Effect of prior aspirin use on stroke severity in the trial of Org 10172 in acute stroke treatment (TOAST).

BACKGROUND AND PURPOSE: Although the efficacy of aspirin in reducing stroke incidence is clear, its role in reducing stroke severity is disputed. This study compares stroke severity between patients who did or did not take aspirin in the week before stroke and enrollment in the Trial of Org 10172 in Acute Stroke Treatment (TOAST). METHODS: Of 1275 patients randomized, 509 reported aspirin use in the week before stroke; 766 did not. Clinical stroke severity was assessed with the National Institutes of Health Stroke Scale (NIHSS) and the Supplementary Motor Examination (SME) at trial entry and at 3 months. Using these scales, we compared the categorization of stroke severity (mild, moderate, and severe) and mean scores between aspirin users and nonusers. RESULTS: The difference in distribution of baseline NIHSS scores was statistically significant between aspirin users and nonusers (P=0.006), with a greater percentage of milder strokes among aspirin users. The difference in mean baseline NIHSS scores was also significantly lower in aspirin users (8.2) and nonusers (9.3) (P=0.003). The distribution of baseline SME scores and mean SME scores also showed lower stroke severity in aspirin users than in nonusers (P=0.048 and P=0.004, respectively). At 3 months, differences in stroke severity measured by the SME but not the NIHSS remained statistically significant. Seven-day and 3-month mortality did not differ significantly. CONCLUSIONS: In this study aspirin use is associated with milder clinical deficits at stroke onset. These deficits may affect prognosis and influence response to treatment. Future clinical trials should ensure that prestroke aspirin use is comparable in study groups.

Stroke in young adults and children.

Data from studies of 337 children and 1606 young adults are summarized to identify the major causes of stroke in these age groups. In children under 15 years of age, stroke occurs in patients with congenital heart disease, nonatherosclerotic vasculopathies, infection, and hematologic defects like sickle cell disease. In patients 15 to 35 years of age, dissection, cardioembolism, nonatheroslerotic vasculopathies, and prothrombotic states cause a significant percentage of strokes. In adults over 35 years of age, traditional atherosclerotic risk factors predominate. Lifestyle choices (e.g., cigarette smoking, alcohol consumption, and illicit drug use) can significantly increase the rate of stroke among young adults in a community. Limited access to healthcare may increase the role of infectious disease and peripartum complications.

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.

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 > or =16 forecasts a high probability of death or severe disability whereas a score of < or =6 forecasts a good recovery. Only the TOAST subtype of lacunar stroke predicts outcomes independent of the NIHSS score.

CNS pseudovasculitis in a patient with pheochromocytoma.

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 Horner's 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.

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.

Application of contrast agents in the evaluation of stroke: conventional MR and echo-planar MR imaging.

The availability of new therapeutic interventions, including neuroprotective agents and endovascular thrombolysis, has given new hope to patients suffering an acute stroke. Early intervention remains a key factor in the effectiveness of these new and traditional treatments. More importantly, the capability to assess the viability and reversibility of the ischemic tissue became essential for better delineation and differentiation of infarcted versus ischemic tissue and patient management. Abnormal MR imaging (MRI) findings during acute stroke usually reflect the underlying pathophysiologic changes, which can be classified into three sequential stages: (a) hypoperfusion, (b) cellular dysfunction and (c) breakdown of the blood-brain barrier. The first stage is a kinetic phenomenon (not biologic) and, therefore, can be detected immediately. Contrast agents accentuate the abnormal flow kinetics and facilitate the early diagnosis of ischemia using either conventional MRI or newly developed echo-planar perfusion imaging (EPPI). The demonstration of abnormal arterial or parenchymal enhancement on conventional MRI during acute stroke provides the earliest sign of vascular occlusion/stenosis. EPPI, in contrast, provides information related to microcirculation (< 100 microns) and tissue reserve (cerebral blood volume) that cannot be obtained by conventional angiography and is directly related to the target end-organ. Further information obtained from both contrast MRI and EPPI may have a predictive value in the clinical outcome of acute stroke patients.

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 < 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 = 0.0070), male sex (OR 1.78, p = 0.0094), and race (OR 2.43, p = 0.0004). After including interaction terms with age and hypertension and age, sex, and race, hypertension was also a significant risk factor.

Effects of hydrocyclones on the integrity of animal and microbial cells.

The comparative effects of passing mammalian and nucleated red blood cells through liquid/liquid (low shear) and solid/liquid (high shear) hydrocyclones have been examined. Cell disruption was only found when the rig was operated in conjunction with a solid/liquid hydrocyclone apparently as a result of the higher operating pressures required for this type of hydrocyclone. Yeast cells were not disrupted even by the highest operating pressures but there was some evidence for effects on the growth rate of yeast after passage through a solid/liquid hydrocyclone.

Properties and applications of a new type of iodinated gradient medium.

This paper reports on the properties of a new iodinated density-gradient medium, Iotrolan, and its potential application for separating dense cells. Iotrolan is a dimeric, nonionic, iodinated compound which is distinguished by its ability to form dense, non-viscous gradients of low osmolarity. Isotonic gradients of up to 1.30 g/ml can be formed, allowing even dense cells such as sperm to be separated under isotonic conditions.

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.

Interphysician agreement in the diagnosis of subtypes of acute ischemic stroke: implications for clinical trials. The TOAST Investigators.

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 trial's 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.

Vascular dementia: a concept in flux.

Vascular dementia describes global cognitive decline attributed to the cumulative effects of ischemic vascular disease. Discrete and multiple cognitive skills, including memory, are successively lost as a result of focal cerebrovascular insults. Our understanding of vascular dementia has evolved over time, in part through our ability to neuroradiologically image changes in patients, and also through our increased understanding of the neuropsychologic organization of the brain. This paper reviews the development of our present understanding of vascular dementia, examines the status of "leukoaraiosis," pointing out current areas of controversy, and discusses clinical management.

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 physician's 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.

Cholesterol emboli neuropathy.

We report the clinical and pathologic features of a patient with peripheral neuropathy that was the first clinical expression of cholesterol emboli syndrome (CES). Biopsy of skeletal muscle and peripheral nerve revealed cholesterol clefts in lumens of small arteries, necrotizing arteritis, and severe degeneration of peripheral and intramuscular nerves. At autopsy, the peripheral nervous system was extensively affected by similar changes. We conclude that (1) peripheral neuropathy may be the initial manifestation of CES. Presumably, deposition of cholesterol leads to arteritis. (2) The underlying pathology of CES neuropathy is chronic axonal degeneration, possibly due to chronic ischemia of epineurial arteries. (3) Muscle biopsy is important in the antemortem diagnosis of CES. Nerve biopsy may show involvement of epineurial vessels. (4) CES may resemble polyarteritis nodosa clinically and pathologically. (5) CES may be under-recognized and should be included in the differential diagnosis of any neuropathy of uncertain cause, particularly when there is a history of vascular catheterization, or severe aortic atherosclerosis.

Sulfadiazine-associated obstructive nephropathy occurring in a patient with the acquired immunodeficiency syndrome.

A 45-year-old man with the Acquired Immunodeficiency Syndrome (AIDS) and CNS toxoplasmosis presented with acute renal failure, hematuria, and renal colic shortly after starting treatment with sulfadiazine. Ultrasound examination of his kidneys was suggestive of intraparenchymal crystallization of sulfadiazine. His renal failure and ultrasound findings rapidly resolved with alkaline hydration. On rechallenge with sulfadiazine, he again developed renal insufficiency and ultrasonic findings consistent with stones. The use of sulfadiazine in the treatment of CNS toxoplasmosis in AIDS patients should be monitored carefully with the recognition that this form of crystalline-induced acute renal failure can occur in a dehydrated patient.