Stroke: Hope Through Research

Table of Contents

Introduction
More than 2,400 years ago the father of medicine, Hippocrates, recognized and described stroke-the sudden onset of paralysis. Until recently, modern medicine has had very little power over this disease, but the world of stroke medicine is changing and new and better therapies are being developed every day. Today, some people who have a stroke can walk away from the attack with no or few disabilities if they are treated promptly. Doctors can finally offer stroke patients and their families the one thing that until now has been so hard to give: hope.

In ancient times stroke was called apoplexy,^* a general term that physicians applied to anyone suddenly struck down with paralysis. Because many conditions can lead to sudden paralysis, the term apoplexy did not indicate a specific diagnosis or cause. Physicians knew very little about the cause of stroke and the only established therapy was to feed and care for the patient until the attack ran its course.

The first person to investigate the pathological signs of apoplexy was Johann Jacob Wepfer. Born in Schaffhausen, Switzerland, in 1620, Wepfer studied medicine and was the first to identify postmortem signs of bleeding in the brains of patients who died of apoplexy. From autopsy studies he gained knowledge of the carotid and vertebral arteries that supply the brain with blood. He also was the first person to suggest that apoplexy, in addition to being caused by bleeding in the brain, could be caused by a blockage of one of the main arteries supplying blood to the brain; thus stroke became known as a cerebrovascular disease ("cerebro" refers to a part of the brain; "vascular" refers to the blood vessels and arteries).

Medical science would eventually confirm Wepfer's hypotheses, but until very recently doctors could offer little in the area of therapy. Over the last two decades basic and clinical investigators, many of them sponsored and funded in part by the National Institute of Neurological Disorders and Stroke (NINDS), have learned a great deal about stroke. They have identified major risk factors for the disease and have developed surgical techniques and drug treatments for the prevention of stroke. But perhaps the most exciting new development in the field of stroke research is the recent approval of a drug treatment that can reverse the course of stroke if given during the first few hours after the onset of symptoms.

Studies with animals have shown that brain injury occurs within minutes of a stroke and can become irreversible within as little as an hour. In humans, brain damage begins from the moment the stroke starts and often continues for days afterward. Scientists now know that there is a very short window of opportunity for treatment of the most common form of stroke. Because of these and other advances in the field of cerebrovascular disease stroke patients now have a chance for survival and recovery.

^*Terms in Italics are defined in the glossary.

Cost of Stroke to the United States

• total cost of stroke to the United States: estimated at about $43 billion / year
• direct costs for medical care and therapy: estimated at about $28 billion / year
• indirect costs from lost productivity and other factors: estimated at about $15 million / year
• average cost of care for a patient up to 90 days after a stroke: $15,000*
• for 10% of patients, cost of care for the first 90 days after a stroke: $35,000*
• percentage of direct cost of care for the first 90 days*:

initial hospitalization = 43%
rehabilitation = 16%
physician costs = 14%
hospital readmission = 14%
medications and other expenses = 13%

* From "The Stroke/Brain Attack Reporter's Handbook," National Stroke Association, Englewood, CO, 1997

What is Stroke?
A stroke occurs when the blood supply to part of the brain is suddenly interrupted or when a blood vessel in the brain bursts, spilling blood into the spaces surrounding brain cells. In the same way that a person suffering a loss of blood flow to the heart is said to be having a heart attack, a person with a loss of blood flow to the brain or sudden bleeding in the brain can be said to be having a "brain attack."

Brain cells die when they no longer receive oxygen and nutrients from the blood or when they are damaged by sudden bleeding into or around the brain. Ischemia is the term used to describe the loss of oxygen and nutrients for brain cells when there is inadequate blood flow. Ischemia ultimately leads to infarction, the death of brain cells which are eventually replaced by a fluid-filled cavity (or infarct) in the injured brain.

When blood flow to the brain is interrupted, some brain cells die immediately, while others remain at risk for death. These damaged cells make up the ischemic penumbra and can linger in a compromised state for several hours. With timely treatment these cells can be saved. The ischemic penumbra is discussed in more detail in the Appendix.

Even though a stroke occurs in the unseen reaches of the brain, the symptoms of a stroke are easy to spot. They include sudden numbness or weakness, especially on one side of the body; sudden confusion or trouble speaking or understanding speech; sudden trouble seeing in one or both eyes; sudden trouble walking, dizziness, or loss of balance or coordination; or sudden severe headache with no known cause. All of the symptoms of stroke appear suddenly, and often there is more than one symptom at the same time. Therefore stroke can usually be distinguished from other causes of dizziness or headache. These symptoms may indicate that a stroke has occurred and that medical attention is needed immediately.

There are two forms of stroke: ischemic - blockage of a blood vessel supplying the brain, and hemorrhagic - bleeding into or around the brain. The following sections describe these forms in detail.

Ischemic Stroke
An ischemic stroke occurs when an artery supplying the brain with blood becomes blocked, suddenly decreasing or stopping blood flow and ultimately causing a brain infarction. This type of stroke accounts for approximately 80 percent of all strokes. Blood clots are the most common cause of artery blockage and brain infarction. The process of clotting is necessary and beneficial throughout the body because it stops bleeding and allows repair of damaged areas of arteries or veins. However, when blood clots develop in the wrong place within an artery they can cause devastating injury by interfering with the normal flow of blood. Problems with clotting become more frequent as people age.

Blood clots can cause ischemia and infarction in two ways. A clot that forms in a part of the body other than the brain can travel through blood vessels and become wedged in a brain artery. This free-roaming clot is called an embolus and often forms in the heart. A stroke caused by an embolus is called an embolic stroke. The second kind of ischemic stroke, called a thrombotic stroke, is caused by thrombosis, the formation of a blood clot in one of the cerebral arteries that stays attached to the artery wall until it grows large enough to block blood flow.

Ischemic strokes can also be caused by stenosis, or a narrowing of the artery due to the buildup of plaque (a mixture of fatty substances, including cholesterol and other lipids) and blood clots along the artery wall. Stenosis can occur in large arteries and small arteries and is therefore called large vessel disease or small vessel disease, respectively. When a stroke occurs due to small vessel disease, a very small infarction results, sometimes called a lacunar infarction, from the French word "lacune" meaning "gap" or "cavity."

The most common blood vessel disease that causes stenosis is atherosclerosis. In atherosclerosis, deposits of plaque build up along the inner walls of large and medium-sized arteries, causing thickening, hardening, and loss of elasticity of artery walls and decreased blood flow. The role of cholesterol and blood lipids with respect to stroke risk is discussed in the section on cholesterol under "Who is at Risk for Stroke?".

Hemorrhagic Stroke
In a healthy, functioning brain, neurons do not come into direct contact with blood. The vital oxygen and nutrients the neurons need from the blood come to the neurons across the thin walls of the cerebral capillaries. The glia (nervous system cells that support and protect neurons) form a blood-brain barrier, an elaborate meshwork that surrounds blood vessels and capillaries and regulates which elements of the blood can pass through to the neurons.

When an artery in the brain bursts, blood spews out into the surrounding tissue and upsets not only the blood supply but the delicate chemical balance neurons require to function. This is called a hemorrhagic stroke. Such strokes account for approximately 20 percent of all strokes.

Hemorrhage can occur in several ways. One common cause is a bleeding aneurysm, a weak or thin spot on an artery wall. Over time, these weak spots stretch or balloon out under high arterial pressure. The thin walls of these ballooning aneurysms can rupture and spill blood into the space surrounding brain cells.

Hemorrhage also occurs when arterial walls break open. Plaque-encrusted artery walls eventually lose their elasticity and become brittle and thin, prone to cracking. Hypertension, or high blood pressure, increases the risk that a brittle artery wall will give way and release blood into the surrounding brain tissue.

A person with an arteriovenous malformation (AVM) also has an increased risk of hemorrhagic stroke. AVMs are a tangle of defective blood vessels and capillaries within the brain that have thin walls and can therefore rupture.

Bleeding from ruptured brain arteries can either go into the substance of the brain or into the various spaces surrounding the brain. Intracerebral hemorrhage occurs when a vessel within the brain leaks blood into the brain itself. Subarachnoid hemorrhage is bleeding under the meninges, or outer membranes, of the brain into the thin fluid-filled space that surrounds the brain.

The subarachnoid space separates the arachnoid membrane from the underlying pia mater membrane. It contains a clear fluid (cerebrospinal fluid or CSF) as well as the small blood vessels that supply the outer surface of the brain. In a subarachnoid hemorrhage, one of the small arteries within the subarachnoid space bursts, flooding the area with blood and contaminating the cerebrospinal fluid. Since the CSF flows throughout the cranium, within the spaces of the brain, subarachnoid hemorrhage can lead to extensive damage throughout the brain. In fact, subarachnoid hemorrhage is the most deadly of all strokes.

Transient Ischemic Attacks
A transient ischemic attack (TIA), sometimes called a mini-stroke, starts just like a stroke but then resolves leaving no noticeable symptoms or deficits. The occurrence of a TIA is a warning that the person is at risk for a more serious and debilitating stroke. Of the approximately 50,000 Americans who have a TIA each year, about one-third will have an acute stroke sometime in the future. The addition of other risk factors compounds a person's risk for a recurrent stroke. The average duration of a TIA is a few minutes. For almost all TIAs, the symptoms go away within an hour. There is no way to tell whether symptoms will be just a TIA or persist and lead to death or disability. The patient should assume that all stroke symptoms signal an emergency and should not wait to see if they go away.

Recurrent Stroke
Recurrent stroke is frequent; about 25 percent of people who recover from their first stroke will have another stroke within 5 years. Recurrent stroke is a major contributor to stroke disability and death, with the risk of severe disability or death from stroke increasing with each stroke recurrence. The risk of a recurrent stroke is greatest right after a stroke, with the risk decreasing with time. About 3 percent of stroke patients will have another stroke within 30 days of their first stroke and one-third of recurrent strokes take place within 2 years of the first stroke.

How Do You Recognize Stroke?
Symptoms of stroke appear suddenly. Watch for these symptoms and be prepared to act quickly for yourself or on behalf of someone you are with:

• Sudden numbness or weakness of the face, arm, or leg, especially on one side of the body.
• Sudden confusion, trouble talking, or understanding speech.
• Sudden trouble seeing in one or both eyes.
• Sudden trouble walking, dizziness, or loss of balance or coordination.
• Sudden severe headache with no known cause.

If you suspect you or someone you know is experiencing any of these symptoms indicative of a stroke, do not wait. Call 911 emergency immediately. There are now effective therapies for stroke that must be administered at a hospital, but they lose their effectiveness if not given within the first 3 hours after stroke symptoms appear. Every minute counts!

How is the Cause of Stroke Determined?
Physicians have several diagnostic techniques and imaging tools to help diagnose the cause of stroke quickly and accurately. The first step in diagnosis is a short neurological examination. When a possible stroke patient arrives at a hospital, a health care professional, usually a doctor or nurse, will ask the patient or a companion what happened and when the symptoms began. Blood tests, an electrocardiogram, and CT scans will often be done. One test that helps doctors judge the severity of a stroke is the standardized NIH Stroke Scale, developed by the NINDS. Health care professionals use the NIH Stroke Scale to measure a patient's neurological deficits by asking the patient to answer questions and to perform several physical and mental tests. Other scales include the Glasgow Coma Scale, the Hunt and Hess Scale, the Modified Rankin Scale, and the Barthel Index.

Imaging for the Diagnosis of Acute Stroke
Health care professionals also use a variety of imaging devices to evaluate stroke patients. The most widely used imaging procedure is the computed tomography (CT) scan. Also known as a CAT scan or computed axial tomography, CT creates a series of cross-sectional images of the head and brain. Because it is readily available at all hours at most major hospitals and produces images quickly, CT is the preferred diagnostic technique for acute stroke. CT also has unique diagnostic benefits. It will quickly rule out a hemorrhage, can occasionally show a tumor that might mimic a stroke, and may even show evidence of early infarction. Infarctions generally show up on a CT scan about 6 to 8 hours after the start of stroke symptoms.

If a stroke is caused by hemorrhage, a CT can show evidence of bleeding into the brain almost immediately after stroke symptoms appear. Hemorrhage is the primary reason for avoiding certain drug treatments for stroke, such as thrombolytic therapy, the only proven acute stroke therapy for ischemic stroke (see section on "What Stroke Therapies are Available?"). Thrombolytic therapy cannot be used until the doctor can confidently diagnose the patient as suffering from an ischemic stroke because this treatment might increase bleeding and could make a hemorrhagic stroke worse.

Another imaging device used for stroke patients is the magnetic resonance imaging (MRI) scan. MRI uses magnetic fields to detect subtle changes in brain tissue content. One effect of stroke is an increase of water content in the cells of brain tissue, a condition called cytotoxic edema. MRI can detect edema as soon as a few hours after the onset of stroke. The benefit of MRI over CT imaging is that MRI is better able to detect small infarcts soon after stroke onset. Unfortunately, not every hospital has access to an MRI device and the procedure is time-consuming and expensive. It also is not as accurate in determining when hemorrhage is present. Finally, because MRI takes longer to perform than CT, it should not be used if it delays treatment.

Other types of MRI scans, often used for the diagnosis of cerebrovascular disease and to predict the risk of stroke, are magnetic resonance angiography (MRA) and functional magnetic resonance imaging (fMRI). Neurosurgeons use MRA to detect stenosis (blockage) of the brain arteries inside the skull by mapping flowing blood. Functional MRI uses a magnet to pick up signals from oxygenated blood and can show brain activity through increases in local blood flow. Duplex Doppler ultrasound and arteriography are two diagnostic imaging techniques used to decide if an individual would benefit from a surgical procedure called carotid endarterectomy. This surgery is used to remove fatty deposits from the carotid arteries and can help prevent stroke (see information on carotid endarterectomy.

Doppler ultrasound is a painless, noninvasive test in which sound waves above the range of human hearing are sent into the neck. Echoes bounce off the moving blood and the tissue in the artery and can be formed into an image. Ultrasound is fast, painless, risk-free, and relatively inexpensive compared to MRA and arteriography, but it is not considered to be as accurate as arteriography. Arteriography is an X-ray of the carotid artery taken when a special dye is injected into the artery. The procedure carries its own small risk of causing a stroke and is costly to perform. The benefits of arteriography over MR techniques and ultrasound are that it is extremely reliable and still the best way to measure stenosis of the carotid arteries. Even so, significant advances are being made every day involving noninvasive imaging techniques such as fMRI.

Who is at Risk for Stroke?
Some people are at a higher risk for stroke than others. Unmodifiable risk factors include age, gender, race/ethnicity, and stroke family history. In contrast, other risk factors for stroke, like high blood pressure or cigarette smoking, can be changed or controlled by the person at risk.

Unmodifiable Risk Factors
It is a myth that stroke occurs only in elderly adults. In actuality, stroke strikes all age groups, from fetuses still in the womb to centenarians. It is true, however, that older people have a higher risk for stroke than the general population and that the risk for stroke increases with age. For every decade after the age of 55, the risk of stroke doubles, and two-thirds of all strokes occur in people over 65 years old. People over 65 also have a seven-fold greater risk of dying from stroke than the general population. And the incidence of stroke is increasing proportionately with the increase in the elderly population. When the baby boomers move into the over-65 age group, stroke and other diseases will take on even greater significance in the health care field.

Gender also plays a role in risk for stroke. Men have a higher risk for stroke, but more women die from stroke. The stroke risk for men is 1.25 times that for women. But men do not live as long as women, so men are usually younger when they have their strokes and therefore have a higher rate of survival than women. In other words, even though women have fewer strokes than men, women are generally older when they have their strokes and are more likely to die from them.

Stroke seems to run in some families. Several factors might contribute to familial stroke risk. Members of a family might have a genetic tendency for stroke risk factors, such as an inherited predisposition for hypertension or diabetes. The influence of a common lifestyle among family members could also contribute to familial stroke.

The risk for stroke varies among different ethnic and racial groups. The incidence of stroke among African-Americans is almost double that of white Americans, and twice as many African-Americans who have a stroke die from the event compared to white Americans. African-Americans between the ages of 45 and 55 have four to five times the stroke death rate of whites. After age 55 the stroke mortality rate for whites increases and is equal to that of African-Americans.

Compared to white Americans, African-Americans have a higher incidence of stroke risk factors, including high blood pressure and cigarette smoking. African-Americans also have a higher incidence and prevalence of some genetic diseases, such as diabetes and sickle cell anemia, that predispose them to stroke.

Hispanics and Native Americans have stroke incidence and mortality rates more similar to those of white Americans. In Asian-Americans stroke incidence and mortality rates are also similar to those in white Americans, even though Asians in Japan, China, and other countries of the Far East have significantly higher stroke incidence and mortality rates than white Americans. This suggests that environment and lifestyle factors play a large role in stroke risk.

The "Stroke Belt"
Several decades ago, scientists and statisticians noticed that people in the southeastern United States had the highest stroke mortality rate in the country. They named this region the stroke belt. For many years, researchers believed that the increased risk was due to the higher percentage of African-Americans and an overall lower socioeconomic status (SES) in the southern states. A low SES is associated with an overall lower standard of living, leading to a lower standard of health care and therefore an increased risk of stroke. But researchers now know that the higher percentage of African-Americans and the overall lower SES in the southern states does not adequately account for the higher incidence of, and mortality from, stroke in those states. This means that other factors must be contributing to the higher incidence of and mortality from stroke in this region.

Recent studies have also shown that there is a stroke buckle in the stroke belt. Three southeastern states, North Carolina, South Carolina, and Georgia, have an extremely high stroke mortality rate, higher than the rate in other stroke belt states and up to two times the stroke mortality rate of the United States overall. The increased risk could be due to geographic or environmental factors or to regional differences in lifestyle, including higher rates of cigarette smoking and a regional preference for salty, high-fat foods.

Other Risk Factors
The most important risk factors for stroke are hypertension, heart disease, diabetes, and cigarette smoking. Others include heavy alcohol consumption, high blood cholesterol levels, illicit drug use, and genetic or congenital conditions, particularly vascular abnormalities. People with more than one risk factor have what is called "amplification of risk." This means that the multiple risk factors compound their destructive effects and create an overall risk greater than the simple cumulative effect of the individual risk factors.

Hypertension
Of all the risk factors that contribute to stroke, the most powerful is hypertension, or high blood pressure. People with hypertension have a risk for stroke that is four to six times higher than the risk for those without hypertension. One-third of the adult U.S. population, about 50 million people (including 40-70 percent of those over age 65) have high blood pressure. Forty to 90 percent of stroke patients have high blood pressure before their stroke event.

A systolic pressure of 120 mm of Hg over a diastolic pressure of 80 mm of Hg^* is generally considered normal. Persistently high blood pressure greater than 140 over 90 leads to the diagnosis of the disease called hypertension. The impact of hypertension on the total risk for stroke decreases with increasing age, therefore factors other than hypertension play a greater role in the overall stroke risk in elderly adults. For people without hypertension, the absolute risk of stroke increases over time until around the age of 90, when the absolute risk becomes the same as that for people with hypertension.

Like stroke, there is a gender difference in the prevalence of hypertension. In younger people, hypertension is more common among men than among women. With increasing age, however, more women than men have hypertension. This hypertension gender-age difference probably has an impact on the incidence and prevalence of stroke in these populations.

Antihypertensive medication can decrease a person's risk for stroke. Recent studies suggest that treatment can decrease the stroke incidence rate by 38 percent and decrease the stroke fatality rate by 40 percent. Common hypertensive agents include adrenergic agents, beta-blockers, angiotensin converting enzyme inhibitors, calcium channel blockers, diuretics, and vasodilators.

Heart Disease
After hypertension, the second most powerful risk factor for stroke is heart disease, especially a condition known as atrial fibrillation. Atrial fibrillation is irregular beating of the left atrium, or left upper chamber, of the heart. In people with atrial fibrillation, the left atrium beats up to four times faster than the rest of the heart. This leads to an irregular flow of blood and the occasional formation of blood clots that can leave the heart and travel to the brain, causing a stroke.

Atrial fibrillation, which affects as many as 2.2 million Americans, increases an individual's risk of stroke by 4 to 6 percent, and about 15 percent of stroke patients have atrial fibrillation before they experience a stroke. The condition is more prevalent in the upper age groups, which means that the prevalence of atrial fibrillation in the United States will increase proportionately with the growth of the elderly population. Unlike hypertension and other risk factors that have a lesser impact on the ever-rising absolute risk of stroke that comes with advancing age, the influence of atrial fibrillation on total risk for stroke increases powerfully with age. In people over 80 years old, atrial fibrillation is the direct cause of one in four strokes.

Other forms of heart disease that increase stroke risk include malformations of the heart valves or the heart muscle. Some valve diseases, like mitral valve stenosis or mitral annular calcification, can double the risk for stroke, independent of other risk factors.

Heart muscle malformations can also increase the risk for stroke. Patent foramen ovale (PFO) is a passage or a hole (sometimes called a "shunt") in the heart wall separating the two atria, or upper chambers, of the heart. Clots in the blood are usually filtered out by the lungs, but PFO could allow emboli or blood clots to bypass the lungs and go directly through the arteries to the brain, potentially causing a stroke. Research is currently under way to determine how important PFO is as a cause for stroke. Atrial septal aneurysm (ASA), a congenital (present from birth) malformation of the heart tissue, is a bulging of the septum or heart wall into one of the atria of the heart. Researchers do not know why this malformation increases the risk for stroke. PFO and ASA frequently occur together and therefore amplify the risk for stroke. Two other heart malformations that seem to increase the risk for stroke for unknown reasons are left atrial enlargement and left ventricular hypertrophy. People with left atrial enlargement have a larger than normal left atrium of the heart; those with left ventricular hypertrophy have a thickening of the wall of the left ventricle.

Another risk factor for stroke is cardiac surgery to correct heart malformations or reverse the effects of heart disease. Strokes occurring in this situation are usually the result of surgically dislodged plaques from the aorta that travel through the bloodstream to the arteries in the neck and head, causing stroke. Cardiac surgery increases a person's risk of stroke by about 1 percent. Other types of surgery can also increase the risk of stroke.

Blood Cholesterol Levels
Most people know that high cholesterol levels contribute to heart disease. But many don't realize that a high cholesterol level also contributes to stroke risk. Cholesterol, a waxy substance produced by the liver, is a vital body product. It contributes to the production of hormones and vitamin D and is an integral component of cell membranes. The liver makes enough cholesterol to fuel the body's needs and this natural production of cholesterol alone is not a large contributing factor to atherosclerosis, heart disease, and stroke. Research has shown that the danger from cholesterol comes from a dietary intake of foods that contain high levels of cholesterol. Foods high in saturated fat and cholesterol, like meats, eggs, and dairy products, can increase the amount of total cholesterol in the body to alarming levels, contributing to the risk of atherosclerosis and thickening of the arteries.

Cholesterol is classified as a lipid, meaning that it is fat-soluble rather than water-soluble. Other lipids include fatty acids, glycerides, alcohol, waxes, steroids, and fat-soluble vitamins A, D, and E. Lipids and water, like oil and water, do not mix. Blood is a water-based liquid, therefore cholesterol does not mix with blood. In order to travel through the blood without clumping together, cholesterol needs to be covered by a layer of protein. The cholesterol and protein together are called a lipoprotein.

There are two kinds of cholesterol, commonly called the "good" and the "bad." Good cholesterol is high-density lipoprotein, or HDL; bad cholesterol is low-density lipoprotein, or LDL. Together, these two forms of cholesterol make up a person's total serum cholesterol level. Most cholesterol tests measure the level of total cholesterol in the blood and don't distinguish between good and bad cholesterol. For these total serum cholesterol tests, a level of less than 200 mg/dL^** is considered safe, while a level of more than 240 is considered dangerous and places a person at risk for heart disease and stroke.

Most cholesterol in the body is in the form of LDL. LDLs circulate through the bloodstream, picking up excess cholesterol and depositing cholesterol where it is needed (for example, for the production and maintenance of cell membranes). But when too much cholesterol starts circulating in the blood, the body cannot handle the excessive LDLs, which build up along the inside of the arterial walls. The buildup of LDL coating on the inside of the artery walls hardens and turns into arterial plaque, leading to stenosis and atherosclerosis. This plaque blocks blood vessels and contributes to the formation of blood clots. A person's LDL level should be less than 130 mg/dL to be safe. LDL levels between 130 and 159 put a person at a slightly higher risk for atherosclerosis, heart disease, and stroke. A score over 160 puts a person at great risk for a heart attack or stroke.

The other form of cholesterol, HDL, is beneficial and contributes to stroke prevention. HDL carries a small percentage of the cholesterol in the blood, but instead of depositing its cholesterol on the inside of artery walls, HDL returns to the liver to unload its cholesterol. The liver then eliminates the excess cholesterol by passing it along to the kidneys. Currently, any HDL score higher than 35 is considered desirable. Recent studies have shown that high levels of HDL are associated with a reduced risk for heart disease and stroke and that low levels (less than 35 mg/dL), even in people with normal levels of LDL, lead to an increased risk for heart disease and stroke.

A person may lower his risk for atherosclerosis and stroke by improving his cholesterol levels. A healthy diet and regular exercise are the best ways to lower total cholesterol levels. In some cases, physicians may prescribe cholesterol-lowering medication, and recent studies have shown that the newest types of these drugs, called reductase inhibitors or statin drugs, significantly reduce the risk for stroke in most patients with high cholesterol. Scientists believe that statins may work by reducing the amount of bad cholesterol the body produces and by reducing the body's inflammatory immune reaction to cholesterol plaque associated with atherosclerosis and stroke.

^*mm of Hg-or millimeters of mercury-is the standard means of expressing blood pressure, which is measured using an instrument called a sphygmomanometer. Using a stethoscope and a cuff that is wrapped around the patient's upper arm, a health professional listens to the sounds of blood rushing through an artery. The first sound registered on the instrument gauge (which measures the pressure of the blood in millimeters on a column of mercury) is called the systolic pressure. This is the maximum pressure produced as the left ventricle of the heart contracts and the blood begins to flow through the artery. The second sound is the diastolic pressure and is the lowest pressure in the artery when the left ventricle is relaxing.

^**mg/dL describes the weight of cholesterol in milligrams in a deciliter of blood. This is the standard way of measuring blood cholesterol levels.

Diabetes
Diabetes is another disease that increases a person's risk for stroke. People with diabetes have three times the risk of stroke compared to people without diabetes. The relative risk of stroke from diabetes is highest in the fifth and sixth decades of life and decreases after that. Like hypertension, the relative risk of stroke from diabetes is highest for men at an earlier age and highest for women at an older age. People with diabetes may also have other contributing risk factors that can amplify the overall risk for stroke. For example, the prevalence of hypertension is 40 percent higher in the diabetic population compared to the general population.

Modifiable Lifestyle Risk Factors
Cigarette smoking is the most powerful modifiable stroke risk factor. Smoking almost doubles a person's risk for ischemic stroke, independent of other risk factors, and it increases a person's risk for subarachnoid hemorrhage by up to 3.5 percent. Smoking is directly responsible for a greater percentage of the total number of strokes in young adults than in older adults. Risk factors other than smoking - like hypertension, heart disease, and diabetes - account for more of the total number of strokes in older adults.

Heavy smokers are at greater risk for stroke than light smokers. The relative risk of stroke decreases immediately after quitting smoking, with a major reduction of risk seen after 2 to 4 years. Unfortunately, it may take several decades for a former smoker's risk to drop to the level of someone who never smoked.

Smoking increases the risk of stroke by promoting atherosclerosis and increasing the levels of blood-clotting factors, such as fibrinogen. In addition to promoting conditions linked to stroke, smoking also increases the damage that results from stroke by weakening the endothelial wall of the cerebrovascular system. This leads to greater damage to the brain from events that occur in the secondary stage of stroke. (The secondary effects of stroke are discussed in greater detail in the Appendix.)

High alcohol consumption is another modifiable risk factor for stroke. Generally, an increase in alcohol consumption leads to an increase in blood pressure. While scientists agree that heavy drinking is a risk for both hemorrhagic and ischemic stroke, in several research studies daily consumption of smaller amounts of alcohol has been found to provide a protective influence against ischemic stroke, perhaps because alcohol decreases the clotting ability of platelets in the blood. Moderate alcohol consumption may act in the same way as aspirin to decrease blood clotting and prevent ischemic stroke. Heavy alcohol consumption, though, may seriously deplete platelet numbers and compromise blood clotting and blood viscosity, leading to hemorrhage. In addition, heavy drinking or binge drinking can lead to a rebound effect after the alcohol is purged from the body. The consequences of this rebound effect are that blood viscosity (thickness) and platelet levels skyrocket after heavy drinking, increasing the risk for ischemic stroke.

The use of illicit drugs, such as cocaine and crack cocaine, can cause stroke. Cocaine may act on other risk factors, such as hypertension, heart disease, and vascular disease, to trigger a stroke. It decreases relative cerebrovascular blood flow by up to 30 percent, causes vascular constriction, and inhibits vascular relaxation, leading to narrowing of the arteries. Cocaine also affects the heart, causing arrhythmias and rapid heart rate that can lead to the formation of blood clots.

Marijuana smoking may also be a risk factor for stroke. Marijuana decreases blood pressure and may interact with other risk factors, such as hypertension and cigarette smoking, to cause rapidly fluctuating blood pressure levels, damaging blood vessels.

Other drugs of abuse, such as amphetamines, heroin, and anabolic steroids (and even some common, legal drugs, such as caffeine and L-asparaginase and pseudoephedrine found in over-the-counter decongestants), have been suspected of increasing stroke risk. Many of these drugs are vasoconstrictors, meaning that they cause blood vessels to constrict and blood pressure to rise.

Head and Neck Injuries
Injuries to the head or neck may damage the cerebrovascular system and cause a small number of strokes. Head injury or traumatic brain injury may cause bleeding within the brain leading to damage akin to that caused by a hemorrhagic stroke. Neck injury, when associated with spontaneous tearing of the vertebral or carotid arteries caused by sudden and severe extension of the neck, neck rotation, or pressure on the artery, is a contributing cause of stroke, especially in young adults. This type of stroke is often called "beauty-parlor syndrome," which refers to the practice of extending the neck backwards over a sink for hair-washing in beauty parlors. Neck calisthenics, "bottoms-up" drinking, and improperly performed chiropractic manipulation of the neck can also put strain on the vertebral and carotid arteries, possibly leading to ischemic stroke.

Infections
Recent viral and bacterial infections may act with other risk factors to add a small risk for stroke. The immune system responds to infection by increasing inflammation and increasing the infection-fighting properties of the blood. Unfortunately, this immune response increases the number of clotting factors in the blood, leading to an increased risk of embolic-ischemic stroke.

Genetic Risk Factors
Although there may not be a single genetic factor associated with stroke, genes do play a large role in the expression of stroke risk factors such as hypertension, heart disease, diabetes, and vascular malformations. It is also possible that an increased risk for stroke within a family is due to environmental factors, such as a common sedentary lifestyle or poor eating habits, rather than hereditary factors.

Vascular malformations that cause stroke may have the strongest genetic link of all stroke risk factors. A vascular malformation is an abnormally formed blood vessel or group of blood vessels. One genetic vascular disease called CADASIL, which stands for cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is a rare, genetically inherited, congenital vascular disease of the brain that causes strokes, subcortical dementia, migraine-like headaches, and psychiatric disturbances. CADASIL is very debilitating and symptoms usually surface around the age of 45. Although CADASIL can be treated with surgery to repair the defective blood vessels, patients often die by the age of 65. The exact incidence of CADASIL in the United States is unknown.

What Stroke Therapies are Available?
Physicians have a wide range of therapies to choose from when determining a stroke patient's best therapeutic plan. The type of stroke therapy a patient should receive depends upon the stage of disease. Generally there are three treatment stages for stroke: prevention, therapy immediately after stroke, and post-stroke rehabilitation. Therapies to prevent a first or recurrent stroke are based on treating an individual's underlying risk factors for stroke, such as hypertension, atrial fibrillation, and diabetes, or preventing the widespread formation of blood clots that can cause ischemic stroke in everyone, whether or not risk factors are present. Acute stroke therapies try to stop a stroke while it is happening by quickly dissolving a blood clot causing the stroke or by stopping the bleeding of a hemorrhagic stroke. The purpose of post-stroke rehabilitation is to overcome disabilities that result from stroke damage.

Therapies for stroke include medications, surgery, or rehabilitation.

Medications
Medication or drug therapy is the most common treatment for stroke. The most popular classes of drugs used to prevent or treat stroke are antithrombotics (antiplatelet agents and anticoagulants), thrombolytics, and neuroprotective agents.

Antithrombotics prevent the formation of blood clots that can become lodged in a cerebral artery and cause strokes. Antiplatelet drugs prevent clotting by decreasing the activity of platelets, blood cells that contribute to the clotting property of blood. These drugs reduce the risk of blood-clot formation, thus reducing the risk of ischemic stroke. In the context of stroke, physicians prescribe antiplatelet drugs mainly for prevention. The most widely known and used antiplatelet drug is aspirin. Other antiplatelet drugs include clopidogrel and ticlopidine. The NINDS sponsors a wide range of clinical trials to determine the effectiveness of antiplatelet drugs for stroke prevention.

Anticoagulants reduce stroke risk by reducing the clotting property of the blood. The most commonly used anticoagulants include warfarin (also known as Coumadin<® ) and heparin. The NINDS has sponsored several trials to test the efficacy of anticoagulants versus antiplatelet drugs. The Stroke Prevention in Atrial Fibrillation (SPAF) trial found that, although aspirin is an effective therapy for the prevention of a second stroke in most patients with atrial fibrillation, some patients with additional risk factors do better on warfarin therapy. Another study, the Trial of Org 10127 in Acute Stroke Treatment (TOAST), tested the effectiveness of low-molecular weight heparin (Org 10172) in stroke prevention. TOAST showed that heparin anticoagulants are not generally effective in preventing recurrent stroke or improving outcome.

Thrombolytic agents are used to treat an ongoing, acute ischemic stroke caused by an artery blockage. These drugs halt the stroke by dissolving the blood clot that is blocking blood flow to the brain. Recombinant tissue plasminogen activator (rt-PA) is a genetically engineered form of t-PA, a thombolytic substance made naturally by the body. It can be effective if given intravenously within 3 hours of stroke symptom onset, but it should be used only after a physician has confirmed that the patient has suffered an ischemic stroke. Thrombolytic agents can increase bleeding and therefore must be used only after careful patient screening. The NINDS rt-PA Stroke Study showed the efficacy of t-PA and in 1996 led to the first FDA-approved treatment for acute ischemic stroke. Other thrombolytics are currently being tested in clinical trials.

Neuroprotectants are medications that protect the brain from secondary injury caused by stroke (see Appendix). Although only a few neuroprotectants are FDA-approved for use at this time, many are in clinical trials. There are several different classes of neuroprotectants that show promise for future therapy, including calcium antagonists, glutamate antagonists, opiate antagonists, antioxidants, apoptosis inhibitors, and many others. One of the calcium antagonists, nimodipine, also called a calcium channel blocker, has been shown to decrease the risk of the neurological damage that results from subarachnoid hemorrhage. Calcium channel blockers, such as nimodipine, act by reducing the risk of cerebral vasospasm, a dangerous side effect of subarachnoid hemorrhage in which the blood vessels in the subarachnoid space constrict erratically, cutting off blood flow.

Surgery
Surgery can be used to prevent stroke, to treat acute stroke, or to repair vascular damage or malformations in and around the brain. There are two prominent types of surgery for stroke prevention and treatment: carotid endarterectomy and extracranial/intracranial (EC/IC) bypass.

Carotid endarterectomy is a surgical procedure in which a doctor removes fatty deposits (plaque) from the inside of one of the carotid arteries, which are located in the neck and are the main suppliers of blood to the brain. As mentioned earlier, the disease atherosclerosis is characterized by the buildup of plaque on the inside of large arteries, and the blockage of an artery by this fatty material is called stenosis. The NINDS has sponsored two large clinical trials to test the efficacy of carotid endarterectomy: the North American Symptomatic Carotid Endarterectomy Trial (NASCET) and the Asymptomatic Carotid Atherosclerosis Trial (ACAS). These trials showed that carotid endarterectomy is a safe and effective stroke prevention therapy for most people with greater than 50 percent stenosis of the carotid arteries when performed by a qualified and experienced neurosurgeon or vascular surgeon.

Currently, the NINDS is sponsoring the Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST), a large clinical trial designed to test the effectiveness of carotid endarterectomy versus a newer surgical procedure for carotid stenosis called stenting. The procedure involves inserting a long, thin catheter tube into an artery in the leg and threading the catheter through the vascular system into the narrow stenosis of the carotid artery in the neck. Once the catheter is in place in the carotid artery, the radiologist expands the stent with a balloon on the tip of the catheter. The CREST trial will test the effectiveness of the new surgical technique versus the established standard technique of carotid endarterectomy surgery.

EC/IC bypass surgery is a procedure that restores blood flow to a blood-deprived area of brain tissue by rerouting a healthy artery in the scalp to the area of brain tissue affected by a blocked artery. The NINDS-sponsored EC/IC Bypass Study tested the ability of this surgery to prevent recurrent strokes in stroke patients with atherosclerosis. The study showed that, in the long run, EC/IC does not seem to benefit these patients. The surgery is still performed occasionally for patients with aneurysms, some types of small artery disease, and certain vascular abnormalities.

One useful surgical procedure for treatment of brain aneurysms that cause subarachnoid hemorrhage is a technique called "clipping." Clipping involves clamping off the aneurysm from the blood vessel, which reduces the chance that it will burst and bleed.

A new therapy that is gaining wide attention is the detachable coil technique for the treatment of high-risk intracranial aneurysms. A small platinum coil is inserted through an artery in the thigh and threaded through the arteries to the site of the aneurysm. The coil is then released into the aneurysm, where it evokes an immune response from the body. The body produces a blood clot inside the aneurysm, strengthening the artery walls and reducing the risk of rupture. Once the aneurysm is stabilized, a neurosurgeon can clip the aneurysm with less risk of hemorrhage and death to the patient.

Rehabilitation Therapy
Stroke is the number one cause of serious adult disability in the United States. Stroke disability is devastating to the stroke patient and family, but therapies are available to help rehabilitate post-stroke patients.

For most stroke patients, physical therapy (PT) is the cornerstone of the rehabilitation process. A physical therapist uses training, exercises, and physical manipulation of the stroke patient's body with the intent of restoring movement, balance, and coordination. The aim of PT is to have the stroke patient relearn simple motor activities such as walking, sitting, standing, lying down, and the process of switching from one type of movement to another.

Another type of therapy involving relearning daily activities is occupational therapy (OT). OT also involves exercise and training to help the stroke patient relearn everyday activities such as eating, drinking and swallowing, dressing, bathing, cooking, reading and writing, and toileting. The goal of OT is to help the patient become independent or semi-independent.

Speech and language problems arise when brain damage occurs in the language centers of the brain. Due to the brain's great ability to learn and change (called brain plasticity), other areas can adapt to take over some of the lost functions. Speech therapy helps stroke patients relearn language and speaking skills, or learn other forms of communication. Speech therapy is appropriate for patients who have no deficits in cognition or thinking, but have problems understanding speech or written words, or problems forming speech. A speech therapist helps stroke patients help themselves by working to improve language skills, develop alternative ways of communicating, and develop coping skills to deal with the frustration of not being able to communicate fully. With time and patience, a stroke survivor should be able to regain some, and sometimes all, language and speaking abilities.

Many stroke patients require psychological or psychiatric help after a stroke. Psychological problems, such as depression, anxiety, frustration, and anger, are common post-stroke disabilities. Talk therapy, along with appropriate medication, can help alleviate some of the mental and emotional problems that result from stroke. Sometimes it is also beneficial for family members of the stroke patient to seek psychological help as well.

For more information on rehabilitation, contact the National Rehabilitation Information Center , a service of the National Institute on Disability and Rehabilitation Research (see Where I can get more information).

What Disabilities Can Result From a Stroke?
Although stroke is a disease of the brain, it can affect the entire body. Some of the disabilities that can result from a stroke include paralysis, cognitive deficits, speech problems, emotional difficulties, daily living problems, and pain.

Paralysis:
A common disability that results from stroke is paralysis on one side of the body, called hemiplegia. A related disability that is not as debilitating as paralysis is one-sided weakness or hemiparesis. The paralysis or weakness may affect only the face, an arm, or a leg or may affect one entire side of the body and face. A person who suffers a stroke in the left hemisphere of the brain will show right-sided paralysis or paresis. Conversely, a person with a stroke in the right hemisphere of the brain will show deficits on the left side of the body. A stroke patient may have problems with the simplest of daily activities, such as walking, dressing, eating, and using the bathroom. Motor deficits can result from damage to the motor cortex in the frontal lobes of the brain or from damage to the lower parts of the brain, such as the cerebellum, which controls balance and coordination. Some stroke patients also have trouble eating and swallowing, called dysphagia.

Cognitive deficits:
Stroke may cause problems with thinking, awareness, attention, learning, judgment, and memory. If the cognitive problems are severe, the stroke patient may be said to have apraxia, agnosia, or "neglect." In the context of stroke, neglect means that a stroke patient has no knowledge of one side of his or her body, or one side of the visual field, and is unaware of the deficit. A stroke patient may be unaware of his or her surroundings, or may be unaware of the mental deficits that resulted from the stroke.

Language deficits:
Stroke victims often have problems understanding or forming speech. A deficit in understanding speech is called aphasia. Trouble speaking or forming words is called dysarthria. Language problems usually result from damage to the left temporal and parietal lobes of the brain.

Emotional deficits:
A stroke can lead to emotional problems. Stroke patients may have difficulty controlling their emotions or may express inappropriate emotions in certain situations. One common disability that occurs with many stroke patients is depression. Post-stroke depression may be more than a general sadness resulting from the stroke incident. It is a clinical behavioral problem that can hamper recovery and rehabilitation and may even lead to suicide. Post-stroke depression is treated as any depression is treated, with antidepressant medications and therapy.

Pain:
Stroke patients may experience pain, uncomfortable numbness, or strange sensations after a stroke. These sensations may be due to many factors including damage to the sensory regions of the brain, stiff joints, or a disabled limb. An uncommon type of pain resulting from stroke is called central stroke pain or central pain syndrome (CPS). CPS results from damage to an area in the mid-brain called the thalamus. The pain is a mixture of sensations, including heat and cold, burning, tingling, numbness, and sharp stabbing and underlying aching pain. The pain is often worse in the extremities - the hands and feet - and is made worse by movement and temperature changes, especially cold temperatures. Unfortunately, since most pain medications provide little relief from these sensations, very few treatments or therapies exist to combat CPS.

What Special Risks do Women Face?
Some risk factors for stroke apply only to women. Primary among these are pregnancy, childbirth, and menopause. These risk factors are tied to hormonal fluctuations and changes that affect a woman in different stages of life. Research in the past few decades has shown that high-dose oral contraceptives, the kind used in the 1960s and 1970s, can increase the risk of stroke in women. Fortunately, oral contraceptives with high doses of estrogen are no longer used and have been replaced with safer and more effective oral contraceptives with lower doses of estrogen. Some studies have shown the newer low-dose oral contraceptives may not significantly increase the risk of stroke in women.

Other studies have demonstrated that pregnancy and childbirth can put a woman at an increased risk for stroke. Pregnancy increases the risk of stroke as much as three to 13 times. Of course, the risk of stroke in young women of childbearing years is very small to begin with, so a moderate increase in risk during pregnancy is still a relatively small risk. Pregnancy and childbirth cause strokes in approximately eight in 100,000 women. Unfortunately, 25 percent of strokes during pregnancy end in death, and hemorrhagic strokes, although rare, are still the leading cause of maternal death in the United States. Subarachnoid hemorrhage, in particular, causes one to five maternal deaths per 10,000 pregnancies.

A study sponsored by the NINDS showed that the risk of stroke during pregnancy is greatest in the post-partum period - the 6 weeks following childbirth. The risk of ischemic stroke after pregnancy is about nine times higher and the risk of hemorrhagic stroke is more than 28 times higher for post-partum women than for women who are not pregnant or post-partum. The cause is unknown.

In the same way that the hormonal changes during pregnancy and childbirth are associated with increased risk of stroke, hormonal changes at the end of the childbearing years can increase the risk of stroke. Several studies have shown that menopause, the end of a woman's reproductive ability marked by the termination of her menstrual cycle, can increase a woman's risk of stroke. Fortunately, some studies have suggested that hormone replacement therapy can reduce some of the effects of menopause and decrease stroke risk. Currently, the NINDS is sponsoring the Women's Estrogen for Stroke Trial (WEST), a randomized, placebo-controlled, double-blind trial, to determine whether estrogen therapy can reduce the risk of death or recurrent stroke in postmenopausal women who have a history of a recent TIA or non-disabling stroke. The mechanism by which estrogen can prove beneficial to postmenopausal women could include its role in cholesterol control. Studies have shown that estrogen acts to increase levels of HDL while decreasing LDL levels.

Are Children at Risk For Stroke?
The young have several risk factors unique to them. Young people seem to suffer from hemorrhagic strokes more than ischemic strokes, a significant difference from older age groups where ischemic strokes make up the majority of stroke cases. Hemorrhagic strokes represent 20 percent of all strokes in the United States and young people account for many of these.

Clinicians often separate the "young" into two categories: those younger than 15 years of age, and those 15 to 44 years of age. People 15 to 44 years of age are generally considered young adults and have many of the risk factors mentioned above, such as drug use, alcohol abuse, pregnancy, head and neck injuries, heart disease or heart malformations, and infections. Some other causes of stroke in the young are linked to genetic diseases.

Medical complications that can lead to stroke in children include intracranial infection, brain injury, vascular malformations such as moyamoya syndrome, occlusive vascular disease, and genetic disorders such as sickle cell anemia, tuberous sclerosis, and Marfan's syndrome.

The symptoms of stroke in children are different from those in adults and young adults. A child experiencing a stroke may have seizures, a sudden loss of speech, a loss of expressive language (including body language and gestures), hemiparesis (weakness on one side of the body), hemiplegia (paralysis on one side of the body), dysarthria (impairment of speech), convulsions, headache, or fever. It is a medical emergency when a child shows any of these symptoms.

In children with stroke the underlying conditions that led to the stroke should be determined and managed to prevent future strokes. For example, a recent clinical study sponsored by the National Heart, Lung, and Blood Institute found that giving blood transfusions to young children with sickle cell anemia greatly reduces the risk of stroke. The Institute even suggests attempting to prevent stroke in high-risk children by giving them blood transfusions before they experience a stroke.

Most children who experience a stroke will do better than most adults after treatment and rehabilitation. This is due in part to the immature brain's great plasticity, the ability to adapt to deficits and injury. Children who experience seizures along with stroke do not recover as well as children who do not have seizures. Some children may experience residual hemiplegia, though most will eventually learn how to walk.

What Research is Being Done by the NINDS?
The NINDS is the leading supporter of stroke research in the United States and sponsors a wide range of experimental research studies, from investigations of basic biological mechanisms to studies with animal models and clinical trials.

Currently, NINDS researchers are studying the mechanisms of stroke risk factors and the process of brain damage that results from stroke. Some of this brain damage may be secondary to the initial death of brain cells caused by the lack of blood flow to the brain tissue. This secondary wave of brain injury is a result of a toxic reaction to the primary damage and mainly involves the excitatory neurochemical, glutamate. Glutamate in the normal brain functions as a chemical messenger between brain cells, allowing them to communicate. But an excess amount of glutamate in the brain causes too much activity and brain cells quickly "burn out" from too much excitement, releasing more toxic chemicals, such as caspases, cytokines, monocytes, and oxygen-free radicals. These substances poison the chemical environment of surrounding cells, initiating a cascade of degeneration and programmed cell death, called apoptosis. NINDS researchers are studying the mechanisms underlying this secondary insult, which consists mainly of inflammation, toxicity, and a breakdown of the blood vessels that provide blood to the brain. Researchers are also looking for ways to prevent secondary injury to the brain by providing different types of neuroprotection for salvagable cells that prevent inflammation and block some of the toxic chemicals created by dying brain cells. From this research, scientists hope to develop neuroprotective agents to prevent secondary damage. For more information on excitotoxicity, neuroprotection, and the ischemic cascade, please refer to the Appendix.

Another area of research involves experiments with vasodilators, medications that expand or dilate blood vessels and thus increase blood flow to the brain. Vasodilators have long been used to treat many disorders, including heart disease. Researchers hope that vasodilators may aid in the rehabilitation of stroke victims by increasing blood flow to the brain. So far, unfortunately, they have shown limited success, possibly because they have not been given soon enough after the onset of stroke.

Basic research has also focused on the genetics of stroke and stroke risk factors. One area of research involving genetics is gene therapy. Gene therapy involves putting a gene for a desired protein in certain cells of the body. The inserted gene will then "program" the cell to produce the desired protein. If enough cells in the right areas produce enough protein, then the protein could be therapeutic. Scientists must find ways to deliver the therapeutic DNA to the appropriate cells and must learn how to deliver enough DNA to enough cells so that the tissues produce a therapeutic amount of protein. Gene therapy is in the very early stages of development and there are many problems to overcome, including learning how to penetrate the highly impermeable blood-brain barrier and how to halt the host's immune reaction to the virus that carries the gene to the cells. Some of the proteins used for stroke therapy could include neuroprotective proteins, anti-inflammatory proteins, and DNA/cellular repair proteins, among others.

The NINDS supports and conducts a wide variety of studies in animals, from genetics research on zebrafish to rehabilitation research on primates. Much of the Institute's animal research involves rodents, specifically mice and rats. For example, one study of hypertension and stroke uses rats that have been bred to be hypertensive and therefore stroke-prone. By studying stroke in rats, scientists hope to get a better picture of what might be happening in human stroke patients. Scientists can also use animal models to test promising therapeutic interventions for stroke. If a therapy proves to be beneficial to animals, then scientists can consider testing the therapy in human subjects.

One promising area of stroke animal research involves hibernation. The dramatic decrease of blood flow to the brain in hibernating animals is extensive - extensive enough that it would kill a non-hibernating animal. During hibernation, an animal's metabolism slows down, body temperature drops, and energy and oxygen requirements of brain cells decrease. If scientists can discover how animals hibernate without experiencing brain damage, then maybe they can discover ways to stop the brain damage associated with decreased blood flow in stroke patients. Other studies are looking at the role of hypothermia, or decreased body temperature, on metabolism and neuroprotection.

Both hibernation and hypothermia have a relationship to hypoxia and edema. Hypoxia, or anoxia, occurs when there is not enough oxygen available for brain cells to function properly. Since brain cells require large amounts of oxygen for energy requirements, they are especially vulnerable to hypoxia. Edema occurs when the chemical balance of brain tissue is disturbed and water or fluids flow into the brain cells, making them swell and burst, releasing their toxic contents into the surrounding tissues. Edema is one cause of general brain tissue swelling and contributes to the secondary injury associated with stroke.

The basic and animal studies discussed above do not involve people and fall under the category of preclinical research; clinical research involves people. One area of investigation that has made the transition from animal models to clinical research is the study of the mechanisms underlying brain plasticity and the neuronal rewiring that occurs after a stroke.

New advances in imaging and rehabilitation have shown that the brain can compensate for function lost as a result of stroke. When cells in an area of the brain responsible for a particular function die after a stroke, the patient becomes unable to perform that function. For example, a stroke patient with an infarct in the area of the brain responsible for facial recognition becomes unable to recognize faces, a syndrome called facial agnosia. But, in time, the person may come to recognize faces again, even though the area of the brain originally programmed to perform that function remains dead. The plasticity of the brain and the rewiring of the neural connections make it possible for one part of the brain to change functions and take up the more important functions of a disabled part. This rewiring of the brain and restoration of function, which the brain tries to do automatically, can be helped with therapy. Scientists are working to develop new and better ways to help the brain repair itself to restore important functions to the stroke patient.

One example of a therapy resulting from this research is the use of transcranial magnetic stimulation (TMS) in stroke rehabilitation. Some evidence suggests that TMS, in which a small magnetic current is delivered to an area of the brain, may possibly increase brain plasticity and speed up recovery of function after a stroke. The TMS device is a small coil which is held outside of the head, over the part of the brain needing stimulation. Currently, several studies at the NINDS are testing whether TMS has any value in increasing motor function and improving functional recovery.

Clinical Trials
Clinical research is usually conducted in a series of trials that become progressively larger. A phase I clinical trial is directly built upon the lessons learned from basic and animal research and is used to test the safety of therapy for a particular disease and to estimate possible efficacy in a few human subjects. A phase II clinical trial usually involves many subjects at several different centers and is used to test safety and possible efficacy on a broader scale, to test different dosing for medications or to perfect techniques for surgery, and to determine the best methodology and outcome measures for the bigger phase III clinical trial to come.

A phase III clinical trial is the largest endeavor in clinical research. This type of trial often involves many centers and many subjects. The trial usually has two patient groups who receive different treatments, but all other standard care is the same and represents the best care available. The trial may compare two treatments, or, if there is only one treatment to test, patients who do not receive the test therapy receive instead a placebo. The patients are told that the additional treatment they are receiving may be either the active treatment or a placebo. Many phase III trials are called double-blind, randomized clinical trials. Double-blind means that neither the subjects nor the doctors and nurses who are treating the subjects and determining the response to the therapy know which treatment a subject receives. Randomization refers to the placing of subjects into one of the treatment groups in a way that can't be predicted by the patients or investigators. These clinical trials usually involve many investigators and take many years to complete. The hypothesis and methods of the trial are very precise and well thought out. Clinical trial designs, as well as the concepts of blinding and randomization, have developed over years of experimentation, trial, and error. At the present time, researchers are developing new designs to maximize the opportunity for all subjects to receive therapy.

Most treatments for general use come out of phase III clinical trials. After one or more phase III trials are finished, and if the results are positive for the treatment, the investigators can petition the FDA for government approval to use the drug or procedure to treat patients. Once the treatment is approved by the FDA, it can be used by qualified doctors throughout the country. The back packet of this brochure contains cards with information on some of the many stroke clinical trials the NINDS supports or has completed.

NINDS-Sponsored Stroke Clinical Trials: April 2004

Clinical trials give researchers a way to test new treatments in human subjects. Clinical trials test surgical devices and procedures, medications, rehabilitation therapies, and lifestyle and psychosocial interventions to determine how safe and effective they are and to establish the proper amount or level of treatment. Because of their scope and the need for careful analysis of data and outcomes, clinical trials are usually conducted in three phases and can take several years or more to complete.

• Phase I clinical trials are small (involving fewer than 100 people) and are designed to define side effects and tolerance of the medication or therapy.
• Phase II trials are conducted with a larger group of subjects and seek to measure the effects of a therapy and establish its proper dosage or level of treatment.
• Phase III trials often involve hundreds (sometimes thousands) of volunteer patients who are assigned to treatment and non-treatment groups to test how well the treatment works and how safe it is at the recommended dosage or level of therapy. Many of these trials use a controlled, randomized, double-blind study design. This means that patients are randomly assigned to groups and neither the subject nor the study staff knows to which group a patient belongs. Phase III randomized clinical trials are often called the gold standard of clinical trials.

NINDS conducts clinical trials at the NIH Clinical Center and also provides funding for clinical trials at hospitals and universities across the United States and Canada. Below are findings from some of the largest and most significant recent clinical trials, as well as summaries of some of the most promising clinical trials in progress.

Findings From Recently Completed Clinical Trials

Warfarin vs. Aspirin Recurrent Stroke Study (WARSS)
WARSS was a 7-year double-blind randomized clinical trial that enrolled more than 200 patients at 48 participating centers. It was the largest clinical trial ever to compare the benefits of aspirin to warfarin for the prevention of recurrent stroke. Findings from the study were published in the The New England Journal of Medicine (November 15, 2001), which showed that aspirin works as well as warfarin in helping to prevent recurrent strokes in most patients. Whether warfarin was superior to aspirin for stroke prevention was unclear prior to WARSS. Most clinicians believed that warfarin was a better blood thinner than aspirin, although it had three drawbacks: it was more expensive, it required monthly blood tests for proper monitoring, and it had a greater risk for side effects. The WARSS trial demonstrated that aspirin was not only cheaper and safer than warfarin for preventing stroke, it was just as effective – without the additional costs of monthly monitoring.

African-American Antiplatelet Stroke Prevention Study (AAASPS)
The AAASPS study was a randomized double-blind trial that enrolled 1,800 African-American stroke patients at more than 60 sites to compare the benefits of ticlopidine to aspirin in preventing recurrent stroke. A previous clinical trial of ticlopidine had indicated that the antiplatelet drug might be particularly effective for stroke reduction among non-whites, primarily African-Americans. The trial ended early when data analysis suggested that there was less than a 1 percent chance that ticlopidine would be shown to be superior to aspirin if the study were carried to completion. Results showed that 650 mg of aspirin per day is just as effective as ticlopidine in preventing recurrent stroke and has the added benefit of easy availability, lower cost, and less risk for side effects. The findings were published in the Journal of the American Medical Association (June 11, 2003).

Ongoing Clinical Trials

The Family Intervention in Recovery from Stroke Trial (FIRST)
This study is testing whether or not the daily involvement and support of family, friends, and neighbors can improve the functional abilities of elderly stroke patients. An intervention has been designed to mobilize the social networks of stroke patients to provide effective emotional and practical support. Close to 300 patients from two large city hospitals have been randomly assigned to two groups: one that receives the intervention, and one that receives the usual care. At 3 months and 6 months, members of each group are being assessed for functional ability based both on how well they think they are doing as well as their performance on tests that measure functional abilities. A number of previous studies have indicated that psychosocial interventions can improve emotional adjustment in stroke patients and promote longer survival rates in patients with chronic illnesses. This is the first study to focus specifically on the impact of such psychosocial interventions on physical function in stroke survivors.

The Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST)
The use of dilation and stenting techniques similar to those used to unclog and open heart arteries has been proposed as a less invasive alternative to carotid endarterectomy (a surgical procedure that opens and widens blocked carotid arteries on either side of the neck). This trial is comparing the two techniques for safety and effectiveness. The standard carotid endarterectomy surgical procedure is being used on one set of patients. A procedure that inserts an expanding metal scaffold (stent) into the neck artery after widening it with balloon dilation is being tested on another group. If stenting is shown to be safe, effective, and durable, this less invasive procedure is likely to have a wider application in medical practice. A small add-on study to CREST is using genetic sampling and screening techniques to identify specific genes that could increase the risk for stroke.

Warfarin vs. Aspirin for Intracranial Arterial Stenosis (WASID)
The goal of this trial is to compare the effectiveness of warfarin to aspirin in preventing subsequent strokes or other vascular-related events, such as heart attacks, in patients with clogged arteries in the brain (intracranial arterial stenosis). This is a randomized multicenter trial that is following two groups of patients who have had a transient ischemic attack (TIA, commonly called a mini-stroke), or a minor stroke caused by blocked or narrowed arteries in the brain. One group is receiving warfarin; the other is taking aspirin. Patients are being followed for 4 years to compare the rates of death due to stroke and vascular-related diseases. This study hopes to show which treatment is better for patients with intracranial arterial stenosis.

Extremity Constraint-Induced Therapy Evaluation (EXCITE)
Impaired movement in the arms and legs is a major consequence of stroke. Therapeutic interventions to improve motor function and promote independent use of arms and hands are limited. One technique that has been shown to be successful in basic research studies with animal and human subjects is constraint-induced (CI) movement therapy (also called forced use). The CI technique involves restriction of the less affected arm, while the more affected arm is forced to perform repetitive motions. This trial has randomized stroke patients with at least minimal ability in their arms to two groups – one that receives customary care and one that receives CI therapy. A year after the trial begins, the customary care group will cross over to also receive CI therapy, in order to test whether or not delayed therapy can be effective. Changes in both groups in terms of increased motor function and psychosocial function will be measured.

Secondary Prevention of Small Subcortical Strokes (S