Adverse haematological effects of ticlopidine. Prevention, recognition and management.

Ticlopidine is an antiplatelet agent that is used to reduce the occurrence of atherothrombotic arterial events. There have been major multicentre placebo-controlled trials evaluating its use in stroke, peripheral arterial disease and unstable angina. In rare cases, adverse haematological effects have been seen with ticlopidine. Ticlopidine has been associated with neutropenia in some of the major trials and in subsequent case reports it has been associated with aplastic anaemia, thrombocytopenia and thrombotic thrombocytopenic purpura, which have been fatal in some instances. Ticlopidine should be used only in patients with an established indication for its use. Patients should be educated about the potential adverse effects and complications associated with ticlopidine, including possible death. Finally, there should be careful attention to haematological monitoring to screen for and promptly detect any adverse effects.

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.

Ischemic stroke in young adults. Experience in 329 patients enrolled in the Iowa Registry of stroke in young adults.

OBJECTIVES: To describe the likely causes of ischemic stroke in a population of young adults and to report the influence of strict algorithms on the diagnosis of the likely cause of stroke in this cohort. DESIGN: Between July 1, 1977, and January 1, 1993, we registered 329 young adults with ischemic stroke in our registry. Diagnostic studies were selected on a case-by-case basis. Presumed causes of stroke were determined using clinical information and the results of diagnostic tests. In each case, a second causative diagnosis was made using the criteria developed for a large clinical trial. SETTING: Patients referred to the Division of Cerebrovascular Diseases in the Department of Neurology at the University of Iowa Hospitals and Clinics, Iowa City, by physicians in Iowa and adjacent states. PATIENTS: Three hundred twenty-nine young adults (182 men and 147 women) aged 15 to 45 years with ischemic stroke; 102 persons, 48 men and 54 women, were aged 30 years or younger. RESULTS: Cerebral arteriography was performed in 227 cases, and the findings were abnormal in 146. Transthoracic echocardiography revealed abnormalities in 82 of 221 patients examined. We identified approximately 60 different disorders that were presumed to be the cause of stroke. There were no major changes in the frequency of subtype diagnoses between the first 144 patients and the subsequent 185. Use of strict diagnostic criteria increased the number of cases of stroke of undetermined etiology (from 45 to 113), and the number attributed to large artery atherosclerosis declined from 71 to 32. CONCLUSIONS: The causes of ischemic stroke in young adults are numerous. Because treatment options in this group are influenced by a presumed cause, an evaluation on a case-by-case basis is warranted. Our experience suggests that a likely cause will be detected in most cases and that a regimented battery of tests may not be required. If strict diagnostic criteria are used, the diagnosis of stroke of undetermined etiology considerably increases. While such strict criteria are important in clinical trials that test new interventions, the value of the application of such methodologies to an unusual population, such as stroke in young adults, needs clarification. In particular, the usefulness of categorizing a stroke as undetermined when two or more possible causes are identified needs to be explored.

Diabetes and stroke.

Diabetes is a major risk factor for development of ischemic cerebrovascular disease. Patients with diabetes are at least two times more likely to have a stroke than nondiabetics. In addition, they are more likely to suffer increased morbidity and mortality after stroke. The mechanism of production of stroke secondary to diabetes may be due to cerebrovascular atherosclerosis, cardiac embolism, or rheologic abnormalities. The evaluation of cerebrovascular disease in diabetic patients is similar to the nondiabetic patient, with particular attention paid to adequate hydration prior to the administration of contrast agents. Treatment options for stroke in diabetics requires individualization but should include risk factor modification, and may include platelet antiaggregants, anticoagulation, or, in a well-defined subgroup, carotid endarterectomy.

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.

Controversies in the management of cerebrovascular disease in older patients.

Several ongoing studies are evaluating the optimal management of patients with cerebrovascular disease. The Carotid Artery Stenosis with Asymptomatic Narrowing: Operation Versus Aspirin (CASANOVA) study has shown that carotid endarterectomy is not recommended for asymptomatic patients with less than 90% carotid stenosis. The North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the European Carotid Surgical Trial (ECST) have demonstrated that endarterectomy should be considered for patients who had recent carotid artery territory ischemic symptoms associated with angiographically defined stenosis of greater than 70%. These and other trials are expected to provide further data regarding management of cerebrovascular disease, including treatment of those patients with moderate (30 to 69%) carotid stenosis. Until that time, treatment decisions must be made on a case-to-case basis.

Coronary artery disease and cardiac events with asymptomatic and symptomatic cerebrovascular disease.

BACKGROUND AND PURPOSE: The purpose of this study was to evaluate the prevalence of coronary artery disease and coronary events during follow-up in patients with asymptomatic carotid stenosis, transient ischemic attacks, or small strokes. METHODS: We prospectively studied 60 consecutive patients with thallium-201 scintigraphy followed by coronary arteriography according to an established protocol. RESULTS: The 201Tl testing was abnormal in seven of 15 patients (47%) with asymptomatic carotid stenosis and in 19 of 44 patients (43%) with transient ischemic attacks or small strokes (p greater than 0.05). In 33 patients with no history of coronary artery disease, 11 (33%) had reversible 201Tl defects. In 26 patients with a history of coronary artery disease, 15 (58%) had reversible and/or fixed defects (p = 0.054 compared with patients with no history). A history of peripheral vascular disease was the only risk factor significantly associated with an abnormal 201Tl test (p = 0.032). Coronary artery stenosis of greater than 50% was identified in one or more vessels in 14 of 15 patients undergoing coronary arteriography. Over a mean follow-up period of 311 days, four patients (7%) developed new onset of angina. There were four coronary events among 14 patients (29%) with both a reversible area on the 201Tl and abnormal coronary arteriography. In comparison, there were only four coronary events among 46 patients (9%) without reversible defects on the 201Tl studies (p = 0.055). CONCLUSIONS: Our study demonstrates that one third of patients with no history of coronary artery disease had an abnormal 201Tl test and that nearly one half of patients with either symptomatic or asymptomatic cerebrovascular disease had abnormal 201Tl tests. Patients with a reversible 201Tl defect and significant stenosis by coronary arteriography were at higher risk for subsequent cardiac events. These findings demonstrate the utility of screening patients with asymptomatic and symptomatic cerebrovascular disease for cardiac disease.

Diagnosis of pulmonary arteriovenous malformation by ultrafast chest computed tomography in Rendu-Osler-Weber syndrome with cerebral ischemia--a case report.

Pulmonary arteriovenous malformations occur in 15-20% of patients with Rendu-Osler-Weber syndrome and can be the source of paradoxical emboli causing cerebral ischemia, septic emboli leading to brain abscesses, or polycythemia causing hyperviscosity and cerebral ischemia. The diagnosis of these malformations may be elusive, since classic clinical or radiologic findings may be absent in some patients. The authors report a patient with Rendu-Osler-Weber syndrome with cerebral ischemia who had normal findings from a pulmonary examination and chest roentgenogram. An ultrafast computed tomography scan of the chest demonstrated, however, a pulmonary arteriovenous malformation in the right upper lobe that was successfully resected. Ultrafast computed tomography of the chest is a relatively noninvasive method of screening for a pulmonary arteriovenous malformation in a patient with Rendu-Osler-Weber syndrome and otherwise unexplained neurologic symptoms.

Medical management of acute cerebral ischemia in the elderly.

Stroke ranks third as a cause of death in much of the industrial world, surpassed only by heart disease and cancer. Thrombotic and embolic arterial occlusions are the leading causes of cerebral infarction. Once a major cerebral infarction has occurred, therapy is limited to the prevention of complications and rehabilitation. Identification and treatment of stroke-prone patients are now not a standard part of medical practice. However, the proper management of the patient with acute cerebral ischemic or progressing stroke is a subject of debate. Treatment of progressing or acute cerebral ischemia is aimed at prevention of infarction in areas of the brain that are still viable. A number of therapeutic strategies are currently being investigated in the management of ischemic stroke.

Mortality in acute cerebral infarction in young adults--a ten-year experience.

We reviewed the one-month mortality among 213 patients aged fifteen to forty-five years (mean thirty-five) with acute cerebral infarction (CI) evaluated during the period July 1, 1977, to February 1, 1988. Atherosclerotic cerebral infarction (ACI) was diagnosed in 59 (27.7%) patients, 53 (24.9%) had non-atherosclerotic vasculopathies (NAV); 46 (21.6%) had cardioembolic infarcts (CEI). Hematologically related disorders were diagnosed in 30 (14.1%) patients; the cause of CI could not be established in 25 (11.7%) patients. Fourteen patients (9 men, 5 women, mean age 34.8 years), (6.6%) died within thirty days of their CI: 7 had CEI (7/46,15.2%); 4 had ACI (4/59, 6.7%); and 3 had NAV (3/53, 5.6%). Our data suggest that young patients with acute CI have a thirty-day mortality rate lower than older patients. Deaths were most common in patients with CEI. Brain edema and herniation accounted for 6 (43%) of the deaths.

Circadian variation in onset of acute ischemic stroke.

A circadian pattern for the onset of myocardial and cerebral infarction has been identified. To evaluate this phenomenon further, we analyzed prospectively collected data from 151 patients with acute ischemic stroke. The number of strokes per 6-hour period were the following: midnight to 6 AM, 20 (13%); 6 AM to noon, 86 (57%); noon to 6 PM, 21 (14%); and 6 PM to midnight, 24 (16%). This pattern was not affected by previous use of aspirin. The most frequent time of onset was 6 AM to noon for all subgroups of ischemic stroke: small artery, 71%; cardioembolic, 62%; large artery atherothrombotic, 57%; large artery atheroembolic, 46%; and "other" or unknown cause, 40%. We also investigated the time between awakening and stroke onset in 145 patients and found that 24% of ischemic strokes occurred within the first hour after awakening. Our data demonstrate that an early morning peak exists for all subtypes of stroke. Our data also suggest that the most critical period is the first hour after awakening.

Spontaneous improvement after acute ischemic stroke. A pilot study.

Recent clinical studies emphasize the importance of early (less than 12 hours after onset) treatment of patients with acute ischemic stroke. Therapies have been proposed as being effective because of early clinical improvement. The frequency and degree of spontaneous improvement in such patients, however, is unknown. We prospectively evaluated the course of 29 patients (19 men, 10 women) aged 33-82 years who were seen less than or equal to 12 hours after the onset of acute ischemic stroke. Seventeen patients were first evaluated less than or equal to 6 hours and the remaining patients at 6-12 hours after onset. All patients were examined using a modified National Institutes of Health Stroke Scale at baseline, 1, 2, 3, and 6 hours. No specific treatment for acute ischemic stroke was given during this time. Improvement (defined as a decrease of greater than or equal to 2 points from baseline score) was noted at 1 hour in seven patients (24%). By 6 hours 15 patients (52%) had improved, 12 (41%) were unchanged, and two (7%) were worse. Our results suggest that spontaneous, often dramatic improvement occurs in patients with acute ischemic stroke and should be taken into consideration in the design of any trial of acute treatment.

Comparison of two-dimensional echocardiography and ultrafast cardiac computed tomography for evaluating intracardiac thrombi in cerebral ischemia.

Two-dimensional echocardiography has a high specificity for the detection of intracardiac thrombi, but technically difficult studies are often encountered. Ultrafast cardiac computed tomography may be useful in such cases. Using transthoracic two-dimensional echocardiography and ultrafast cardiac computed tomography, we studied 36 patients with cerebral ischemia; one patient had the studies performed on two occasions, making a total of 37 sets of studies. Technical difficulties occurred in 12 echocardiographic (32%) and two ultrafast cardiac computed tomographic (5%) studies. The two techniques agreed in 29 sets of studies (78%). Among the eight discrepant sets of studies, two-dimensional echocardiography was positive for a left ventricular thrombus while ultrafast cardiac computed tomography was negative in three and equivocal in one and echocardiography was equivocal while ultrafast cardiac computed tomography was negative in two and positive in one. In the latter case, a left ventricular thrombus was confirmed at autopsy. In the other discrepant set of studies echocardiography was negative while ultrafast cardiac computed tomography revealed a left atrial and appendage thrombus. Because of its ease of performance and safety, two-dimensional echocardiography is the appropriate initial screening test for left ventricular thrombus. Ultrafast cardiac computed tomography can provide additional information in patients with technically difficult or equivocal two-dimensional echocardiographic studies or patients with cardiac disorders predisposing to atrial thrombi formation.

Cigarette smoking. A risk factor for cerebral infarction in young adults.

To assess the impact of cigarette smoking on stroke in young adults (15 to 45 years old), we compared smoking data from 181 patients with cerebral infarction with that of 307 control subjects matched for age, gender, geographic location, and hospital admission dates. While controlling for these matching variables and hypertension, an analysis based on a conditional logistic regression model indicated that a smoker was 1.6 times more likely to have a cerebral infarction than a non-smoker (95% confidence interval, 1.07 to 2.42). There was a cumulative dose effect with each additional pack-year causing a greater risk of having a cerebral infarction. In fact, after adjusting for all other risk factors, there was a significant quadratic component to the dose-response relationships, with the result that individuals with a larger number of pack-years were invariably the stroke patients. There was no significant difference in smoking status among the various subtypes of cerebral infarction (atherosclerotic, nonatherosclerotic vasculopathy, cardioembolic, hematologic related, undetermined). These data indicate that cigarette smoking is an important risk factor for cerebral infarction in young adults. Risk factor modification through cessation of smoking may reduce the risk of ischemic stroke in young adults.