons aged 20-70 years visiting the University Medical Centre Utrecht for first screening for familial IA was approached between 2017-2020. E-questionnaires were administered at six time points, consisting of the EQ-5D for health-related quality of life (QoL), HADS for emotional functioning and USER-P for social participation. QoL outcomes were compared with the general population, and between participants with a positive and negative screening for IA. Predictors of QoL outcomes were assessed with linear mixed effects models. RESULTS: 105 participants from 75 families were included; in 10 (10%) an IA was found. During the first year after screening we found no negative effect on QoL, except for a temporary decrease in QoL six months after screening in participants with a positive screen (EQ-5D -11.3 [95%CI:-21.7 to -0.8]). Factors associated with worse QoL were psychiatric disease (EQ-5D -10.3 [95%CI:-15.1 to -5.6]), physical complaints affecting mood (EQ-5D -8.1 [95%CI:-11.7 to -4.4]), and a passive coping style (EQ-5D decrease per point increase on the Utrecht Coping List -1.1 [95%CI:-1.5 to -0.6]). DISCUSSION AND CONCLUSION: We did not find a lasting negative effect on QoL during the first year after screening for familial IA. Predictors for a worse QoL were psychiatric disease, physical complaints affecting mood, and a passive coping style. This information can be used in counselling about familial IA screening.

Safety and pharmacodynamic efficacy of eculizumab in aneurysmal subarachnoid hemorrhage (CLASH): A phase 2a randomized clinical trial.

INTRODUCTION: Complement C5 antibodies reduce brain injury after experimental subarachnoid hemorrhage. PATIENTS AND METHODS: In this randomized, controlled, open-label, phase 2a clinical trial with blinded-outcome assessment, we included adult aneurysmal subarachnoid hemorrhage (aSAH) patients admitted to a tertiary referral center ⩽11 h after ictus. Patients were randomized (1:1) to eculizumab plus care as usual or to care as usual. Eculizumab (1200 mg) was administered <12 h, and on days 3 and 7 after ictus. In the intervention group, all patients received prophylactic antibiotics and, after a protocol amendment, fluconazole if indicated. Primary outcome was C5a concentration in cerebrospinal fluid (CSF) on day 3 after ictus. Safety was monitored during 4 weeks. In each group, 13 patients with CSF assessments were needed to detect a 55% reduction in CSF C5a concentration. RESULTS: From October 2018 to May 2021, we enrolled 31 patients of whom 26 with CSF samples, 13 per group. Median C5a concentration in CSF on day 3 was 251 pg/ml [IQR: 103-402] in the intervention group and 371 pg/ml [IQR: 131-534] in the control group (p = 0.29). Infections occurred in two patients in the intervention group and four patients in the control group. One patient in the intervention group developed a C. albicans meningitis prior to the protocol amendment. DISCUSSION AND CONCLUSION: One dose of eculizumab did not result in a ⩾ 55% decrease in C5a concentration in CSF on day 3 after aSAH. The study did not reveal new safety concerns, except for a C. albicans drain-related infection prior to antifungal monitoring and treatment. TRIAL REGISTRATION: EudraCT 2017-004307-51, https://www.clinicaltrialsregister.eu/.

Screening for intracranial aneurysms in persons ⩾35 years with hypertension and atherosclerotic disease who smoke(d).

INTRODUCTION: Lifetime risk of aneurysmal subarachnoid haemorrhage (aSAH) is high (7%) in persons ⩾35 years with hypertension who smoke(d). Whether screening for intracranial aneurysms (IAs) to prevent aSAH is effective in these patients is unknown. PATIENTS AND METHODS: Participants were retrieved from a cohort of patients with clinically manifest atherosclerotic vascular disease included between 2012 and 2019 at the University Medical Centre Utrecht (SMART-ORACLE, NCT01932671) in whom CT-angiography (CTA) of intracranial arteries was performed. We selected patients ⩾35 years with hypertension who smoke(d). CTAs were reviewed for the presence of IAs by experienced neuroradiologists. Patients with IAs were offered follow-up imaging to detect aneurysmal growth. We determined aneurysm prevalence and developed a diagnostic model for IA risk at screening using multivariable logistic regression. RESULTS: IA were found in 25 of 500 patients (5.0% prevalence, 95%CI: 3.3%-7.3%). Median 5 year risk of rupture assessed with the PHASES score was 0.9% (IQR: 0.7%-1.3%). During a median follow-up of 57 months (IQR: 39-83 months) no patients suffered from aSAH. Aneurysmal growth was detected in one patient for whom preventive treatment was advised. IA risk at screening ranged between 1.6% and 13.4% with predictors being age, female sex and current smoking. DISCUSSION AND CONCLUSION: IA prevalence in persons ⩾35 years with hypertension and atherosclerotic vascular disease who smoke(d) was 5%. Given the very small proportion of IA that needed preventive treatment, we currently do not advise screening for Caucasian persons older than 35 years of age who smoke and have hypertension in general. Whether screening may be effective for certain subgroups (e.g. women older than 50 years of age) or other ethnic populations should be the subject of future studies.

Aneurysm treatment within 6 h versus 6-24 h after rupture in patients with subarachnoid hemorrhage.

BACKGROUND: The risk of rebleeding after aneurysmal subarachnoid hemorrhage (aSAH) is the highest during the initial hours after rupture. Emergency aneurysm treatment may decrease this risk, but is a logistic challenge and economic burden. We aimed to investigate whether aneurysm treatment <6 h after rupture is associated with a decreased risk of poor functional outcome compared to aneurysm treatment 6-24 h after rupture. METHODS: We used data of patients included in the ULTRA trial (NCT02684812). All patients in ULTRA were admitted within 24 h after aneurysm rupture. For the current study, we excluded patients in whom the aneurysm was not treated <24 h after rupture. We calculated crude and adjusted risk ratios (aRR) with 95% confidence intervals using Poisson regression analyses for poor functional outcome (death or dependency, assessed by the modified Rankin Scale) after aneurysm treatment <6 h versus 6-24 h after rupture. Adjustments were made for age, sex, clinical condition on admission (WFNS scale), amount of extravasated blood (Fisher score), aneurysm location, tranexamic acid treatment, and aneurysm treatment modality. RESULTS: We included 497 patients. Poor outcome occurred in 63/110 (57%) patients treated within 6 h compared to 145/387 (37%) patients treated 6-24 h after rupture (crude RR: 1.53, 95% CI: 1.24-1.88; adjusted RR: 1.36, 95% CI: 1.11-1.66). CONCLUSION: Aneurysm treatment <6 h is not associated with better functional outcome than aneurysm treatment 6-24 h after rupture. Our results do not support a strategy aiming to treat every patient with a ruptured aneurysm <6 h after rupture.

Validation of the German version of the subarachnoid haemorrhage outcome tool (SAHOT).

Objective: The subarachnoid haemorrhage (SAH) outcome tool (SAHOT) is the first SAH-specific patient reported outcome measure, and was developed in the UK. We aimed to validate the SAHOT outside the UK, and therefore endeavored to adapt the SAHOT into German and to test its psychometric properties. Methods: We adapted and pilot tested the German version. We applied the SAHOT, Quality of Life after Brain Injury, Hospital Anxiety and Depression Scale, and EuroQol questionnaires in a cohort of 89 patients with spontaneous SAH after discharge. We assessed internal consistency by Cronbach's α, test-retest reliability by intraclass correlation, and validity by Pearson correlations with established measures. Sensitivity to change was evaluated following neurorehabilitation by effect sizes. Results: The translation of SAHOT resulted in a German version that is semantically and conceptually equivalent to the English version. Internal consistency was good regarding the physical domain (α = 0.83) and excellent for the other domains (α = 0.92-0.93). Test-retest reliability indicated a high level of stability with an intraclass correlation of 0.85 (95% CI: 0.83-0.86). All domains correlated moderately or strongly with established measures (r = 0.41-0.74; p < 0.01). SAHOT total scores showed moderate sensitivity to change (Cohen's d = -0.68), while mRS and GOSE showed no significant sensitivity to change. Conclusion: The SAHOT can be adapted to other health care systems and societies than the UK. The German version of the SAHOT is a reliable and valid instrument, and can be used in future clinical studies and individual assessment after spontaneous SAH.

Antifibrinolytic therapy for aneurysmal subarachnoid haemorrhage.

BACKGROUND: Rebleeding is an important cause of death and disability in people with aneurysmal subarachnoid haemorrhage. Rebleeding is probably related to the dissolution of the blood clot at the site of the aneurysm rupture by natural fibrinolytic activity. This review is an update of previously published Cochrane Reviews. OBJECTIVES: To assess the effects of antifibrinolytic treatment in people with aneurysmal subarachnoid haemorrhage. SEARCH METHODS: We searched the Cochrane Stroke Group Trials Register (May 2022), CENTRAL (in the Cochrane Library 2021, Issue 1), MEDLINE (December 2012 to May 2022), and Embase (December 2012 to May 2022). In an effort to identify further published, unpublished, and ongoing studies, we searched reference lists and trial registers, performed forward tracking of relevant references, and contacted drug companies (the latter in previous versions of this review). SELECTION CRITERIA: Randomised trials comparing oral or intravenous antifibrinolytic drugs (tranexamic acid, epsilon amino-caproic acid, or an equivalent) with control in people with subarachnoid haemorrhage of suspected or proven aneurysmal cause. DATA COLLECTION AND ANALYSIS: Two review authors (MRG & WJD) independently selected trials for inclusion, and extracted the data for the current update. In total, three review authors (MIB & MRG in the previous update; MRG & WJD in the current update) assessed risk of bias. For the primary outcome, we dichotomised the outcome scales into good and poor outcome, with poor outcome defined as death, vegetative state, or (moderate) severe disability, assessed with either the Glasgow Outcome Scale or the Modified Rankin Scale. We assessed death from any cause, rates of rebleeding, delayed cerebral ischaemia, and hydrocephalus per treatment group. We expressed effects as risk ratios (RR) with 95% confidence intervals (CI). We used random-effects models for all analyses. We assessed the quality of the evidence with GRADE. MAIN RESULTS: We included one new trial in this update, for a total of 11 included trials involving 2717 participants. The risk of bias was low in six studies. Five studies were open label, and we rated them at high risk of performance bias. We also rated one of these studies at high risk for attrition and reporting bias.  Five trials reported on poor outcome (death, vegetative state, or (moderate) severe disability), with a pooled risk ratio (RR) of 1.03 (95% confidence interval (CI) 0.94 to 1.13; P = 0.53; 5 trials, 2359 participants; high-quality evidence), which showed no difference between groups. All trials reported on death from all causes, which showed no difference between groups, with a pooled RR of 1.02 (95% CI 0.90 to 1.16; P = 0.77; 11 trials, 2717 participants; high-quality evidence). In trials that combined short-term antifibrinolytic treatment (< 72 hours) with preventative measures for delayed cerebral ischaemia, the RR for poor outcome was 0.98 (95% CI 0.81 to 1.18; P = 0.83; 2 trials, 1318 participants; high-quality evidence).  Antifibrinolytic treatment reduced the risk of rebleeding, reported at the end of follow-up (RR 0.65, 95% CI 0.47 to 0.91; P = 0.01; 11 trials, 2717 participants; absolute risk reduction 7%, 95% CI 3 to 12%; moderate-quality evidence), but there was heterogeneity (I² = 59%) between the trials. The pooled RR for delayed cerebral ischaemia was 1.27 (95% CI 1.00 to 1.62; P = 0.05; 7 trials, 2484 participants; moderate-quality evidence). However, this effect was less extreme after the implementation of ischaemia preventative measures and < 72 hours of treatment (RR 1.10, 95% CI 0.83 to 1.46; P = 0.49; 2 trials, 1318 participants; high-quality evidence). Antifibrinolytic treatment showed no effect on the reported rate of hydrocephalus (RR 1.09, 95% CI 0.99 to 1.20; P = 0.09; 6 trials, 1992 participants; high-quality evidence). AUTHORS' CONCLUSIONS: The current evidence does not support the routine use of antifibrinolytic drugs in the treatment of people with aneurysmal subarachnoid haemorrhage. More specifically, early administration with concomitant treatment strategies to prevent delayed cerebral ischaemia does not improve clinical outcome. There is sufficient evidence from multiple randomised controlled trials to incorporate this conclusion in treatment guidelines.

European Stroke Organisation (ESO) guidelines on management of unruptured intracranial aneurysms.

Unruptured intracranial aneurysms (UIA) occur in around 3% of the population. Important management questions concern if and how to perform preventive UIA occlusion; if, how and when to perform follow up imaging and non-interventional means to reduce the risk of rupture. Using the Standard Operational Procedure of ESO we prepared guidelines according to GRADE methodology. Since no completed randomised trials exist, we used interim analyses of trials, and meta-analyses of observational and case-control studies to provide recommendations to guide UIA management. All recommendations were based on very low evidence. We suggest preventive occlusion if the estimated 5-year rupture risk exceeds the risk of preventive treatment. In general, we cannot recommend endovascular over microsurgical treatment, but suggest flow diverting stents as option only when there are no other low-risk options for UIA repair. To detect UIA recurrence we suggest radiological follow up after occlusion. In patients who are initially observed, we suggest radiological monitoring to detect future UIA growth, smoking cessation, treatment of hypertension, but not treatment with statins or acetylsalicylic acid with the indication to reduce the risk of aneurysm rupture. Additionally, we formulated 15 expert-consensus statements. All experts suggest to assess UIA patients within a multidisciplinary setting (neurosurgery, neuroradiology and neurology) at centres consulting >100 UIA patients per year, to use a shared decision-making process based on the team recommendation and patient preferences, and to repair UIA only in centres performing the proposed treatment in >30 patients with (ruptured or unruptured) aneurysms per year per neurosurgeon or neurointerventionalist. These UIA guidelines provide contemporary recommendations and consensus statement on important aspects of UIA management until more robust data come available.

Development of a questionnaire to identify persons with a family history of aneurysmal subarachnoid hemorrhage.

BACKGROUND: Preventive screening for intracranial aneurysms is effective in persons with a positive family history of aneurysmal subarachnoid hemorrhage (aSAH), but for many relatives of aSAH patients, it can be difficult to assess whether their relative had an aSAH or another type of stroke. AIM: We aimed to develop a family history questionnaire for people in the population who believe they have a first-degree relative who had a stroke and to assess its accuracy to identify relatives of aSAH patients. METHODS: A questionnaire to distinguish between aSAH and other stroke types (ischemic stroke and intracerebral hemorrhage) was developed by a team of clinicians and consumers. The level of agreement between the questionnaire outcome and medical diagnosis was pilot tested in 30 previously admitted aSAH patients. Next, the sensitivity and specificity of the questionnaire were assessed in 91 first-degree relatives (siblings/children) of previously admitted stroke patients. RESULTS: All 30 aSAH patients were identified by the questionnaire in the pilot study; 29 of 30 first-degree relatives of aSAH patients were correctly identified. The questionnaire had a sensitivity of 97% (95% confidence interval (CI) = 83-100%) and a specificity of 93% (95% CI = 84-98%) when tested in the first-degree relatives of stroke patients. CONCLUSION: Our questionnaire can help persons to discriminate an aSAH from other types of stroke in their affected relative. This family history questionnaire is developed in the Netherlands but could also be used in other countries after validation.

Preventive screening for intracranial aneurysms.

BACKGROUND: Subarachnoid hemorrhage from rupture of an intracranial aneurysm (aneurysmal subarachnoid hemorrhage) is a devastating subset of stroke. Since brain damage from the initial hemorrhage is a major cause for the poor outcome after aneurysmal subarachnoid hemorrhage, prevention of aneurysmal subarachnoid hemorrhage has the highest potential to prevent poor outcome from aneurysmal subarachnoid hemorrhage. AIM: In this review, we describe the groups at high risk of aneurysmal subarachnoid hemorrhage who may benefit from preventive screening for unruptured intracranial aneurysms followed by preventive treatment of unruptured intracranial aneurysms found. Furthermore, we describe the advantages and disadvantages of screening and advise how to perform counseling on screening. SUMMARY OF REVIEW: Modeling studies show that persons with two or more affected first-degree relatives with aneurysmal subarachnoid hemorrhage and patients with autosomal dominant polycystic kidney disease (ADPKD) are candidates for screening for unruptured intracranial aneurysms. One modeling study also suggests that persons with only one affected first-degree relative with aneurysmal subarachnoid hemorrhage are also likely candidates for screening. Another group who may benefit from screening are persons ≥35 years who smoke(d) and are hypertensive, given their high lifetime risk of aneurysmal subarachnoid hemorrhage of up to 7%, but the prevalence of unruptured intracranial aneurysms in such persons and the efficiency and cost-effectiveness of screening in this group are not yet known. The ultimate goal of screening is to increase the number of quality years of life of the screening candidates, and therefore the benefits but also many downsides of screening -such as risk of incidental findings, very small unruptured intracranial aneurysms that require regular follow-up, preventive treatment with inherent risk of complications and anxiety - should be discussed with the candidate so that an informed decision can be made before intracranial vessels are imaged. CONCLUSIONS: Several groups of persons who may benefit from screening have been identified, but since these constitute only a minority of all aneurysmal subarachnoid hemorrhage patients, additional high-risk groups still need to be identified. Further research is also needed to identify persons at low or high risk of aneurysmal development and rupture within the groups identified thus far to improve the efficiency of screening. Moreover, if new medical treatment strategies that can reduce the risk of rupture of unruptured intracranial aneurysm become available, the groups of persons who may benefit from screening could increase considerably.

Long-term prognosis after intracerebral haemorrhage.

INTRODUCTION: The aim of this study was to determine the risk of recurrent intracerebral haemorrhage (ICH), ischaemic stroke, all stroke, any vascular event and all-cause mortality in 30-day survivors of ICH, according to age and sex. PATIENTS AND METHODS: We linked national hospital discharge, population and cause of death registers to obtain a cohort of Dutch 30-day survivors of ICH from 1998 to 2010. We calculated cumulative incidences of recurrent ICH, ischaemic stroke, all stroke and composite vascular outcome, adjusted for competing risk of death and all-cause mortality. Additionally, we compared survival with the general population. RESULTS: We included 19,444 ICH-survivors (52% male; median age 72 years, interquartile range 61-79; 78,654 patient-years of follow-up). First-year cumulative incidence of recurrent ICH ranged from 1.5% (95% confidence interval 0.9-2.3; men 35-54 years) to 2.4% (2.0-2.9; women 75-94 years). Depending on age and sex, 10-year risk of recurrent ICH ranged from 3.7% (2.6-5.1; men 35-54 years) to 8.1% (6.9-9.4; women 55-74 years); ischaemic stroke 2.6% to 7.0%, of all stroke 9.9% to 26.2% and of any vascular event 15.0% to 40.4%. Ten-year mortality ranged from 16.7% (35-54 years) to 90.0% (75-94 years). Relative survival was lower in all age-groups of both sexes, ranging from 0.83 (0.80-0.87) in 35- to 54-year-old men to 0.28 (0.24-0.32) in 75- to 94-year-old women. DISCUSSION: ICH-survivors are at high risk of recurrent ICH, of ischaemic stroke and other vascular events, and have a sustained reduced survival rate compared to the general population. CONCLUSION: The high risk of recurrent ICH, other vascular events and prolonged reduced survival-rates warrant clinical trials to determine optimal secondary prevention treatment after ICH.

Contrast leakage distant from the hematoma in patients with spontaneous ICH: A 7 T MRI study.

Disruption of the blood-brain barrier (BBB) might play a role in the pathophysiology of cerebral small vessel disease-related ICH. The aim of this study was to assess presence and extent of contrast agent leakage distant from the hematoma as a marker of BBB disruption in patients with spontaneous ICH. We prospectively performed 7 tesla MRI in adult patients with spontaneous ICH and assessed contrast leakage distant from the hematoma on 3D FLAIR images. Thirty-one patients were included (mean age 60 years, 29% women). Median time between ICH and MRI was 20 days (IQR 9-67 days). Seventeen patients (54%; seven lobar, nine deep, one infratentorial ICH) had contrast leakage, located cortical in 16 and cortical and deep in one patient. Patients with contrast leakage more often had lobar cerebral microbleeds (CMBs; 77%) than those without (36%; RR 2.5, 95% CI 1.1-5.7) and a higher number of lobar CMBs (patients with contrast leakage: median 2, IQR 1-8 versus those without: median 0, IQR 0-2; p = 0.02). This study shows that contrast leakage distant from the hematoma is common in days to weeks after spontaneous ICH. It is located predominantly cortical and related to lobar CMBs and therefore possibly to cerebral amyloid angiopathy.

Aneurysm characteristics and risk of rebleeding after subarachnoid haemorrhage.

INTRODUCTION: Knowledge of risk factors for rebleeding after aneurysmal subarachnoid haemorrhage can help tailoring ultra-early aneurysm treatment. Previous studies have identified aneurysm size and various patient-related risk factors for early (≤24 h) rebleeding, but it remains unknown if aneurysm configuration is also a risk factor. We investigated whether irregular shape, aspect- and bottleneck ratio of the aneurysm are independent risk factors for early rebleeding after aneurysmal subarachnoid haemorrhage. PATIENTS AND METHODS: From a prospectively collected institutional database, we investigated data from consecutive aneurysmal subarachnoid haemorrhage patients who were admitted ≤24 h after onset between December 2009 and January 2015. The admission computed tomographic angiogram was used to assess aneurysm size and configuration. With Cox regression, we calculated stepwise-adjusted hazard ratios (HRs) with 95% confidence intervals (CIs) for irregular shape, aspect ratio ≥1.6 mm and bottleneck ratio ≥1.6 mm. RESULTS: Of 409 included patients, 34 (8%) patients had in-hospital rebleeding ≤24 h after ictus. Irregular shape was an independent risk factor for rebleeding (HR: 3.9, 95% CI: 1.3-11.3) after adjustment for age, sex, PAASH score, aneurysm location, aneurysm size and aspect- and bottleneck ratio. Aspect ratio ≥1.6 mm (HR: 2.3, 95% CI: 0.8-6.5) and bottleneck ratio ≥1.6 mm (HR: 1.7, 95% CI: 0.8-3.6) were associated with an increased risk of rebleeding, but were not independent risk factors after multivariable adjustment. CONCLUSIONS: Irregular shape is an independent risk factor for early rebleeding. However, since the majority of subarachnoid haemorrhage patients have an irregular aneurysm, additional risk factors have to be found for aneurysm treatment prioritisation.

Radiosurgical, neurosurgical, or no intervention for cerebral cavernous malformations: A decision analysis.

INTRODUCTION: We aimed to evaluate the preferred treatment strategy for patients with symptomatic cerebral cavernous malformations (CCM). METHODS: In a decision model, we compared neurosurgical, radiosurgical, and conservative management. A literature review yielded the risks and outcomes of interventions, intracerebral hemorrhage (ICH), and seizures. Patients with CCM rated their quality of life to determine utilities. We estimated the expected number of quality-adjusted life years (QALYs) and the ICH recurrence risk over five years, according to mode of presentation and CCM location (brainstem vs. other). We performed analyses with a time horizon of five years. RESULTS: Using the best available data, the expected number of QALYs for brainstem CCM presenting with ICH or focal neurological deficit was 2.84 (95% confidence interval [CI]: 2.54-3.08) for conservative, 3.01 (95% CI: 2.86-3.16) for neurosurgical, and 3.03 (95% CI: 2.88-3.18) for radiosurgical intervention; those for non-brainstem CCM presenting with ICH or focal neurological deficit were 3.08 (95% CI: 2.85-3.31) for conservative, 3.21 (95% CI: 3.01-3.36) for neurosurgical, and 3.19 (95% CI: 2.98-3.37) for radiosurgical intervention. For CCM presenting with epilepsy, QALYs were 3.09 (95% CI: 3.03-3.16) for conservative, 3.33 (95% CI: 3.31-3.34) for neurosurgical, and 3.27 (95% CI: 3.24-3.30) for radiosurgical intervention. DISCUSSION AND CONCLUSION: For the initial five years after presentation, our study provides Class III evidence that for CCM presenting with ICH or focal neurological deficit conservative management is the first option, and for CCM presenting with epilepsy CCM intervention should be considered. More comparative studies with long-term follow-up are needed.

Consensus statements and recommendations from the ESO-Karolinska Stroke Update Conference, Stockholm 11-13 November 2018.

The purpose of the European Stroke Organisation-Karolinska Stroke Update Conference is to provide updates on recent stroke therapy research and to give an opportunity for the participants to discuss how these results may be implemented into clinical routine. The meeting started 22 years ago as Karolinska Stroke Update, but since 2014 it is a joint conference with European Stroke Organisation. Importantly, it provides a platform for discussion on the European Stroke Organisation guidelines process and on recommendations to the European Stroke Organisation guidelines committee on specific topics. By this, it adds a direct influence from stroke professionals otherwise not involved in committees and work groups on the guideline procedure. The discussions at the conference may also inspire new guidelines when motivated. The topics raised at the meeting are selected by the scientific programme committee mainly based on recent important scientific publications. This year's European Stroke Organisation-Karolinska Stroke Update Meeting was held in Stockholm on 11-13 November 2018. There were 11 scientific sessions discussed in the meeting including two short sessions. Each session except the short sessions produced a consensus statement (Full version with background, issues, conclusions and references are published as web-material and at www.eso-karolinska.org and http://eso-stroke.org) and recommendations which were prepared by a writing committee consisting of session chair(s), scientific secretary and speakers. These statements were presented to the 250 participants of the meeting. In the open meeting, general participants commented on the consensus statement and recommendations and the final document were adjusted based on the discussion from the general participants Recommendations (grade of evidence) were graded according to the 1998 Karolinska Stroke Update meeting with regard to the strength of evidence. Grade A Evidence: Strong support from randomised controlled trials and statistical reviews (at least one randomised controlled trial plus one statistical review). Grade B Evidence: Support from randomised controlled trials and statistical reviews (one randomised controlled trial or one statistical review). Grade C Evidence: No reasonable support from randomised controlled trials, recommendations based on small randomised and/or non-randomised controlled trials evidence.

Preventable poor outcome from rebleeding by emergency aneurysm occlusion in patients with aneurysmal subarachnoid haemorrhage.

INTRODUCTION: The risk of rebleeding is highest during the initial hours after aneurysmal subarachnoid haemorrhage (aSAH), but the aneurysm is not occluded in all patients immediately after admission.Our aim was to determine the proportion of aSAH patients with poor outcome from early in-hospital rebleeding that can be prevented by three emergency aneurysm occlusion regimes. PATIENTS AND METHODS: From our prospectively collected database, we retrieved from all aSAH patients admitted between July 2007 and July 2017 data on clinical condition on admission, time of rebleeding, and outcome at 3 months. RESULTS: Of 1391 consecutive aSAH patients, 923 were in good clinical condition and had an aneurysm on initial imaging that was amenable for treatment. Poor outcome from rebleeding could have been avoided by treatment <4 h during day time shifts in 4 (0.4% [95% CI: 0.2-1.1]) patients (number needed to treat [NNT]: 250), by treatment and <1 h during daytime shift in 9 (1.0% [95% CI: 0.5-1.8]; NNT: 111), and treatment <1 h at 24/7 basis in 16 (1.7% [95% CI: 1.1-2.8%]; NNT: 59). DISCUSSION: Emergency aneurysm occlusion can reduce poor outcome due to rebleeding, but only in small proportions of patients. Whether such strategies lead to improved outcome for all patients and are cost-effective is highly uncertain. CONCLUSION: We do not recommend instalment of a treatment regimen where occlusion of ruptured aneurysm is performed within 1 h on a 24/7 basis.

Hospital case-volume is associated with case-fatality after aneurysmal subarachnoid hemorrhage.

BACKGROUND: Inverse association between hospital case-volume and case-fatality has been observed for various nonsurgical interventions and surgical procedures. AIMS: To study the impact of hospital case-volume on outcome after aneurysmal subarachnoid hemorrhage (aSAH). METHODS: We included aSAH patients who underwent aneurysm coiling or clipping from tertiary care medical centers across three continents using the Dr Foster Stroke GOAL database 2007-2014. Hospitals were categorized by annual case-volume (low volume: <41/year; intermediate: 41-70/year; high: >70/year). Primary outcome was 14-day in-hospital case-fatality. We calculated proportions, and used multiple logistic regression to adjust for age, sex, differences in comorbidity or disease severity, aneurysm treatment modality, and hospital. RESULTS: We included 8525 patients (2363 treated in low volume hospitals, 3563 treated in intermediate volume hospitals, and 2599 in high-volume hospitals). Crude 14-day case-fatality for hospitals with low case-volume was 10.4% (95% confidence interval (CI) 9.2-11.7%), for intermediate volume 7.0% (95% CI 6.2-7.9%; adjusted odds ratio (OR) 0.63 (95%CI 0.47-0.85)) and for high volume 5.4% (95% CI 4.6-6.3%; adjusted OR 0.50 (95% CI 0.33-0.74)). In patients with clipped aneurysms, adjusted OR for 14-day case-fatality was 0.46 (95% CI 0.30-0.71) for hospitals with intermediate case-volume and 0.42 (95% CI 0.25-0.72) with high case-volume. In patients with coiled aneurysms, adjusted OR was 0.77 (95% CI 0.55-1.07) for hospitals with intermediate case-volume and 0.56 (95% CI 0.36-0.87) with high case-volume. CONCLUSIONS: Even within a subset of large, tertiary care centers, intermediate and high hospital case-volume is associated with lower case-fatality after aSAH regardless of treatment modality, supporting centralization to higher volume centers.