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Large-scale imaging of brain activity with high spatio-temporal resolution is crucial for advancing our understanding of brain function. The existing neuroimaging techniques are largely limited by restricted field of view, slow imaging speed, or otherwise do not have the adequate spatial resolution to capture brain activities on a capillary and cellular level. To address these limitations, we introduce fluorescence localization microscopy aided with sparsely-labeled red blood cells for cortex-wide morphological and functional cerebral angiography with 4.9 µm spatial resolution and 1 s temporal resolution. When combined with fluorescence calcium imaging, the proposed method enables extended recordings of stimulus-evoked neuro-vascular changes in the murine brain while providing simultaneous multiparametric readings of intracellular neuronal activity, blood flow velocity/direction/volume, and vessel diameter. Owing to its simplicity and versatility, the proposed approach will become an invaluable tool for deciphering the regulation of cortical microcirculation and neurovascular coupling in health and disease., (© 2024. The Author(s).)

Background: Impaired cerebrovascular reactivity (CVR) has been correlated with recurrent ischemic stroke. However, for clinical purposes, most CVR techniques are rather complex, time-consuming, and lack validation for quantitative measurements. The recent adaptation of a standardized hypercapnic stimulus in combination with a blood-oxygenation-level-dependent (BOLD) magnetic resonance imaging signal as a surrogate for cerebral blood flow offers a potential universally comparable CVR assessment. We investigated the association between impaired BOLD-CVR and risk for recurrent ischemic events., Methods: We conducted a retrospective analysis of patients with symptomatic cerebrovascular large vessel disease who had undergone a prospective hypercapnic-challenged BOLD-CVR protocol at a single tertiary stroke referral center between June 2014 and April 2020. These patients were followed up for recurrent acute ischemic events for up to 3 years. BOLD-CVR (%BOLD signal change per mm Hg CO 2 ) was calculated on a voxel-by-voxel basis. Impaired BOLD-CVR of the affected (ipsilateral to the vascular pathology) hemisphere was defined as an average BOLD-CVR, falling 2 SD below the mean BOLD-CVR of the right hemisphere in a healthy age-matched reference cohort (n=20). Using a multivariate Cox proportional hazards model, the association between impaired BOLD-CVR and ischemic stroke recurrence was assessed and Kaplan-Meier survival curves to visualize the acute ischemic stroke event rate., Results: Of 130 eligible patients, 28 experienced recurrent strokes (median, 85 days, interquartile range, 5-166 days). Risk factors associated with an increased recurrent stroke rate included impaired BOLD-CVR, a history of atrial fibrillation, and heart insufficiency. After adjusting for sex, age group, and atrial fibrillation, impaired BOLD-CVR exhibited a hazard ratio of 10.73 (95% CI, 4.14-27.81; P <0.001) for recurrent ischemic stroke., Conclusions: Among patients with symptomatic cerebrovascular large vessel disease, those exhibiting impaired BOLD-CVR in the affected hemisphere had a 10.7-fold higher risk of recurrent ischemic stroke events compared with individuals with nonimpaired BOLD-CVR., Competing Interests: Disclosures The device used in this study was developed by Thornhill Medical, Inc (TMI) a for-profit spin-off from the University Health Network, University of Toronto, to enable cerebrovascular reactivity studies. It is not a commercial product and is made available to academic centers for certified research under ethics board approval. Drs Fisher and Mikulis are appointees at the University of Toronto and employees of, and own shares in, TMI. Dr Katant is a consultant for AstraZeneca and Brahms GmbH, and receives funding from Bayer Healthcare, both of which are not related to the current article. Currently, Dr Katant has a dual appointment at the University Hospital of Zürich and the University Hospital Basel. Dr Wegener receives funding through the following institutes: Baugarten Stiftung, the Betty and David Koetser Foundation, Hartmann Müller-Stiftung für Medizinische Forschung, and the Swiss National Science Foundation and is the co-applicant of the UZH CRPP Stroke of the University Hospital of Zürich. Dr Luft is a consultant for Amgen, Boehringer Ingelheim, and Moleac Ltd. Dr Kulcsár is a consultant for Johnson and Johnson International, Medtronic, and Stryker. The other authors report no conflicts.

Background: This study aimed to assess if there are sex differences in the functional outcome of intravenous thrombolysis (IVT) among patients with lacunar stroke (LS)., Methods: Consecutive patients admitted from 1 January 2014 to 31 January 2020 to hospitals participating in the Swiss Stroke Registry presenting with LS and treated with IVT were included. The study population was then divided into two groups based on patient sex, and a multivariable ordinal logistic regression analysis was performed to uncover sex differences in the modified Rankin Scale (mRS) score at 90 days after stroke., Results: A total of 413 patients with LS were treated with IVT: 177 (42.9%) women and 236 (57.1%) men. Women were older than men (median age 74 years, 25th-75th percentiles 67-84 years versus 70 years, 25th-75th percentiles 60-80 years, value of p 0.001) and, after adjustment for meaningful variables, showed more frequently increased odds of a higher mRS score at 90 days after stroke (adjusted odds ratio 1.49, 95% confidence interval 1.01-2.19, value of p 0.044)., Conclusion: This study showed that female sex increased the odds of a worse functional response to IVT in patients with LS. Future studies should further elucidate the mechanisms underlying such sex differences., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2024 Wueger, Noseda, Pagnamenta, Bianco, Seiffge, Michel, Nedeltchev, Bonati, Kägi, Niederhauser, Nyffeler, Luft, Wegener, Schelosky, Medlin, Rodic, Peters, Renaud, Mono, Carrera, Fischer, De Marchis and Cereda.)

Background: We investigated outcomes in patients with intracerebral haemorrhage (ICH) according to prior anticoagulation treatment with Vitamin K antagonists (VKAs), direct oral anticoagulants (DOACs) or no anticoagulation., Methods: This is an individual patient data study combining two prospective national stroke registries from Switzerland and Norway (2013-2019). We included all consecutive patients with ICH from both registries. The main outcomes were favourable functional outcome (modified Rankin Scale 0-2) and mortality at 3 months., Results: Among 11 349 patients with ICH (mean age 73.6 years; 47.6% women), 1491 (13.1%) were taking VKAs and 1205 (10.6%) DOACs (95.2% factor Xa inhibitors). The median percentage of patients on prior anticoagulation was 23.7 (IQR 22.6-25.1) with VKAs decreasing (from 18.3% to 7.6%) and DOACs increasing (from 3.0% to 18.0%) over time. Prior VKA therapy (n=209 (22.3%); adjusted ORs (aOR), 0.64; 95% CI, 0.49 to 0.84) and prior DOAC therapy (n=184 (25.7%); aOR, 0.64; 95% CI, 0.47 to 0.87) were independently associated with lower odds of favourable outcome compared with patients without anticoagulation (n=2037 (38.8%)). Prior VKA therapy (n=720 (49.4%); aOR, 1.71; 95% CI, 1.41 to 2.08) and prior DOAC therapy (n=460 (39.7%); aOR, 1.28; 95% CI, 1.02 to 1.60) were independently associated with higher odds of mortality compared with patients without anticoagulation (n=2512 (30.2%))., Conclusions: The spectrum of anticoagulation-associated ICH changed over time. Compared with patients without prior anticoagulation, prior VKA treatment and prior DOAC treatment were independently associated with lower odds of favourable outcome and higher odds of mortality at 3 months. Specific reversal agents unavailable during the study period might improve outcomes of DOAC-associated ICH in the future., Competing Interests: Competing interests: MBo: personal fees from AstraZeneca, a company that produces Andexanet alfa (a specific reversal agent for factor Xa-inhibitor-associated ICH, discussed in this study). SW: consultancy fees from Bayer, a company that produces Rivaroxaban (a DOAC discussed in this study). BV: personal fees from Pfizer AG/Bristol-Myers Squibb SA and Bayer AG, producesr of Apixaban and Rivaroxaban, two drugs discussed in this study. DJS: grants from Alexion/AstraZeneca, producer of andexanet alfa discussed in this study. Personal fees from Bayer, producer of Rivaroxaban, discussed in this study. Consultancy fees from VarmX (producer of VarmX, a compound under development for the treatment of FXaI-associated bleeding). All other authors have nothing to disclose., (© Author(s) (or their employer(s)) 2024. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background and Objectives: Cerebral small vessel disease (SVD) is the major cause of intracerebral hemorrhage (ICH). There is no comprehensive, easily applicable classification of ICH subtypes according to the presumed underlying SVD using MRI. We developed an MRI-based classification for SVD-related ICH., Methods: We performed a retrospective study in the prospectively collected Swiss Stroke Registry (SSR, 2013-2019) and the Stroke InvestiGation in North And central London (SIGNAL) cohort. Patients with nontraumatic, SVD-related ICH and available MRI within 3 months were classified as Cerebral Amyloid angiopathy (CAA), Deep perforator arteriopathy (DPA), Mixed CAA-DPA, or Undetermined SVD using hemorrhagic and nonhemorrhagic MRI markers (CADMUS classification). The primary outcome was inter-rater reliability using Gwet's AC1. Secondary outcomes were recurrent ICH/ischemic stroke at 3 months according to the CADMUS phenotype. We performed Firth penalized logistic regressions and competing risk analyses., Results: The SSR cohort included 1,180 patients (median age [interquartile range] 73 [62-80] years, baseline NIH Stroke Scale 6 [2-12], 45.6% lobar hematoma, systolic blood pressure on admission 166 [145-185] mm Hg). The CADMUS phenotypes were as follows: mixed CAA-DPA (n = 751 patients, 63.6%), undetermined SVD (n = 203, 17.2%), CAA (n = 154, 13.1%), and DPA (n = 72, 6.3%), with a similar distribution in the SIGNAL cohort (n = 313). Inter-rater reliability was good (Gwet's AC1 for SSR/SIGNAL 0.69/0.74). During follow-up, 56 patients had 57 events (28 ICH, 29 ischemic strokes). Three-month event rates were comparable between the CADMUS phenotypes., Discussion: CADMUS, a novel MRI-based classification for SVD-associated ICH, is feasible and reproducible and may improve the classification of ICH subtypes in clinical practice and research.

Background: A major clinical challenge is the adequate identification of patients with acute (<1 week) and subacute (1-6 weeks) ischemic stroke due to internal carotid artery (ICA) occlusion who could benefit from a surgical revascularization after a failure of endovascular and/or medical treatment. Recently, two novel quantitative imaging modalities have been introduced: (I) quantitative magnetic resonance angiography (qMRA) with non-invasive optimal vessel analysis (NOVA) for quantification of blood flow in major cerebral arteries (in mL/min), and (II) blood oxygenation level-dependent (BOLD) functional magnetic resonance imaging to assess cerebrovascular reactivity (CVR). The aim of this study is to present our cohort of patients who underwent surgical revascularization in the acute and subacute phase of ischemic stroke as well as to demonstrate the importance of hemodynamic and flow assessment for the decision-making regarding surgical revascularization in patients with acute and subacute stroke and ICA-occlusion., Methods: Symptomatic patients with acute and subacute ischemic stroke because of persistent ICA-occlusion despite optimal medical/endovascular recanalization therapy who were treated at the Neuroscience Clinical Center of the University Hospital Zurich underwent both BOLD-CVR and qMRA-NOVA to study the hemodynamic and collateral vessel status. Patients selected for surgical revascularization according to our previously published flowchart were included in this prospective cohort study. Repeated NOVA and BOLD-CVR investigations were done after bypass surgery as follow up as well as clinical follow up. Continuous BOLD-CVR and qMRA-NOVA variables were compared using paired Student t -test., Results: Between May 2019 and September 2022, superficial temporal artery-middle cerebral artery (STA-MCA) bypass surgery was performed in 12 patients with acute and subacute stroke because of ICA-occlusion despite of optimal endovascular and/or medical treatment prior to the surgery. Impaired BOLD-CVR in the occluded vascular territory [MCA territory: ipsilateral vs. contralateral: -0.03±0.07 vs. 0.11±0.07 %BOLD/mmHgCO 2 , P<0.001] as well as reduced hemispheric flow with qMRA-NOVA (ipsilateral vs. contralateral: 228.00±54.62 vs. 384.50±70.99 mL/min, P=0.01) were measured indicating insufficient collateralization. Post-operative qMRA-NOVA showed improved hemispheric flow (via bypass) (pre-bypass vs. post-bypass: 236.60±76.45 vs. 334.20±131.33 mL/min, P=0.02) and the 3-month-follow-up with BOLD-CVR showed improved cerebral hemodynamics (MCA territory: pre-bypass vs. post-bypass: -0.01±0.05 vs. 0.06±0.03 %BOLD/mmHgCO 2 , P=0.02) in all patients studied., Conclusions: Quantitative assessment with BOLD-CVR and qMRA-NOVA allows us to evaluate the pre- and post-operative cerebral hemodynamics and collateral vessel status in patients with acute/subacute stroke due to ICA occlusion who may benefit from surgical revascularization after failure of endovascular/medical treatment., Competing Interests: Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://qims.amegroups.com/article/view/10.21037/qims-23-876/coif). A.R.L. reports consulting fees from Boehringer Ingelheim and Speaker honoraria from Moleac Snc. G.E. reports honoraria for lectures and presentations for Aesculap B Braun and Baxter, and also reports president of the board of the Brain Disease Foundation. The other authors have no conflicts of interest to declare., (2024 Quantitative Imaging in Medicine and Surgery. All rights reserved.)

Background: Retinal artery occlusion (RAO) may lead to irreversible blindness. For acute RAO, intravenous thrombolysis (IVT) can be considered as treatment. However, due to the rarity of RAO, data about IVT safety and effectiveness is limited., Methods: From the multicenter database ThRombolysis for Ischemic Stroke Patients (TRISP), we retrospectively analyzed visual acuity (VA) at baseline and within 3 months in IVT and non-IVT treated RAO patients. Primary outcome was difference of VA between baseline and follow up (∆VA). Secondary outcomes were rates of visual recovery (defined as improvement of VA ⩾ 0.3 logMAR), and safety (symptomatic intracranial hemorrhage (sICH) according to ECASS II criteria, asymptomatic intracranial hemorrhage (ICH) and major extracranial bleeding). Statistical analysis was performed using parametric tests and a linear regression model adjusted for age, sex and baseline VA., Results: We screened 200 patients with acute RAO and included 47 IVT and 34 non-IVT patients with complete information about recovery of vision. Visual Acuity at follow up significantly improved compared to baseline in IVT patients (∆VA 0.5 ± 0.8, p  < 0.001) and non-IVT patients (∆VA 0.40 ± 1.1, p  < 0.05). No significant differences in ∆VA and visual recovery rate were found between groups at follow up. Two asymptomatic ICH (4%) and one (2%) major extracranial bleeding (intraocular bleeding) occurred in the IVT group, while no bleeding events were reported in the non-IVT group., Conclusion: Our study provides real-life data from the largest cohort of IVT treated RAO patients published so far. While there is no evidence for superiority of IVT compared to conservative treatment, bleeding rates were low. A randomized controlled trial and standardized outcome assessments in RAO patients are justified to assess the net benefit of IVT in RAO., Competing Interests: Declaration of conflicting interestsThe author(s) declared the following potential conflicts of interest with respect to the research, authorship, and/or publication of this article: PB: Research funds by the Gottfried and Julia Bangerter-Rhyner Foundation and Swiss Academy of Medical Sciences and funding for travel and conference fees from BMS/Pfizer. SW: Research funds by the Swiss National Science Foundation, the UZH Clinical research priority program (CRPP) stroke, the Swiss Heart foundation, the Zurich Neuroscience Center (ZNZ), speaker honoraria from Springer, Teva Pharma and consultancy fees from Bayer and Novartis. STE has received funding for travel or speaker honoraria from Bayer, Boehringer Ingelheim and Daiichi-Sankyo. He has served on scientific advisory boards for Bayer, Boehringer Ingelheim, BMS/Pfizer, and MindMaze and on the editorial board of Stroke. His institutions have received an educational grant from Pfizer, compensation from Stago for educational efforts and research support from Daiichi-Sankyo, the Science Funds [Wissenschaftsfonds] of the University Hospital Basel, the University Basel, from the “Wissenschaftsfonds Rehabilitation” of the University Department for Geriatric Medicine Felix Platter, the “Freiwillige Akademische Gesellschaft Basel,” the Swiss Heart Foundation, and the Swiss National Science Foundation. PR has received honoraria for advisory board participation from Boehringer Ingelheim and Pfizer and lecture fees from Boehringer Ingelheim, Bayer, Pfizer and Daiichi Sankyo. His institution has received a grant from Boehringer Ingelheim for the ECASS-4 Study. RRL received funding for speaker honoraria from Pfizer, Boehringer Ingelheim, Biogen and Iscehma View. He has served on scientific advisory boards for Novo-Nordisk and Bayer.

In acute ischemic stroke due to large-vessel occlusion (LVO), the clinical outcome after endovascular thrombectomy (EVT) is influenced by the extent of autoregulatory hemodynamic impairment, which can be derived from blood oxygenation level-dependent cerebrovascular reactivity (BOLD-CVR). BOLD-CVR imaging identifies brain areas influenced by hemodynamic steal. We sought to investigate the presence of steal phenomenon and its relationship to DWI lesions and clinical deficit in the acute phase of ischemic stroke following successful vessel recanalization.From the prospective longitudinal IMPreST (Interplay of Microcirculation and Plasticity after ischemic Stroke) cohort study, patients with acute ischemic unilateral LVO stroke of the anterior circulation with successful endovascular thrombectomy (EVT; mTICI scale ≥ 2b) and subsequent BOLD-CVR examination were included for this analysis. We analyzed the spatial correlation between brain areas exhibiting BOLD-CVR-associated steal phenomenon and DWI infarct lesion as well as the relationship between steal phenomenon and NIHSS score at hospital discharge.Included patients (n = 21) exhibited steal phenomenon to different extents, whereas there was only a partial spatial overlap with the DWI lesion (median 19%; IQR, 8-59). The volume of steal phenomenon outside the DWI lesion showed a positive correlation with overall DWI lesion volume and was a significant predictor for the NIHSS score at hospital discharge.Patients with acute ischemic unilateral LVO stroke exhibited hemodynamic steal identified by BOLD-CVR after successful EVT. Steal volume was associated with DWI infarct lesion size and with poor clinical outcome at hospital discharge. BOLD-CVR may further aid in better understanding persisting hemodynamic impairment following reperfusion therapy., (© 2023. The Author(s).)

The intricate and delicate anatomy of the brain poses significant challenges for the treatment of cerebrovascular and neurodegenerative diseases. Thus, precise local drug delivery in hard-to-reach brain regions remains an urgent medical need. Microrobots offer potential solutions; however, their functionality in the brain remains restricted by limited imaging capabilities and complications within blood vessels, such as high blood flows, osmotic pressures, and cellular responses. Here, we introduce ultrasound-activated microrobots for in vivo navigation in brain vasculature. Our microrobots consist of lipid-shelled microbubbles that autonomously aggregate and propel under ultrasound irradiation. We investigate their capacities in vitro within microfluidic-based vasculatures and in vivo within vessels of a living mouse brain. These microrobots self-assemble and execute upstream motion in brain vasculature, achieving velocities up to 1.5 µm/s and moving against blood flows of ~10 mm/s. This work represents a substantial advance towards the therapeutic application of microrobots within the complex brain vasculature., (© 2023. Springer Nature Limited.)

Background and Objectives: IV thrombolysis (IVT) for suspected ischemic stroke in patients with intracranial neoplasms is off-label. However, data on risks of intracranial hemorrhage (ICH) are scarce., Methods: In a multicenter registry-based analysis within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration, we assessed frequencies of symptomatic and fatal ICH after IVT for suspected ischemic stroke in patients with intracranial tumors by descriptive statistics and analyzed associations with clinical and imaging characteristics by binary logistic regression. Definition of symptomatic ICH was based on the clinical criteria of the European Cooperative Acute Stroke-II trial including hemorrhage at any site in cranial imaging and concurrent clinical deterioration., Results: Screening data of 21,289 patients from 14 centers, we identified 105 patients receiving IVT; among them were 29 patients (28%) with additional endovascular treatment, with suspected, that is, imaging-based, or histologically confirmed diagnosis of intracranial tumors. Among 104 patients with CT or MRI after IVT available, symptomatic and fatal ICH were observed in 9 and 4 patients (9% and 4%, respectively). Among 82 patients with suspected or confirmed meningioma, symptomatic and fatal ICH occurred in 6 and 3 patients (7% and 4%), respectively. In 18 patients with intra-axial suspected or confirmed primary or secondary brain tumors, there was 1 symptomatic nonfatal ICH (6%). Of 4 patients with tumors of the pituitary region, 2 patients (50%) had symptomatic ICH including 1 fatal ICH (25%). Tumor size was not associated with the occurrence of symptomatic ICH (odds ratio 2.8, 95% CI 0.3-24.8, p = 0.34)., Discussion: In our dataset from routine clinical care, we provide insights on the safety of IVT for suspected ischemic stroke in patients with intracranial tumors, a population that is commonly withheld thrombolysis in clinical practice and prospective trials. Except for a potential high risk of symptomatic ICH after IVT in patients with tumors of the pituitary region, frequencies of symptomatic ICH in patients with intracranial tumors in our cohort seem to be in the upper range of rates observed in previous studies within the TRISP cooperation. These results may guide individual treatment decisions in patients with acute stroke and intracranial tumors with potential benefit of IVT., (© 2023 American Academy of Neurology.)

In many medical applications, interpretable models with high prediction performance are sought. Often, those models are required to handle semistructured data like tabular and image data. We show how to apply deep transformation models (DTMs) for distributional regression that fulfill these requirements. DTMs allow the data analyst to specify (deep) neural networks for different input modalities making them applicable to various research questions. Like statistical models, DTMs can provide interpretable effect estimates while achieving the state-of-the-art prediction performance of deep neural networks. In addition, the construction of ensembles of DTMs that retain model structure and interpretability allows quantifying epistemic and aleatoric uncertainty. In this study, we compare several DTMs, including baseline-adjusted models, trained on a semistructured data set of 407 stroke patients with the aim to predict ordinal functional outcome three months after stroke. We follow statistical principles of model-building to achieve an adequate trade-off between interpretability and flexibility while assessing the relative importance of the involved data modalities. We evaluate the models for an ordinal and dichotomized version of the outcome as used in clinical practice. We show that both tabular clinical and brain imaging data are useful for functional outcome prediction, whereas models based on tabular data only outperform those based on imaging data only. There is no substantial evidence for improved prediction when combining both data modalities. Overall, we highlight that DTMs provide a powerful, interpretable approach to analyzing semistructured data and that they have the potential to support clinical decision-making., (© 2022 Wiley-VCH GmbH.)

Recurrent stroke is a dreaded complication of symptomatic internal carotid artery occlusion (ICAO). Transcranial Duplex (TCD)-derived increased flow velocity in the ipsilateral posterior cerebral artery (PCA)-P2 segment indicates activated leptomeningeal collateral recruitment and hemodynamic impairment. Leptomeningeal collaterals are pial vascular connections between the anterior and posterior vascular territories. These secondary collateral routes are activated when primary collaterals via the Circle of Willis are insufficient. Our goal was to test the TCD parameter PCA-P2 flow for prediction of ipsilateral ischemia recurrence. We retrospectively analyzed clinical and ultrasound parameters in patients with ICAO. Together with clinical variables, we tested systolic PCA-P2 flow velocity as predictor of a recurrent ischemic event using logistic regression models. Of 111 patients, 13 showed a recurrent ischemic event within the same vascular territory. Increased flow in the ipsilateral PCA-P2 on transcranial ultrasound (median and interquartile range [IQR]: 60 cm/s [IQR 26] vs. 86 cm/s [IQR 41], p  = <0.001), as well as previous transient ischemic attack (TIA) and low NIHSS were associated with ischemia recurrence. Combined into one model, accuracy of these parameters to predict recurrent ischemia was 89.2%. Our data suggest that in patients with symptomatic ICAO, flow increases in the ipsilateral PCA-P2 suggest intensified compensatory efforts when other collaterals are insufficient. Together with the clinical variables, this non-invasive and easily assessable duplex parameter detects ICAO patients at particular risk of recurrent ischemia., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Jud, Klövekorn, van Niftrik, Herzog, Sebök, Schweizer, Luft, Fierstra and Wegener.)

Background: Evidence-based hemostatic treatment for intracerebral hemorrhage (ICH) associated with non-vitamin K antagonist oral anticoagulants (NOACs) is lacking. Tranexamic acid (TXA) is an antifibrinolytic drug potentially limiting hematoma expansion. We aimed to assess the efficacy and safety of TXA in NOAC-ICH., Methods: We performed a double-blind, randomized, placebo-controlled trial at 6 Swiss stroke centers. Patients with NOAC-ICH within 12 hours of symptom onset and 48 hours of last NOAC intake were randomized (1:1) to receive either intravenous TXA (1 g over 10 minutes followed by 1 g over 8 hours) or matching placebo in addition to standard medical care via a centralized Web-based procedure with minimization on key prognostic factors. All participants and investigators were masked to treatment allocation. Primary outcome was hematoma expansion, defined as ≥33% relative or ≥6 mL absolute volume increase at 24 hours and analyzed using logistic regression adjusted for baseline hematoma volume on an intention-to-treat basis., Results: Between December 12, 2016, and September 30, 2021, we randomized 63 patients (median age, 82 years [interquartile range, 76-86]; 40% women; median hematoma volume, 11.5 [4.8-27.4] mL) of the 109 intended sample size before premature trial discontinuation due to exhausted funding. The primary outcome did not differ between TXA (n=32) and placebo (n=31) arms (12 [38%] versus 14 [45%]; adjusted odds ratio, 0.63 [95% CI, 0.22-1.82]; P =0.40). There was a signal for interaction with onset-to-treatment time ( P interaction =0.024), favoring TXA when administered within 6 hours of symptom onset. Between the TXA and placebo arms, the proportion of participants who died (15 [47%] versus 13 [42%]; adjusted odds ratio, 1.07 [0.37-3.04]; P =0.91) or had major thromboembolic complications within 90 days (4 [13%] versus 2 [6%]; odds ratio, 1.86 [0.37-9.50]; P =0.45) did not differ. All thromboembolic events occurred at least 2 weeks after study treatment, exclusively in participants not restarted on oral anticoagulation., Conclusions: In a smaller-than-intended NOAC-ICH patient sample, we found no evidence that TXA prevents hematoma expansion, but there were no major safety concerns. Larger trials on hemostatic treatments targeting an early treatment window are needed for NOAC-ICH., Registration: URL: https://clinicaltrials.gov; Unique identifier: NCT02866838.

Background: The DEFUSE-3 and DAWN trials showed that mechanical thrombectomy (MT) improves the outcome of selected patients with anterior circulation large vessel occlusions (LVO) up to 24 h after stroke onset. However, it is unknown whether only those patients fulfilling the trial inclusion criteria benefit, or whether benefit is seen in a broader range of patients presenting between 6 and 24 h., Aims: We determined whether fulfilling the DEFUSE-3 and DAWN selection criteria affects outcomes in MT patients in clinical practice., Methods: We reviewed adult patients with LVO treated with MT between 6 and 24 h after stroke onset at five Swiss stroke centers between 2014 and 2021. We compared two groups: (1) patients who satisfied neither DEFUSE-3 nor DAWN criteria (NDND) and (2) those who satisfied DEFUSE-3 or DAWN criteria (DOD). We used logistic regression to examine the impact of trial eligibility on two safety outcomes (symptomatic intracranial hemorrhage [sICH] and all-cause mortality at 3 months) and two efficacy outcomes (modified Rankin Score [mRS] shift toward lower categories and mRS of 0-2 at 3 months)., Results: Of 174 patients who received MT, 102 (59%) belonged to the NDND group. Rates of sICH were similar between the NDND group and the DOD group (3% vs. 4%, p  =  1.00). Multivariable regression revealed no differences in 3-month all-cause mortality (aOR 2.07, 95% CI 0.64-6.84, p  = 0.23) or functional outcomes (mRS shift: acOR 0.81, 95% CI 0.37-1.79, p  = 0.60; mRS 0-2: aOR 0.91, 95% CI 0.31-2.57, p  = 0.85 )., Conclusion: Among adult patients with LVO treated with MT between 6 and 24 h, safety and efficacy outcomes were similar between DEFUSE-3/DAWN eligible and ineligible patients. Our data provide a compelling rationale for randomized trials with broader inclusion criteria for MT.

Background: Despite evolving treatments, functional recovery in patients with large vessel occlusion stroke remains variable and outcome prediction challenging. Can we improve estimation of functional outcome with interpretable deep learning models using clinical and magnetic resonance imaging data?, Methods: In this observational study, we collected data of 222 patients with middle cerebral artery M1 segment occlusion who received mechanical thrombectomy. In a 5-fold cross validation, we evaluated interpretable deep learning models for predicting functional outcome in terms of modified Rankin scale at 3 months using clinical variables, diffusion weighted imaging and perfusion weighted imaging, and a combination thereof. Based on 50 test patients, we compared model performances to those of 5 experienced stroke neurologists. Prediction performance for ordinal (modified Rankin scale score, 0-6) and binary (modified Rankin scale score, 0-2 versus 3-6) functional outcome was assessed using discrimination and calibration measures like area under the receiver operating characteristic curve and accuracy (percentage of correctly classified patients)., Results: In the cross validation, the model based on clinical variables and diffusion weighted imaging achieved the highest binary prediction performance (area under the receiver operating characteristic curve, 0.766 [0.727-0.803]). Performance of models using clinical variables or diffusion weighted imaging only was lower. Adding perfusion weighted imaging did not improve outcome prediction. On the test set of 50 patients, binary prediction performance between model (accuracy, 60% [55.4%-64.4%]) and neurologists (accuracy, 60% [55.8%-64.21%]) was similar when using clinical data. However, models significantly outperformed neurologists when imaging data were provided, alone or in combination with clinical variables (accuracy, 72% [67.8%-76%] versus 64% [59.8%-68.4%] with clinical and imaging data). Prediction performance of neurologists with comparable experience varied strongly., Conclusions: We hypothesize that early prediction of functional outcome in large vessel occlusion stroke patients may be significantly improved if neurologists are supported by interpretable deep learning models., Competing Interests: Disclosures Dr Heldner reports grants from the Bangerter Foundation, the Swiss National Science Foundation, SITEM (Center for Translational Medicine and Biomedical Entrepreneurship) Support Funds, and the Swiss Heart Foundation, all outside the submitted work. Dr Antonenko reports a grant from the Swiss National Science Foundation. Dr Dobrocky reports consultant fees for MicroVention, Inc. Dr Fischer reports grants from Alexion, CSL Behring, Medtronic, Penumbra, Inc, Phenox, Inc, Rapid Medical, Ltd, and Stryker. Dr Gralla reports interests with Medtronic USA, Inc. Dr Arnold reports consultancy fees from Amgen, AstraZeneca, Bayer, Bristol Myers Squibb, Covidien, Daiichi Sankyo, Novartis, Pfizer, Boehringer Ingelheim, Covidien, Medtronic, and Novo Nordisk. Dr Luft reports consultancy fees from Amgen and Moleac, Ltd. Susanne Wegener received research funds by the Swiss National Science Foundation, the UZH Clinical research priority program (CRPP) stroke, the Swiss Heart foundation, the Zurich Neuroscience Center (ZNZ), speaker honoraria from Springer, Teva Pharma, and consultancy fees from Bayer and Novartis. The other authors report no conflicts.

Super-resolution optoacoustic imaging of microvascular structures deep in mammalian tissues has so far been impeded by strong absorption from densely-packed red blood cells. Here we devised 5 µm biocompatible dichloromethane-based microdroplets exhibiting several orders of magnitude higher optical absorption than red blood cells at near-infrared wavelengths, thus enabling single-particle detection in vivo. We demonstrate non-invasive three-dimensional microangiography of the mouse brain beyond the acoustic diffraction limit (<20 µm resolution). Blood flow velocity quantification in microvascular networks and light fluence mapping was also accomplished. In mice affected by acute ischemic stroke, the multi-parametric multi-scale observations enabled by super-resolution and spectroscopic optoacoustic imaging revealed significant differences in microvascular density, flow and oxygen saturation in ipsi- and contra-lateral brain hemispheres. Given the sensitivity of optoacoustics to functional, metabolic and molecular events in living tissues, the new approach paves the way for non-invasive microscopic observations with unrivaled resolution, contrast and speed., (© 2023. The Author(s).)

Background and Purpose: This study aimed to investigate the effect of endovascular treatment (EVT, with or without intravenous thrombolysis [IVT]) versus IVT alone on outcomes in patients with acute ischemic stroke (AIS) and intracranial large vessel occlusion (LVO) attributable to cervical artery dissection (CeAD)., Methods: This multinational cohort study was conducted based on prospectively collected data from the EVA-TRISP (EndoVAscular treatment and ThRombolysis for Ischemic Stroke Patients) collaboration. Consecutive patients (2015-2019) with AIS-LVO attributable to CeAD treated with EVT and/or IVT were included. Primary outcome measures were (1) favorable 3-month outcome (modified Rankin Scale score 0-2) and (2) complete recanalization (thrombolysis in cerebral infarction scale 2b/3). Odds ratios with 95% confidence intervals (OR [95% CI]) from logistic regression models were calculated (unadjusted, adjusted). Secondary analyses were performed in the patients with LVO in the anterior circulation (LVOant) including propensity score matching., Results: Among 290 patients, 222 (76.6%) had EVT and 68 (23.4%) IVT alone. EVT-treated patients had more severe strokes (National Institutes of Health Stroke Scale score, median [interquartile range]: 14 [10-19] vs. 4 [2-7], P<0.001). The frequency of favorable 3-month outcome did not differ significantly between both groups (EVT: 64.0% vs. IVT: 86.8%; ORadjusted 0.56 [0.24-1.32]). EVT was associated with higher rates of recanalization (80.5% vs. 40.7%; ORadjusted 8.85 [4.28-18.29]) compared to IVT. All secondary analyses showed higher recanalization rates in the EVT-group, which however never translated into better functional outcome rates compared to the IVT-group., Conclusion: We observed no signal of superiority of EVT over IVT regarding functional outcome in CeAD-patients with AIS and LVO despite higher rates of complete recanalization with EVT. Whether pathophysiological CeAD-characteristics or their younger age might explain this observation deserves further research.

Background: Autoregulation of the cerebral vasculature keeps brain perfusion stable over a range of systemic mean arterial pressures to ensure brain functioning, e.g., in different body positions. Verticalization, i.e., transfer from lying (0°) to upright (70°), which causes systemic blood pressure drop, would otherwise dramatically lower cerebral perfusion pressure inducing fainting. Understanding cerebral autoregulation is therefore a prerequisite to safe mobilization of patients in therapy., Aim: We measured the impact of verticalization on cerebral blood flow velocity (CBFV) and systemic blood pressure (BP), heart rate (HR) and oxygen saturation in healthy individuals., Methods: We measured CBFV in the middle cerebral artery (MCA) of the dominant hemisphere in 20 subjects using continuous transcranial doppler ultrasound (TCD). Subjects were verticalized at 0°, -5°, 15°, 30°, 45° and 70° for 3-5 min each, using a standardized Sara Combilizer chair. In addition, blood pressure, heart rate and oxygen saturation were continuously monitored., Results: We show that CBFV progressively decreases in the MCA with increasing degrees of verticalization. Systolic and diastolic BP, as well as HR, show a compensatory increase during verticalization., Conclusion: In healthy adults CBFV changes rapidly with changing levels of verticalization. The changes in the circulatory parameters are similar to results regarding classic orthostasis., Registration: ClinicalTrials.gov, identifier: NCT04573114., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2023 Deseoe, Schwarz, Pipping, Lehmann, Veerbeek, Luft, Wegener, Globas and Held.)

Purpose: Dual-energy computed tomography (DECT) has been shown to be able to differentiate between intracranial hemorrhage (ICH) and extravasation of iodinated contrast media (contrast staining [CS]). TwinSpiral DECT is a recently introduced technique, which allows image acquisition at two different energy levels in two consecutive spiral scans. The aim of this study was to evaluate the feasibility and accuracy of TwinSpiral DECT to distinguish between ICH and CS after endovascular thrombectomy (EVT) in patients with acute ischemic stroke., Methods: This retrospective single-center study conducted between November 2019 and July 2020 included non-contrast TwinSpiral DECT scans (tube voltages 80 and 150Sn kVp) of 39 ischemic stroke patients (18 females, 21 males, mean age 69 ± 11 years) within 48-72 h after endovascular thrombectomy. Parenchymal hyperdensity was assessed for the presence of ICH or/and CS by two board certified and fellowship-trained, blinded and independent neuroradiologists using standard mixed images and virtual non-contrast (VNC) images with corresponding iodine maps from TwinSpiral DECT. Follow-up examinations (FU; CT or MRI) were used as a standard of reference. Sensitivity, specificity, and accuracy for the detection of ICH as well as the inter-reader agreement were calculated., Results: Parenchymal hyperdensities were detected in 17/39 (44%) patients. Using DECT, they were classified by both readers as ICH in 9 (53%), CS in 8 (47%), and mixture of both in 6 (35%) cases with excellent agreement (κ = 0.81, P < 0.0001). The sensitivity, specificity, and accuracy for the detection of ICH in DECT was 90% (95% confidence interval [CI]: 84-96%), 100% (95% CI 94-100%) and 95% (95% CI 89-100%), and in mixed images 90% (95% CI 84-96%), 86% (95% CI 80-92%) and 88% (95% CI 82-94%), respectively. Inter-reader agreement for detecting ICH on DECT compared to the mixed images was κ = 1.00 (P < 0.0001) vs. κ = 0.51 (P = 0.034)., Conclusion: TwinSpiral DECT demonstrates high accuracy and excellent specificity for differentiating ICH from CS in patients after mechanical thrombectomy due to acute ischemic stroke, and improves inter-reader agreement for detecting ICH compared to the standard mixed images., (© 2022. The Author(s).)

Background: We assessed the efficacy and safety of mechanical thrombectomy (MT) in adult stroke patients with anterior circulation large vessel occlusion presenting in the late time window not fulfilling the DEFUSE-3 (Thrombectomy for Stroke at 6 to 16 Hours With Selection by Perfusion Imaging trial) and DAWN (Thrombectomy 6 to 24 Hours After Stroke With a Mismatch Between Deficit and Infarct trial) inclusion criteria., Methods: Cohort study of adults with anterior circulation large vessel occlusion admitted between 6 and 24 hours after last-seen-well at 5 participating Swiss stroke centers between 2014 and 2021. Mismatch was assessed by computer tomography or magnetic resonance imaging perfusion with automated software (RAPID or OLEA). We excluded patients meeting DEFUSE-3 and DAWN inclusion criteria and compared those who underwent MT with those receiving best medical treatment alone by inverse probability of treatment weighting using the propensity score. The primary efficacy end point was a favorable functional outcome at 90 days, defined as a modified Rankin Scale score shift toward lower categories. The primary safety end point was symptomatic intracranial hemorrhage within 7 days of stroke onset; the secondary was all-cause mortality within 90 days., Results: Among 278 patients with anterior circulation large vessel occlusion presenting in the late time window, 190 (68%) did not meet the DEFUSE-3 and DAWN inclusion criteria and thus were included in the analyses. Of those, 102 (54%) received MT. In the inverse probability of treatment weighting analysis, patients in the MT group had higher odds of favorable outcomes compared with the best medical treatment alone group (modified Rankin Scale shift: acOR, 1.46 [1.02-2.10]; P =0.04) and lower odds of all-cause mortality within 90 days (aOR, 0.59 [0.37-0.93]; P =0.02). There were no significant differences in symptomatic intracranial hemorrhage (MT versus best medical treatment alone: 5% versus 2%, P =0.63)., Conclusions: Two out of 3 patients with anterior circulation large vessel occlusion presenting in the late time window did not meet the DEFUSE-3 and DAWN inclusion criteria. In these patients, MT was associated with higher odds of favorable functional outcomes without increased rates of symptomatic intracranial hemorrhage. These findings support the enrollment of patients into ongoing randomized trials on MT in the late window with more permissive inclusion criteria.

Importance: International guidelines recommend avoiding intravenous thrombolysis (IVT) in patients with ischemic stroke who have a recent intake of a direct oral anticoagulant (DOAC)., Objective: To determine the risk of symptomatic intracranial hemorrhage (sICH) associated with use of IVT in patients with recent DOAC ingestion., Design, Setting, and Participants: This international, multicenter, retrospective cohort study included 64 primary and comprehensive stroke centers across Europe, Asia, Australia, and New Zealand. Consecutive adult patients with ischemic stroke who received IVT (both with and without thrombectomy) were included. Patients whose last known DOAC ingestion was more than 48 hours before stroke onset were excluded. A total of 832 patients with recent DOAC use were compared with 32 375 controls without recent DOAC use. Data were collected from January 2008 to December 2021., Exposures: Prior DOAC therapy (confirmed last ingestion within 48 hours prior to IVT) compared with no prior oral anticoagulation., Main Outcomes and Measures: The main outcome was sICH within 36 hours after IVT, defined as worsening of at least 4 points on the National Institutes of Health Stroke Scale and attributed to radiologically evident intracranial hemorrhage. Outcomes were compared according to different selection strategies (DOAC-level measurements, DOAC reversal treatment, IVT with neither DOAC-level measurement nor idarucizumab). The association of sICH with DOAC plasma levels and very recent ingestions was explored in sensitivity analyses., Results: Of 33 207 included patients, 14 458 (43.5%) were female, and the median (IQR) age was 73 (62-80) years. The median (IQR) National Institutes of Health Stroke Scale score was 9 (5-16). Of the 832 patients taking DOAC, 252 (30.3%) received DOAC reversal before IVT (all idarucizumab), 225 (27.0%) had DOAC-level measurements, and 355 (42.7%) received IVT without measuring DOAC plasma levels or reversal treatment. The unadjusted rate of sICH was 2.5% (95% CI, 1.6-3.8) in patients taking DOACs compared with 4.1% (95% CI, 3.9-4.4) in control patients using no anticoagulants. Recent DOAC ingestion was associated with lower odds of sICH after IVT compared with no anticoagulation (adjusted odds ratio, 0.57; 95% CI, 0.36-0.92). This finding was consistent among the different selection strategies and in sensitivity analyses of patients with detectable plasma levels or very recent ingestion., Conclusions and Relevance: In this study, there was insufficient evidence of excess harm associated with off-label IVT in selected patients after ischemic stroke with recent DOAC ingestion.

To improve risk stratification in extracranial internal carotid artery disease (CAD), patients who would benefit maximally from revascularization must be identified. In cardiology, the fractional flow reserve (FFR) has become a reference standard for evaluating the functional severity of coronary artery stenosis, and noninvasive surrogates thereof relying on computational fluid dynamics (CFD) have been developed. Here, we present a CFD-based workflow using digital twins of patients' carotid bifurcations derived from computed tomography angiography for the noninvasive functional assessment of CAD. We reconstructed patient-specific digital twins of 37 carotid bifurcations. We implemented a CFD model using common carotid artery peak systolic velocity (PSV) acquired with Doppler ultrasound (DUS) as inlet boundary condition and a two-element Windkessel model as oulet boundary condition. The agreement between CFD and DUS on the PSV in the internal carotid artery (ICA) was then compared. The relative error for the agreement between DUS and CFD was 9% ± 20% and the intraclass correlation coefficient was 0.88. Furthermore, hyperemic simulations in a physiological range were feasible and unmasked markedly different pressure drops along two ICA stenoses with similar degree of narrowing under comparable ICA blood flow. Hereby, we lay the foundation for prospective studies on noninvasive CFD-based derivation of metrics similar to the FFR for the assessment of CAD., Competing Interests: Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper., (Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.)

Wide-field fluorescence imaging is an indispensable tool for studying large-scale biodynamics. Limited space-bandwidth product and strong light diffusion make conventional implementations incapable of high-resolution mapping of fluorescence biodistribution in three dimensions. We introduce a volumetric wide-field fluorescence microscopy based on optical astigmatism combined with fluorescence source localization, covering 5.6×5.6×0.6 mm 3  imaging volume. Two alternative configurations are proposed exploiting multifocal illumination or sparse localization of point emitters, which are herein seamlessly integrated in one system. We demonstrate real-time volumetric mapping of the murine cortical microcirculation at capillary resolution without employing cranial windows, thus simultaneously delivering quantitative perfusion information across both brain hemispheres. Morphological and functional changes of cerebral vascular networks are further investigated after an acute ischemic stroke, enabling cortex-wide observation of concurrent collateral recruitment events occurring on a sub-second scale. The reported technique thus offers a wealth of unmatched possibilities for non- or minimally invasive imaging of biodynamics across scales., (© 2022. The Author(s).)

Background: Cancer in stroke patients is associated with higher levels of inflammatory biomarkers and unfavorable poststroke outcomes. We thus explored whether there is a link between cancer and stroke-associated infections., Methods: Medical records of patients with ischemic stroke in 2014-2016 registered in the Swiss Stroke Registry of Zurich were retrospectively analyzed. Incidence, characteristics, treatment, and outcome of stroke-associated infections diagnosed within 7 days after stroke onset were tested for an association with cancer., Results: Among 1181 patients with ischemic stroke, 102 patients with cancer were identified. Stroke-associated infections occurred in 179 and 19 patients (17% and 19%) without and with cancer ( P = .60), respectively, among them pneumonia in 95 and 10 patients (9% and 10%) and urinary tract infections in 68 and 9 patients (6% and 9%) ( P = .74 and P = .32). Use of antibiotics was similar between groups. Levels of C-reactive protein (CRP) ( P < .001), erythrocyte sedimentation rate (ESR) ( P = .014) and procalcitonin ( P = .015) were higher and levels of albumin ( P = .042) and protein ( P = .031) were lower in patients with cancer than without cancer. Among patients without cancer, higher CRP ( P < .001), ESR ( P < .001) and procalcitonin ( P = .04) and lower albumin ( P < .001) were associated with stroke-associated infections. Among cancer patients with or without infections, no significant differences in these parameters were observed. In-hospital mortality was associated with cancer ( P < .001) and with stroke-associated infections ( P < .001). However, among patients with stroke-associated infections, cancer was not associated with in-hospital mortality ( P = .24) or 30-day mortality ( P = .66)., Conclusions: Cancer does not represent a risk factor for stroke-associated infections in this patient cohort., Competing Interests: MK has received funding from the Swiss Science Foundation, the Swiss Heart Foundation, Göhner Foundation and in kind contributions from BRAHMS/Thermofisher Scientific and Roche, as well as honoraria for lectures or advisory board participation or consulting from Bayer, Medtronic and Astra Zeneca. AL has received honoraria from Moleac, Amgen, Bayer and Daiichi Sankyo. SW received research funds by the Swiss National Science Foundation, the UZH Clinical research priority program (CRPP) stroke, Boehringer-Ingelheim, a speakers honorarium from Amgen and a consultancy fee from Bayer and Novartis. MWe has received research grants from Apogenix, Merck, Sharp & Dohme, Merck (EMD) and Quercis, and honoraria for lectures or advisory board participation or consulting from Adastra, Bristol Meyer Squibb, Medac, Merck, Sharp & Dohme, Merck (EMD), Nerviano Medical Sciences, Novartis, Orbus, Philogen and yMabs. The other authors report no conflicts of interest., (© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology and the European Association of Neuro-Oncology. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background and Purpose: Knowledge about different etiologies of non-traumatic intracerebral hemorrhage (ICH) and their outcomes is scarce., Methods: We assessed prevalence of pre-specified ICH etiologies and their association with outcomes in consecutive ICH patients enrolled in the prospective Swiss Stroke Registry (2014 to 2019)., Results: We included 2,650 patients (mean±standard deviation age 72±14 years, 46.5% female, median National Institutes of Health Stroke Scale 8 [interquartile range, 3 to 15]). Etiology was as follows: hypertension, 1,238 (46.7%); unknown, 566 (21.4%); antithrombotic therapy, 227 (8.6%); cerebral amyloid angiopathy (CAA), 217 (8.2%); macrovascular cause, 128 (4.8%); other determined etiology, 274 patients (10.3%). At 3 months, 880 patients (33.2%) were functionally independent and 664 had died (25.1%). ICH due to hypertension had a higher odds of functional independence (adjusted odds ratio [aOR], 1.33; 95% confidence interval [CI], 1.00 to 1.77; P=0.05) and lower mortality (aOR, 0.64; 95% CI, 0.47 to 0.86; P=0.003). ICH due to antithrombotic therapy had higher mortality (aOR, 1.62; 95% CI, 1.01 to 2.61; P=0.045). Within 3 months, 4.2% of patients had cerebrovascular events. The rate of ischemic stroke was higher than that of recurrent ICH in all etiologies but CAA and unknown etiology. CAA had high odds of recurrent ICH (aOR, 3.38; 95% CI, 1.48 to 7.69; P=0.004) while the odds was lower in ICH due to hypertension (aOR, 0.42; 95% CI, 0.19 to 0.93; P=0.031)., Conclusions: Although hypertension is the leading etiology of ICH, other etiologies are frequent. One-third of ICH patients are functionally independent at 3 months. Except for patients with presumed CAA, the risk of ischemic stroke within 3 months of ICH was higher than the risk of recurrent hemorrhage.

Background: Cortical spreading depolarization (CSD) is a massive neuro-glial depolarization wave, which propagates across the cerebral cortex. In stroke, CSD is a necessary and ubiquitous mechanism for the development of neuronal lesions that initiates in the ischemic core and propagates through the penumbra extending the tissue injury. Although CSD propagation induces dramatic changes in cerebral blood flow, the vascular responses in different ischemic regions and their consequences on reperfusion and recovery remain to be defined., Methods: Ischemia was performed using the thrombin model of stroke and reperfusion was induced by r-tPA (recombinant tissue-type plasminogen activator) administration in mice. We used in vivo electrophysiology and laser speckle contrast imaging simultaneously to assess both electrophysiological and hemodynamic characteristics of CSD after ischemia onset. Neurological deficits were assessed on day 1, 3, and 7. Furthermore, infarct sizes were quantified using 2,3,5-triphenyltetrazolium chloride on day 7., Results: After ischemia, CSDs were evidenced by the characteristic propagating DC shift extending far beyond the ischemic area. On the vascular level, we observed 2 types of responses: some mice showed spreading hyperemia confined to the penumbra area (penumbral spreading hyperemia) while other showed spreading hyperemia propagating in the full hemisphere (full hemisphere spreading hyperemia). Penumbral spreading hyperemia was associated with severe stroke-induced damage, while full hemisphere spreading hyperemia indicated beneficial infarct outcome and potential viability of the infarct core. In all animals, thrombolysis with r-tPA modified the shape of the vascular response to CSD and reduced lesion volume., Conclusions: Our results show that different types of spreading hyperemia occur spontaneously after the onset of ischemia. Depending on their shape and distribution, they predict severity of injury and outcome. Furthermore, our data show that modulating the hemodynamic response to CSD may be a promising therapeutic strategy to attenuate stroke outcome.

Objective: Endovascular recanalization trials have shown a positive impact on the preservation of ischemic penumbra in patients with acute large vessel occlusion (LVO). The concept of penumbra salvation can be extended to surgical revascularization with bypass in highly selected patients. For selecting these patients, the authors propose a flowchart based on multimodal MRI., Methods: All patients with acute stroke and persisting internal carotid artery (ICA) or M1 occlusion after intravenous lysis or mechanical thrombectomy undergo advanced neuroimaging in a time window of 72 hours after stroke onset including perfusion MRI, blood oxygenation level-dependent functional MRI to evaluate cerebrovascular reactivity (BOLD-CVR), and noninvasive optimal vessel analysis (NOVA) quantitative MRA to assess collateral circulation., Results: Symptomatic patients exhibiting persistent hemodynamic impairment and insufficient collateral circulation could benefit from bypass surgery. According to the flowchart, a bypass is considered for patients 1) with low or moderate neurological impairment (National Institutes of Health Stroke Scale score 1-15, modified Rankin Scale score ≤ 3), 2) without large or malignant stroke, 3) without intracranial hemorrhage, 4) with MR perfusion/diffusion mismatch > 120%, 5) with paradoxical BOLD-CVR in the occluded vascular territory, and 6) with insufficient collateral circulation., Conclusions: The proposed flowchart is based on the patient's clinical condition and multimodal MR neuroimaging and aims to select patients with acute stroke due to LVO and persistent inadequate collateral flow, who could benefit from urgent bypass.

Secondary prevention of ischemic stroke: laboratory and imaging biomarkers Abstract. Identifying the cause of stroke is pivotal to prevent stroke recurrence. Large artery atherosclerosis, cardiac embolism, small vessel disease or other, rarer pathologies can induce ischemic stroke. Recently, laboratory and imaging biomarkers have been proposed to contribute to a better stratification of stroke etiology. This article summarizes current knowledge in the field of biomarkers in secondary prevention of stroke; and highlights the potential for future application in clinical stroke patient care.

[Figure: see text].

Background and Purpose: Increased Transcranial Doppler flow velocity in the ipsilateral P2-segment of the posterior cerebral artery (PCA-P2: cm/second) is associated with recurrent cerebrovascular events in patients with unilateral internal carotid artery occlusion. However, its predictive value and correlation with hemodynamic impairment in an overall stroke patient cohort remains to be determined., Methods: Transcranial doppler PCA-P2 flow velocity was measured in 88 patients with symptomatic unilateral steno-occlusive disease who also underwent blood oxygenation-level dependent cerebrovascular reactivity imaging (blood oxygenation-level dependent [BOLD]-cerebrovascular reactivity [CVR]). A multivariate linear regression was used to evaluate the independent correlation between the ipsilateral PCA-P2 flow velocity measurements and hemispheric BOLD-CVR. Follow-up BOLD-CVR imaging data, available in 25 patients, were used to evaluate the temporal evolution of the BOLD-CVR and PCA-P2 flow velocity association using a mixed-effect model. Furthermore, a transcranial doppler cutoff for hemodynamic failure stage 2 was determined., Results: The ipsilateral systolic PCA-P2 flow velocity strongly correlated with hemispheric BOLD-CVR (R=0.79; R 2 =0.61), which remained unchanged when evaluating the follow-up data. Using a PCA-P2 systolic flow velocity cutoff value of 85 cm/second, patients with BOLD-CVR based hemodynamic failure stage 2 were diagnosed with an area under the curve of 95., Conclusions: In patients with symptomatic unilateral steno-occlusive disease, increased ipsilateral transcranial doppler PCA-P2 systolic flow velocity independently correlates with BOLD-CVR based hemodynamic failure. A cutoff value of 85 cm/second appears to indicate hemodynamic failure stage 2, but this finding needs to be validated in an independent patient cohort.

Background: In patients with steno-occlusive disease, recent findings suggest that hemodynamic alterations may also be associated with crossed cerebellar diaschisis (CCD) rather than a functional disruption alone., Purpose: To use a quantitative multiparametric hemodynamic MRI to gain a better understanding of hemodynamic changes related to CCD in patients with unilateral anterior circulation stroke., Study Type: Prospective cohort study., Population: Twenty-four patients (25 datasets) with symptomatic unilateral anterior circulation stroke., Field Strength/sequence: 3T/two sequences: single-shot (echo-planar imaging) EPI sequence and T 2 * gradient echo perfusion-weighted imaging study., Assessment: The presence of CCD was inferred from the cerebellar asymmetry index (CAI) of the blood oxygenation-level dependent cerebrovascular reactivity (BOLD-CVR) exam, which was calculated from the mean BOLD-CVR and standard deviation of the CAI of the healthy control group. For all perfusion-weighted (PW)-MRI parameters, the cerebellar and middle cerebral artery (MCA) territory asymmetry indices were calculated., Statistical Tests: Independent Student's t-test to compare the variables from the CCD positive(+) and CCD negative(-) groups and analysis of covariance (ANCOVA) to statistically control the effect of covariates (infarct volume and time since ischemia onset)., Results: CCD was present in 33% of patients. In the MCA territory of the affected hemisphere, BOLD-CVR was significantly more impaired in the CCD(+) group as compared to the CCD(-) group (mean BOLD-CVR ± SD [%BOLD signal/ΔmmHgCO 2 ]: -0.03 ± 0.12 vs. 0.11 ± 0.13, P < 0.05). Moreover, the mean transit time (MTT) (asymmetry index (%) CCD(+) vs. CCD(-): 28 ± 23 vs. 4 ± 11, P < 0.05) and time to peak (TTP) (10 ± 10 vs. 2 ± 5, P < 0.05) in the MCA territory of the affected hemisphere were significantly prolonged, while cerebral blood volume was, on average, increased in the CCD(+) group (25 ± 15 vs. 4 ± 19, P < 0.05)., Data Conclusion: Our findings show that, in patients with symptomatic unilateral anterior circulation stroke, CCD is associated with hemodynamic impairment in the ipsilateral MCA territory, which further supports the concept of a vascular component of CCD., Level of Evidence: 3 TECHNICAL EFFICACY STAGE: 3., (© 2020 International Society for Magnetic Resonance in Medicine.)

Crossed cerebellar diaschisis (CCD) in internal carotid artery (ICA) stroke refers to attenuated blood flow and energy metabolism in the contralateral cerebellar hemisphere. CCD is associated with an interruption of cerebro-cerebellar tracts, but the precise mechanism is unknown. We hypothesized that in patients with ICA occlusions, CCD might indicate severe hemodynamic impairment in addition to tissue damage. Duplex sonography and clinical data from stroke patients with unilateral ICAO who underwent blood oxygen-level-dependent MRI cerebrovascular reserve (BOLD-CVR) assessment were analysed. The presence of CCD (either CCD+ or CCD-) was inferred from BOLD-CVR. We considered regions with negative BOLD-CVR signal as areas suffering from hemodynamic steal. Twenty-five patients were included (11 CCD+ and 14 CCD-). Stroke deficits on admission and at 3 months were more severe in the CCD+ group. While infarct volumes were similar, CCD+ patients had markedly larger BOLD steal volumes than CCD- patients (median [IQR] 122.2 [111] vs. 11.6 [50.6] ml; p < 0.001). Furthermore, duplex revealed higher peak-systolic flow velocities in the intracranial collateral pathways. Strikingly, posterior cerebral artery (PCA)-P2 velocities strongly correlated with the National Institute of Health Stroke Scale on admission and BOLD-CVR steal volume. In patients with strokes due to ICAO, the presence of CCD indicated hemodynamic impairment with larger BOLD-defined steal volume and higher flow in the ACA/PCA collateral system. Our data support the concept of a vascular component of CCD as an indicator of hemodynamic failure in patients with ICAO.

New-Onset Headache in Adults: Evidence-Based Assessment in the Primary Care Setting Abstract. Many people suffer from headaches. Primary (idiopathic) headaches such as migraine and tension type headaches are most common. They may significantly affect occupational and social aspects of daily life, but are usually not dangerous. On the contrary, secondary (symptomatic) headaches may be a symptom for an underlying life-threatening disorder. In these cases, the primary care physician may need to organize certain diagnostic measures such as brain imaging, blood work or lumbar puncture. Sometimes, emergency hospital admission may be required. In this article we summarize the recommended steps for the assessment of new-onset headaches in patients visiting the primary care practice.

Objective: To evaluate whether pretreatment with metformin (MET) is associated with less stroke severity and better outcome after IV thrombolysis (IVT), we analyzed a cohort of 1,919 patients with stroke with type 2 diabetes mellitus in a multicenter exploratory analysis., Methods: Data from patients with diabetes and ischemic stroke treated with IVT were collected within the European Thrombolysis in Ischemic Stroke Patients (TRISP) collaboration. We applied propensity score matching (PSM) to obtain balanced baseline characteristics of patients treated with and without MET., Results: Of 1,919 patients with stroke with type 2 diabetes who underwent IVT, 757 (39%) had received MET before stroke (MET+), whereas 1,162 (61%) had not (MET-). MET+ patients were younger with a male preponderance. Hypercholesterolemia and pretreatment with statins, antiplatelets, or antihypertensives were more common in the MET+ group. After PSM, the 2 groups were well balanced with respect to demographic and clinical aspects. Stroke severity on admission (NIH Stroke Scale 10.0 ± 6.7 vs 11.3 ± 6.5), 3-month degree of independence on modified Rankin Scale (2 [interquartile range (IQR) 1.0-4.0] vs 3 [IQR 1.0-4.0]), as well as mortality (12.5% vs 18%) were significantly lower in the MET+ group. The frequency of symptomatic intracerebral hemorrhages did not differ between groups. HbA1c levels were well-balanced between the groups., Conclusions: Patients with stroke and diabetes on treatment with MET receiving IVT had less severe strokes on admission and a better functional outcome at 3 months. This suggests a protective effect of MET resulting in less severe strokes as well as beneficial thrombolysis outcome., (© 2020 American Academy of Neurology.)

Aims: Effective stroke treatments beyond reperfusion remain scant. The natural steroid hormone progesterone has shown protective effects in experimental models of brain injury and cardiovascular disease. However, unfavourable bioavailability limits its clinical use. Desogestrel and drospirenone are new generation progestins with progesterone-like properties, developed as oral contraceptives with excellent bioavailability and safety profile. We investigated the neuroprotective properties of these progestins in vivo using transient middle cerebral artery occlusion (MCAO) and in vitro using an oxygen-glucose deprivation and reoxygenation (OGD/R) model in primary neuronal cells., Methods and Results: MCAO was induced in female, female ovariectomized (modelling postmenopausal females) and male mice. Treatment with the progestins resulted in less severe strokes after MCAO and less neuronal death in OGD/R. Desogestrel and drospirenone induced higher expression levels of GABAAR α4 and delta subunits within the brain, suggesting changes in GABAAR configuration favouring tonic inhibition as potential mechanism of action. Treatment with the GABAAR blocker picrotoxin abolished the protection afforded by the progestins in vivo and in vitro., Conclusion: For the first time, here, we delineate a potential role of desogestrel and drospirenone, both clinically approved and safe drugs in mitigating the consequences of stroke. Contraception with desogestrel and drospirenone in progestin-only preparations may be particularly beneficial for women at risk of stroke., (Published on behalf of the European Society of Cardiology. All rights reserved. © The Author(s) 2018. For permissions, please email: journals.permissions@oup.com.)

Objective: To study blood oxygen level-dependent cerebrovascular reactivity (BOLD-CVR) as a surrogate imaging marker for crossed cerebellar diaschisis (CCD)., Methods: Twenty-five participants with symptomatic unilateral cerebrovascular steno-occlusive disease underwent a BOLD-CVR and an acetazolamide challenged ( 15 O)-H 2 O-PET study. CCD and cerebellar asymmetry index were determined from PET and compared to BOLD-CVR quantitative values. Neurologic status at admission and outcome after 3 months were determined with NIH Stroke Scale (NIHSS) and modified Rankin Scale (mRS) scores., Results: For both the BOLD-CVR and PET examination, a significant cerebellar asymmetry index was found for participants exhibiting CCD (CCD+ vs CCD-: for BOLD-CVR 13.11 ± 9.46 vs 1.52 ± 4.97, p < 0.001; and for PET 7.31 ± 2.75 vs 1.68 ± 2.98, p < 0.001). The area under the curve for BOLD-CVR was 0.89 (95% confidence interval: 0.75-1.0) with 0.91 sensitivity and 0.81 specificity to detect CCD. Participants exhibiting CCD were in poorer clinical condition at baseline (CCD+ vs CCD-: NIHSS 7 vs 1, p = 0.003; mRS 3 vs 1, p = 0.001) and after 3-month follow-up (NIHSS 2 vs 0, p = 0.02; mRS 1 vs 0, p = 0.04). Worse performance on both scores showed an agreement with a larger BOLD-CVR cerebellar asymmetry index. This was not found for PET., Conclusions: BOLD-CVR demonstrates similar sensitivity to detect CCD as compared to ( 15 O)-H 2 O-PET in patients with symptomatic unilateral cerebrovascular steno-occlusive disease. Furthermore, participants exhibiting CCD had a poorer baseline neurologic performance and neurologic outcome at 3 months., Classification of Evidence: This study provides Class II evidence that BOLD-CVR identifies CCD in patients with symptomatic unilateral cerebrovascular steno-occlusive disease., (© 2018 American Academy of Neurology.)

Background and Purpose: The volume of decreased cerebral blood flow (CBF) in acute stroke perfusion-weighted imaging frequently overestimates final infarct volume. We hypothesized that surviving tissue exists even in patients without recanalization and tried to determine perfusion thresholds from initial MR imaging., Methods: Stroke MR imaging including MR angiography was carried out at days 0, 1, and 7 after stroke onset in 19 patients without recanalization at least until day 1. The following lesions were defined: L0 = diffusion restriction at day 0; LG1 = lesion growth until day 1; LG7 = lesion growth until day 7; ST7 = initially hypoperfused, but surviving tissue. These lesions were transferred on initial MR imaging within 4.7 hours and perfusion values at day 0 were determined., Results: Median lesion volume L0 at day 0 was 18.2 mL and increased to 39.4 and 43.8 mL at days 1 and 7. Volume of decreased rCBF not progressing to infarction was 148.5 mL (ST7). Mean ST7 perfusion values were different from L0 and LG1, but only mean relative cerebral blood volume (rCBV) was different from LG7, discriminating survival against death of tissue. A threshold value of 0.82 CBV for death versus survival was determined with a sensitivity of 0.56 and specificity of 0.95. Carotid T occlusions showed the greatest potential of lesion growth., Conclusion: Even when vessel occlusion persists, hypoperfused tissue on MR imaging does not necessarily progress toward infarction. The most conclusive inferences can be drawn from CBV images. The site of arterial occlusion also determines progression to infarction.