- Scientific Inquiry Into Stroke: Clinical-Neuropathological Studies
- Epidemiology of Stroke: Prospective Studies
- Prevention of Stroke by Risk Factor Modification
- Antiplatelet Therapy and Anticoagulation
- Carotid Endarterectomy
- Brain Imaging With CT and MRI
- Cerebral Blood Flow and Demonstration of Ischemic Penumbra
- Laboratory Stroke Models
- Info & Metrics
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 ≈75% of stroke events in the United States today.
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.
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 ≈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.
Dr Wolf is supported by NIH/NHLBI contract N01-HC-38038 and grant NINDS R01-NS17950. Dr Grotta is supported by NINDS R01-NS23979.
Reprint requests to Philip A. Wolf, MD, Neurological Epidemiology and Genetics, Boston University School of Medicine, 715 Albany St, B608, Boston, MA 02118-2526.
- Copyright © 2000 by American Heart Association
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