Transient cerebral ischemia - Europe PMC

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.

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1950

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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 .

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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


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.

References 1. Mortality Part A, vol 2 of Vital Statistics of the United States, 1982, National Center for Health Statistics, Washington, 1986: 6-8 2. Perspectives Canada III, Statistics Canada, Ottawa, 1980: 62 3. Statistical Abstract of the United States: 1986, 106th ed, US Bureau of the Census, Washington, 1985: 73-77 4. Ziegler DK, Hassanein RS: Prognosis in patients with transient ischemic attacks. Stroke 1973; 4: 666-673 5. Wolf PA, Kannel WB, Verter J: Current status of risk factors for stroke. In Barnett HJM (ed): Symposium on Cerebrovascular Disease (Neurol Clin ser, vol 1, no 1), Saunders, Philadelphia, 1983: 317-343 6. Health United States, National Center for Health Statistics, Washington, 1983: 113 7. Garraway WM, Whisnant JP, Furlan AJ et al: The declining incidence of stroke. NEngliMed 1979; 300: 449-452 8. Haberman S, Capiledo R, Rose RC: The changing mortality of cerebrovascular disease. Q J Med 1978; 47: 71-88 9. Wolf PA: Risk factors for stroke. Stroke 1985; 16: 359-360 10. Vinters HV: Cerebral amyloid angiopathy. A critical review. Stroke 1987; 18: 311-324 11. Freidman GD, Wilson WS, Mosier JM et al: Transient ischemic attacks in a community. JAMA 1969; 210: 14281434 12. Heyman A, Wilkinson WE, Hurwitz BJ et al: Risk of ischemic heart disease in patients with transient ischemic attacks. Neurology 1984; 34: 626-630 13. Cartlidge NEF, Whisnant JP, Elveback LR: Carotid and vertebrobasilar transient cerebral ischemic attacks. Mayo Clin Proc 1977; 52: 117-120 14. Whisnant JP, Matsumoto N, Elveback LR: Transient cerebral ischemic attacks in a community: Rochester, Minnesota, 1955 through 1969. Mayo Clin Proc 1973; 48: 194-198 15. Pearce JMS, Gubbay SS, Walton JN: Long-term anticoagulant therapy in transient cerebral ischaemic attacks. Lancet 1965; 1: 6-9 16. Report of the Veterans Administration Cooperative Study of Atherosclerosis, Neurology Section: an evaluation of anticoagulant therapy in the treatment of cerebrovascular disease. Neurology 1961; 11 (suppl): 132-138 17. Baker RN, Schwartz WS, Ramseyer JC: Prognosis among survivors of ischemic stroke. Neurology 1968; 18: 933-941 18. Olsson JE, Muller R, Berneli S: Long-term anticoagulant therapy for TIAs and minor strokes with minimum residuum. Stroke 1976; 7: 444-451 19. Acheson J, Hutchinson EC: Observations on the natural history of transient cerebral ischaemia. Lancet 1964; 2: 871874 20. Acheson J, Danta G, Hutchinson EC: Controlled trial of dipyridamole in cerebral vascular disease. Br Med J 1969; 1: 614-615 21. Milliken CH: The pathogenesis of transient focal cerebral ischemia. Circulation 1975; 32: 438-443 22. Marshall J, Hill AB, Shaw DA: Cerebrovascular disease: trial of long-term anticoagulant therapy. Br Med J 1962; 2:

1003-1006 23. Baker RN: Anticoagulant therapy in cerebral infarction. 32


Report on cooperative study. Neurology 1962; 12: 823-835 24. Easton JD, Hart RG, Sherman DG et al: Diagnosis and management of ischemic stroke: 1. Threatened stroke and its management. Curr Probi Cardiol 1983; 8 (5): 1-76 25. Frederick MW: The potential stroke patient: statement of the problem [abstrl. Cardiovasc Rev Rep 1982; 3: 1615 26. Barnett HJM, Plum F, Walton J: Carotid endarterectomy an expression of concern [E]. Stroke 1984; 15: 941-943 27. Fischer CM: Transient monocular blindness associated with hemiplegia. Arch Ophthalmol 1952; 47: 167-203 28. Hollenhorst RW: Significance of bright plaques in the retinal arterioles. JAMA 1961; 128: 23-31 29. Bunt TJ, Haynes JL: Carotid endarterectomy: one solution to the stroke problem. Am Surg 1985; 51: 61-69 30. Swanson PD, Calanchiri PR, Dyken ML et al: Cooperative study of hospital frequency and character of transient ischemic attacks in angiography. JAMA 1977; 237: 22022206 31. Hurst JW, Hopkins LG, Smith RB et al: Noises in the neck [E]. N EnglJ Med 1980; 302: 862-863 32. Hennerici M, Aublich A, Sandmann W et al: Incidence of asymptomatic extracranial arterial disease. Stroke 1981; 12: 750-758 33. Comerota AJ, Cranley JJ, Cook SE: Real-time B-mode carotid imaging in diagnosis of cerebrovascular disease. Surgery 1981; 89: 718-729 34. Lusby RJ, Woodcock JP, Skidmore R et al: Carotid artery disease: a prospective evaluation of pulsed Doppler imaging. Ultrasound Med Biol 1981; 7: 365-370 35. Roederer GO, Langlois YE, Chan ATW et al: Ultrasonic duplex scanning of extracranial arteries. J Cardiovasc Ultrason 1982; 1: 374-380 36. Driesbach JN: Duplex ultrasound evaluation of carotid disease. Clin Diagn Ultrasound 1984; 13: 69-103 37. Little JR, Furlan AJ, Modic MT et al: Intravenous digital subtraction angiography in brain ischemia. JAMA 1982; 247: 3213-3216 38. Russell JB, Watson TM, Modi JR et al: Digital subtraction angiography for evaluation of extracranial carotid occlusive disease: comparison with conventional angiography. Surgery 1983; 94: 604-611 39. Little JR, Furlan AJ, Modic MT et al: Digital subtraction angiography in cardiovascular disease. Stroke 1982; 13: 557-566 40. Brant-Zawadzski M, Gould R, Norman D et al: Digital subtraction cerebral angiography by intra-arterial injection: comparison with conventional angiography. Am J Roentgenol 1983; 140: 347-353 41. Levin DC: Digital subtraction angiography: myths and reality [abstr]. Radiology 1984; 151: 803 42. Hass WK, Fields WS, North RR et al: Joint study of extracranial arterial occlusion: 2. Arteriography, techniques, sites, and complications. JAMA 1968; 203: 961-968 43. Kuller LH, Sutton KC: Carotid artery bruit: Is it safe and effective to auscultate the neck? Stroke 1984; 15: 944-947 44. Chikos PM, Fisher LD, Hirsch JH et al: Observer variability in evaluating extracranial carotid artery stenosis. Stroke 1983; 14: 885-892 45. Cranley ni: Presidential address: Stroke - a perspective. Surgery 1982; 91: 537-549 46. Cusimano M, D'Alton J, Cooper PW et al: Risks of angiography in cerebrovascular patients. Presented at the 8th Canadian Congress of Neurological Sciences, Toronto, June 23-26, 1982 47. Eastcott HHG, Pickering GW, Rob CG: Reconstruction of intemal carotid artery in patient with intermittent attacks of hemiplegia. Lancet 1954; 2: 994-996 48. Dyken ML, Kolar OJ, Jones FH: Differences in the occurrence of carotid transient ischemic attacks associated with antiplatelet aggregation therapy. Stroke 1973; 4: 732-736 49. Evans G: Effect of drugs that suppress platelet surface interaction on incidence of amaurosis fugax and transient

cerebral ischemia. Surg Forum 1972; 23: 239-241 50. Harrison MJ, Marshall J, Meadows JC et al: Effect of aspirin

in amaurosis fugax. Lancet 1971; 2: 743-744 51. Fields WS, Lemak NA, Frankowski RF et al: Controlled trial of aspirin in cerebral ischemia. Stroke 1977; 8: 301-314 52. Canadian Cooperative Study Group: A randomized trial of aspirin and sulfinpyrazone in threatened stroke. N Engl J Med 1978; 299: 53-59 53. Fields WS, Lemak NA, Frankowski RF et al: Controlled trial of aspirin in cerebral ischemia: 2. Surgical group. Stroke 1978; 9: 309-319 54. Ruether R, Dorndorf W: Aspirin in patients with cerebral ischemia and normal angiograms or nonsurgical lesions: the results of a double-blind trial. In Breddin K, Dorndorf W, Loew D et al (eds): Acetylsalicylic Acid in Cerebral Ischemia and Coronary Heart Disease, Schattauer, Stuttgart, 1978: 97-107 55. Sorensen PS, Pedersen H, Marquardsen J et al: Acetylsalicylic acid in the prevention of stroke in patients with reversible cerebral ischemic attacks. A Danish cooperative study. Stroke 1983; 14: 15-22 56. Bousser MG, Eschwege E, Haguenau M et al: "AICLA" controlled trial of aspirin and dipyridamole in the secondary prevention of athero-thrombotic cerebral ischemia. Ibid: 5-14 57. Dyken ML: Anticoagulant and platelet antiaggregation therapy in stroke and threatened stroke. Neurol Clin 1983; 1: 223-242 58. Idem: Transient ischemic attacks and stroke: Aspirin trials. In Bang N, Glover J, Holden R et al (eds): Thrombosis and Atherosclerosis, Year Bk Med, Chicago, 1982: 393-404 59. Dyken ML: Antiplatelet aggregative agents in transient ischemic attacks and the relationship of risk factors. In Breddin K, Loew D, Uberla K et al (eds): Prophylaxis of Venous, Peripheral, Cardiac, and Cerebral Vascular Diseases with Acetylsalicylic Acid, Fifth Colfarit-Symposium, Mainz, 13-15.11.1980, Schattauer, Stuttgart, 1981: 141-148 60. Barnett HJM: Progress toward stroke prevention. Robert Wartenberg Lecture. Neurology 1980; 30: 1212-1225 61. Moncada S: The role of prostacyclin and thromboxane A2 in the regulation in platelet behavior. In Herman AG, Van Houtte PM, Denolin H et al (eds): Cardiovascular Pharmacology of the Prostaglandins, Raven, New York, 1982: 101-114 62. O'Reilly R: Antithrombotic and thrombolytic drugs. In Gilman AG, Goodman LS, Gilman A et al (eds): Goodman and Gilman's The Pharmacological Basis of Therapeutics, 6th ed, Macmillan, New York, 1980: 1341-1367 63. Boysen G, Bottcher J, Olsen IS: Minimal daily dosage of ASA for platelet inhibition [C]. Stroke 1982; 13: 721-722 64. UK-TIA Study Group: Design and protocol of the UK-TIA aspirin study. In Tognoni G, Garattini S (eds): Drug Treatment and Prevention in Cerebrovascular Disorders, Elsevier, Amsterdam, 1979: 387-403 65. Gryglewski RJ, Nowak S, Kosta-Trabka E et al: Treatment of ischemic stroke with prostacyclin. Stroke 1983; 14: 197202 66. Robertson JT: Carotid endarterectomy. Neurol Clin 1983; 1: 119-129 67. Robertson iT, Aver NJ: Extracranial occlusive disease of the carotid artery. In Youmans JR (ed): Neurological Surgery, 2nd ed, vol 3, Saunders, Philadelphia, 1982: 1559-1583 68. Imparato AM, Riles TS, Ramirez AA et al: Early complications of carotid surgery. Int Surg 1984; 69: 223-229 69. Bernstein EF, Humber PD, Collins GM et al: Life expectancy and late stroke following carotid endarterectomy. Ann Surg 1983; 198: 80-86 70. DeWeese JA, Rob CG, Satran R et al: Results of carotid endarterectomies for transient ischemic attacks - 5 years later. Am J Surg 1973; 178: 258-264 71. Stanford JR, Lobow M, Vasko JJ: Prevention of stroke by carotid endarterectomy. Surgery 1978; 83: 259-263 72. Young JR, Humphries AW, Beven EG et al: Carotid endarterectomy without a shunt. Arch Surg 1969; 99: 293297 73. Thompson JE, Patman RD: Endarterectomy for asymptomatic carotid bruits. Heart Bull 1970; 19: 116-120

74. McNamara JO, Heyman A, Silver D et al: The value of carotid endarterectomy in treating transient cerebral ischemia of the posterior circulation. Neurology 1977; 27:

682-684 75. Fields WS, Maslenikov V, Meyer JS et al: Joint Study of Extracranial Arterial Occlusion: 5. Progress report of prognosis following surgery or nonsurgical treatment for transient cerebral ischemic attacks and cervical carotid artery lesions. JAMA 1970; 211: 1993-2003 76. Thompson JE, Patman RD, Talkington CM: Asymptomatic carotid bruit: long term outcome of patients having endarterectomy compared with unoperated controls. Ann Surg 1978; 188: 308-316 77. Allen GS, Preziosi TJ: Carotid endarterectomy: a prospective study of its efficacy and safety. Medicine (Baltimore) 1981; 60: 298-309 78. Sundt TM Jr, Sharbrough FW, Piepgras DG et al: Correlation of cerebral blood flow and electroencephalographic changes during carotid endarterectomy: with results of surgery and hemodynamics of cerebral ischemia. Mayo Clin Proc 1981; 56: 533-543 79. Ferguson GG: Extracranial carotid artery surgery. Clin Neurosurg 1982; 29: 543-574 80. Toronto Cerebrovascular Study Group: Risks of carotid endarterectomy. Stroke 1986; 17: 848-852 81. Ojemann RG, Crowell RH, Robertson GH et al: Surgical treatment of extracranial carotid occlusive disease. Clin Neurosurg 1975; 22: 214-263 82. Easton JD, Sherman DG: Stroke and mortality rate in carotid endarterectomy: 228 consecutive operations. Stroke 1977; 8: 565-568 83. Toole JF, Yuson CP, Janeway R et al: Transient ischemic attacks: a prospective study of 225 patients. Neurology 1978; 28: 746-753 84. Sundt TM, Sandok BA, Whisnant JP: Carotid endarterectomy: complications and preoperative assessment of risk. Mayo Clin Proc 1975; 50: 301-306 85. Lees CD, Hertzer NR: Postoperative stroke and late neurologic complications after carotid endarterectomy. Arch Surg 1981; 116: 1561-1568 86. Muuronen A: Outcome of surgical treatment of 110 patients with transient ischemic attack. Stroke 1984; 15: 959-963 87. Hertzer NR: Late results of carotid endarterectomy. In Ameli FM, Johnston KW (eds): Advances and Controversies in Vascular Surgezy - 1985 Conference Syllabus, Toronto, May 28-29, 1985, 88. Cusimano MD: The carotid endarterectomy study [E]. Can J Surg 1988; 31: 3-4 89. EC-IC Bypass Study Group: Failure of extracranial-intracranial arterial bypass to reduce the risk of ischemic stroke. Results of an international randomized trial. N Engl J Med 1985; 313: 1191-1200 90. Relman AS: The extracranial-intracranial arterial bypass study: What have we leamed? N Engl J Med 1987; 316: 809-810 91. Sundt M Jr: Was the international randomized trial of

extracranial-intracranial arterial bypass representative of the population at risk? Ibid: 814-816 92. Goldring S, Zervas N, Langfitt T: The Extracranial-Intracranial Bypass Study: a report of the committee appointed by the American Association of Neurological Surgeons to examine the study. Ibid: 817-820 93. Barnett HJM, Sackett D, Taylor DW et al: Are the results of the extracranial-intracranial bypass trial generalizable? Ibid: 820-824 94. Heifetz MD: The EC-IC Bypass Study [C]. N Engl J Med 1987; 317: 1030 95. Moore S: The EC-IC Bypass Study [C]. Ibid: 1030 96. Chalmers TC, Meier P, Plum F: The EC-IC Bypass Study [C]. Ibid: 1030-1031 97. Johnson GT: The EC-IC Bypass Study [C]. Ibid: 1031 98. Dupont WD: The EC-IC Bypass Study [C]. Ibid: 1031 99. Barnett HJM, Peerless SJ, Fox A et al: The EC-IC Bypass Study [C]. Ibid: 1031-1032


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