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RationaleIntracranial atherosclerotic disease (ICAD) is the most common cause of ischemic stroke with the highest rate of recurrence, despite aggressive medical management. Diverse mechanisms may be responsible for ICAD-related cerebral ischemia, with potential therapeutic implications. Here we present the rationale, design and methods of the Mechanisms of Early Recurrence in Intracranial Atherosclerotic Disease (MyRIAD) study. The aim of MyRIAD is to determine the mechanisms of stroke in ICAD through physiologic imaging biomarkers that evaluate impaired antegrade flow, poor distal perfusion, abnormal vasoreactivity, artery to artery embolism, and their interaction.Methods and designThis is a prospective observational study of patients with recently symptomatic (<21 days) ICAD with 50-99% stenosis treated medically and monitored for up to 1 year. An estimated 110 participants are recruited at 10 sites to identify the association between the presence of each mechanism of ischemia and recurrent stroke. The primary outcome is ischemic stroke in the territory of the symptomatic artery. Secondary outcomes include new cerebral infarction on MRI at 6-8 weeks and recurrent TIA in the territory of the symptomatic artery.DiscussionMyRIAD is positioned to define the role of specific mechanisms of recurrent ischemia in patients with symptomatic ICAD. This knowledge will allow the development and implementation of effective and specific treatments for this condition.

Imaging of stroke and neurovascular disorders has profoundly enhanced clinical practice and related research during the last 40 years since the introduction of computed tomography (CT) and magnetic resonance imaging (MRI) enabled mapping of the brain. We highlight recent advances in neurovascular imaging. We describe how the convergence of readily available data and new clinical trial paradigms will recast our methods for studying the neurovascular patient. The application of a precision medicine approach to the collaterome, a comprehensive synthesis of neurovascular pathophysiology, will entail novel methods for clinical trial randomization, collection of routine and clinical trial imaging results, data archiving, and analysis.

BackgroundCollaterals may affect revascularization, ischemic severity, and clinical outcomes in acute stroke owing to internal carotid artery (ICA) occlusion.ObjectiveTo examine the hypothesis that morphology of occlusive thrombus and collateral flow patterns may influence the outcome of ICA occlusions after mechanical thrombectomy.MethodsPooled analyses of ICA occlusions in the MERCI and Multi-MERCI trials employed central angiography review readings to categorize lesions as I, L, or T clots and functional lesions based on collateral flow patterns. Demographic variables, procedural details, and clinical outcomes were compared across ICA lesion types.ResultsA total of 72 subjects (mean age 67 years (SD 16), 51% female, median National Institutes of Health Stroke Scale 20 (range 8-35)) were included, with 90-day modified Rankin score ≤2 in 28% and 51% mortality. Clots were categorized as an I lesion in 9/72 (12.5%), L lesion in 12/72 (16.7%), and T lesion in 51/72 (70.8%). Based on collateral flow patterns, cases were categorized as having a functional I lesion in 7/72 (9.7%), functional L in 38/72 (52.8%), and functional T in only 27/72 (37.5%). Multivariate analyses showed that a functional T lesion, with insufficient collateral flow to ipsilateral anterior cerebral arteries via the contralateral ICA, was a strong predictor of both revascularization success and subsequent clinical outcomes.ConclusionsCollateral flow patterns distinguish the nature and impact of ICA occlusions on expected revascularization and subsequent clinical outcomes in acute ischemic stroke. The nomenclature of terminal ICA occlusions introduced here (carotid I's, L's, and T's) may enhance future endovascular trials targeting such proximal occlusions.Trial registration numberNCT00318071 (http://clinicaltrials.gov). MERCI was not registered because enrollment began before July 1, 2005.

Background and purposeFractional flow may identify hemodynamic effects and ischemic risk beyond percent stenosis of an artery. We hypothesized that diminished TOF-MRA signal intensity distal to an intracranial stenosis predicts stroke risk.MethodsTOF-MRA was acquired prospectively in the SONIA-WASID trials. The distal/proximal signal intensity ratio (SIR) was calculated from 3 mm regions of interest, blinded to outcome. Univariate and multivariate analyses included clinical variables, SIR, and invasive angiography measures to identify predictors for risk of stroke in the territory.Results189 patients with 50-99% symptomatic intracranial stenosis in SONIA-WASID had TOF-MRA available. In univariate analysis, the hazard ratio (HR) for stroke in the territory of the symptomatic artery with SIR < .9 was 5.2 (1.8, 15.3; P < .001) as compared to SIR ≥ .9. Multivariate analysis correcting for baseline systolic blood pressure, LDL, centrally measured percent stenosis, recency of symptoms, TICI and downstream collaterals, the HR for SIR < .9 was 10.9 (2.0, 58.9; P < .001). In those with <70% stenosis, a SIR < .9 maintained a significant association with recurrent stroke in the territory (P = .006), with a 2-year event rate of 17.3%.ConclusionsFractional flow assessed by TOF-MRA SIR may be a useful noninvasive tool to identify high-risk intracranial lesions.Clinical trial registration-urlThis trial was not registered because enrollment began prior to July 1, 2005.

The recent culmination of imaging-endowed endovascular stroke trials has decisively proven the utility of clinically relevant neuroimaging in improving the outcome of patients with potentially debilitating neurological disorders. These large multicenter trials conducted across several continents notably utilized a variety of multimodal CT/MRI modalities to rapidly identify a favorable collateral profile that presages clinically beneficial revascularization. The modern clinical neuroimager may accelerate complex decision-making through the rational use of a variety of imaging modalities and an active feedback loop of imaging at the bedside. The modern clinical neuroimager is often the initial care provider for a wide range or type of stroke patients from hemorrhage to ischemia, armed with the incredibly important aspects of clinical history and examination findings and best poised to utilize imaging to guide therapy from acute stroke to recovery and prevention. The next generation in stroke should not exclusively focus on whether to order a CT or MRI counting minutes at the bedside, but actively and efficiently integrate the vast wealth of information available when imaging is used in the proper clinical context. The novel endovascular era in stroke provides an ideal venue for the synergistic goals of translating research advances, improving patient outcomes and ongoing education as a modern neuroimager.

BackgroundPrecision medicine in cerebrovascular disorders may be greatly advanced by the use of innovative interventional and imaging-intensive registries. Registries have remained subsidiary to randomized controlled trials, yet vast opportunities exist to leverage big data in stroke.SummaryThis overview builds upon the rationale for innovative, imaging-intensive interventional registries as a pivotal step in realizing precision medicine for several cerebrovascular disorders. Such enhanced registries may serve as a model for expansion of our translational research pipeline to fully leverage the role of phase IV investigations. The scope and role of registries in precision medicine are considered, followed by a review on the history of stroke and interventional registries, data considerations, critiques or barriers to such initiatives, and the potential modernization of registry methods into efficient, searchable, imaging-intensive resources that simultaneously offer clinical, research and educational added value.Key messagesRecent advances in technology, informatics and endovascular stroke therapies converge to provide an exceptional opportunity for registries to catapult further progress. There is now a tremendous opportunity to deploy registries in acute stroke, intracranial atherosclerotic disease and carotid disease where other clinical trials leave questions unanswered. Unlike prior registries, imaging-intensive and modernized methods may leverage current technological capabilities around the world to efficiently address key objectives and provide added clinical, research and educational value.

Background and purposeThe Alberta Stroke Program Early CT Score (ASPECTS) on baseline imaging is an established predictor of acute ischemic stroke outcomes. We analyzed change on serial ASPECTS at baseline and 24-hour imaging in the Solitaire Flow Restoration with the Intention for Thrombectomy (SWIFT) study to determine prognostic value and to identify subgroups with extensive injury after intervention.MethodsASPECTS at baseline and 24 hours was independently scored in all anterior circulation SWIFT cases, blinded to all other trial data. ASPECTS at baseline, at 24 hours, and serial changes were analyzed with univariate and multivariate approaches.ResultsOne hundred thirty-nine patients (mean age, 67 [SD, 12] years; 52% women; median National Institutes of Health Stroke Scale, 18 [interquartile range, 8-28]) with complete data at both time points were studied. Multivariate analyses showed that higher 24-hour ASPECTS predicted good clinical outcome (day 90 modified Rankin Scale, 0-2; odds ratio, 1.67; P<0.001). Among patients with high baseline ASPECTS (8-10; n=109), dramatic infarct progression (decrease in ASPECTS ≥6 points at 24 hours) was noted in 31 of 109 (28%). Such serial ASPECTS change was predicted by higher baseline systolic blood pressure (P=0.019), higher baseline blood glucose (P=0.133), and failure to achieve Thrombolysis in Cerebral Infarction score of 2b/3 reperfusion (P<0.001), culminating in worse day 90 modified Rankin Scale outcomes (mean modified Rankin Scale, 4.4 versus 2.7; P<0.001).ConclusionsTwenty-four-hour ASPECTS provides better prognostic information compared with baseline ASPECTS. Predictors of dramatic infarct progression on ASPECTS are hyperglycemia, hypertension, and nonreperfusion. Serial ASPECTS change from baseline to 24 hours predicts clinical outcome, providing an early surrogate end point for thrombectomy trials.Clinical trial registration urlhttp://www.clinicaltrials.gov. Unique identifier: NCT01054560.

Data drive the analyses of any ischemic stroke trial, culminating in the main results and potential next steps. The distinct purpose of a given trial, advancing a novel treatment or examining routine clinical practice, determines the nature of essential data elements. Information gathering for an effective trial depends on ample data, adequate infrastructure, and properly planned statistical analyses. This review highlights the fact that successful future trials will require appropriate expertise that extends far beyond these basic considerations in order to move from identification of basic risk factors that are associated with outcomes to knowledge of pathophysiology and causation of outcomes. Efficient and productive data collection by local and central sites must be complemented by expert core lab adjudications. Source data archiving, including complete DICOM imaging datasets or biological specimens, are needed to maximize the potential for study interpretation and financial investment. Standard terminology, such as common data elements and definitions, enhance study comparisons. Screening logs attest to generalizability of a study. Real-time data transmission and core lab evaluation will be critical to guide adaptive trial design. Despite the overwhelming focus on the intervention in a particular treatment trial, individual pathophysiology must be considered. Understanding individual subject characteristics is a tenet of the coming era of precision stroke care, where the course of a given patient and eventual outcome is paramount. This will require a new approach to data collection in clinical trials.

Background and purposeEndovascular strategies provide unique opportunity to correlate angiographic measures of collateral circulation at the time of endovascular therapy. We conducted systematic analyses of collaterals at conventional angiography on recanalization, reperfusion, and clinical outcomes in the endovascular treatment arm of the Interventional Management of Stroke (IMS) III trial.MethodsProspective evaluation of angiographic collaterals was conducted via central review of subjects treated with endovascular therapy in IMS III (n=331). Collateral grade before endovascular therapy was assessed with the American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology scale, blinded to all other data. Statistical analyses investigated the association between collaterals with baseline clinical variables, angiographic measures of recanalization, reperfusion and clinical outcomes.ResultsAdequate views of collateral circulation to the ischemic territory were available in 276 of 331 (83%) subjects. Collateral grade was strongly related to both recanalization of the occluded arterial segment (P=0.0016) and downstream reperfusion (P<0.0001). Multivariable analyses confirmed that robust angiographic collateral grade was a significant predictor of good clinical outcome (modified Rankin Scale score≤2) at 90 days (P=0.0353), adjusted for age, history of diabetes mellitus, National Institutes of Health Stroke Scale strata, and Alberta Stroke Program Early CT Score. The relationship between collateral flow and clinical outcome may depend on the degree of reperfusion.ConclusionsMore robust collateral grade was associated with better recanalization, reperfusion, and subsequent better clinical outcomes. These data, from the largest endovascular trial to date, suggest that collaterals are an important consideration in future trial design.Clinical trial registration urlhttp://www.clinicaltrials.gov. Unique identifier: NCT00359424.

Numerous acute ischemic stroke trials have recently published detailed results, providing an opportunity to consider the role of collaterals in stroke pathophysiology and their influential effect on patient outcomes. Safety and Efficacy of NeuroFlo Technology in Ischemic Stroke (SENTIS), the largest randomized controlled trial of device therapy to date, tested the potential augmentation of collateral perfusion. SYNTHESIS Expansion, Mechanical Retrieval and Recanalization of Stroke Clots Using Embolectomy (MR RESCUE), and Interventional Management of Stroke (IMS) III chronicled the saga of endovascular therapy trialed against medical treatment for acute ischemic stroke. These recent randomized studies, however, largely neglect current device technology available for endovascular therapy as advanced by the TREVO2 and SOLITAIRE™(TM) FR With the Intention For Thrombectomy (SWIFT) studies. Such exhaustive efforts in recent trials have failed to introduce a new treatment for stroke that unequivocally improves patient outcomes. Collateral perfusion is widely recognized to vary across individuals in any population and exerts a dramatic effect on baseline variables including the time course of ischemic injury, stroke severity, imaging findings, and therapeutic opportunities. Similarly, collaterals have been recognized to influence recanalization, reperfusion, hemorrhagic transformation, and subsequent neurological outcomes after stroke. Collateral lessons may be gleaned from these trials, to expand consideration of overall study results and perhaps most importantly, alter ongoing and new trials in development. Detailed analyses of available information on collaterals from these trials demonstrate that collaterals may be more influential than the choice of treatment modality or intervention.

Background and purposeCollaterals at angiography before endovascular therapy were analyzed to ascertain the effect on a novel end point of successful revascularization without symptomatic hemorrhage in the Solitaire FR With the Intention for Thrombectomy (SWIFT) study.MethodsCollateral grade (American Society of Interventional and Therapeutic Neuroradiology/Society of Interventional Radiology) on baseline angiography was independently assessed, blind to other data, with statistical analyses delineating the relationship with clinical, laboratory, and imaging parameters.ResultsAngiographic data on collaterals were available in 119 of 144 subjects (mean age, 67±12 years; 52% woman; median National Institutes of Health Stroke Scale, 18 [range, 8-28]). Worse collaterals were noted in subjects with elevated baseline blood glucose (P=0.013) and those with elevated baseline systolic blood pressure (P=0.039). Multivariate predictors of partial or worse collaterals included absence of prior hypertension (odds ratio, 4.049, P=0.012), smoking history (odds ratio, 3.822; P=0.013), and higher blood glucose (odds ratio, 1.017; P=0.022). Collaterals were strongly related to Alberta Stroke Program Early CT Score (ASPECTS) at baseline (0-1: median 8 [3-10]; 2-9 [5-10]; 3-9 [7-10]; 4-9 [8-10]; P<0.001) and 24 hours (0-1: median 1 [0-5]; 2-6 [0-10]; 3-8 [0-10]; 4-8 [4-8]; P<0.001). Better collaterals were linked with Thrombolysis in Cerebral Infarction 2b/3 reperfusion (P=0.019), better median National Institutes of Health Stroke Scale at day 7/discharge (P<0.001), and better day 90 modified Rankin Scale (P<0.001). Better collateral grade was associated with successful revascularization without symptomatic hemorrhage, mean 2.3 (95% confidence interval, 2.1-2.5) versus 1.9 (95% confidence interval, 1.7-2.2), P=0.021.ConclusionsBetter collaterals were associated with lower glucose, lower blood pressure, smaller baseline infarcts in SWIFT, and greater likelihood of successful

BackgroundThe Stroke Outcomes and Neuroimaging of Intracranial Atherosclerosis (SONIA) study validated noninvasive imaging tests of intracranial atherosclerosis against catheter angiography in a prospective, blinded, multicenter setting. Critical evaluation of transcranial Doppler (TCD) and magnetic resonance angiography in the SONIA study standardized their performance and interpretation. We performed a similar analysis of computed tomography angiography (CTA) for the detection of intracranial stenosis.MethodsMulticenter standardization of image acquisition and blinded, central interpretation of CTA performance were conducted in concert with the Warfarin-Aspirin Symptomatic Intracranial Disease (WASID) trial. Measurements of the intracranial arterial diameter were obtained to derive stenosis values. Correlation with catheter angiography was used to assess CTA performance characteristics.ResultsCTA measurements of intracranial stenosis were obtained in 120 vessel segments, with angiographic correlation in 52. CTA was performed as a noninvasive study prior to conventional angiography. CTA stenoses of 50-99% or a flow gap were identified in 15 of 52 vessel segments, stenoses of <50% in 5 of 52, and normal arterial diameters in 32 of 52 vessel segments. Based on the digital subtraction angiography (DSA) stenosis defined as 50-99%, the positive predictive value (PPV) of CTA was only 46.7% (95% CI 21.3-73.4) and the negative predictive value (NPV) was 73.0% (95% CI 55.9-86.2). For DSA stenosis defined as 70-99%, the PPV of CTA was 13.3% (95% CI 1.7-40.5) and the NPV was 83.8% (95% CI 68.0-93.8).ConclusionsCTA can accurately rule out the presence of severe stenosis due to intracranial atherosclerosis and may eliminate the need for angiography in many cases. Further prospective, blinded evaluation of CTA and optimization of cutpoints to predict angiographic disease will facilitate future trials of intracranial atherosclerosis.

Revascularization remains the most intuitive strategy to reverse ischemic injury associated with arterial occlusion in acute stroke. Revascularization may lead to opening of an occluded artery, or recanalization, yet restoration of downstream flow, or reperfusion, may not ensue. Revascularization strategies and novel devices continue to broaden options for the treatment of acute stroke, but it is increasingly apparent that selection criteria to identify ideal cases are needed to refine triage and minimize adverse events. The results of recent work on reperfusion may rapidly alter routine clinical practice for evolving ischemia in the brain.

Revascularization remains the most intuitive strategy to reverse ischemic injury associated with arterial occlusion in acute stroke. Revascularization may lead to opening of an occluded artery, or recanalization, yet restoration of downstream flow, or reperfusion, may not ensue. Revascularization strategies and novel devices continue to broaden options for the treatment of acute stroke, but it is increasingly apparent that selection criteria to identify ideal cases are needed to refine triage and minimize adverse events. The results of recent work on reperfusion may rapidly alter routine clinical practice for evolving ischemia in the brain.