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Background and Purpose— We sought to estimate risk of recurrent stroke/TIA/death in the subgroup of the Patent Foramen Ovale in the Cryptogenic Stroke Study (PICSS) cohort with patent foramen ovale (PFO) and antiphospholipid antibodies (aPL) and to estimate risk of recurrent stroke/TIA/death in aPL-positive patients who have thickened left-side heart valves (VaT). PFO is associated with cryptogenic ischemic stroke. Also, the presence of aPL is associated with ischemic cerebrovascular disease. Methods— Combined data from 2 major substudies of the Warfarin Aspirin Recurrent Stroke Trial (WARSS) were evaluated. PICSS subjects were included if they were enrolled in the Antiphospholipid Antibodies and Stroke Study (APASS) and underwent a baseline aPL test (lupus anticoagulant, anticardiolipin antibodies, or both) within 1 month of the stroke. All patients in PICSS underwent transesophageal echocardiography for PFO as well as VaT, which was performed blinded to aPL status and treatment arm (325 mg/day aspirin or adjusted dose warfarin; target international normalized ratio, 1.4–2.8). The primary outcome event was the 2-year risk of recurrent stroke/TIA/death and was evaluated using Cox proportional hazards model. Because there was no treatment effect, warfarin and aspirin groups were combined to increase power. For the combined end point, power to detect HR of 2 was 47.8% for the PFO and aPL-positive group, and 75.3% for the valve thickening and aPL-positive group, assuming 2-sided type I error of 0.05. Results— Five hundred twenty-five subjects were tested for the combined presence of PFO and aPL and were available for evaluation. The primary outcome event rate was 23.9% (HR, 1.39; 95% CI, 0.75–2.59) in the PFO-positive/aPL-positive group, compared to 13.9% (HR, 0.83; 95% CI, 0.44–1.56) in the PFO-positive/aPL-negative group, and 19.9% (HR, 1.16; 95% CI, 0.68–1.90) in the PFO-negative/aPL-positive group. Five hundred forty-five subjects tested for combined presence of aPL and left-side cardiac VaT were available for evaluation. The primary event rate was 22.6% (HR, 1.65; 95% CI, 0.88–3.09) in the VaT-positive/aPL-positive group, compared to 19.4% (HR, 1.50; 95% CI, 0.82–2.75) in the VaT-positive/aPL-negative group, and 20.2% (HR, 1.63; 95% CI, 0.81–3.25) in the VaT-negative/aPL-positive group. Conclusions— The combined presence of aPL either with a PFO or with left-side cardiac VaT did not significantly increase risk of subsequent cerebrovascular events in this PICCS/APASS cohort of patients.

Background and Purpose— Biochemical markers of acute neuronal injury may aid in the diagnosis and management of acute ischemic stroke. Serum samples from the National Institute for Neurological Disorders and Stroke (NINDS) recombinant tissue plasminogen activator Stroke Study were analyzed for the presence of 4 biochemical markers of neuronal, glial, and endothelial cell injury. These biochemical markers, myelin basic protein (MBP), neuron-specific enolase (NSE), S100β, and soluble thrombomodulin, were studied for an association with initial stroke severity, infarct volume, and functional outcome. Methods— In the original NINDS study, serum samples were drawn from all patients on presentation to the Emergency Department and at ≈2 and 24 hours after initiation of study therapy. In this analysis, stored serum samples were available for 359 patients; 107 patients had samples for all 3 time points. Serum marker concentrations were measured by ELISA techniques. We examined the relation between serum concentrations of each marker and the degree of baseline neurological deficit, functional outcome, and infarct size on computed tomography at 24 hours and the effect of fibrinolytic therapy. Results— Higher 24-hour peak concentrations of MBP, NSE, and S100β were associated with higher National Institutes of Health Stroke Scale baseline scores ( r =0.186, P r =0.117, P =0.032; and r =0.263, P r =0.209, P r =0.239, P P Conclusions— This study corroborates previous work demonstrating correlations of MBP, NSE, and S100β with clinical and radiographic features in acute stroke. Despite significantly better outcomes in the tissue plasminogen activator–treated group, we found no difference in the early release of the 4 biomarkers between treatment groups. Further study will define the role of biomarkers in acute stroke management and prognostication.

Background and Purpose— Most large, randomized phase III efficacy trials of therapeutic agents in ischemic stroke have failed to find treatment benefit. We determined whether some phase III studies could have been avoided if preceded by smaller single-arm phase II studies to evaluate the futility of proceeding to phase III. Methods— To provide examples of the application of phase II methodology, we obtained primary outcome data for the active treatment group of 6 phase III ischemic stroke therapy trials. For each study, we estimated the sample size number required for a multistage single-arm study using parameters specified in the original study. We evaluated outcome data for the first number of subjects in the phase III study treatment arm ordered by enrollment dates. We compared the proportion of favorable outcomes to prespecified stopping criteria derived from a single-arm phase II futility design. If the observed proportion of favorable outcomes was less than the stopping criterion, we declared the treatment not sufficiently effective to warrant further evaluation in phase III. Results— We identified 3 trials as futile in phase II; none of 3 showed treatment efficacy in phase III. In the 3 remaining phase II trials in which we did not show futility, one showed efficacy in phase III. Conclusion— Single-arm phase II futility studies have been underused in stroke research, but provide a strategy for discarding treatments likely to be ineffective in phase III trials.

Background and Purpose —We examined the frequency, course, and treatment of hypertension in the NINDS rt-PA Stroke Trial. Methods —Blood pressure (BP) was measured at the time of admission, at randomization, and then 36 times during the first 24 hours after randomization. Patients with a systolic BP of >185 mm Hg and a diastolic BP of >110 mm Hg at admission were defined as hypertensive before randomization, and those with a systolic BP of >180 mm Hg or a diastolic BP of >105 mm Hg within the first 24 hours after randomization were defined as hypertensive after randomization. Standardized clinical assessments were conducted at 24 hours and at 3 months. Post hoc analyses were conducted to evaluate the association of antihypertensive therapy with clinical outcomes. Results —Of the 624 patients, 121(19%) had hypertension on admission and 372 (60%) had hypertension in the 24 hours after randomization. The use of antihypertensive therapy before randomization (tPA 9%, placebo 9%) and after randomization (tPA 24%, placebo 29%) was similar between placebo- and tPA-treated patients. No adverse effects of prerandomization antihypertensive therapy on 3-month favorable outcome were detected for either the placebo- or tPA-treated groups. For placebo patients with hypertension in the 24 hours after randomization, clinical outcome measures were similar for those patients who did and did not receive antihypertensive therapy after randomization ( P ≥0.26); antihypertensive therapy was not associated with declines in BP ( P =0.44) or with abrupt declines ( P =0.14). Those tPA patients who were hypertensive after randomization and received antihypertensive therapy were less likely to have a favorable outcome at 3 months ( P Conclusions —The frequency of hypertension and the use of antihypertensive therapy were similar between the tPA and placebo groups in the NINDS rt-PA Stroke Trial. In the placebo group, antihypertensive therapy was not associated with less favorable outcomes at 3 months; postrandomization antihypertensive therapy was associated with less favorable outcomes for the tPA patients who were hypertensive. However, because of the nonrandomized use of antihypertensive therapy and the many post hoc comparisons leading to type 1 errors, the significance of this observation is unclear. Careful attention to BP and gentle management remain warranted for stroke patients treated with tPA.

Background The National Institute of Neurological Disorders and Stroke (NINDS) held a workshop on statistical approaches to analysis of acute stroke trials that have multiple prespecified outcomes. An objective was to plan for statistical analysis of the NINDS t-PA Stroke Trial, a randomized, double-blind, placebo-controlled trial of recombinant tissue plasminogen activator (rt-PA) for patients with acute ischemic stroke. Treatment success was defined as a “consistent and persuasive difference” in the proportion of patients achieving favorable outcomes on the Barthel Index, Modified Rankin Scale, Glasgow Outcome Scale, and National Institutes of Health Stroke Scale. The Data and Safety Monitoring Committee for the trial recommended this outcome because the committee did not believe that a positive result for a single outcome would provide sufficient evidence of efficacy. Summary of Comment Workshop participants accepted the global test as a viable approach to testing the primary trial hypothesis. Clinician participants advocated categorizing outcomes as favorable/unfavorable, outcomes more clinically meaningful than continuous outcomes for evaluating a drug with potentially serious side effects. They agreed that a global test was appropriate for ischemic stroke when no single outcome is accepted. Hypothetical, special-case examples illustrate that highly correlated outcomes diminish the power of the global test. NINDS t-PA Stroke Trial data demonstrate the clinical interpretability of the global test. Conclusions Workshop participants concluded that a global statistic should be used to test the trial's primary hypothesis accompanied by secondary tests of individual outcomes. Workshop participants recommended familiarizing the clinical/scientific community with the global approach.

See related articles, p 1163 and 1171. The 2 articles in this issue1,2 are based on the recent European Stroke Organization Outcomes Workshop and provide an excellent basis for discussion of outcomes used in stroke trials. Bath, Lees, and colleagues raise important points to consider when choosing an outcome measure or an analysis plan. The authors speculate that trials to identify therapeutic benefits of effective drugs may fail to find benefits because of problems inherent in choice of outcome measures or methods of analysis. Early in their article, Bath and colleagues give examples of multiple ways to define an outcome and show that trial results vary based on the definitions used. The emphasis throughout the article is on increasing power to detect differences so effective treatments will not be missed. There are many ways to increase power, but not all lead to the identification of clinically meaningful differences. The authors give little mention to the possibility of a Type 1 error, that is, declaring an ineffective therapy effective. Type I errors can result from searches for outcomes and analytic approaches to increase the power to detect treatment differences after a trial is completed. It is as important to patients that ineffective treatments are kept out of clinical practice as it is to assure that effective treatments are not missed. The authors recognize that 1 outcome and 1 analytic approach may not fit all trials. In choosing an outcome or approach, the most important consideration is the research question of interest. It is the trial hypothesis that should drive the choices. As an example, at a workshop to identify outcomes and an analytic approach for the National Institute of Neurological Disorders and Stroke Tissue Plasminogen Activator (NINDS tPA) Stroke Trial,3 Thomas Brott stated that he would …

In Parkinson Disease (PD) as well as in stroke research there is an urgent need to both optimize the use of resources (number of patients, costs, and time) and select potential effective neuroprotective agents. The processes used to identify and study new therapies for PD may be applicable to the search for new therapies in stroke. The National Institute of Neurological Disorders and Stroke (NINDS) organized the Committee to Identify Neuroprotective Agents for Parkinson’s (CINAPS). CINAPS broadly solicited suggestions for agents and evaluated these agents using rigorous criteria. NINDS also created the NIH Exploratory Trials in PD program (NET-PD), a clinical network where CINAPS recommendations could be tested. Given multiple recommended agents, NET-PD investigators used Phase II futility designs with calibration controls, tested against an historical standard, to screen agents for testing in Phase III trials. Investigators also used the Phase II trial to assess ancillary outcome measures for use in Phase III. The observed value for the calibration controls in the first NET-PD Phase II trial was outside the 95% CI for the historical standard. Using bootstrap methodology it appeared unlikely this outcome happened by chance. The historical standard was updated using more contemporaneous data than were available at the start of the futility trials and a re-evaluation using the new threshold was conducted. Assessment of ancillary outcome measures led to a reduced set of outcome measures for use in Phase III. The CINAPS process, and lessons learned from NET-PD futility studies, particularly with respect to calibration controls and assessment of outcome measures, could enhance the choice and testing of new agents for stroke treatment.

Background and Purpose— Early thrombolytic therapy with intravenous recombinant tissue plasminogen activator (rtPA) improves clinical outcome in acute ischemic stroke (AIS), but impaired endogenous fibrinolysis, thrombin generation, and vascular injury may hamper the efficacy of thrombolysis. We investigated in an exploratory, post hoc analysis the relationship between hemostatic markers and clinical outcomes among patients included in the National Institute of Neurological Disorders and Stroke (NINDS) rtPA Stroke Study. Methods— Tissue plasminogen activator (tPA) antigen, thrombin-antithrombin complex (TAT), soluble thrombomodulin, and fibrinogen levels were measured in patients with AIS included in the NINDS rtPA Stroke Study from plasma samples collected at baseline, at 2 hours after treatment, and after 24 hours. Results— TAT and tPA antigen levels peaked at 2 hours selectively in the rtPA treatment group, whereas fibrinogen levels dropped at 2 hours and remained low after 24 hours ( P Conclusions— Hemostatic activation after AIS appears to be independently associated with clinical outcome in patients treated with rtPA. However, because we have tested for multiple associations, some may have been identified by chance alone and require further confirmatory studies. On the basis of this exploratory analysis, there is a rationale to investigate the safety and efficacy of protocols in which rtPA is complemented by agents that are antithrombotic and enhance fibrinolysis.

Background and Purpose—The National Institutes of Health (NIH) estimates that stroke costs now exceed $45 billion 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 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.Conclusion—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.

Background and Purpose —We sought to identify the most powerful binary measures of the treatment effect of tissue plasminogen activator (tPA) in the National Institute of Neurological Disorders and Stroke (NINDS) rTPA Stroke Trial. Methods —Using the Classification and Regression Tree (CART) algorithm, we evaluated binary cut points and combination of binary cut points with the 4 clinical scales and head CT imaging measures in the NINDS tPA Stroke Trial at 4 times after treatment: 2 hours, 24 hours, 7 to 10 days, and 3 months. The first analysis focused on detecting evidence of “early activity” of tPA with the use of outcome measures derived from the 2-hour and 24-hour clinical and radiographic measures. The second analysis focused on longer-term outcome and “efficacy” and used outcome measures derived from 7- to 10-day and 3-month measures. After identifying the cut points with the ability to classify patients into the tPA and placebo groups using part I data from the trial, we then used data from part II of the trial to validate the results. Results —Of the 5 most powerful outcome measures for early activity of tPA, 4 involved the National Institutes of Health Stroke Scale (NIHSS) score at 24 hours or changes in the NIHSS score from baseline to 24 hours. The best overall single outcome measure was an NIHSS score ≤2 at 24 hours, which provided an odds ratio of 5.4 (95% CI, 2.4 to 12.1) and a projected sample size of 58 per treatment group assuming an α of 0.05 (2-sided test) and a power of 80% using part I data. The top 2 and 3 of the top 5 outcome measures for detecting the longer-term efficacy of tPA also involved the NIHSS score. A Rankin score of 0 or 1 at 3 months was the third most powerful outcome measure. Outcome measures identified by CART from part I data were not as sensitive in detecting the effectiveness of tPA when applied to part II data. Conclusions —Measures using the NIHSS and a Rankin score ≤1 were the most sensitive discriminators of the effectiveness of tPA in the NINDS tPA Stroke Trial compared with the other clinical and radiological measures. The outcome measures identified in this exploratory analysis (eg, NIHSS score ≤2 at 24 hours) would be best used as an outcome measure in future phase II trials of recanalization begun within the first 3 hours after stroke onset, with inclusion and exclusion criteria similar to those in the NINDS tPA Stroke Trial.

Background and Purpose —Ischemic changes identified on CT scans performed in the first few hours after stroke onset, which are thought to possibly represent early cytotoxic edema and development of irreversible injury, may have important implications for subsequent treatment. However, insecurity and conflicting data exist over the ability of clinicians to correctly recognize and interpret these changes. We performed a detailed review of selected baseline CT scans from the NINDS rt-PA Stroke Trial to test agreement among experienced stroke specialists and other physicians on the presence of early CT ischemic changes. Methods —Seventy baseline CT scans from the NINDS Stroke Trial were read and classified for the presence or absence of various early findings of ischemia by 16 individuals, including NINDS trial investigators, other neurologists, other emergency medicine physicians, and radiology or stroke fellows. CT scans included normal scans and scans from patients who later developed symptomatic intracranial hemorrhage, as well as scans on which the NINDS rt-PA Stroke Trial neuroradiologist identified clear-cut early CT changes. For each CT finding, κ-statistics were used to assess the proportion of agreement beyond chance. Results —κ-Values (95% confidence interval [CI]) ranged from 0.20 (−0.20, 0.61) (fair agreement) to 0.41 (0.37, 0.45) (moderate agreement) among the 16 viewers, and the κ-value was only 0.39 (0.29, 0.49) (fair) in answer to the question “do early CT changes involve more than one third of the MCA [middle cerebral artery] territory?” There was substantial variability within each specialty group and between groups. κ-Values were only fair to moderate even among physicians experienced in selecting and treating acute stroke patients with rtPA. Observed agreement ranged from 68% to 85%. Physicians agreed on the finding of early CT changes involving >33% of the MCA territory 77% of the time, although the κ-value of 0.39 suggested only moderate agreement beyond chance. Conclusions —There is considerable lack of agreement, even among experienced clinicians, in recognizing and quantifying early CT changes. Improved methods of recognizing and quantifying early ischemic brain damage are needed.

Intracerebral hemorrhage (ICH) is more than twice as common as subarachnoid hemorrhage (SAH) and is much more likely to result in death or major disability than cerebral infarction or SAH.1 Although >315 randomized clinical therapeutic trials for acute ischemic stroke and 78 trials for SAH were complete or ongoing (oral communication, Cochrane Collaboration, May 16, 1995) as of 1995, only the results of 4 small randomized surgical trials (353 total patients)2 3 4 5 and 4 small medical trials (513 total patients)6 7 8 9 of ICH had been published. In these small randomized studies, neither surgical nor medical treatment has been shown conclusively to benefit patients with ICH. Advancing age and hypertension are the most important risk factors for ICH.10 11 12 13 14 15 ICH occurs slightly more frequently among men than women and is significantly more common among young and middle-aged blacks than whites of similar ages.10 16 Reported incidence rates of ICH among Asian populations are also higher than those reported for whites in the United States and Europe. Pathophysiological change in small arteries and arterioles due to sustained hypertension is generally regarded as the most important cause of ICH.11 12 14 17 18 Cerebral amyloid angiopathy is increasingly recognized as a cause of lobar ICH in the elderly.19 20 21 22 23 Other causes of ICH include vascular malformations, ruptured aneurysms, coagulation disorders, use of anticoagulants and thrombolytic agents, hemorrhage into a cerebral infarct, bleeding into brain tumors, and drug abuse.10 Of the estimated 37 000 Americans who experienced an ICH in 1997, 35% to 52% were dead at 1 month; half of the deaths occurred within the first 2 days.1 17 24 Only 10% of patients were living independently at 1 month; 20% were independent …

Despite the frequent use of clinical rating scales in multicenter therapeutic stroke trials, no generally acceptable method exists to train and certify investigators to use the instrument consistently. We desired to train investigators to use the National Institutes of Health Stroke Scale in a study of acute stroke therapy so that all examiners rated patients comparably. We devised a two-camera videotape method that optimizes the visual presentation of examination findings. We then measured the effectiveness of the training by asking each investigator to evaluate a set of 11 patients, also on videotape. We tabulated the evaluations, devised a scoring system, and calculated measures of interobserver agreement among the participants in this study. We trained and certified 162 investigators. We found moderate to excellent agreement on most Stroke Scale items (unweighted kappa > 0.60). Two items, facial paresis and ataxia, exhibited poor agreement (unweighted kappa < 0.40) and should be revised in future editions of the scale. Performance improved with video training compared with previous studies. Inclusion of the motor rating of the unaffected limbs in the total score did not affect reliability. Video training and certification is a practical and effective method to standardize the use of examination scales. Two cameras must be used during the taping of patients to accurately present the clinical findings. This method is easily adapted to any study in which a large number of investigators will be enrolling patients at multiple clinical centers.

Regional cerebral blood flow was measured by the 133Xe inhalation technique in patients with unilateral carotid occlusion, unilateral carotid occlusion and contralateral carotid stenosis, bilateral carotid occlusion, or normal arteriograms. After adjusting for age, sex, and history of stroke, hemispheric blood flow asymmetry was shown to be a predictor of unilateral carotid occlusion with a sensitivity of 80.6% and a specificity of 80.5%. Asymmetry of regional cerebral blood flow is useful in the assessment of patients with extracranial cerebrovascular disease.