Birgitte H. Bendixen

Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment.

Background and Purpose The etiology of ischemic stroke affects prognosis, outcome, and management. Trials of therapies for patients with acute stroke should include measurements of responses as influenced by subtype of ischemic stroke. A system for categorization of subtypes of ischemic stroke mainly based on etiology has been developed for the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Methods A classification of subtypes was prepared using clinical features and the results of ancillary diagnostic studies. “Possible” and “probable” diagnoses can be made based on the physicians certainty of diagnosis. The usefulness and interrater agreement of the classification were tested by two neurologists who had not participated in the writing of the criteria. The neurologists independently used the TOAST classification system in their bedside evaluation of 20 patients, first based only on clinical features and then after reviewing the results of diagnostic tests. Results The TOAST classification denotes five subtypes of ischemic stroke: 1) large-artery atherosclerosis, 2) cardioembolism, 3) small-vessel occlusion, 4) stroke of other determined etiology, and 5) stroke of undetermined etiology. Using this rating system, interphysician agreement was very high. The two physicians disagreed in only one patient. They were both able to reach a specific etiologic diagnosis in 11 patients, whereas the cause of stroke was not determined in nine. Conclusions The TOAST stroke subtype classification system is easy to use and has good interobserver agreement. This system should allow investigators to report responses to treatment among important subgroups of patients with ischemic stroke. Clinical trials testing treatments for acute ischemic stroke should include similar methods to diagnose subtypes of stroke.

Baseline NIH Stroke Scale score strongly predicts outcome after stroke A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST)

Objective: To compare the baseline National Institutes of Health Stroke Scale (NIHSS) score and the Trial of Org 10172 in Acute Stroke Treatment (TOAST) stroke subtype as predictors of outcomes at 7 days and 3 months after ischemic stroke. Methods: Using data collected from 1,281 patients enrolled in a clinical trial, subtype of stroke was categorized using the TOAST classification, and neurologic impairment at baseline was quantified using the NIHSS. Outcomes were assessed at 7 days and 3 months using the Barthel Index (BI) and the Glasgow Outcome Scale (GOS). An outcome was rated as excellent if the GOS score was 1 and the BI was 19 or 20 (scale of 0 to 20). Analyses were adjusted for age, sex, race, and history of previous stroke. Results: The baseline NIHSS score strongly predicted outcome, with one additional point on the NIHSS decreasing the likelihood of excellent outcomes at 7 days by 24% and at 3 months by 17%. At 3 months, excellent outcomes were noted in 46% of patients with NIHSS scores of 7 to 10 and in 23% of patients with scores of 11 to 15. After multivariate adjustment, lacunar stroke had an odds ratio of 3.1 (95% CI, 1.5 to 6.4) for an excellent outcome at 3 months. Conclusions: The NIHSS score strongly predicts the likelihood of a patient’s recovery after stroke. A score of ≥16 forecasts a high probability of death or severe disability whereas a score of ≤6 forecasts a good recovery. Only the TOAST subtype of lacunar stroke predicts outcomes independent of the NIHSS score.

Antithrombotic treatment of ischemic stroke among patients with occlusion or severe stenosis of the internal carotid artery A report of the Trial of Org 10172 in Acute Stroke Treatment (TOAST)

Objective: To examine the responses to early IV administration of an anticoagulant or placebo started within 24 hours of stroke among persons with an ipsilateral occlusion or severe stenosis of the internal carotid artery (ICA) identified by carotid duplex imaging. Background: Patients with ischemic stroke of the cerebral hemisphere secondary to an ipsilateral occlusion or severe stenosis of the ICA generally have a poor prognosis. Early, accurate identification of these patients might permit improved treatment. Methods: Exploratory analysis of outcomes at 7 days and 3 months was performed among patients enrolled in the Trial of Org 10172 in Acute Stroke Treatment (TOAST) who had an ischemic stroke in the cerebral hemisphere ipsilateral to an occlusion or a stenosis >50% of the ICA identified by carotid duplex imaging. Results: Regardless of treatment, patients with duplex evidence of an occlusion of the ICA had more severe strokes and poorer outcomes at 7 days and 3 months than patients who had a stenosis. Favorable outcomes at 7 days were noted in 64 of 119 patients given danaparoid (53.8%) and 41 of 108 patients treated with placebo (38.0%; p = 0.023). By 3 months, favorable outcomes were noted in 82 patients given danaparoid (68.3%) and 58 patients administered placebo (53.2%; p = 0.021). Conclusions: Early identification by duplex imaging of an occlusion or severe stenosis of the ICA ipsilateral to a hemispheric ischemic stroke might improve selection of patients who could be treated with emergent anticoagulation. Further testing of this approach is needed.

Interphysician agreement in the diagnosis of subtypes of acute ischemic stroke Implications for clinical trials

To test interphysician agreement on the diagnosis of subtype of ischemic stroke, we sent subtype definitions and 18 case summaries (clinical features and pertinent laboratory data) to 24 neurologists who have a special interest in stroke, and asked them to determine the most likely subtype diagnosis. The overall agreement was 0.64 (Kappa [K]=0.54). Interphysician agreement was highest for the diagnoses of stroke secondary to cardioembolism (K=0.75) or to large-artery atherosclerosis (K=0.69). Individual physicians varied widely; four agreed with the consensus diagnosis in all 18 cases, while six others disagreed with the consensus diagnosis in three to five cases. Our level of interphysician agreement is greater than that reported in other studies and was substantial. However, despite using subtype definitions and being given extensive information often not available in the acute setting, physicians still disagree about the etiology of stroke, particularly in regard to stroke due to small-artery occlusion or of undetermined etiology. Physicians seem reluctant not to attribute stroke to a specific etiology. The uncertainty about subtype diagnosis will affect interpretation of the results of clinical trials in patients selected by the subtype of ischemic stroke and also suggests that results of treatment as affected by subtype should be cautiously interpreted unless efforts to assure uniformity are included in the trials operations. Refinement of algorithms for determining subtype of ischemic stroke do improve interphysician agreement. Such criteria should be applied strictly, and trials should include measures to assure the most uniform diagnosis of stroke subtype possible.

Silent cerebral infarction in patients enrolled in the TOAST study

To determine the frequency, location, size, and risk factors for silent cerebral infarctions (SCIs) on brain CT, we identified 629 patients without a history of previous stroke who were enrolled in a multicenter clinical trial of therapy for acute ischemic stroke.On the baseline CT, 143 patients (22.7%) had SCIs; 34.3% of the lesions were in the right hemisphere, 38.5% in the left hemisphere, and 27.3% were bilateral. The lesion size was less than 1 cm in 65.7%, and the most common site was the basal ganglia (48.3%). Patients with SCI were compared with controls without SCI to determine the odds ratios (ORs) for each risk factor. On univariate analysis, race (black versus white) had an OR of 1.80 (95% confidence interval [CI], 1.14 to 2.85), male sex an OR of 1.68 (95% CI, 1.12 to 2.51), and congestive heart failure an OR of 1.88 (95% CI, 1.07 to 3.31). Significant risk factors on multivariate analysis include age (OR 1.03 per year, p equals 0.0070), male sex (OR 1.78, p equals 0.0094), and race (OR 2.43, p equals 0.0004). After including interaction terms with age and hypertension and age, sex, and race, hypertension was also a significant risk factor. NEUROLOGY 1996;46: 942-948

Design of the Trial of Org 10172 in Acute Stroke Treatment (TOAST)

TOAST is a multicenter, randomized, placebo-controlled clinical trial testing the usefulness of a new antithrombotic drug in improving the outcome of persons with acute ischemic stroke. Until recently, no clinical trial testing a treatment for ischemic stroke had demonstrated efficacy in outcome. Design problems of previously conducted trials with inconclusive results may partly explain their failures. During the design of TOAST, the investigators addressed several issues so the trial could test the treatment accurately. We report the strategies used in designing, implementing, and coordinating the trial.

CNS pseudovasculitis in a patient with pheochromocytoma

Article abstract The authors report a patient with angiographic findings resembling CNS vasculitis (CNS pseudovasculitis) who was found to have a pheochromocytoma. The angiographic changes resolved after surgical resection of the pheochromocytoma. Pheochromocytoma should be included in the differential diagnosis of angiographic findings suggestive of CNS vasculitis.

Brief, transient Horner's syndrome can be the hallmark of a carotid artery dissection

We describe a 41-year-old woman in whom the diagnosis of carotid artery dissection was suspected based on a recent history of anisocoria and ipsilateral ptosis that lasted 2 days. She had a normal neurologic examination, including no clinical evidence of anisocoria or ptosis. Subsequently, a cocaine test demonstrated pharmacologic Horners syndrome. MRI confirmed the carotid dissection. This patient illustrates that a history of transient pupillary and eyelid abnormalities can lead to the diagnosis of a carotid dissection. Specific questioning about transient anisocoria and ptosis should be considered when a carotid artery dissection is suspected. Pharmacologic testing may be a useful tool in such instances.

Low- versus high-dose aspirin in prevention of ischemic stroke.

Aspirin is the most extensively studied drug for the prevention of ischemic vascular disease. Meta-analyses confirm that aspirin is effective in prevention of ischemic events, including stroke. Recently, there has been considerable discussion about the best dose of aspirin to prevent stroke. Several studies tested aspirin in a daily dose of 975 mg or more alone or in combination with another drug, most commonly dipyridamole, and noted that aspirin was effective. Successively lower doses of aspirin were tested and recent studies demonstrate that low doses (< 100 mg/day) are effective. Only one study, enrolling patients with transient ischemic attack or minor stroke, has examined aspirin in a daily dose of approximately 325 mg. Side effects of aspirin are dose related; gastrointestinal bleeding and epigastric pain are less with low doses. Available data cannot confirm that low doses (< 100 mg/day) of aspirin are either more or less effective than larger (975 mg/day) doses. A direct comparison of the usefulness of low doses (< 100 mg/day) or large doses (approximately 1,000 mg/day) in patients at high risk of stroke is needed. Until the results of such a study are known, the better safety profile of low doses favors aspirin in a daily dose of 100 mg or less.

Physician Attitudes towards Acute Stroke – A Comparison of Primary Care Physicians in Iowa and The Netherlands

Randomly selected primary care physicians in Iowa (n = 250) or The Netherlands (n = 250) received a questionnaire asking their opinions about management of patients with ischemic stroke of recent onse