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Pathophysiology and mechanisms of acute ischemic stroke.

Introduction

Stroke is a major health care problem; it is the third leading cause of death and the leading cause of major disability among adult Americans.[5] Stroke patients account for more than half of all neurological hospitalizations.[1] Though stroke has remained a major health care dilemma, less attention has been given to this devastating disease compared to other more "visible" diseases which actually impact the lives of fewer patients. Over the past decade much has been learned about the physiology of stroke, and it has become clear that stroke is a medical emergency: "Time is Brain." Until recently there was no proven therapy for acute stroke victims, and this has made it difficult to change the perception of health care providers toward stroke and its treatment. However, in December, 1995 the results of the NINDS t-PA Stroke Trial were published,[9] and in June, 1996 the Food and Drug Administration (FDA) approved recombinant tissue plasminogen activator (rt-PA) for treatment of acute ischemic stroke patients. An understanding of the pathophysiology of acute ischemic stroke makes the importance of rapid treatment clear. This article reviews the anatomy and physiology of cerebral circulation and pathophysiology of ischemia in stroke.

Cerebral Circulation

Anterior Circulation

The brain is perfused by both anterior and posterior vessels which supply the brain with oxygen and glucose required for neurons to function normally. The anterior circulation consists of the common carotid arteries, which bifurcate in the neck at the angle of the jaw to form the internal and external carotid arteries. The left common carotid artery originates from the aortic arch, while the right common carotid artery originates from the innominate artery. The common carotid, proximal internal and external carotid arteries are extracranial vessels. As the internal carotid arteries enter the skull they become intracranial vessels. The internal carotid, anterior cerebral and middle cerebral arteries supply the cerebral hemispheres (Fig 1).

[Figure 1 ILLUSTRATION OMITTED]

The anterior cerebral arteries are the major blood supply for the medial surfaces of the cerebral hemispheres. The middle cerebral arteries supply blood to the majority of the lateral surface of the frontal, parietal and temporal lobes and basal ganglia. Clinical manifestations of anterior circulation territory strokes are listed in Table 1.

Table 1. Clinical Manifestations of Anterior Circulation Stroke
Anterior Circulation

Anterior Cerebral Artery

 * abulia, flat affect, apathy
 * aphasia (dominant hemisphere)
 * gaze deviation toward affected side
 * contralateral hemiparesis or hemiplegia (leg involvement
greater than arm)
 * apraxia on affected side

Middle Cerebral Artery

 * aphasia (dominant hemisphere)
 * dysarthria
 * gaze deviation toward affected side
 * homonymous hemianopia
 * contralateral hemiparesis or hemiplegia
 * contralateral sensory deficits
 * visual and sensory neglect (nondominant hemisphere)

Posterior Circulation

Posterior Cerebral Artery

 * memory deficits
 * Wernicke's aphasia
 * contralateral homonymous hemianopia

Verterbrobasilar Arteries

 * improved level of consciousness
 * cranial nerve palsies
 * nystagmus
 * dysarthria
 * dysphagia
 * ipsilateral Homer's syndrome
 * vertigo
 * nausea and vomiting
 * contralateral hemiparesis or hemiplegia (arm and leg)
 * ataxia
 * ipsilateral face, contralateral body sensory deficits
 * locked-in syndrome




Patients with a given syndrome may have a few, many or all of the signs and symptoms listed under each syndrome heading.

The eyes are supplied via the ophthalmic artery, a branch of the internal carotid artery. The external carotid arteries supply blood to the face, neck and scalp.

Posterior Circulation

The posterior circulation includes the vertebral arteries, basilar artery and posterior cerebral arteries (Fig 2). The vertebral arteries originate from the subclavian arteries and travel up the posterior aspect of the neck where they are protected by the vertebral column. The vertebral arteries then travel along the side of the medulla. The posterior inferior cerebellar arteries arise from the vertebral arteries and supply the lateral medulla and inferior part of the cerebellum. The vertebral arteries continue until they form the basilar artery at the union of the medulla and pons. The basilar artery has small penetrating vessels that supply the base of the pons. The anterior inferior cerebellar and superior cerebellar arteries also branch off the basilar artery and supply the rest of the cerebellum. At the union of the pons and the midbrain, the basilar artery divides into the right and left posterior cerebral arteries. The posterior cerebral arteries supply the midbrain, thalami, occipital lobes and medial-posterior parts of the temporal lobes. The clinical manifestations of posterior circulation strokes are listed in Table 1.

[Figure 2 ILLUSTRATION OMITTED]

Collateral Circulation

The anterior and posterior circulations are connected by the posterior communicating arteries. The right and left anterior cerebral arteries are joined by the anterior communicating artery. These communicating arteries connect the blood vessels of the right and left cerebral hemispheres providing collateral blood supply. This connecting system is known as the Circle of Willis (Fig 2).

Stroke Classification

A stroke occurs when there is a disruption of blood flow to an area of the brain. Disruption of blood flow can be caused by either an obstruction of the cerebral blood flow (ischemia) or rupture of the wall of a vessel supplying the brain (hemorrhage). Eighty percent of all strokes are classified as ischemic and 20% are classified as hemorrhagic.[2] Thrombus and embolus are the two major causes of ischemic stroke. The focus of this discussion is on acute ischemic stroke.

Thrombotic Stroke

Thrombotic strokes are more common than embolic strokes. They are classified as either large or small vessel. Thrombotic strokes are caused by an obstruction of blood flow in an artery due to a pathologic process within that artery.

Large vessel strokes are caused by blockage of a major vessel. Major vessels include the common carotid arteries, internal carotid arteries, anterior cerebral, middle cerebral, posterior cerebral, vertebral and the basilar arteries. Large vessel strokes often occur in arteries that have been narrowed by atherosclerosis. Common sites for development of atherosclerosis are vessel bifurcations and arterial origins. Patients with a history of smoking, hypertension, diabetes or hypercholesteremia are at an increased risk for developing atherosclerosis.[3]

Atherosclerosis may create a site for a blood clot to form which may then cause thrombosis of the artery. Thrombus formation secondary to atherosclerosis starts with plaque formation in the lumen of the artery. The plaque may continue to enlarge over years and cause stenosis of the artery. The rough, irregular surface of the plaque becomes a site for platelet aggregation. As platelets clump together, fibrin networks develop. Blood clots tend to form at the plaque site when red bloods cells become trapped in the platelet-fibrin mesh. This escalates as the artery narrows and blood flow through the narrow area becomes sluggish.

There are other less common disorders which can narrow an artery. These include inflammation of the arteries (arteritis or vasculitis), inherited disorders which cause abnormal growth or weakening of the artery (eg, fibromuscular dysplasia), and dissection, where blood dissects between the arterial walls and decreases the lumen size.

Small vessel strokes are caused by occlusion of the smaller diameter vessels that branch off from the major vessels and penetrate deep into the brain. Small vessels include the lenticulostriate, basilar penetrating and medullary arteries. The smaller vessels are primarily affected by hypertension. Hypertension causes hyalinosis which disorganizes and disrupts the wall of the vessel resulting in thickening of the vessel wall and stenosis.[2] Diabetes can also contribute to this process. Small vessel strokes are sometimes called lacunar strokes:

Embolic Strokes

Embolic strokes are caused when occlusive material (eg, blood clots or atheromatous debris) forms outside the brain, detaches and flows through the cerebral circulation until it lodges in and blocks a cerebral artery. This results in cessation of blood to the brain territory supplied by that vessel. Emboli commonly originate from either the left-sided chambers of the heart or the proximal arteries (internal carotid arteries or vertebral arteries) that supply the brain. Irregular surfaces, diseased surfaces and stasis of the heart promote embolus formation or allow embolus passage. Patients with atrial fibrillation, valvular heart disease, coronary artery disease and cardiomyopathy are at significant risk for embolus formation. Emboli that originate from the proximal arteries are known as artery-to-artery emboli. Artery-to-artery emboli frequently result from detachment of thrombi from the internal carotid artery at the site of an ulcerated atheromatous plaque. These detached thrombi then travel further into the cerebral circulation until they lodge into a smaller vessel.

Cerebral Ischemia

Cerebral Blood Flow

Brain cells do not tolerate an absence of blood flow regardless of the mechanism. When blood flow is cut off completely, neurons sustain irreversible damage (infarction) within minutes. In acute ischemic stroke, a complete cessation of blood flow occurs only in the core of the ischemic area. The territory between the ischemic core and the surrounding, normally perfused tissue, is known as the penumbra. The penumbral region blood flow is reduced, causing the neurons to function abnormally, but for a limited period of time these neurons are able to maintain energy metabolism and are considered viable. The duration of reduced blood flow that the brain is able to withstand and still survive (ie, the "therapeutic window") varies from less than 10 minutes in the ischemic core or after cardiac arrest where the cerebral blood flow (CBF) is essentially zero, to 3-6 hours in the penumbral region.[8]

In addition to its duration, the depth of blood flow reduction is another critical variable that affects the ability of neurons in the penumbral area to return to normal function. Normal CBF in the gray matter of the brain is approximately 55 ml/100g/min.[8] Animal experiments suggest that ischemia occurs when CBF falls to a level of 20-23 ml/100g/min and infarction occurs when CBF falls below 10-17 ml/100g/min.[8] When the blood flow is decreased to a level of ischemia, brain cells begin to lose their ability to maintain homeostasis. During this time, a series of events occurs which is known as the ischemic cascade.

It is important to remember that the penumbra is a region of varying degrees of CBF reduction, with CBF becoming progressively decreased closer to the cote of the ischemia. Unfortunately, focal CBF cannot be continuously measured at the bedside. Because of this, the acute ischemic stroke patient's CBF should be assumed to be near the threshold between ischemia and infarction. Thus, attempts must be made to restore CBF emergently in order to prevent the penumbral tissue from becoming part of the infarcted core.

Ischemic Cascade

The ischemic cascade is a complex process that occurs at the cellular level. Protein synthesis is most sensitive to reductions in CBF, and is rapidly inhibited when CBF is reduced.[7] With further reduction in CBF, there is disturbance of glucose utilization and depletion of the cell's intracellular energy stores. Because energy is depleted, the cell cannot maintain ion gradients and membrane depolarization occurs. Membrane depolarization allows opening of voltage-operated calcium channels resulting in a disruption of normal regulation of neuronal calcium homeostasis. Calcium enters the cells causing the release of neurotransmitters from the presynaptic neuron (notably glutamate). These neurotransmitters then cause an increase in intracellular sodium with cellular swelling and a further increase in intracellular calcium. Ultimately, if the ischemic cascade is not interrupted, cell death will occur.[6,7]

Interventions

Two basic pharmacologic approaches have been investigated in an attempt to promote recovery from ischemic cell injury: 1) drugs which restore blood flow, for instance, thrombolysis or dissolution of an obstructing clot. 2) pharmacologic agents which may alter or stop the progression of the ischemic cascade known as neuroprotection. Both approaches must be used soon after reduction in blood flow to be of benefit.

Thrombolytic Therapy

The first US Food and Drug Administration approved therapy for acute ischemic stroke is recombinant tissue plasminogen activator (rt-PA). The rationale behind thrombolytic therapy is to dissolve the arterial occlusion (thrombus or embolus) and reestablish blood flow to ischemic brain before the area becomes infarcted. rt-PA is classified as an endogenous thrombolytic agent. When rt-PA is administered into the systemic circulation it binds to fibrin in a thrombus. rt-PA then activates the conversion of plasminogen (which is bound within the thrombus) into plasmin. The thrombus or embolus is consequently dissolved and blood flow is restored to the ischemic tissue region. Because of its fibrin binding action, rt-PA is relatively clot specific as compared to other thrombolytic agents, such as streptokinase, which are not clot specific.[4] The clot-specific property of rt-PA decreases the likelihood of systemic fibrinolysis and consequent bleeding.

Still, the major risk of rt-PA therapy is bleeding, and the most severe bleeding complication is cerebral hemorrhage. Cerebral hemorrhage results from reperfusion into a brain area where advanced ischemia has caused damage to the vascular endothelium, disruption of the blood brain barrier and necrosis of neurons and glia. As already discussed, the extent of this damage is dependent on the duration and degree of ischemia. This only reemphasizes the need for ultra-rapid treatment in order to decrease the degree of injury and risk of cerebral hemorrhage.

Neuroprotection

Presently, there are no neuroprotective agents approved for treatment of acute ischemic stroke. However, there are several ongoing clinical studies evaluating different classes of neuroprotective drugs that have demonstrated efficacy in animal studies. Neuroprotective therapy is directed at the various biochemical events that occur during the ischemic cascade (eg, calcium channel blockers help prevent damage from excessive calcium entering the cell). These drugs are designed to inhibit the ischemic tissue from progressing to infarction. Neuroprotection is aimed primarily at penumbral areas. As discussed earlier, neurons cannot sustain even relatively short periods of reduced blood flow. The window of opportunity for treatment with neuroprotective therapy is also narrow, requiring emergency action.

Summary

The recent approval of rt-PA draws attention to acute ischemic stroke therapy. An understanding of the pathophysiology of stroke is helpful in understanding the need for ultra-rapid interventions. Acute ischemic strokes are caused by an interruption in the blood supply to the brain causing a core of infarct with a surrounding penumbra of ischemic brain cells. Decreased blood flow initiates an ischemic cascade resulting in the eventual death of these underperfused cells if the ischemic condition is not rapidly reversed. With the approval of rt-PA, health care professionals have a drug which can dissolve the offending clot and restore perfusion to penumbral brain region, greatly improving stroke outcome. Neuroprotective agents, designed at sustaining the underperfused cells until blood flow can be restorid, are also being studied. Future therapy for ischemic stroke will probably utilize a combination of thrombolysis and neuroprotection. The importance of prompt treatment cannot be overemphasized.

References

[1.] Barker E: Neuroscience Nursing. Mosby - Year Book, Inc, 1994.

[2.] Barnett HJM, Mohr JP, Stein BM, Yatsu FM: Stroke, Pathophysiology, Diagnosis, and Management, 2nd ed. Churchill Livingstone Inc., 1992.

[3.] Bierman EL: Atherosclerosis and other forms of arteriosclerosis. Pages 1106-1116 in: Harrison's Principles of Internal Medicine, 13th edition, Isselbacher KJ, Braunwald E, Wilson JD et al (editors). McGraw-Hill, Inc, 1994.

[4.] Del Zoppo GJ: Current concepts of cerebrovascular disease and stroke: Thrombolytic therapy in cerebrovascular disease. Stroke 1988;19(9):1174-1179.

[5.] Division of Chronic Disease Control and Community Intervention: Cardiovascular Disease Surveillance: Stroke, 1980-1989. Centers for Disease Control Prevention, 1994.

[6.] Ginsberg MD: Neuroprotection in brain ischemia: An update. The Neuroscientist 1995; 1(2):95-103.

[7.] Hossmann KA: Viability thresholds and the penumbra of focal ischemia. Ann Neurol 1994; 36:557-565.

[8.] Jones TH, Morawetz RB, Crowell RM et al: Thresholds of focal cerebral ischemia in awake monkeys. J Neurosurg 1981;54:773-782.

[9.] The National Institute of Neurological Disorders and Stroke rt-PA Stroke Study Group: Tissue plasminogen activator for acute ischemic stroke. N Engl J Med 1995; 333:1581-1587.

[10.] Ruby EB: Advanced Neurological and Neurosurgical Nursing. The CV Mosby Company, 1984.

Patti Bratina, Karen Rapp, Carol Barch, Gail Kongable, Rosario Donnarumma, Judith Spilker, Sheila Daley, Janet Braimah, Sharion Sailor and the NINDS rt-PA Stroke Study Group

Questions or comments about this article may be directed to: Patti Bratina, RN, University of Texas Health Science Center. Department of Neurology, Suite 7044, 6431 Fannin, Houston, Texas 77030.
COPYRIGHT 1997 American Association of Neuroscience Nurses
No portion of this article can be reproduced without the express written permission from the copyright holder.
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Title Annotation:Special Issue on rt-PA Stroke Treatment; recombinant tissue plasminogen activator
Author:Bratina, Patti; Rapp, Karen; Barch, Carol; Kongable, Gail; Donnarumma, Rosario; Spilker, Judith; Dal
Publication:Journal of Neuroscience Nursing
Date:Dec 1, 1997
Words:2643
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