Devastating delayed cerebral ischemia after aneurysmal subarachnoid hemorrhage

BACKGROUND: We investigated the proportion of patients in an initial good clinical condition who developed devastating DCI, and aimed to characterize these patients by aneurysm location, blood pressure instability prior to DCI, and the extent of cerebral ischemia. METHODS: We included aSAH patients admitted between 2010 and 2021 with a Glasgow Coma Scale of 11 or higher 24 h after aneurysm treatment, who developed devastating DCI, defined as DCI leading to coma for at least 48 h with cerebral infarction on the subsequent scan. Blood pressure instability was defined as nimodipine-induced blood pressure drops, dosage adjustments, or the use of blood pressure drugs before onset of DCI. Descriptive statistics were used to summarize the data. RESULTS: Out of 1,211 consecutive aSAH patients, 617 patients had a good clinical condition after aneurysm treatment of whom 16 (3%) patients [14 (88%) women] were included in this study. Thirteen (81%) patients had an aneurysm in the anterior circulation. Thirteen patients (81%) had blood pressure instability: twelve (75%) had nimodipine-induced blood pressure drops, eleven (69%) received antihypertensive drugs, and 7 (44%) received hypertension induction before onset of DCI. Thirteen (81%) patients had bilateral ischemia, mainly in the anterior circulation (56%). CONCLUSIONS: The proportion of aSAH patients with a good clinical condition after aneurysm treatment who develop devastating DCI is small. The vast majority of these patients had blood pressure instability. Future studies are needed to investigate if a reduction in the number and extent of blood pressure fluctuations decreases the incidence of devastating DCI

Management decisions on unruptured intracranial aneurysms before and after implementation of the PHASES score

Background: In management decisions on saccular unruptured intracranial aneurysms (UIAs) the risk of rupture is an important factor. The PHASES score, introduced in 2014, provides absolute 5-year risks of rupture based on six easily retrievable patient and aneurysm characteristics. We assessed whether management decisions on UIAs changed after implementation of the PHASES score. Patient and methods: We included all patients with UIAs who were referred to two Dutch tertiary referral centers for aneurysm care in the Netherlands (University Medical Center Utrecht (UMCU) and Leiden University Medical Center (LUMC)) between 2011 and 2017. Analyses were done on an aneurysm level. We calculated the overall proportion of UIAs with a decision to treat before and after PHASES implementation and studied the influence of age and center on post-implementation management changes. Results: We included 623 patients with 803 UIAs. The proportion of UIAs with a decision to treat was 123/360 (34.2%) before and 117/443 (26.4%) after PHASES implementation (absolute risk difference: −7.8%; 95% CI: −14.1 to −1.4). The decision to treat was made at a higher median PHASES score after implementation (7 points (IQR 5;10) pre- versus 8 points (IQR 5;10) post-implementation; p = 0.14). The reduced proportion with a treatment decision after implementation was most pronounced in patients <50 years (−22.3%; 95% CI: −39.2 to −3.4) and was restricted to treatment decisions made at the UMCU (−10.6%; 95% CI: −18.5 to −2.5). Discussion and conclusions: Management of UIAs changed following implementation of the PHASES score, but the impact of PHASES implementation on treatment decisions differed across age subgroups and centers

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

Scanxiety and quality of life around follow-up imaging in patients with unruptured intracranial aneurysms: a prospective cohort study

Objectives: Patients with an unruptured intracranial aneurysm (UIA) may experience scanxiety around follow-up imaging. We studied the prevalence and temporal pattern of scanxiety, and compared quality of life (QoL) outcomes in patients with and without scanxiety. Methods: We performed a prospective cohort study in a tertiary referral center in the Netherlands between October 2021 and November 2022. We sent questionnaires to patients ≥ 18 years old undergoing UIA follow-up imaging 4 weeks before (T1), immediately after (T2), and 6 weeks after the scan (T3) to assess health-related QoL (HRQoL) and emotional functioning. At T3, we also assessed scanxiety with a purpose-designed questionnaire. We compared differences in QoL outcomes between respondents with and without scanxiety using mixed models. Results: Of 158 eligible patients, 106 (67%) participated (mean age 61 years ± 11 [standard deviation], 84 women). Sixty of the 91 respondents (66%) who completed the purpose-designed questionnaire experienced scanxiety. Of the 49 respondents who experienced scanxiety after the scan, it resolved in 22 (45%) within a day after receiving the radiology report. HRQoL did not differ between respondents with or without scanxiety. Emotional functioning was worse for respondents with scanxiety (mean Hospital Anxiety and Depression Scale sum score difference at T1, 3.6 [95% CI, 0.9–6.3]; T2, 4.1 [95% CI, 1.5–6.8]; and T3, 4.0 [95% CI, 1.5–6.5]). Conclusions: Two-thirds of the respondents experienced scanxiety around follow-up imaging, which often resolved within a day after receiving results. Patients with scanxiety had similar HRQoL but worse emotional functioning compared to patients without scanxiety. The time between the scan and receiving the results should be minimized to decrease the duration of scanxiety. Clinical relevance statement: We showed that scanxiety is common in UIA patients, and negatively associated with emotional functioning. Since scanxiety often disappears immediately after receiving the radiology report, it should be communicated to the patient as early as possible to alleviate patients’ distress. Key Points: • Many patients with an unruptured intracranial aneurysm experience emotional distress around follow-up imaging, termed “scanxiety.” • Patients with scanxiety had worse emotional functioning compared to patients without scanxiety. • Scanxiety often resolved within a day after receiving the radiology report

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

Complement C5 contributes to brain injury after subarachnoid hemorrhage

Previous studies showed that complement activation is associated with poor functional outcome after aneurysmal subarachnoid hemorrhage (SAH). We investigated whether complement activation is underlying brain injury after aneurysmal SAH (n = 7) and if it is an appropriate treatment target. We investigated complement expression in brain tissue of aneurysmal SAH patients (n = 930) and studied the role of common genetic variants in C3 and C5 genes in outcome. We analyzed plasma levels (n = 229) to identify the functionality of a single nucleotide polymorphism (SNP) associated with outcome. The time course of C5a levels was measured in plasma (n = 31) and CSF (n = 10). In an SAH mouse model, we studied the extent of microglia activation and cell death in wild-type mice, mice lacking the C5a receptor, and in mice treated with C5-specific antibodies (n = 15 per group). Brain sections from aneurysmal SAH patients showed increased presence of complement components C1q and C3/C3b/iC3B compared to controls. The complement component 5 (C5) SNP correlated with C5a plasma levels and poor disease outcome. Serial measurements in CSF revealed that C5a was > 1400-fold increased 1 day after aneurysmal SAH and then gradually decreased. C5a in plasma was 2-fold increased at days 3–10 after aneurysmal SAH. In the SAH mouse model, we observed a ≈ 40% reduction in both microglia activation and cell death in mice lacking the C5a receptor, and in mice treated with C5-specific antibodies. These data show that C5 contributes to brain injury after experimental SAH, and support further study of C5-specific antibodies as novel treatment option to reduce brain injury and improve prognosis after aneurysmal SAH

Glial cell response and microthrombosis in aneurysmal subarachnoid hemorrhage patients: An autopsy study

Neuroinflammation and microthrombosis may be underlying mechanisms of brain injury after aneurysmal subarachnoid hemorrhage (aSAH), but they have not been studied in relation to each other. In postmortem brain tissue, we investigated neuroinflammation by studying the microglial and astrocyte response in the frontal cortex of 11 aSAH and 10 control patients. In a second study, we investigated the correlation between microthrombosis and microglia by studying the microglial surface area around vessels with and without microthrombosis in the frontal cortex and hippocampus of 8 other aSAH patients. In comparison with controls, we found increased numbers of microglia (mean ± SEM 50 ± 8 vs 20 ± 5 per 0.0026 mm3, p < 0.01), an increased surface area (%) of microglia (mean ± SEM 4.2 ± 0.6 vs 2.2 ± 0.4, p < 0.05), a higher intensity of the astrocytic intermediate filament protein glial fibrillary acidic protein (GFAP) (mean ± SEM 184 ± 28 vs 92 ± 23 arbitrary units, p < 0.05), and an increased GFAP surface area (%) (mean ± SEM 21.2 ± 2.6 vs 10.7 ± 2.1, p < 0.01) in aSAH tissue. Microglia surface area was approximately 40% larger around vessels with microthrombosis than those without microthrombosis (estimated marginal means [95% CI]; 6.1 [5.4-6.9] vs 4.3 [3.6-5.0], p < 0.001). Our results show that the microglial and astrocyte surface areas increased after aSAH and that microthrombosis and microglia are interrelated

Outcomes Associated With Intracranial Aneurysm Treatments Reported as Safe, Effective, or Durable:A Systematic Review and Meta-Analysis

Importance: Testing new medical devices or procedures in terms of safety, effectiveness, and durability should follow the strictest methodological rigor before implementation. Objectives: To review and analyze studies investigating devices and procedures used in intracranial aneurysm (IA) treatment for methods and completeness of reporting and to compare the results of studies with positive, uncertain, and negative conclusions. Data Sources: Embase, MEDLINE, Web of Science, and The Cochrane Central Register of Clinical Trials were searched for studies on IA treatment published between January 1, 1995, and the October 1, 2022. Grey literature was retrieved from Google Scholar. Study Selection: All studies making any kind of claims of safety, effectiveness, or durability in the field of IA treatment were included. Data Extraction and Synthesis: Using a predefined data dictionary and analysis plan, variables ranging from patient and aneurysm characteristics to the results of treatment were extracted, as were details pertaining to study methods and completeness of reporting. Extraction was performed by 10 independent reviewers. A blinded academic neuro-linguist without involvement in IA research evaluated the conclusion of each study as either positive, uncertain, or negative. The study followed Preferring Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Main Outcomes and Measures: The incidence of domain-specific outcomes between studies with positive, uncertain, or negative conclusions regarding safety, effectiveness, or durability were compared. The number of studies that provided a definition of safety, effectiveness, or durability and the incidence of incomplete reporting of domain-specific outcomes were evaluated.Results: Overall, 12 954 studies were screened, and 1356 studies were included, comprising a total of 410 993 treated patients. There was no difference in the proportion of patients with poor outcome or in-hospital mortality between studies claiming a technique was safe, uncertain, or not safe. Similarly, there was no difference in the proportion of IAs completely occluded at last follow-up between studies claiming a technique was effective, uncertain, or noneffective. Less than 2% of studies provided any definition of safety, effectiveness, or durability, and only 1 of the 1356 studies provided a threshold under which the technique would be considered unsafe. Incomplete reporting was found in 546 reports (40%).Conclusions and Relevance: In this systematic review and meta-analysis of IA treatment literature, studies claiming safety, effectiveness, or durability of IA treatment had methodological flaws and incomplete reporting of relevant outcomes supporting these claims.</p

International practice variability in treatment of aneurysmal subarachnoid hemorrhage

Prior research suggests substantial between-center differences in functional outcome following aneurysmal subarachnoid hemorrhage (aSAH). One hypothesis is that these differences are due to practice variability. To characterize practice variability, we sent a survey to 230 centers, of which 145 (63%) responded. Survey respondents indicated that an estimated 65% of ruptured aneurysms were treated endovascularly. Sixty-five percent of aneurysms were treated within 24 h of symptom onset, 18% within 24–48 h, and eight percent within 48–72 h. Centers in the United States (US) and Europe (EU) treat aneurysms more often endovascularly (72% and 70% vs. 51%, respectively, US vs. other p < 0.001, and EU vs. other p < 0.01) and more often within 24 h (77% and 64% vs. 46%, respectively, US vs. other p < 0.001, EU vs. other p < 0.01) compared to other centers. Most centers aim for euvolemia (96%) by administrating intravenous fluids to 0 (53%) or +500 mL/day (41%) net fluid balance. Induced hypertension is more often used in US centers (100%) than in EU (87%, p < 0.05) and other centers (81%, p < 0.05), and endovascular therapies for cerebral vasospasm are used more often in US centers than in other centers (91% and 60%, respectively, p < 0.05). We observed significant practice variability in aSAH treatment worldwide. Future comparative effectiveness research studies are needed to investigate how practice variation leads to differences in functional outcome

Outcomes Associated With Intracranial Aneurysm Treatments Reported as Safe, Effective, or Durable: A Systematic Review and Meta-Analysis

Importance: Testing new medical devices or procedures in terms of safety, effectiveness, and durability should follow the strictest methodological rigor before implementation. Objectives: To review and analyze studies investigating devices and procedures used in intracranial aneurysm (IA) treatment for methods and completeness of reporting and to compare the results of studies with positive, uncertain, and negative conclusions. Data Sources: Embase, MEDLINE, Web of Science, and The Cochrane Central Register of Clinical Trials were searched for studies on IA treatment published between January 1, 1995, and the October 1, 2022. Grey literature was retrieved from Google Scholar. Study Selection: All studies making any kind of claims of safety, effectiveness, or durability in the field of IA treatment were included. Data Extraction and Synthesis: Using a predefined data dictionary and analysis plan, variables ranging from patient and aneurysm characteristics to the results of treatment were extracted, as were details pertaining to study methods and completeness of reporting. Extraction was performed by 10 independent reviewers. A blinded academic neuro-linguist without involvement in IA research evaluated the conclusion of each study as either positive, uncertain, or negative. The study followed Preferring Reporting Items for Systematic Reviews and Meta-Analyses guidelines. Main Outcomes and Measures: The incidence of domain-specific outcomes between studies with positive, uncertain, or negative conclusions regarding safety, effectiveness, or durability were compared. The number of studies that provided a definition of safety, effectiveness, or durability and the incidence of incomplete reporting of domain-specific outcomes were evaluated. Results: Overall, 12 954 studies were screened, and 1356 studies were included, comprising a total of 410 993 treated patients. There was no difference in the proportion of patients with poor outcome or in-hospital mortality between studies claiming a technique was safe, uncertain, or not safe. Similarly, there was no difference in the proportion of IAs completely occluded at last follow-up between studies claiming a technique was effective, uncertain, or noneffective. Less than 2% of studies provided any definition of safety, effectiveness, or durability, and only 1 of the 1356 studies provided a threshold under which the technique would be considered unsafe. Incomplete reporting was found in 546 reports (40%). Conclusions and Relevance: In this systematic review and meta-analysis of IA treatment literature, studies claiming safety, effectiveness, or durability of IA treatment had methodological flaws and incomplete reporting of relevant outcomes supporting these claims