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Purpose: Scleritis is an extremely painful and potentially blinding inflammation of the sclera with unknown pathogenesis and unpredictable course. To gain insight in its disease process and identify biomarker candidates, we performed extensive proteomics in serum and tear fluid. Design: Prospective multicenter cohort study. Participants: A total of 121 patients with noninfectious scleritis (of which 39 active cases), 30 healthy controls, and 23 disease controls (uveitis and rheumatoid arthritis) were enrolled in the Netherlands from 2020 to 2022. Methods: Serum, tear fluid of both eyes, and clinical data were gathered. The level of 368 inflammatory proteins was measured using proximity extension assays. Results were validated in an independent cohort of 15 patients with scleritis, and using addressable laser bead immunoassay, or enzyme-linked immunoassays. In addition, we studied an extended panel of matrix metalloproteinases in tear fluid of necrotizing scleritis with addressable laser bead immunoassay. Main Outcome Measures: Statistically significant differences in the level of inflammatory proteins between patients with scleritis and control groups. Results: Proteomics revealed 18 significantly upregulated or downregulated serum proteins in active scleritis cases compared with all control groups in both the discovery cohort and the validation cohort. The most upregulated protein was nuclear migration protein nudC (NudC; P = 0.0032), a protein involved in neurogenesis. The other significant hits included proteins involved in T-cell activation, apoptosis, epithelial barrier maintenance, and angiogenesis. Our tear fluid analysis showed matrix metalloproteinase 9 (MMP9) to be upregulated in the tear fluid of patients with scleral necrosis. Conclusions: The results of our proteomics analysis suggest a role for neurogenesis, T-cell activation, disruption of epithelial barrier, and angiogenesis in the pathogenesis of scleritis, and highlight MMP9 and NudC as biomarkers with potential clinical relevance. Funding Disclosure(s): The authors have no proprietary or commercial interest in any materials discussed in this article.

Background: Although electrocardiographic (ECG) abnormalities are well known in ischemic stroke and subarachnoid hemorrhage, these changes have only rarely been investigated systematically in patients with intracerebral hemorrhage (ICH). The purpose of this study is to investigate the prevalence and type of ECG abnormalities in a consecutive series of ICH patients, and their possible association with pre-defined neurological and radiological parameters.Methods: The study population consisted of all consecutive patients with non-traumatic, intraparenchymal ICH admitted to the Academic Medical Center (AMC) between January 1, 2007 and October 1, 2007. Baseline information was prospectively registered in the AMC Stroke Register. ECGs obtained within 2 days after the initial hemorrhage were analyzed by one blinded observer. Admission cranial CT scans were re-analyzed by two blinded observers.Results: Thirty-one patients were included. Twenty-five patients (81%) had one or more ECG abnormalities. The most frequently observed ECG abnormality was QTc prolongation (36%), followed by ST-T morphologic changes (23%), sinus bradycardia (16%), and inverted T wave (16%). No patient was initially misdiagnosed for having myocardial ischemia. QTc prolongation was associated with ICH involvement of the insular cortex [OR 10.9 (95% CI 1.0-114.6)] and presence of intraventricular blood and hydrocephalus on admission CT scan [OR 10.8 (95% CI 1.6-70.9)].Conclusions: In ICH patients ECG abnormalities are common. QTc prolongation seems associated with insular cortex involvement, with the presence of intraventricular blood, and with hydrocephalus. A larger cohort of continuously monitored ICH patients is necessary to investigate whether these ECG abnormalities are associated with poor outcome or death. [ABSTRACT FROM AUTHOR]

Background: Myoclonus-dystonia (M-D) is an autosomal dominant inherited movement disorder. Various mutations within the epsilon-sarcoglycan (SGCE) gene have been associated with M-D, but mutations are detected in only about 30% of patients. The lack of stringent clinical inclusion criteria and limitations of mutation screens by direct sequencing might explain this observation.Methods: Eighty-six M-D index patients from the Dutch national referral centre for M-D underwent neurological examination and were classified according to previously published criteria into definite, probable and possible M-D. Sequence analysis of the SGCE gene and screening for copy number variations were performed. In addition, screening was carried out for the 3 bp deletion in exon 5 of the DYT1 gene.Results: Based on clinical examination, 24 definite, 23 probable and 39 possible M-D patients were detected. Thirteen of the 86 M-D index patients carried a SGCE mutation: seven nonsense mutations, two splice site mutations, three missense mutations (two within one patient) and one multiexonic deletion. In the definite M-D group, 50% carried an SGCE mutation and one single patient in the probable group (4%). One possible M-D patient showed a 4 bp deletion in the DYT1 gene (c.934_937delAGAG).Conclusions: Mutation carriers were mainly identified in the definite M-D group. However, in half of definite M-D cases, no mutation could be identified. Copy-number variations did not play a major role in the large cohort. [ABSTRACT FROM AUTHOR]

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., Competing Interests: Declaration of Conflicting InterestThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: MDIV reports funding from the Dutch Heart Foundation (clinical established investigator grant number 2018T0769). RvdB reports grants from Cerenovus neurovascular, outside the submitted work; YBWEMR is a minor shareholder of Nico-Lab. All other authors declare no competing interests.

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/., Competing Interests: Declaration of conflicting interestsThe author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

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.

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., Competing Interests: Declaration of conflicting interests: The author(s) declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article., (© European Stroke Organisation 2022.)

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., (© European Stroke Organisation 2019.)

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.

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.

Rationale: Unruptured intracranial aneurysms are currently left untreated if the presumed complication risk of preventive endovascular or neurosurgical intervention is higher than the risk of rupture. Aneurysm wall inflammation and blood pressure are attractive modifiable risk factors of aneurysm rupture and growth., Aim: To investigate in patients with an unruptured intracranial aneurysm who do not qualify for preventive endovascular or neurosurgical intervention whether a treatment strategy of acetylsalicylic acid 100 mg/day plus intensive blood pressure treatment (targeted systolic blood pressure < 120 mmHg, monitored with a home blood pressure measuring device) reduces the risk of aneurysm rupture or growth compared with care as usual (no acetylsalicylic acid, targeted office systolic blood pressure < 140 mmHg, no home blood pressure measuring device)., Sample Size: We aim to randomize 776 patients 1:1 to the intervention arm or care as usual., Design: Bi-national (Germany and the Netherlands) multicenter, prospective, randomized, open-label phase III trial with blinded outcome assessment., Outcomes: The primary outcome is aneurysm rupture or growth (increase in any aneurysm diameter by ≥ 1 mm) on repeated MR or CT angiography within 36 ± 6 months after randomization., Discussion: The Prospective Randomized Open-label Trial to Evaluate risk faCTor management in patients with Unruptured intracranial aneurysms (PROTECT-U) is the first randomized trial to investigate if a medical strategy reduces the risk of rupture or growth of intracranial aneurysms in patients not undergoing preventive endovascular or neurosurgical aneurysm treatment. Clinical trial Registration: NCT03063541.

Background: Aneurysms of the extracranial carotid artery (ECAA) are rare. Although most ECAA are identified in asymptomatic patients, serious neurological complications may occur. Current literature on treatment outcome contains mainly case reports and small case series with incomplete data and lack of long-term follow-up. There is clear lack on natural follow-up data, and there is no clear treatment algorithm. An international web-based registry to collect data on patients with ECAA is designed to provide clinical guidance on this scarce pathology., Methods: The Carotid Aneurysm Registry (CAR) is open for inclusion of all patients with a fusiform or saccular ECAA. Patients with primary or secondary ECAA can be enrolled in CAR independent of the type of treatment (conservative or invasive). CAR participation does not interfere with the local physician's treatment policy. Follow-up and imaging can also be scheduled according to local clinical practice. The primary endpoint of the CAR in conservative patients is occurrence of symptoms related to the aneurysm at 30 days, one, three, and five years. The primary endpoint in invasively treated patients is freedom from symptoms of the aneurysm at 30 days, one, three, and five years., Results: Analyses will relate outcome to etiology, imaging characteristics, ECAA growth patterns, and (if applicable) revascularization technique applied. The aim of the registry is to prospectively collect follow-up data on patients with an ECAA, being either treated conservatively or by invasive aneurysm exclusion strategies. The CAR database will be used to address diagnostic and therapeutic research questions., Conclusions: Collecting and analyzing the data gained from the registry could be the first step towards development of treatment guidelines and expert consensus for the management of ECAA.

Background: Around 30% of people who are admitted to hospital with aneurysmal subarachnoid haemorrhage (SAH) will rebleed in the initial month after the haemorrhage if the aneurysm is not treated. The two most commonly used methods to occlude the aneurysm for prevention of rebleeding are microsurgical clipping of the neck of the aneurysm and occlusion of the lumen of the aneurysm by means of endovascular coiling. This is an update of a systematic review that was previously published in 2005., Objectives: To compare the effects of endovascular coiling versus neurosurgical clipping in people with aneurysmal SAH on poor outcome, rebleeding, neurological deficit, and treatment complications., Search Methods: We searched the Cochrane Stroke Group Trials Register (March 2018). In addition, we searched CENTRAL (2018, Issue 2), MEDLINE (1966 to March 2018), Embase (1980 to March 2018), US National Institutes of Health Ongoing Trials Register (March 2018), and World Health Organization (WHO) International Clinical Trials Registry Platform (ICTRP) (last searched March 2018). We also contacted trialists., Selection Criteria: We included randomised trials comparing endovascular coiling with neurosurgical clipping in people with SAH from a ruptured aneurysm., Data Collection and Analysis: Two review authors independently extracted data, and assessed trial quality and risk of bias using the GRADE approach. We contacted trialists to obtain missing information. We defined poor outcome as death or dependence in daily activities (modified Rankin scale 3 to 6 or Glasgow Outcome Scale (GOS) 1 to 3). In the special worst-case scenario analysis, we assumed all participants in the group with better outcome with missing follow-up information had a poor outcome and those in the other group with missing data a good outcome., Main Results: We included four randomised trials involving 2458 participants (range per trial: 20 to 2143 participants). Evidence is mostly based on the largest trial. Most participants were in good clinical condition and had an aneurysm on the anterior circulation. None of the included trials was at low risk of bias in all domains. One trial was at unclear risk in one domain, two trials at unclear risk in three domains, and one trial at high risk in one domain.After one year of follow-up, 24% of participants randomised to endovascular treatment and 32% of participants randomised to the surgical treatment group had poor functional outcome. The risk ratio (RR) of poor outcome (death or dependency) for endovascular coiling versus neurosurgical clipping was 0.77 (95% confidence interval (CI) 0.67 to 0.87; 4 trials, 2429 participants, moderate-quality evidence), and the absolute risk reduction was 7% (95% CI 4% to 11%). In the worst-case scenario analysis for poor outcome, the RR for endovascular coiling versus neurosurgical clipping was 0.80 (95% CI 0.71 to 0.91), and the absolute risk reduction was 6% (95% CI 2% to 10%). The RR of death at 12 months was 0.80 (95% CI 0.63 to 1.02; 4 trials, 2429 participants, moderate-quality evidence). In a subgroup analysis of participants with an anterior circulation aneurysm, the RR of poor outcome was 0.78 (95% CI 0.68 to 0.90; 2 trials, 2157 participants, moderate-quality evidence), and the absolute risk decrease was 7% (95% CI 3% to 10%). In subgroup analysis of those with a posterior circulation aneurysm, the RR was 0.41 (95% CI 0.19 to 0.92; 2 trials, 69 participants, low-quality evidence), and the absolute decrease in risk was 27% (95% CI 6% to 48%). At five years, 28% of participants randomised to endovascular treatment and 32% of participants randomised to surgical treatment had poor functional outcome. The RR of poor outcome for endovascular coiling versus neurosurgical clipping was 0.87 (95% CI 0.75 to 1.01, 1 trial, 1724 participants, low-quality evidence). At 10 years, 35% participants allocated to endovascular and 43% participants allocated to surgical treatment had poor functional outcome. At 10 years RR of poor outcome for endovascular coiling versus neurosurgical clipping was 0.81 (95% CI 0.70 to 0.92; 1 trial, 1316 participants, low-quality evidence). The RR of delayed cerebral ischaemia at two to three months for endovascular coiling versus neurosurgical clipping was 0.84 (95% CI 0.74 to 0.96; 4 trials, 2450 participants, moderate-quality evidence). The RR of rebleeding for endovascular coiling versus neurosurgical clipping was 1.83 (95% CI 1.04 to 3.23; 4 trials, 2458 participants, high-quality evidence) at one year, and 2.69 (95% CI 1.50 to 4.81; 1 trial, 1323 participants, low-quality evidence) at 10 years. The RR of complications from intervention for endovascular coiling versus neurosurgical clipping was 1.05 (95% CI 0.44 to 2.53; 2 trials, 129 participants, low-quality evidence)., Authors' Conclusions: The evidence in this systematic review comes mainly from one large trial, and long-term follow-up is available only for a subgroup of participants within that trial. For people in good clinical condition with ruptured aneurysms of either the anterior or posterior circulation the data from randomised trials show that, if the aneurysm is considered suitable for both neurosurgical clipping and endovascular coiling, coiling is associated with a better outcome. There is no reliable trial evidence that can be used directly to guide treatment in people with a poor clinical condition.

Background: Stroke is an important cause of death and disability worldwide. Since high blood pressure is an important risk factor for stroke and stroke recurrence, drugs that lower blood pressure might play an important role in secondary stroke prevention., Objectives: To investigate whether blood pressure-lowering drugs (BPLDs) started at least 48 hours after the index event are effective for the prevention of recurrent stroke, major vascular events, and dementia in people with stroke or transient ischaemic attack (TIA). Secondary objectives were to identify subgroups of people in which BPLDs are effective, and to investigate the optimum systolic blood pressure target after stroke or TIA for preventing recurrent stroke, major vascular events, and dementia., Search Methods: In August 2017, we searched the Trials Registers of the Cochrane Stroke Group and the Cochrane Hypertension Group, the Cochrane Central Register of Controlled Trials (CENTRAL; 2017, Issue 8), MEDLINE Ovid (1946 to August 2017), Embase Ovid (1974 to August 2017), ClinicalTrials.gov, the ISRCTN Registry, Stroke Trials Registry, Trials Central, and the World Health Organization (WHO) International Clinical Trials Registry Platform Portal., Selection Criteria: Randomised controlled trials (RCTs) of BPLDs started at least 48 hours after stroke or TIA., Data Collection and Analysis: Two review authors independently screened all titles and abstracts, selected eligible trials, extracted the data, assessed risk of bias, and used GRADE to assess the quality of the evidence. If necessary, we contacted the principal investigators or corresponding authors for additional data., Main Results: We included 11 studies involving a total of 38,742 participants: eight studies compared BPLDs versus placebo or no treatment (35,110 participants), and three studies compared different systolic blood pressure targets (3632 participants). The risk of bias varied greatly between included studies. The pooled risk ratios (RRs) of BPLDs were 0.81 (95% confidence interval (CI) 0.70 to 0.93; 8 RCTs; 35,110 participants; moderate-quality evidence), 0.90 (95% CI 0.78 to 1.04; 4 RCTs; 28,630 participants; high-quality evidence) for major vascular event, and 0.88 (95% CI 0.73 to 1.06; 2 RCTs; 6671 participants; high-quality evidence) for dementia. We mainly observed a reduced risk of recurrent stroke in the subgroup of participants using an angiotensin-converting enzyme (ACE) inhibitor or a diuretic (I 2 statistic for subgroup differences 72.1%; P = 0.006). The pooled RRs of intensive blood pressure-lowering were 0.80 (95% CI 0.63 to 1.00) for recurrent stroke and 0.58 (95% CI 0.23 to 1.46) for major vascular event., Authors' Conclusions: Our results support the use of BPLDs in people with stroke or TIA for reducing the risk of recurrent stroke. Current evidence is primarily derived from trials studying an ACE inhibitor or a diuretic. No definite conclusions can be drawn from current evidence regarding an optimal systolic blood pressure target after stroke or TIA.

OBJECTIVE This study investigated whether the increased incidence of aneurysmal subarachnoid hemorrhage (SAH) in winter is related to temperature or increased incidence of influenza. Such relationships may elucidate the pathogenesis of intracranial aneurysm rupture. METHODS A nationwide sample of 18,714 patients with SAH was linked with weekly temperature and influenza-like illness consultation data. Poisson regression analyses were used to calculate incidence density ratios (IDRs) with corresponding 95% CIs for the association of SAH incidence with temperature and influenza epidemics; IDRs were adjusted for study year (aIDR). In addition, SAH incidence data from 30 European population-based studies were linked with daily temperature data from the European Climate Assessment. RESULTS The aIDR for SAH during influenza epidemics was 1.061 (95% CI 1.022-1.101) in the univariable and 1.030 (95% CI 0.989-1.074) in the multivariable analysis. This association declined gradually during the weeks after epidemics. Per 1°C temperature drop, the aIDR was 1.005 (95% CI 1.003-1.008) in the univariable and 1.004 (95% CI 1.002-1.007) in the multivariable analysis. In the European population-based studies, the IDR was 1.143 (95% CI 1.129-1.157) per 1°C temperature drop. CONCLUSIONS The incidence of SAH is increased during cold temperatures and epidemic influenza. Future studies with individual patient data are needed to investigate causality between temperature or influenza and SAH.

Objective: External validation of prognostic models is crucial but rarely done. Our aim was to externally validate a prognostic model to predict 60-day case fatality after aneurysmal subarachnoid hemorrhage developed from the International Subarachnoid Aneurysm Trial in a retrospective unselected cohort of subarachnoid hemorrhage patients., Design: The model's predictors were age, aneurysm size, Fisher grade, and World Federation of Neurological Surgeons grade. Two versions of the model were validated: one with World Federation of Neurological Surgeons grade scored at admission and the other with World Federation of Neurological Surgeons grade at treatment decision. The outcome was 60-day case fatality. Performance of the model was assessed by studying discrimination, expressed by the area under the receiver operating characteristic curve, and calibration., Setting: University hospital., Patients: We analyzed data from 307 consecutive aneurysmal subarachnoid hemorrhage patients admitted between 2007 and 2011 (validation cohort)., Interventions: None., Measurements and Main Results: The observed 60-day case fatality rate was 30.6%. Discrimination was good, and differed between the model with World Federation of Neurological Surgeons grade at treatment decision (area under the receiver operating characteristic curve, 0.89) and at admission (area under the receiver operating characteristic curve, 0.82). Mean predicted probabilities were lower than observed: 17.0% (model with World Federation of Neurological Surgeons grade at admission) and 17.7% (model with World Federation of Neurological Surgeons grade at treatment decision)., Conclusions: The model discriminated well between patients who died or survived within 60 days. In addition, we found that using World Federation of Neurological Surgeons grade at moment of treatment decision of the ruptured aneurysm improved model performance. However, since predicted probabilities were much lower than observed probabilities, the International Subarachnoid Aneurysm Trial prediction model needs to be adapted to be used in clinical practice.

Background and Purpose: Follow-up imaging is often performed in intracranial aneurysms that are not treated. We performed a systematic review and meta-analysis on patient- and aneurysm-specific risk factors for aneurysm growth., Methods: We searched EMBASE and MEDLINE for cohort studies describing risk factors for aneurysm growth. Two authors independently assessed study eligibility and rated quality with the Newcastle Ottawa Scale. With univariable Poisson regression analysis, we calculated risk ratios (RRs) with corresponding 95% confidence intervals (95% CI) of risk factors for aneurysm growth. Heterogeneity was assessed with I(2)., Results: Eighteen studies on 15 patient-populations described 3990 patients with 4972 unruptured aneurysms. A total of 437 aneurysms (9%) enlarged during 13 987 aneurysm-years of follow-up. Compared with aneurysms ≤4 mm, RRs were 2.56 (95% CI, 1.93-3.39; I(2)=98%) for ≥5 mm, 2.80 (95% CI, 2.01-3.90; I(2)=96%) for ≥7 mm, and 5.38 (95% CI, 3.76-7.70; I(2)=97%) for ≥10 mm. Compared with aneurysms on the middle cerebral artery, the RR for basilar artery was 1.94 (95% CI, 1.32-2.83; I(2)=57%). RRs were 2.03 (95% CI, 1.52-2.71; I(2)=59%) for smoking at baseline, 2.04 (95% CI, 1.56-2.66; I(2)=90%) for multiple unruptured aneurysms, 1.26 (95% CI, 0.97-1.62; I(2)=59%) for women, 1.24 (95% CI, 0.98-1.58; I(2)=40%) for hypertension, and 2.32 (95% CI, 1.46-3.68; I(2)=91%) for irregular aneurysm shape. Compared with other regions, RR was 0.75 (95% CI, 0.58-0.96) for Japan and 0.64 (95% CI, 0.45-0.90) for Finland., Conclusions: Most risk factors for aneurysm growth are consistent with risk factors for rupture. In contrast with rupture, the risk of growth was smaller in Japanese and Finnish cohorts compared with other regions. Pooling of individual patient data from low- and high-risk geographical regions is needed to assess independent predictors of aneurysm growth., (© 2016 American Heart Association, Inc.)

Introduction: Cardiac dysfunction may occur after aneurysmal subarachnoid hemorrhage (aSAH). Although it is associated with poor outcome, the pathophysiological mechanism of this association remains unclear. We investigated the relationship between cardiac function and cerebral perfusion in patients with aSAH., Methods: We studied 72 aSAH patients admitted within 72 h after ictus with echocardiography and cerebral CT perfusion within 24 h after admission. Cardiac dysfunction was defined as myocardial wall motion abnormalities or positive troponin. In patients with and without cardiac dysfunction, we calculated the mean perfusion [cerebral blood flow (CBF) and time-to-peak (TTP)] in standard regions of interest and calculated differences with 95% confidence intervals (95% CI)., Results: In 35 patients with cardiac dysfunction minimal CBF was 15.83 mL/100 g/min compared to 18.59 in 37 without (difference of means -2.76; 95% CI -5.43 to -0.09). Maximal TTP was 26.94 s for patients with and 23.10 s for patients without cardiac dysfunction (difference of means 3.84; 95% CI 1.63-6.05). Mean global CBF was 21.71 mL/100 g/min for patients with cardiac dysfunction and 24.67 mL/100 g/min for patients without cardiac dysfunction (-2.96; 95% CI -6.19 to 0.27). Mean global TTP was 25.27 s for patients with cardiac dysfunction and 21.26 for patients without cardiac dysfunction (4.01; 95% CI 1.95-6.07)., Conclusion: aSAH patients with cardiac dysfunction have decreased focal and global cerebral perfusion. Further studies should evaluate whether this relation is explained by a direct effect of cardiac dysfunction on cerebral circulation or by an external determinant, such as a hypercatecholaminergic or hypometabolic state, influencing both cardiac function and cerebral perfusion.

Introduction: Delayed cerebral ischemia (DCI) is an important contributor to poor outcome after aneurysmal subarachnoid haemorrhage (aSAH). Development of DCI is multifactorial, and inflammation, with or without infection, is one of the factors independently associated with development of DCI and poor outcome. We thus postulated that preventive antibiotics might be associated with a reduced risk of DCI and subsequent poor outcome in aSAH patients., Methods: We performed a retrospective cohort-study in intensive care units (ICU) of three university hospitals in The Netherlands. We included consecutive aSAH patients with minimal ICU stay of 72 h who received either preventive antibiotics (SDD: selective digestive tract decontamination including systemic cefotaxime or SOD: selective oropharyngeal decontamination) or no preventive antibiotics. DCI was defined as a new hypodensity on CT with no other explanation than DCI. Hazard ratio's (HR) for DCI and risk ratio's (RR) for 28-day case-fatality and poor outcome at 3 months were calculated, with adjustment (aHR/aRR) for clinical condition on admission, recurrent bleeding, aneurysm treatment modality and treatment site., Results: Of 459 included patients, 274 received preventive antibiotics (SOD or SDD) and 185 did not. With preventive antibiotics, the aHR for DCI was 1.0 (95% CI 0.6-1.8), the aRR for 28-day case-fatality was 1.1 (95% CI 0.7-1.9) and the aRR for poor functional outcome 1.2 (95% CI 1.0-1.4)., Conclusions: Preventive antibiotics were not associated with reduced risk of DCI or poor outcome in aSAH patients in the ICU.

Objective: To compare causes of in-hospital death after aneurysmal subarachnoid hemorrhage (aSAH) in 2 time periods within the same institution., Methods: From a prospectively collected institutional database, we retrieved data on 844 consecutive patients with aSAH admitted ≤3 days after ictus in 1999-2002 and 2009-2012. We assessed case-fatality <90 days and causes of in-hospital death and used Poisson regression analyses to calculate adjusted risk ratios (aRR) with corresponding 95% confidence intervals (CI) for change in individual causes of death, with the first time period as the reference group., Results: Ninety-day case-fatality declined from 150/381 patients (39%) in 1999-2002 to 140/463 (30%) in 2009-2012 (aRR 0.74 [95% CI 0.62-0.88]). Compared with 1999-2002, the aRR for specific cause of in-hospital death in 2009-2012 was 1.06 (95% CI 0.72-1.56) for death from the initial bleeding, 0.47 (95% CI 0.31-0.71) for death from rebleeding, and 0.91 (95% CI 0.50-1.65) for death from delayed cerebral ischemia. Over time, the proportion of patients with in-hospital rebleeding declined from 90/381 (24%) to 78/463 (17%) (aRR 0.68 [95% CI 0.52-0.90]), median day of rebleeding from day 5 (IQR 1-10) to day 0 (IQR 0-1), and median day of aneurysm treatment from day 4 (IQR 2-13) to day 1 (IQR 1-2)., Conclusions: An important contributor to the reduction in in-hospital death is the reduction in death from rebleeding, which probably results from earlier aneurysm treatment. Our results stress the need for early occlusion of the aneurysm and the need for other strategies that improve outcome by reducing the risk of rebleeding., (© 2015 American Academy of Neurology.)

Objective: We endeavored to develop an unruptured intracranial aneurysm (UIA) treatment score (UIATS) model that includes and quantifies key factors involved in clinical decision-making in the management of UIAs and to assess agreement for this model among specialists in UIA management and research., Methods: An international multidisciplinary (neurosurgery, neuroradiology, neurology, clinical epidemiology) group of 69 specialists was convened to develop and validate the UIATS model using a Delphi consensus. For internal (39 panel members involved in identification of relevant features) and external validation (30 independent external reviewers), 30 selected UIA cases were used to analyze agreement with UIATS management recommendations based on a 5-point Likert scale (5 indicating strong agreement). Interrater agreement (IRA) was assessed with standardized coefficients of dispersion (vr*) (vr* = 0 indicating excellent agreement and vr* = 1 indicating poor agreement)., Results: The UIATS accounts for 29 key factors in UIA management. Agreement with UIATS (mean Likert scores) was 4.2 (95% confidence interval [CI] 4.1-4.3) per reviewer for both reviewer cohorts; agreement per case was 4.3 (95% CI 4.1-4.4) for panel members and 4.5 (95% CI 4.3-4.6) for external reviewers (p = 0.017). Mean Likert scores were 4.2 (95% CI 4.1-4.3) for interventional reviewers (n = 56) and 4.1 (95% CI 3.9-4.4) for noninterventional reviewers (n = 12) (p = 0.290). Overall IRA (vr*) for both cohorts was 0.026 (95% CI 0.019-0.033)., Conclusions: This novel UIA decision guidance study captures an excellent consensus among highly informed individuals on UIA management, irrespective of their underlying specialty. Clinicians can use the UIATS as a comprehensive mechanism for indicating how a large group of specialists might manage an individual patient with a UIA., (© 2015 American Academy of Neurology.)

Introduction: Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) can be reversible or progress to cerebral infarction. In patients with a deterioration clinically diagnosed as DCI, we investigated whether CT perfusion (CTP) can distinguish between reversible ischemia and ischemia progressing to cerebral infarction., Methods: From a prospectively collected series of aSAH patients, we included those with DCI, CTP on the day of clinical deterioration, and follow-up imaging. In qualitative CTP analyses (visual assessment), we calculated positive and negative predictive value (PPV and NPV) with 95% confidence intervals (95%CI) of a perfusion deficit for infarction on follow-up imaging. In quantitative analyses, we compared perfusion values of the least perfused brain tissue between patients with and without infarction by using receiver-operator characteristic curves and calculated a threshold value with PPV and NPV for the perfusion parameter with the highest area under the curve., Results: In qualitative analyses of 33 included patients, 15 of 17 patients (88%) with and 6 of 16 patients (38%) without infarction on follow-up imaging had a perfusion deficit during clinical deterioration (p = 0.002). Presence of a perfusion deficit had a PPV of 71% (95%CI: 48-89%) and NPV of 83% (95%CI: 52-98%) for infarction on follow-up. Quantitative analyses showed that an absolute minimal cerebral blood flow (CBF) threshold of 17.7 mL/100 g/min had a PPV of 63% (95%CI: 41-81%) and a NPV of 78% (95%CI: 40-97%) for infarction., Conclusions: CTP may differ between patients with DCI who develop infarction and those who do not. For this purpose, qualitative evaluation may perform marginally better than quantitative evaluation.

Background: Neck stiffness can be the only diagnostic clue for subarachnoid haemorrhage (SAH) at neurological examination in patients with a clinical suspicion of nontraumatic SAH who present with a normal level of consciousness and no focal neurologic deficits. Since the clinical impression is that neck stiffness may take several hours to develop, we determined time-dependent test characteristics of neck stiffness., Methods: We retrieved the presence of neck stiffness from the medical records of consecutive patients presenting between 2005 and 2013 with a clinical suspicion of SAH, a normal level of consciousness and no focal neurologic deficits. Test characteristics with corresponding 95% confidence intervals (CIs) were calculated for the evaluation of neck stiffness ≤6 h and 6-72 h after symptom onset for the diagnosis of nontraumatic SAH. In a secondary analysis, multiple imputation was used to account for missing values., Results: 114 of 247 included patients were diagnosed with nontraumatic SAH. Neck stiffness at neurological examination performed ≤6 h after symptom onset had a positive predictive value (PPV) of 90% (95% CI: 78%-97%) and negative predictive value (NPV) of 69% (95% CI: 59%-78%). Between 6 and 72 h after symptom onset the PPV was 76% (95% CI: 58%-89%) and NPV 91% (95% CI: 78%-98%). Multiple imputation to account for missing values yielded similar results., Conclusion: In patients with a normal level of consciousness without focal neurologic deficits the presence of neck stiffness is helpful but not pathognomic for the diagnosis of SAH. Moreover, the absence of neck stiffness does not rule out SAH, especially when evaluated ≤6 h after symptom onset., (Copyright © 2015 Elsevier B.V. All rights reserved.)

Background: Nosocomial infections after aneurysmal subarachnoid hemorrhage (aSAH) are associated with prolonged length of stay and poor functional outcome. It remains unclear if infections result in prolonged length of stay or, vice versa, if prolonged length of stay results in more infections. Before strategies can be designed to reduce infections after aneurysmal subarachnoid hemorrhage, more data are needed on time course and causative pathogens of infections., Aim: To investigate the time course of infection onset and bacterial microorganisms that cause nosocomial infections after aSAH., Methods: In consecutive patients with aneurysmal subarachnoid hemorrhage admitted to the University Medical Center Utrecht between 2009 and 2011, we analyzed the proportion of patients with infections, day of infection onset, and culture results., Results: Of the 291 included patients, 107 (37%) patients developed 115 nosocomial infections. Fifty-six patients (19%) developed an infection within the first week. Median day of infection onset was for pneumonia (n = 49; 17%) day 4 (interquartile range 3-9), respiratory tract infection (n = 16; 6%) day 4 (interquartile range 1-7), urinary tract infection (n = 27; 9%) day 11 (interquartile range 7-14), and meningitis/ventriculitis (n = 10; 3%) day 19 (interquartile range 9-33). Cultures of infections mostly yielded Staphylococcus aureus (20%), Haemophilus influenzae (15%), and Escherichia coli (14%),, Conclusion: Nosocomial infections after subarachnoid hemorrhage are common and mostly occur in the first week after ictus. Future studies should investigate if general hygienic measures, infection awareness, minimizing the duration of mechanical ventilation and use of catheters/drains, or prophylactic antibiotics reduce infections and improve functional outcome., (© 2015 World Stroke Organization.)

In clinical trials, endothelin receptor antagonists (ETRAs) reduced vasospasm but did not improve functional outcome after subarachnoid hemorrhage (SAH). We assessed the effects of treatment with ETRAs on clinically relevant outcomes in animal studies modelling SAH by performing a systematic review of the literature for controlled animal studies of ETRAs for the treatment of SAH. Primary outcomes were neurobehavioral outcomes and case fatality. Secondary outcomes were cerebral vasospasm and cerebral blood flow. Summary estimates were calculated using normalized mean difference random effects meta-analysis. We included 27 studies (55 experiments, 639 animals). Neurobehavioral scores were reported in none of the experiments, and case fatality in 8 (15%). Treatment with ETRAs was associated with a pooled odds ratio for case fatality of 0.61 (95% confidence interval (CI), 0.27 to 1.39); a 54% increase (95% CI, 39 to 69) in cerebral arterial diameter; and a 93% increase (95% CI, 58 to 129) in cerebral blood flow. We conclude that there is no evidence from animal studies that treatment with an ETRA improves clinically relevant outcomes after SAH. The reduction in cerebral vasospasm observed in animal studies is consistent with that observed in clinical trials, an effect that is not associated with better functional outcome in patients.

Background and Purpose: The eventual goal of preventive treatment of unruptured intracranial aneurysms is to increase the number of life years with high life satisfaction. Insight in the time with reduced functioning, working capacity, and life satisfaction after aneurysm treatment is pivotal to balance the pros and cons of preventive aneurysm occlusion., Methods: We sent a questionnaire on time-to-recovery to preintervention functioning and return-to-work and life satisfaction to patients treated for an unruptured aneurysm between 2000 and 2013. Changes in life satisfaction before treatment, during recovery, and at follow-up were assessed with Wilcoxon signed-rank tests., Results: The questionnaire was sent to 159 patients of whom 110 (69%) responded. The mean follow-up time after aneurysm treatment was 6 years (SD 4). Fifty-four patients had endovascular and 56 had microsurgical occlusion. Complete recovery to preintervention functioning was reported by 81% (95% confidence interval [CI], 74-88) of patients, with a median time-to-recovery of 3 months (range 0-48). Complete work recovery was reported by 78% (95% CI, 66-87) of patients. The proportion of patients with high life satisfaction reduced from 76% (95% CI, 67-84) before treatment to 52% (95% CI, 43-61) during the period of recovery (P<0.01) and restored largely at long-term follow-up (67% [95% CI, 59-76], P=0.08)., Conclusion: Life satisfaction is significantly reduced during the period of recovery after treatment of unruptured aneurysms. In the long-term, ≈1 out of 5 patients reports incomplete recovery. These treatment effects should be kept in mind when considering preventive aneurysm treatment. Prospective studies are needed to better compare these losses in patients treated for unruptured aneurysms with those who had subarachnoid hemorrhage., (© 2015 American Heart Association, Inc.)

Objective: To investigate whether staff radiologists working in nonacademic hospitals can adequately rule out subarachnoid hemorrhage (SAH) on head CT <6 hours after headache onset., Methods: In a multicenter, retrospective study, we studied a consecutive series of patients presenting with acute headache to 11 nonacademic hospitals. Inclusion criteria were (1) normal level of consciousness without focal deficits, (2) head CT <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist, and (3) subsequent CSF spectrophotometry. Two neuroradiologists and one stroke neurologist from 2 academic tertiary care centers independently reviewed admission CTs of patients with CSF results that were considered positive for presence of bilirubin according to local criteria. We investigated the negative predictive value for detection of SAH by staff radiologists in nonacademic hospitals on head CT in patients scanned <6 hours after onset of acute headache., Results: Of 760 included patients, CSF analysis was considered positive for bilirubin in 52 patients (7%). Independent review of these patients' CTs identified one patient (1/52; 2%) with a perimesencephalic nonaneurysmal SAH. Negative predictive value for detection of subarachnoid blood by staff radiologists working in a nonacademic hospital was 99.9% (95% confidence interval 99.3%-100.0%)., Conclusions: Our results support a change of practice wherein a lumbar puncture can be withheld in patients with a head CT scan performed <6 hours after headache onset and reported negative for the presence of SAH by a staff radiologist in the described nonacademic setting., (© 2015 American Academy of Neurology.)

Introduction: Tracer delay-sensitive perfusion algorithms in CT perfusion (CTP) result in an overestimation of the extent of ischemia in thromboembolic stroke. In diagnosing delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH), delayed arrival of contrast due to vasospasm may also overestimate the extent of ischemia. We investigated the diagnostic accuracy of tracer delay-sensitive and tracer delay-insensitive algorithms for detecting DCI., Methods: From a prospectively collected series of aSAH patients admitted between 2007-2011, we included patients with any clinical deterioration other than rebleeding within 21 days after SAH who underwent NCCT/CTP/CTA imaging. Causes of clinical deterioration were categorized into DCI and no DCI. CTP maps were calculated with tracer delay-sensitive and tracer delay-insensitive algorithms and were visually assessed for the presence of perfusion deficits by two independent observers with different levels of experience. The diagnostic value of both algorithms was calculated for both observers., Results: Seventy-one patients were included. For the experienced observer, the positive predictive values (PPVs) were 0.67 for the delay-sensitive and 0.66 for the delay-insensitive algorithm, and the negative predictive values (NPVs) were 0.73 and 0.74. For the less experienced observer, PPVs were 0.60 for both algorithms, and NPVs were 0.66 for the delay-sensitive and 0.63 for the delay-insensitive algorithm., Conclusion: Test characteristics are comparable for tracer delay-sensitive and tracer delay-insensitive algorithms for the visual assessment of CTP in diagnosing DCI. This indicates that both algorithms can be used for this purpose.

Background and Purpose: Growth of an intracranial aneurysm occurs in around 10% of patients at 2-year follow-up imaging and may be associated with aneurysm rupture. We investigated whether PHASES, a score providing absolute risks of aneurysm rupture based on 6 easily retrievable risk factors, also predicts aneurysm growth., Methods: In a multicenter cohort of patients with unruptured intracranial aneurysms and follow-up imaging with computed tomography angiography or magnetic resonance angiography, we performed univariable and multivariable Cox regression analyses for the predictors of the PHASES score at baseline, with aneurysm growth as outcome. We calculated hazard ratios and corresponding 95% confidence intervals (CI), with the PHASES score as continuous variable and after division into quartiles., Results: We included 557 patients with 734 unruptured aneurysms. Eighty-nine (12%) aneurysms in 87 patients showed growth during a median follow-up of 2.7 patient-years (range 0.5-10.8). Per point increase in PHASES score, hazard ratio for aneurysm growth was 1.32 (95% CI, 1.22-1.43). With the lowest quartile of the PHASES score (0-1) as reference, hazard ratios were for the second (PHASES 2-3) 1.07 (95% CI, 0.49-2.32), the third (PHASES 4) 2.29 (95% CI, 1.05-4.95), and the fourth quartile (PHASES 5-14) 2.85 (95% CI, 1.43-5.67)., Conclusions: Higher PHASES scores were associated with an increased risk of aneurysm growth. Because higher PHASES scores also predict aneurysm rupture, our findings suggest that aneurysm growth can be used as surrogate outcome measure of aneurysm rupture in follow-up studies on risk prediction or interventions aimed to reduce the risk of rupture., (© 2015 American Heart Association, Inc.)

Delayed cerebral ischemia (DCI) after aneurysmal subarachnoid hemorrhage (aSAH) has been associated with microthrombosis, which can result from activated hemostasis, inhibited fibrinolysis, or both. We systematically searched the PUBMED and EMBASE databases to identify hemostatic or fibrinolytic parameters that can be used for the prediction or diagnosis of DCI, or that inform on the pathogenesis of DCI and may serve as treatment targets. We included 24 studies that fulfilled predefined criteria and described 39 biomarkers. Only one study fulfilled predefined criteria for high quality. Since no parameter on admission was associated with DCI and in none of the included studies blood was drawn at the time of clinical deterioration, none of the studied parameters can presently be used for the prediction or diagnosis of DCI. Regarding the pathogenesis of DCI, it was shown that compared with patients without DCI those with DCI had higher levels of von Willebrand factor and platelet activating factor in plasma 5 to 9 days after aSAH, membrane tissue factor in cerebrospinal fluid 5 to 9 days after aSAH, and D-dimer in plasma 11 to 14 days after aSAH. Confirmation in high-quality studies is needed to investigate whether these parameters can serve as targets for new intervention studies.

Autosomal dominant polycystic kidney disease (ADPKD) is a genetic systemic disorder, which is associated with cyst formation in several organs, renal function decline and a higher prevalence of intracranial aneurysms. We report a 52-year-old, otherwise healthy, man with ADPKD who had asymptomatic, bilateral, multiple cysts in the choroid plexus, which is an extremely rare abnormality. Recent evidence suggests that the polycystin proteins, which are dysfunctional in ADPKD, are found in ciliated choroid plexus cells that are involved with regulation of cerebrospinal fluid homeostasis. We hypothesize therefore that choroid plexus cysts may be part of the ADPKD phenotype, which has not been described before., (© The Author 2014. Published by Oxford University Press on behalf of ERA-EDTA. All rights reserved.)

Many survivors of aneurysmal subarachnoid haemorrhage (aSAH) have persistent cognitive deficits. Underlying causes of these deficits have not been elucidated. We aimed to investigate if cerebral perfusion in the acute phase after aSAH measured with CT perfusion (CTP) is associated with cognitive outcome 3 months after aSAH. We included 71 patients admitted to the University Medical Center Utrecht who had CTP performed within 24 h after ictus and neuropsychological examination after 3 months. Perfusion values were measured in predefined regions of interest for cerebral blood flow (CBF), cerebral blood volume (CBV), mean transit time (MTT), and time to peak (TTP). The relationship with global cognitive functioning, as measured with a mean z score of all cognitive tests, was examined by linear regression analyses. Adjustments were made for age, education, method of aneurysm treatment, and presence of non-acute medical complications. TTP was associated with cognitive functioning in the univariable analysis (B = -0.042, 95 % CI -0.076 to -0.008), but not after adjustment for age (B = -0.030, 95 % CI -0.065 to 0.004). For CBF, CBV and MTT no relationship with cognitive functioning was observed. Cerebral perfusion measured with CTP within 24 h after onset of aSAH is not associated with cognitive outcome after 3 months. The lack of an association might be explained by the delay between onset of aSAH and CTP. However, CTP assessment within the first minutes after aSAH is impossible in large series of patients.

Researchers and other stakeholders continue to express concern about the failure of randomized clinical trials (RCT) in subarachnoid hemorrhage (SAH) to show efficacy of new treatments. Pooled data may be particularly useful to generate hypotheses about causes of poor outcomes and reasons for failure of RCT in SAH, and strategies to improve them. Investigators conducting SAH research collaborated to share data with the intent to develop a large repository of pooled individual patient data for exploratory analysis and testing of new hypotheses relevant to improved trial design and analysis in SAH. This repository currently contains information on 11,443 SAH patients from 14 clinical databases, of which 9 are datasets of recent RCTs and 5 are datasets of prospective observational studies and hospital registries. Most patients were managed in the last 15 years. Data validation and quality checks have been conducted and are satisfactory. Data is available on demographic, clinical, neuroimaging, and laboratory results and various outcome measures. We have compiled the largest known dataset of patients with SAH. The SAHIT repository may be an important resource for advancing clinical research in SAH and will benefit from contributions of additional datasets.

Introduction: In patients with aneurysmal subarachnoid hemorrhage (aSAH), it is unclear whether aneurysm treatment <24 h after ictus results in better outcomes than treatment 24-72 h after aSAH. We studied whether aneurysm occlusion <24 h is associated with better outcomes than occlusion 24-72 h after aSAH., Methods: We used two cohorts of patients with aSAH: (1) the UMC Utrecht cohort with patients admitted between 2008 and 2012 and (2) the International Subarachnoid Aneurysm Trial cohort. Aneurysm treatment was categorized into <24 h and 24-72 h after ictus. We calculated adjusted risk ratios (aRRs) with 95% confidence intervals (CIs) using Poisson regression analyses for poor functional outcome (death or dependency) for both cohorts separately, and performed a pooled analysis based on individual patient data. We also performed a worst-case scenario analysis wherein all patients with rebleeding >3 h after admission were re-categorized into the group with aneurysm treatment 24-72 h after aSAH., Results: We included 1,238 patients (UMC Utrecht cohort: n = 330; ISAT: n = 908). The aRR for poor outcome after treatment <24 h was in the UMC Utrecht cohort 1.84 (95% CI: 1.25-2.70), in ISAT 1.14 (95% CI 0.84-1.55), in the pooled analysis 1.37 (95% CI 1.11-1.68), and in the worst-case scenario pooled analysis 1.24 (95% CI 1.01-1.52)., Conclusion: Our results suggest that aneurysm occlusion can be performed in day time within 72 h after ictus, instead of on an emergency basis. However, due to the retrospective, non-randomized design of our study, our results cannot be considered as definitive evidence.

Background: A common complication after aneurysmal subarachnoid hemorrhage (SAH) is delayed cerebral ischemia (DCI), which is associated with vasospasm and other mechanisms such as microthrombosis. ADAMTS-13 activity plays a role in the prevention of thrombus formation in the cerebral microvasculature. Previously, we observed that patients with DCI have lower levels of ADAMTS-13., Objectives: To examine whether recombinant human ADAMTS-13 (rADAMTS-13) reduces cerebral microthrombus formation and brain injury in an experimental mouse model of SAH including wild-type and ADAMTS-13(-/-) mice., Methods: Experimental SAH was induced with the prechiasmatic blood injection model. The following experimental groups were investigated: (i) C57BL/6J mice (n = 10); (ii) C57BL/6J mice (n = 10) treated with rADAMTS-13 20 min after SAH; (iii) ADAMTS-13(-/-) mice (n = 10); and (iv) ADAMTS-13(-/-) mice (n = 10) treated with rADAMTS-13 20 min after SAH. Mice were killed at 48 h. Results are presented as means with standard errors of the mean., Results: Infusion with rADAMTS-13 reduced the extent of microthrombosis by ~ 50% in both wild-type mice (mean fibrinogen area: 0.28% ± 0.09% vs. 0.15% ± 0.04%; P = 0.20) and ADAMTS-13(-/-) mice (mean fibrinogen area: 0.32% ± 0.05% vs. 0.16% ± 0.03%; P = 0.016). In addition, rADAMTS-13 reduced brain injury by > 60% in both wild-type mice (mean microglia area: 0.65% ± 0.18% vs. 0.18% ± 0.04%; P = 0.013) and ADAMTS-13(-/-) mice (mean microglia area: 1.24% ± 0.36% vs. 0.42% ± 0.13%; P = 0.077)., Conclusions: Our results support the further study of rADAMTS-13 as a treatment option for the prevention of microthrombosis and brain injury after SAH., (© 2014 International Society on Thrombosis and Haemostasis.)

Background and Purpose: Prediction of the risk of rupture of unruptured intracranial aneurysms is mainly based on aneurysm size and location. Previous studies identified features of aneurysm shape and flow angles as additional risk factors for aneurysm rupture, but these studies were at risk for confounding by patient-specific risk factors such as hypertension and age. In this study, we avoided this risk by comparing characteristics of ruptured and unruptured aneurysms in patients with both aneurysmal subarachnoid hemorrhage and multiple intracranial aneurysms., Methods: We included patients with aneurysmal subarachnoid hemorrhage and multiple aneurysms who presented to our hospital between 2003 and 2013. We identified the ruptured aneurysm based on bleeding pattern on head computed tomography or surgical findings. Aneurysm characteristics (size, location, shape, aspect ratio [neck-to-dome length/neck-width], flow angles, sidewall or bifurcation type, and contact with bone) were evaluated on computed tomographic angiograms. We calculated odds ratios with 95% confidence intervals with conditional univariable logistic regression analysis. Analyses were repeated after adjustment for aneurysm size and location., Results: The largest aneurysm had not ruptured in 36 (29%) of the 124 included patients with 302 aneurysms. Odds ratios for aspect ratio≥1.3 was 3.3 (95% confidence intervals [1.3-8.4]) and odds ratios for irregular shape was 3.0 (95% confidence intervals [1.0-8.8]), both after adjustment for aneurysm size and location., Conclusions: Aspect ratio≥1.3 and irregular shape are associated with aneurysm rupture independent of aneurysm size and location, and independent of patient characteristics. Additional studies need to assess to what extent these factors increase the risks of rupture of small aneurysms in absolute terms.