Donate Help Contact The AHA Sign In Home
American Heart Association
Circulation
Search: search_blue_button Advanced Search
« Previous Article | Table of Contents | Next Article »
Circulation. 2000;102:IV-75-IV-80

This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wolf, P. A.
Right arrow Articles by Grotta, J. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wolf, P. A.
Right arrow Articles by Grotta, J. C.
Related Collections
Right arrow Thrombolysis
Right arrow Carotid endarterectomy
Right arrow Brain Circulation and Metabolism
Right arrow Computerized tomography and Magnetic Resonance Imaging
Right arrow Primary and Secondary Stroke Prevention

(Circulation. 2000;102:IV-75.)
© 2000 American Heart Association, Inc.

Special Anniversary Issue

Cerebrovascular Disease

Philip A. Wolf, MD; James C. Grotta, MD

From Boston University School of Medicine, Boston, Mass, and the Department of Neurology, University of Texas–Houston Medical School.


Key Words: imaging • epidemiology • prevention • stroke • thrombolysis

On December 19, 1952, Dr C. Miller Fisher, in a lecture to the Montreal Medico-Chirurgical Society, "Concerning Strokes," noted "... I was under the impression that the subject of cerebrovascular disease had already been well cut and dried by the pioneers of Neuropathology. ... It became apparent that this was far from true, for many aspects of the subject had not yet been investigated and many details lacked clarity. What is more, few laboratories seemed interested in the subject, although as a cause of disability, illness and death, vascular disease of the brain has few rivals."1 The leading textbook, H. Houston Merritt’s A Textbook of Neurology2 offered little diagnostic guidance for stroke beyond noting that shift of a calcified pineal and bloody spinal fluid favored hemorrhage over infarction. The treatment proffered was largely palliative.

During this 50-year period, stroke as a discipline has moved forward. Advances in the past 30 years have occurred at a remarkable pace, and progress in cerebrovascular disease would appear to rival that of any other aspect of cardiovascular disease. Diagnosis and treatment of stroke patients in 1950 was based on a detailed clinical examination that virtually neurologists alone could perform and interpret. However, the neurologists of the day had few facts with which to analyze cases and even less in the way of diagnostic tools or therapies. In the interim, improvements have occurred in our understanding of the pathophysiological mechanisms of stroke, the availability of powerful diagnostic imaging tools, and the recent development of effective therapeutic measures. Importantly, stroke has repeatedly been shown to be preventable through risk factor modification, medications, and surgery.

Scientific Inquiry Into Stroke: Clinical-Neuropathological Studies

Just over 50 years ago, C.M. Fisher began his studies of the neuropathological basis and clinical manifestations of stroke. His contribution to the present understanding of cerebrovascular diseases cannot be overestimated. In a classic clinicopathological study of occlusion of the internal carotid artery in the neck, he focused attention on the importance of this diagnosis as the basis for stroke.3 4 He emphasized the failure to demonstrate thrombosis of the middle cerebral artery in case after case of stroke in which this diagnosis had been made clinically.3 By contrast, occlusion of the ipsilateral carotid artery was routinely undiagnosed but was frequently found at postmortem examination. He noted that the cervical portion of the carotid artery lay in the "no-man’s land" between general pathology and neuropathology, citing Chiari5 and Hunt,6 who had emphasized the importance of examining the carotid vessels in the neck in all cases of apoplexy. In addition, he linked the transient episodes of neurological dysfunction, particularly transient monocular blindness, to arterial stenosis of the extracranial carotid artery, thereby removing "spasm" as the basis of this phenomenon. Dr Fisher’s meticulous neuropathological and clinical observations superseded seemingly erudite professorial speculation and declarations on the mechanism of stroke and transient ischemic attacks.7

His work demonstrated that a thromboembolic mechanism underlay most ischemic strokes and that the source of thrombus might be the heart or a proximal arterial lesion. The embolus might arise after myocardial infarction, in the fibrillating atrial appendage,8 or from a thrombus at the site of stenosis in the cervical internal carotid artery.4 Further studies of lacunar stroke and the associated neurological syndromes permitted the diagnosis of this extremely common ischemic stroke to be made clinically decades before these lesions became visible on imaging studies of the brain, thereby guiding treatment.9 10 11 Noting the importance of thrombus formation in the genesis of ischemic stroke, Dr Fisher was an early advocate of anticoagulants and antiplatelet agents.12 In other studies, Fisher defined the clinical picture of hypertensive intracerebral hemorrhage and delineated the clinical picture of the major sites of hemorrhage. This proved crucial for the clinical diagnosis of cerebellar hemorrhage, a frequently fatal occurrence that usually went unsuspected. Accurate clinical diagnosis and prompt surgical drainage were often life-saving.13

Epidemiology of Stroke: Prospective Studies

Wide variation in stroke death rates, geographically and over time, suggested that environmental factors played an important role in stroke incidence. Hypertension, particularly severe diastolic and malignant hypertension, had long been acknowledged to predispose to stroke, particularly intracerebral hemorrhage. As is usually the case, clinical observation followed by case-control studies identified certain risk factors for stroke, but the importance of each and the benefit of risk factor modification were unclear. Data from the Framingham Study and other prospective epidemiological studies corroborated the importance of elevated blood pressure in stroke, infarction, and hemorrhage.14 Framingham data showed that hypertension directly increased the incidence of ischemic stroke. Increased levels of blood pressure, the systolic and the diastolic components, were directly related to increased incidence of stroke in men and women and at all ages. It was suggested that the increasing blood pressure levels so common in the elderly were not innocuous and postulated that blood pressure reduction would prevent, not precipitate, ischemic stroke. At that time, conventional wisdom drove clinical teaching and blamed reduction of blood pressure in elderly hypertensives for the precipitation of stroke. Hypertensives were thought to require a high level of blood pressure to perfuse the brain through atherosclerotic narrowed arteries.

In addition, other important risk factors for stroke were identified. Chief among them were impaired cardiac function, overt or occult; diabetes; nonvalvular atrial fibrillation (NVAF); migraine; family history of stroke; and others. Modifiable risk factors were also recognized, principally cigarette smoking, low levels of physical activity, and abdominal obesity.15 Newer factors amenable to modification include elevated levels of homocysteine, increased C-reactive protein (and other indices of inflammation), increased fibrinogen and clotting factors, and others.16

Prevention of Stroke by Risk Factor Modification

Beginning in 1967, a landmark series of randomized trials conducted by Dr Edward Fries compared antihypertensive medication with placebo in patients with severe diastolic hypertension.17 Subsequent trials comparing treatment versus placebo (or routine care) in patients with moderate, then mild, diastolic hypertension demonstrated incontrovertibly that reduction of elevated blood pressure reduced stroke incidence.18 19 These trials focused on diastolic hypertension in persons <65 years old. In more recent trials, reduction of systolic pressure in elderly persons with isolated systolic hypertension consistently prevented stroke, and the benefit far exceeded the risk.20 21 These seminal studies have clearly outlined the major path of stroke prevention. But even today, blood pressure is adequately controlled in only 20% of the 50 million hypertensives in the United States.

The advent of modern double-blind randomized clinical trials has also provided other clear answers for stroke prevention. In a series of trials of HMG-CoA reductase inhibitors, in persons with coronary heart disease and elevated LDL cholesterol concentrations, stroke and transient ischemic attack (TIA) incidence was reduced by 20% to 30%.22 23 In the Heart Outcomes Prevention Evaluation Study (HOPE), use of the ACE inhibitor ramipril in high-risk patients with cardiovascular diseases resulted in a reduction in a wide array of vascular outcomes, including stroke.24 The potential benefit of this class of medications, over and above blood pressure control, holds considerable promise for the next 50 years.

In the near future, newer methods of detecting subclinical atherosclerosis in asymptomatic persons will permit a further refinement in defining the profile of the stroke-prone individual. With detection of increased intimal-medial wall thickness in the carotid artery or atherosclerotic plaque in the aorta by ultrasonography, or impaired endothelial function in the brachial artery, persons still free of clinical disease but with risk factor abnormalities and early atherosclerosis may be specifically targeted to arrest the process.

Antiplatelet Therapy and Anticoagulation

During the past 30 to 40 years, paralleling efforts using aspirin to reduce subsequent clinical events in patients with coronary atherosclerosis, a series of randomized clinical trials for stroke prevention in patients with TIA or minor stroke was carried out.25 26 27 The benefit of aspirin was demonstrated in reducing the incidence of stroke in patients with prior symptomatic cerebrovascular disease: aspirin has become the mainstay of secondary stroke prevention. Demonstration of some degree of further benefit by other antiplatelet agents was again facilitated by well-designed clinical trials. Ticlopidine, clopidogrel, and most recently, a combination of sustained-release dipyridamole plus aspirin are the drugs available for patients requiring a drug other than aspirin.28 29 30

After the clinical and autopsy studies linking NVAF to stroke, data from epidemiological studies demonstrated this condition to be the most powerful precursor of stroke, particularly in the elderly.31 The 5-fold increased incidence of stroke in patients with NVAF was reduced by >66% in a remarkable series of randomized clinical trials of warfarin anticoagulation conducted in the late 1980s and early 1990s.32 Anticoagulation with warfarin to achieve a well-defined level of anticoagulation (INR between 2 and 3) has been shown to be effective and generally safe.

As with other preventive measures, warfarin anticoagulation has been underused, with <50% of the eligible AF patients being so treated. As with control of blood pressure and smoking cessation, application of this proven treatment would clearly prevent stroke. In fact, those 3 measures have been estimated to prevent {approx}75% of stroke events in the United States today.

Carotid Endarterectomy

Identification of atherosclerotic narrowing of the cervical portion of the internal carotid artery as an important basis for ischemic stroke was followed by angiographic visualization and surgical treatment of the carotid lesion. During the past 50 years, neuroradiology has identified the offending lesion, and surgeons have developed techniques to safely remove the offending blockage. However, even 30 years after the first surgical treatment of carotid stenosis in 1954, responsible physicians were questioning the utility of the procedure in light of the high rates of complications and postoperative stroke, myocardial infarction, and death. Once again, randomized clinical trial methodology provided answers to the difficult questions being posed. An early trial led by William S. Fields demonstrated the benefit of the procedure in stroke prevention, but the high rate of complications tarnished the result. However, this early multicenter clinical trial of a surgical versus nonsurgical treatment was the forerunner of the definitive study.33 A team led by Henry J.M. Barnett, MD, with the support of the Stroke and Trauma branch of the National Institute of Neurological Diseases and Stroke, designed and completed a large-scale clinical trial of the risks and benefits of this surgical procedure in symptomatic patients with TIA or minor stroke, the North American Symptomatic Carotid Endarterectomy Trial (NASCET).34 They demonstrated that surgery was quite effective, but only if rates of complications were held to a consistently low level. The expertise of the surgeon and radiologist were thus key to the benefit. Patients with the tightest level of stenosis and the highest level of risk factor abnormalities were at greatest risk and received the greatest benefit. Use of carotid ultrasonography and magnetic resonance angiography to delineate the stenosis without risking the neurological complications of angiography has further improved the care of these patients. The findings derived from another series of clinical trials, those of asymptomatic carotid stenosis, have proved less compelling and continue to be debated.16 35

Brain Imaging With CT and MRI

The introduction of CT scanning to clinical practice in the mid-1970s revolutionized the field of stroke.36 In fact, it forever changed the way neurologists approach all diseases of the brain. Before CT, we could only see negatives of the brain outline through pneumoencephalography, the anatomy of the vascular lumen through arteriography, and the status of the blood-brain barrier through radionuclide brain scans. Specialists could infer the presence of a mass by seeing displacement of vessels on the arteriogram, but we could not be absolutely sure whether the mass was a hematoma, tumor, abscess, or swollen infarct until pathological "brain cutting." The inability to image the brain was largely responsible for determining the traditional qualities of a good neurologist. Neurologists made diagnoses by examining the pattern of symptoms obtained by taking a careful history and by localizing the lesion by detecting abnormalities on a detailed neurological examination. This careful attention to the minutiae of the neurological examination became the almost mystical domain of the neurologist.

With CT, for the first time, we could actually see the offending lesion. Neurologists felt affirmed when they saw exactly what had been predicted, but all too often an unexpected finding was obtained. Thus, it was soon apparent that modern technology certainly gave us far more information than could be obtained solely by a history and examination. However, brain imaging did not make neurologists obsolete. Although it made the diagnoses and management more precise, some of the neurologists’ traditional clinical skills became rusty. Neurologists were quick to recognize the power of brain imaging, but as a specialty, we were slow to master its technological aspects, losing control of this valuable tool to the neuroradiologists.

In the area of vascular disease, CT facilitated the rapid detection of the presence of hemorrhage, and by its absence, inferred the occurrence of infarction. It further helped in the determination of the cause of the stroke by distinguishing the small subcortical lesions characteristic of lacunae, the wedge-shaped cortical lesions caused by an embolus, or the watershed hemodynamic features of a carotid obstruction. In the case of hemorrhage, it was possible to discern vascular malformations, subarachnoid blood indicating aneurysmal bleeding, or the characteristic location of hypertensive hemorrhage.

More recently, MRI has provided images of the brain in even greater detail. By adjustment of the sequence of magnetic pulses, the age and characteristics of the lesion can be determined, minute amounts of blood can be detected, and regions of the brain invisible or poorly visualized on CT of the brain (such as posterior fossa structures) can readily be seen. For cerebrovascular disease, the ability to simultaneously and noninvasively image both the brain and brain vasculature with MR angiography allows a complete anatomic evaluation of the patient. Finally, by determination of changes in the diffusion constant of water, ischemic lesions can be detected and quantified within minutes of stroke onset. In the next decade, MRI and other imaging modalities may help us identify those patients who are the best candidates for therapeutic intervention, having lesions that are still reversible, and by comparison with the ultimate infarct size, may be used to detect a therapeutic response.37 –38A

Cerebral Blood Flow and Demonstration of Ischemic Penumbra

Whereas brain imaging ushered in the modern era of stroke diagnosis, our ability to measure and consequently understand cerebral blood flow (CBF) and metabolism has led to the modern era of stroke therapy. CBF was first determined in living patients by measurement of brain uptake and washout of radiolabeled tracers.38B ,39 Using 133Xe or stable xenon and water labeled with positron-emitting 15O to measure CBF, researchers found that ischemic strokes are composed of regions of tissue with various degrees of hypoperfusion.40 41 42 43 44 Extending observations from laboratory animals to humans, thresholds of hypoperfusion were established that predicted irreversible injury.45 46 47 When these were coupled with measurements of cerebral metabolism of glucose or oxygen, it was determined that acute strokes harbored brain regions that, while underperfused, were still metabolically viable and could potentially be salvaged. This led to the concept of the ischemic "penumbra" identified by L. Symon and colleagues as the region in the shadow of the infarct where the ultimate fate of tissue was still undetermined. Within minutes of stroke onset, this penumbral region becomes established and then over minutes to hours gradually becomes incorporated into the region of irreversible function.

The concept of penumbra eventually led to the notion that the damage from ischemic strokes might be limited by timely therapeutic reperfusion (and worsened by overzealous reduction of blood pressure). Numerous studies in animals showed that restoring near-normal CBF to brain regions within the first 2 to 5 hours after the onset of focal ischemia would result in submaximal injury, with less injury the earlier normal flow was reestablished.48 49 Although initial attempts to achieve this in stroke patients through surgical thrombectomy, vasodilators, and hemodilution were unsuccessful, eventually the results of these CBF studies predicted the positive outcome obtained with thrombolytic drugs.50

Another application of CBF measurements takes advantage of the close link between CBF and metabolism in the normal brain.51 52 By measuring regional increases of CBF in response to various stimuli,53 we could map out those regions of the brain in which metabolic rate was increased by the activity. Eventually, this would lead to functional imaging of brain activity and recovery by use of positron-emitting isotopes and most recently MRI.54 55 56 57

In the next decade, these techniques will facilitate our understanding of mechanisms of how the brain reorganizes itself after injury and may allow us to determine how such reorganization might be augmented or retarded by attempts at rehabilitation.

Laboratory Stroke Models

Over the past 25 years, models of global and focal ischemia in laboratory animals have been developed. These models allowed researchers to learn the biological bases of ischemic cellular injury in exquisite detail and achieve substantial pharmacological neuroprotection at least in these laboratory models. Paradoxically, however, we have been unable to translate these advances into effective neuroprotection for stroke patients.

The first models of global forebrain ischemia showed that ischemic damage was related to the duration of blood flow reduction and was prominent in selectively vulnerable regions such as the CA1 area of the hippocampus.58 Furthermore, it was apparent that cell death was not immediate but was delayed for hours, suggesting the opportunity to intervene. At the same time, studies in cell culture and in vitro hippocampal slices demonstrated that neuron death was dependent on the presence of calcium and that excessive amounts of the excitatory neurotransmitter glutamate could produce calcium-mediated toxicity.59 60 These studies suggested therapeutic strategies for neuroprotection. Hypothermia was found to dramatically reduce injury (and fever to increase it) and that calcium and glutamate antagonists could provide pharmacological neuroprotection.61 62 63 64 65 66

The development of rat models of focal ischemia produced by permanent or transient middle cerebral artery occlusion allowed us to more accurately reproduce the type of pathological lesions caused by human stroke.67 68 We could demonstrate penumbral tissue, confirm time windows for seeing the beneficial effects of either reperfusion or neuroprotection, and unravel downstream events mediated by nitric oxide, free radicals, and inflammatory response. More recently, the contribution of apoptotic cell death has been recognized after both focal and global ischemia.69 70 71 Over the past 15 years, there has been an explosion of clinical trials attempting to reproduce at the bedside the same therapeutic success as achieved in the laboratory.72 The studies of reperfusion that have most closely mimicked the rat focal ischemia model and adhered to its time windows have been successful. All others have failed.

It is hoped that over the next decade we will learn to improve the precision of clinical trial design to carry out the "rat experiment in humans" and consequently be able to prove that pharmacological neuroprotection can be achieved in stroke patients. At the same time, the development of more effective neuroprotective agents will be sought whose benefits will be clinically apparent in more than just a handful of carefully selected patients.

Thrombolysis

Arteriography remained a risky and invasive procedure, not widely carried out in stroke patients, until the advent of transfemoral placement of microcatheters in selected cerebral and precerebral arteries.

It was not until the pioneering studies by Fieschi and others that embolic or thrombotic arterial occlusion in the corresponding cerebral vessel was demonstrated in the great majority of patients within the first hours after stroke onset.73 Spontaneous clot lysis and the adequacy of collateral flow were also appreciated as contributing to eventual outcome after stroke. These findings gave further impetus to efforts at thrombolysis. Larger clots, refractory to intravenously administered lytics, can be lysed by a direct endovascular approach. The successful treatment of acute ischemic stroke with thrombolytics has been the culmination of the work listed above. It has galvanized the stroke community, has bred a new generation of neurointerventionalists, and promises further advances in reducing morbidity and mortality from stroke.

In 1995, investigators contracted by NINDS reported the results of 2 consecutive trials of intravenously administered recombinant tissue plasminogen activator (rtPA).50 CT scanning before treatment allowed the exclusion of patients with hemorrhage. An understanding of CBF, penumbra, and time windows for reperfusion mandated treatment of all patients within 3 hours (half within 90 minutes), and the knowledge that arterial occlusion would be present in the vast majority of patients within this time window permitted treatment based on clinical symptoms rather than requiring time-consuming vascular studies. The percentage of patients who recovered completely by 3 months was increased by 10% to 15% (relative increase of 30% to 50%), depending on the outcome measure used. For instance, those with virtually normal neurological examinations were increased from 21% to 34%. Further analyses showed that rtPA treatment saved money for the healthcare system, was effective across all stroke subtypes and degrees of severity, and was more effective the earlier treatment was started. On the downside, rtPA-treated patients had a 6.4% rate of symptomatic hemorrhaging into the brain. This was more likely in patients with severe strokes and was often fatal. When both the increased rate of hemorrhages and increased rate of improvement were considered together, there was still a net benefit, even in severely affected patients. Nevertheless, concerns over the risk of bleeding, plus the difficulty in evaluating and treating patients within the 3-hour time window, have resulted in overall treatment of <5% of all stroke patients in the United States since rtPA was approved for use in stroke.

Some patients may benefit from thrombolysis beyond the 3-hour time window. A study of intra-arterial administration of prourokinase given, on average, 5 to 6 hours after the onset of main trunk middle cerebral artery occlusion showed high rates of recanalization and improved outcome compared with controls.74 However, trials of intravenous rtPA or streptokinase given beyond 3 hours have been equivocal.75 76 77 78 79 Remembering that it takes {approx}1 hour for intravenously administered rtPA to achieve recanalization,80 it is likely that a 4- to 6-hour time window for reperfusion exists in some patients who might be selected by newer imaging techniques.

In the future, we need to amplify the results obtained with intravenous rtPA by finding newer thrombolytics, combining intravenous and intra-arterial administration,81 adding antithrombotic therapy such as glycoprotein IIb/IIIa antagonists, and using mechanical, laser, or ultrasonic energy. Furthermore, building on what we have learned in laboratory stroke models, we might improve outcome by combining reperfusion with neuroprotective drugs.72 Finally, we need to strive harder to educate the public to recognize stroke symptoms and react urgently, and we need to train the next generation of physicians in how to diagnose stroke patients and treat them emergently.

Through these past 5 decades, the Stroke Section of the American Heart Association (and the recently established American Stroke Association) and the journal Stroke have played important roles in generating interest in the field and in actively disseminating knowledge of cerebrovascular diseases. The scientific meeting of the Stroke Council met as part of the annual Scientific Sessions of the American Heart Association until the 1970s, when the annual AHA Stroke Meeting met independently and became the premier international forum for presentation of scientific advances in clinical and research aspects of stroke. This meeting, which now attracts thousands annually, and the journal Stroke are in the vanguard of the dissemination of laboratory and clinical stroke research findings.

Acknowledgments

Dr Wolf is supported by NIH/NHLBI contract N01-HC-38038 and grant NINDS R01-NS17950. Dr Grotta is supported by NINDS R01-NS23979.

Footnotes

Reprint requests to Philip A. Wolf, MD, Neurological Epidemiology and Genetics, Boston University School of Medicine, 715 Albany St, B608, Boston, MA 02118-2526.

References

  1. Fisher CM. Concerning Strokes. Can Med Assoc J. 1953;69:257–268.
  2. Merritt HH. Chapter 2, Vascular Lesions. In: A Textbook of Neurology. Philadelphia, Pa: Lea & Febiger; 1955:159–201.
  3. Fisher M. Occlusion of the internal carotid artery. Arch Neurol. 1951;65:346–377.
  4. Fisher M. Occlusion of the carotid arteries. Arch Neurol Psychiatry. 1954;72:187–204.
  5. Chiari H. Über das Verhalten des Teilungswinkels der Carotis communis bei der Endarteriitis chronica deformans. Verh Dtsch Ges Pathol. 1905;9:326.
  6. Hunt JR. The role of the carotid arteries, in the causation of vascular lesions of the brain, with remarks on certain special features of the symptomatology. Am J Med Sci. 1914;704–713.
  7. Denny-Brown D. The treatment of recurrent cerebrovascular symptoms and the question of "vasospasm." Med Clin North Am. 1951;35:1457–1474.
  8. Fisher CM. Treatment of chronic atrial fibrillation. Lancet. 1972;1:1284.
  9. Fisher CM. Capsular infarcts: the underlying vascular lesions. Arch Neurol. 1979;36:65–73.[Medline]
  10. Fisher CM. Lacunes: small, deep cerebral infarcts. Neurology. 1965;15:774–784.
  11. Fisher CM, Curry HB. Pure motor hemiplegia of vascular origin. Arch Neurol. 1965;13:30–44.
  12. Fisher CM. Anticoagulant therapy in cerebral thrombosis and cerebral embolism: a national cooperative study, interim report. Neurology. 1961;11(pt 2):119–131.
  13. Fisher CM, Picard EH, Polak A, et al. Acute hypertensive cerebellar hemorrhage: diagnosis and surgical treatment. J Nerv Ment Dis. 1965;140:38–57.
  14. Kannel WB, Wolf PA, Verter J, et al. Epidemiologic assessment of the role of blood pressure in stroke: the Framingham study. JAMA. 1970;214:301–310.[Medline]
  15. Wolf PA. Lewis A. Conner Lecture. Contributions of epidemiology to the prevention of stroke. Circulation. 1993;88(5 pt 1):2471–2478.
  16. Wolf PA. Prevention of stroke. Lancet. 1998;352(suppl III):SIII15–SIII18.
  17. Veteran’s Administration Cooperative Study Group on Antihypertensive Agents. Effects of treatment on morbidity in hypertension, I: results in patients with diastolic blood pressure averaging 115 through 129 mm Hg. JAMA. 1967;202:116–122.[Medline]
  18. Taguchi J, Freis ED. Partial reduction of blood pressure and prevention of complications in hypertension. N Engl J Med. 1974;291:329–331.[Medline]
  19. Collins R, Peto R, MacMahon S, et al. Blood pressure, stroke, and coronary heart disease, II: short-term reductions in blood pressure: overview of randomised drug trials in their epidemiological context. Lancet. 1990;335:827–838.[Medline]
  20. SHEP Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension: final results of the Systolic Hypertension in the Elderly Program (SHEP). JAMA. 1991;265:3255–3264.[Medline]
  21. Staessen JA, Fagard R, Thijs L, et al, for the Systolic Hypertension in Europe (Syst-Eur) Trial Investigators. Randomised double-blind comparison of placebo and active treatment for older patients with isolated systolic hypertension. Lancet. 1997;350:757–764.[Medline]
  22. Plehn JF, Davis BR, Sacks FM, et al, for the Care Investigators. Reduction of stroke incidence after myocardial infarction with pravastatin: the Cholesterol and Recurrent Events (CARE) study. Circulation. 1999;99:216–223.[Abstract/Full Text]
  23. The Long-Term Intervention with Pravastatin in Ischaemic Disease (LIPID) Study Group. Prevention of cardiovascular events and death with pravastatin in patients with coronary heart disease and a broad range of initial cholesterol levels. N Engl J Med. 1998;339:1349–1357.[Medline]
  24. Yusuf S, Sleight P, Pogue J, et al, for the Heart Outcomes Prevention Evaluation Study Investigators. Effects of an angiotensin-converting-enzyme inhibitor, ramipril, on cardiovascular events in high-risk patients. N Engl J Med. 2000;342:145–153.[Medline]
  25. Antiplatelet Trialists’ Collaboration. Collaborative overview of randomised trials of antiplatelet therapy, I: prevention of death, myocardial infarction, and stroke by prolonged antiplatelet therapy in various categories of patients. BMJ. 1994;308:81–106.[Abstract/Full Text]
  26. Barnett HJ. Aspirin in stroke prevention: an overview. Stroke. 1990;21(suppl IV):IV-40–IV-43.
  27. Fields WS, Lemak NA, Frankowski RF, et al. Controlled trial of aspirin in cerebral ischemia. Stroke. 1977;8:301–314.[Abstract]
  28. Hass WK, Easton JD, Adams HP Jr, et al for the Ticlopidine Aspirin Stroke Study Group. A randomized trial comparing ticlopidine hydrochloride with aspirin for the prevention of stroke in high-risk patients. N Engl J Med. 1989;321:501–507.[Medline]
  29. CAPRIE Steering Committee. A randomised, blinded, trial of clopidogrel versus aspirin in patients at risk of ischaemic events (CAPRIE). Lancet. 1996;348:1329–1339.[Medline]
  30. Diener HC, Cunha L, Forbes C, et al. European Stroke Prevention Study, II: dipyridamole and acetylsalicylic acid in the secondary prevention of stroke. J Neurol Sci. 1996;143:1–13.[Medline]
  31. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation: a major contributor to stroke in the elderly: the Framingham Study. Arch Intern Med. 1987;147:1561–1564.[Medline]
  32. Atrial Fibrillation Investigators. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation: analysis of pooled data from five randomized controlled trials. Arch Intern Med. 1994;154:1449–1457.[Medline]
  33. Fields WS, Maslenikov V, Meyer JS, et al. Joint study of extracranial arterial occlusion, V: progress report of prognosis following surgery or nonsurgical treatment for transient cerebral ischemic attacks and cervical carotid artery lesions. JAMA. 1970;211:1993–2003.[Medline]
  34. North American Symptomatic Carotid Endarterectomy Trial Collaborators. Beneficial effect of carotid endarterectomy in symptomatic patients with high-grade carotid stenosis. N Engl J Med. 1991;325:445–452.[Medline]
  35. Executive Committee of the Asymptomatic Carotid Atherosclerosis Study. Endarterectomy for asymptomatic carotid artery stenosis. JAMA. 1995;273:1421–1428.[Medline]
  36. Ambrose J, Hounsfield G. Computerized transverse axial tomography. Br J Radiol. 1973;46:148–9.[Medline]
  37. Baird AE, Warach S. Magnetic resonance imaging of acute stroke. J Cereb Blood Flow Metab. 1998;18:583–609.[Medline]
  38. Mosely ME, Cohen Y, Mintovitch J, et al. Early detection of regional cerebral ischemia in cats: comparison of diffusion- and T2-weighted MRI and spectroscopy. Magn Reson Med. 1990;14:330–346.[Medline]
  39. Reivich M, Jehle J, Sokoloff L, et al. Measurement of regional cerebral blood flow with antipyrine-14C in awake cats. J Appl Physiol. 1969;27:296–300.[Medline]
  40. Olesen J, Paulson OB, Lassen NA. Regional cerebral blood flow in man determined by the initial slope of the clearance of intra-arterially injected 133Xe. Stroke. 1971;2:519–540.[Medline]
  41. Hoedt-Rasmussen K, Skinjoh E, Paulson O, et al. Regional cerebral blood flow in acute apoplexy: the "luxury perfusion syndrome" of brain tissue. Arch Neurol. 1967;17:271–281.[Medline]
  42. Rao NS, Ali ZA, Omar HM, et al. Regional cerebral blood flow in acute stroke: preliminary experience with the 133 xenon inhalation method. Stroke. 1974;5:8–12.[Medline]
  43. Meyer JS, Hayman LA, Sakai F, et al. High-resolution three-dimensional measurement of localized cerebral blood flow by CT scanning and stable xenon clearance: effect of cerebral infarction and ischemia. Trans Am Neurol Assoc. 1979;104:85–89.[Medline]
  44. Ackerman RH, Correia JA, Alpert NM, et al. Positron imaging in ischemic stroke disease using compounds labeled with oxygen 15: initial results of clinicophysiologic correlations. Arch Neurol. 1981;38:537–543.[Medline]
  45. Wise RJ, Bernardi S, Frackowiak RS, et al. Measurement of regional cerebral blood flow, oxygen extraction ratio and oxygen utilization in stroke patients using positron emission tomography. Exp Brain Res. 1982;(suppl 5):182–186.
  46. Astrup J, Symon L, Branston NM, et al. Cortical evoked potential and extracellular K+ and H+ at critical levels of brain ischemia. Stroke. 1977;8:51–57.[Abstract]
  47. Astrup J, Siesjo BK, Symon L. Thresholds in cerebral ischemia: the ischemic penumbra. Stroke. 1981;12:723–725.[Medline]
  48. Hossmann KA. Viability thresholds and penumbra of focal ischemia. Ann Neurol. 1994;36:557–565.[Medline]
  49. Jones TH, Morawetz RB, Crowell RM, et al. Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg. 1981;54:773–782.[Medline]
  50. Kaplan B, Brint S, Tanabe J, et al. Temporal thresholds for neocortical infarction in rats subjected to reversible focal cerebral ischemia. Stroke. 1991;22:1032–1039.[Abstract]
  51. The NINDS rtPA Stroke Study Group. Tissue plasminogen activator for acute ischemic stroke. N Engl J Med. 1995;333:1581–1587.[Medline]
  52. Meyer JS, Fukuuchi Y, Shimazu K, et al. Abnormal hemispheric blood flow and metabolism in cerebrovascular disease, I: disordered patterns of hemispheric metabolism. Stroke. 1972;3:141–156.[Medline]
  53. Carter CC, Eichling JO, Davis DO, et al. Correlation of regional cerebral blood flow with regional oxygen uptake using 15 O method. Neurology. 1972;22:755–762.[Medline]
  54. Olesen J. Contralateral focal increase of cerebral blood flow in man during arm work. Brain. 1971;94:635–646.[Medline]
  55. Heiss WD, Herholz K, Pawlik G, et al. Positron emission tomography in neuropsychology. Neuropsychologia. 1986;24:141–149.[Medline]
  56. Ginsberg MD, Chang JY, Kelley RE, et al. Increases in both cerebral glucose utilization and blood flow during execution of a somatosensory task. Ann Neurol. 1988;23:152–160.[Medline]
  57. Belliveau JW, Kennedy DN Jr, McKinstry RC, et al. Functional mapping of the human visual cortex by magnetic resonance imaging. Science. 1991;254:716–719.[Medline]
  58. Frackowiak R. Functional imaging of recovery from stroke: a review of personal experience. Cerebrovasc Dis. 1999;9(suppl 5):23–28.
  59. Pulsinelli WA, Brierley JB. A new model of bilateral hemispheric ischemia in the unanesthetized rat. Stroke. 1979;10:267–272.[Abstract]
  60. Wieloch T, Harris RJ, Siesjo BK. Brain metabolism and ischemia: mechanism of cell damage and principles of protection. J Cereb Blood Flow Metab. 1982;2(suppl 1):S5–S9.
  61. Choi DW. Glutamate neurotoxicity in cortical cell culture is calcium dependent. Neurosci Lett. 1985;5:293–297.
  62. Busto R, Dietrich WD, Globus MY, et al. Postischemic moderate hypothermia inhibits CA1 hippocampal ischemic neuronal injury. Neurosci Lett. 1989;101:299–304.[Medline]
  63. Steen PA, Newberg LA, Milde JH, et al. Nimodipine improves cerebral blood flow and neurologic recovery after complete cerebral ischemia in the dog. J Cereb Blood Flow Metab. 1983;3:38–43.[Medline]
  64. Barnett GH, Bose B, Little JR, et al. Effects of nimodipine on acute focal cerebral ischemia. Stroke. 1986;17:884–890.[Abstract]
  65. Grotta JC, Spydell J, Hunter D, et al. The effect of nicardipine on neuronal function following ischemia. Stroke. 1989;17:213–219.[Abstract]
  66. Kochhar A, Zivin JA, Lyden PD, et al. Glutamate antagonist therapy reduces neurologic deficits produced by focal central nervous system ischemia. Arch Neurol. 1988;45:148–153.[Medline]
  67. Park CK, Nehls DG, Graham DI, et al. The glutamate antagonist MK-801 reduces focal ischemic brain damage in the rat. Ann Neurol. 1988;24:543–551.[Medline]
  68. Chen ST, Hsu CY, Hogan EL, et al. A model of focal ischemic stroke in the rat: reproducible extensive cortical infarction. Stroke. 1986;17:738–743.[Abstract]
  69. Brint S, Jacewicz M, Kiessling M, et al. Focal brain ischemia in the rat: methods for reproducible neocortical infarction using tandem occlusion of the distal middle cerebral and ipsilateral common carotid arteries. J Cereb Blood Flow Metab. 1988;8:474–485.[Medline]
  70. Linnik MD, Zobrist RH, Hatfield MD. Evidence supporting a role for programmed cell death in focal cerebral ischemia in rats. Stroke. 1993;24:2002–2008.[Medline]
  71. Li Y, Chopp M, Jiang N, et al. Induction of DNA fragmentation after 10 to 120 minutes of focal cerebral ischemia in rats. Stroke. 1995;26:1252–1257.[Abstract/Full Text]
  72. Johnson EM JR, Greenlund LJ, Akins PT, et al. Neuronal apoptosis: current understanding of molecular mechanisms and potential role in ischemic brain injury. J Neurotrauma. 1995;12:843–852.[Medline]
  73. Grotta JC. Acute stroke therapy at the millennium: consummating the marriage between the laboratory and bedside: the Feinberg Lecture. Stroke. 1999;30:1722–1728.[Full Text]
  74. Fieschi C, Argentino C, Lenzi GL, et al. Clinical and instrumental evaluation of patients with ischemic stroke within the first six hours. J Neurol Sci. 1989;91:311–321.[Medline]
  75. Furlan A, Higashida R, Wechsler L, et al, for the PROACT Investigators. Intra-arterial prourokinase for acute ischemic stroke: the PROACT II Study: a randomized controlled trial. JAMA. 1999;282:2003–2011.[Medline]
  76. Hacke W, Kaste M, Dieschi C, et al. Intravenous thrombolysis with recombinant tissue plasminogen activator for acute hemispheric stroke: the European Cooperative Acute Stroke Study (ECASS). JAMA. 1995;274:1017–1025.[Medline]
  77. Multicentre Acute Stroke Trial–Italy (MAST-I) Group. Randomised controlled trial of streptokinase, aspirin, and combination of both in treatment of acute ischaemic stroke. Lancet. 1995;356:1509–1514.
  78. Donnan GA, Davis SM, Chambers BR, et al. Streptokinase for acute ischaemic stroke with relationship to time administration. JAMA. 1996;276:961–966.[Medline]
  79. Multicenter Acute Stroke Trial–Europe Study Group. Thrombolytic therapy with streptokinase in acute ischaemic stroke. N Engl J Med. 1996;35:145–150.
  80. Hacke W, Kaste M, Fieschi C, et al, for the Second European-Australasian Acute Stroke Study Investigators. Randomized double-blind placebo-controlled trial of thrombolytic therapy with intravenous alteplase in acute ischaemic stroke (ECASS II). Lancet. 1998;352:1245–1251.[Medline]
  81. Christou I, Alexandrov A, Burgin WS, et al. Timing of recanalization after TPA therapy determined by transcranial Doppler correlates with clinical recovery from ischemic stroke. Stroke. 2000;31:1812–1816.[Abstract/Full Text]
  82. Lewandowski CA, Frankel M, Tomsick TA, et al, and the EMS Bridging Trial Investigators. Combined intravenous and intra-arterial r-TPA versus intra-arterial therapy of acute ischemic stroke: emergency management of stroke (EMS) bridging trial. Stroke. 1999;30:2598–2605.[Abstract/Full Text]




This Article
Right arrow Full Text (PDF)
Right arrow Alert me when this article is cited
Right arrow Alert me if a correction is posted
Services
Right arrow Email this article to a friend
Right arrow Similar articles in this journal
Right arrow Similar articles in PubMed
Right arrow Alert me to new issues of the journal
Right arrow Download to citation manager
Right arrow Request Permissions
Citing Articles
Right arrow Citing Articles via Google Scholar
Google Scholar
Right arrow Articles by Wolf, P. A.
Right arrow Articles by Grotta, J. C.
Right arrow Search for Related Content
PubMed
Right arrow PubMed Citation
Right arrow Articles by Wolf, P. A.
Right arrow Articles by Grotta, J. C.
Related Collections
Right arrow Thrombolysis
Right arrow Carotid endarterectomy
Right arrow Brain Circulation and Metabolism
Right arrow Computerized tomography and Magnetic Resonance Imaging
Right arrow Primary and Secondary Stroke Prevention

Circulation Home | Subscriptions | Archives | Feedback | Authors | Help | AHA Journals Home | Search
Copyright © 2000 American Heart Association, Inc. All rights reserved. Unauthorized use prohibited.