Adjunctive Intravenous Argatroban or Eptifibatide for Ischemic Stroke.

BACKGROUND: Intravenous thrombolysis is a standard treatment of acute ischemic stroke. The efficacy and safety of combining intravenous thrombolysis with argatroban (an anticoagulant agent) or eptifibatide (an antiplatelet agent) are unclear. METHODS: We conducted a phase 3, three-group, adaptive, single-blind, randomized, controlled clinical trial at 57 sites in the United States. Patients with acute ischemic stroke who had received intravenous thrombolysis within 3 hours after symptom onset were assigned to receive intravenous argatroban, eptifibatide, or placebo within 75 minutes after the initiation of thrombolysis. The primary efficacy outcome, the utility-weighted 90-day modified Rankin scale score (range, 0 to 10, with higher scores reflecting better outcomes), was assessed by means of centralized adjudication. The primary safety outcome was symptomatic intracranial hemorrhage within 36 hours after randomization. RESULTS: A total of 514 patients were assigned to receive argatroban (59 patients), eptifibatide (227 patients), or placebo (228 patients). All the patients received intravenous thrombolysis (70% received alteplase, and 30% received tenecteplase), and 225 patients (44%) underwent endovascular thrombectomy. At 90 days, the mean (±SD) utility-weighted modified Rankin scale scores were 5.2±3.7 with argatroban, 6.3±3.2 with eptifibatide, and 6.8±3.0 with placebo. The posterior probability that argatroban was better than placebo was 0.002 (posterior mean difference in utility-weighted modified Rankin scale score, -1.51±0.51) and that eptifibatide was better than placebo was 0.041 (posterior mean difference, -0.50±0.29). The incidence of symptomatic intracranial hemorrhage was similar in the three groups (4% with argatroban, 3% with eptifibatide, and 2% with placebo). Mortality at 90 days was higher in the argatroban group (24%) and the eptifibatide group (12%) than in the placebo group (8%). CONCLUSIONS: In patients with acute ischemic stroke treated with intravenous thrombolysis within 3 hours after symptom onset, adjunctive treatment with intravenous argatroban or eptifibatide did not reduce poststroke disability and was associated with increased mortality. (Funded by the National Institute of Neurological Disorders and Stroke; MOST ClinicalTrials.gov number, NCT03735979.).

Trends in Disparities in Advanced Neuroimaging Utilization in Acute Stroke: A Population-Based Study.

BACKGROUND: Our primary objective was to evaluate if disparities in race, sex, age, and socioeconomic status (SES) exist in utilization of advanced neuroimaging in year 2015 in a population-based study. Our secondary objective was to identify the disparity trends and overall imaging utilization as compared with years 2005 and 2010. METHODS: This was a retrospective, population-based study that utilized the GCNKSS (Greater Cincinnati/Northern Kentucky Stroke Study) data. Patients with stroke and transient ischemic attack were identified in the years 2005, 2010, and 2015 in a metropolitan population of 1.3 million. The proportion of imaging use within 2 days of stroke/transient ischemic attack onset or hospital admission date was computed. SES determined by the percentage below the poverty level within a given respondent's US census tract of residence was dichotomized. Multivariable logistic regression was used to determine the odds of advanced neuroimaging use (computed tomography angiogram/magnetic resonance imaging/magnetic resonance angiogram) for age, race, gender, and SES. RESULTS: There was a total of 10 526 stroke/transient ischemic attack events in the combined study year periods of 2005, 2010, and 2015. The utilization of advanced imaging progressively increased (48% in 2005, 63% in 2010, and 75% in 2015 [P<0.001]). In the combined study year multivariable model, advanced imaging was associated with age and SES. Younger patients (≤55 years) were more likely to have advanced imaging compared with older patients (adjusted odds ratio, 1.85 [95% CI, 1.62-2.12]; P<0.01), and low SES patients were less likely to have advanced imaging compared with high SES (adjusted odds ratio, 0.83 [95% CI, 0.75-0.93]; P<0.01). A significant interaction was found between age and race. Stratified by age, the adjusted odds of advanced imaging were higher for Black patients compared with White patients among older patients (>55 years; adjusted odds ratio, 1.34 [95% CI, 1.15-1.57]; P<0.01), but no racial differences among the young. CONCLUSIONS: Racial, age, and SES-related disparities exist in the utilization of advanced neuroimaging for patients with acute stroke. There was no evidence of a change in trend of these disparities between the study periods.

The relevance of rich club regions for functional outcome post-stroke is enhanced in women.

This study aimed to investigate the influence of stroke lesions in predefined highly interconnected (rich-club) brain regions on functional outcome post-stroke, determine their spatial specificity and explore the effects of biological sex on their relevance. We analyzed MRI data recorded at index stroke and ~3-months modified Rankin Scale (mRS) data from patients with acute ischemic stroke enrolled in the multisite MRI-GENIE study. Spatially normalized structural stroke lesions were parcellated into 108 atlas-defined bilateral (sub)cortical brain regions. Unfavorable outcome (mRS > 2) was modeled in a Bayesian logistic regression framework. Effects of individual brain regions were captured as two compound effects for (i) six bilateral rich club and (ii) all further non-rich club regions. In spatial specificity analyses, we randomized the split into "rich club" and "non-rich club" regions and compared the effect of the actual rich club regions to the distribution of effects from 1000 combinations of six random regions. In sex-specific analyses, we introduced an additional hierarchical level in our model structure to compare male and female-specific rich club effects. A total of 822 patients (age: 64.7[15.0], 39% women) were analyzed. Rich club regions had substantial relevance in explaining unfavorable functional outcome (mean of posterior distribution: 0.08, area under the curve: 0.8). In particular, the rich club-combination had a higher relevance than 98.4% of random constellations. Rich club regions were substantially more important in explaining long-term outcome in women than in men. All in all, lesions in rich club regions were associated with increased odds of unfavorable outcome. These effects were spatially specific and more pronounced in women.

Association Between CT Angiogram Collaterals and CT Perfusion in Delayed Time Windows for Large Vessel Occlusion Ischemic Strokes.

OBJECTIVES: Recent endovascular trials have established the use of CT perfusion (CTP) in endovascular treatment selection for patients with large vessel occlusions (LVO). However, the relationship between CTP and collateral circulation is unclear in delayed time windows. We explored the relationship between CT Angiogram (CTA) collaterals and CTP parameters in delayed time windows (6-24 hours). MATERIALS AND METHODS: We utilized a single institutional, retrospective stroke registry of consecutive patients between May 2016 and May 2018 with anterior LVO with CTA and CTP imaging within 6-24 hours of stroke onset. We graded baseline collaterals on single phase CTA using modified Tan collateral score (0-3) and dichotomized into good (2-3) and poor (0-1) collaterals. We recorded automated CTP parameters, including estimated ischemic core (cerebral blood flow (CBF)<30%), penumbra (Tmax>6 s), and mismatch ratio. We used Mann-Whitney test and linear regression to assess associations. RESULTS: We included 48 patients with median age of 62 years (IQR= 52-72), median core of 17.5 mL (IQR=0-47), and median penumbra of 117.5 mL (IQR= 62-163.5). Patients with good collaterals had smaller median core (0 mL, IQR=0-12 mL vs. 40.5 mL, IQR=15-60 mL) (p < 0.001), smaller median penumbra (83.5 mL, IQR=43-135 mL vs. 142.5 mL, IQR=77-190 mL) (p = 0.04), larger median mismatch ratio (13.7, IQR=5.7-58.0 vs. 3.1, IQR=2.1-5.0) (p < 0.001), and lower median hypoperfusion intensity ratio (0.23, IQR=0-0.44 vs. 0.52, IQR=0.45-0.63) (p < 0.001) than patients with poor collaterals. CONCLUSIONS: In delayed time window LVO patients, good CTA collaterals are significantly associated with smaller CTP core, smaller penumbra, larger mismatch ratio, and lower hypoperfusion intensity ratio. CTA collateral assessment could be a potential valuable surrogate to perfusion imaging, particularly in stroke centers where CTP is unavailable.

Correlation of Alberta Stroke Program Early Computed Tomography Score With Computed Tomography Perfusion Core in Large Vessel Occlusion in Delayed Time Windows.

BACKGROUND AND PURPOSE: The Alberta Stroke Program Early Computed Tomography (CT) Score (ASPECTS) and CT perfusion (CTP) are commonly used to predict the ischemic core in acute ischemic strokes. CT angiography source images (CTA-SI) can also provide additional information to identify the extent of ischemia. Our objective was to investigate the correlation of noncontrast CT (NCCT) ASPECTS and CTA-SI ASPECTS with CTP core volumes. METHODS: We utilized a single institutional, retrospective registry of consecutive patients with acute ischemic stroke with large vessel occlusion between May 2016 and May 2018. We graded ASPECTS both on baseline NCCT and CTA-SI and measured CTP core using automated RAPID software (cerebral blood flow <30%). We used Spearman's correlation coefficients to evaluate the correlation between continuous variables. RESULTS: A total of 52 patients fit the inclusion criteria of large vessel occlusion in 6 to 24 hours and baseline imaging work up of NCCT, CTA, and CTP. The median age was 63 (interquartile range=53.5-75) and 38.46% were female. The median NCCT ASPECTS was 7 (interquartile range=6-9), CTA-SI ASPECTS was 5 (interquartile range=4-7), and CTP core was 14.5 mL (interquartile range=0-46 mL). There was a moderate correlation between NCCT ASPECTS and CTP core (rs=-0.55, P<0.0001) and between CTA-SI ASPECTS and CTP core (rs=-0.50, P=0.0002). The optimal NCCT ASPECTS cutoff score to detect CTP core ≤70 mL was ≥6 (sensitivity, 0.84; specificity, 0.57; positive predictive value, 0.93; negative predictive value, 0.36) and the optimal CTA-SI ASPECTS was ≥5 (sensitivity, 0.76; specificity, 0.71; positive predictive value, 0.94; negative predictive value, 0.31). CONCLUSIONS: There was a moderate correlation between NCCT and CTA-SI ASPECTS in predicting CTP defined ischemic core in delayed time windows. Further studies are needed to determine if NCCT and CTA imaging could be used for image-based patient selection when CTP imaging is not available.

Acute Stroke Imaging Research Roadmap IV: Imaging Selection and Outcomes in Acute Stroke Clinical Trials and Practice.

BACKGROUND AND PURPOSE: The Stroke Treatment Academic Industry Roundtable (STAIR) sponsored an imaging session and workshop during the Stroke Treatment Academic Industry Roundtable XI via webinar on October 1 to 2, 2020, to develop consensus recommendations, particularly regarding optimal imaging at primary stroke centers. METHODS: This forum brought together stroke neurologists, neuroradiologists, neuroimaging research scientists, members of the National Institute of Neurological Disorders and Stroke, industry representatives, and members of the US Food and Drug Administration to discuss imaging priorities in the light of developments in reperfusion therapies, particularly in an extended time window, and reinvigorated interest in brain cytoprotection trials. RESULTS: The imaging session summarized and compared the imaging components of recent acute stroke trials and debated the optimal imaging strategy at primary stroke centers. The imaging workshop developed consensus recommendations for optimizing the acquisition, analysis, and interpretation of computed tomography and magnetic resonance acute stroke imaging, and also recommendations on imaging strategies for primary stroke centers. CONCLUSIONS: Recent positive acute stroke clinical trials have extended the treatment window for reperfusion therapies using imaging selection. Achieving rapid and high-quality stroke imaging is therefore critical at both primary and comprehensive stroke centers. Recommendations for enhancing stroke imaging research are provided.

Controversies in Imaging of Patients With Acute Ischemic Stroke: AJR Expert Panel Narrative Review.

The development of reperfusion therapies has profoundly impacted stroke care, initially with the advent of IV thrombolytic treatment and, more recently, with the development and refinement of endovascular treatment (EVT). Progress in neuroim-aging has supported the paradigm shift of stroke care, and advanced neuroimaging now has a fundamental role in triaging patients for both IV thrombolytic treatment and EVT. As the standard of care for acute ischemic stroke (AIS) evolves, controversies remain in certain clinical scenarios. This article explores the use of multimodality imaging for treatment selection of patients with AIS in the context of recent guidelines, highlighting controversial topics and providing guidance for clinical practice. The results of major randomized trials supporting EVT are reviewed. The advantages and disadvantages of CT, CTA, MRI, and MRA in stroke diagnosis are summarized with attention to level 1 evidence supporting the role of vascular imaging and perfusion imaging. Patient selection is compared between approaches based on time thresholds and physiologic approaches based on infarct core measurement using imaging. Moreover, various imaging approaches to core measurement are described. As ongoing studies push treatment boundaries, advanced imaging is expected to help identify a widening range of patients who may benefit from therapy.

Isolated Third Cranial Nerve Palsy in Pituitary Apoplexy: Case Report and Systematic Review.

OBJECTIVES: To report a case of isolated third nerve palsy from pituitary apoplexy and perform a systematic literature review. MATERIALS AND METHODS: MEDLINE/EMBASE databases were searched up to September 2020. INCLUSION CRITERIA: Age≥18, isolated third nerve palsy from pituitary apoplexy. EXCLUSION CRITERIA: Age<18, presence of other neurological findings, no hemorrhage or infarction of pituitary. RESULTS: Case report: A 76-year-old woman presented with headache and right-sided ptosis. Right-eye exam revealed complete ptosis, absent pupillary constriction and accommodation, depressed and abducted eye on primary gaze, and -1 impaired depression, adduction, elevation, without other neurological findings. Brain MRI was suggestive of pituitary apoplexy. Pathology after transsphenoidal resection revealed an infarcted pituitary adenoma. Third nerve palsy resolved completely in 21 days. Systematic review: Twenty-three studies reporting 35 patients were selected from 182 abstracts. Twenty-nine (83%) had complete isolated third nerve palsy. Headache was reported in 31 (97%). Thirty-one had hemorrhage and 1 had infarction of pituitary. Cavernous sinus invasion occurred in 14 (50%). Twenty-eight were managed surgically (80%) and 7 medically (20%). Nerve palsy resolved completely in 27 (82%) and partially in 4 (11%). CONCLUSIONS: Pituitary apoplexy is an important differential diagnosis in patients with isolated third nerve palsy. Isolated third nerve palsy in apoplexy appears to have favorable prognosis.

The Impact of the COVID-19 Pandemic on the Radiology Research Enterprise: Radiology Scientific Expert Panel.

The current coronavirus disease 2019 (COVID-19) crisis continues to grow and has resulted in marked changes to clinical operations. In parallel with clinical preparedness, universities have shut down most scientific research activities. Radiology researchers are currently grappling with these challenges that will continue to affect current and future imaging research. The purpose of this article is to describe the collective experiences of a diverse international group of academic radiology research programs in managing their response to the COVID-19 pandemic. The acute response at six distinct institutions will be described first, exploring common themes, challenges, priorities, and practices. This will be followed by reflections about the future of radiology research in the wake of the COVID-19 pandemic.

Big Data Approaches to Phenotyping Acute Ischemic Stroke Using Automated Lesion Segmentation of Multi-Center Magnetic Resonance Imaging Data.

Background and Purpose- We evaluated deep learning algorithms' segmentation of acute ischemic lesions on heterogeneous multi-center clinical diffusion-weighted magnetic resonance imaging (MRI) data sets and explored the potential role of this tool for phenotyping acute ischemic stroke. Methods- Ischemic stroke data sets from the MRI-GENIE (MRI-Genetics Interface Exploration) repository consisting of 12 international genetic research centers were retrospectively analyzed using an automated deep learning segmentation algorithm consisting of an ensemble of 3-dimensional convolutional neural networks. Three ensembles were trained using data from the following: (1) 267 patients from an independent single-center cohort, (2) 267 patients from MRI-GENIE, and (3) mixture of (1) and (2). The algorithms' performances were compared against manual outlines from a separate 383 patient subset from MRI-GENIE. Univariable and multivariable logistic regression with respect to demographics, stroke subtypes, and vascular risk factors were performed to identify phenotypes associated with large acute diffusion-weighted MRI volumes and greater stroke severity in 2770 MRI-GENIE patients. Stroke topography was investigated. Results- The ensemble consisting of a mixture of MRI-GENIE and single-center convolutional neural networks performed best. Subset analysis comparing automated and manual lesion volumes in 383 patients found excellent correlation (ρ=0.92; P<0.0001). Median (interquartile range) diffusion-weighted MRI lesion volumes from 2770 patients were 3.7 cm3 (0.9-16.6 cm3). Patients with small artery occlusion stroke subtype had smaller lesion volumes ( P<0.0001) and different topography compared with other stroke subtypes. Conclusions- Automated accurate clinical diffusion-weighted MRI lesion segmentation using deep learning algorithms trained with multi-center and diverse data is feasible. Both lesion volume and topography can provide insight into stroke subtypes with sufficient sample size from big heterogeneous multi-center clinical imaging phenotype data sets.

Imaging-based Selection for Endovascular Treatment in Stroke.

Treatment of acute ischemic stroke (AIS) has evolved significantly in the past few years. Endovascular treatment (EVT) is now proved to be efficacious up to 24 hours from onset in properly selected patients. The recently updated 2018 American Heart Association-American Stroke Association guidelines reflect the important role of imaging in triage and patient selection for EVT of AIS. Pretreatment imaging in patients with acute stroke should (a) allow assessment for intracranial hemorrhage and demonstrate (b) the extent of early ischemic changes, (c) the presence of large arterial occlusion, and (d) in some cases potential salvageable tissue before the decision to proceed with EVT. The authors review how multimodality imaging can be used for EVT selection in the context of the recent guidelines. They highlight the importance of having streamlined imaging workflows that are integrated with clinical decision making to maximize treatment efficiency. Knowledge of the various imaging criteria including perfusion imaging used for EVT selection is highlighted. The authors discuss variable imaging paradigms used for selection of patients in the early and late windows (who present before vs after 6 hours from onset of symptoms), as reflected in the latest guidelines and in relation to their level of evidence. Finally, they focus on challenges in the subgroups of patients who were excluded from recent EVT trials and with limited evidence to prove the efficacy of EVT, such as patients with low NIHSS (National Institutes of Health Stroke Scale) score, distal occlusion, or large ischemic core. ©RSNA, 2019 See discussion on this article by Leslie-Mazwi.

CT for Treatment Selection in Acute Ischemic Stroke: A Code Stroke Primer.

CT is the primary imaging modality used for selecting appropriate treatment in patients with acute stroke. Awareness of the typical findings, pearls, and pitfalls of CT image interpretation is therefore critical for radiologists, stroke neurologists, and emergency department providers to make accurate and timely decisions regarding both (a) immediate treatment with intravenous tissue plasminogen activator up to 4.5 hours after a stroke at primary stroke centers and (b) transfer of patients with large-vessel occlusion (LVO) at CT angiography to comprehensive stroke centers for endovascular thrombectomy (EVT) up to 24 hours after a stroke. Since the DAWN and DEFUSE 3 trials demonstrated the efficacy of EVT up to 24 hours after last seen well, CT angiography has become the operational standard for rapid accurate identification of intracranial LVO. A systematic approach to CT angiographic image interpretation is necessary and useful for rapid triage, and understanding common stroke syndromes can help speed vessel evaluation. Moreover, when diffusion-weighted MRI is unavailable, multiphase CT angiography of collateral vessels and source-image assessment or perfusion CT can be used to help estimate core infarct volume. Both have the potential to allow distinction of patients likely to benefit from EVT from those unlikely to benefit. This article reviews CT-based workup of ischemic stroke for making tPA and EVT treatment decisions and focuses on practical skills, interpretation challenges, mimics, and pitfalls.©RSNA, 2019.

Cerebellar Hippocampal and Basal Nuclei Transient Edema with Restricted diffusion (CHANTER) Syndrome.

BACKGROUND: Abnormal restricted diffusion on magnetic resonance imaging is often associated with ischemic stroke or anoxic injury, but other conditions can present similarly. We present six cases of an unusual but consistent pattern of restricted diffusion in bilateral hippocampi and cerebellar cortices. This pattern of injury is distinct from typical imaging findings in ischemic, anoxic, or toxic injury, suggesting it may represent an under-recognized clinicoradiographic syndrome. Despite initial presentation with stupor or coma in the context of obstructive hydrocephalus, patients may have acceptable outcomes if offered early intervention. METHODS: We identified an ad hoc series of patients at our two institutions between years 2014 and 2017 who presented to the neurocritical care unit with severe, otherwise unexplained cerebellar edema and retrospectively identified several commonalities in history, presentation, and imaging. RESULTS: Between two institutions, we identified six patients-ages 33-59 years, four male-with similar presentations of decreased level of consciousness in the context of intoxicant exposure, with acute cytotoxic edema of the cerebellar cortex, hippocampi, and aspects of the basal nuclei. All patients presented with severe cerebellar edema which led to obstructive hydrocephalus requiring aggressive medical and/or surgical management. The five patients who survived to discharge demonstrated variable degrees of physical and memory impairment on discharge and at follow-up. CONCLUSIONS: We present findings of a potentially novel syndrome involving a distinct pattern of cerebellar and hippocampal restricted diffusion, with imaging and clinical characteristics distinct from ischemic stroke, hypoxic injury, and known toxidromes and leukoencephalopathies. Given the potential for favorable outcome despite early obstructive hydrocephalus, early identification and treatment of this syndrome are critical.

Collateral Clock Is More Important Than Time Clock for Tissue Fate.

Background and Purpose- Although perfusion abnormality is an increasingly important therapeutic target, the natural history of tissue at risk without reperfusion treatment is understudied. Our objective was to determine how time affects penumbral salvage and infarct growth in untreated acute ischemic stroke patients and whether collateral status affects this relationship. Methods- We used a prospectively collected, multicenter acute stroke registry to assess acute stroke patients who were not treated with intravenous thrombolysis or endovascular treatment. We analyzed baseline computed tomography angiogram and computed tomography perfusion within 24 hours of stroke onset along with follow-up imaging and assessed time from stroke onset to baseline imaging, ASPECTS (Alberta Stroke Program Early CT Score), vessel occlusion, collaterals, ischemic core, and penumbra. Penumbral salvage and infarct growth were calculated. Correlations between time and penumbral salvage and infarct growth were evaluated with Spearman correlation. Penumbral salvage and infarct growth were compared between subjects with good versus poor collateral status using the Wilcoxon rank-sum test. Clinical and imaging factors affecting penumbral salvage and infarct growth were evaluated by linear regression. Results- Among 94 untreated stroke patients eligible for this analysis, the mean age was 65 years, median National Institutes of Health Stroke Scale score was 13, and median (range) time from stroke onset to baseline imaging was 2.9 (0.4-23) hours. There was no correlation between time and salvaged penumbra ( r=0.06; P=0.56) or infarct growth ( r=-0.05; P=0.61). Infarct growth was higher among those with poor collaterals versus those with good collaterals (median, 52.3 versus 0.9 cm3; P<0.01). Penumbral salvage was lower among those with poor collaterals compared with those with good collaterals (poor, 0 [0-0]; good, 5.9 cm3 [0-29.4]; P<0.01). Multivariable linear regression demonstrated that collaterals, but not time, were significantly associated with infarct growth and penumbral salvage. Conclusions- In this natural history study, penumbral salvage and infarct growth were less time dependent and more a measure of collateral flow.

Diagnostic accuracy of MRI texture analysis for grading gliomas.

PURPOSE: Texture analysis (TA) can quantify variations in surface intensity or patterns, including some that are imperceptible to the human visual system. The purpose of this study was to determine the diagnostic accuracy of radiomic based filtration-histogram TA to differentiate high-grade from low-grade gliomas by assessing tumor heterogeneity. METHODS: Patients with a histopathological diagnosis of glioma and preoperative 3T MRI imaging were included in this retrospective study. A region of interest was manually delineated on post-contrast T1 images. TA was performed using commercially available research software. The histogram parameters including mean, standard deviation, entropy, mean of the positive pixels, skewness, and kurtosis were analyzed at spatial scaling factors ranging from 0 to 6 mm. The parameters were correlated with WHO glioma grade using Spearman correlation. Areas under the curve (AUC) were calculated using ROC curve analysis to distinguish tumor grades. RESULTS: Of a total of 94 patients, 14 had low-grade gliomas and 80 had high-grade gliomas. Mean, SD, MPP, entropy and kurtosis each showed significant differences between glioma grades for different spatial scaling filters. Low and high-grade gliomas were best-discriminated using mean of 2 mm fine texture scale, with a sensitivity and specificity of 93% and 86% (AUC of 0.90). CONCLUSIONS: Quantitative measurement of heterogeneity using TA can discriminate high versus low-grade gliomas. Radiomic data of texture features can provide complementary diagnostic information for gliomas.

Prehospital Triage of Acute Ischemic Stroke Patients to an Intravenous tPA-Ready versus Endovascular-Ready Hospital: A Decision Analysis.

BACKGROUND: American Stroke Association guidelines for prehospital acute ischemic stroke recommend against bypassing an intravenous tPA-ready hospital (IRH), if additional transportation time to an endovascular-ready hospital (ERH) exceeds 15-20 min. However, it is unknown when the benefit of potential endovascular therapy at an ERH outweighs the harm from delaying intravenous therapy at a closer IRH, especially since large vessel occlusion (LVO) status is initially unknown. We hypothesized that current time recommendations for IRH bypass are too short to achieve optimal outcomes for certain patient populations. METHODS: A decision analysis model was constructed using population-based databases, a detailed literature review, and interventional trial data containing time-dependent modified Rankin Scale distributions. The base case was triaged by Emergency Medical Services (EMS) 110 min after stroke onset and had a 23.6% LVO rate. Base case triage choices were (1) transport to the closest IRH (12 min), (2) transport to the ERH (60 min) bypassing the IRH, or (3) apply the Cincinnati Stroke Triage Assessment Tool and transport to the ERH if positive for LVO. Outcomes were assessed using quality-adjusted life years (QALYs). Sensitivity analyses were performed for all major variables, and alternative prehospital stroke scales were assessed. RESULTS: In the base case, transport to the IRH was the optimal choice with an expected outcome of 8.47 QALYs. Sensitivity analyses demonstrated that transport to the ERH was superior until bypass time exceeded 44 additional minutes, or when the onset to EMS triage interval exceeded 99 min. As the probability of LVO increased, ERH transport was optimal at longer onset to EMS triage intervals. The optimal triage strategy was highly dependent on specific interactions between the IRH transportation time, ERH transportation time, and onset to EMS triage interval. CONCLUSIONS: No single time difference between IRH and ERH transportation optimizes triage for all patients. Allowable IRH bypass time should be increased and acute ischemic stroke guidelines should incorporate the onset to EMS triage interval, IRH transportation time, and ERH transportation time.

Effect of Alteplase vs Aspirin on Functional Outcome for Patients With Acute Ischemic Stroke and Minor Nondisabling Neurologic Deficits: The PRISMS Randomized Clinical Trial.

Importance: More than half of patients with acute ischemic stroke have minor neurologic deficits (National Institutes of Health Stroke Scale [NIHSS] score of 0-5) at presentation. Although prior major trials of alteplase included patients with low NIHSS scores, few without clearly disabling deficits were enrolled. Objective: To evaluate the efficacy and safety of alteplase in patients with NIHSS scores of 0 to 5 whose deficits are not clearly disabling. Design, Setting, and Participants: The PRISMS trial was designed as a 948-patient, phase 3b, double-blind, double-placebo, multicenter randomized clinical trial of alteplase compared with aspirin for emergent stroke at 75 stroke hospital networks in the United States. Patients with acute ischemic stroke whose deficits were scored as 0 to 5 on the NIHSS and judged not clearly disabling and in whom study treatment could be initiated within 3 hours of onset were eligible and enrolled from May 30, 2014, to December 20, 2016, with final follow-up on March 22, 2017. Interventions: Participants were randomized to receive intravenous alteplase at the standard dose (0.9 mg/kg) with oral placebo (n = 156) or oral aspirin, 325 mg, with intravenous placebo (n = 157). Main Outcomes and Measures: The primary outcome was the difference in favorable functional outcome, defined as a modified Rankin Scale score of 0 or 1 at 90 days via Cochran-Mantel-Haenszel test stratified by pretreatment NIHSS score, age, and time from onset to treatment. Because of early termination of the trial, prior to unblinding or interim analyses, the plan was revised to examine the risk difference of the primary outcome by a linear model adjusted for the same factors. The primary safety end point was symptomatic intracranial hemorrhage (sICH) within 36 hours of intravenous study treatment. Results: Among 313 patients enrolled at 53 stroke networks (mean age, 62 [SD, 13] years; 144 [46%] women; median NIHSS score, 2 [interquartile range {IQR}, 1-3]; median time to treatment, 2.7 hours [IQR, 2.1-2.9]), 281 (89.8%) completed the trial. At 90 days, 122 patients (78.2%) in the alteplase group vs 128 (81.5%) in the aspirin group achieved a favorable outcome (adjusted risk difference, -1.1%; 95% CI, -9.4% to 7.3%). Five alteplase-treated patients (3.2%) vs 0 aspirin-treated patients had sICH (risk difference, 3.3%; 95% CI, 0.8%-7.4%). Conclusions and Relevance: Among patients with minor nondisabling acute ischemic stroke, treatment with alteplase vs aspirin did not increase the likelihood of favorable functional outcome at 90 days. However, the very early study termination precludes any definitive conclusions, and additional research may be warranted. Trial Registration: ClinicalTrials.gov Identifier: NCT02072226.

Significance of Cerebral Small-Vessel Disease in Acute Intracerebral Hemorrhage.

BACKGROUND AND PURPOSE: The significance of structural changes associated with cerebral small-vessel disease (SVD), including white matter lesions (WML), lacunes, and brain atrophy, to outcome from acute intracerebral hemorrhage is uncertain. We determined associations of computed tomographic radiological manifestations of cerebral SVD and outcomes, and in terms of any differential effect of early intensive blood pressure-lowering treatment, in the large-scale Intensive Blood Pressure Reduction in Acute Cerebral Hemorrhage Trial (INTERACT2). METHODS: We graded WML (van Swieten scale), the presence of lacunes, and brain atrophy (2 linear measurements and visual rating) for 2069 of 2839 patients with available baseline brain computed tomography (<6 hours of intracerebral hemorrhage onset) by 3 independent neurologists blind to clinical data. RESULTS: WML grade and 2 linear measurements of brain atrophy were associated with death or major disability at 90 days: multivariable-adjusted odds ratios for WML (grade 3 and 4 versus 0), frontal ratio, and third ventricle Sylvian fissure distance (most versus least severe atrophy quartile) were 1.42 (95% confidence interval, 1.02-1.98), 1.47 (1.08-1.99), and 1.64 (1.21-2.22), respectively (all P for trend <0.05). There was no association between lacunes and outcomes. There were no significant differences in the effects of intensive blood pressure-lowering across subgroups of cerebral SVD. CONCLUSIONS: Preexisting cerebral SVD manifestations of WML and brain atrophy predict poor outcome in acute intracerebral hemorrhage. There is no apparent hazard of early intensive lowering of blood pressure according to the INTERACT2 protocol, in patients with underlying cerebral SVD. CLINICAL TRIAL REGISTRATION: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00716079.

Association Between CT Angiogram Collaterals and CT Perfusion in the Interventional Management of Stroke III Trial.

BACKGROUND AND PURPOSE: Collateral flow can determine ischemic core and tissue at risk. Using the Interventional Management of Stroke (IMS) III trial data, we explored the relationship between computed tomography angiogram (CTA) collateral status and CT perfusion (CTP) parameters. METHODS: Baseline CTA collaterals were trichotomized as good, intermediate, and poor, and CTP studies were analyzed to quantify ischemic core, tissue at risk, and mismatch ratios. Kruskal-Wallis and Spearman tests were used to measure the strength of association and correlation between CTA collaterals and CTP parameters. RESULTS: A total of 95 patients had diagnostic CTP studies in the IMS III trial. Of these, 53 patients had M1/M2 middle cerebral artery±intracranial internal carotid artery occlusion, where baseline CTA collateral grading was performed. CTA collaterals were associated with smaller CTP measured ischemic core volume (P=0.0078) and higher mismatch (P=0.0004). There was moderate negative correlation between collaterals and core (rs=-0.45; 95% confidence interval, -0.64 to -0.20) and moderate positive correlation between collaterals and mismatch (rs=0.53; 95% confidence interval, 0.29-0.71). CONCLUSION: Better collaterals were associated with smaller ischemic core and higher mismatch in the IMS III trial. Collateral assessment and perfusion imaging identify the same biological construct about ischemic tissue sustenance.