Stroke is an abrupt disturbance in cerebral circulation causing neurological deficits. It is most often due to either cellular ischemia/infarction or intracranial hemorrhage. Since it occurs in adults in the middle and later years of life, it is responsible for considerable morbidity and mortality of older individuals. Risk factors for the occurrence of a stroke include: hypertension, cardiac arrhythmias, alcohol abuse, and cocaine abuse. Although stroke can and does occur in infants and children, the focus of this article is the adult population.

Cerebral ischemia is reduction in blood flow that can last from several seconds to minutes. Symptoms occur in about 10 seconds due to hypoxia and energy depletion.1,2 The return of function can occur if blood flow is restored within a few minutes. When the symptoms are only transient (ie, less than 24 hours), this would be considered a transient ischemic attack (TIA). Infarction or death of brain tissue occurs if the lack of blood flow lasts for more than a few minutes. In cerebral infarction, the symptom duration persists due to cell death and often results in permanent disability. The symptoms of cerebral hemorrhage are due to either pressure on surrounding tissues or the toxic effects of blood on the tissue. The extent of the cellular damage and neurologic deficit is determined by actual destruction of neural tissue.3

Epidemiology

Stoke is the third leading cause of death in the United States accounting for 1 out of every 15 deaths. The direct and indirect costs associated with stroke are about $56.8 billion.4 Approximately 700,000 people are diagnosed with a stroke each year, and approximately 200,000 of them are experiencing their second stroke. Men have strokes at a younger age than women, therefore the age adjusted incidence of stroke is 1.25 times greater for men than for women.4 The risk of stroke for blacks is almost double that of whites, and Hispanics have a greater incidence hemorrhagic stroke at a younger age.5 Most strokes (88%) are ischemic events, while other etiologies include intracerebral hemorrhage (9%) and subacrachnoid hemorrhage (3%).4,6

Risk Factors

The major or more common risk factors for cerebral ischemia and infarction include family history, hypertension, smoking tobacco, diabetes mellitus, higher body mass index, and other risk factors for the development of atherosclerosis such as hypercholesterolemia. Smoking increases the risk of a stroke due to either arterial wall damage and atherosclerosis or formation and rupture of aneurysms. Cardiac risk factors of stroke include atrial fibrillation and a recent myocardial infarction. Evidence of a prior TIA also increases the risk of a stroke. Additionally, the risk of having a stroke increases with age.7-9 The use of hormonal contraceptives can also increase the risk of cerebral ischemia or infarction.10 The risk of hemorrhagic stroke is increased in persons of Asiatic or African decent. Other risk factors include hypertension, trauma, advanced age, heavy alcohol consumption, and cocaine and amphetamine abuse.4

Overview of Anatomy and Physiology of the Brain

The Brain

The brain is divided into the cerebrum, cerebellum, and the brain stem. At the base of the skull is the foramen magnum, an opening through which the spinal cord forms a continuous connection with the brain. The brain has 3 coverings. They are the pia mater (the innermost layer), the arachnoid (the middle), and the dura mater (the outermost, tough layer). Pia is directly continuous with the brain and spinal cord. It is a vascular layer through with blood vessels pass to the internal central nervous system (CNS) to nourish the neural tissue. The area between the pia and the avascular arachnoid is the subarachnoid space, and it contains the cerebral arteries. The dura is composed of two layers; the inner most is referred to as the meninges. The brain contains gray matter and white matter. Gray matter is external and the myelinated white matter is internal.

CEREBRUM

The cerebrum is the largest part of the brain and is divided into 2 hemispheres and consists of 4 lobes: frontal, parietal, temporal, and occipital. On its surface, or cortex, are located the centers from which motor impulses are carried to the muscles and to which sensory impulses come from the various sensory nerves. It contains an area in its inner core referred to as the thalamus. The thalamus is composed of 2 ovoid structures and is an important relay station in the brain. All the main sensory pathways form synapses with the thalamic nuclei on their way to the cerebral cortex. These pathways also serve as vehicles for transmitting pain, emotions, etc.

The location of specific functions within the brain is related to the concept of complementary specialization. The cerebral hemisphere associated with language comprehension skills and sequential analytic processes is referred to as the categorical hemisphere. This was previously referred to as the dominant hemisphere; however, the other cerebral hemisphere is not considered to be nondominant, it just has a different type of specialization. The other hemisphere focuses primarily on recognition of faces, music, and visual spatial relationships; therefore, it is referred to as the representational hemisphere.1

For approximately 96% of right-handed individuals, the left hemisphere is the categorical hemisphere. Thus, the left hemisphere contains areas for language comprehension (Wernicke's area) and speech and word formation (Broca's area). Injury to this hemisphere is associated with language disorders.1

CEREBELLUM AND BRAIN STEM

The cerebellum regulates coordinated activities such as gait and performance of motor tasks.8 The brain stem includes the midbrain, pons, and medulla oblongata. The midbrain connects the pons and the cerebellum with the cerebral hemispheres. The cerebellum is located below and behind the cerebrum. The pons is located in front of the cerebellum between the midbrain and the medulla. It serves a bridge between the 2 halves of the cerebellum as well as between the medulla and the cerebrum. It contains important centers for controlling the heart, respiration, and blood pressure and gives rise to 4 cranial nerves.2

CEREBRAL CORTEX

Cells appear quite similar, but functions will vary depending on their location within the cortex. There are 4 lobes: frontal, parietal, occipital, and temporal. The frontal lobes are thought to contain areas associated with emotional attitudes and the development of thought processes. Nerve fibers from all portions of the cortex converge in each hemisphere and make their exit in the form of tight bundles ("internal capsule"). These cross the corresponding bundle from the opposite side; therefore, a right stroke means left-sided weakness.

Cerebrospinal Fluid

Each cerebral hemisphere has a central cavity, a ventricle that is filled with clear cerebrospinal fluid. It traverses from the ventricle through narrow tubular openings to the subarachnoid space to bathe the entire surface of the brain and spinal cord. The average amount of cerebrospinal fluid (CSF) is 150 mL.

Neural Tissue

NEURONS

The neuron is the structural, genetic, and functional unit of the nervous system and is composed of cell bodies, dendrites, and axons. The cell bodies are located in layers on the surface of the brain, or cortex, and comprise what is referred to as gray matter. The neurons contain intracellular structures found in many cells, such as the nucleolus, microtubules, golgi apparatus, and rough endoplasmic reticulum. Intracellular structures specific for neurons include neurofilaments, synaptic vesicles, and Nissl substance.11 Neurons use glucose as their energy source and are dependent on oxidative metabolism. They produce and release neurotransmitters.

Neurotransmitters are chemicals synthesized in the neurons that are stored in synaptic vesicles in the axon terminals. They are released from the axon terminal by exocytosis and are also reabsorbed and recycled. These chemicals cause changes in the cell permeability of neuron, making it more or less able to conduct an impulse.

NEUROGLIA

Neuroglia are the supporting cells for the neurons of the CNS, whereas Schwann cells have this function in the peripheral nervous system (PNS). The neuroglia comprise about 40% of the brain and spinal cord. They outnumber the neurons approximately 4 to 1. Four distinct neuroglia cell types have been identified: microglia, ependyma, astroglia, and oligodendroglia. Microglia have phagocytic properties to ingest and digest tissue debris. They are found throughout out the CNS and are also believed to have a role in fighting infection. Ependyma line the ventricular system and are involved in the production of CSF. Oligodendroglia are the glial cells responsible for myelin production within the CNS. Astroglia (astrocytes) are located between blood vessels and neurons, possibly controlling movement of macromolecules between the blood, CSF, and brain as the blood-brain barrier. When there is death of neurons due to injury, astrocytes proliferate and fill in the space formerly occupied by the nerve cell body and its processes. This activity is known as replacement gliosis.

MYELIN

Myelin is a white lipid-protein complex that provides insulation along a nerve process. It prevents the flow of sodium and potassium ions across the neuronal membrane almost completely where it is present. Within the CNS, nerve fibers with myelin sheaths are found within the white matter. Fibers that have no myelin are found within the gray matter.

Cerebral Circulation

The CNS, like all body tissue, is dependent upon an adequate blood supply for its nutrients and for removal of metabolic waste products. The arterial blood supply to the brain is complex. However, an understanding of blood flow enables some correlation of area of injury with symptoms.

CAROTID ARTERIAL SUPPLY

On the right, the brachiocephalic trunk (innominate) artery divides into the right common carotid and the right subclavian. On the left, the left common carotid and left subclavian arteries each arise directly from the aortic arch. There are both internal and external carotid arteries that branch off from the common carotids at about the level of the thyroid gland (carotid sinus). The carotid sinuses respond to changes in arterial blood pressure to reflexively maintain blood supply to the brain and the rest of the body. The external carotids branch off into vessels that supply the face. The internal carotids enter the skull and divide into the anterior and middle cerebral arteries. The middle cerebral arteries are considered to be continuations of the internal carotid arteries (see Figure 1).12

Figure 1. Carotid circulation. Reprinted with permission from Book D. Disorders of brain function. In: Porth CM, ed.

VERTEBRAL-BASILAR ARTERIAL SUPPLY

Right and left vertebral arteries originate from the subclavian arteries of their respective sides. The vertebrals enter the skull via the foramen magnum. At the level of the brainstem, they fuse to form the basilar artery. This continues to the level of the midbrain where it branches to form the posterior cerebral arteries.

CEREBRAL ARTERIES

Cerebral arteries are classified as either penetrating or conducting. The conducting arteries form an extensive network over the surface of the brain. The penetrating arteries are nutrient vessels that are derived from the conduction arteries. They enter the brain at right angles and provide the blood supply for the deep cerebral structures.

ARTERIAL CIRCLE OF WILLIS

The internal caro-tids and the vertebral-basilar arteries are 2 separate systems delivering blood to the brain. They do however, unite to form the crcle of Willis through a specialized system of communicating arteries. There is usually only slight blood flow through these arteries; however, they serve as a fail-safe mechanism in case of dramatic changes in arterial blood pressure. Collateral circulation may gradually develop when there is an alteration in normal blood flow. Most cerebral collateral circulation is between major arteries via the circle of Willis (see Figure 2).12

Figure 2. Circle of Willis. Reprinted with permission from Book D. Disorders of brain function. In: Porth CM, ed.

Brain Metabolism

Brain metabolism is steady and continuous with no rest periods, requiring a continuous supply of glucose and oxygen. It is highly depended upon oxygen and accounts for 20% of the body's oxygen usage.1,2,11 Consciousness may be lost in as little as 10 seconds once blood flow has ceased. Dependent upon oxygen, the brain does not switch to anaerobic metabolism, and a lapse of even a few minutes may cause irreversible damage. Sustained hypoglycemia may also damage brain tissue, since glucose is its major energy source.1 Neurons do not store glycogen, so energy depletion is rapid.3

Although glutamate is an excitatory neurotransmitter within the brain, metabolically, it has a neuroprotective action. It aids in the removal of the ammonium ion through conversion to glutamine. Since ammonia is very toxic to brain cells, this glutamate-glutamine conversion serves as a detoxifying mechanism.1

Autoregulation of Blood Flow

The normal brain has the ability to regulate its own blood supply to maintain arterial pressure between 65 and 140 mm Hg.1,2 Factors that affect this can be viewed as extrinsic (outside the brain) and intrinsic (inside the brain).

The extrinsic factors affecting cerebral blood flow (CBF) are related primarily to the cardiovascular system and include blood pressure (BP), cardiovascular function, and blood viscosity. If systemic mean BP drops below 60 mm Hg, the brain's autoregulatory mechanism becomes less effective. The brain will initially attempt to compensate by extracting more oxygen from the available blood supply. If BP continues to drop, signs of cerebral ischemia will occur. Alterations in cardiovascular function that affect cardiac output also can reduce CBF. If the cardiac output is decreased by more than one third, there is often a fall in CBF. Cerebral blood flow increases with anemia, but the increased viscosity of polycythemia may reduce it by 50%.

The intrinsic factors are influenced by cerebral perfusion pressure. This is the pressure difference between the cerebral arteries and veins. The goal is that cerebral perfusion pressure will remain constant despite changes in systemic BP. Cerebral vascular resistance increases or decreases in response to systemic BP to maintain a constant flow of blood to the brain. Cerebral blood vessels are important because of their response in maintaining constancy of flow. Cerebral blood vessels are under the control of the sympathetic nervous system or sympatho-adrenal response. Sympathetic reflexes are believed to cause vasospasm in some types of brain damage.1,2

Intracranial pressure (ICP) is also an important regulatory mechanism. An increase in ICP will increase cerebrovascular resistance, reducing cerebral blood flow. Cerebral blood flow will not decrease until there is a considerable increase in ICP.1 ICP is affected by these 3 metabolic factors: CO₂ concentration, H⁺ concentration, and O₂ concentration. High CO₂ tension is a strong vasodilator and can produce a marked increase in cerebral blood flow.1 A decreased pH (increased H⁺ levels) will increase blood flow. Low O₂ tension is a powerful vasodilator, and high O₂ Levels are a moderate vasoconstrictor.2

Cerebral Perfusion Pressure

Cerebral perfusion pressure (CPP) is the difference between mean arterial blood pressure (MAP) and the ICP. The normal range is 60 to 80 mm Hg.

The cranial cavity contains the brain, blood, and CSF. Of this, the brain takes up 80% with the blood volume and CSF each comprising 10%. Together, they maintain normal ICP of 50 to 200 mm H₂O (4 to 15 mm Hg). Changes in one will cause a compensatory change in the other to maintain normal ICP. This is referred to as the Monro-Kellie hypothesis. The ICP will remain within normal range as long as any increase that occurs does not exceed the compensatory displacement of blood or CSF. If an overcompensatory displacement occurs, the ICP will rise, resulting in cerebral hypoxia, or brain herniation, or sideways or downward movement of the brain. If the CPP falls below 50 mm Hg, cellular death occurs.2,11

Equation (Uncited)

When the pressure in the ICP exceeds MAP, tissue perfusion falls and demand exceeds supply, and cellular hypoxia occurs. The neurons of the cortex are the most sensitive to changes in oxygenation. That is why one of the earliest and most reliable signs is "changing level of consciousness." 2

Increases in ICP cause the CNS ischemic response. This is evidenced by a marked increase in MAP, reflexive slowing of heart rate, and widened pulse pressure. This triad of signs, Cushing reflex, is an important but a late indicator of increased ICP.2

Stroke Subtypes

Ischemia and Infarction

Cerebral ischemia and infarction occur from decreased or disrupted blood flow. Ischemia occurs when there is a decrease in blood flow to less than 20 mL/100 g of brain tissue per minute. Reduction of blood flow to less than 16 mL/100 g of brain tissue per minute leads to tissue death within one hour. In the absence of blood flow, death of brain tissue occurs within 4 to 10 minutes.3

The most common etiology that results in cerebral ischemia or infarction is local damage to a vessel wall from atherosclerosis. This may occur in the aortic arch, carotid arteries, or cerebral vessels. The development of atherosclerosis begins with endothelial injury and inflammation, leading to plaque formation. The plaque becomes thick and fibrous with loss of muscle cells. The sclerotic material partially fills and/or occludes the lumen of the vessel. Platelets adhere to this, releasing factors that initiate the coagulation-clotting cascade, forming a clot or thrombus. The clot may either break off as an embolus traveling to a distal vessel or remain in place, occluding the vessel.8 Lacunar infarcts occur with complete occlusion of end-arteries that supply a small area of brain tissue.3 Symptoms from ischemic events occur fairly rapidly since the brain is very dependent upon adequate oxygen and circulation. Lack of adequate oxygenation to the cerebral cortex can produce unconsciousness in a little as 10 seconds.1

Thrombotic events most often affect the internal carotids, middle cerebral, or basilar arteries.8,11 Strokes that are the result of emboli are frequently considered to be cardiac in origin. Referred to as cardioembolic stroke, these account for about 20% of all strokes.3 Although the embolus is from a thrombus in the either the atria or the ventricle, the actual thrombus is often not observed. The diagnosis of a cardiac origin is based on known cardiac etiology of emboli, such as atrial fibrillation or recent myocardial infarction. Cardioembolic strokes most often occlude the middle cerebral artery or the posterior cerebral artery.3 However, emboli may also develop from the aortic arch or carotid arteries.8

In contrast to an atherosclerotic event, symptoms due to an embolus are often sudden with immediate, noticeable maximal neurological deficits. In embolic events, the effected tissue often contains petechial hemorrhages, or red infarction (see Figure 3). The appearance of brain tissue in thrombotic events is different. With thrombotic ischemia, the tissue is often paler, or non hemorrhagic infarct.11

Figure 3. Gross anatomy of hemorrhagic infarction. A, Sections of the brain showing a large, discolored, focally hemorrhagic region in the left middle cerebral artery distribution (hemorrhagic, or red, infarction). B, A hemorrhagic infarction is present in the inferior temporal lobe of the left side of this brain. C, A bland infarct with punctate hemorrhages, consistent with ischemia-reperfusion injury, is present in the temporal lobe. Reprinted with permission from

Since atherosclerotic occlusion of the vessel can occur gradually, symptoms are progressive. The symptoms or deficits increase over several hours to several days. There is a large area of tissue ischemia that increases over time. Survival of this ischemic tissue is dependent upon 2 major factors: (1) the availability of collateral circulation and (2) the duration of the ischemia.11 If the blood flow is not restored, the ischemic tissue becomes necrotic and cell death occurs. As cerebral blood flow falls to zero, death of brain tissue can occur within 4 to 10 minutes.3 Anoxic encephalopathy may occur with cerebral thrombosis. The brain distal to the clot becomes swollen. There may discoloration, with the appearance being "muddy-looking" due to changes in the line between gray and white matter. As nerve cells disintegrate, they are replaced by the neuroglia (gliosis).

At the onset of the cerebral ischemic event, there is a gradation in brain perfusion. Whereas the central area may become infarcted, the surrounding tissue exhibits zones of ischemia and injury, the ischemic penumbra. The area of ischemia and injury is "at-risk" tissue. The normal cerebral autoregulation of circulation is not operating and is unable to restore blood flow to the area. Unless treatment is begun immediately, that tissue will become necrotic as well.3

Ischemia affects both gray and white matter portions of the brain equally, thus the size of ischemic area is equally distributed. However, the volume of at-risk tissue is greater in gray matter than in white matter. Despite this, it appears that more white matter is potentially viable and responsive to therapy than gray matter.13

Cerebral infarction is also associated with cerebral edema. About 5 to 10 stroke patients develop severe cerebral edema, increasing the risk of brain herniation.3

CELLULAR CHANGES

Acute neuronal injury is the result of CNS hypoxia and ischemia. Injured cells respond with a series of reversible and irreversible changes. These responses include recruitment of white blood cell release, inflammatory mediators, and elevation in C reactive protein levels.11,14

During ischemic injury, there is failure of the ion pumps. Potassium flows out of the cell into the extracellular space. The altered potassium gradient causes depolarization of neuronal membranes and increased intracellular calcium levels.3 With depolarization, there is the release of neurotransmitters into the synaptic space. Glutamate, an excitatory neurotransmitter, accumulates at excitatory synapses and in the extracellular space. Glutamate further damages the neurons through overstimulation and opening of membrane channels. The increased influx of calcium ions and overstimulation ultimately lead to cell death.1,8,11

Cellular death occurs either through irreversible neuronal cellular damage or through the apoptotic pathway of programmed cell death. Altered mitochondrial function with increased release of free radicals damages cell membranes and alters cellular functions. Once the necrotic changes begin, there is currently no treatment to stop the process.3

Irreversible changes accompanying cell death include shrinkage of the cell body, disappearance of the nucleolus, and loss of Nissl substance. Since the cytoplasm stains red with hematoxylin and eosin (H & E) staining preparations, they are referred to as red neurons (see Figure 4).11

Figure 4. Cellular changes with cerebral infarction. A, At low magnification, it is possible to see the demarcated areas of an acute infarction. In the underlying white matter, the areas of infarction are well shown by the myelin stain. B, Acute ischemic injury causes diffuse eosinophilia of neurons, which are beginning to shrink. C, Infiltration of a cerebral infarct by neutrophils begins at the edges of the lesion where vascular supply has remained intact. D, After about 10 days, an area of infarction is characterized by the presence of macrophages and surrounding reactive gliosis. E, Remote small intracortical infarcts are seen as areas of tissue loss with a small amount of residual gliosis. Reprinted with permission from

CLINICAL PRESENTATION

Regardless of the etiology, the clinical presentation of symptoms in a cerebral ischemic/infarction event depend upon: (1) the location of the vessels and (2) the presence of collateral circulation (see Table 1). However, embolic strokes have a greater risk of subsequent bleeding into the infarcted area than thrombotic strokes.3

TABLE 1 Clinical Presentation in Ischemic Stroke

Lacunar infarcts

These are small cavity infarcts (usually <15 mm wide) are usually associated with hypertension. They can be either silent with no associated clinical symptoms or present with very obvious symptoms.11 The most common symptoms seen with lacunar infarcts are either pure motor deficits or pure sensory deficits.8

The middle cerebral artery

Complete occlusion of the middle cerebral artery results in loss of movement and sensation on the contralateral or opposite side of the infarction. However, there may be a gaze preference to the ipsilateral or same side as the injury. If this is the categorical hemisphere, there is also a global aphasia.3 If it is the representational hemisphere, there is a neglect syndrome, or forgetting that there are 2 sides of the body. Partial occlusion of the middle cerebral artery could include weakness of a hand or arm, facial weakness, and partial aphasia.8

The posterior cerebral artery

There are 2 syndromes observed with occlusion of the posterior cerebral artery: P1 and P2. The P1 syndrome includes the midbrain, subthalamic, and thalamic regions of the brain. The symptoms include a third-nerve palsy with weakness and ataxia. Extensive infarction in this area can result in coma, unreactive pupils, and decerebrate rigidity. The P2 syndrome results in injury to the medial temporal and occipital lobes. This results in memory loss, disturbances, or loss of vision on the contralateral or opposite side of the infarct. In some individuals, visual disturbances can produce hallucinations.3

The basilar artery

The clinical presentation seen with occlusion of the basilar artery includes the "locked-in" state of preserved consciousness with total quadriplegia. A TIA in this area may produce dizziness or a feeling of light-headedness.3

Superior cerebellar artery

Occlusion of this vessel causes cerebellar ataxia, partial deafness, nausea, vomiting, and loss of pain and temperature sensation on the opposite extremities.3

Anterior inferior cerebellar artery

The symptoms seen with occlusion of this vessel include ipsilateral deafness, facial weakness, and vertigo.3

Cerebral Hemorrhage

Cerebral hemorrhage is the third most common cause of stroke and is associated with about a 50% mortality rate.3 In addition to intraparenchymal hemorrhage, symptoms can occur from subdural or epidural hematomas. These are usually the result of some sort of trauma and may occur several hours after the initial injury. Subarachnoid hemorrhage can occur either as a result of trauma or from the rupture of an aneurysm. Intraparenchymal hemorrhages usually occur from the rupture of small penetrating arteries. They are most often the result of hypertension. They usually occur in the basal ganglia, thalamus, pons, and cerebellum. However, they can also occur from vascular malformations. Substance abuse of cocaine and amphetamines results in a rapid increase in blood pressure, leading to vessel rupture.8

Ruptured cerebral arteries are the usual source of the bleed.11 Extravasation of blood occurs in the brain and/or the subarachnoid space. The adjacent tissue may be displaced and compressed. Movement of the blood into the ventricles is associated with increased morbidity and mortality.3 Exposure to blood irritates and causes vasospasms of adjacent vessels. A clot will form that will eventually resolve and decrease in size. However, the brain tissue next to the clot can become swollen and necrotic (see Figure 5).8

Figure 5. Hypertensive intraparenchymal hemorrhage. A, Massive hypertensive hemorrhage rupturing into a lateral ventricle. B, Hypertensive hemorrhage in the pons, with extension to fill the fourth ventricle. Reprinted with permission from

Neurological deficits depend upon the site and severity of the hemorrhage. The onset is usually abrupt and rapid developing over 30 to 90 minutes. This is often seen in hypertensive intraparenchymal hemorrhage. In contrast to this rapid onset, bleeding association with anticoagulant therapy will develop slowly over 24 to 48 hours. The clinical presentation can include complaints of: severe headache, vomiting, nuchal rigidity, stupor, coma, and convulsions. However, almost one half of the patients with hypertensive cerebral hemorrhage die.3

CELLULAR CHANGES

In acute hemorrhage, the volume of blood pushes against and compresses the adjacent tissue, ultimately leading to ischemic injury of that tissue. Eventually, the tissue will be come swollen and necrotic. Macrophages begin to phagocytize the hemorrhagic area within 48 hours of onset. Both the blood and necrotic tissue are phagocytized by the macrophages. As part of the inflammatory response, the area is liquefied and a cavity is formed. Astrocytes begin to fill in the cavity and new capillaries are formed.11

Assessment and Diagnosis

Any patient with a sudden alteration in neurologic function should be evaluated for a TIA or stroke. With ischemia or infarction, it is imperative that thrombolytic therapy be given within 180 minutes of onset of symptoms. Therefore, patients should use the 911 Emergency Medical Service system for transport to the nearest hospital that can determine the need for and administer tissue plasminogen activator (t-PA).9

There is no reliable clinical presentation to differentiate between ischemia, infarction, and hemorrhage. However, a more depressed level of consciousness with an elevated blood pressure is more suggestive of hemorrhage. Improvement of neurologic deficits would most often indicate ischemia.3

Diagnostic criteria are used to provide optimal patient care and treatment during a stroke. Patients can then be classified according to symptoms and disease progression as well as the underlying etiology of the event. The initial examination should include a full neurological and cardiovascular assessment. This would include auscultation of carotid arteries for bruits, comparison of blood pressure in both arms, and ophthalmoscopic examination of retina for effects of hypertension. Diagnostic testing would include an electrocardiogram (EKG), chest X-ray, urinalysis, blood work, and brain imaging including computed tomographic (CT) scan or magnetic resonance imaging (MRI). The National Institute of Neurological Disorders and Stroke, as part of the National Institutes of Health, has developed specific criteria to aid in categorizing deficits due to a stroke.

Differential diagnosis should identify the presence of a TIA or stroke while ruling out other pathologic processes with symptoms that could mimic a TIA or stroke. The most common factors would be hypoglycemia, hyperglycemia, vasculitis, migraine, seizure disorders, metabolic encephalopathy, recent head trauma, and tumors. Thus, diagnostic blood work would include: complete blood count with platelet count, electrolyte levels, blood glucose level, blood urea nitrogen, creatinine, and coagulation studies.3,9,15

Computed Tomographic Scan

Computed tomography scans can identify or exclude a hemorrhage as the cause of the stroke. They can also identify neoplasms, abcesses, or other conditions that can produce similar symptoms. However, ischemia and infarctions may not be evident on a CT scan during the first 24 hours of the stroke. Some infarcts are not evident on CT scan even 48 hours after onset of symptoms. The use of contrast enables visualization of larger cerebral vessels (see Figure 6).3,16 The use of a CT scan is often preferred during the acute phase.15

Figure 6. Neuroimaging of middle cerebral artery infarction. A, Computed tomography (CT) scan of the brain of a patient with a left middle cerebral artery (MCA) stroke of 3 hours duration. As an earliest indicator of infarction, the "insular ribbon sign" is caused by edema (darker signal) within the left insular cortex and basal ganglia (arrow). B, Embolic occlusion of the MCA imaged with CT angiography during the acute stroke (arrow). C, Cerebral blood flow measured with CT perfusion; blood flow is reduced over a wider region of brain than appeared edematous in A. D, CT angiogram of a carotid artery showing high-grade stenosis (arrow) from atheroma in another patient. Reprinted with permission from Smith WS, Johnston S, Easton JD. Cerebrovascular diseases. In: Kasper DL, Fauci AS, Longo DL, Braunwald E, Hauser SL, Jameson JL, eds.

Magnetic Resonance Imaging

New advances in imaging studies have enabled the magnetic resonance imaging (MRI) to become an ultrafast imaging method that is able examine some of the physiologic aspects of brain disorders. Diffusion-weighted imaging (DWI) methods, used as part of the MRI study, provide additional information as to the extent of the ischemia and irreversible injury.17,18 Therefore, an MRI is able to identify the presence of an infarction within the brain as well as hemorrhagic transformation or an ischemic infarct.19 In the future, it will also be possible to use the MRI to distinguish between reversible or irreversible tissue injury.17,18

An MRI can also be used to determine the presence of a clot or dissection of a vessel wall. This can be particularly useful in diagnosing severe carotid occlusive disease.18 Additional modification of MRI stimulation relaxation rates can provide different types of information about stroke damage. These modifications are referred to as T1W and T2W. T1W images are more sensitive for identifying subacute hemorrhage and fat structures. T2W images are used to identify edema, demyelination, infarctions, and chronic hemorrhage.16 Thus, an MRI is a better option for studying cerebral ischemia and infarction.

National Institutes of Health Stroke Scale

The National Institutes of Health Stoke Scale (NIHSS) was developed as a graded neurologic examination to rate deficits that occur as a result of a stroke (see Table 2).20 The examination evaluates motor function, visual fields, ataxia, speech, language, cognition, and motor and sensory impairments. Points are given for levels of functioning in each of these areas. The points are then combined for a total score. The higher the score on the scale, the greater neurologic deficits present following a stroke. Training methods have been developed in order to ensure valid and reproducible results when this scale is used to quantify neurologic deficits. Therefore, this score is a fairly reliable measure that can be used to both evaluate treatment and research new treatment modalities. It is possible to correlate the score with the patients' clinical presentation. Scores <5 indicate mild neurologic impairment, between 5 and 15 indicate mild to moderately severe impairment, between 15 to 25 indicate severe impairment, and scores >25 indicate very severe neurologic impairment.20,21

TABLE 2 National Institute of Health Stroke Scale

The NIHSS score in combination with the volume of the ischemia as measured with DWI-MRI, and the time since onset of symptoms until obtaining the MRI enables the identification of patients who have the best potential for a good recovery from a stroke (see Table 3). Essentially, the smaller the size of the infarct, the better the potential of recovery; additionally, those patients with lower NIHSS scores did better as well. Combining the information from the NIHSS and the DWI-MRI resulted in a 7-point score. Analysis of this scoring system demonstrated the following: scores of 5 to 7 had the best outcome, with 87% demonstrating recovery. Of those patients who scores ranged from 3 to 4, 57% recovered from the stroke. As expected, only 7% of patient with scores ranging from 0 to 2 recovered from the stroke.21-23

TABLE 3 Three-item Scale for the Prediction of Stroke Recovery

Treatment

Treatment goals include stabilization of the patient and prevention of further brain injury by improving cerebral perfusion to ischemic tissue. The treatment should include supportive medical therapy. Of utmost importance is to maintain a patent airway in the event that the patient suffers a loss of consciousness. Both blood pressure and cardiac rhythm need to be stabilized as well.3 The next step in treatment protocol is based on the determination as to whether the stroke is due to a hemorrhage versus a thrombus or embolus. Therefore, a CT scan should be obtained as soon as possible.

Supportive medical therapy should include [beta]1 adrenergic antagonists to reduce the workload of the heart and maintain blood pressure. Since fever and hyperglycemia have been shown to be detrimental to recovery, regulation of glucose level and body temperature is important as well. Blood glucose levels should be below 200 mg/dL.3

Ischemic/Infarction

Upon determination that the patient is suffering from an ischemic event, treatment will involve the used of thrombolytic therapy, anticoagulants, antiplatelet agents, and neuroprotection. It is important to maintain adequate cerebral perfusion pressure. Even minor drops in blood pressure could effect the recovery of the area of ischemic penumbra. It is therefore recommended that the patient's blood pressure should not be lowered unless it is greater than 185/110 mm Hg and thrombolytic therapy is being used.3 However, patients with the following conditions should have their blood pressure reduced: acute myocardial infarction, hypertensive crises or encephalopathy, renal failure, aortic dissection, or retinal hemorrhage. When antihypertensive therapy is begun, blood pressure reduction should be done gradually to prevent further ischemia.3,11,23-25

Improvement of blood flow to the ischemic area of the brain involves the use of thrombolytic therapy, which should be initiated as soon as possible. However, there are several caveats associated with the use of this therapy, the most serious being the risk of hemorrhage. Therefore, recombinant t-PA is the preferred treatment for acute ischemic stroke.3,23

It is extremely important to identify the patients who will benefit most from the administration of t-PA. Certain types of stroke, such as lacunar infarcts, have not shown any major improvement in outcome with the use of t-PA. Therefore, diagnostic imaging needs to be reviewed to identify the presence of ischemic tissue that could be reperfused through thrombolysis.18

The risk of hemorrhage following the use of thrombolytic agents increases with larger strokes, higher doses of medication, and longer time intervals from the onset of symptoms.3 Since timing is an important issue, it is recommended that the thrombolytic agent be administered within 180 minutes of the onset of symptoms. Prompt administration of thrombolytic agents decreases the risk of disability following stroke by as much as 30%. The patients with the most improvement were younger, had smaller ischemic areas and lower NIHSS scores. Overall, judicious use of t-PA demonstrated improvement of 4 or more points on the NIHSS score.24-26

Recommended criteria for treatment with t-PA includes: (1) an ischemic stroke with a clearly defined time of onset of no more than 180 minutes, (2) evidence of neurologic deficit measurable on the NIHSS, and (3) a CT scan of the brain with no evidence of intracranial hemorrhage. Additionally, patients should not be given thrombolytic therapy if they have had: (1) a stroke or serious head trauma within the past 3 months, (2) have had major surgery within the past two weeks, (3) have a prior history of intracranial hemorrhage or bleeding from any other body site such as a gastrointestinal hemorrhage, and (4) have a systolic blood pressure above 185 mm Hg or diastolic blood pressure above 110 mm Hg.27

When appropriate guidelines are followed for the administration of t-PA, the rate of hemorrhage as a result of thrombolytic use was approximately 5.2% in one study28 and 6.5%24 in another. However, for patients who did not receive t-PA, the risk of hemorrhage after cerebral infarction was 0.6%. The National Institute of Neurologic Disorders and Stroke has identified these factors related to an increase risk of hemorrhage following the administration of t-PA: over the age of 70, NIHSS score of more than 20 points, blood glucose levels greater than 300 mg/dL, and evidence of cerebral edema on CT scan. The risk of hemorrhage was greater in those patients who had more than one risk factor. 24

There have been studies that have examined intracranial administration of thrombolytics. Although these studies demonstrated reversal of ischemia with less systemic bleeding, this method is not yet approved by the Food and Drug Administration for use in the United States.3

Other agents that are used in the treatment of stroke include antiplatelet therapy and the use of anticoagulants. Aspirin used within 48 hours of onset of symptoms have been shown to reduce risk and mortality. The use of the anticoagulant heparin is also beneficial in preventing further clot formation. Current research is being done to develop neuroprotective agents that would block amino acid pathways and decrease neurotransmitter activity of injured tissue.3

Cerebral Hemorrhagic

Most cerebral hemorrhages develop rapidly over 30 to 90 minutes, often with rapid loss of consciousness. Therefore, it is imperative to maintain a patent airway. Initial treatment includes intubation, hyperventilation, elevation of the head of the bed, and administration of intravenous mannitol to prevent and reduce elevated intracranial pressure.3

Other than reversal of pre-existing anticoagulation, nothing can be done to stop the hemorrhage once it begins. If ICP is elevated, osmotic agents and hyperventilation are used to reduce it. Cerebral spinal fluid can also be removed from the ventricles in an attempt to lower ICP.3

Patients who survive a cerebral hemorrhage have the potential for good recovery. However, the prognosis is dependent upon the size of the hemorrhage. A hemorrhage volume <30 mL may have a good prognosis, whereas a volume >60 mL has a much poorer prognosis.3

Recovery Phase

Blood pressure levels usually stabilize during the first 2 weeks following a stroke. For many patients, their blood pressure is lower and then gradually increases. Any patient with persistent elevation in blood pressure should be evaluated for end-organ damage.25 Patients whose blood pressure is controlled with angiotensin-converting enzyme (ACE) inhibitors have done better than those treated with other antihypertensive medications.14

Prevention

Prevention of a stroke involves lifestyle changes as well as medication and surgery. It is important to review the risk factors with patients to be able to identify areas that need to be addressed. Additionally, it is hoped that by discussing these issues with patients, they will be more likely to comply with the therapeutic regimen. Both diet and exercise can be used to help control both blood pressure and cholesterol levels. Smoking cessation and reduction of alcohol intake also must be part of lifestyle modifications. There is a much greater risk of having a stroke in smokers, with the risk increasing with the number of cigarettes smoked per day.7 Patients can also find further information from the following organizations' Web sites: (1) National Instituted of Neurological Disorders and Stroke at: http://www.ninds.nih.gov/, (2) National Institute of Health Stroke Scale at: http://www.ninds.nih.gov/doctors/index.htm, (3) American Stroke Association: A Division of American Heart Association at: http://www.strokeassociation.org, and (4) National Stroke Association at: http://www.stroke.org.

Medications may be needed to control blood pressure. Adequate control of blood pressure has been shown to reduce the risk of stroke in older adults. The use of ACE inhibitors appears to be helpful in preventing strokes, possibly through the reduction of C reactive protein levels. Treatment goals should include maintaining blood pressure <130/80 mm Hg.3,14,25 Additional research is also examining the use of angiotensin receptor blocking agents, such as losartan, for stroke prevention.29

Elevated cholesterol levels are a risk factor for the development of atherosclerosis and can be viewed as a risk factor for ischemic stroke. Elevated high-density lipoprotein (HDL) levels and lower total cholesterol (TC) HDL ratios have been associated with a decreased incidence of stroke. However, for many people, diet and exercise do not sufficiently lower the TC-HDL ratio. Therefore, the use of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-C0-2A) reductase inhibitors, such as pravastatin, is recommended to reduce the risk of ischemic stroke.30

Medical therapy also includes the use of antiplatelet agents. The most frequently used agents are aspirin, clopidogrel, and the combination of aspirin plus dipyridamole. The use of antiplatelet agents is currently preferred rather than using anticoagulants such as warfarin. For patient with atrial fibrillation, warfarin is preferred. However, the International Normalized Ratio measurement for anticoagulant action should be maintained at 2.0 or greater for the best effect. Surgical intervention with endarterectomy can improve circulation in patients with carotid stenosis.3,24,31

Future Directions for Stroke Care and Research

Just as designated trauma centers have improved treatment and outcome for patients involved in major trauma, the hope for the future is the development of specific stroke centers. Since not all hospitals are equipped with advanced radiological imaging methods such as DWI-MRI, transport of patients to hospitals that do have them can aid in rapid diagnosis and early intervention and treatment. Thus, the National Institute of Neurological Disorders and Stroke is developing guidelines for the establishment of designated stroke centers.32

In addition to the development of stroke centers, The National Institute of Neurological Disorders and Stroke is identifying new avenues of research for stroke prevention and treatment. Specific areas of interest include defining the biology of stroke through the examination of genetic factors, inflammatory mediators, and the process of stroke recovery.32,33

Genetic research can be a valuable part of the biology of stroke research. There are genetic responses involved in cellular adaptation to injury in ischemic events. Further research into their role can provide additional insight into mechanisms of neuronal survival during hypoxia and ischemia. This could be used to minimize the negative effects of ischemia.6,33

Since the inflammatory response plays an integral role in the stroke injury, further research should examine the relationship between BP levels, inflammatory mediators, and C reactive protein levels. Initial studies of patients taking ACE inhibitors have demonstrated that levels of C reactive protein levels are reduced.14 Thus, further study could determine if there are neuroprotective effects from the action of ACE inhibitors.14

Agents such as abciximab (ReoPro), an antiplatelet agent that exerts its effects through the glycoprotein IIb/IIIa receptor, are being studied. It is hoped that administering them during the first 6 hours following the onset of symptoms will also be beneficial. Current research is examining their role either alone or in conjunction with thrombolytic therapy.34

The role of neuroprotective agents in the treatment of stroke is also an important area for research. Anti-excitatory agents can be developed with the goal of blocking of glutamate activity,1 although it was postulated that the administration of magnesium, since it normally blocks the glutamate receptor, would provide neuroprotective effects. Early studies have only demonstrated a reduction in patient blood pressure.35 However, more research still needs to be done on neuroprotective agents. Most of the studies36,37 examining the role of neuroprotective agents have not used them in combination with thrombolytic therapy to examine their effectiveness with concurrent effective reperfusion.

Additional suggested research would examine the role of other imaging techniques such as perfusion-weighted MRI (PWI) in providing information about the status of microvascular perfusion and in the clinical setting is an index of cerebral blood flow. This would enable the identification of patients who will derive greatest benefit with the least risk from t-PA.33,37

Currently research is being done examining the use of endovascular photoacoustic recanalization. This new technology uses laser technology for mechanical clot fragmentation. The goal of this therapy is to rapidly open cerebral vessels and reduce the use of thrombolytjcs.38

New treatment options also need to be explored. This includes direct intra-arterial injection of thrombolytic agents, use of defibrinogenating agents such as ancrod, and carotid artery stenting. Additionally, work is being done to determine of ultrasound technology can be used to enhance clot lyses in combination with thrombolytic agents.3,33,37,39

Conclusion

Cerebrovascular disease and its sequelae are a significant cause of morbidity and mortality among older adults. Although lifestyle modifications can reduce the risk of developing a stroke, for many individuals, medications are part of their risk reduction regimen. Once a stroke has occurred, there needs to be rapid identification of the type and extent of the event so that immediate and appropriate treatment can be initiated. Future designation of specific stroke centers would be a significant step in improving patient outcome. However, much research still needs to be done to promote the best level of neurological recovery following a stroke.

References