Stroke:

Challenges, Progress, and Promise

February 2009 National Institute of Neurological Disorders and Stroke National Institutes of Health Contents

older people, it can occur in individuals of any age, including young adults, children, infants, and Introduction ______1 Introduction fetuses in the womb.

Fortunately, the prospects for preventing and 1 treating stroke are far better than they were just Stroke Basics ______3 a few decades ago, thanks in part to research Ischemic Stroke and Transient Ischemic Attack ______3 supported by the NIH’s National Institute of Hemorrhagic Stroke ______5 Neurological Disorders and Stroke (NINDS).

Vascular Cognitive Impairment ______6 NINDS-funded investigators have identified many risk factors for stroke, such as hypertension (high blood pressure), arming people with the ability to reduce their risk through lifestyle changes or medication. 2 Stroke Diagnostics and Brain Imaging ______7 Clinical trials supported by NINDS also led to the only drug approved by the Food and Drug Administration specifically for treating acute ischemic stroke—the “clot-buster” tPA. When given 3 Chances are within three hours of stroke onset, the drug significantly Stroke Risk Factors______9 reduces the likelihood of long-term disability. Unmodifiable Risk Factors ______9 that nearly everyone...

Modifiable Risk Factors______10 ...reading this has already had an unwelcome Current NINDS priorities in stroke research are set introduction to stroke, perhaps through by its Stroke Progress Review Group (SPRG), firsthand experience or by witnessing its effects an advisory body made up of scientists, clinicians, patient advocates, and industry representatives. 4 on a relative. Research sponsored by the National Current Stroke Treatment and Prevention ______14 Institutes of Health (NIH) shows that about one One such priority is to develop new and more

Medications ______14 in six Americans will experience a stroke at some effective treatments for acute stroke. NINDS is point after age 65. Stroke is fatal in about 10 to supporting research on novel ways to restore Surgeries and Other Procedures ______17 20 percent of cases and, among survivors, it can blood flow to the ischemic brain, as well as Rehabilitation ______19 cause a host of disabilities, including loss of mobility, treatments that would act directly on brain cells to impaired speech, and cognitive problems. These protect them from the effects of stroke.

trends have made stroke the third leading cause Another priority is to improve post-stroke recovery

5 of death in the U.S. (behind heart disease and by tapping into the brain’s capacity to repair Research and Hope for the Future ______20 cancer) and a major cause of disability. itself; for example, by using drugs to stimulate Prevention ______20 the growth of new brain cells or physical therapy A stroke is a sudden event affecting the brain’s regimens to stimulate the re-wiring of existing cells. Acute Stroke and Post-Stroke Therapy ______23 blood supply. In an ischemic stroke, a blood Finally, stroke prevention and the identification of Neuroprotection ______25 vessel that supplies the brain becomes blocked. stroke risk factors remain important parts of the In a hemorrhagic stroke, a blood vessel in the NINDS portfolio. brain bursts. Although stroke is most common in 6 Changing Stroke’s Impact by Changing Attitudes ______32

Stroke: Challenges, Progress, and Promise 1 The long-term outcomes after a stroke vary considerably and depend partly on the type of stroke and the age of the affected person. 1. Stroke Although most stroke survivors regain their functional independence, 15 to 30 percent will have a permanent physical disability. Some will basics experience a permanent decline in cognitive function known as post-stroke or vascular dementia. Unfortunately, many stroke survivors face a danger of recurrent stroke in the future. About 20 percent of people who experience a first-ever stroke between ages 40 and 69 will have another stroke within five years. Finding treatments to help prevent stroke in this high-risk group is a major focus of NINDS-supported research.

An ischemic stroke occurs when a blood ve sel A hemorrhagic stroke occurs when a blood vessel supplying the brain becomes blocked, as by a clot. bursts, leaking blood into the brain. Ischemic Stroke and Transient Ischemic Attack he effects of stroke manifest themselves rapidly. Ischemic strokes make up about 80 percent NINDS supports several complementary treatments in animal models. Finally, NINDS T The five most common symptoms of stroke are: of all strokes. Just as a heart attack occurs networks of research centers aimed at outreach programs help bridge research and when there is insufficient blood flow to the improving treatment and care for individuals practice by educating individuals, their loved n Sudden weakness or numbness of the face or heart, an ischemic stroke (sometimes called with acute stroke. The Specialized Program ones, and healthcare providers about the latest limbs, especially on one side of the body. a “brain attack”) occurs when there is a sudden of Translational Research in Acute Stroke advances in treatment and prevention. n S udden confusion or difficulty speaking or interruption in blood flow to one or more (SPOTRIAS) helps move experimental therapies understanding speech. regions of the brain. Like all cells in the body, for acute stroke from the lab into early-phase neurons and other brain cells require oxygen clinical studies. SPOTRIAS sites are located n Sudden trouble seeing in one or both eyes. and glucose delivered through the blood in at major academic medical centers across n Sudden trouble walking, dizziness, or loss of order to function and survive. A few minutes of the country, where scientists studying the NINDS is supporting balance or coordination. oxygen deprivation—called ischemia—is enough molecular and cellular mechanisms of stroke research on novel ways to to kill millions of neurons. Moreover, ischemia can work closely with clinicians who have n S udden severe headache with no known cause. can provoke inflammation, swelling (edema), expertise in acute stroke care. The Neurological restore blood flow to the and other processes that can continue to cause Emergencies Treatment Trials (NETT) network The exact symptoms depend on where in the ischemic brain, as well as damage for hours to days after the initial insult. creates a similar collaborative framework among treatments that would act directly brain’s vascular system the blockage or rupture neurologists, neurosurgeons, and emergency has occurred. Strokes that predominantly affect Obstructive blood clots are the most common medicine physicians to facilitate clinical trials one hemisphere of the brain are common. Since on brain cells to protect them cause of ischemic stroke. Clotting (or coagulation) on stroke in the emergency room. Meanwhile, each hemisphere controls the opposite side of from the effects of stroke. is a vital function that helps prevent bleeding through the Stroke Preclinical Trials Consortia, the body, a stroke in the left hemisphere will when a blood vessel is damaged, but clots can NINDS is forging collaboration among cause motor and sensory deficits on the right side also obstruct normal blood flow. When a clot investigators who are testing potential stroke of the body, and vice versa. forms in association with the wall of a blood

2Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 3 Cerebral Amyloid Angiopathy

Immediately after an ischemic stroke, the brain about these treatments, see the chart on p. 10 Cerebral amyloid angiopathy (CAA) refers to a usually contains an irreversibly damaged core and “Current Stroke Treatment and Prevention” buildup of protein deposits known as amyloid Medical Terms for Common of tissue and an area of viable but at-risk tissue on p. 14.) on the inside wall of blood vessels. It is a major Stroke Symptoms and Disabilities called the ischemic penumbra. Restoring contributing factor to intracerebral hemorrhage normal blood flow—a process known as Hemorrhagic Stroke Hemiplegia: paralysis on one side of the body. reperfusion—is essential to rescuing the in older people and is sometimes associated with penumbra. The longer reperfusion is delayed, An intracerebral hemorrhage occurs when small ischemic infarctions and vascular cognitive Hemiparesis: weakness on one side of the body. the more cells in the penumbra will die. The a blood vessel ruptures within the brain. impairment. region of brain tissue that is finally damaged is Several conditions can render blood vessels in the brain prone to rupture and bleeding. Hemineglect: lack of awareness of one side of called an infarct. CAA is regarded as a disease of aging. It is rarely Chronic hypertension and a condition known the body or one side of the visual field. observed in individuals under age 50, but is If a stroke were a storm, a transient ischemic as cerebral amyloid angiopathy can weaken the seen in about 50 percent of individuals over age attack (TIA), or “mini-stroke,” would be an blood vessel wall. Poor blood clotting ability Dysphagia: difficulty swallowing. 90. The proportion of intracerebral hemorrhage ominous thunderclap. Symptoms of a TIA due to blood disorders or blood-thinning cases in older people that are causally linked to are similar to those of a full-blown stroke but medications like warfarin further increase Dysarthria: difficulty talking, caused by resolve within 24 hours, typically in less than one the risk of bleeding. Finally, structural CAA is unclear, but recent estimates place that facial weakness. hour. Still, the short-lived nature of TIAs does abnormalities that can form in blood vessels number as high as 50 percent. not mean that they leave the brain unharmed. during brain development also a play a role. Aphasia: difficulty speaking or understanding speech, In about 40 to 50 percent of people who have For instance, an arteriovenous malformation The buildup of amyloid inside blood vessels caused by damage to the brain’s language centers. experienced a TIA, a tiny dot of infarct can be (AVM) is a tangled mass of thin-walled cerebral weakens the vessel wall and may lead to blood vessels in the brain. AVMs are thought to seen by brain imaging. blood vessel rupture. In recent years, a be present from birth in one percent or less of poorly understood connection has emerged Even when there is no sign of brain infarction, the population. between CAA and Alzheimer’s disease. vessel and grows large enough to impair blood a TIA is both a warning and an opportunity flow, it is called a thrombus; a clot that breaks Beta-amyloid—the toxic protein fragment that for intervention. While someone who has aneurysm off the vessel wall and travels through the blood experienced a full-blown stroke has a two to accumulates in clumps (called plaques) within is an embolus. A cardioembolic stroke is seven percent risk of having another stroke the brain tissue of people with Alzheimer’s caused by a clot that originates in the heart. within the next 90 days; the 90-day risk of stroke disease—is a component of the amyloid Cardiac emboli are most likely to form in people following a TIA is 10 to 20 percent. In many deposits found in people with CAA. Moreover, with heart conditions such as atrial fibrillation cases, TIAs may be caused by an unstable clot Alzheimer’s disease and CAA share similar (AF, an irregular heartbeat), heart failure, stenosis, that could create a more permanent blockage genetic risk factors, such as the gene encoding or infections within the valves of the heart. within the brain’s blood supply at any moment. They may also occur post-heart attack. Fortunately, there are a variety of treatments apolipoprotein E (APOE). A variant of this that can reduce the risk of stroke following gene known as e4 increases the risk of Another contributor to ischemic stroke is chronic a TIA, including medications to lower blood Alzheimer’s disease and the risk of recurrent atherosclerosis, which is a buildup of fatty deposits pressure and inhibit blood clotting. If necessary, arteriovenous intracerebral hemorrhage. and cellular debris (plaque) on the inside of the surgical procedures can clear away plaque in the malformation blood vessel wall. As atherosclerotic plaques arteries that supply the brain, or a procedure grow, they cause narrowing of the blood vessel called stenting can be used to widen the arteries. An aneurysm is a bulge in a blood vessel and an (a condition called stenosis). Atherosclerosis can also Severe strokes could be avoided if more people arteriovenous malformation is a tangled mass activate cells involved in clotting. sought medical attention after a TIA. (For more of thin-walled vessels. Both of these structures are associated with a risk of hemorrhagic stroke.

4Curing Epilepsy: The Promise of Research Stroke:Curing Epilepsy:Challenges, The Pr Promiogress,se and of Research Promise 5 A subarachnoid hemorrhage is the rupture of Unlike other tissues in the body, neural tissue differentiate ischemic from hemorrhagic stroke, a blood vessel located within the subarachnoid normally is shielded from direct contact identify which blood vessels have been damaged, space—a fluid-filled space between layers of with blood by the blood-brain barrier, which and determine the extent and location of the infarct. connective tissue (meninges) that surround is a tightly sealed network of cellular and 2. Stroke the brain. The first sign of a subarachnoid extracellular components that lines blood Computed tomography (CT) and magnetic hemorrhage is typically a severe headache vessels in the brain. The blood-brain barrier resonance imaging (MRI) are the two most with a split-second onset and no known cause. is permeable to oxygen and other nutrients in Diagnostics common imaging techniques used to identify Neurologists call this a thunderclap headache the blood, but generally impermeable to red infarctions caused by stroke. CT uses X-ray and it demands immediate medical attention. and white blood cells, and large molecules. and brain beams passed through the head at multiple angles The rupture may occur in an AVM, but typically During a hemorrhagic stroke, these cells and to generate high-resolution brain images. It is it occurs at a site where a blood vessel has molecules are released en masse into the faster, more widely available, and less expensive weakened and bulged, called an aneurysm. delicate environment that surrounds neurons. Imaging than MRI. Aneurysms affect as much as one percent of Meanwhile, the accumulation of blood, known the population, and are sometimes hereditary. as a hematoma, can cause an increase in MRI, which does not involve X-rays, exposes the NINDS-funded studies have shown that the risk intracranial pressure that further impairs brain to a magnetic field in combination with a that an aneurysm will rupture is related to its normal blood flow and damages the brain radio wave pulse. The brain’s absorption of this size and shape, its location, and the person’s age. by compression. pulse and the rate at which energy is released The risk is increased by smoking. Information about when the pulse ends varies in different brain these risks helps doctors advise individuals on whether Vascular Cognitive tissues and yields an image. Diffusion-weighted an asymptomatic aneurysm should be treated. imaging (DWI) is a highly sensitive type of MRI Impairment hen a stroke is suspected, a physician that measures the diffusion of water in brain will carry out a detailed assessment of the Even in the absence of a clinically obvious stroke W tissue, which changes during an ischemic stroke. individual’s signs and symptoms. One common or TIA, impaired blood flow in the brain may DWI is especially useful for detecting small assessment tool is the NIH Stroke Scale, eventually lead to vascular cognitive impairment infarcts and is superior to CT for diagnosing developed by NINDS. This is a checklist of (VCI). At one extreme, VCI includes vascular ischemic stroke. Research studies suggest that questions and tasks that scores an individual’s dementia, but it also refers to a gradual decline DWI in combination with a brain blood perfusion level of alertness and ability to communicate and in mental function caused by multiple strokes, study can be used to help identify the ischemic perform simple movements. Other common some silent, over time. It is often associated penumbra—brain tissue that is blood-starved, but diagnostic procedures include blood tests and an with a more diffuse small vessel disease, caused salvageable if blood flow can be restored quickly. electrocardiogram to check for cardiac abnormalities by narrowing of small-diameter blood vessels In many individuals, the extent of ischemic that might have contributed to the stroke. that supply limited territories within the brain. penumbra is related to the degree of diffusion- Clinically, VCI may resemble Alzheimer’s perfusion mismatch, which is a DWI signal that Brain imaging techniques play an important disease (AD) and many older individuals with occurs in brain tissue with normal water diffusion role in stroke diagnosis, in the evaluation of dementia meet the diagnostic criteria for both but abnormal blood flow. individuals with stroke for clinical trials, and, diseases. However, while AD primarily affects to a growing extent, assessment of stroke risk. memory, VCI appears to primarily affect the Several imaging techniques are used to examine Several imaging techniques can be used to brain’s executive function—the ability to plan cerebral blood vessels. These techniques can generate visual “slices” of the brain or even activities from getting dressed in the morning to reveal the site of blockage in an ischemic stroke three-dimensional reconstructions. This in-depth negotiating a business deal. or detect stenosis or vascular malformations (such Immediately after an ischemic stroke (top left), a core look at the brain helps to: rule out other potential as an aneurysm or AVM) that put a person at risk of irreversibly damaged brain tissue (red) is surrounded neurological conditions such as a brain tumor, by an area of viable but at-risk tissue called the for stroke. Angiography of the brain involves penumbra (green). Unless blood flow is restored quickly, the tissue within the penumbra will be lost (bottom right).

6Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 7 Unmodifiable Risk Factors

The risk of stroke varies by age, sex, race, and 3. Stroke risk even where we live. Although these risk factors are considered unmodifiable, they help inform Factors stroke prevention strategies at the individual and population levels.

Stroke and Age The effects of age on the cardiovascular system, combined with the insidious nature of other types of risk over the life span, make it a key risk factor for stroke. A major source of information about stroke risk is the Framingham Heart Study, which began tracking the cardiovascular health of some 5,000 individuals from the Framingham, Massachusetts area in 1948 and has since expanded to include their children. MRI scans are commonly used to check for damage to the brain and the brain’s vasculature in people suspected of having a stroke. The study, which receives primary support from iven that stroke is caused by blockage or NIH’s National Heart, Lung, and Blood Institute G rupture of a blood vessel, it should be no (NHLBI) and support for its stroke component imaging after a contrast agent that shows up dark surprise that similar modifiable risk factors from NINDS, has shown that the risk of stroke on a scan has been injected into a vein in the arm contribute to stroke and cardiovascular disease, doubles for each decade between the ages Brain imaging or leg, which yields a map of the brain’s blood vessels. including hypertension, smoking, diabetes, of 55 and 85. techniques play an important high cholesterol, and lack of physical activity. It is possible to dramatically reduce these risks Stroke in young adults is relatively infrequent, A procedurally similar technique called perfusion role in stroke diagnosis...and through healthier lifestyle choices or medications but it does happen. The Northern Manhattan imaging is sensitive for detecting abnormal to a growing extent, in the (such as blood pressure-lowering drugs). In fact, Study, supported by NINDS, found that, among blood flow in the brain. Doppler ultrasound since 1950, there has been about a 60 percent people living in that area in the mid-1990s, the assessment of stroke risk. Several involves passing high-frequency, inaudible sound decline in the mortality rate from stroke and a annual incidence of stroke was about two per waves into the neck or head. These sound waves imaging techniques can be used smaller but significant decline in the age-adjusted 10,000 among people age 20 to 44, and about bounce off of cells moving through the blood, annual incidence of stroke—the number of 56 per 10,000 among people ages 45 and older. to generate visual “slices” of the producing an image and providing information people who have a stroke each year, adjusted to This study and others in the U.S. have found that on how fast the blood is traveling. In general, brain or even three-dimensional account for the increasing age of the population. hemorrhagic and ischemic strokes tend to occur blood cells speed up as they move through a Many experts attribute these trends to increasing in roughly equal proportion in young people. reconstructions. narrow vessel. awareness and control of stroke risk factors. The increased risk of stroke that occurs with age (For quick facts about the most potent modifiable therefore appears to be mostly an increased risk stroke risk factors and ways to counteract them, of ischemic stroke. (Also see “Stroke in Infants see “Modifiable Risk Factors ” on p. 10.) and Children” on p. 11.)

8Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 9 Modifiable Risk Factors Stroke in Infants and Children abnormalities, head trauma, and blood- Risk factor How much it affects stroke risk Why it affects stroke risk What you can do Compared to stroke in the adult brain, stroke clotting disorders. An important risk factor Hypertension Hypertension causes a two- to Hypertension promotes blood pressure medications, for African American children is sickle cell four-fold increase in the risk of atherosclerosis and causes mechanical such as thiazide diuretics and in the young, growing brain is associated with stroke before age 80. after age damage to the walls of blood vessels. angiotensin-converting enzyme unique symptoms, risk factors, and outcomes— disease. Although sickle cell disease is known 80, the impact of hypertension (aCe) inhibitors, can reduce the for its effect on red blood cells—causing them declines and other risk factors risk of stroke by 30 to 40 percent. and with more uncertainty in all three of these become more important. early treatment is essential. areas. Although stroke is often considered a to take on a sickle shape—it can also cause a among older people with narrowing of cerebral arteries. A 1998 study of normal blood pressure, prior disease of aging, the risk of stroke in childhood mid-life hypertension increases is actually highest during the perinatal period, some 3,000 people with sickle cell disease found stroke risk up to 92 percent. that 11 percent experienced a stroke before age Guidelines from the Centers for which encompasses the last few months of fetal Disease Control and Prevention life and the first few weeks after birth. 20. Fortunately, that same year, a study funded recommend a target blood pressure by NHLBI showed that repeated transfusions to of less than 140/90 mm Hg. As in adults, the symptoms of stroke in infants replace sickled blood cells with normal blood Cigarette smoking Smoking causes about a two-fold Smoking promotes atherosclerosis Stroke risk decreases significantly cells reduced the risk of stroke by 92 percent. increase in the risk of ischemic and aneurysm formation, and two years after quitting smoking and children include headache, hemiplegia, and stroke and up to a four-fold increase stimulates blood clotting factors. and is at the level of nonsmokers hemiparesis. But very young children with stroke Yearly Doppler ultrasound imaging is recommended in the risk of hemorrhagic stroke. by five years. are more likely than adults to experience other for young children with sickle cell disease and, symptoms, such as seizures, breathing problems, if stenosis is found, repeated transfusions can or loss of consciousness. Because the incidence be used as a means of stroke prevention. Diabetes In terms of stroke and cardiovascular In diabetes, glucose is not blood pressure medications, of childhood stroke is relatively low, parents disease risk, having diabetes is the efficiently taken up by the body’s dietary changes, and weight loss Strokes during the perinatal period have been equivalent of aging 15 years. cells and accumulates in the blood can lower stroke risk. Controlling and doctors often mistakenly attribute these instead, where it can damage the blood sugar appears to reduce the symptoms to other causes, leading to delays in associated with premature birth, maternal vascular system. Hypertension risk of recurrent stroke. infections, maternal drug abuse, prior infertility is common among diabetics diagnosis. Moreover, the time of onset is usually and accounts for much of their unknown for strokes during the perinatal period. treatments, and maternal health conditions such increased stroke risk. as autoimmune disease and preeclampsia (a

Physical inactivity and Waist-to-hip ratio equal to or Obesity is associated with While no clinical studies have Investigators know less about the risk of potentially serious combination of hypertension obesity above the median (mid-value for hypertension, diabetes, tested the effects of exercise or childhood stroke than they know about the and kidney problems that affects about six the population) increases the risk and heart disease. weight loss on stroke risk, both percent of pregnant women). of ischemic stroke three-fold. tend to reduce hypertension and risk of adult stroke. However, well-documented boost cardiovascular health. risk factors include congenital (inborn) heart The outcome of stroke in the very young is difficult to predict. A stroke during fetal atrial fibrillation (aF) aF affects fewer than one percent aF refers to irregular contraction of Warfarin, a blood-thinning of people under age 60, but is the atrium—the chamber where medication, can reduce the risk of development may lead to cerebral palsy—a more prevalent in older people. blood enters the heart. aF can stroke in people with aF. People permanent problem with body movement and It is responsible for one in four lead to blood stagnation and under age 60 with aF and no other strokes after age 80, and is associated increased clotting. stroke risk factors may benefit from muscle coordination that appears in infancy or with high mortality and disability. aspirin. Importantly, pacemakers early childhood. A stroke that occurs during have no effect on the risk of stroke associated with aF. infancy or childhood can also cause permanent disability. Generally, outcomes are worse in Cholesterol imbalance High-density lipoprotein (HDL) LDL and HDL are needed to carry Clinical trials have shown that cholesterol is generally considered cholesterol (a fatty substance) cholesterol-lowering drugs known children under age one and in those who protective against ischemic stroke. through the blood (made up as statins reduce the risk of stroke. experience decreased consciousness or seizures. Low-density lipoprotein (LDL) mostly of water), and deliver it However, some studies point to cholesterol, when present in excess, to cells. because LDL delivers only a weak association between Fortunately, the developing brain is also known is considered harmful. cholesterol to cells throughout stroke and cholesterol, and there for its remarkable capacity to replace lost nerve the body, excess LDL can cause is speculation that statins reduce cholesterol to build up in blood stroke risk by acting through some cells and fix damaged connections between them. vessels, leading to atherosclerosis. unknown mechanism. Healthy areas of the brain are often still pliable HDL sends cholesterol to the liver enough to compensate for damaged areas. to be eliminated.

10 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 11 A child with serious deficits immediately after a occur during the first several weeks after delivery, have the highest stroke risk. Finally, the stroke can make an impressive recovery. suggesting that the drop in blood volume or the relatively high percentage of African Americans rapid hormonal changes following childbirth living in Stroke Belt states does not explain the Treatment of stroke in children presents unique also play a role. Pregnancy-related stroke is Stroke Belt’s existence, since Caucasians living challenges. Delays in diagnosis, which can be more likely to occur in women who experience there also have an increased risk of stroke. especially prolonged in cases of perinatal stroke, certain complications, such as infections or mean that valuable time is lost. Moreover, most preeclampsia, or who have other risk factors for With an eye toward improving stroke prevention treatments for acute stroke were developed stroke, such as hypertension or diabetes. in high-risk communities, NINDS is supporting based on studies in adults and the guidelines for two studies to confront these issues: the Reasons their use in children are still being refined. To Hormone replacement therapy (HRT) may for Geographic and Racial Differences in Stroke address some of these issues, NINDS and NIH’s ease the discomfort and the loss of bone (REGARDS) study and the Northern Manhattan National Institute of Child Health and Human density associated with menopause. It was once In the U.S., stroke mortality is unusually high in a cluster Study (NOMAS). Launched in 2003, REGARDS of Southeastern states known as the Stroke Belt. In the Development (NICHD) sponsored a workshop considered a possible means of stroke prevention has enrolled more than 30,000 participants Belt’s “buckle” (gold), stroke mortality may be double the on perinatal stroke in August 2006 that brought in post-menopausal women. However, a series national average. (including 12,000 African Americans), with together experts in pediatrics, neurology, of placebo-controlled clinical trials sponsored half of the participants coming from the Stroke cardiology, and public health. Goals set by this by NINDS and NHLBI has shown that HRT Stroke is a global health problem. In some Belt and half from the 40 other mainland states. group include the development and testing increases the risk of stroke. NHLBI’s Women’s Eastern European countries and in the Far East, REGARDS investigators have found that, in of new therapies for perinatal stroke, a better Health Initiative showed that treatment with the stroke rates are much higher than in the U.S. individuals with hypertension, awareness and understanding of the risk factors for it, and hormones estrogen and progestin increased the Within the U.S., stroke mortality is unusually treatment of it is more common in African improved brain imaging methods to diagnose it. risk of stroke by 31 percent in women with an high in people living in a cluster of Southeastern Americans, but that effective treatment—lowering intact uterus. In women who had undergone states—Alabama, Arkansas, Georgia, Louisiana, blood pressure to the normal range—is more Stroke in Adults a hysterectomy, treatment with estrogen alone Mississippi, North Carolina, South Carolina, common in Caucasians. They have also found and Tennessee—known as the “Stroke Belt.” A evidence that strokes are more likely to occur From ages 55 to 75, the annual incidence and increased the risk of stroke by 39 percent. recent study funded by NIH’s National Institute without diagnosis in African Americans than in short-term risk of stroke are higher in men than The NINDS Women’s Estrogen for Stroke Trial on Aging suggests that the “belt” is worn from Caucasians, and in Stroke Belt residents than in in women. However, because women generally (WEST) found that women who had experienced childhood. That is, people who lived in the non-residents. Thus, a lack of awareness about live longer than men, their lifetime risk of stroke a prior ischemic stroke and received estrogen Stroke Belt during grade school but later moved stroke and a failure to intervene at the first signs is higher and they account for a larger fraction were more likely to have a fatal recurrent stroke. away had the elevated stroke risk characteristic of of disease may explain the high stroke mortality (about 61 percent) of stroke deaths each year. Stroke Across Races and Regions the area, while people who moved to the Stroke of certain groups. Belt as adults did not have an elevated stroke risk. Women have unique stroke risks associated People from certain ethnic groups have a higher Launched in 1990, the NOMAS study has been with pregnancy and menopause. In women of risk of stroke. Many studies show that the Although clearly influenced by differences in tracking stroke incidence, risk factors, and childbearing age, the risk of stroke is relatively age-adjusted incidence of stroke is about twice the prevalence of known stroke risk factors, the outcomes in Northern Manhattan, where about low (with an annual incidence of one in 10,000), as high in African Americans and Hispanic basis for these ethnic and geographic trends 60 percent of residents now identify themselves but a recent study estimates that pregnancy Americans as in Caucasians. Moreover, several is not fully understood. For example, higher as Hispanic and 15 percent identify as African increases that risk three-fold. studies have found that, on average, African and rates of hypertension and diabetes explain some, American. NOMAS investigators have found Hispanic Americans tend to experience stroke but not all, of the increased stroke risk among that AF has an especially high impact on Several factors contribute to the increased risk of at younger ages than Caucasians. The stroke African Americans and residents of the Stroke stroke risk in Caucasians, while a trend for stroke during pregnancy. The activity of blood mortality rate is higher in African Americans Belt. Socioeconomic disadvantages in income hypertension and diabetes has a higher impact clotting proteins is naturally amplified during than in Caucasians or Hispanics. The incidence and education level also appear to play a role. in Hispanics and African Americans. Physical pregnancy, increasing the chances of ischemic of the various stroke subtypes also varies However, within a given geographic area, the inactivity appears to be a strong risk factor in all stroke for the mother (and perhaps contributing considerably in different ethnic groups. most disadvantaged groups do not necessarily three ethnic groups. to perinatal stroke). Most maternal strokes

12 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 13 Thrombolytic Drugs leaking along the blood-brain barrier, it carries 1990s, individuals received aspirin, subcutaneous In treating acute ischemic stroke (acute meaning a risk of intracerebral hemorrhage. Therefore, heparin injections, or neither treatment within 48 that the stroke has occurred within the past few it is not recommended for some people, such hours of an ischemic stroke. Aspirin significantly 4. Current hours), the immediate goal is to break apart the as those with a history of brain hemorrhage or reduced the risk of a recurrent ischemic stroke offending clot, a process known as thrombolysis. significantly elevated blood pressure (greater at two weeks. A similar benefit from heparin The body produces its own thrombolytic proteins, than 185/110 mm Hg). The risk of tPA-induced was offset by an increased risk of hemorrhagic Stroke and some of these have been engineered into hemorrhage increases over time from stroke stroke. Around the same time, NINDS-funded drugs. One, called tissue plasminogen activator onset, which has limited its use to the first three researchers tested whether acute stroke could Treatment (tPA), had a proven track record for treating hours after stroke (where benefit was most clearly be treated with intravenous Org 10172, a form of heart attacks. In the late 1980s, NINDS-funded established in the U.S. trials). heparin considered less likely to cause bleeding. investigators laid the plans for the first placebo- This study, Trial of Org 10172 in Acute Stroke and controlled trial of tPA to treat acute ischemic Antiplatelet Drugs and Anticoagulants Treatment (TOAST), found that Org 10172 stroke. They knew from animal studies that produced no significant benefit. The study authors Blood-thinning medications fall into two irreversible brain injury is likely to occur if blood also developed the TOAST criteria, a set of guidelines Prevention classes: antiplatelet drugs and anticoagulants. flow is not restored within the first few hours after for classifying different subtypes of ischemic Antiplatelet drugs inhibit the activity of cells ischemic stroke. Therefore, the NINDS tPA Study stroke that are now widely used in other studies. called platelets, which stick to damaged areas Group tested the drug within a three-hour time inside blood vessels and lay the foundation for window. Compared to individuals given placebo, Another issue is whether individuals at risk blood clots. The most common antiplatelet those given intravenous tPA were more likely to for ischemic stroke should be placed on a drug is aspirin. Anticoagulants, such as heparin have minimal or no disability three months after daily maintenance program of aspirin or oday, there is a small but growing arsenal (produced by inflammatory cells in the body) and treatment—a finding that persuaded the U.S. anticoagulants. For many years, aspirin and of treatments that can markedly improve warfarin (found in plants and also known by the T Food and Drug Administration to approve tPA warfarin were used as a means of stroke the chances of recovering from a stroke. There is trade name Coumadin©), inhibit proteins in the for use against acute stroke. Trials in Europe and prevention in individuals with AF, but until also a wealth of knowledge about what causes stroke blood that stimulate clotting. the U.S. subsequently confirmed those results. recently, this practice was based more on and how to reduce the chances of having one. Recent studies attempt to identify individuals who anecdotal evidence than on scientific data. Antiplatelet drugs and anticoagulants can help may benefit even after three hours of stroke onset. A systematic analysis of warfarin’s benefits was prevent a variety of potentially life-threatening Medications In any case, more brain tissue will be saved the especially important since it is an expensive drug conditions for which individuals with stroke are earlier the treatment is delivered. at risk, such as myocardial infarction, pulmonary As described in the chart on p. 10 (Modifiable embolism, and deep vein thrombosis—which are Risk Factors), medicines that lower blood A 1998 follow-up analysis of the NINDS trial caused by clots in the heart, lungs and deep veins pressure and cholesterol can protect against found that, after their initial hospitalization, of the legs, respectively. In recent years, the value atherosclerosis and reduce a person’s risk of people who received tPA were less likely to of these drugs in treating and preventing stroke stroke. Aspirin and other blood-thinning require inpatient rehabilitation or nursing home itself has been more closely scrutinized. medications have been used for years to reduce care. The authors estimated that this lower the risk of ischemic stroke in individuals with dependency on long-term care would translate One focus of this research has been to determine AF or prior stroke. Recent studies have helped into a savings to the healthcare system of more if there is any benefit in giving antiplatelet refine the use of these drugs to maximize safety than $4 million for every 1,000 individuals drugs or anticoagulants during an acute and efficacy. This section, however, begins with a treated with tPA. ischemic stroke, as an adjunct to tPA, or as discussion of what happens when prevention fails an alternative for people ineligible to receive and a person requires emergency treatment for Because treatment with tPA interferes with blood Platelets (magnified here thousands of times) home to tPA. In an international trial coordinated by an acute ischemic stroke. clotting and has also been shown to increase damaged areas of blood vessels and contribute to the researchers in the United Kingdom in the late formation of clots. Antiplatelet drugs can help reduce the risk of ischemic stroke.

14 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 15 Robert, Jim, a 58 year-old a 74 year-old retiree… businessman…

…had just stepped inside after watering the lawn and, like heparin, is associated with an increased meaning that it works by blocking the entry of …was spending a Saturday morning preparing for when he suddenly felt odd. He tried to speak to risk of hemorrhagic stroke. The NINDS Boston calcium into cells. Nimodipine has been shown a church retreat, when he was struck by a headache his wife, Alma, but realized that he couldn’t. He held Area Anticoagulation Trial for Atrial Fibrillation to reduce infarction and improve outcome in and a strange feeling in his throat. Thinking maybe her hand and stared at her. He didn’t know what (BAATAF) and the Stroke Prevention in Atrial individuals with subarachnoid hemorrhage. he had strep throat, he asked his wife Judy to drive was happening to him, but fortunately, she did. Fibrillation (SPAF) trials showed that daily him to an urgent care center. He felt too drained to drive himself. warfarin is best for people with AF who are As an avid reader of health information, Alma over age 65 or who have additional vascular Surgeries and Other The urgent care doctor quickly recognized that Jim immediately recognized that Robert was having risk factors. Daily aspirin provides adequate Procedures a stroke. She dialed 911, and about 30 minutes was having a stroke, and sent the couple to the protection against stroke among young people later, Robert was in an emergency room. Doctors nearest emergency department. On the way, Jim’s with AF. Surgery is sometimes used to clear the congested quickly took pictures of Robert’s brain using a CT speech slurred, the right side of his face drooped, blood vessels that cause ischemic stroke or to scan and determined that his stroke was ischemic in and the limbs on his right side grew heavy. Two other NINDS-sponsored trials compared repair the vascular abnormalities that contribute nature. In other words, a clot was blocking the flow the effectiveness of daily warfarin and aspirin to hemorrhagic stroke. of blood to vital brain areas, including the speech At the hospital, a CT scan indicated damage to the for individuals who did not have AF, but who center. They also determined that Robert was a left side of Jim’s brainstem. This is the part of the had experienced a prior stroke—and thus were A surgery called carotid endarterectomy involves good candidate for tPA, a clot-busting drug that brain that connects to the spinal cord, so the CT removing plaque to widen the carotids, a pair of had been approved for use against acute ischemic at risk for another. The Warfarin vs. Aspirin findings fit with the weakness Jim had on the right arteries that ascend each side of the neck and are stroke by the Food and Drug Administration in 1996, Recurrent Stroke Study (WARSS) showed that side of his body. The stroke was caused by a blood just four years earlier. aspirin was as effective as warfarin in preventing the main suppliers of blood to the brain. Stenosis clot, but for medical reasons, Jim was not eligible recurrent stroke in people with no history of AF that narrows a carotid artery by more than 50 for the clot-busting drug tPA. While the doctors administered tPA intravenously, or other cardioembolic causes of stroke. The percent is considered clinically significant. In they asked Robert a series of simple questions to Warfarin-Aspirin Symptomatic Intracranial some cases, carotid stenosis is first detected after Jim stayed under observation in intensive care for test his ability to think and speak – questions like Disease (WASID) trial focused more narrowly on a person experiences a stroke or other symptoms, 3 days. When he was released, he could not walk “Do you know where you are?” and “Can you name individuals with stenosis of arteries in the brain such as a TIA. It is also sometimes detected in or use his right hand, so he spent a month at an your wife and children? Your grandchildren?” and was terminated early because of a high rate the absence of symptoms, as when a physician inpatient rehabilitation center, where he received At first, his speech continued to fail him, but after of adverse events in participants treated with presses a stethoscope to the neck and hears a physical and occupational therapy. When he left a few minutes, he was answering every question. warfarin. Both trials concluded that aspirin is bruit—a sound made by blood flowing past an the center, he had little function in his right hand, He was released from the hospital 6 days later, and equivalent to warfarin for reducing the risk of obstruction. The presence of carotid stenosis but he was able to walk with a four-pronged cane. after some speech therapy, he was soon reading to stroke in people without AF. can be confirmed by angiography or Doppler It has been more than 7 years since Jim’s stroke. his grandchildren again. ultrasound. Medication for Subarachnoid He exercises regularly and can walk unassisted, but he still has trouble with his right hand. By During Robert’s treatment and evaluation at the Hemorrhage Data from NINDS-funded research show that the hospital, doctors discovered that he had atrial participating in clinical research, he is receiving an The drug nimodipine is used to treat cerebral risk of ischemic stroke from clinically significant fibrillation (AF), which is an abnormal heart rhythm experimental treatment called constraint-induced vasospasm, a complication that sometimes follows asymptomatic carotid stenosis is about two to and a risk factor for stroke. He now takes warfarin, movement therapy. This involves wearing a large subarachnoid hemorrhage. This refers to a three percent per year (meaning that out of 100 a medication that inhibits blood clotting and has mitt that limits movement of his left hand, forcing individuals with this condition, two or three will proven effective for reducing the risk of stroke in constriction of blood vessels in the brain that him to use his right hand for daily activities. have a stroke each year). The risk of ischemic people with AF and other stroke risk factors. He can significantly reduce blood flow, leading to Researchers expect the therapy to be most effective stroke from clinically significant symptomatic hasn’t experienced any more strokes. ischemia and infarction. Although its precise within the first year after a stroke, but Jim has origins are unclear, cerebral vasospasm is thought carotid stenosis is much higher—about 25 noticed some improvement. Although writing and percent during the first two years following the Robert and Alma have seven grandchildren and one to be triggered in part by an influx of calcium eating remain easier with his left hand, he can do appearance of symptoms. great-granddaughter. Robert continues to enjoy into the smooth muscles that control blood vessel both with his right. He continues to be very active reading to the youngest ones. diameter. Nimodipine is a calcium antagonist, at church and in his community.

16 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 17 during the procedure can send emboli into Rehabilitation on one side of the body). It involves constant the bloodstream, or cause a clot at the site of restraint of the unaffected hand and arm with surgery. NINDS supports the investigation of an a mitt shaped like a boxing glove, so that the Stroke rehabilitation includes physical therapy alternative procedure known as carotid artery person is forced to use the affected hand and and other approaches intended to help stenting, which involves inserting a stent (a tube- arm for daily activities. Meanwhile, the person individuals achieve long-term recovery from like device that is made of mesh-like material) receives regular training sessions to exercise stroke. Physical therapy involves using exercises into the carotid artery. The stent is compressed the weakened arm. In the Extremity Constraint to restore movement and coordination. Many until the radiologist threads it into position, and Induced Therapy Evaluation (EXCITE) trial, people also receive occupational therapy, which is then expanded to mechanically widen the funded by NINDS and NICHD, individuals who focuses on improving daily activities such as artery. It is also equipped with a downstream experienced a hemiparetic stroke in the prior eating, drinking, dressing, bathing, reading, and “umbrella” to catch dislodged plaque. The three to nine months received either CIMT writing. Speech therapy may help people who Carotid Revascularization Endarterectomy vs. for just two weeks or customary care, ranging have problems producing or understanding Stenting Trial (CREST) is designed to compare from no treatment to standard physical therapy. speech. Finally, since depression, anxiety, and these two procedures in individuals with Those who received CIMT were more likely to social isolation are common among individuals symptomatic carotid stenosis. show improvement after one year, and much of who have had a stroke, the potential benefits of this improvement was sustained even after two psychological or psychiatric treatment should be Several techniques are used to eliminate the years. The Interdisciplinary Comprehensive considered. vascular abnormalities linked to hemorrhagic Arm Rehabilitation Evaluation (I-CARE) trial stroke, or at least to reduce the risk that they is testing the efficacy of CIMT combined with The carotid and vertebral arteries ascend through Importantly, the goal of rehabilitation is not the neck and divide into branches that supply blood will rupture. Arteriovenous malformations task-specific training and 30 hours of one-on-one to different parts of the brain. simply for the individual to cope with disability, (AVMs) can be surgically removed through a therapy within one to three months after a stroke. but to relearn skills that have been lost. This procedure known as surgical resection. They relearning is made possible by the brain’s NINDS-supported research has compared the can also be treated non-invasively (without the Another technique involves using a body weight- plasticity—its ability to reorganize itself by benefits of standard medical therapy alone need to cut into the skull) using radiosurgery supported treadmill (BWST) to help people forming new connections between neurons. (treatment with aspirin, blood pressure-lowering or embolization. Radiosurgery involves who have trouble walking. Individuals walk on a Plasticity soars in the developing brain and wanes drugs, and cholesterol-lowering drugs) with directing a beam of radiation at the AVM, while treadmill while being supported by an overhead as the brain matures, but even the aged brain standard medical therapy plus endarterectomy embolization involves injecting artificial emboli harness, which protects them from falling and appears to retain some plasticity and thus some for both types of carotid stenosis. The (usually made of foam) into the AVM to block it allows them to concentrate on coordination capacity to repair itself after a stroke. Asymptomatic Carotid Atherosclerosis Study off from its parent vessel. and speed. Recently, investigators have begun (ACAS) found that endarterectomy cut the to combine BWST training with “overground” Basic research on the brain has shown that the risk of stroke in half among individuals with Clipping and coiling are procedures used to training, where individuals immediately practice most active neural connections tend to become asymptomatic carotid stenosis of 60 percent treat intracerebral aneurysms. Clipping involves what they have learned on the treadmill by stronger while the quietest connections tend or greater. The NINDS North American opening the skull and placing a clip near the walking with assistance and encouragement to weaken until they disappear. Inspired by Symptomatic Carotid Endarterectomy Trial aneurysm, to separate it from its parent blood from a physical therapist. In the Locomotor these findings, researchers are testing a few (NASCET) found major benefits for individuals vessel. In endovascular coiling, a wire topped Experience Applied Post-Stroke (LEAPS) trial, innovative techniques that follow a “use it or lose with symptomatic carotid stenosis of 70 percent with a detachable coil is inserted into a leg artery NINDS-funded investigators will compare it” approach to stroke rehabilitation. or greater. Their risk of stroke over a two-year and threaded into the aneurysm. Once in place, outcomes at one year in people who receive either period was cut to less than 10 percent. the coil is released into the aneurysm, where it standard physical therapy or a program of BWST One technique, called constraint-induced stimulates blood clotting and strengthens the training plus overground training. movement therapy (CIMT), focuses on improving Endarterectomy itself is associated with a small blood vessel wall. Stents are also used in some upper limb function in people with stroke risk of stroke because the disruption of plaque cases to divert blood flow away from an aneurysm. who are affected by hemiparesis (weakening

18 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 19 NIH-Supported Resources for Human Genetic Research

association study, researchers scan the genome n The International HapMap is creating a catalog of SNPs and haplotypes (sets of associated of thousands of individuals, some who have a SNPs) in different populations. This catalog is disease and some who do not, to determine if expected to contain up to 10 million SNPs upon any SNPs are more common in people with 5. research completion, and is used by researchers to design the disease. genome-wide association studies.

and Hope n The NINDS Human Genetics Repository houses In 2003, researchers completed a genome-wide samples of DNA and cells that have been association study of stroke in Iceland, where donated by individuals for use in genetic studies. for the extensive genealogical records make it easier to trace genetic inheritance patterns. They n T he NIH Neuroscience Microarray Consortium reported that ischemic stroke was associated with Future provides researchers with services such as SNP variation in the phosphodiesterase-4D (PDE4D) genotyping and gene expression profiling gene. A recent study of about 500 American (examining when and where specific genes are women (funded in part by NINDS) found that active in the body). It is funded by the NIH some variations in PDE4D increase the risk of Neuroscience Blueprint, a joint effort among ischemic stroke in women ages 15-49, and that 16 subdivisions of NIH, including NINDS. the risk is further magnified by cigarette smoking. In other populations, researchers have failed to find a link between PDE4D and stroke.

cientists continue to investigate ways to subcortical infarcts and leukoencephalopathy More recently, researchers supported by NINDS better understand, diagnose, and treat stroke. (CADASIL) may offer clues to the mechanisms S found an association between intracranial Much of this research is conducted by the stroke behind ischemic stroke. Younger individuals aneurysms and SNPs located near genes on community at the NIH or through research grants with CADASIL typically experience migraine chromosomes 2, 8, and 9. The chromosome 9 to academic centers throughout the United States. that is accompanied by an increased sensitivity gene, Sox 17, was already known to be required to light or sound, while older people experience for proper development of blood vessels in TIAs and ischemic strokes. Researchers have laboratory animals, so it makes sense that this Prevention traced the disease to mutations in the Notch3 gene appears to affect the risk of aneurysm formation. gene, which encodes a protein on the surface of Clinical tests for variations in Sox 17 and other Genetic Risk Factors the smooth muscle cells that line blood vessels. genes might be used to predict a person’s risk of In an effort to make stroke prevention more Notch proteins, of which there are many, are developing an intracranial aneurysm. effective and more personalized, NINDS is also receptors for signals that guide cellular supporting research to identify additional risk movements during embryonic development. There is evidence that clinical testing for SNPs factors (including genetic factors) involved in Several researchers supported by NINDS are might be useful for guiding preventative care stroke. Several rare inherited disorders cause an studying Notch function in the adult brain. in people who are already known to be at risk unusual predisposition toward stroke. With an for stroke. For example, although it is known eye toward finding disease-specific treatments An alternative to studying rare genetic diseases that children and adults with sickle cell disease and gaining general insights into stroke, scientists that dramatically affect stroke risk is to search for are at high risk for stroke, it is not clear why have begun to hunt down the responsible genes. common genetic variations that have more subtle some people with the disease experience strokes effects—typically single-letter changes in the at an earlier age and with greater frequency. For instance, a rare disorder called cerebral DNA code (or genome) called single nucleotide Researchers supported in part by NINDS have autosomal dominant arteriopathy with polymorphisms (SNPs). In a genome-wide

20 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 21 Stroke Therapy Gets Cooler

Fever is a frequent complication of stroke and a predictor of poor outcome, so measures to Biomarkers Combination Therapies for bring body temperature to a normal level (about In recent years, other risk factors have emerged Stroke Prevention 37.5°C) are common in acute stroke care. Recently that might be more appropriately called Many people at risk for stroke take multiple though, scientists have begun to explore whether Several rare biomarkers. These are changes in the body (for preventative medications, including antiplatelet hypothermia (cooling the body below its normal inherited disorders cause an drugs, ACE inhibitors, and/or statins. In 2006, temperature) might have neuroprotective effects example, changes in blood chemistry or gene NINDS-supported researchers completed the against stroke. unusual predisposition toward expression) that indicate an ongoing disease first study to explore whether using these three stroke. With an eye toward process or a risk of disease but do not necessarily Many people have heard stories of children who play causative roles in the disease. drugs in combination is more beneficial than drowned in icy cold water and recovered with finding disease-specific using just one or two of them. The researchers surprisingly little neurological impairment. This examined the medication history and tracked treatments and gaining general In the late 1990s, for example, many studies recovery is possible (at least in part) in hypothermia the outcomes of more than 200 individuals (including the Framingham study) found because the brain slows its metabolic rate and insights into stroke, scientists who sought care within 24 hours of an ischemic an association between stroke and elevated consumes less energy. In the 1950s, scientists began stroke. Individuals taking all three drugs had have begun to hunt down the blood levels of homocysteine, a relative of the investigating whether controlled hypothermia strokes that were less severe, based on symptoms amino acids the body uses to make proteins. could prevent the neurological damage associated responsible genes. measured by the NIH Stroke Scale and on with severe cardiac arrest. Unfortunately, these Homocysteine levels tend to rise in people who MRI scans showing they had less at-risk tissue early studies tested extreme reductions in body consume inadequate amounts of the vitamins surrounding the damaged regions of their brains. temperature and found a high rate of dangerous B and B (folate), which are needed to convert 12 9 Individuals on triple therapy also had shorter side effects. In 2002, however, two studies showed homocysteine into useful amino acids. It is hospital stays and better function at hospital that mild to moderate hypothermia (32-36°C), which found several SNPs in different genes that modify unclear whether elevated homocysteine plays discharge. Although these data are preliminary, was induced with a cooling blanket in one study and the risk of stroke associated with sickle cell a causative role in stroke or is just an innocent ice packs in the other, led to improved neurological they highlight the possibility of improving stroke disease. Thus, testing for these SNPs could be bystander. The NINDS Vitamin Intervention for outcome after cardiac arrest. outcomes by targeting multiple risk factors. used to identify people with sickle cell disease Stroke Prevention (VISP) trial found that vitamin who are at highest risk for stroke, and to provide supplementation leading to modest reductions in Animal studies suggest that hypothermia not only them with early therapeutic intervention. homocysteine did not reduce the risk of recurrent helps the brain resist ischemia, but may directly Acute Stroke and inhibit other harmful reactions that occur during stroke over a two-year period. It remains possible Post-Stroke Therapy stroke, including excitotoxicity and reperfusion Finally, genetic testing might be useful for that B vitamin supplements are beneficial over a predicting how different people will respond to longer period or in people with no history of stroke. injury. A trial supported by the NINDS SPOTRIAS Better Thrombolysis in different stroke therapies. For example, because program will test whether hypothermia offers Ischemic Stroke enough protection against stroke to extend tPA’s people metabolize warfarin at different rates, it Researchers also have discovered several effective time window to six hours after onset. is difficult to determine optimal dosing of the biomarkers of advanced atherosclerosis that could Although tens of thousands of people benefit drug, which could cause severe bleeding if given be used to identify people in danger of stroke. from tPA each year, this represents only a small in excess. Traditionally, physicians have had to For example, elevated levels of two proteins in the fraction of people affected by ischemic stroke. The use of tPA is limited by concerns that it estimate the initial dose based on a formula that blood, C-reactive protein and phospholipase A2, includes the individual’s age, blood pressure, and are associated with atherosclerosis and increased could cause hemorrhage and many hospitals lack other factors, and then adjust the dose through risk of stroke. Irregularities in the appearance the infrastructure required to treat individuals trial and error. It is now known that certain of atherosclerotic plaques, observed by high- within tPA’s short window of efficacy. NINDS’ variants in two genes, CYP2C9 and VKORC1, resolution ultrasound, are also tied to higher professional outreach efforts are helping cause increased sensitivity to warfarin. Taking stroke risk. hospitals establish coordinated stroke care these variations into account and plugging them teams capable of rapidly delivering treatments, into the traditional formula appear to predict an including tPA if warranted (see “Changing optimal warfarin dosage with greater accuracy. Stroke’s Impact by Changing Attitudes,” p. 32).

22 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 23 evaluate the extent of salvageable penumbra to receive tPA received infrared laser light Controlling Blood Pressure and in each individual. Researchers suspect that applied over the scalp. Although its mechanism Blood Flow in Hemorrhagic Stroke individuals with larger areas of salvageable brain is unclear, the treatment improved functional Hemorrhagic stroke is usually accompanied by tissue might have a better chance of benefiting outcome when given within 24 hours of stroke onset. acute hypertension. Aggressive lowering of blood from therapy delivered after the three-hour mark. pressure is sometimes used in an attempt to Recently, the FDA approved two clot-removal reduce bleeding and hematoma volume, but its A strategy known as bridging therapy involves devices for use in treating acute ischemic stroke. value is unclear. In the NINDS Antihypertensive supplementing intravenous tPA (the standard The Penumbra System involves threading a Treatment in Acute Cerebral Hemorrhage means of tPA delivery) with intra-arterial catheter through cerebral blood vessels to (ATACH) trial, investigators are using the tPA injected directly at the site of the clot. the site of blockage and vacuuming out the drug nicardipine to lower blood pressure in The NINDS Interventional Management of clot. Meanwhile, MERCI (Mechanical Embolus individuals with acute intracerebral hemorrhage Stroke (IMS) study is comparing the effects Removal in Cerebral Ischemia) is a corkscrew- and acute hypertension. These individuals are of bridging therapy and standard intravenous like device that can be extended from the tip of being divided into three groups in order to test tPA for ischemic stroke. Another strategy is to a catheter and used to snare the clot and pull three target blood pressure levels. combine intravenous tPA with new generation it out. Although both devices are effective at anticoagulants and antiplatelet drugs. Clinical restoring blood flow when used within 8 hours of Just as anticoagulants are under study for studies coordinated by the NINDS SPOTRIAS stroke onset, no data yet exists to indicate if their treating acute ischemic stroke, drugs that Meanwhile, research efforts are underway to network are testing tPA in combination with use improves outcome. The NINDS Magnetic promote coagulation are being eyed for their reduce the risk of hemorrhage from tPA. For argatroban (which inhibits the blood clotting Resonance and Recanalization of Stroke Clots potential benefits against hemorrhagic stroke. example, NINDS-funded investigators are testing protein thrombin) and eptifibatide (which inhibits Using Embolectomy (MR RESCUE) trial is Recombinant activated factor VII (rFVIIa), a derivatives of tPA that may carry less risk of adhesion proteins on the surface of platelets). comparing MERCI to standard care within this modified version of a blood clotting factor, is hemorrhage. Another strategy is to tease apart time window. FDA-approved to treat excessive bleeding in tPA’s destructive effect on the blood-brain barrier Innovative strategies include mechanically hemophilia. In two industry-sponsored trials, and identify drugs that block this effect. Along disrupting the clot as either a supplement or rFVIIa significantly reduced hematoma volume those lines, NINDS-funded studies have shown an alternative to tPA. Doppler ultrasound, the 24 hours after hemorrhagic stroke, but in one trial that proteins called matrix metalloproteinases same technique used to image blood vessels it failed to significantly reduce mortality at 90 days. (MMPs) degrade the blood-brain barrier during and locate a clot, is being tested as a means an acute stroke, and that treatment with tPA of delivering sound waves capable of breaking appears to enhance MMP activity. NINDS- apart the clot. The NINDS Combined Lysis of Neuroprotection funded investigators have found that tPA also An interruption Thrombus in Brain Ischemia with Transcranial increases blood-brain barrier permeability by in the brain’s blood supply leads Ultrasound and Systemic TPA (CLOTBUST) While some stroke treatments are aimed at acting through a protein called platelet-derived study was a small trial that compared tPA plus to a cascade of harmful reactions correcting the vascular problems that cause growth factor-CC (PDGF-CC). They showed that ultrasound to tPA plus placebo. Results showed that may continue for hours to stroke, another strategy, called neuroprotection, Gleevec©, a drug already approved for treating that individuals who received tPA plus continuous aims to shield neurons from the effects of stroke. certain cancers, blocked PDGF-CC signaling and days, even after blood flow has ultrasound were more likely to experience An interruption in the brain’s blood supply leads reduced hemorrhage in mice treated with tPA complete restoration of blood flow by two hours been restored. to a cascade of harmful reactions—mostly in after ischemic stroke. after the start of the procedure. In addition to the ischemic penumbra—that may continue for sound energy, researchers have also tested light hours to days, even after blood flow has been Research is also underway to enhance tPA’s clot- energy against acute ischemic stroke. In the restored. The most important reactions are busting effects and extend its window of efficacy placebo-controlled NeuroThera Effectiveness and excitotoxicity, reperfusion injury, and breakdown beyond three hours. To that end, many clinical Safety Trial (NEST-1), people who were ineligible trials now include brain imaging protocols to

24 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 25 Meanwhile, if blood flow is successfully restored of the blood-brain barrier. In recent years, to eliminate drug side effects or changing the after an acute stroke, the reintroduction of thanks to an improved understanding of how protocol for drug delivery. As in the case of tPA, oxygen to energy-starved tissues can lead these reactions unfold, researchers have begun to there are strong indications that timing could to reperfusion injury. This refers to a burst develop and test many neuroprotectant drugs. mean everything for many neuroprotectant drugs. in oxygen-containing free radicals that are produced when damaged mitochondria suddenly Still, research on neuroprotectant drugs Excitotoxicity and Reperfusion Injury resume taking up oxygen to produce ATP. remains at a relatively early stage. Studies using To understand how just a few moments of animal models of stroke (mostly rodents) are ischemia can lead to a cascade of damaging essential to this research, just as they were for Antioxidants, which neutralize oxygen-based events in the brain, it is necessary to know the development of tPA. In two common animal free radicals, may have beneficial effects against something about how neurons extract models of ischemic stroke, a string or suture both excitotoxicity and reperfusion injury. energy from oxygen and glucose. Essential is used to occlude either the carotid artery or NINDS is supporting research to determine if to energy production in all our cells are the the middle cerebral artery (a branch off of the individuals with acute ischemic stroke benefit mitochondria—cellular factories that use oxygen carotid). These techniques allow researchers from intravenous albumin, a blood protein with to break down glucose and convert it into the energy to carefully monitor the timing of post-stroke antioxidant properties. A pilot trial involving molecule ATP. During ischemia, mitochondrial changes in the brain and to carefully plan the 80 individuals showed that albumin is safe when production of ATP runs down and neurons lose timing of therapeutic intervention. Several given within 16 hours of stroke. Results also control over the internal machinery that allows possible neuroprotectants have shown positive showed that individuals treated with tPA tended them to generate electrical and chemical signals. results when tested in an animal model, only to to have better outcomes if they also received high- yield negative results in clinical trials. With each dose albumin. The Albumin in Acute Stroke disappointment, however, investigators learn Ischemic neurons release excessive amounts (ALIAS) trial, a NETT-supported trial, has a non-ischemic brain tissue. Thus, non-specific things that help them refine the development of glutamate, a chemical signal (or neurotransmitter) target enrollment of nearly 900 individuals and glutamate antagonists can cause serious side of candidate drugs; for example, by taking steps that excites neighboring neurons. As these will test the efficacy of albumin given within effects—such as hallucinations, extreme sedation, neurons become active and release their own 5 hours of stroke, with or without tPA. and respiratory depression—and the tolerated doses glutamate, excitation builds upon itself and are apparently too low to suppress excitotoxicity. spreads through the brain. Inside each neuron, Glutamate antagonists have attracted considerable this wave of excitation triggers a variety of To address this problem, NINDS is supporting attention as a possible treatment for excitotoxicity. responses. It activates enzymes capable of research on a glutamate receptor blockade that Most of these drugs work by blocking the remodeling a neuron’s internal skeleton and is matched to the level of glutamate signaling. interaction between glutamate and the NMDA outer membrane, and stimulates the production For example, the drug memantine is an open- receptor, which is a type of pore, or ion channel, of oxygen-containing molecules that are channel blocker that slips into the NMDA which opens when glutamate attaches to it. capable of diffusing freely across the membrane receptor only after the receptor has already Unfortunately, while these drugs have shown and acting as short-lived, short-distance been opened by glutamate. Other glutamate promise in the middle cerebral artery occlusion neurotransmitters. Although these processes are antagonists under development would become (MCAO) model of stroke, they have not been effective otherwise normal, the ramped-up excitation—or active only when exposed to the slight increase in individuals who have had a stroke. The likely excitotoxicity—that accompanies stroke sends in acidity that occurs in ischemic brain tissue. reason is that the glutamate antagonists tested so them into overdrive and causes neuronal Finally, an innovative trial is testing if individuals far do not specifically target abnormal glutamate damage. The over-excited neuron’s skeleton and who have experienced a stroke might benefit Mitochondria are cellular factories that use oxygen signaling. It is important to remember that while and glucose to produce energy. When mitochondria membrane begin to break down. Perhaps worst from intravenous magnesium sulfate delivered run out of oxygen during a stroke, a chain reaction glutamate is pathologically elevated in ischemic of all, the neuron churns out oxygen-containing in the ambulance before they get to the hospital. of damaging events can ensue. brain tissue, it is also required for normal function in free radicals, compounds that can degrade Magnesium is abundant in the brain and proteins, lipids, and DNA.

26 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 27 which are protein-degrading enzymes that eat the anti-inflammatory cytokine interferon-beta away at this extracellular matrix. (For more stabilized the blood-brain barrier and reduced information, see “Better Thrombolysis in the size of the infarct when given to rats up to Ischemic Stroke” on p. 23.) 6 hours following MCAO. Interferon-beta is already an FDA-approved treatment for multiple NINDS-funded research has led to an evolving sclerosis. NINDS is supporting a clinical trial to view about the role of MMPs in stroke. Early assess the drug’s safety in individuals with acute studies on animal models confirmed that MMPs ischemic stroke. help destroy the blood-brain barrier during acute stroke, but more recent studies show that by several Apoptosis and the Alzheimer’s Connection days after a stroke, the activity of MMPs might As neurons in the core of an ischemic infarct actually help repair damaged neurons and blood lose their ability to produce ATP, they undergo vessels. In this late phase, MMPs appear to necrosis, the cellular equivalent of accidental The neurovascular unit consists of neurons (yellow), liberate growth factors that are trapped in the death. In the ischemic penumbra, however, the the blood vessels that supply them (pink), astrocytes (blue) and possibly other types of glial cells (green). extracellular matrix. Thus, researchers envision buildup of free radicals may trigger a form of By virtue of their contacts with neurons and blood vessels, drugs that could be used to carefully adjust cell suicide known as apoptosis. An apoptotic astrocytes help match cerebral blood flow to neuronal the activity of MMPs—first downward and then cell activates protein-cutting enzymes called energy demands. In a process known as excitotoxicity, neurons become upward—in order to improve recovery from stroke. damaged when nearby cells release excess levels of caspases that disassemble the cell’s working parts. the chemical signal glutamate. NINDS-funded investigators have shown that in Other Targets for Neuroprotection the MCAO model of ischemic stroke, caspases apoptosis in AD, they are finding other connections become activated within 9 hours, and caspase between AD and stroke. Apoptosis is associated acts as a natural open-channel blocker of the Inflammation inhibitors reduce the spread of ischemic injury with increased activity of two enzymes known to NMDA receptor. In the Field Administration of Inflammation occurs when immune cells, or during this time. generate beta-amyloid, which is the toxic protein Stroke Therapy-Magnesium (FAST-MAG) trial, leukocytes, mobilize to an injured part of the fragment that accumulates in the brain during investigators hope to boost this natural blockade body to clean up dead and dying cells. When AD. Recent studies show that these enzymes, Apoptosis and the activation of caspases have during the first few hours after stroke. A pilot a blood clot or hemorrhage occurs somewhere called beta- and gamma-secretase, are also activated also been implicated in Alzheimer’s disease (AD). trial showed that paramedics were able to deliver in the brain’s vascular system, leukocytes after MCAO in rodents. These findings have led As researchers learn more about the role of magnesium sulfate to 70 percent of individuals accumulate at that site and invade the brain to the idea that abnormal blood flow might be a within two hours of onset, a finding that has positive through openings in the blood-brain barrier. precipitating event for AD. implications for emergency stroke care in general. The first leukocytes to arrive release cytokines, which are chemicals that modulate the activity Astrocytes and the Neurovascular Unit

Breakdown of the Blood-Brain Barrier of other inflammatory cells. Some of these Researchers envision Neurons may be the workhorses of the brain, cytokines attract cells called macrophages A hemorrhagic stroke necessarily tears open someday using drugs that but they are far outnumbered by glia. While (literally “big eaters”), which engulf and break the blood-barrier barrier. But even an ischemic could be used to carefully these cells once were considered mere structural down cellular debris. support in the brain (glia is Greek for “glue”), stroke can damage the blood-brain barrier, adjust the activity of matrix through reperfusion injury or other reactions. they actually serve important functions. How much inflammation contributes to long- The barrier is composed of tightly interlocked metalloproteinases (MMPs) Oligodendrocytes, for example, form sheaths term damage after stroke is an open question; endothelial cells within the blood vessel wall, that insulate the electrical signals relayed by like other responses to stroke, certain types of in order to improve recovery surrounded by a dense meshwork of proteins, neurons. Astrocytes, so named because they inflammatory responses at the right time might known as an extracellular matrix. During acute from stroke. form branches that give them a star-like shape, even be beneficial. Still, one study showed that stroke, endothelial cells appear to release MMPs, are perhaps the most versatile type of glia and

28 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 29 the most relevant to stroke. The branches of of new neurons (called neurogenesis) and their astrocytes make contact with neurons and with migration to damaged brain regions, although the endothelial cells of blood vessels. Together, most of the newly born neurons fail to survive these cell types form a structure recently named long-term. Fortunately, as scientists learn more the neurovascular unit. about this repair response, they are discovering possible ways to enhance it. For example, Stroke researchers have begun to direct more investigators funded by NINDS have found that attention toward astrocytes and how they interact astrocytes and endothelial cells provide neurons with other parts of the neurovascular unit. with a physical scaffold for migration, and that Thanks to their close contact with blood vessels, they release proteins that stimulate neuronal astrocytes appear able to regulate cerebral blood birth, migration, and survival. Delivering these flow, helping match the delivery of blood to the neurotrophic proteins in the right combination activity and energy demands of different brain at the right time might boost the survival of regions. Scientists hypothesize that a breakdown newborn neurons and of mature, damaged of cerebral blood flow regulation not only neurons that are struggling to stay alive. increases the risk of stroke, but might increase the risk of AD by impairing the clearance of beta- amyloid from the brain.

Astrocytes are able to store glucose, which Transplantation of neural stem cells themselves study involved injecting human bone marrow stem probably allows them to serve as a reserve energy also offers the possibility to repair damage cells into the rat carotid artery one day after stroke. source for neurons. They are also capable of caused by stroke. A few studies supported by In all three studies, some of the injected stem taking up glutamate and potentially “buffering” NINDS have explored stem cell transplantation cells migrated to damaged parts of the brain the effects of excitotoxicity. Finally, after stroke in rodent models of stroke, each using distinct and took on characteristics of neurons or glia. and other injuries to the brain, astrocytes strategies to increase the likelihood that the Moreover, all three studies found functional enlarge, undergo shape changes, and begin transplanted cells would reach the damaged parts improvements in the treated rodents, some even producing signals that stimulate inflammation, a of the brain and become functional neurons. lasting up to one year in the bone marrow study. response called reactive astrocytosis. All of these In one study, mouse embryonic stem cells were Many issues remain to be resolved before stem properties have researchers looking at astrocytes primed to become neurons using genetic cell transplants can move to clinical trials in as a possible target for neuroprotective drugs. engineering, and then injected directly into individuals with acute stroke, including the site the mouse brain one day after stroke. In another and timing of injection, how to track the fate of Neural Stem Cells study, stem cells were isolated from the the cells after injection, and the type of cell most developing mouse brain, pre-sorted for a cell likely to yield benefit. Ever-present are concerns adult brain could not generate new neurons. It surface protein that helps them migrate through that transplanted stem cells could be destroyed by is now known that neural stem cells—the cells the extracellular matrix, and then injected into the body’s immune defenses, or that they could that build the embryonic brain—persist in the carotid artery two days after stroke. A third divide uncontrollably and form tumors. pockets deep within the adult brain. Following stroke and other injuries, these cells make a weak attempt to replace neurons that have been lost. After a stroke, neurons may undergo a type of cell suicide known as apoptosis, dismantling their internal In rodents, stroke by MCAO leads to the birth machinery and even breaking down their DNA.

30 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 31 many state health departments now use the stroke or TIA). When the survey was repeated in recommendations to certify and evaluate primary 2000, 72 percent of respondents could name one stroke centers across the country. 6. Changing risk factor and 32 percent could name two—a small but significant improvement. Meanwhile, the SPOTRIAS and NETT programs create an infrastructure for acute stroke care Stroke’s Results from those surveys also suggest that at participating medical centers by supporting people are getting better at recognizing the five clinical testing of acute stroke therapies. common symptoms of stroke (see “Stroke Basics,” Impact by p. 3), knowledge that could help save lives by The number of individuals with ischemic stroke reducing delays in treatment. In 1995, 57 percent who receive tPA nationally remains at one to two of respondents could name at least one stroke Changing percent. However, the experience at certified warning sign, but by 2000, that number had stroke centers and SPOTRIAS centers has shown increased to 70 percent. attitudes that it is possible to improve an individual’s access to tPA with a coordinated stroke team in Recognizing that lack of awareness about stroke NINDS also supports efforts to provide hospitals place. Stroke centers designated by the state remains a barrier to effective treatment, in May with the organization they need to rapidly of New York (using BAC guidelines) treat more 2001, NINDS launched its Know Stroke campaign triage and treat people who have experienced individuals with ischemic stroke with tPA and (www.stroke.nih.gov) to educate the public about a stroke. One lesson learned from tPA is that deliver it faster than nondesignated hospitals in stroke symptoms and risk factors, and emphasize hospitals cannot put the best stroke treatments the state. Similarly, Joint Commission-certified the importance of treating stroke as a medical into practice unless they are capable of rapid primary stroke centers have reported higher s late as the 1950s, stroke treatment and emergency. The campaign has produced a stroke case management. When tPA was approved in rates of tPA use after their certification. Finally, A prevention were almost non-existent. education kit and multiple publications that are 1996, most hospitals were not equipped to utilize NINDS SPOTRIAS centers have reported that up There were no medications for acute stroke available in both English and Spanish. The Know it within its short window of efficacy and, by 2000, to 15 percent of individuals with ischemic stroke and surgeries were still very experimental. Stroke in the Community campaign, launched in only about one to two percent of individuals with are treated with tPA. Moreover, with very little knowledge about stroke partnership between NINDS and the Centers for acute ischemic stroke were receiving it nationwide. risk factors, there was no basis for primary or Disease Control and Prevention in 2004, recruits As more stroke therapies emerge from the research secondary prevention. Mary Lasker, a health “Stroke Champions” who are trained to use these That same year, the Brain Attack Coalition pipeline, NINDS will continue to support efforts advocate and a powerful force behind the educational materials within their communities. establishment of NINDS in 1950, once said that (BAC), a partnership that includes NINDS, to ensure that clinicians are well-equipped to several medical societies, and patient advocacy implement them. at the time, “Whether you recovered or not was NINDS recognizes that providing resources groups, developed a set of recommendations for really largely by chance.” and education for the medical profession is just establishing primary stroke centers. These are CREDITS: as important as reaching out to the public at hospitals that are capable of providing emergency Page 5: Friedlander, Robert M. Arteriovenous Malformation of the Brain. NINDS has supported a variety of outreach large. Although NINDS originally developed the New England Journal of Medicine 2007;356:2704-12. Copyright © 2007 care for individuals with acute stroke. The efforts since the early 1990s to translate gains NIH Stroke Scale in the early 1990s as a tool for Massachusetts Medical Society. All Rights Reserved; Page 6: van der recommendations emphasize creating an acute Worp, H Bart and van Gijn, Jan. Acute Ischemic Stroke. New England in research into gains in public health. In evaluating people with stroke in clinical trials, Journal of Medicine 2007; 357:572-9. Copyright © 2007 Massachusetts stroke team that is available around the clock 1995, a NINDS-funded survey of about 20,000 the Scale’s utility in clinical practice quickly Medical Society. All Rights Reserved; Page 8: John Crawford, MedArts, and includes physicians, nurses, paramedics, and NIH; Page 13: George Howard, School of Public Health at the households in and around Cincinnati, Ohio became apparent. (For more information, see emergency department staff, with at least one University of Alabama at Birmingham; Page 15: Martin, Mathew J., found that 68 percent of respondents could “Stroke Diagnostics and Brain Imaging,” p. 7.) et al. Enhanced Detection of Thromboemboli with the Use of Targeted physician who is an expert in cerebrovascular name one modifiable stroke risk factor and that NINDS now links to an online version of the Scale, Microbubbles. Stroke 2007; 358:2726-2732. Copyright © 2007 American disease. The recommendations also call for Heart Association; Page 21: National Institute of General Medical 25 percent could name two (where the correct and offers an interactive DVD that provides simple Sciences, NIH; Page 29: del Zoppo, Gregory J. Stroke and Neurovascular rapid access to blood tests, brain imaging, and responses included hypertension, smoking, heart instructions and case studies illustrating its use. Protection. New England Journal of Medicine 2006; 354:553-555. disease, diabetes, high cholesterol, and prior neurosurgery. The Joint Commission and Copyright © 2006 Massachusetts Medical Society. All Rights Reserved.

32 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 33 U.S. DEPARTMENT OF HEALTH AND HUMAN SERVICES National Institutes of Health National Institute of Neurological Disorders and Stroke

NIH Publication No. 09-6451 February 2009