Stroke is the third most common cause of death (after heart disease and cancer) in the U.S. and Europe. Thrombosis and embolism account for approximately 75% of all strokes, whereas about 20% are due to hemorrhage. Up to 70% of all major stroke victims are usually permanently and significantly disabled. Of those who survive, the five year accumulative risk of repeated stroke is about 40% in men and 25% in women.
STROKE: CEREBRAL INFARCTION
When the brain is not adequately perfused with blood and is deprived of oxygen and nutrients, nerve cells begin to die and a variety of neurological, neuropsychiatric, and neuropsychological abnormalties may result depending on how long and which portions of the cerebrum are involved. As is well known, the complete deprivation of blood for longer than 3 minutes produces neuronal, glial and vascular necrosis and irreversible brain damage; i.e. cerebral infarction (stroke) and ischemic necrosis. If blood flow is reduced for a shorter time period transient neurological abnormalties may occur.
For example, at rest the human brain consumes about 20% of the total oxygen consumed by the body and 70% of the total glucose. However, unlike other organs, the brain is without oxygen or glucose storage capacity and is therefore completely dependent on the blood supply. Thus disruption of the blood supply and/or a loss of oxygen and glucose for a little as 10-30 seconds can induce dizziness, confusion, and loss of consciousness. Similarly, if cerebral blood flow drops below 40% of what is normal, electrocortigraphic silence is produced, followed by anoxic depolorization, depletion of cellular energy metabolites coupled with massive increases in extracellular potassium ions, which is followed by neuronal death (Ginsberg 1995).
Thus a cerebral infarct and the neurological symptoms which accompany it may develop quite aburptly and in a manner of seconds. However, the full symptomatic development of an infarct can be more prolonged taking perhaps minutes, hours or days; i.e. stroke in evolution.
Specifically, cerebral infarction is characterized by lack of oxygen, nutrients, and/or the impaired removal of metabolic products --conditions which result in the death of neurons, glia and the vasculature. Moreover, when cells die their membrains burst releasing lipids, fatty acids, and other substances which can produce systemic and local effects which magnify damage in surrounding zones. In addition, although the brain requires glucose in order to function effectively, increases in blood glucose levels following or during acute ischemic stroke can markedly worsen the outcome in nonlacunar strokes and can increase the risk of hemorrhagic infarction (Bruno, et., al., 1999). Hyperglycemia aguments the degree and severity of ischemic injury.
Cerebral infarction or stroke is often secondary to cerebrovascular disease and vascular abnormalities involving the heart and/or blood vessels. This includes atherosclerosis, occulusion of the cerebral arteries by thrombus or embolus, or rupture of a vessel which causes hemorrhage. Other major risk factors for stroke include hypertension, diabetes mellitus, atrial fibrillation, transient ischemic attacks, left ventricular hypertrophy, congestive heart failure, and coronary heart disease (Alter et al. 1994; Bornstein & Kelly 1991; Kimura, et al., 1999; Toole, 1990; Wolf et al. 1983). Diseases or damage involving the heart, including myocardial infarction, are leading contributors to stroke.
In addition, there are seasonal factors which contribute to stroke, due in large part to reductions in temperature (Lanska & Hoffmann, 1999). Specifically, patients are more likely to suffer a stroke and to suffer stroke-related mortality in the colder winter months. Mortality secondary to a winter-time stroke is also directly related to the increased risk for respiratory disease during the colder months of the year.
CEREBRAL-VASCULAR DISEASE OF THE ARTERIES
By definition, an artery (with the exception of the pulmonary artery) is a vessel which carries oxygenated blood away from the heart to other parts of the body. Small arteries are referred to as arterioles. Capillaries are microscopic vessels which transport blood from the arterioles to venules. Venules carry blood to veins. In general, the capillary density is greater in the gray than white matter, and the gray receives about five times as much blood and 7 times as much oxygen as the white matter.
Arteries consist of an outer coat of tough fibrous tissue, an inner lining of endothelium, and a smooth inner coat of muscle which acts to constrict and dilate the vessel. Any alteration in the smoothness of this muscular coat can give rise to the development of blood clots and thrombi. Most rough spots are secondary to atherosclerosis. Atherosclerosis is a major risk factor for stroke, and the longer the duration of initial symptoms, such as in the case of transient ischemic attacks, the more likely is it that aterial disease is a facto.
Atherosclerosis is a noninfammatory degenerative disease of the arterial blood supply to the brain and the body. Atherosclerosis includes a wide range of arterial abnormalities, such as roughening of the blood vessel intima, elongation and stiffening of the artery which may cause it to kink and buckle (which in turn reduces blood flow and pressure), reductions in the caliber or dissection or tearing of the lumen (the inner arterial walls), obstruction or occulsion of the lumen with possible diversion of flow through collateral channels, focal dilations, and plaque formation coupled with occlusion and a severe reduction in blood flow, which results in ischemia and stroke.
Atherosclerosis exerts its effects indirectly on the brain by decreasing perfusion pressure and reducing flow through the tissues supplied by the various blood vessels. This is accomplished by promoting the development of thrombi and emboli (fibrin, platelets, or cholersterol crystals),which in turn increasingly occlude the arterial lumen. The metabolic demands of many areas of the brain can thus become partially deprived of oxygen and glucose.
Hypertension is a leading cause of vascular hypertrophy, arteriosclerosis, stroke, and hemorrhage. Approximately 40% of those with arteriosclerosis are hypertensive (Toole, 1990). However, in some respects hypertension and arteriosclerosis are directly linked in that hypertension can injure the artery, which can result in aterioscolerosis, which increases blood pressure, which injures the vessel wall, which can result in clot formation (thrombi and emobli) as blood cells burst and/or collect in the area of the damaged vessels, which in turn act to obstruct blood flow passage thus increasing (at least proximal) blood pressure, which results in increased vessel damage and occlusion, and so on.
Specifically, chronic hypertension acts to reduce arterial elasticity by stretching and thickening the walls of the blood vessels including the capillaries. It can also potentiate the development of thrombi via pressure induced erosion or roughening of vessel walls. Hence, frequently the space within the vessel through which the blood flows will decrease in size. However, sometimes it is actually enlarged.
Chronic hypertension, although associated with increased blood pressure, actually can cause generalized blood flow reductions, particularly in regions served by the middle cerebral artery, i.e. the frontal-parietal and temporal lobes (Rodriguez, et al. 1987). Hence, one consequence of hypertension is an increased risk for ischemic infarcts (Alter et al. 1994; Bornstein & Kelly 1991). That is, because the caliber of the lumen becomes fixed and rigid, the ability to dilate and thus compensate for alterations in blood pressure is lost. In consequence, if there were a decrease in blood pressure, this inability to compensate would result in a signficant reduction in blood flow and thus cerebral ischemia.
If, on the otherhand, blood pressure were to increase, this lack of flexibility would predispose the vessels to burst and hemorrhage. Hence, there is a strong correlation between the incidence of stroke and high blood pressure.
Hypertensive Encephalopathy
Hypertensive encephalopathy refers to an acute syndrome in which there is an absence of warning signs and a rapid development (from minutes to hours) of deficits. Patients often complain of headache, nausea, vomiting, visual disturbances, and confusion and they may develop convulsions, focal neurological signs, and/or lapse into a deepening coma or stuporous state.
Onset is often preceded by an extreme and rapid rise in blood pressure and severe hypertension. Autoregulatory responses may become abnormal such that widespread vasospasms occur accompanied by ischemia and/or the rupturing of arterioles and capillaries. The blood vessles of the brain may then begin to hemorrhage.
Clot Formation
Atherosclerotic development usually begins early in life, and may be due to diet, lack of exercise, and genetics. Initially, atherosclerotic disease exerting its injurious and roughening effects at the bifurcation of the various blood vessels. Endothelial cells lining the blood vessel begin to die due to the constant erosion, ulceration occurs, and blood platelets, lipids and cholersterol begin to be deposited in the arterial intima thus forming a mound of tissue. Indeed, within a matter of seconds of blood vessel injury (regardless of cause), blood platelets will begin to adhere to the damaged areas. Indeed, blood platelets will begin to adhere to any portion of a vessel which is not perfectly smooth and contains rough spots (e.g. a patch-like accumulation of lipid or cholesterol).
When blood platelets begin to build up, they will rupture which in turn triggers the formation of thrombin and insoluable fibrin proteins, thromboplastin. These thrombin proteins act to create blood clots which further occlude the vessel.
Specifically, these fibrin proteins resemble web-like threads which are tangled together. These tangles act like nets which act to trap more blood cells and other debri which then clot together. Once started the clot tends to grow as more and more platelets are enmeshed and rupture thereby releasing more thromboplastin fibrin proteins. Furthermore, the plaques which narrow the lumen may serve as a nidus upon which even more thrombi come to adhere and from which emboli may be dislodged. Hence, these elevated fibrous plaques (thrombi) invariably grow larger and may even become vascularized. A complicated lesion is thus formed.
Obstructive Influences
As the clot grows blood flow is reduced which causes even more thromboplastin to accumulate; particularly in that these deposits create turbulence or eddy current which further damage the smooth endothelium of the artery as well as reduce resilience.
As the clot grows and thrombi increase in thickness, the lumen becomes progressivley smaller which results in arterial dilation. By reducing the resilience and the diameter of the large arteries atherosclerosis can induce systolic hypertension. The driving force of the blood against vessel walls is therefore increased which causes further roughening and more plaque formation. Atherosclerosis is thus an insidious process.
When the lumen of the artery is narrowed by about 50%, pressure in the proximal segment increases whereas distal to the clot pressure begins to fall. With 70% reduction, flow is significantly decreased and neurological functioning may be altered. Typically, however, patients remain asymptomatic until there is a sudden reduction in blood flow, or thrombi or emboli are thrown off creating a complete obstruction. However, if the core of the plaque becomes necrotic and calcifies, the surface may disintegrate thus exposing the weakened underlying surface of the vessel. When this occurs the vessel may rupture and hemorrhage.
Obstruction of the artery due to atherosclerosis may produce disasterous neurological consequences or be associated with no symptoms whatsoever. The outcome depends upon 1) the configuration of the arterial tree with which the patient was born; 2) the segment of artery involved; 3) rapidity of obstruction development; 4) the presence or absence of collateral vessels; 5) associated diseases such as hypertension; 6) triggering mechanisms, such as a sudden blow or turn of the head.
Susceptible Arteries
There is a tendency for atheromatous plaques to form at branching and curves of cerebral arteries--most frequently the internal carotid artery and carotid sinus, the vertebral arteries and their junction which froms the basilar, the main bifurcation of the middle cerebral artery, the posterior cerebral arteries as they wind around the midbrain, and in the anterior cerebrals as they curve over the corpus callosum.
Atherosclerosis seldom exists in either the coronary of cerebral artery system without the other being involved as well--it occurs in both. When the heart is involved this can lead to myocardial infarction and mural thrombi may be cast off which then flow directly to the lungs and brain. Atherosclerototic heart disease can also cause caridiac dysrhythmias or decreases in cardiac output--possibly to such a degree that cerebrovascular insufficiency results.
Risk Factors
Risk factors for cerebrovascular and carotid atherosclerosis include hypertension, increased age, diabetis mellitus, and cigarette smoking; age and hypertension being the most important. In general, the onset of atherosclerotic disease is usually in childhood and remains silent, growing slowly for 20 or 30 years before becoming symptomatic.It appears to reach its peak incidence between the ages of 50-70 and men are twice as likely as women to suffer.
Ischemia leads to hypoxia and impaired delivery of glucose as well as a failure to remove metabolites and waste such as lactic acid and carbon dioxide (Qureshi, et al., 1999; Welch & Levine 1991). As infarction evolves, local edema results which may cause an increase in tissue pressure and further reduce tissue perfusion by compressing capillaries, thereby enlarging the infarction. The severity and extent of the neurological deficit is increased even further.
There is usually reduced blood flow during ischemic attacks which extends far beyond the infarct borders. This further reduce neuronal activity such that transient (as well as permanent) neurological deterioration occurs. These transient blood flow reduction are due to metabolic changes, compression of the local vasculature and temporary cessation of neural activity (due to disconnection). Initially this may make the functional effects of the stroke appear more pervasive and profound. Nevertheless blood flow is still sufficient in these border areas so as to keep this tissue alive. Hence, as the ischemia subsides and blood flow is increased to these depressed areas there occurs a considerable degree of what appears to be recovery.
The majority of infarcts are sharply delineated. Nevertheless, surrounding the area of ischemia is a concentric zone of hyperemia caused by a local loss of autoregulatory capacity and vasomotor paralysis (Ginsberg 1995). That is, there is an increase in flow to the immediately surrounding area which acts to divert blood from other areas of the brain as well as from the ischemic zone thereby increasing ischemic damage to this area. This loss of autoregulation is most evident during the acute phase of cerebral infarction. As the infarction evolves there is local edema and swelling. This causes an increase in tissue pressure and further reduced tissue perfusion by compressing capillaries. The infarction is enlarged even further.
The pathological effects of ischemia and reduced blood flow may be massive, if, for example, the internal carotid or middle cerebral artery is obstructed. Or, the effects may be minute if impaired circulation is limited to the smaller arteries and arterioles.
With moderate or massive infarction, even if quite focal, regions within the opposite hemisphere also exhibit similar but less extensive changes due perhaps to local reflexia, increased intracranial pressure, or the spillage and spread of vasoactive chemicals which effect the entire brain. That is, the otehr half of the brain may also suffer a stroke.
Moreover, infarction of one hemisphere may cause so much swelling that it leads to symptoms of increased intracranial pressure. When pressure increases blood flow decreases. Blood flow tends toward normal in those who recover, but remains slow throughout the affected hemisphere in those who do poorly.
Risk Factors
Risk factors for ischemic stroke include, older age, male sex, hypertension, TIAs, hypertensive heart disease, coronary heart disease, congestive heart failure, diabetes mellitus, and cold winter months.
The major determinants for short-term mortality are intraventicular hemorrhage, pulmonary edeman, impaired consciousness, leg weakneness, respiratory diease and increasing age -with level of consciousnes following stroke being the single most important predictor of short-term survival. The major determinants for long term mortality are low activity level, advanced age, male sex, heart disease and hypertension. However, those who suffer intraventricular hemorrhagic infarcts have a higher mortality rate than those with infarcts due to other causes (Chambers, et al. 1987; Roos et al. 1995; Schievink et al. 1995). As noted in chapter 10, those with right hemisphere damage tend to have poorer outcomes as well as higher mortality rates. In particular right parietal lobule infarcts are associated with very poor outcomes (Valdimarsson et al. 1982).
Hyperglycemia and diabetes are also associated with poor neurological recovery, and higher short-term mortality as well as increasing the risk for stroke in general. This is because diabetes and hyperglycemia both accentuate ischemic damage. Hyperglycemia also appears to have a negative effect on energy metabolism due to the generation of severe lactic acidosis (Rehncrona et al. 1980) --factors which act to retard neuronal recovery.
Some authors have argued that luxury perfusion and increased cerebral blood flow (CBF) within an infarcted cite is often indicative of a good prognosis, wheras low CBF is a bad prognosis (Olsen et al. 1981). Presumably increased flow acts to nourish damaged tissue. Other studies however, indiate that initial CBF levels are not predictive of clinical outcome (Burke et al. 1986). Apparently this is because once damage occurs during the initial period of ischemia, these cells cannot be salvaged (Heiss & Rosner, 1983).
Hence, blood flow increases only when undamaged neurons return to a functionally active state (Burke et al., 1986) rather than acting to rejuvinate injured tissue. In fact, hyperperfusion may endanger neuronal recovery. On the otherhand oxygen metabolism seems to correlates better with clinical status and functional recovery than does blood flow (Wise et al., 1983).
Recovery is often greatest during the first 30 days after stroke, but continues up to 6 months in some patients. It has been estimated that although about 60% of stroke patients are able to achieve total independence in activities of daily living (Meier & Strauman 1991; Wade & Hewer, 1987) only approximately 10 to 30% of initial survivors return to their jobs without gross or obvious disability. Depending on the nature of the stroke, about 40% demonstate mild disability, 40% are severely disabled, and 10% require institutionalization .
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