of patients with stroke have had transient ischemic attacks (TIAs) .... fiable cause of transient cerebral ischemia is con- ... such as dysarthria, diplopia and ataxia.
I Curren t Review
Transient cerebral ischemia Michael D. Cusimano, MD F. Michael Ameli, MB, ChB, FRCS (Edin), FRCSC, FACS
Stroke is a major cause of disability and death in North America. About 30% to 40% of patients with stroke have had transient ischemic attacks (TIAs). The recognition and treatment of TIAs and possibly of asymptomatic stenoses of the carotid arteries may be beneficial in preventing stroke. We review the epidemiologic features, natural history, pathogenetic features, clinical presentation, methods of investigation and management of patients with TIAs. La mortalite et le taux d'invalidite par accidents
cerebrovasculaires sont importants en Amerique du Nord. De 30% 'a 40% des malades ont prealablement presente des episodes d'ischemie cerebrale transitoire (ICT). Le diagnostic et le traitement de ces episodes et peut4tre des stenoses carotidiennes asymptomatiques sont susceptibles de prevenir les accidents cerebrovasculaires. On passe donc en revue les ICT sous les rapports de l'epidemiologie, de l'evolution, de la pathogenese, de la clinique, de la recherche et du traitement.
S-1 troke is the third commonest cause of death in North America and the commonest cause of disability." Approximately 30% to 40% of patients with stroke have had transient ischemic attacks (TIAs),4 which are episodes of focal reduction in cerebral blood supply that result in loss of
neurologic function for short periods without residual disability. Although most TIAs last only minutes, some may be as long as 24 hours. Reversible ischemic neurologic deficits (RINDs) present with
similar symptoms but usually last 24 to 48 hours and sometimes as long as 1 week. Amaurosis fugax (transient blindness in one eye) and vertebrobasilar insufficiency are terms used to describe transient ischemia in the retinal and posterior cerebral circulations respectively.
Epidemiologic features The rate of death from cerebral vascular disease has declined since 1915, when statistics first became available; the annual decrease in the rate of death from stroke has accelerated in recent years from 1% to 5%, the overall decrease having been 45% between 1968 and 1981 (Fig. 1).5-8 This decline does not seem to be due to prolonged survival but, rather, to a true decrease in the incidence of stroke. The incidence of hypertensive intracerebral hemorrhage has decreased substantially, whereas the decrease in the rate of cerebral infarction and subarachnoid hemorrhage has been smaller.7-9 Among the elderly a proportion of spontaneous intracerebral hemorrhages may be due to amyloid angiopathy rather than to hypertension.10 The most important modifiable risk factor of stroke is hypertension, and every effort to control
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251 Dr. Cusimano is a senior resident in neurosurgery at- the University of Toronto, and Dr. Ameli is in the Division of Vascular Surgery, Wellesley Hospital and the University of Toronto.
Reprint requests
to: Dr. F. Michael Ameli, Ste. 313, E.K Jones Building, Wellesley Hospital, 160 Wellesley St. E, Toronto, Ont.
M4 Y 1J3
I
1950
1960
p
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I
I
1970
1980
1990
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Fig. 1 - Annual rate of death from stroke per 100 000 population. CMAJ, VOL. 140, JANUARY 1, 1989
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it must be made. Other major risk factors include increased age, ischemic heart disease, polycythemia and diabetes mellitus.5'9 Smoking and a family history of stroke are minor risk factors.9 The secondary prevention of stroke is carried out through the diagnosis and treatment of TIAs and possibly of asymptomatic stenoses of the carotid arteries.
carotid artery but also the innominate and proximal carotid vessels and the heart.29 About one-third to one-half of the patients will not have ipsilateral carotid artery disease to explain the symptoms.30 Diagnosis History
Natural history The clinical features of recurring TIAs are often similar in a particular patient but can vary greatly from person to person. Forty percent of the patients have had a single TIA, 50% have had between 2 and 10 TIAs, and about 10% have had more than 10 TIAs at presentation.1" Vertebrobasilar insufficiency, classically considered to be a benign condition, is about twice as common as anterior circulatory insufficiency and is associated with difficulties in diagnosis and controversies regarding management.4 TIAs may indicate cerebrovascular atherosclerosis, and it is not surprising that atherosclerotic disease in other vascular territories contributes significantly to the mortality rate after the development of transient cerebral ischemia. Myocardial infarction remains the commonest cause of death after TIA and indicates the essential importance of the heart in the management of cerebral vascular disease. As precursors TIAs are as important to stroke as they are to myocardial infarction and death.12 Despite all efforts, the 10-year survival rate after TIAs is 40%, as compared with 60% among age-matched control subjects.13 The risk of stroke after TIAs has repeatedly been shown to be greatly increased.13-23 Cartlidge and associatesg3 have shown that the risk in the general population increases from about 1% to about 17% in the first year after TIAs and that 25% of strokes will occur in the first month.13-23 After the first year the annual risk of stroke is about 5 %.13 24 The presence of a highly obstructive lesion with a lumen less than 3 mm in diameter or the presence of ulceration also increases the risk of subsequent stroke; in this group of patients the incidence of myocardial infarction and death is also high.
Pathogenetic features Frederick25 reviewed 2732 cases from five major series and noted a consistent incidence (from
78% to 85%) of thromboembolic causes for stroke.
Data from postmortem studies, databases and registries have revealed that among patients in hospital 15% to 25% of ischemic events occur in those whose hearts might be a source of thromboembolism.26 The evidence that embolism is a major identifiable cause of transient cerebral ischemia is considerable, and embolism is now believed to be the commonest cause of TIAs.27,28 The sources of the emboli include not only the bifurcation of the 28
CMAJ, VOL. 140, JANUARY 1, 1989
TIAs usually occur in middle-aged and elderly men and postmenopausal women. The onset of symptoms is usually unprovoked and can occur at any time. The degree of disability is often greatest within minutes after an attack. Patients usually remain conscious but may experience mild confusion. Dizziness or lightheadedness alone is insufficient to diagnose ischemia of the vertebrobasilar area. Vertebrobasilar insufficiency should be diagnosed on the basis of multiple neurologic signs such as dysarthria, diplopia and ataxia. A disturbance of at least two of the motor, sensory, cerebellar and cranial nerve systems is required to make the diagnosis.
Physical examination The general physical examination should include a search for signs of atherosclerosis, and a complete cardiovascular examination should try to detect signs of hypertensive heart disease, dysrhythmias, congestive heart failure, coexisting aneurysms or occlusive vascular disease. The location of bruits heard in the neck should be determined; if the sounds are generalized along the neck they usually originate in the heart. Bruits are not detected in 20% of patients with severe stenosis or in any patient with an occlusion.31 In 77% of patients with bruits the diameter of the carotid artery is decreased by more than 50%, as shown by means of continuous-wave Doppler ultrasonography.32 Bruits may eminate from other sources and do not necessarily indicate disease of the intemal carotid arteries; they may be due to external carotid artery disease, increased blood flow resulting from an occlusion in the opposite carotid artery, a kinked or diseased innominate artery or a cardiac abnormality.
Investigations A complete blood count, a blood film, the differential leukocyte count, the erythrocyte sedimentation rate, the platelet count, the prothrombin and partial thromboplastin times, the results of serologic tests for syphilis, the serum levels of electrolytes, glucose, creatinine and urea nitrogen, and chest x-ray films should be obtained. Electrocardiography and echocardiography must be done as early as possible to assess cardiac status and function and to further investigate a possible source of emboli.
Specific investigations should include noninvasive vascular testing, various forms of angiography and computed tomography (CT). Noninvasive investigations
Beta-mode ultrasonography enables anatomic visualization of structures at the bifurcation of the carotid artery through reflection of pulsed sound signals from tissue interfaces with differing acoustic impedance. The specificity is about 86% and the sensitivity, which improves with experience, about 65%.33 This technique is poor for detecting minor stenosis and ulceration and for distinguishing severe stenosis from occlusion. Duplex ultrasonography combines the pulsed Doppler and the real-time f-mode forms of ultrasonography. If duplex ultrasonography is combined with fast Fourier transform spectral analysis the sensitivity improves to about 93% and the specificity to between about 94% and 100%.34'35 Driesbach36 found that sensitivity and specificity improved as the degree of stenosis increased (e.g., 100% sensitivity and 98% specificity were associated with stenosis of more than 60%). The sensitivity and specificity rates were 94% and 96% respectively with the use of the duplex method to detect occlusion. Thus, with an accuracy rate of about 90%, noninvasive techniques can be used to exclude healthy subjects from further testing, to assess carotid artery disease in subjects undergoing nonneurologic surgery, and to monitor carotid artery lesions in patients at risk for stroke and in those who have undergone carotid endarterectomy. Invasive investigations Intravenous digital subtraction angiography (DSA) has been promoted as being safer and less expensive than other methods of direct visualization of the arterial system. Little and colleagues37 reviewed the results of 6000 procedures and found no reports of death or significant side effects. In a study at New York University of 2400 patients the systemic complication rate was 0.12%, with no permanent complications, as compared with 1.2% for conventional angiography.38 The radiation exposure associated with DSA is 5% of that associated with the conventional technique. However, in 10% of the studies the results of DSA were uninterpretable, and in up to 22% the image provided diagnostic information that could have been misinterpreted.39 The future of DSA lies with the intra-arterial application, which is currently under investigation.40'41 Conventional angiography remains the gold standard against which all other techniques are compared. Hass and collaborators42 and others30'43 have reported that multiple lesions are present in two-thirds of the patients but that a single lesion is detected in only 30% to 50%. Chikos and coworkers44 showed that interradiologist agreement be-
tween categories of stenosis was 57% and that radiologists were consistent with their own diagnosis of the degree of stenosis only 75% of the time. Among 4748 patients Hass and collaborators42 reported a mortality rate of 0.7%, a stroke rate of 0.5% and a minor complication rate of 5.3%. Cusimano and associates46 found no significant difference in the complication rates among patients with clinical evidence of atherosclerotic indications for angiography (e.g., TIA or stroke) and those with nonatherosclerotic indications (e.g., subarachnoid hemorrhage) in 653 angiograms. However, permanent complications (0.35%) and death (0.15%) occurred only in the atherosclerotic patient population. Thus, the risks of angiography should never be overlooked, and the procedure should be performed only. on patients considered candidates for surgical reconstruction.
Management Management of cerebral vascular disease has become increasingly controversial since the first carotid endarterectomy was reported, by Eastcott and colleagues, in 1954.47 There is little question that risk factors, especially hypertension, should be managed in all patients.
Drug therapy In a number of anecdotal studies it was suggested that platelet antiaggregants decreased the incidence of TIA and stroke.48-50 This led to several prospective randomized controlled studies in patients with TIAs.5156 Although all of these randomized controlled studies can be criticized for various reasons, all but one showed a significant decrease in the rates of cerebral infarction and death among patients treated with acetylsalicylic acid (ASA) (Table I). The Canadian Cooperative Study52 was the only one to have sufficient numbers of patients to avoid type II statistical errors. The overall incidence rate of TIA, stroke and death was decreased by 19% and that for stroke and death by 31% (p < 0.05). Subgroup analysis revealed that the benefits were limited to men (48% reduction in the rates of stroke and death, p < 0.005);52 however, all of the studies of platelet antiaggregant therapy have indicated that women have fewer strokes and lower mortality rates than men.57-60 The daily dose of ASA in the clinical trials has varied from 1000 to 1500 mg. The drug inhibits cyclo-oxygenase; this action in turn blocks thromboxane A2 production in platelets and prostacyclin production in vessel walls.61'62 However, the platelets are considered to be much more sensitive to ASA than the vessel walls. Boysen, Bottcher and Olsen63 reported that the daily dose needed to fully inhibit platelet aggregation is at most only 125 mg. A controlled prospective trial in Britain is comparing the effects of high doses of ASA on men and women."r The results of a pilot study of prostacyCMAJ, VOL. 140, JANUARY 1, 1989
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clin infusion in 10 patients with ischemic stroke have been promising.65
Carotid endarterectomy Many indications for carotid endarterectomy have been described,66-68 but the only one that has been generally accepted is TIA or recent nondisabling completed stroke in the presence of a localized, surgically accessible stenosis or ulceration of the carotid artery. Carotid endarterectomy has been found to decrease the likelihood of late strokes in patients with TIAs.69-77 However, only one of those studies was randomized and controlled;75 316 patients received either surgical or medical treatment after they were divided into subgroups on the basis of lesions found through angiography. Carotid endarterectomy was reported to be beneficial, but the immediate postoperative deaths in the surgical group were not included in the statistical analysis. If all strokes and deaths in both groups are considered, the surgical group fared no better than the medical group. However, more recent studies have shown considerably lower rates of surgical risk than the rate of 9% reported in that study.77-80 Perioperative stroke and death rates have varied from 1% to 21%70 81-83 and are clearly affected by patient selection and surgical skill. Patients thought to be at highest risk include those who are neurologically unstable before surgery,84 those with significant stenosis of the opposite carotid artery85 and those undergoing surgery for occlusion of the carotid artery.83'86 Indeed, the high risks and lack of proven benefit of carotid endarterectomy for the treatment of carotid artery occlusion have suggested that the procedure should rarely be done in such circumstances.83'86 There have been few reports of the long-term results of carotid endarterectomy using life-table analysis to determine postoperative survival rates ibe .
30
and freedom from stroke. Hertzer87 reported on the 10-year follow-up of 329 patients who had undergone successful carotid endarterectomy between 1969 and 1973. The actuarial 5-year and 10-year survival rates were 72% and 42% respectively. Fatal myocardial infarctions accounted for two to three times as many deaths as late neurologic events. Late strokes were more frequent among hypertensive patients, those who had had a stroke before surgery and those with contralateral carotid artery stenosis of more than 50%. Fatal strokes occurred in 12% of the patients and nonfatal in
27%; only 10% of the strokes occurred on the
same side as the repaired carotid artery. These results reaffirmed the fact that coronary artery disease accounts for most of the deaths in patients with cerebrovascular disease. In addition, the data suggest that carotid endarterectomy lowers the risk of subsequent stroke to a level expected for people without atherosclerosis and that continued surveillance and surgical correction of the opposite carotid artery may improve the long-term prognosis. Whether these results can be compared with those of medical treatment is a difficult question, and the answers may ultimately be found through controlled trials, such as the current British64 and North American symptomatic carotid endarterectomy trials.88
Extracranial-intracranial bypass The primary goal of the randomized Extracranial-Intracranial (EC-IC) Bypass Study was to determine whether extracranial-intracranial arterial bypass decreased the risk of subsequent stroke and death among patients with TIAs or completed stroke who had stenosis of the middle cerebral artery or the upper portion of the carotid artery.89 The results for graft patency and the perioperative morbidity and mortality rates were better than any previously reported. Despite this the surgically
- Results of prospective double-blind studies of the efe1 asient ischemic attacks TlAs)i oi flIAs and strklke
CMAJ, VOL. 140, JANUARY 1, 1989
of acetylsalicylir
ASA' r pataen'
treated patients fared no better (those with stenosis of the middle cerebral artery did worse) than the medically treated patients. The tremendous controversy since this report was published has mainly dealt with its methods, results, interpretation and generalizability.90-99
Maryland, have approved a North American randomized prospective clinical trial to determine whether carotid endarterectomy added to the currently best medical therapy reduces the risk of stroke and stroke-related death in patients with recent TIAs or nondisabling stroke and stenosis of the carotid artery on the same side as the TIAs or stroke. Three thousand patients will enter the study over the next 2 to 3 years and then be followed up for 5 years by an independent neurologist.
Management protocol Management schemes, such as that described in Fig. 2, will be controversial until questions regarding natural history and treatment are answered. When a patient presents with suspected TIAs history-taking and physical examination will often determine whether the source is cardiac, hematologic or atherosclerotic. CT scanning will identify hemorrhages and brain tumours. Some clinicians will decide to investigate further on the basis of the results of Doppler ultrasonography. The particular risks and potential benefits of surgery are then assessed, and if the results are favourable standard angiography is performed. Carotid endarterectomy is generally recommended if the lesion is operable. Currently patients considered candidates for carotid endarterectomy should be referred to centres involved in the North American Symptomatic Carotid Endarterectomy
Summary
Stroke is a major contributor to disability and death from cardiovascular disease. Its incidence has been decreasing steadily since the turn of the century, mainly because of primary preventive measures. Secondary prevention through recognition and treatment of TIAs and possibly asymptomatic stenosis of the carotid artery may be beneficial. Reviews of medical and surgical treatments have suggested that surgery, performed by an experienced team, is beneficial in low-risk patients with TIAs who have localized operable stenoses or ulcerations. Medical treatment has been shown to be better than no treatment but not necessarily better than surgery combined with the treatment of cerebrovascular risk factors. There is still no definitive management protocol for patients with transient cerebral ischemia. It is hoped that by the 1990s the North American Symptomatic Carotid Endarterectomy Trial will
Trial. The North American Symptomatic Carotid Endarterectomy Trial The National Institutes of Health, Bethesda,
History-taking and physical examination
I
Diagnosis of transient ischemic attacks Atherosclerotic source
Cardiac or hematologic source
I Computed tomography
Cerebral hemorrhage or tumour
Ischemic disease Noninvasiv investigations
Negative results
| Positive results
Clinical assessment High-risk patient
Medical management
Low-risk patient
Angiography Inoperable lesion
Operable lesion
I
Surgical management
Fig. 2- Management protocol for suspected TIAs. CMAJ, VOL. 140, JANUARY 1, 1989
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provide scientifically based strategies for the management of these patients. We thank Professor Nosrat 0. Ameli for reviewing the manuscript, the Department of Instructional Media Services, Wellesley Hospital, for producing Fig. 1 and Mrs. Linda Thompson for secretarial assistance. This paper is dedicated to Mr. Anthony Cusimano, Sr., and to all those who have been unfortunate enough to have suffered the consequences of cerebral infarctions.
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