Measurement of the ischemic penumbra with MRI: it's about time.
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Animals↗
Biomedical subjects
Steven Warach
Publications and source records attributed to Steven Warach.
Trial design and reporting standards for intra-arterial cerebral thrombolysis for acute ischemic stroke.
BACKGROUND AND PURPOSE: The National Institutes of Health (NIH) estimates that stroke costs now exceed 45 billion dollars per year. Stroke is the third leading cause of death and one of the leading causes of adult disability in North America, Europe, and Asia. A number of well-designed randomized stroke trials and case series have now been reported in the literature to evaluate the safety and efficacy of thrombolytic therapy for the treatment of acute ischemic stroke. These stroke trials have included intravenous studies, intra-arterial studies, and combinations of both, as well as use of mechanical devices for removal of thromboemboli and of neuroprotectant drugs, alone or in combination with thrombolytic therapy. At this time, the only therapy demonstrated to improve outcomes from an acute stroke is thrombolysis of the clot responsible for the ischemic event. There is room for improvement in stroke lysis studies. Divergent criteria, with disparate reporting standards and definitions, have made direct comparisons between stroke trials difficult to compare and contrast in terms of overall patient outcomes and efficacy of treatment. There is a need for more uniform definitions of multiple variables such as collateral flow, degree of recanalization, assessment of perfusion, and infarct size. In addition, there are multiple unanswered questions that require further investigation, in particular, questions as to which patients are best treated with thrombolysis. One of the most important predictors of clinical success is time to treatment, with early treatment of <3 hours for intravenous tissue plasminogen activator and <6 hours for intra-arterial thrombolysis demonstrating significant improvement in terms of 90-day clinical outcome and reduced cerebral hemorrhage. It is possible that improved imaging that identifies the ischemic penumbra and distinguishes it from irreversibly infarcted tissue will more accurately select patients for therapy than duration of symptoms. There are additional problems in the assessment of patients eligible for thrombolysis. These include being able to predict whether a particular site of occlusion can be successfully revascularized, predict an individual patient's prognosis and outcome after revascularization, and in particular, to predict the development of intracerebral hemorrhage, with and without clinical deterioration. It is not clear to assume that achieving immediate flow restoration due to thrombolytic therapy implies clinical success and improved outcome. There is no simple correlation between recanalization and observed clinical benefit in all ischemic stroke patients, because other interactive variables, such as collateral circulation, the ischemic penumbra, lesion location and extent, time to treatment, and hemorrhagic conversion, are all interrelated to outcome. METHODS: This article was written under the auspices of the Technology Assessment Committees for both the American Society of Interventional and Therapeutic Neuroradiology and the Society of Interventional Radiology. The purpose of this document is to provide guidance for the ongoing study design of trials of intra-arterial cerebral thrombolysis in acute ischemic stroke. It serves as a background for the intra-arterial thrombolytic trials in North America and Europe, discusses limitations of thrombolytic therapy, defines predictors for success, and offers the rationale for the different considerations that might be important during the design of a clinical trial for intra-arterial thrombolysis in acute stroke. Included in this guidance document are suggestions for uniform reporting standards for such trials. These definitions and standards are mainly intended for research trials; however, they should also be helpful in clinical practice and applicable to all publications. This article serves to standardize reporting terminology and includes pretreatment assessment, neurologic evaluation with the NIH Stroke Scale score, imaging evaluation, occlusion sites, perfusion grades, follow-up imaging studies, and neurologic assessments. Moreover, previously used and established definitions for patient selection, outcome assessment, and data analysis are provided, with some possible variations on specific end points. This document is therefore targeted to help an investigator to critically review the scales and scores used previously in stroke trials. This article also seeks to standardize patient selection for treatment based on neurologic condition at presentation, baseline imaging studies, and utilization of standardized inclusion/exclusion criteria. It defines outcomes from therapy in phase I, II, and III studies. Statistical approaches are presented for analyzing outcomes from prospective, randomized trials with both primary and secondary variable analysis. A discussion on techniques for angiography, intra-arterial thrombolysis, anticoagulation, adjuvant therapy, and patient management after therapy is given, as well as recommendations for posttreatment evaluation, duration of follow-up, and reporting of disability outcomes. Imaging assessment before and after treatment is given. In the past, noncontrast CT brain scans were used as the initial screening examination of choice to exclude cerebral hemorrhage. However, it is now possible to quantify the volume of early infarct by using contiguous, discrete (nonhelical) images of 5 mm. In addition, CT angiography by helical scanning and 100 mL of intravenous contrast agent can be used expeditiously to obtain excellent vascular anatomy, define the occlusion site, obtain 2D and 3D reformatted vascular images, grade collateral blood flow, and perform tissue-perfusion studies to define transit times of a contrast bolus through specific tissue beds and regions of interest in the brain. Dynamic CT perfusion scans to assess the whole dynamics of a contrast agent transit curve can now be routinely obtained at many hospitals involved in these studies. The rationale, current status of this technology, and potential use in future clinical trials are given. Many hospitals are also performing MR brain studies at baseline in addition to, or instead of, CT scans. MRI has a high sensitivity and specificity for the diagnosis of ischemic stroke in the first several hours from symptom onset, identifies arterial occlusions, and characterizes ischemic pathology noninvasively. Case series have demonstrated and characterized the early detection of intraparenchymal hemorrhage and subarachnoid hemorrhage by MRI. Echo planar images, used for diffusion MRI and, in particular, perfusion MRI are inherently sensitive for the susceptibility changes caused by intraparenchymal blood products. Consequently, MRI has replaced CT to rule out acute hemorrhage in some centers. The rationale and the potential uses of MR scanning are provided. In addition to established criteria, technology is continuously evolving, and imaging techniques have been introduced that offer new insights into the pathophysiology of acute ischemic stroke. For example, a better patient stratification might be possible if CT and/or MRI brain scans are used not only as exclusion criteria but also to provide individual inclusion and exclusion criteria based on tissue physiology. Imaging techniques might also be used as a surrogate outcome measure in future thrombolytic trials. The context of a controlled study is the best environment to validate emerging imaging and treatment techniques. The final section details reporting standards for complications and adverse outcomes; defines serious adverse events, adverse events, and unanticipated adverse events; and describes severity of complications and their relation to treatment groups. Recommendations are made regarding comparing treatment groups, randomization and blinding, intention-to-treat analysis, quality-of-life analysis, and efficacy analysis. This document concludes with an analysis of general costs associated with therapy, a discussion regarding entry criteria, outcome measures, and the variability of assessment of the different stroke scales currently used in the literature is also featured. CONCLUSIONS: In summary, this article serves to provide a more uniform set of criteria for clinical trials and reporting outcomes used in designing stroke trials involving intra-arterial thrombolytic agents, either alone or in combination with other therapies. It is anticipated that by having a more uniform set of reporting standards, more meaningful analysis of the data and the literature will be able to be achieved.
Acute Disease↗
Editorial comment--Is there a perihematomal ischemic penumbra? More questions and an overlooked clue.
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Brain↗
Impact of establishing a primary stroke center at a community hospital on the use of thrombolytic therapy: the NINDS Suburban Hospital Stroke Center experience.
BACKGROUND AND PURPOSE: To increase the proportion of ischemic stroke patients treated with thrombolytic therapy, the establishment of primary stroke centers in community hospitals has been advocated. We evaluated the use of thrombolytic therapy before and after institution of a primary stroke center in a community hospital. METHODS: The availability of an on-call stroke emergency response team was the only significant additional resource required for this hospital. All eligible patients were treated with intravenous tissue plasminogen activator (tPA). The number of patients with cerebrovascular disease, number and proportion of patients treated with tPA, times to treatment, and patient outcomes were recorded during the first 2 years of the stroke center. RESULTS: During the 12 months before institution of the stroke center, 3 ischemic stroke patients (1.5%) were treated with tPA. During the 2-year period of around-the-clock coverage, 44 of 420 ischemic stroke patients (10.5%) were treated with intravenous tPA, a significant increase in tPA use (P<0.0001). CONCLUSIONS: Establishment of a primary stroke center at a community hospital resulted in a substantial increase in the proportion of patients receiving thrombolytic therapy for ischemic stroke. If this experience is generalized, the beneficial impact of primary stroke centers on stroke outcomes and costs to the healthcare system may be substantial.
Adult↗
Patterns of perfusion-weighted imaging in patients with carotid artery occlusive disease.
BACKGROUND: The importance of hemodynamic factors in the pathophysiology of stroke and transient ischemic attacks in patients with internal carotid artery (ICA) stenosis or occlusion remains controversial. OBJECTIVE: To investigate whether perfusion-weighted imaging (PWI) could identify pathophysiologically meaningful categories in patients with symptomatic and asymptomatic ICA occlusive disease. METHODS: Thirty-eight consecutive patients with occlusion (22 patients) or severe stenosis (16 patients) of the ICA, determined by ultrasonography or magnetic resonance angiography, were identified from the Beth Israel Deaconess Medical Center Stroke Database, Boston, Mass. Thirty-five patients were symptomatic (29 who had strokes and 6 who had transient ischemic attacks) and 3 were asymptomatic. All symptomatic patients underwent PWI within the first 24 hours after symptom onset. The patterns of PWI were analyzed according to the degree of ICA stenosis and the clinical presentation. RESULTS: Three patterns of perfusion abnormalities were identified: extensive hypoperfusion involving the middle cerebral arterial and/or anterior cerebral arterial territories (25 patients), localized perfusion deficits involving predominantly the ipsilateral border zone areas (8 patients), and normal perfusion (5 patients). All 3 patterns were found whether or not the ICA was occluded. Patients who had acute stroke most frequently had extensive perfusion deficits involving 1 or 2 territories while patients who had transient ischemic attacks often had hypoperfusion affecting the border zone regions. All asymptomatic patients had normal perfusion. CONCLUSIONS: In our sample the pattern of PWI related to the clinical presentation but not to the degree of ICA disease (occlusive vs severe stenosis). Our study findings add further support to the hypothesis that hypoperfusion is a major contributing factor in the pathophysiology of carotid artery occlusive disease.
Adult↗
Early ischemic lesion recurrence within a week after acute ischemic stroke.
Previous observations suggested that multiple ischemic lesions on diffusion-weighted imaging (DWI) are common in acute stroke patients. We hypothesized that a source of these multiple lesions was the recurrence of ischemic lesions within a week after a clinically symptomatic stroke. We analyzed 99 acute ischemic stroke patients scanned within 6 hours of onset and at subsequent times within the first week. Ischemic lesion recurrence was defined as any new lesion separate from the index lesion. Recurrent lesions occurring outside initial perfusion deficit were termed 'distant lesion recurrence'. We estimated the hazard ratio (HR) of recurrence associated with clinical and imaging characteristics using log-rank test. Any lesion recurrence was found in 34%, with distant lesion recurrence in 15%, while clinical recurrence was evident in 2%. Initial multiple DWI lesions were associated with any lesion recurrence (HR, 2.83; 95% confidence interval [CI], 1.65-10.29; p = 0.002) and with distant lesion recurrence (HR, 5.99; 95% CI, 4.05-64.07; p < 0.0001). Large-artery atherosclerosis was the most frequent stroke subtype associated with any lesion recurrence (p = 0.026). These results may indicate a prolonged state of increased ischemic risk over the first week and suggest DWI as a possible surrogate measure for recurrent stroke.
Acute Disease↗
Reversal of perfusion and diffusion abnormalities after intravenous thrombolysis for a lacunar infarction.
Perfusion and diffusion magnetic resonance imaging (MRI) have been used to guide therapy in patients with large vessel occlusions. In an analogous fashion, the authors used perfusion and diffusion MRI to demonstrate a perfusion deficit and a matching diffusion lesion in a patient with lacunar infarct. Following thrombolytic therapy, the authors observed a reversal of the perfusion deficit, the diffusion lesion, and clinical recovery. This case suggests that perfusion and diffusion MRI may be informative in patients with lacunar infarction who are candidates for thrombolysis.
Aged↗
Thrombolysis in stroke beyond three hours: Targeting patients with diffusion and perfusion MRI.
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Humans↗
Cerebral spinal fluid contamination of the measurement of the apparent diffusion coefficient of water in acute stroke.
The measurement of the apparent diffusion coefficient (ADC) of water in brains of stroke patients is used in models developed to help distinguish reversible from irreversible ischemic injury. The ADC by conventional methods may be overestimated by the presence of cerebral spinal fluid (CSF) in sulci and perivascular spaces. In this study the hypothesis that DWI with CSF suppression (FLAIR-DWI) would result in different ADC values than those obtained with the conventional DWI technique was investigated. Thirty-one patients with stroke onset of less than 6 hr and an acute lesion on conventional DWI were studied. Both conventional isotropic DWI and FLAIR-DWI were performed using a single-shot echo-planar technique. In all 31 patients, CSF-suppressed ADC was lower than conventional ADC. The mean (SD) of the 31 patients' lesion ADC was 0.64 (0.08) x 10(-3) mm(2) s(-1) with FLAIR-DWI and 0.72 (0.09) x 10(-3) mm(2) s(-1) with conventional DWI (P < 0.001). The overestimation of ADC in conventional DWI corresponded to the percentage of the voxel that contained CSF. Suppression of CSF leads to lesion ADC values that are more homogeneous and more than 15% lower than those obtained with conventional DWI techniques. This suggests that FLAIR-DWI ADC measurements are more accurate than conventional ADC maps.
Acute Disease↗
Significance of early CT signs in acute stroke. A CT scan-diffusion MRI study.
OBJECTIVE: To study the pathophysiology of early CT signs. BACKGROUND: Early CT signs, due to an increase in tissue water content, are commonly attributed to cytotoxic edema and development of irreversible injury. This may have important implications for thrombolysis. METHODS: In patients with acute ischemic stroke in the middle cerebral artery territory, the areas of early CT signs and diffusion weighted imaging (DWI) hypersignal were independently assessed and drawn on a standardized atlas. Then, patients were classified into three groups (early CT signs larger than, similar to or smaller than DWI hypersignal) and compared with perfusion weighted imaging (PWI). RESULTS: Of 16 patients, CT scanning was performed with a median time of 3 h after onset and early CT scan signs were recorded in 10/16 patients (62.5%). DWI signal hyperintensity was present in 15/16 (94%) patients. In 7/16 (43%) patients, the area with early CT scan signs was larger than the DWI lesion ('CT-larger group'). Only in 2/16 (12%) patients were the areas matching ('matching group'). In 7/16 (43%) the DWI lesion was larger than the early CT scan signs area ('DWI-larger group'). When compared with PWI, the areas of early CT signs were larger than DWI hypersignal and were matching with PWI abnormalities (rMTT) in 2 cases, suggesting that they may represent a reversible process. CONCLUSIONS: Early CT signs might have a potential dual fate: infarction or reversibility. Other techniques of recognizing reversible ischemic damage, such as DWI-PWI, are needed to improve acute stroke diagnosis and management.
Acute Disease↗
Oral citicoline in acute ischemic stroke: an individual patient data pooling analysis of clinical trials.
BACKGROUND AND PURPOSE: No single neuroprotective agent has been shown to influence outcome after acute stroke. Citicoline has been studied worldwide in many clinical trials with positive findings, but only 1 trial has obtained significant results in the primary efficacy variables. Our objective was to evaluate the effects of oral citicoline in patients with acute ischemic stroke by a data pooling analysis of clinical trials. The primary efficacy end point chosen was the common evaluation of recovery, combining National Institutes of Health Stroke Scale </=1, modified Rankin Scale score </=1, and Barthel Index >/=95 at 3 months using the generalized estimating equations analysis. METHODS: A systematic search of all prospective, randomized, placebo-controlled, double-blind clinical trials with oral citicoline (MEDLINE, Cochrane, and Ferrer Group bibliographic databases) was undertaken. Individual patient data were extracted from each study and pooled in a single data file. The main inclusion criteria included compatible neuroimaging with ischemic stroke, National Institutes of Health Stroke Scale >/=8, and prior modified Rankin Scale score </=1. Four clinical trials using various doses of oral citicoline (500, 1000, and 2000 mg) were identified. RESULTS: Of 1652 randomized patients, 1372 fulfilled the inclusion criteria (583 received placebo, 789 received citicoline). Recovery at 3 months was 25.2% in citicoline-treated patients and 20.2% in placebo-treated patients (odds ratio [OR], 1.33; 95% CI, 1.10 to 1.62; P=0.0034). The dose showing the largest difference with placebo was 2000 mg, with 27.9% of patients achieving recovery (OR, 1.38; 95% CI, 1.10 to 1.72; P=0.0043). The overall safety of citicoline was similar to placebo. CONCLUSIONS: Treatment with oral citicoline within the first 24 hours after onset in patients with moderate to severe stroke increases the probability of complete recovery at 3 months.
Acute Disease↗
Use of diffusion and perfusion magnetic resonance imaging as a tool in acute stroke clinical trials.
In light of the slow progress in developing effective therapies for ischemic stroke, magnetic resonance imaging techniques have emerged as new tools in stroke clinical trials. Rapid imaging with magnetic resonance imaging, diffusion weighted imaging, perfusion imaging and angiography are being incorporated into phase II and phase III stroke trials to optimize patient selection based on positive imaging diagnosis of the ischemic pathophysiology specifically related to a drug's mechanism of action and as a direct biomarker of the effect of a treatment's effect on the brain.
Journal Article↗