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Background: The extent of ischemic injury in acute stroke is assessed in clinical practice using the Acute Stroke Prognosis Early CT Score (ASPECTS) rating system. However, current ASPECTS semi-quantitative topographic scales assess only the middle cerebral artery (MCA) (original ASPECTS) and posterior cerebral (PC-ASPECTS) territories. For treatment decision-making in patients with anterior cerebral artery (ACA) occlusions and internal carotid artery (ICA) occlusions with large ischemic cores, measures of all hemispheric regions are desirable., Methods: In this cohort study, anatomic rating systems were developed for the anterior cerebral (AC-ASPECTS, 3 points) and anterior choroidal artery (ACh-ASPECTS, 1 point) territories. In addition, a total supratentorial hemisphere (H-ASPECTS, 16 points) score was calculated as the sum of the MCA ASPECTS (10 regions), supratentorial PC-ASPECTS (2 regions), AC-ASPECTS (3 regions), and ACh-ASPECTS (1 region). Three raters applied these scales to initial and 24 h CT and MR images in consecutive patients with ischemic stroke (IS) due to ICA, M1-MCA, and ACA occlusions., Results: Imaging ratings were obtained for 96 scans in 50 consecutive patients with age 74.8 (±14.0), 60% female, NIHSS 15.5 (9.25-20), and occlusion locations ICA 34%; M1-MCA 58%; and ACA 8%. Treatments included endovascular thrombectomy +/- thrombolysis in 72%, thrombolysis alone in 8%, and hemicraniectomy in 4%. Among experienced clinicians, inter-rater reliability for AC-, ACh-, and H-ASPECTS scores was substantial (kappa values 0.61-0.80). AC-ASPECTS abnormality was present in 14% of patients, and ACh-ASPECTS abnormality in 2%. Among patients with ACA and ICA occlusions, H-ASPECTS scores compared with original ASPECTS scores were more strongly associated with disability level at discharge, ambulatory status at discharge, discharge destination, and combined inpatient mortality and hospice discharge., Conclusion: AC-ASPECTS, ACh-ASPECTS, and H-ASPECTS expand the scope of acute IS imaging scores and increase correlation with functional outcomes. This additional information may enhance prognostication and decision-making, including endovascular thrombectomy and hemicraniectomy., Competing Interests: DL Consultant as Imaging Core Lab to Cerenovus, Genentech, Medtronic, Stryker, Rapid Medical. JS has received, for service on clinical trial steering committees and DSMBs advising on rigorous study design and conduct, hourly payments from Medtronic, Abbott, NeuroVasc, Phillips Medical, Bayer, Biogen, Roche, BrainsGate, BrainQ, CSL Behring, Stream Medical, and Occlutech, and stock options from Rapid Medical, NeuroMerit, Neuronics, and QuantalX. LetsGetProof. The remaining 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 Rodriguez, Taleb, Lee, Liebeskind and Saver.)

Background: Validating the National Institutes of Health NIH Stroke Scale (NIHSS) as a tool to assess deficit severity and prognosis in patients with acute intracerebral hemorrhage would harmonize the assessment of intracerebral hemorrhage (ICH) and acute ischemic stroke (AIS) patients, enable clinical use of a readily implementable and non-imaging dependent prognostic tool, and improve monitoring of ICH care quality in administrative datasets., Methods: Among randomized trial ICH patients, the relation between NIHSS scores early after Emergency Department arrival and 3-month outcomes of dependency or death (modified Rankin Scale, mRS 3-6) and case fatality was examined. NIHSS predictive performance was compared to a current standard prognostic scale, the intracerebral hemorrhage score (ICH score)., Results: Among the 384 patients, the mean age was 65 (±13), with 66% being male. The median NIHSS score was 16 (interquartile range (IQR) 9-25), the mean initial hematoma volume was 29 mL (±38), and the ICH score median was 1 (IQR 0-2). At 3 months, the mRS had a median of 4 (IQR 2-6), with dependency or death occurring in 70% and case fatality in 26%. The NIHSS and ICH scores were strongly correlated ( r  = 0.73), and each was strongly correlated with the 90-day mRS (NIHSS, r  = 0.61; ICH score, r  = 0.62). The NIHSS performed comparably to the ICH score in predicting both dependency or death ( c  = 0.80 vs. 0.80, p  = 0.83) and case fatality ( c  = 0.78 vs. 0.80, p  = 0.29). At threshold values, the NIHSS predicted dependency or death with 74.1% accuracy (NIHSS 17.5) and case fatality with 75.0% accuracy (NIHSS 18.5)., Conclusion: The NIHSS forecasts 3-month functional and case fatality outcomes with accuracy comparable to the ICH Score. Widely documented in routine clinical care and administrative data, the NIHSS can serve as a valuable measure for clinical prognostication, therapy development, and case-mix risk adjustment in ICH patients. Clinical trial registration Clinicaltrials.gov, NCT00059332., 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 Kazaryan, Shkirkova, Saver, Liebeskind, Starkman, Bulic, Poblete, Kim-Tenser, Guo, Conwit, Villablanca, Hamilton and Sanossian.)

Introduction: Stroke interventions that increase collateral flow have the potential to salvage penumbral tissue and increase the number of patients eligible for reperfusion therapy. We compared the efficacy of two different collateral therapeutics during transient middle cerebral artery occlusion (tMCAO) in normotensive and hypertensive rats., Methods: The change in collateral and core perfusion was measured using dual laser Doppler in response to either a pressor agent (phenylephrine, 10 mg/kg iv or vehicle) or a collateral vasodilator (TM5441, 5 mg/kg iv or vehicle) given 30 min into tMCAO in male Wistar and spontaneously hypertensive rats (SHRs)., Results: Pressor therapy increased collateral flow in the Wistar rats but was ineffective in the SHRs. The increase in collateral flow in the Wistar rats was associated with impaired cerebral blood flow autoregulation (CBFAR) that was intact in the SHRs. TM5441 caused a decrease in collateral perfusion in the Wistar rats and a modest increase in the SHRs. The pressor therapy reduced early infarction in both groups but increased edema in the SHRs, whereas TM5441 did not have any beneficial effects in either group., Conclusions: Thus, the pressor therapy was superior to a collateral vasodilator in increasing collateral flow and improving outcomes in the Wistar rats, likely due to pial collaterals that were pressure passive; the lack of CBF response in the SHRs to pressor therapy was likely due to intact CBFAR that limited perfusion. While TM5441 modestly increased CBF in the SHRs but not in the Wistar rats, it did not have a beneficial effect on stroke outcomes. These results suggest that collateral therapies may need to be selected for certain comorbidities., 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 Cipolla, Hunt, Liebeskind and Tremble.)

In the reperfusion era, a new paradigm of treating patients with endovascular treatment (EVT) and neuroprotective drugs is emerging as a promising therapeutic option for patients with acute ischemic stroke (AIS). In this context, ApTOLL, a Toll-like receptor 4 (TLR4) antagonist with proven neuroprotective effect in preclinical models of stroke and a very good pharmacokinetic and safety profile in healthy volunteers, is a promising first-in-class aptamer with the potential to address this huge unmet need. This protocol establishes the clinical trial procedures to conduct a Phase Ib/IIa clinical study (APRIL) to assess ApTOLL tolerability, safety, pharmacokinetics, and biological effect in patients with AIS who are eligible for EVT. This will be a multicenter, double-blind, randomized, placebo-controlled, Phase Ib/IIa clinical study to evaluate the administration of ApTOLL together with EVT in patients with AIS. The study population will be composed of men and non-pregnant women with confirmed AIS with a <6h window from symptoms onset to ApTOLL/placebo administration. The trial is currently being conducted and is divided into two parts: Phase Ib and Phase IIa. In Phase Ib, 32 patients will be allocated to four dose ascending levels to select, based on safety criteria, the best two doses to be administered in the following Phase IIa in which 119 patients will be randomized to three arms of treatment (dose A, dose B, and placebo)., Identification of the Trial: EudraCT: 2020-002059-38 and ClinicalTrials.gov Identifier: NCT04734548 https://clinicaltrials.gov/ct2/show/NCT04734548?term=ApTOLL&cond=Stroke&draw=2&rank=1., Competing Interests: MH-J is an employee of AptaTargets S.L. MR receives payment from Philips as co-principal investigator of the WE TRUST study and he has a consulting agreement with Medtronic, Stryker, Cerenovus, CVAid, Methinks, Anaconda Biomed, and AptaTargets S.L. JC is founder and CEO of Aldebaran Health Intelligence, S.L. MD is employed by Cureteq AG and has provided consultancy services for AptaTargets S.L. BJ is a consultant to AptaTargets S.L. and Guardian Therapeutics, Inc. FA-S has been consultant or investigator in clinical trials sponsored by the following pharmaceutical companies: Abbott, Alter, AptaTargets, Chemo, Cinfa, FAES Farma, Farmalíder, Ferrer, GlaxoSmithKline, Galenicum, Gilead, Italfarmaco, Janssen-Cilag, Kern Pharma, Normon, Novartis, Servier, Silverpharma, Teva, and Zambon. The remaining 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 Hernández-Jiménez, Abad-Santos, Cotgreave, Gallego, Jilma, Flores, Jovin, Vivancos, Molina, Montaner, Casariego, Dalsgaard, Hernández-Pérez, Liebeskind, Cobo and Ribo.)

The objective of this study is to quantify the increase in brain-under-protection time that may be achieved with pre-hospital compared with the post-arrival start of neuroprotective therapy among patients undergoing endovascular thrombectomy. In order to do this, a comparative analysis was performed of two randomized trials of neuroprotective agents: (1) pre-hospital strategy: Field administration of stroke therapy-magnesium (FAST-MAG) Trial; (2) in-hospital strategy: Efficacy and safety of nerinetide for the treatment of acute ischemic stroke (ESCAPE-NA1) Trial. In the FAST-MAG trial, among 1,041 acute ischemic stroke patients, 44 were treated with endovascular reperfusion therapy (ERT), including 32 treated with both intravenous thrombolysis and ERT and 12 treated with ERT alone. In the ESCAPE-NA1 trial, among 1,105 acute ischemic stroke patients, 659 were treated with both intravenous thrombolysis and ERT, and 446 were treated with ERT alone. The start of the neuroprotective agent was sooner after onset with pre-hospital vs. in-hospital start: 45 m (IQR 38-56) vs. 122 m. The neuroprotective agent in FAST-MAG was started 8 min prior to ED arrival compared with 64 min after arrival in ESCAPE-NA1. Projecting modern endovascular workflows to FAST-MAG, the total time of "brain under protection" (neuroprotective agent start to reperfusion) was greater with pre-hospital than in-hospital start: 94 m (IQR 90-98) vs. 22 m. Initiating a neuroprotective agent in the pre-hospital setting enables a faster treatment start, yielding 72 min additional brain protection time for patients with acute ischemic stroke. These findings provide support for the increased performance of ambulance-based, pre-hospital treatment trials in the development of neuroprotective stroke therapies., 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 © 2022 Matossian, Starkman, Sanossian, Stratton, Eckstein, Conwit, Liebeskind, Sharma, Tenser and Saver.)

Recurrent stroke risk secondary to intracranial atherosclerotic disease remains high despite aggressive medical treatment. This risk is further amplified in subgroups possessing biomarkers of hemodynamic insufficiency and potential for embolization, which have been shown to be independently and synergistically predictive of recurrent stroke. Luminal stenosis was predominantly used as entry criteria in major treatment trials, discounting the potential role of hemodynamics from primary analyses, limiting the strength of evidence and conclusions of these biomarkers to post-hoc analyses and other natural history studies. Future treatment trials should consider stratifying patients using a combination of these high-risk biomarkers. In the absence of trials, risk stratifying patients based on the presence of these markers may lend to more individualized clinical decisions. We aimed to summarize the studies that have investigated the relationship between biomarkers and their role in predicting recurrent stroke risk in intracranial atherosclerotic disease., 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 © 2022 Ballout and Liebeskind.)

Background and Purpose: Cerebral venous systems play a key role in regulating stroke outcomes. We aimed to elucidate the effect of the transverse sinus (TS) filling patterns on edema expansion and neurological outcomes in patients with acute large artery occlusion (LAO)., Materials and Methods: We recruited consecutive patients with acute M1 middle cerebral artery and/or internal carotid artery occlusion who underwent pretreatment computed tomographic perfusion (CTP). On the reconstructed 4-dimensional computed tomographic angiography derived from CTP, the filling defect of the ipsilateral transverse sinus (FDITS) was defined as the length of contrast filling defect occupying at least half of the ipsilateral TS. An unfavorable outcome was defined as having a modified Rankin Scale (mRS) score of 3-6 at 3 months., Results: A total of 318 patients were enrolled in the final analysis and 70 (22.0%) patients had baseline FDITS. The presence of FDITS was associated with the baseline NIHSS (odds ratio [ OR ] 1.119; 95% CI , 1.051-1.192; p < 0.001) and poor arterial collaterals ( OR 3.665; 95% CI 1.730-7.766; p = 0.001). In addition, FDITS was associated with 24-h brain edema expansion ( OR 7.188; 95% CI , 3.095-16.696; p < 0.001) and 3-month unfavorable outcome ( OR 8.143; 95% CI 2.547-26.041; p < 0.001) independent of arterial collateral status. In the subgroup analysis of patients with FDITS who received reperfusion therapy, no significant difference was found in the rate of edema expansion and unfavorable outcome between non-reperfusion and reperfusion subgroups (both p > 0.05)., Conclusion: Filling defect of the ipsilateral transverse sinus was associated with edema expansion and an unfavorable outcome irrespective of the baseline arterial collateral status in patients with acute LAO, indicating that FDITS may be an important stroke-related prognostic imaging marker., 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 © 2022 Chen, Zhang, Yan, Zhang, Zhang, Shi, Liebeskind, Parsons and Lou.)

In acute stroke management, time window has been rigidly used as a guide for decades and the reperfusion treatment is only available in the first few limited hours. Recently, imaging-based selection of patients has successfully expanded the treatment window out to 16 and even 24 h in the DEFUSE 3 and DAWN trials, respectively. Recent guidelines recommend the use of imaging techniques to guide therapeutic decision-making and expanded eligibility in acute ischemic stroke. A tissue window is proposed to replace the time window and serve as the surrogate marker for potentially salvageable tissue. This article reviews the evolution of time window, addresses the advantage of a tissue window in precision medicine for ischemic stroke, and discusses both the established and emerging techniques of neuroimaging and their roles in defining a tissue window. We also emphasize the metabolic imaging and molecular imaging of brain pathophysiology, and highlight its potential in patient selection and treatment response prediction in ischemic stroke., 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 © 2021 Lu, Mei, Hou, Manaenko, Zhou, Liebeskind, Zhang, Li and Hu.)

Background and Purpose: The benefits of mechanical thrombectomy (MT) in vertebrobasilar artery occlusions have not been well-studied. We compared clinical, procedural, and safety outcomes of MT for posterior circulation (PC) vs. anterior circulation (AC) occlusions among patients in the STRATIS registry. Methods: Data from STRATIS including patient demographics, procedural characteristics, and outcomes including symptomatic intracranial hemorrhage (sICH) at 24 h, serious adverse events (SAE), substantial reperfusion [modified thrombolysis in cerebral infarction (mTICI) 2b/3], 90-day functional independence [modified Rankin Scale (mRS) 0-2], and 90-day mortality were analyzed. Univariate logistic regression was used to calculate predictors of good clinical outcome. Results: Of 984 STRATIS patients, 43 (4.4%) patients with PC occlusions [mean age 63.0 ± 13.6, 25.6% (11/43) female] and 932 (94.7%) with AC occlusions [mean age 68.5 ± 14.8, 46.9% (437/932) female] were included for analysis. Median National Institutes of Health Stroke Scale (NIHSS) scores at baseline were 17.0 (13.0, 12.0) for the AC group and 12.0 (11.0, 24.0) for the PC group. Time from onset to procedure end was longer for the PC group [median (IQR): 322.0 min (255.0-421.0) vs. 271.0 min (207.0-360.0); p = 0.007]. PC and AC groups had similar rates of substantial reperfusion [89.2% (33/37) vs. 87.7% (684/780)], procedure-related SAE [0.0% (0/43) vs. 1.7% (16/932)], sICH [0.0% (0/38) vs. 1.5% (12/795)], 90-day functional independence [66.7% (26/39) vs. 55.9% (480/858)] and mortality [12.8% (5/39) vs. 15.8% (136/861)]. National Institutes of Health Stroke Scale score and patient sex were significant univariate predictors of good clinical outcome ( p < 0.05). Conclusions: Despite longer reperfusion times, MT in PC stroke has similar rates of 90-day functional independence with no significant difference in procedure-related SAE, sICH, or mortality, supporting the use of MT in PC acute ischemic stroke (AIS). Clinical Trial Registration: https://www.clinicaltrials.gov, Identifier: NCT02239640., Competing Interests: RJ receives funding for his services as a scientific consultant regarding trial design and conduct to Medtronic/Covidien. DL serves as an imaging core lab consultant for Cerenovus, Genentech, Medtronic, and Stryker. OZ serves as a consultant for Neuravi/Cerenovus, Stryker, Penumbra, and Medtronic. NM-K serves as a scientific consultant regarding trial design and conduct to Medtronic. MF serves as a scientific consultant to Medtronic, Corindus, Balt, Cerenovus, Viz.ai, and Genentech, and has received research funding from the National Institutes of Health NIH, Stryker, Medtronic, Microvention, and Endophys. JS reports contracted hourly payments for service on clinical trial steering committee advising on rigorous trial design and conduct for Abbott, Medtronic, Stryker, and Cerenovus, and contracted stock options for service on clinical trial steering committee advising on rigorous trial design and conduct for Rapid Medical. The handling editor DH declared a past co-authorship/collaboration as part of large working groups with one of the authors OZ., (Copyright © 2021 Jahan, Liebeskind, Zaidat, Mueller-Kronast, Froehler and Saver.)

Background: The indications for mechanical thrombectomy in acute ischemic stroke continue to broaden, leading neurointerventionalists to treat vessel occlusions at increasingly distal locations farther in time from stroke onset. Accessing these smaller vessels raises the concern of iatrogenic subarachnoid hemorrhage (SAH) owing to increasing complexity in device navigation and retrieval. This study aims to determine the prevalence of SAH following mechanical thrombectomy, associated predictors, and resulting functional outcomes using a multicenter registry and compare this with a systematic review and meta-analysis of the literature. Methods: Data from STRATIS (The Systematic Evaluation of Patients Treated with Neurothrombectomy Devices for Acute Ischemic Stroke) registry were analyzed dichotomized by the presence or absence of SAH after thrombectomy. Only patients with 24-h post-procedural neuroimaging were included ( n = 841). Multivariable logistic regression was performed to identify significant predictors of SAH. A systematic review and random-effects meta-analysis was also conducted in accordance with the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) protocol. Results: The prevalence of post-thrombectomy SAH was 5.23% in STRATIS with 15.9% (1.84% overall) experiencing neurological decline. Distal location of vessel occlusion (OR 3.41 [95% CI: 1.75-6.63], p < 0.001) and more than 3 device passes (OR 1.34 [95% CI: 1.09-1.64], p = 0.01) were associated with a higher probability of SAH in contrast to a reduction with administration of intravenous tissue plasminogen activator (tPA) (OR 0.48 [95% CI: 0.26-0.89], p = 0.02). There was a trend toward a higher discharge NIHSS (8.3 ± 8.7 vs. 5.3 ± 6.6, p = 0.07) with a significantly reduced proportion achieving functional independence at 90 days (modified Rankin Score 0-2: 32.5% vs. 57.8%, p = 0.002) in SAH patients. Pooled analysis of 10,126 patients from 6 randomized controlled trials and 64 observational studies demonstrated a prevalence of 5.85% [95% CI: 4.51-7.34%, I 2 : 85.2%]. Only location of vessel occlusion was significant for increased odds of SAH at distal sites (OR 2.89 [95% CI: 1.14, 7.35]). Conclusions: Iatrogenic SAH related to mechanical thrombectomy is more common with treatment of distally-situated occlusions and multiple device passes. While low in overall prevalence, its effect is not benign with fewer patients reaching post-procedural functional independence, particularly if symptomatic., 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. The reviewer KK declared a past co-authorship with one of the authors DL to the handling Editor., (Copyright © 2021 Lee, Qureshi, Mueller-Kronast, Zaidat, Froehler, Liebeskind and Pereira.)

Background and Purpose: End-of-procedure substantial reperfusion [modified Treatment in Cerebral Ischemia (mTICI) 2b-3], the leading endpoint for thrombectomy studies, has several limitations including a ceiling effect, with recent achieved rates of ~90%. We aimed to identify a more optimal definition of angiographic success along two dimensions: (1) the extent of tissue reperfusion, and (2) the speed of revascularization. Methods: Core-lab adjudicated TICI scores for the first three passes of EmboTrap and the final all-procedures result were analyzed in the ARISE II multicenter study. The clinical impact of extent of reperfusion and speed of reperfusion (first-pass vs. later-pass) were evaluated. Clinical outcomes included 90-day functional independence [modified Rankin Scale (mRS) 0-2], 90-day freedom-from-disability (mRS 0-1), and dramatic early improvement [24-h National Institutes of Health Stroke Scale (NIHSS) improvement ≥ 8 points]. Results: Among 161 ARISE II subjects with ICA or MCA M1 occlusions, reperfusion results at procedure end showed substantial reperfusion in 149 (92.5%), excellent reperfusion in 121 (75.2%), and complete reperfusion in 79 (49.1%). Reperfusion rates on first pass were substantial in 81 (50.3%), excellent reperfusion in 62 (38.5%), and complete reperfusion in 44 (27.3%). First-pass excellent reperfusion (first-pass TICI 2c-3) had the greatest nominal predictive value for 90-day mRS 0-2 (sensitivity 58.5%, specificity 68.6%). There was a progressive worsening of outcomes with each additional pass required to achieve TICI 2c-3. Conclusions: First-pass excellent reperfusion (TICI 2c-3), reflecting rapid achievement of extensive reperfusion, is the technical revascularization endpoint that best predicted functional independence in this international multicenter trial and is an attractive candidate for a lead angiographic endpoint for future trials. Clinical Trial Registration: http://www.clinicaltrials.gov, identifier NCT02488915., Competing Interests: AY is a consultant for Cerenovus, Penumbra, and Zoll, receives research grants from Medtronic, Cerenovus, Penumbra, Stryker, and Genentech, and has equity interest in Insera Therapeutics. TA is a consultant for Neuravi, Ablynx, Amnis Therapeutics, Medtronic, Rapid Medical, and Stryker. The University of California, Regents receives funding for JSa's services as a scientific consultant regarding trial design and conduct for Covidien and Stryker; JSa is an employee of the University of California, which holds a patent on retriever devices for stroke. MR is a shareholder in Anaconda Biomed, consultant for Cerenovus, Medtronic, Stryker, Apta Targets, and Vesalio. HB serves as a modest consultant for Cerenovus/Neuravi, and Stryker. GD serves as a consultant for Medtronic, Microvention, Penumbra, and Cerenovus. DL serves as an imaging core lab consultant for Cerenovus, Genentech, Medtronic, Stryker, and Vesalio. HM reports personal fees from Covidien/Medtronic, Neuravi/Cerenovus, Servier, and Bayer outside the submitted work, and served on the steering committees of the SWIFT PRIME and ARISE studies. OZ serves as a consultant for Neuravi, Stryker, Penumbra, and Medtronic. The remaining 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 © 2021 Yoo, Soomro, Andersson, Saver, Ribo, Bozorgchami, Dabus, Liebeskind, Jadhav, Mattle and Zaidat.)

Intracranial atherosclerotic disease (ICAD) has been characterized by the degree of arterial stenosis and downstream hypoperfusion, yet microscopic derangements of endothelial shear stress at the luminal wall may be key determinants of plaque growth, vascular remodeling and thrombosis that culminate in recurrent stroke. Platelet interactions have similarly been a principal focus of treatment, however, the mechanistic basis of anti-platelet strategies is largely extrapolated rather than directly investigated in ICAD. Platelet FcγRIIa expression has been identified as a potent risk factor in cardiovascular disease, as elevated expression markedly increases the risk of recurrent events. Differential activation of the platelet FcγRIIa receptor may also explain the variable response of individual patients to anti-platelet medications. We review existing data on endothelial shear stress and potential interactions with the platelet FcγRIIa receptor that may alter the evolving impact of ICAD, based on local pathophysiology at the site of arterial stenosis. Current methods for quantification of endothelial shear stress and platelet activation are described, including tools that may be readily adapted to the clinical realm for further understanding of ICAD., 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 © 2021 Liebeskind, Hinman, Kaneko, Kitajima, Honda, De Havenon, Feldmann, Nogueira, Prabhakaran, Romano, Callas and Schneider.)

Diagnostic and therapeutic strategies for intracranial atherosclerotic disease (ICAD) have vastly expanded within the last several years. Challenges and concrete initiatives have emerged in the implementation of precision medicine for ICAD, focusing personalized treatment for the prevention of stroke and cognitive impairment around pathophysiology. Theranostics for ICAD incorporates an integrated diagnostic and therapeutic approach tailored to a specific individual. The ICAS 2019 meeting provided a roadmap for accelerating global innovation, underscoring the epidemiology, prior scientific evidence from trials, diagnostic tools or imaging, novel biomarkers, management approaches, and a broad range of treatments including many new medications, endovascular, and surgical strategies. This thematic overview provides perspective on current definitions for arterial stenosis, symptomatic lesions and outcomes or endpoints in clinical trials. Imaging correlates are reviewed, from routine multimodal CT or MRI to advanced angiographic techniques. The temporal features of ICAD and longitudinal observation are considered with respect to management and risk factor modification. The evolving science of multivariable interactions in ICAD and use of big data are explored, followed by an overview of recently launched clinical trials., Competing Interests: The author declares 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 © 2021 Liebeskind.)

Introduction: While much is known about recurrent clinical events in patients with intracranial atherosclerotic disease (ICAD), there is limited data on characteristics of recurrent infarcts. Methods: The NIH-funded MyRIAD prospective, observational study was designed to identify mechanisms of ischemia and predictors of recurrence in ICAD. Recurrent infarction was assessed on MRI at 6-8 weeks. We reviewed the DWI/ADC and FLAIR sequences in patients with recurrent stroke and characterized the number of infarcts, infarct location, size, and patterns based on whether they were borderzone (BZ), perforator (SC/P), cortical or territorial (C/T), and mixed. Temporal characteristics were delineated by ADC/FLAIR correlation. Results: Of the 89 patients with 6-8 weeks MRI, 22 (24.7%) had recurrent infarcts in the territory of the symptomatic artery. Recurrent infarcts were evident on DWI in 63.6% and single infarcts in 54.5%. The median recurrent infarct volume was 2.0 cm 3 compared to median index infarct volumes of 2.5 cm 3 . A mixed infarct pattern was most common (40.9%), followed by borderzone (22.7%), cortical or territorial (27.3%), while only 9.1% were in a perforator artery distribution. Amongst those with a mixed pattern, 8/9 had a borderzone distribution infarct as part of their mixed infarct pattern. Conclusion: These findings provide novel data on the characteristics of early recurrent infarcts in patients with symptomatic ICAD., 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 © 2021 Sangha, Prabhakaran, Feldmann, Honda, Nizam, Cotsonis, Campo-Bustillo, Romano and Liebeskind.)

Background: Chronic subdural hematoma (cSDH) is a debilitating condition with a high rate of recurrence after surgical evacuation. Summary: This review is focused on middle meningeal artery (MMA) embolization to treat cSDH. We discuss the underlying pathophysiology of chronic subdural hematoma and how cessation of arterial flow may resolve a venous hemorrhage. We also present the current evidence for MMA embolization and the roadmap for future trials. Conclusion: Frequent multimodal imaging and cSDH sampling would enable us to understand mechanisms of MMA embolization in cSDH treatment and therefore improve our ability to offer MMA embolization to the eligible population., (Copyright © 2020 Moshayedi and Liebeskind.)

Background and Purpose: This study aims to quantify the reperfusion status within severely damaged brain tissue and to evaluate its relationship with high grade of hemorrhagic transformation (HT). Methods: Pseudo-continuous ASL was performed along with DWI in 102 patients within 24 h post-treatments. The infarction core was identified using ADC values <550 × 10 -6 mm 2 /s. CBF within the infarction core and its contralateral counterpart were acquired. CBF at the 25th, median, and 75th percentiles of the contralateral counterpart were used as thresholds and the ASL reperfusion volume above the threshold was labeled as vol-25, -50, and -75, respectively. Recanalization was defined according to Thrombolysis in Myocardial Infarction (TIMI) criteria. Results: Quantified reperfusion within the infarction core differed significantly in patients with complete and incomplete recanalization. In the ROC analysis for the prediction of parenchymal hematoma (PH), ASL reperfusion vol-25 had the highest area under the curve (AUC) when compared with ASL vol-50 and ASL vol-75. ASL reperfusion vol-25 had significantly higher AUC compared with ADC threshold volume in the prediction of PH (0.783 vs. 0.685, P = 0.0036) and PH-2 (0.844 vs. 0.754, P = 0.0035). In stepwise multivariate logistic regression analysis, only ASL reperfusion vol-25 emerged as an independent predictor of PH (OR = 3.51, 95% CI: 1.65-7.45, P < 0.001) and PH-2 (OR = 2.32, 95% CI: 1.13-4.76, P = 0.022). Conclusions: Increased reperfusion volume within severely damaged brain tissue is associated with the occurrence of higher grade of HT., (Copyright © 2020 Yu, Ma, Liebeskind, Qiao, Yan, Saver, Salamon and Wang.)

The outbreak of COVID-19 has posed a significant challenge to global healthcare. Acute stroke care requires rapid bedside attendance, imaging, and intervention. However, for acute stroke patients who have a diagnosis of or are under investigation for COVID-19, the concern for nosocomial transmission moderates operational procedures for acute stroke care. We present our experience with an in-hospital stroke code called on a COVID-19-positive patient with a left middle cerebral artery syndrome and the challenges faced for timely examination, imaging, and decision to intervene. The outlook for the ongoing COVID-19 pandemic necessitates the development of protocols to sustain timely and effective acute stroke care while mitigating healthcare-associated transmission., (Copyright © 2020 Moshayedi, Ryan, Mejia, Nour and Liebeskind.)

Background and Purpose: Primary stroke center (PSC) certification is associated with improvements in stroke care and outcome. However, these improvements may reflect a higher baseline level of care delivery in hospitals eventually achieving certification. This study examines whether advancements in acute stroke care at PSCs are due to certification or factors intrinsic to the hospital. Methods: Data was obtained from the Field Administration of Stroke Therapy-Magnesium (FAST-MAG) trial with participation of 40 Emergency Medical System agencies, 315 ambulances, and 60 acute receiving hospitals in Los Angeles and Orange Counties. Subjects were transported to one of three types of destinations: PSC certified hospitals (PSCs), hospitals that were not PSCs at time of enrollment but would later become certified (pre-PSCs), and hospitals that would never be certified (non-PSCs). Metrics of acute stroke care quality included time arrival to imaging, use of intravenous tPA, and arrival to treatment. Results: Of 1,700 cases, 856(50%) were at certified PSCs, 529(31%) were at pre-PSCs, and 315 (19%) were at non-PSCs. Mean (SD) was 33min (±76.1) at PSCs, 47(±86.6) at pre-PSCs, and 49(±71.7) at non-PSCs. Of 1,223 cerebral ischemia cases, rate of tPA utilization was 43% at PSCs, 27% at pre-PSCs, and 28% at non-PSCs. Mean ED arrival to thrombolysis was 71(±32.7) at PSC, 98(±37.6) at pre-PSC, and 95(±45.0) at non-PSCs. PSCs had improved time to imaging ( p = 0.014), percent tPA use ( p < 0.001), and time to treatment ( p = 0.003). Conclusions: Stroke care at hospitals prior to PSC certification is equivalent to care at non-PSCs. Clinical Trial Registration : http://www.clinicaltrials.gov. Unique identifier: NCT00059332., (Copyright © 2020 Shkirkova, Wang, Vartanyan, Liebeskind, Eckstein, Starkman, Stratton, Pratt, Hamilton, Kim-Tenser, Conwit, Saver and Sanossian.)

Background: The benefits of heparization during mechanical thrombectomy (MT) with newer generation thrombectomy devices, and if it is counterbalanced by the increased risk of intracranial hemorrhage (ICH) remain unknown. Methods: We included eligible patients who underwent MT from the ANGEL registry study (2015-2017) in China. Subjects in the current analysis were dichotomized into two groups according to whether adequate heparinization during MT was performed. In the heparinization group, unfractionated heparin was infused at 50-100 IU/Kg at first and additional 1,000 IU at intervals of an hour during the operation. Safety outcomes (symptomatic intracerebral hemorrhage [sICH], ICH and distal embolization) and efficacy outcomes (artery recanalization and functional outcomes at 3-month follow-up) were compared between groups. Results: We included 619 patients from the entire cohort of 917 patients. The average age of them was 63.9 ± 13.7 years, 269 (43.5%) were treated with heparinization during MT. Heparinization during MT didn't significantly influence recanalization rates, total ICH and long-term mortality (adjusted p > 0.05 for all). But sICH and distal embolization occurred more frequently (9.3 vs. 5.1%, adjusted p = 0.02; 7.1 vs. 3.1%, adjusted p = 0.04, respectively), while functional independence appeared less likely (39.8 vs. 47.4%, adjusted p = 0.01) in heparinization group than that in non-heparinization group. Multivariable logistic regression analyses showed that heparinization during MT was an independent predictor for sICH (Odds ratio 2.36 [1.19-4.67], p = 0.01) in addition to cardio-embolism stroke and posterior circulation stroke (PCS), and an independent predictor for poor outcome (Odds ratio 1.79 [1.23-2.59], p < 0.01) besides age, bridging intravenous thrombolysis, admission NIHSS, drinking and PCS. Conclusion: Heparinization during MT may be associated with increased risk of safety outcomes over sICH and distal embolization, as well as efficacy outcomes over long-term poor outcome. Further randomized controlled trials are needed.

Background: Dynamic susceptibility contrast (DSC) MR perfusion is a frequently-used technique for neurovascular imaging. The progress of a bolus of contrast agent through the tissue of the brain is imaged via a series of T2 * -weighted MRI scans. Clinically relevant parameters such as blood flow and Tmax can be calculated by deconvolving the contrast-time curves with the bolus shape (arterial input function). In acute stroke, for instance, these parameters may help distinguish between the likely salvageable tissue and irreversibly damaged infarct core. Deconvolution typically relies on singular value decomposition (SVD): however, studies have shown that these algorithms are very sensitive to noise and artifacts present in the image and therefore may introduce distortions that influence the estimated output parameters. Methods: In this work, we present a machine learning approach to the estimation of perfusion parameters in DSC-MRI. Various machine learning models using as input the raw MR source data were trained to reproduce the output of an FDA approved commercial implementation of the SVD deconvolution algorithm. Experiments were conducted to determine the effect of training set size, optimal patch size, and the effect of using different machine-learning models for regression. Results: Model performance increased with training set size, but after 5,000 samples (voxels) this effect was minimal. Models inferring perfusion maps from a 5 by 5 voxel patch outperformed models able to use the information in a single voxel, but larger patches led to worse performance. Random Forest models produced had the lowest root mean squared error, with neural networks performing second best: however, a phantom study revealed that the random forest was highly susceptible to noise levels, while the neural network was more robust. Conclusion: The machine learning-based approach produces estimates of the perfusion parameters invariant to the noise and artifacts that commonly occur as part of MR acquisition. As a result, better robustness to noise is obtained, when evaluated against the FDA approved software on acute stroke patients and simulated phantom data.

Background and Aims: Assessment of ischemic lesions on computed tomography or MRI diffusion-weighted imaging (DWI) using the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) is widely used to guide acute stroke treatment. However, it has never been defined how many voxels need to be affected to label a DWI-ASPECTS region ischemic. We aimed to assess the effect of various lesion load thresholds on DWI-ASPECTS and compare this automated analysis with visual rating., Materials and Methods: We analyzed overlap of individual DWI lesions of 315 patients from the previously published predictive value of fluid-attenuated inversion recovery study with a probabilistic ASPECTS template derived from 221 CT images. We applied multiple lesion load thresholds per DWI-ASPECTS region (>0, >1, >10, and >20% in each DWI-ASPECTS region) to compute DWI-ASPECTS for each patient and compared the results to visual reading by an experienced stroke neurologist., Results: By visual rating, median ASPECTS was 9, 84 patients had a DWI-ASPECTS score ≤7. Mean DWI lesion volume was 22.1 (±35) ml. In contrast, by use of >0, >1-, >10-, and >20%-thresholds, median DWI-ASPECTS was 1, 5, 8, and 10; 97.1% (306), 72.7% (229), 41% (129), and 25.7% (81) had DWI-ASPECTS ≤7, respectively. Overall agreement between automated assessment and visual rating was low for every threshold used (>0%: κ w  = 0.020 1%: κ w  = 0.151; 10%: κ w  = 0.386; 20% κ w  = 0.381). Agreement for dichotomized DWI-ASPECTS ranged from fair to substantial (≤7: >10% κ = 0.48; >20% κ = 0.45; ≤5: >10% κ = 0.528; and >20% κ = 0.695)., Conclusion: Overall agreement between automated and the standard used visual scoring is low regardless of the lesion load threshold used. However, dichotomized scoring achieved more comparable results. Varying lesion load thresholds had a critical impact on patient selection by ASPECTS. Of note, the relatively low lesion volume and lack of patients with large artery occlusion in our cohort may limit generalizability of these findings.

Introduction: The specific protein composition of stroke-causing emboli is unknown. Because ischemic stroke has a varied etiology, it is possible that the composition of the thrombus from which an embolus originated will have distinctive molecular characteristics reflective of the underlying pathophysiology. We used mass spectrometry to evaluate the protein composition of retrieved emboli from patients with differing stroke etiologies and correlated the protein levels to serum predictors of atherosclerosis., Methods: Emboli from 20 consecutive acute stroke patients were retrieved by thrombectomy during routine stroke care. Thrombus proteins were extracted, digested, and multidimensional fractionation of peptides was performed. Fractionated peptides underwent nano-liquid chromatography with tandem mass spectrometry. Spectra were searched using Mascot software in which results with p  < 0.05 (95% confidence interval) were considered significant and indicating identity. The results were correlated to A 1 C, low-density lipoprotein (LDL), and erythrocyte sedimentation rate (ESR) taken on admission., Results: Eleven patients had atrial fibrillation, four had significant proximal vessel atherosclerosis, two were cryptogenic, and three had other identified stroke risk factors (left ventricular thrombus, dissection, endocarditis). Eighty-one common proteins (e.g., hemoglobin, fibrin, actin) were found in all 20 emboli. Serum LDL levels correlated with Septin-2 ( r s  = 0.78, p  = 0.028), Phosphoglycerate Kinase 1 ( r s  = 0.75, p  = 0.036), Integrin Alpha-M ( r s  = 0.68, p  = 0.033) and Glucose-6-phosphate dehydrogenase ( r s  = 0.63, p  = 0.05). Septin-7 levels inversely correlated to ESR ( r s  = -0.84, p  = 0.01). No significant protein correlations to A 1 C or tPA use were found., Conclusion: Our exploratory study presents mass spectrometry analysis of thrombi retrieved from acute stroke patients and correlates the thrombus proteome to clinical features of the patient. Notably, we found proteins associated with inflammation (e.g., Integrin Alpha-M) in emboli from patients with high LDL. Although these findings are tempered by a small sample size, we provide preliminary support for the feasibility of utilizing proteomic analysis of emboli to discover proteins that may be used as markers for stroke etiology.

Recent successful endovascular stroke trials have provided unequivocal support for these therapies in selected patients with large-vessel occlusive acute ischemic stroke. In this piece, we briefly review these trials and their utilization of advanced neuroimaging techniques that played a pivotal role in their success through targeted patient selection. In this context, the unique challenges and opportunity for advancement in current stroke networks' routine delivery of care created by these trials are discussed and recommendations to change current national stroke system guidelines are proposed.

Imaging protocols of acute ischemic stroke continue to hold significant uncertainties regarding patient selection for reperfusion therapy with thrombolysis and mechanical thrombectomy. Given that patient inclusion criteria can easily introduce biases that may be unaccounted for, the reproducibility and reliability of the patient screening method is of utmost importance in clinical trial design. The optimal imaging screening protocol for selection in targeted populations remains uncertain. Acute neuroimaging provides a snapshot in time of the brain parenchyma and vasculature. By identifying the at-risk but still viable penumbral tissue, imaging can help estimate the potential benefit of a reperfusion therapy in these patients. This paper provides a perspective about the assessment of the penumbral tissue in the context of acute stroke and reviews several neuroimaging models that have recently been developed to assess the penumbra in a more reliable fashion. The complexity and variability of imaging features and techniques used in stroke will ultimately require advanced data driven software tools to provide quantitative measures of risk/benefit of recanalization therapy and help aid in making the most favorable clinical decisions.

In the 10 years since the FDA first cleared the use of endovascular devices for the treatment of acute stroke, definitive evidence that such therapy improves outcomes remains lacking. The decision to intubate patients undergoing stroke thrombectomy impacts multiple variables that may influence outcomes after stroke. Three main areas where intubation may deleteriously affect acute stroke management include the introduction of delays in revascularization, fluctuations in peri-procedural blood pressure, and hypocapnia, resulting in cerebral vasoconstriction. In this mini-review, we discuss the evidence supporting these limitations of intubation during stroke thrombectomy and encourage neurohospitalists, neurocritical care specialists, and neurointerventionalists to carefully consider the decision to intubate during thrombectomy and provide strategies to avoid potential complications associated with its use in acute stroke.

Stroke experts stand at the cusp of a unique opportunity to advance the care of patients with cerebrovascular disorders across the globe through improved imaging approaches. NIH initiatives including the Stroke Progress Review Group promotion of imaging in stroke research and the newly established NINDS Stroke Trials network converge with the rapidly evolving concept of precision medicine. Precision stroke imaging portends the coming shift to individualized approaches to cerebrovascular disorders where big data may be leveraged to identify and manage stroke risk with specific treatments utilizing an improved neuroimaging infrastructure, data collection, and analysis. We outline key aspects of the stroke imaging field where precision medicine may rapidly transform the care of stroke patients in the next few years.

Despite the advent of and exciting advances in novel endovascular therapies, t-PA remains the only proven treatment for acute ischemic stroke to date. Although a variety of reasons likely underlie why past trials of endovascular strategies have been unsuccessful, we address in this perspective piece one critical unknown for which a solution is undoubtedly necessary if future ones are to meet with success: determination and selection of patients that are "just right" for endovascular treatments, or the Goldilocks dilemma. Key clinical criteria highlighted in past trials may help provide a solution to this critical problem. However, for them to do so, we propose that they must be applied in service of a model that accounts for the nuanced, dynamic nature of acute ischemic stroke better than the prevailing "time is brain" model. We provide and examine three clinical cases to illustrate this proposal towards solving the Goldilocks dilemma and advancing treatment in acute ischemic stroke. Further, we address our field's ongoing challenge and mission in the meantime to best care for the "not-so-right" patients, by far the majority of the affected stroke population.

Background and Purpose: Moyamoya disease has been classically described by the Asian experience, yet clinical aspects of moyamoya phenomena in the United States remain vastly undefined. The multifocal occlusive arterial disorder may be linked with numerous conditions; however, later stages of this syndrome share common vascular pathophysiology. This study is aimed at characterizing inpatient moyamoya cases in the United States over a broad time span., Methods: A comprehensive analysis of the Nationwide Inpatient Sample of the Healthcare Cost and Utilization Project (Releases 1-13, 1988-2004) based on ICD-9-CM code 437.5 was performed. Annual percentages and trends analyses were conducted for demographic variables, admission characteristics, co-morbidities, and procedures., Result: 2247 admissions of moyamoya cases were analyzed from a wide geographic distribution throughout the United States between 1988 and 2004. Age at admission varied considerably (mean 29.6 ± 18.5 years), affecting women more frequently than men (61.9%). Various racial groups were identified (35.4% White, 19.7% African American, 5.6% Hispanic, 8.3% Asian or Pacific Islander, 1.4% Native American). Admissions were typically emergent (38.8%) or urgent (18.7%), although elective admissions occurred (24.4%). Aside from moyamoya, sickle cell disease was diagnosed in 13.6%, ischemic stroke in 20.7%, intracerebral hemorrhage in 7.4%, transient ischemic attack in 3.4%, and subarachnoid hemorrhage in 3.1%. Cerebral angiography was performed in 24.9% while extracranial-intracranial bypass was done in 8.4% of patients., Conclusion: Moyamoya in the United States is a heterogeneous condition affecting individuals of all ages across a diverse racial spectrum and wide geographic distribution. Further recognition of moyamoya syndrome may facilitate ongoing research and future therapeutic approaches.