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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.

Background: Neurofilament light chain (NfL), a biomarker reflecting neuro-axonal damage, may be useful in improving clinical outcome prediction after aneurysmal subarachnoid hemorrhage (aSAH). We explore the robust and additional value of NfL to neurologic and radiologic grading scales in predicting poor outcome after aSAH., Methods: In this prospective cohort study conducted in a single tertiary center, blood samples were collected of aSAH patients within 24 hours after ictus and before endovascular/surgical intervention. The primary endpoint was poor outcome at 6 months' follow-up. Receiver operating curves (ROC), area under the curve (AUC, 95% CI) and model-fit (Nagelkerke R 2 ) were calculated for NfL, neurologic grading scale (WFNS), modified Fisher, age ,and sex. A combined ROC and AUC were calculated for variables with an AUC ≥ 0.70., Results: A total of 66 (42%) had poor outcome. The AUC of NfL for poor outcome was 0.70 (0.62-0.78). Combining NfL and WFNS resulted in a slightly higher model fit and not-significantly higher AUC for predicting poor outcome (R 2 0.51; AUC 0.86, 0.80-0.92) compared with WFNS alone. When patients were stratified according to hemorrhage severity, median NfL [IQR] levels were significantly higher in poor grade (14 [7-32] pg/mL) than good grade patients (7 [5-14] pg/mL). Within poor grade patients, median NfL [IQR] levels were significantly higher in non-survivors (19 [11-36] pg/mL) than survivors (7 [6-13] pg/mL)., Conclusion: In the entire aSAH cohort, plasma NfL has an acceptable predictive performance but does not improve clinical outcome prediction. However, NfL may have potential value in subgroups based on hemorrhage severity., (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Objectives: The results of the ULTRA trial showed that ultra-early and short-term treatment with tranexamic acid (TXA) does not improve clinical outcome after aneurysmal subarachnoid hemorrhage (aSAH). Possibly, the lack of a beneficial effect in all patients with aSAH is masked by antagonistic effects of TXA in certain subgroups. In this post hoc subgroup analysis, we investigated the effect of TXA on clinical outcome in patients with good-grade and poor-grade aSAH., Methods: The ULTRA trial was a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment. Participants received ultra-early and short-term TXA in addition to usual care or usual care only. This post hoc subgroup analysis included only ULTRA participants with confirmed aSAH and available World Federation of Neurosurgical Societies (WFNS) grade on admission. Patients were categorized into those with good-grade (WFNS 1-3) and poor-grade (WFNS 4-5) aSAH. The primary outcome was clinical outcome assessed by the modified Rankin scale (mRS). Odds ratios (ORs) and adjusted ORs (aORs) with 95% CIs were calculated using ordinal regression analyses. Analyses were performed using the as-treated principle. In all patients with aSAH, no significant effect modification of TXA on clinical outcome was observed for admission WFNS grade ( p = 0.10)., Results: Of the 812 ULTRA participants, 473 patients had (58%; N = 232 TXA, N = 241 usual care) good-grade and 339 (42%; N = 162 TXA, N = 176 usual care) patients had poor-grade aSAH. In patients with good-grade aSAH, the TXA group had worse clinical outcomes (OR: 0.67, 95% CI 0.48-0.94, aOR 0.68, 95% CI 0.48-0.94) compared with the usual care group. In patients with poor-grade aSAH, clinical outcomes were comparable between treatment groups (OR: 1.04, 95% CI 0.70-1.55, aOR 1.05, 95% CI 0.70-1.56)., Discussion: This post hoc subgroup analysis provides another important argument against the use of TXA treatment in patients with aSAH, by showing worse clinical outcomes in patients with good-grade aSAH treated with TXA and no clinical benefit of TXA in patients with poor-grade aSAH, compared with patients treated with usual care., Trial Registration Information: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24, 2013)., Classification of Evidence: This study provides Class II evidence that tranexamic acid, given for <24 hours within the first 24 hours, does not improve the 6-month outcome in good-grade or poor initial-grade aneurysmal SAH.

Background and Objectives: Treatment of patients who present with poor clinical condition is often postponed until neurological improvement is observed. Despite previous studies, it is still unclear how survivors perceive their quality of life (QoL). This study aimed to evaluate self-perceived QoL in patients with aneurysmal subarachnoid hemorrhage who present with poor clinical condition, as defined by World Federation of Neurosurgical Societies (WFNS) grades 4 to 5, compared with those who present in more favorable clinical condition (WFNS 1-3)., Methods: Between 2011 and 2021, 1160 patients with aneurysmal subarachnoid hemorrhage were admitted to the Amsterdam UMC. Among the 845 patients who survived, 537 participated in the QoL questionnaires. Patient characteristics, complications, EQ-5D questionnaires, modified Rankin Scale, and Hospital Anxiety and Depression Scale were analyzed using the nonparametric Mann-Whitney U test for continuous variables or the Pearson χ2 test for categorical variables., Results: Of the 537 responders, 452 (84%) presented with low grade (WFNS 1-3) and 85 (16%) presented with high grade (WFNS 4-5). The high-grade group reported a self-perceived QoL score of 70 (of 100), while the low-grade group reported a score of 75 (P = .12). The mean EQ-5D index value was 0.74 for the high-grade group and 0.81 for the low-grade group (P < .01). In the high-grade group, 61 patients (72%) had a favorable outcome (modified Rankin Scale 0-3) compared with 419 (94%) in the low-grade group (P < .001)., Conclusion: High-grade WFNS patients rated their QoL as satisfactory, with only a marginal 5-point difference on a 100-point scale compared with low-grade WFNS patients. In addition, almost three-quarters of high-grade WFNS survivors achieved a favorable outcome. Given that a subset of patients, despite presenting with a poor clinical condition, still achieve a favorable outcome, these findings reinforce our perspective advocating for early and comprehensive treatment., (Copyright © Congress of Neurological Surgeons 2024. All rights reserved.)

Background: Decompressive neurosurgery is recommended for patients with cerebral venous thrombosis (CVT) who have large parenchymal lesions and impending brain herniation. This recommendation is based on limited evidence. We report long-term outcomes of patients with CVT treated by decompressive neurosurgery in an international cohort., Methods: DECOMPRESS2 (Decompressive Surgery for Patients With Cerebral Venous Thrombosis, Part 2) was a prospective, international cohort study. Consecutive patients with CVT treated by decompressive neurosurgery were evaluated at admission, discharge, 6 months, and 12 months. The primary outcome was death or severe disability (modified Rankin Scale scores, 5-6) at 12 months. The secondary outcomes included patient and caregiver opinions on the benefits of surgery. The association between baseline variables before surgery and the primary outcome was assessed by multivariable logistic regression., Results: A total of 118 patients (80 women; median age, 38 years) were included from 15 centers in 10 countries from December 2011 to December 2019. Surgery (115 craniectomies and 37 hematoma evacuations) was performed within a median of 1 day after diagnosis. At last assessment before surgery, 68 (57.6%) patients were comatose, fixed dilated pupils were found unilaterally in 27 (22.9%) and bilaterally in 9 (7.6%). Twelve-month follow-up data were available for 113 (95.8%) patients. Forty-six (39%) patients were dead or severely disabled (modified Rankin Scale scores, 5-6), of whom 40 (33.9%) patients had died. Forty-two (35.6%) patients were independent (modified Rankin Scale scores, 0-2). Coma (odds ratio, 2.39 [95% CI, 1.03-5.56]) and fixed dilated pupil (odds ratio, 2.22 [95% CI, 0.90-4.92]) were predictors of death or severe disability. Of the survivors, 56 (78.9%) patients and 61 (87.1%) caregivers expressed a positive opinion on surgery., Conclusions: Two-thirds of patients with severe CVT were alive and more than one-third were independent 1 year after decompressive surgery. Among survivors, surgery was judged as worthwhile by 4 out of 5 patients and caregivers. These results support the recommendation to perform decompressive neurosurgery in patients with CVT with impending brain herniation., Competing Interests: Disclosures Dr Coutinho reports grants paid to his institution from Boehringer Ingelheim and Bayer. Dr Uyttenboogaart reports grants from Hartstichting and ZonMw. Dr Werring reports grant funding from the Stroke Association and British Heart Foundation, speaking honoraria from Bayer, speaking and chairing honoraria from Alexion and NovoNordisk, and consultancy fees from Alnylam, Bayer, and NovoNordisk. Dr Aguiar de Sousa reports personal fees for AstraZeneca, Organon, and Johnson & Johnson advisory board participation, travel support from Boehringer Ingelheim, DSMB participation for the SECRET trial (University of British Columbia), and speaking fees from Bayer and Bial. Dr Ferro reports personal fees from Bayer. The other authors report no conflicts.

Objectives: To perform a detailed examination of sodium levels, hyponatremia and sodium fluctuations, and their association with delayed cerebral ischemia (DCI) and poor outcome after aneurysmal subarachnoid hemorrhage (aSAH)., Design: An observational cohort study from a prospective SAH Registry., Setting: Tertiary referral center focused on SAH treatment in the Amsterdam metropolitan area., Patients: A total of 964 adult patients with confirmed aSAH were included between 2011 and 2021., Interventions: None., Measurements and Main Results: A total of 277 (29%) developed DCI. Hyponatremia occurred significantly more often in DCI patients compared with no-DCI patients (77% vs. 48%). Sodium levels, hyponatremia, hypernatremia, and sodium fluctuations did not predict DCI. However, higher sodium levels were significantly associated with poor outcome in DCI patients (DCI onset -7, DCI +0, +1, +2, +4, +5, +8, +9 d), and in no-DCI patients (postbleed day 6-10 and 12-14). Also, hypernatremia and greater sodium fluctuations were significantly associated with poor outcome in both DCI and no-DCI patients., Conclusions: Sodium levels, hyponatremia, and sodium fluctuations were not associated with the occurrence of DCI. However, higher sodium levels, hypernatremia, and greater sodium fluctuations were associated with poor outcome after aSAH irrespective of the presence of DCI. Therefore, sodium levels, even with mild changes in levels, warrant close attention., Competing Interests: Dr. Labib disclosed work for hire. The remaining authors have disclosed that they do not have any potential conflicts of interest., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the Society of Critical Care Medicine and Wolters Kluwer Health, Inc.)

Background and Purpose: Endovascular treatment has been increasingly used for anterior cranial fossa dural AVFs. Evidence on the safety and efficacy of different endovascular treatment strategies is limited. We report clinical and angiographic outcomes of patients with anterior cranial fossa dural AVFs who underwent treatment using transarterial embolization with n- BCA as a first-line approach., Materials and Methods: Consecutive patients undergoing treatment for anterior cranial fossa dural AVFs at the Amsterdam University Medical Centers between 2010 and 2023 were retrospectively included. Transarterial embolization was used as a first-line approach, while transvenous treatment and surgery were used in cases of unsuccessful transarterial embolization. Treatment was evaluated on the basis of the angiographic cure rate, procedural complications, and clinical outcome., Results: Fourteen patients were included with 15 anterior cranial fossa dural AVFs. All patients underwent primary endovascular treatment (12 transarterial, 1 transvenous, and 1 combined). Complete occlusion using only transarterial embolization was reached in 69% of patients (9/13), while the overall complete occlusion by endovascular treatment was reached in 79% of patients (11/14). Navigation and embolization were performed through the ophthalmic artery in 13 patients, with no procedural complications. Visual acuity was preserved in all patients. Three patients underwent an operation after failed endovascular treatment. All patients had complete anterior cranial fossa dural AVF occlusion at follow-up., Conclusions: Treatment of anterior cranial fossa dural AVFs using transarterial embolization with n- BCA as a first-line approach is a safe and feasible first-line treatment strategy. No visual complications due to embolization through the ophthalmic artery occurred in this study., (© 2024 by American Journal of Neuroradiology.)

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.

Background: Hypertension induction (HTI) is often used for treating delayed cerebral ischemia (DCI) following aneurysmal subarachnoid hemorrhage (aSAH); however, high-quality studies on its efficacy are lacking. We studied immediate and 3-/6-month clinical efficacy of HTI in aSAH patients with clinical DCI., Methods: A retrospective, multicenter, comparative, observational cohort study in aSAH patients with clinical deterioration due to DCI, admitted to three tertiary referral hospitals in the Netherlands from 2015 to 2019. Two hospitals used a strategy of HTI (HTI group) and one hospital had no such strategy (control group). We calculated adjusted relative risks (aRR) using Poisson regression analyses for the two primary (clinical improvement of DCI symptoms at days 1 and 5 after DCI onset) and secondary outcomes (DCI-related cerebral infarction, in-hospital mortality, and poor clinical outcome [modified Rankin Scale 4-6] assessed at 3 or 6 months), using the intention-to-treat principle. We also performed as-treated and per-protocol analyses., Results: The aRR for clinical improvement on day 1 after DCI in the HTI group was 1.63 (95% CI 1.17-2.27) and at day 5 after DCI 1.04 (95% CI 0.84-1.29). Secondary outcomes were comparable between the groups. The as-treated and per-protocol analyses yielded similar results., Conclusions: No clinical benefit of HTI is observed 5 days after DCI due to spontaneous reversal of DCI symptoms in patients treated without HTI. The 3-/6-month clinical outcome was similar for both groups. Therefore, these data suggest that one may consider to not apply HTI in aSAH patients with clinical DCI., (© 2023 The Authors. European Journal of Neurology published by John Wiley & Sons Ltd on behalf of European Academy of Neurology.)

Delayed cerebral ischemia (DCI) substantially contributes to disability and death in subarachnoid hemorrhage (SAH) patients; however, its pathophysiology is incompletely understood and diagnostic and therapeutic strategies are lacking. Biomarkers may help to elucidate the pathophysiology, optimize early diagnosis, or provide treatment targets. We systematically searched PubMed and Embase on October 13, 2021, for studies that evaluated at least one laboratory biomarker in patients with DCI, using the most up-to-date definition of DCI as proposed by a panel of experts in 2010. Quality of studies was assessed using the Newcastle-Ottawa Scale or Cochrane Collaboration's risk of bias assessment tool. Biomarkers of clinical and radiological DCI were analyzed separately. Results were meta-analyzed if possible, otherwise narratively reviewed. Biomarkers were classified as significant, inconclusive, or nonsignificant. We defined validated biomarkers as those with significant results in meta-analyses, or in at least two studies using similar methodologies within the same time interval after SAH. The search yielded 209 articles with 724 different biomarkers; 166 studies evaluated 646 biomarkers of clinical DCI, of which 141 were significant and 7 were validated biomarkers (haptoglobulin 2-1 and 2-2, ADAMTS13, vWF, NLR, P-selectin, F2-isoprostane); 78 studies evaluated 165 biomarkers of radiological DCI, of which 63 were significant and 1 was a validated biomarker (LPR). Hence, this review provides a selection of seven biomarkers of clinical DCI and one biomarker of radiological DCI as most promising biomarkers of DCI. Future research should focus on determining the exact predictive, diagnostic, and therapeutic potentials of these biomarkers., Competing Interests: Conflicts of interest: The authors declare no conflicts of interest., (Copyright © 2023, The Authors.)

Background and Objectives: The ULTRA trial showed that ultra-early and short-term tranexamic acid treatment after subarachnoid hemorrhage did not improve clinical outcome at 6 months. An expected proportion of the included patients experienced nonaneurysmal subarachnoid hemorrhage. In this post hoc study, we will investigate whether ultra-early and short-term tranexamic acid treatment in patients with aneurysmal subarachnoid hemorrhage improves clinical outcome at 6 months., Methods: The ULTRA trial is a multicenter, prospective, randomized, controlled, open-label trial with blinded outcome assessment, conducted between July 24, 2013, and January 20, 2020. After confirmation of subarachnoid hemorrhage on noncontrast CT, patients were allocated to either ultra-early and short-term tranexamic acid treatment with usual care or usual care only. In this post hoc analysis, we included all ULTRA participants with a confirmed aneurysm on CT angiography and/or digital subtraction angiography. The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin scale (mRS), dichotomized into good (0-3) and poor (4-6) outcomes., Results: Of the 813 ULTRA trial patients who experienced an aneurysmal subarachnoid hemorrhage, 409 (50%) were assigned to the tranexamic acid group and 404 (50%) to the control group. In the intention-to-treat analysis, 233 of 405 (58%) patients in the tranexamic acid group and 238 of 399 (60%) patients in the control group had a good clinical outcome (adjusted odds ratio [aOR] 0.92; 95% CI 0.69-1.24). None of the secondary outcomes showed significant differences between the treatment groups: excellent clinical outcome (mRS 0-2) (aOR 0.76; 95% CI 0.57-1.03), all-cause mortality at 30 days (aOR 0.91; 95% CI 0.65-1.28), and all-cause mortality at 6 months (aOR 1.10; 95% CI 0.80-1.52)., Discussion: Ultra-early and short-term tranexamic acid treatment did not improve clinical outcomes at 6 months in patients with aneurysmal subarachnoid hemorrhage and therefore cannot be recommended., Trial Registration Information: ClinicalTrials.gov (NCT02684812; submission date February 18, 2016, first patient enrollment on July 24, 2013)., Classification of Evidence: This study provides Class II evidence that tranexamic acid does not improve outcomes in patients presenting with aneurysmal subarachnoid hemorrhage., (© 2022 American Academy of Neurology.)

Introduction and Objective: Blood pressure is presumably related to rebleeding and delayed cerebral ischemia (DCI) after subarachnoid hemorrhage (aSAH) and could serve as a target to improve outcome. We assessed the associations between blood pressure and rebleeding or DCI in aSAH-patients., Materials and Methods: In this observational study in 1167 aSAH-patients admitted to the intensive care unit (ICU), adjusted hazard ratio's (aHR) were calculated for the time-dependent association of blood pressure and rebleeding or DCI. The aHRs were presented graphically, relative to a reference mean arterial pressure (MAP) of 100 mmHg and systolic blood pressure (sBP) of 150 mmHg., Results: A MAP below 100 mmHg in the 6, 3 and 1 h before each moment in time was associated with a decreased risk of rebleeding (e.g. within 6 h preceding rebleeding: MAP = 80 mmHg: aHR 0.30 (95% confidence interval (CI) 0.11-0.80)). A MAP below 60 mmHg in the 24 h before each moment in time was associated with an increased risk of DCI (e.g. MAP = 50 mmHg: aHR 2.59 (95% CI 1.12-5.96))., Conclusions: Our results suggest that a MAP below 100 mmHg is associated with decreased risk of rebleeding, and a MAP below 60 mmHg with increased risk of DCI., Competing Interests: Declaration of Competing Interest, (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Young patients with aneurysmal subarachnoid hemorrhage (aSAH) and a history of migraine may have an increased risk of delayed cerebral ischemia. We investigated this potential association in a prospective cohort of aSAH patients under 50 years of age., Methods: In our prospective cohort study, we included patients with aSAH under 50 years of age from 3 hospitals in the Netherlands. We assessed lifetime migraine history with a short screener. Delayed cerebral ischemia was defined as neurological deterioration lasting >1 hour not attributable to other causes by diagnostic workup. Adjustments were made for possible confounders in multivariable Cox regression analyses, and adjusted hazard ratios were calculated., Results: We included 236 young aSAH patients (mean age, 41 years; 64% women) of whom 44 (19%) had a history of migraine (16 with aura). Patients with aSAH and a history of migraine were not at increased risk of developing delayed cerebral ischemia compared with patients without migraine (25% versus 20%; adjusted hazard ratio, 1.16 [95% CI, 0.57-2.35]). Additionally, no increased risk was found in migraine patients with aura (adjusted hazard ratio, 0.85 [95% CI, 0.30-2.44]) or in women (adjusted hazard ratio, 1.24 [95% CI, 0.58-2.68])., Conclusions: Patients with aSAH under the age of 50 years with a history of migraine are not at increased risk of delayed cerebral ischemia.

Background: Literature is inconclusive regarding the association between antiplatelet agents use and outcome after aneurysmal subarachnoid hemorrhage., Aims: To investigate the association between clinical outcome and prehemorrhage use in aneurysmal subarachnoid hemorrhage patients as well as the impact of thrombocyte transfusion on rebleed and clinical outcome., Methods: Data were collected from prospective databases of two European tertiary reference centers for aneurysmal subarachnoid hemorrhage patients. Patients were divided into "antiplatelet-user" and "non-user" according to the use of acetylsalicylic acid prior to the hemorrhage. Primary outcome was poor clinical outcome at six months (Glasgow Outcome Scale score 1-3). Secondary outcomes were in-hospital mortality and impact of thrombocyte transfusion., Results: Of the 1033 patients, 161 (15.6%) were antiplatelet users. The antiplatelet users were older with higher incidence of cardiovascular risk factors. Antiplatelet use was associated with poor outcome and in-hospital mortality. After correction for age, sex, World Federation of Neurosurgical Societies score, infarction and heart disorder, pre-hemorrhage acetylsalicylic acid use was only associated with poor clinical outcome at six months (adjusted OR 1.80, 95% CI 1.08-3.02). Thrombocyte transfusion was not associated with a reduction in rebleed or poor clinical outcome., Conclusion: In this multicenter study, the prehemorrhage acetylsalicylic acid use in aneurysmal subarachnoid hemorrhage patients was independently associated with poor clinical outcome at six months. Thrombocyte transfusion was not associated with the rebleed rate or poor clinical outcome at six months.

From a pathophysiological point of view, early neurosurgical treatment seems essential to prevent secondary brain injury and has been stated as the "time-is-brain" concept. However, the question immediately rises: "Is there an optimal time window for acute intracranial neurosurgical interventions?" In neurosurgery, treatment modality has been studied far more extensively than timing to surgery ("time-to-surgery"). The majority of acute intracranial neurosurgical interventions are carried out for traumatic brain injury and hemorrhagic or ischemic stroke. Current guidelines for traumatic brain injury, spontaneous intracerebral hemorrhage, aneurysmal subarachnoid hemorrhage, and middle cerebral artery infarction are reviewed and lessons learned from the randomized controlled trials mentioned are discussed. In acute intracranial neurosurgical interventions, "delayed consent" procedures could play an important role for this field of research. Whether there is an optimal time window for acute intracranial neurosurgical interventions seems difficult to be answered with randomized controlled trials referred to in the current guidelines. Observational designs, such as comparative effectiveness research, and special statistical techniques, may provide a better understanding in the optimal "time-to-surgery.", (Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background: Delayed cerebral ischemia (DCI) contributes to poor outcomes after subarachnoid hemorrhage (SAH). The pathophysiology of DCI is not fully understood, which has hindered the adoption of a uniform definition. Furthermore, a reliable diagnostic test and an effective evidence-based treatment are lacking. This could lead to variations in care., Methods: A web-based survey on the variations in the definition, diagnosis, and treatment of DCI was designed and sent to 314 intensivists, neurologists, and neurosurgeons of all 9 hospitals in the Netherlands who care for patients with SAH. The responders were categorized into physicians responsible for the coordination of SAH care and those who were not. For questions on the definition and diagnosis, only the responses from the coordinating physicians were evaluated. For the treatment questions, all the responses were evaluated., Results: The response rate was 34% (106 of 314). All 9 hospitals were represented. Of the responses, 27 did not provide answers for the definition, diagnosis, or treatment questions; 79 responses were used for analysis. Signs of vasospasm were required by 21 of the 47 coordinating physicians (44%) when considering DCI. Of the 47 coordinating physicians, 24 (51%) did not use a diagnostic test results for a positive diagnosis of DCI. When patients were discharged within 21 days, 33 of the 73 responders (45%) did not provide a prescription for nimodipine continuation. Finally, all but one hospital had treated DCI with hypertension induction., Conclusions: We found large variations in the definition, diagnosis, and treatment of DCI in the Netherlands. In the absence of evidence-based treatment, standardization of management seems warranted in an effort to optimize DCI care., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: In some acute care trials, immediate informed consent is not possible, but deferred consent is often considered problematic. We investigated the opinions of patients, proxies, and physicians about deferred consent in an acute stroke trial to gain insight into its acceptability and effects., Methods: Paper-based surveys were sent to patients who were randomly assigned in the Ultra-early Tranexamic Acid After Subarachnoid Hemorrhage (ULTRA) trial between 2015 and 2018 in two tertiary referral centers and to physicians of centers who agreed or declined to participate. The primary outcome measure was the proportion of respondents who agreed with deferral of consent in the ULTRA trial. Secondary outcomes included respondents' preferred consent procedure for the ULTRA trial, the effect of deferred consent on trust in physicians and scientific research, and the willingness to participate in future research., Results: Eighty-nine of 135 (66%) patients or proxies and 20 of 30 (67%) physicians completed the survey. Of these, 82 of 89 (92%) patients or proxies and 14 of 20 (70%) physicians agreed with deferral of consent in the ULTRA trial. When asked for their preferred consent procedure for the ULTRA trial, 31 of 89 (35%) patients or proxies indicated deferred consent, 15 of 89 (17%) preferred immediate informed consent, and 32 of 89 (36%) had no preference. None of the patients' or proxies' trust in physicians or scientific research had decreased because of the deferred consent procedure. Willingness to participate in future studies remained the same or increased in 84 of 89 (94%) patients or proxies., Conclusions: A large majority of the surveyed patients and proxies and a somewhat smaller majority of the surveyed physicians agreed with deferred consent in the ULTRA trial. Deferred consent may enable acute care trials in an acceptable manner without decreasing trust in medicine. Future research should investigate factors facilitating the responsible use of deferred consent, such as in-depth interviews, to study the minority of participants who agreed with deferred consent but still preferred immediate informed consent., (© 2021. The Author(s).)

Purpose: Delayed cerebral ischemia (DCI) remains a contributor to poor outcome following aneurysmal subarachnoid hemorrhage (aSAH). We evaluated cerebral circulation time (CCT) on digital subtraction angiography (DSA) during endovascular treatment (EVT) in WFNS grade I aSAH patients as a predictor of DCI., Methods: Of 135 consecutive WNFS grade I aSAH patients, 90 were included. Age, gender, time of DSA from ictus (< 72 h or > 72 h), Fisher scale, severe vasospasm, development of DCI, EVD-dependent hydrocephalus, re-bleeding, and procedural complications were recorded. CCT was calculated retrospectively from multiphase DSA. Association with DCI was established through univariate and, subsequently, multivariable logistic regression. An optimal threshold value was identified using ROC curve analysis. Patient groups defined by threshold CCT value, DCI, and, subsequently, time of DSA from ictus were analyzed using χ 2 and Fisher's exact test., Results: CCT was the only significant factor in the multivariable logistic regression for the outcome development of DCI (OR/second increase in CCT = 1.46 [95% CI 1.14-1.86, p = .003]). When CCT was dichotomized at 8.5 s, the odds ratio for developing DCI was 7.12 (95% CI 1.93-26.34, p = .003) for CCT > 8.5 s compared with < 8.5 s. There was a significant difference for DCI in all patient groups dichotomized by CCT < 8.5 s and > 8.5 s (all patients, p = .001; patients imaged before and after 72 h of ictus, p = .024 and p = .034, respectively)., Conclusion: A CCT > 8.5 s on DSA during EVT in WFNS grade I aSAH patients is associated with an increased risk of developing DCI and may aid in the management of high-risk patients., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany, part of Springer Nature.)

Objective: In patients presenting within 6 hours after signs and symptoms of suspected subarachnoid hemorrhage (SAH), CSF examination is judged to be no longer necessary if a noncontrast CT (NCCT) scan rules out SAH. In this study, the authors evaluated the performance of NCCT to rule out SAH in patients with positive CSF findings., Methods: Between January 2006 and April 2018, 1657 patients were admitted with a nontraumatic SAH. Of these patients, 1546 had positive SAH findings on the initial NCCT and 111 patients had an NCCT scan that was reported as negative in the acute setting, but with positive CSF examination for subarachnoid blood. Demographic data, World Federation of Neurosurgical Societies grade, and SAH time points (ictus, time of NCCT, and time of lumbar puncture) were collected. All 111 NCCT scans were reevaluated by an experienced neuroradiologist., Results: Of the 111 patients with positive CSF findings, SAH was initially missed on NCCT in 25 patients (23%). Reevaluation of 21 patients presenting within 6 hours of symptom onset confirmed NCCT negative findings in 12 (5 aneurysms), an aneurysmal SAH (aSAH) pattern in 8 (7 aneurysms), and a perimesencephalic pattern in 1 patient. Reevaluation of 90 patients presenting after 6 hours confirmed negative NCCT findings in 74 patients (37 aneurysms), aSAH pattern in 10 (4 aneurysms), and a perimesencephalic pattern in 6 (2 aneurysms)., Conclusions: CSF examination is still mandatory to rule out SAH as NCCT can fail to show blood, even within 6 hours after symptom onset. In addition, the diagnosis SAH was frequently missed during initial reporting.

Background: In patients with aneurysmal subarachnoid haemorrhage, short-term antifibrinolytic therapy with tranexamic acid has been shown to reduce the risk of rebleeding. However, whether this treatment improves clinical outcome is unclear. We investigated whether ultra-early, short-term treatment with tranexamic acid improves clinical outcome at 6 months., Methods: In this multicentre prospective, randomised, controlled, open-label trial with masked outcome assessment, adult patients with spontaneous CT-proven subarachnoid haemorrhage in eight treatment centres and 16 referring hospitals in the Netherlands were randomly assigned to treatment with tranexamic acid in addition to care as usual (tranexamic acid group) or care as usual only (control group). Tranexamic acid was started immediately after diagnosis in the presenting hospital (1 g bolus, followed by continuous infusion of 1 g every 8 h, terminated immediately before aneurysm treatment, or 24 h after start of the medication, whichever came first). The primary endpoint was clinical outcome at 6 months, assessed by the modified Rankin Scale, dichotomised into a good (0-3) or poor (4-6) clinical outcome. Both primary and safety analyses were according to intention to treat. This trial is registered at ClinicalTrials.gov, NCT02684812., Findings: Between July 24, 2013, and July 29, 2019, we enrolled 955 patients; 480 patients were randomly assigned to tranexamic acid and 475 patients to the control group. In the intention-to-treat analysis, good clinical outcome was observed in 287 (60%) of 475 patients in the tranexamic acid group, and 300 (64%) of 470 patients in the control group (treatment centre adjusted odds ratio 0·86, 95% CI 0·66-1·12). Rebleeding after randomisation and before aneurysm treatment occurred in 49 (10%) patients in the tranexamic acid and in 66 (14%) patients in the control group (odds ratio 0·71, 95% CI 0·48-1·04). Other serious adverse events were comparable between groups., Interpretation: In patients with CT-proven subarachnoid haemorrhage, presumably caused by a ruptured aneurysm, ultra-early, short-term tranexamic acid treatment did not improve clinical outcome at 6 months, as measured by the modified Rankin Scale., Funding: Fonds NutsOhra., (Copyright © 2021 Elsevier Ltd. All rights reserved.)

Background and Purpose: Delayed cerebral ischemia (DCI) is a major contributor to the high morbidity in patients with aneurysmal subarachnoid hemorrhage (aSAH). Spreading depolarizations may play a role in DCI pathophysiology. Because patients with migraine are probably more susceptible to spreading depolarizations, we investigated whether patients with aneurysmal subarachnoid hemorrhage with migraine are at increased risk for DCI., Methods: We included patients with aneurysmal subarachnoid hemorrhage from 3 hospitals in the Netherlands. We assessed lifetime migraine history with a short screener. DCI was defined as neurological deterioration lasting >1 hour not attributable to other causes by diagnostic work-up. Adjustments were made for possible confounders in multivariable Cox regression analyses and adjusted hazard ratios (aHR) were calculated. We assessed the interaction effects of age and sex., Results: We included 582 patients (mean age 57 years, 71% women) mostly with mild to moderate aneurysmal subarachnoid hemorrhage of whom 108 (19%) had a history of migraine (57 with aura). Patients with migraine were not at increased risk of developing DCI compared with patients without migraine (22% versus 24%, aHR, 0.89 [95% CI, 0.56-1.43]). Additionally, no increased risk was found in patients with migraine with possible aura (aHR, 0.74 [95% CI, 0.39-1.43]), in women (aHR, 0.88 [95% CI, 0.53-1.45], P interaction =0.859), or in young patients aged <50 years (aHR, 1.59 [95% CI, 0.72-3.49]), although numbers in these subgroups were limited. We found an interaction between migraine and age with an increased risk of DCI among young patients with migraine ( P interaction =0.075)., Conclusions: Patients with migraine are in general not at increased risk of DCI. Future studies should focus in particular on young SAH patients, in whom there might be an association between migraine history and development of DCI.

Objective: To prevent complications following decompressive craniectomy (DC), such as sinking skin flap syndrome, studies suggested early cranioplasty (CP). However, several groups reported higher complication rates in early CP. We studied the clinical characteristics associated with complications in patients undergoing CP, with special emphasis on timing., Methods: A single-center observational cohort study was performed, including all patients undergoing CP from 2006 to 2018, to identify predictors of complications., Results: 145 patients underwent CP: complications occurred in 33 (23%): 18 (12%) epi/subdural hemorrhage, 10 (7%) bone flap infection, 4 (3%) hygroma requiring drainage, and 1 (1%) post-CP hydrocephalus. On univariate analysis, acute subdural hematoma as etiology of DC, symptomatic cerebrospinal fluid (CSF) flow disturbance (hydrocephalus) prior to CP, and CP within three months after DC were associated with higher complication rates. On multivariate analysis, only acute subdural hematoma as etiology of DC (OR 7.5; 95% CI 1.9-29.5) and symptomatic CSF flow disturbance prior to CP (OR 2.9; 95% CI 1.1-7.9) were associated with higher complication rates. CP performed within three months after DC was not (OR 1.4; 95% CI 0.5-3.9). Pre-CP symptomatic CSF flow disturbance was the only variable associated with the occurrence of epi/subdural hemorrhage. (OR 3.8; 95% CI 1.6-9.0) CONCLUSION: Cranioplasty has high complication rates, 23% in our cohort. Contrary to recent systematic reviews, early CP was associated with more complications (41%), explained by the higher incidence of pre-CP CSF flow disturbance and acute subdural hematoma as etiology of DC. CP in such patients should therefore be performed with highest caution.

Background: Based on randomized controlled trials (RCTs), clinical guidelines for the treatment of space-occupying hemispheric infarct employ age (≤60 yr) and time elapsed since stroke onset (≤48 h) as decisive criteria whether to perform decompressive craniectomy (DC). However, only few patients in these RCTs underwent DC after 48 h., Objective: To study the association between the timing of DC and (un)favorable outcome in patients with space-occupying middle cerebral artery (MCA) infarct undergoing DC., Methods: We performed a single-center cohort study from 2007 to 2017. Unfavorable outcome at 1 yr was defined as a Glasgow outcome scale 1 to 3. Additionally, we systematically reviewed the literature up to November 2018, including studies reporting on the timing of DC and other predictors of outcome. We performed Firth penalized likelihood and random-effects meta-analysis with odds ratio (OR) on unfavorable outcome., Results: A total of 66 patients were enrolled. A total of 26 (39%) patients achieved favorable and 40 (61%) unfavorable outcomes (13 [20%] died). DC after 48 h since stroke diagnosis did not significantly increase the risk of unfavorable outcome (OR 0.8, 95% CI 0.3-2.3). Also, in the meta-analysis, DC after 48 h of stroke onset was not associated with a higher risk of unfavorable outcome (OR 1.11; 95% CI 0.89-1.38)., Conclusion: The outcome of DC performed after 48 h in patients with malignant MCA infarct was not worse than the outcome of DC performed within 48 h. Contrary to current guidelines, we, therefore, advocate not to set a restriction of ≤48 h on the time elapsed since stroke onset in the decision whether to perform DC., (Copyright © 2020 by the Congress of Neurological Surgeons.)

Background: Recurrent bleeding from an intracranial aneurysm after subarachnoid hemorrhage (SAH) is associated with unfavorable outcome. Recurrent bleeding before aneurysm occlusion can be performed occurs in up to one in five patients and most often happens within the first 6 h after the primary hemorrhage. Reducing the rate of recurrent bleeding could be a major factor in improving clinical outcome after SAH. Tranexamic acid (TXA) reduces the risk of recurrent bleeding but has thus far not been shown to improve functional outcome, probably because of a higher risk of delayed cerebral ischemia (DCI). To reduce the risk of ultraearly recurrent bleeding, TXA should be administered as soon as possible after diagnosis and before transportation to a tertiary care center. If TXA is administered for a short duration (i.e., < 24 h), it may not increase the risk of DCI. The aim of this paper is to present in detail the statistical analysis plan (SAP) of the ULTRA trial (ULtra-early TRranexamic Acid after Subarachnoid Hemorrhage), which is currently enrolling patients and investigating whether ultraearly and short-term TXA treatment in patients with aneurysmal SAH improves clinical outcome at 6 months., Methods/design: The ULTRA trial is a multicenter, prospective, randomized, open, blinded endpoint, parallel-group trial currently ongoing at 8 tertiary care centers and 16 of their referral centers in the Netherlands. Participants are randomized to standard care or to receive TXA at a loading dose of 1 g, immediately followed by 1 g every 8 h for a maximum of 24 h, in addition to standard care, as soon as SAH is diagnosed. In the TXA group, TXA administration is stopped immediately prior to treatment (coil or clip) of the causative aneurysm. Primary outcome is the modified Rankin Scale (mRS) score at 6 months after SAH, dichotomized into good (mRS 0-3) and poor (mRS 4-6) outcomes, assessed blind to treatment allocation. Secondary outcomes include case fatalities at 30 days and at 6 months and causes of poor clinical outcome. Safety outcomes are recurrent bleeding, DCI, hydrocephalus, per-procedural complications, and other complications such as infections occurring during hospitalization. Data analyses will be according to this prespecified SAP., Trial Registration: Netherlands Trial Register, NTR3272. Registered on 25 January 2012. ClinicalTrials.gov, NCT02684812. Registered on 17 February 2016.

Background: Poor-grade subarachnoid hemorrhage (SAH) has been associated with a high case fatality, either in the acute phase or in the later stages. The exact causes of death in these patients are unknown., Methods: We performed a retrospective study of all consecutive patients with SAH with World Federation of Neurosurgical Societies grade IV or V on admission from 2009 to 2013 at 2 tertiary referral centers in Amsterdam, the Netherlands, and Toronto, Ontario, Canada, who had died during their hospital stay., Results: Of 357 patients, 152 (43%) had died. Of these 152 patients, 87 (24%) had not undergone aneurysm treatment. The median interval to death was 3 days (interquartile range, 1-12 days) after initial hemorrhage. The major cause of death in both centers was withdrawal of life support (107 patients [71%]; 74 of 94 [79%] in Amsterdam and 33 of 58 [58%] in Toronto; P < 0.01), followed by brain death in 23 (15%; 16 of 58 [28%] in Amsterdam vs. 7 of 94 [7%] in Toronto; P < 0.01). The remaining causes of death represented <15%., Conclusions: The decision to withdraw life support was the major reason for death of patients with poor-grade SAH for an overwhelming majority of the patients. The exact reasons for withdrawal of life support, other than cultural and referral differences, were undetermined. Insight into the reasons of death should be prospectively studied to improve the care and clinical outcomes of patients with poor-grade SAH., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Background: The amount of blood detected on brain computed tomography scan is frequently used in prediction models for delayed cerebral ischemia (DCI) in patients with aneurysmal subarachnoid hemorrhage (aSAH). These models, which include coarse grading scales to assess the amount of blood, have only moderate predictive value. Therefore, we aimed to develop a predictive model for DCI including automatically quantified total blood volume (TBV)., Methods: We included patients from a prospective aSAH registry. TBV was assessed with an automatic hemorrhage quantification algorithm. The outcome measure was clinical deterioration due to DCI. Clinical and radiologic variables were included in a logistic regression model. The final model was selected by bootstrapped backward selection and internally validated by assessing the optimism-corrected R 2 value, c-statistic, and calibration plot. The c-statistic of the TBV model was compared with models that used the (modified) Fisher scale instead., Results: We included 369 patients. After backward selection, only TBV was included in the final model. The internally validated R 2 value was 6%, and the c-statistic was 0.64. The c-statistic of the TBV model was higher than both the Fisher scale model (0.56; P < 0.001) and the modified Fisher scale model (0.58; P < 0.05)., Conclusions: In our registry, only TBV independently predicted DCI. TBV discriminated better than the (modified) Fisher scale, but still had only moderate value for predicting DCI. Our findings suggest that other factors need to be identified to achieve better accuracy for predicting DCI., (Copyright © 2019 Elsevier Inc. All rights reserved.)

Objective: Since 2009, we have performed skin augmentation using a Gore-Tex patch as a last-resort measure to reduce intracranial pressure (ICP) in uncontrollable brain swelling during decompressive craniectomy (DC). Here, we report our experience and outcome in a consecutive series of patients undergoing DC with skin augmentation (DC+S)., Methods: In 2009-2015, a prospective database was created registering all patients who underwent DC+S when ICP increased >25 mm Hg while approximating the skin edges after DC (or when closing the skin was impossible because of uncontrollable brain swelling in patients without an ICP monitoring catheter). Patients' baseline characteristics and 1-year outcome were compared with patients undergoing DC without the need of skin augmentation in the same time frame. Outcome according to the Glasgow Outcome Scale (GOS) was dichotomized into favorable (GOS score 4-5) and unfavorable (GOS 1-3)., Results: Of a total of 180 consecutive patients with DC, 20 (11%) underwent DC+S. Four (20%) survived favorably, 2 (10%) unfavorably, and 14 (70%) died (compared with 36%, 22%, and 42%, respectively, in patients with standard DC). Four of 7 patients in whom DC+S was performed ≥24 hours after injury or at second surgery survived favorably, versus none of the 13 patients in whom DC+S was performed <24 hours after injury and at first surgery. Two of 10 patients surviving the first week after DC+S had a skinplasty-related infection., Conclusions: Decompressive craniectomy with skin augmentation may be used as a last-resort measure in cases of severe brain swelling despite DC., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Background: Patients with World Federation of Neurosurgical Societies (WFNS) grade V subarachnoid hemorrhage (SAH) mostly have a poor outcome. Correct identification of patients who might benefit from treatment remains challenging. We investigated which disease-related characteristics, present at admission, could identify patients with chance of good outcome., Methods: In total, 146 consecutive patients with WFNS grade V SAH (2002-2013) were included. Demographic and disease-related characteristics were compared between patients with a good outcome (Glasgow Outcome Scale 4 and 5) and a poor outcome (Glasgow Outcome Scale 1-3). Subgroups were made of patients with aneurysm treatment according to outcome; 1) good outcome; 2) poor outcome, with optimal general treatment; and 3) poor outcome, general treatment discontinued., Results: In total, 34 of the 146 patients had a good outcome (36% of all treated patients); 16 (47%) of these presented with a Glasgow Coma Scale score of 3, versus 65 (58%) of patients with a poor outcome (P = 0.33). Eleven (33%) patients in the good outcome group presented with pupillary abnormalities; 4 (12%) even had bilaterally fixed and dilated pupils, versus 49 (46%) in patients with a poor outcome (P < 0.01). In 51 patients, the aneurysm was not treated; all died., Conclusions: More than one third of all treated patients with WFNS grade V SAH had a good outcome. All patients in whom the aneurysm was not treated died. Reliable identification of patients who will reach good outcome, on the basis of symptoms on admission, seems impossible, as these symptoms are not discriminating enough., (Copyright © 2018 The Author(s). Published by Elsevier Inc. All rights reserved.)

Background and Purpose- Delayed cerebral ischemia (DCI) is an important cause of poor outcome after aneurysmal subarachnoid hemorrhage. If clinical signs of DCI occur, induced hypertension is a plausible but unproven therapeutic intervention. There is clinical equipoise if the use of hypertension induction is useful or not with the consequence that this strategy is irregularly used. We explored the effect of blood pressure augmentation in preventing cerebral infarction in patients with clinical signs of DCI. Methods- We performed a retrospective observational study, totaling 1647 patients with aneurysmal subarachnoid hemorrhage admitted at 3 academic hospitals in the Netherlands between 2006 and 2015. To study the primary outcome DCI related cerebral infarcts, we only included patients with no cerebral infarct at the time of onset of clinical signs of DCI. Cox regression was used to test the association between induced hypertension after onset of clinical signs of DCI and the occurrence of DCI related cerebral infarcts. Logistic regression was used to relate hypertension induction with poor outcome after 3 months, defined as a modified Rankin score >3. Results were adjusted for treatment center and baseline characteristics. Results- Clinical signs of DCI occurred in 479 (29%) patients of whom 300 without cerebral infarction on computed tomography scan at that time. Of these 300 patients, 201 (67%) were treated with hypertension induction and 99 were not. Of the patients treated with hypertension induction, 41 (20%) developed a DCI related cerebral infarct compared with 33 (33%) with no induced hypertension: adjusted hazard ratio, 0.59; 95% CI, 0.35 to 0.99. Hypertension induction also prevented poor outcome: adjusted odds ratio, 0.27; 95% CI, 0.14 to 0.55. Conclusions- Hypertension induction seems an effective strategy for preventing DCI related cerebral infarcts if not already present at the time of onset of clinical signs of DCI. This may lead to a reduction in poor clinical outcome.

Background: Patients with an aneurysmal subarachnoid hemorrhage (aSAH) and World Federation of Neurosurgical Societies (WFNS) grade I on admission are generally considered to have a good clinical outcome., Objective: The objective of this study was to assess the actual clinical outcome of WFNS grade I aSAH patients, and to determine which factors are associated with unfavourable outcome., Methods: For this prospective cohort study, 132 consecutive patients (age 18 years or older) with a WFNS grade I aSAH admitted to our hospital between December 2011 and January 2016 were eligible. Clinical outcome was measured using the modified Rankin Scale (mRS) at 6-month follow-up. Unfavorable outcome was defined as an mRS score of 3-6. Univariable analyses were performed using logistic regression models., Results: Of 116 patients, only 5 patients (4%) had an mRS score of 0 and most (65%) had an mRS score of 2. Twenty-five patients (22%) had an unfavorable outcome. Nine (8%) patients died, of whom 4 died during admission. Factors associated with unfavorable outcome were age (per increasing decade: odds ratio [OR]. 1.78; 95% confidence interval [CI], 1.16-2.72), delayed cerebral ischemia (OR, 4.32; 95% CI, 1.63-11.44), pneumonia (OR, 10.75; 95% CI, 1.94-59.46) and meningitis (OR, 28.47; 95% CI, 1.42-571.15)., Conclusions: Despite their neurologically optimal clinical condition on admission, 1 in 5 patients with WFNS grade I aSAH has an unfavorable clinical outcome or is dead at 6-month follow-up. Additional multivariable analysis in larger patient cohorts is necessary to identify the extent to which preventable complications contribute to unfavorable outcomes in these patients., (Copyright © 2018 Elsevier Inc. All rights reserved.)

Background: Delayed cerebral ischemia (DCI) is one of the major causes of delayed morbidity and mortality in patients with aneurysmal subarachnoid hemorrhage (aSAH)., Objective: To evaluate the effect of high-dose nadroparin treatment following endovascular aneurysm treatment on the occurrence of DCI and clinical outcome., Methods: Medical records of 158 adult patients with an aSAH were retrospectively analyzed. Those patients treated endovascularly for their ruptured aneurysm were included in this study. They received either high-dose (twice daily 5700 AxaIE) or low-dose (once daily 2850 AxaIE) nadroparin treatment after occlusion of the aneurysm. Medical charts were reviewed and imaging was scored by 2 independent neuroradiologists. Data with respect to in-hospital complications, peri-procedural complications, discharge location, and mortality were collected., Results: Ninety-three patients had received high-dose nadroparin, and 65 patients prophylactic low-dose nadroparin. There was no significant difference in clinical DCI occurrence between patients treated with high-dose (34%) and low-dose (31%) nadroparin. More patients were discharged to home in patients who received high-dose nadroparin (40%) compared to low-dose (17%; odds ratio [OR] 3.13, 95% confidence interval [95% CI]: 1.36-7.24). Furthermore, mortality was lower in the high-dose group (5%) compared to the low-dose group (23%; OR 0.19, 95% CI: 0.07-0.55), also after adjusting for neurological status on admission (OR 0.21, 95% CI: 0.07-0.63)., Conclusion: Patients who were treated with high-dose nadroparin after endovascular treatment for aneurysmal SAH were more often discharged to home and showed lower mortality. High-dose nadroparin did not, however, show a decrease in the occurrence of clinical DCI after aSAH. A randomized controlled trial seems warranted.

Purpose: Decompressive craniectomy (DC) has been proposed as lifesaving treatment in aneurysmal subarachnoid haemorrhage (aSAH) patients with elevated intracranial pressure (ICP). However, data is sparse and controversy exists whether the underlying cause of elevated ICP influences neurological outcome. The purpose of this study is to clarify the role of the underlying cause of elevated ICP on outcome after DC., Materials and Methods: We retrospectively studied the one-year neurological outcome in a single-centre cohort to identify predictors of favourable (Glasgow Outcome Scale (GOS) 4-5) and unfavourable (GOS 1-3) outcome. Additionally, available individual patient data in the literature was reviewed with a special emphasis on the underlying reason for DC., Results: From 2006-2015, 53 consecutive aSAH patients underwent DC. Nine (17%) achieved favourable, 44 (83%) unfavourable outcome (31 patients died). One fourth of the patients undergoing DC for hematoma or (hematoma-related) oedema survived favourably (increasing to 46% for patients aged <51 years), versus none of the patients undergoing DC for secondary infarction. Analysis of individual data of 105 literature patients showed a similar trend, although overall outcome was much better: half of the patients undergoing DC for hematoma/oedema regained independence, versus less than one-fourth of patients undergoing DC for secondary infarction., Conclusions: DC in aSAH patients is associated with high rates of unfavourable outcome and mortality, but hematoma or oedema as underlying reason for DC is associated with better outcome profiles compared to secondary infarction. Future observational cohort studies are needed to further explore the different outcome profiles among subpopulations of aSAH patients requiring DC.

Objective: Decompressive craniectomy (DC) has been proposed as a lifesaving treatment in patients with elevated intracranial pressure, but its effectiveness on reaching a favorable neurologic outcome remains unclear. We identified predictors of outcome in a large, single-center cohort of patients undergoing DC for different pathologic conditions., Methods: This retrospective study included all patients undergoing DC from 2006 to 2014. The 1-year outcome, assessed using the Glasgow Outcome Scale (GOS), was dichotomized into favorable (GOS 4-5) and unfavorable (GOS 1-3) outcome. Predictors of outcome were identified by analyzing patient characteristics., Results: DC was performed in 204 patients for ischemic stroke (n = 57), traumatic brain injury (n = 50), aneurysmal subarachnoid hemorrhage (aSAH) (n = 44), intracerebral hemorrhage (ICH) (n = 29), cerebral venous thrombosis (CVT) (n = 14), or other indications (n = 10). Overall, 69 (34%) patients survived favorably, 39 (19%) survived unfavorably, and 96 (47%) died. Higher age, poor Glasgow Coma Scale score, intubated status before DC, bilateral absence of pupillary light reflexes, DC for aSAH, and additional surgeries after DC (excluding cranioplasty) were significant predictors of unfavorable outcome. When patients were sorted for pathologic conditions and predictors of outcome, favorable outcome rates differed remarkably, ranging from 91% for CVT patients undergoing uncomplicated DC to 0% for aSAH patients undergoing DC for secondary infarction or ICH patients with unilateral or bilateral abnormal pupillary light reflexes upon admission., Conclusions: Long-term neurologic outcome after DC differed remarkably among subpopulations of patients, with favorable outcome rates ranging from 0% to >90%., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Objective: We studied the yield of MRI of the spinal neuraxis in patients with nonperimesencephalic subarachnoid hemorrhage (NPSAH)., Methods: In a prospective, multicenter study, we performed T1-weighted and T2-weighted MRI of the spinal axis in a consecutive series of patients with a spontaneous NPSAH without intracranial vascular pathology on intracranial vascular imaging., Results: A spinal origin of the hemorrhage was found in 3 of 75 patients (4%; 95% confidence interval 0-8.4). The lesions were 1 lumbar ependymoma and 2 cervical cavernous malformations. All 3 patients presented without focal neurologic deficits and 2 had a CT-negative subarachnoid hemorrhage but positive lumbar puncture. Patients with a spinal origin were younger than patients without a spinal origin (38 vs 56 years; p < 0.05), which was the only significant difference between groups., Conclusions: The yield and clinical relevance of MRI of the spinal axis in patients who present with NPSAH is low. We do not recommend routine MRI of the spinal axis in this patient population, but it might be justified in a subgroup of patients., (© 2015 American Academy of Neurology.)

In 15 % of all spontaneous subarachnoid hemorrhages (SAH), no intracranial vascular pathology is found. Those non-aneurysmal hemorrhages are categorized into perimesencephalic SAH (PMSAH) and non-perimesencephalic SAH (NPSAH). Searching for spinal pathology might reveal a cause for the hemorrhage in some patients. Our goal was to assess the yield of magnetic resonance (MR) imaging of the complete spinal axis in search for a spinal origin in non-aneurysmal SAH. In a prospective, observational study at a tertiary SAH referral center, we assessed clinical and radiological characteristics of patients who consecutively presented with spontaneous non-aneurysmal SAH, diagnosed by computed tomography (CT) or lumbar puncture, and negative CT angiography and digital subtraction angiography (DSA). Eligible patients were enrolled for investigation of the complete spinal axis by standard T1- and T2-weighted MR-imaging. Ninety-seven non-aneurysmal SAH patients were included in the study. Baseline characteristics were comparable between PMSAH and NPSAH patients. DSA and spinal MR-imaging were performed in 95 and 91 % of patients, respectively. This revealed one lumbar ependymoma in a 43-year-old male who was diagnosed by LP (yield 1 %). No spinal origin for the SAH was found in 51 PMSAH patients. The yield of MR-imaging of the complete spinal axis in spontaneous non-aneurysmal SAH patients is low. Routine radiological investigation of the spinal axis in non-aneurysmal SAH patients is therefore not recommended.

In the management of aneurysmal subarachnoid hemorrhage (aSAH), aneurysm treatment as early as feasible is mandatory to minimize the risk of a rebleed and may thus improve outcome. We assessed the different time intervals from the first symptoms of aSAH to start of aneurysm treatment in an effort to identify which factors contribute mostly to a delay in time to treatment. In 278 aSAH patients, time intervals between the different steps from initial hemorrhage to aneurysm treatment were retrospectively reviewed, and delaying factors were determined. Half of the patients presented to a hospital within 115 min (IQR 60-431). The median (IQR) interval from hemorrhage to diagnosis was 169 min (96-513), and from diagnosis to treatment 1,057 min (416-1,428), or 17.6 h. Aneurysm treatment started within 24 h in 76 % of treated patients. Independent factors predicting delay to treatment were primary presentation at a referring hospital and admission to the treatment center later in the day. Delay in treatment was not independently related to poor outcome. The interval to aneurysm treatment might be improved upon by immediate and direct transport to the treatment center combined with optimization of in-hospital logistics, following the 'time-is-brain' concept so successfully adopted in the treatment of ischemic stroke.

Background: A frequent complication in patients with subarachnoid hemorrhage (SAH) is recurrent bleeding from the aneurysm. The risk is highest within the first 6 hours after the initial hemorrhage. Securing the aneurysm within this timeframe is difficult owing to logistical delays. The rate of recurrent bleeding can also be reduced by ultra-early administration of antifibrinolytics, which probably improves functional outcome. The aim of this study is to investigate whether ultra-early and short-term administration of the antifibrinolytic agent tranexamic acid (TXA), as add-on to standard SAH management, leads to better functional outcome., Methods/design: This is a multicenter, prospective, randomized, open-label trial with blinded endpoint (PROBE) assessment. Adult patients with the diagnosis of non-traumatic SAH, as proven by computed tomography (CT) within 24 hours after the onset of headache, will be randomly assigned to the treatment group or the control group. Patients in the treatment group will receive standard treatment with the addition of a bolus of TXA (1 g intravenously) immediately after randomization, followed by continuous infusion of 1 g per 8 hours until the start of aneurysm treatment, or a maximum of 24 hours after the start of medication. Patients in the control group will receive standard treatment without TXA. The primary outcome measure is favorable functional outcome, defined as a score of 0 to 3 on the modified Rankin Scale (mRS), at 6 months after SAH. Primary outcome will be determined by a trial nurse blinded for treatment allocation. We aim to include 950 patients in 3 years., Discussion: The strengths of this study are: 1. the ultra-early and short-term administration of TXA, resulting in a lower dose as compared to previous studies, which should reduce the risk for delayed cerebral ischemia (DCI), an important risk factor in the long-term treatment with antifibrinolytics; 2. the power calculation is based on functional outcome and calculated with use of recent study results of our own population, supported by data from prominent studies; and 3. the participation of several specialized SAH centers, and their referring hospitals, in the Netherlands with comparative treatment protocols., Trial Registration: Nederlands Trial Register (Dutch Trial Registry) number NTR3272.

Small retrospective case series suggest that decompressive hemicraniectomy can be life saving in patients with cerebral venous thrombosis (CVT) and impending brain herniation. Prospective studies of consecutive cases are lacking. Thus, a single centre, prospective study was performed. In 2006 we adapted our protocol for CVT treatment to perform acute decompressive hemicraniectomy in patients with impending herniation, in whom the prognosis with conservative treatment was considered infaust. We included all consecutive patients with CVT between 2006 and 2010 who underwent hemicraniectomy. Outcome was assessed at 12 months with the modified Rankin Scale (mRS). Ten patients (8 women) with a median age of 41 years (range 26-52 years) were included. Before surgery 5 patients had GCS < 9, 9 patients had normal pupils, 1 patient had a unilaterally fixed and dilated pupil. All patients except one had space-occupying intracranial hemorrhagic infarcts. The median preoperative midline shift was 9 mm (range 3-14 mm). Unilateral hemicraniectomy was performed in 9 patients and bilateral hemicraniectomy in one. Two patients died from progressive cerebral edema and expansion of the hemorrhagic infarcts. Five patients recovered without disability at 12 months (mRS 0-1). Two patients had some residual handicap (one minor, mRS 2; one moderate, mRS 3). One patient was severely handicapped (mRS 5). Our prospective data show that decompressive hemicraniectomy in the most severe cases of cerebral venous thrombosis was probably life saving in 8/10 patients, with a good clinical outcome in six. In 2 patients death was caused by enlarging hemorrhagic infarcts.

Recently, two randomized controlled phase II studies showed that acute initiation of statin treatment directly after aneurysmal subarachnoid hemorrhage (SAH) decreases the incidence of radiologic vasospasm and clinical signs of delayed cerebral ischemia (DCI), and even reduces mortality. It was hypothesized that the beneficial effect resulted from pleiotropic effects of statins. The purpose of this study was to investigate the biologic effects of acute statin treatment in patients with SAH. We performed an exploratory single-center, prospective, randomized, double-blind, placebo-controlled trial. Patients were randomized to simvastatin 80 mg or placebo once daily. A total of 32 patients were included. There were no statistically significant differences in clinical baseline characteristics. With regard to primary outcomes, there were significant differences by treatment group for total cholesterol and low-density lipoprotein (LDL) cholesterol (P<0.0001), but not for parameters of coagulation, fibrinolysis, endothelium function, and inflammation. With regard to secondary outcomes, no differences were observed in the incidence of transcranial Doppler vasospasm, clinical signs of DCI, and poor outcome. We conclude that both the primary and secondary outcome results of this study do not support a beneficial effect of simvastatin in patients with SAH.

Patients with aneurysmal subarachnoid hemorrhage (SAH) who experience delayed cerebral ischemia (DCI) have an increased risk of poor outcome. Delayed cerebral ischemia is considered to be caused by vasospasm. However, not all patients with DCI have vasospasm. Inversely, not all patients with vasospasm develop clinical symptoms and signs of DCI. In the past, treatments aiming at vasospasm were not successful in preventing ischemia. The purpose of this review is to give an overview of clinical data showing that DCI cannot always be attributed to vasospasm, and to present an in-depth analysis of clinical and autopsy studies on the role of microthrombosis in the pathogenesis of DCI. Clinical studies show that DCI is associated with an activation of the coagulation cascade within a few days after SAH, preceding the time window during which vasospasm occurs. Furthermore, impaired fibrinolytic activity, and inflammatory and endothelium-related processes, lead to the formation of microthrombi, which ultimately result in DCI. The presence of microthrombi is confirmed by autopsy studies. Insight in the pathophysiology of DCI is crucial for the development of effective therapies against this complication. Because multiple pathways are involved, future research should focus on drugs with pleiotropic effects.

Object: Patients with fusiform aneurysms can present with subarachnoid hemorrhage (SAH), mass effect, ischemia, or unrelated symptoms. The absence of an aneurysm neck impedes the direct application of a clip and endovascular coil deployment. To evaluate the effects of their treatments, the authors retrospectively analyzed a consecutive series of patients with posterior circulation fusiform aneurysms treated at Stanford University Medical Center between 1991 and 2005., Methods: Forty-nine patients (mean age 53 years, male/female ratio 1.2:1) treated at the authors' medical center form the basis of the analysis. Twenty-nine patients presented with an SAH. The patients presenting without SAH had cranial nerve dysfunction (five patients), symptoms of mass effect (eight patients), ischemia (six patients), or unrelated symptoms (one patient). The aneurysms were located on the vertebral artery (VA) or posterior inferior cerebellar artery (PICA) (21 patients); vertebrobasilar junction (VBJ) or basilar artery (BA) (18 patients); and posterior cerebral artery (PCA) (10 patients). Pretreatment clinical grades were determined using the Hunt and Hess scale; for patients with unruptured aneurysms (Hunt and Hess Grade 0) functional subgrades were added. Outcome was evaluated using the Glasgow Outcome Scale (GOS) score during a mean follow-up period of 33 months. Overall long-term outcome was good (GOS Score 4 or 5) in 59%, poor (GOS Score 2 or 3) in 16%, and fatal (GOS Score 1) in 24% of the patients. In a univariate analysis, poor outcome was predicted by age greater than 55 years, VBJ location, pretreatment Hunt and Hess grade in patients presenting with SAH, and incomplete aneurysm thrombosis after endovascular treatment. In a multivariate analysis, age greater than 55 years was the confounding factor predicting poor outcome. Stratification by aneurysm location removed the effect of age. Of 13 patients with residual aneurysm after treatment, five (38%) subsequently died of SAH (three patients) or progressive mass effect/brainstem ischemia (two patients)., Conclusions: Certain posterior circulation aneurysm locations (PCA, VA-PICA, and BA-VBJ) represent separate disease entities affecting patients at different ages with distinct patterns of presentation, treatment options, and outcomes. Favorable overall long-term outcome can be achieved in 90% of patients with PCA aneurysms, in 60% of those with VA-PICA aneurysms, and in 39% of those with BA-VBJ aneurysms when using endovascular and surgical techniques. The natural history of the disease was poor in patients with incomplete aneurysm thrombosis after treatment.

The primary objective of revascularization procedures in the posterior circulation is the prevention of vertebrobasilar ischemic stroke. Specific anatomical and neurophysiologic characteristics such as posterior communicating artery size affect the susceptibility to ischemia. Current indications for revascularization include symptomatic vertebrobasilar ischemia refractory to medical therapy and ischemia caused by parent vessel occlusion as treatment for complex aneurysms. Treatment options include endovascular angioplasty and stenting, surgical endarterectomy, arterial reimplantation, extracranial-to-intracranial anastomosis, and indirect bypasses. Pretreatment studies including cerebral blood flow measurements with assessment of hemodynamic reserve can affect treatment decisions. Careful blood pressure regulation, neurophysiologic monitoring, and neuroprotective measures such as mild brain hypothermia can help minimize the risks of intervention. Microscope, microinstruments and intraoperative Doppler are routinely used. The superficial temporal artery, occipital artery, and external carotid artery can be used to augment blood flow to the superior cerebellar artery, posterior cerebral artery, posterior inferior cerebellar artery, or anterior inferior cerebellar artery. Interposition venous or arterial grafts can be used to increase length. Several published series report improvement or relief of symptoms in 60 to 100% of patients with a reduction of risk of future stroke and low complication rates.