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http://www.ninds.nih.gov/disorders/stroke/detail_stroke.htm#229681105 Hemorrhagic St roke

In a healthy, functioning brain, neurons do not come into direct contact with blood. The vital

oxygen and nutrients the neurons need from the blood come to the neurons across the thin wallsof the cerebral capillaries. The glia (nervous system cells that support and protect neurons) forma blood-brain barrier , an elaborate meshwork that surrounds blood vessels and capillaries andregulates which elements of the blood can pass through to the neurons.

When an artery in the brain bursts, blood spews out into the surrounding tissue and upsets notonly the blood supply but the delicate chemical balance neurons require to function. This iscalled a hemorrhagic stroke. Such strokes account for approximately 20 percent of all strokes.

Hemorrhage can occur in several ways. One common cause is a bleeding aneurysm, a weak orthin spot on an artery wall. Over time, these weak spots stretch or balloon out under high arterial

pressure. The thin walls of these ballooning aneurysms can rupture and spill blood into the spacesurrounding brain cells.

Hemorrhage also occurs when arterial walls break open. Plaque-encrusted artery walls eventuallylose their elasticity and become brittle and thin, prone to cracking. Hypertension , or high blood

pressure , increases the risk that a brittle artery wall will give way and release blood into thesurrounding brain tissue.

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

Bleeding from ruptured brain arteries can either go into the substance of the brain or into thevarious spaces surrounding the brain. Intracerebral hemorrhage occurs when a vessel within the

brain leaks blood into the brain itself. Subarachnoid hemorrhage is bleeding under the meninges,or outer membranes, of the brain into the thin fluid-filled space that surrounds the brain.

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

subarachnoid hemorrhage is the most deadly of all strokes.Who is at Risk for Stroke?

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

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Unmodif iable Risk Factors

It is a myth that stroke occurs only in elderly adults. In actuality, stroke strikes all age groups,from fetuses still in the womb to centenarians. It is true, however, that older people have a higher

risk for stroke than the general population and that the risk for stroke increases with age. Forevery decade after the age of 55, the risk of stroke doubles, and two-thirds of all strokes occur in people over 65 years old. People over 65 also have a seven-fold greater risk of dying from strokethan the general population. And the incidence of stroke is increasing proportionately with theincrease in the elderly population. When the baby boomers move into the over-65 age group,stroke and other diseases will take on even greater significance in the health care field.

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

Stroke seems to run in some families. Several factors might contribute to familial stroke risk.Members of a family might have a genetic tendency for stroke risk factors, such as an inherited

predisposition for hypertension or diabetes. The influence of a common lifestyle among familymembers could also contribute to familial stroke.

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

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

predispose them to stroke.

Hispanics and Native Americans have stroke incidence and mortality rates more similar to thoseof white Americans. In Asian-Americans stroke incidence and mortality rates are also similar tothose in white Americans, even though Asians in Japan, China, and other countries of the Far

East have significantly higher stroke incidence and mortality rates than white Americans. Thissuggests that environment and lifestyle factors play a large role in stroke risk.

The "Stroke Bel t"

Several decades ago, scientists and statisticians noticed that people in the southeastern UnitedStates had the highest stroke mortality rate in the country. They named this region the stroke belt .

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For many years, researchers believed that the increased risk was due to the higher percentage ofAfrican-Americans and an overall lower socioeconomic status (SES) in the southern states. Alow SES is associated with an overall lower standard of living, leading to a lower standard ofhealth care and therefore an increased risk of stroke. But researchers now know that the higher

percentage of African-Americans and the overall lower SES in the southern states does not

adequately account for the higher incidence of, and mortality from, stroke in those states. Thismeans that other factors must be contributing to the higher incidence of and mortality fromstroke in this region.

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

Other Risk Factors

The most important risk factors for stroke are hypertension, heart disease, diabetes, and cigarettesmoking. Others include heavy alcohol consumption, high blood cholesterol levels, illicit druguse, and genetic or congenital conditions, particularly vascular abnormalities. People with morethan one risk factor have what is called "amplification of risk." This means that the multiple riskfactors compound their destructive effects and create an overall risk greater than the simplecumulative effect of the individual risk factors.

Hyper tens ion

Of all the risk factors that contribute to stroke, the most powerful is hypertension, or high blood pressure. People with hypertension have a risk for stroke that is four to six times higher than therisk for those without hypertension. One-third of the adult U.S. population, about 50 million

people (including 40-70 percent of those over age 65) have high blood pressure. Forty to 90 percent of stroke patients have high blood pressure before their stroke event.

A systolic pressure of 120 mm of Hg over a diastolic pressure of 80 mm of Hg * is generallyconsidered normal. Persistently high blood pressure greater than 140 over 90 leads to thediagnosis of the disease called hypertension. The impact of hypertension on the total risk forstroke decreases with increasing age, therefore factors other than hypertension play a greater role

in the overall stroke risk in elderly adults. For people without hypertension, the absolute risk ofstroke increases over time until around the age of 90, when the absolute risk becomes the sameas that for people with hypertension.

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

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

Heart Disease

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

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

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

Heart muscle malformations can also increase the risk for stroke . Patent foramen ovale (PFO) is

a passage or a hole (sometimes called a "shunt") in the heart wall separating the two atria, orupper chambers, of the heart. Clots in the blood are usually filtered out by the lungs, but PFOcould allow emboli or blood clots to bypass the lungs and go directly through the arteries to the

brain, potentially causing a stroke. Research is currently under way to determine how importantPFO is as a cause for stroke. Atrial septal aneurysm (ASA), a congenital (present from birth)malformation of the heart tissue, is a bulging of the septum or heart wall into one of the atria ofthe heart. Researchers do not know why this malformation increases the risk for stroke. PFO andASA frequently occur together and therefore amplify the risk for stroke. Two other heartmalformations that seem to increase the risk for stroke for unknown reasons are left atrialenlargement and left ventricular hypertrophy. People with left atrial enlargement have a largerthan normal left atrium of the heart; those with left ventricular hypertrophy have a thickening of

the wall of the left ventricle.

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

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Blood Cho les terol Levels

Most people know that high cholesterol levels contribute to heart disease. But many don't realizethat a high cholesterol level also contributes to stroke risk. Cholesterol, a waxy substance

produced by the liver, is a vital body product. It contributes to the production of hormones andvitamin D and is an integral component of cell membranes. The liver makes enough cholesterolto fuel the body's needs and this natural production of cholesterol alone is not a largecontributing factor to atherosclerosis, heart disease, and stroke. Research has shown that thedanger from cholesterol comes from a dietary intake of foods that contain high levels ofcholesterol. Foods high in saturated fat and cholesterol, like meats, eggs, and dairy products, canincrease the amount of total cholesterol in the body to alarming levels, contributing to the risk ofatherosclerosis and thickening of the arteries.

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

There are two kinds of cholesterol, commonly called the "good" and the "bad." Good cholesterolis high-density lipoprotein , or HDL ; bad cholesterol is low-density lipoprotein , or LDL. Together,these two forms of cholesterol make up a person's total serum cholesterol level. Most cholesteroltests measure the level of total cholesterol in the blood and don't distinguish between good and

bad cholesterol. For these total serum cholesterol tests, a level of less than 200 mg/dL ** isconsidered safe, while a level of more than 240 is considered dangerous and places a person atrisk for heart disease and stroke.

Most cholesterol in the body is in the form of LDL. LDLs circulate through the bloodstream, picking up excess cholesterol and depositing cholesterol where it is needed (for example, for the production and maintenance of cell membranes). But when too much cholesterol startscirculating in the blood, the body cannot handle the excessive LDLs, which build up along theinside of the arterial walls. The buildup of LDL coating on the inside of the artery walls hardensand turns into arterial plaque, leading to stenosis and atherosclerosis. This plaque blocks bloodvessels and contributes to the formation of blood clots. A person's LDL level should be less than130 mg/dL to be safe. LDL levels between 130 and 159 put a person at a slightly higher risk foratherosclerosis, heart disease, and stroke. A score over 160 puts a person at great risk for a heartattack or stroke.

The other form of cholesterol, HDL, is beneficial and contributes to stroke prevention. HDLcarries a small percentage of the cholesterol in the blood, but instead of depositing its cholesterolon the inside of artery walls, HDL returns to the liver to unload its cholesterol. The liver theneliminates the excess cholesterol by passing it along to the kidneys. Currently, any HDL scorehigher than 35 is considered desirable. Recent studies have shown that high levels of HDL areassociated with a reduced risk for heart disease and stroke and that low levels (less than 35

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mg/dL), even in people with normal levels of LDL, lead to an increased risk for heart disease andstroke.

A person may lower his risk for atherosclerosis and stroke by improving his cholesterol levels. Ahealthy diet and regular exercise are the best ways to lower total cholesterol levels. In somecases, physicians may prescribe cholesterol-lowering medication, and recent studies have shownthat the newest types of these drugs, called reductase inhibitors or statin drugs, significantlyreduce the risk for stroke in most patients with high cholesterol. Scientists believe that statinsmay work by reducing the amount of bad cholesterol the body produces and by reducing the

body's inflammatory immune reaction to cholesterol plaque associated with atherosclerosis andstroke.

* mm of Hg-or millimeters of mercury-is the standard means of expressing blood pressure, which is measured usingan instrument called a sphygmomanometer. Using a stethoscope and a cuff that is wrapped around the patient'supper arm, a health professional listens to the sounds of blood rushing through an artery. The first sound registeredon the instrument gauge (which measures the pressure of the blood in millimeters on a column of mercury) is calledthe systolic pressure. This is the maximum pressure produced as the left ventricle of the heart contracts and the

blood begins to flow through the artery. The second sound is the diastolic pressure and is the lowest pressure in theartery when the left ventricle is relaxing. return to " H ypert ension " section

** mg/dL describes the weight of cholesterol in milligrams in a deciliter of blood. This is the standard way ofmeasuring blood cholesterol levels. return to " Bl ood Chol esterol L evels " section

Diabetes

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

Modif iable Lifes ty le Risk Factors

Cigarette smoking is the most powerful modifiable stroke risk factor. Smoking almost doubles a person's risk for ischemic stroke, independent of other risk factors, and it increases a person's riskfor subarachnoid hemorrhage by up to 3.5 percent. Smoking is directly responsible for a greater

percentage of the total number of strokes in young adults than in older adults. Risk factors otherthan smoking - like hypertension, heart disease, and diabetes - account for more of the totalnumber of strokes in older adults.

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

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

the Appendix .)High alcohol consumption is another modifiable risk factor for stroke. Generally, an increase inalcohol consumption leads to an increase in blood pressure. While scientists agree that heavydrinking is a risk for both hemorrhagic and ischemic stroke, in several research studies dailyconsumption of smaller amounts of alcohol has been found to provide a protective influenceagainst ischemic stroke, perhaps because alcohol decreases the clotting ability of platelets in the

blood. Moderate alcohol consumption may act in the same way as aspirin to decrease bloodclotting and prevent ischemic stroke. Heavy alcohol consumption, though, may seriously deplete

platelet numbers and compromise blood clotting and blood viscosity, leading to hemorrhage. Inaddition, heavy drinking or binge drinking can lead to a rebound effect after the alcohol is

purged from the body. The consequences of this rebound effect are that blood viscosity(thickness) and platelet levels skyrocket after heavy drinking, increasing the risk for ischemicstroke.

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

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

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

Head and Neck Injur ies

Injuries to the head or neck may damage the cerebrovascular system and cause a small number ofstrokes. Head injury or traumatic brain injury may cause bleeding within the brain leading todamage akin to that caused by a hemorrhagic stroke. Neck injury, when associated withspontaneous tearing of the vertebral or carotid arteries caused by sudden and severe extension ofthe neck, neck rotation, or pressure on the artery, is a contributing cause of stroke, especially inyoung adults. This type of stroke is often called "beauty-parlor syndrome," which refers to the

practice of extending the neck backwards over a sink for hair-washing in beauty parlors. Neck

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calisthenics, "bottoms-up" drinking, and improperly performed chiropractic manipulation of theneck can also put strain on the vertebral and carotid arteries, possibly leading to ischemic stroke.

Infect ions

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

Genet ic Risk Factors

Although there may not be a single genetic factor associated with stroke, genes do play a largerole in the expression of stroke risk factors such as hypertension, heart disease, diabetes, andvascular malformations. It is also possible that an increased risk for stroke within a family is dueto environmental factors, such as a common sedentary lifestyle or poor eating habits, rather thanhereditary factors.

Vascular malformations that cause stroke may have the strongest genetic link of all stroke riskfactors. A vascular malformation is an abnormally formed blood vessel or group of bloodvessels. One genetic vascular disease called CADASIL, which stands for cerebral autosomaldominant arteriopathy with subcortical infarcts and leukoencephalopathy. CADASIL is a rare,genetically inherited, congenital vascular disease of the brain that causes strokes, subcorticaldementia, migraine-like headaches, and psychiatric disturbances. CADASIL is very debilitatingand symptoms usually surface around the age of 45. The exact incidence of CADASIL in theUnited States is unknown.

Medicat ions

Medication or drug therapy is the most common treatment for stroke. The most popular classesof drugs used to prevent or treat stroke are antithrombotics (antiplateletagents and anticoagulants ) and thrombolytics .

Antithrombotics prevent the formation of blood clots that can become lodged in a cerebral arteryand cause strokes. Antiplatelet drugs prevent clotting by decreasing the activity of platelets,

blood cells that contribute to the clotting property of blood. These drugs reduce the risk of blood-

clot formation, thus reducing the risk of ischemic stroke. In the context of stroke, physicians prescribe antiplatelet drugs mainly for prevention. The most widely known and used antiplateletdrug is aspirin. Other antiplatelet drugs include clopidogrel, ticlopidine, and dipyridamole. The

NINDS sponsors a wide range of clinical trials to determine the effectiveness of antiplateletdrugs for stroke prevention.

Anticoagulants reduce stroke risk by reducing the clotting property of the blood. The mostcommonly used anticoagulants include warfarin (also known

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as Coumadin ), heparin, and enoxaparin (also known as Lovenox ). The NINDS has sponsoredseveral trials to test the efficacy of anticoagulants versus antiplatelet drugs. The StrokePrevention in Atrial Fibrillation (SPAF) trial found that, although aspirin is an effective therapyfor the prevention of a second stroke in most patients with atrial fibrillation, some patients withadditional risk factors do better on warfarin therapy. Another study, the Trial of Org 10127 in

Acute Stroke Treatment (TOAST), tested the effectiveness of low-molecular weight heparin(Org 10172) in stroke prevention. TOAST showed that heparin anticoagulants are not generallyeffective in preventing recurrent stroke or improving outcome.

Thrombolytic agents are used to treat an ongoing, acute ischemic stroke caused by an artery blockage. These drugs halt the stroke by dissolving the blood clot that is blocking blood flow tothe brain. Recombinant tissue plasminogen activator (rt-PA) is a genetically engineered form oft-PA, a thombolytic substance made naturally by the body. It can be effective if givenintravenously within 3 hours of stroke symptom onset, but it should be used only after a

physician has confirmed that the patient has suffered an ischemic stroke. Thrombolytic agentscan increase bleeding and therefore must be used only after careful patient screening. The

NINDS rt-PA Stroke Study showed the efficacy of t-PA and in 1996 led to the first FDA-approved treatment for acute ischemic stroke. Other thrombolytics are currently being tested inclinical trials.

Neuroprotectants are medications that protect the brain from secondary injury caused bystroke (see Appendix ). Although no neuroprotectants are FDA-approved for use in stroke at thistime, many are in clinical trials. There are several different classes of neuroprotectants that show

promise for future therapy, including glutamate antagonists, antioxidants, apoptosis inhibitors,and many others.

Surgery

Surgery can be used to prevent stroke, to treat acute stroke, or to repair vascular damage ormalformations in and around the brain. There are two prominent types of surgery for stroke

prevention and treatment: carotid endarterectomy and extracranial/intracranial (EC/IC) bypass .

Carotid endarterectomy is a surgical procedure in which a doctor removes fatty deposits (plaque)from the inside of one of the carotid arteries, which are located in the neck and are the mainsuppliers of blood to the brain. As mentioned earlier, the disease atherosclerosis is characterized

by the buildup of plaque on the inside of large arteries, and the blockage of an artery by this fattymaterial is called stenosis. The NINDS has sponsored two large clinical trials to test the efficacyof carotid endarterectomy: the North American Symptomatic Carotid Endarterectomy Trial

(NASCET) and the Asymptomatic Carotid Atherosclerosis Trial (ACAS). These trials showedthat carotid endarterectomy is a safe and effective stroke prevention therapy for most people withgreater than 50 percent stenosis of the carotid arteries when performed by a qualified andexperienced neurosurgeon or vascular surgeon.

Currently, the NINDS is sponsoring the Carotid Revascularization Endarterectomy vs. StentingTrial (CREST), a large clinical trial designed to test the effectiveness of carotid endarterectomyversus a newer surgical procedure for carotid stenosis called stenting. The procedure involves

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inserting a long, thin catheter tube into an artery in the leg and threading the catheter through thevascular system into the narrow stenosis of the carotid artery in the neck. Once the catheter is in

place in the carotid artery, the radiologist expands the stent with a balloon on the tip of thecatheter. The CREST trial will test the effectiveness of the new surgical technique versus theestablished standard technique of carotid endarterectomy surgery.

EC/IC bypass surgery is a procedure that restores blood flow to a blood-deprived area of braintissue by rerouting a healthy artery in the scalp to the area of brain tissue affected by a blockedartery. The NINDS-sponsored EC/IC Bypass Study tested the ability of this surgery to preventrecurrent strokes in stroke patients with atherosclerosis. The study showed that, in the long run,EC/IC does not seem to benefit these patients. The surgery is still performed occasionally for

patients with aneurysms, some types of small artery disease, and certain vascular abnormalities.

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

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

What Special Risks do Women Face?

Some risk factors for stroke apply only to women. Primary among these are pregnancy, childbirth, and

menopause. These risk factors are tied to hormonal fluctuations and changes that affect a woman indifferent stages of life. Research in the past few decades has shown that high-dose oral contraceptives, thekind used in the 1960s and 1970s, can increase the risk of stroke in women. Fortunately, oralcontraceptives with high doses of estrogen are no longer used and have been replaced with safer and moreeffective oral contraceptives with lower doses of estrogen. Some studies have shown the newer low-doseoral contraceptives may not significantly increase the risk of stroke in women.

Other studies have demonstrated that pregnancy and childbirth can put a woman at an increasedrisk for stroke. Pregnancy increases the risk of stroke as much as three to 13 times. Of course, therisk of stroke in young women of childbearing years is very small to begin with, so a moderateincrease in risk during pregnancy is still a relatively small risk. Pregnancy and childbirth cause

strokes in approximately eight in 100,000 women. Unfortunately, 25 percent of strokes during pregnancy end in death, and hemorrhagic strokes, although rare, are still the leading cause ofmaternal death in the United States. Subarachnoid hemorrhage, in particular, causes one to fivematernal deaths per 10,000 pregnancies.

A study sponsored by the NINDS showed that the risk of stroke during pregnancy is greatest inthe post-partum period - the 6 weeks following childbirth. The risk of ischemic stroke after

pregnancy is about nine times higher and the risk of hemorrhagic stroke is more than 28 times

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higher for post-partum women than for women who are not pregnant or post-partum. The causeis unknown.

In the same way that the hormonal changes during pregnancy and childbirth are associated withincreased risk of stroke, hormonal changes at the end of the childbearing years can increase therisk of stroke. Several studies have shown that menopause, the end of a woman's reproductiveability marked by the termination of her menstrual cycle, can increase a woman's risk of stroke.Fortunately, some studies have suggested that hormone replacement therapy can reduce some ofthe effects of menopause and decrease stroke risk. Currently, the NINDS is sponsoring theWomen's Estrogen for Stroke Trial (WEST), a randomized, placebo-controlled, double-blindtrial, to determine whether estrogen therapy can reduce the risk of death or recurrent stroke in

postmenopausal women who have a history of a recent TIA or non-disabling stroke. Themechanism by which estrogen can prove beneficial to postmenopausal women could include itsrole in cholesterol control. Studies have shown that estrogen acts to increase levels of HDL whiledecreasing LDL levels.

Are Children at Risk For Stroke?

The young have several risk factors unique to them. Young people seem to suffer fromhemorrhagic strokes more than ischemic strokes, a significant difference from older age groupswhere ischemic strokes make up the majority of stroke cases. Hemorrhagic strokes represent 20

percent of all strokes in the United States and young people account for many of these.

Clinicians often separate the "young" into two categories: those younger than 15 years of age,and those 15 to 44 years of age. People 15 to 44 years of age are generally considered youngadults and have many of the risk factors mentioned above, such as drug use, alcohol abuse,

pregnancy, head and neck injuries, heart disease or heart malformations, and infections. Someother causes of stroke in the young are linked to genetic diseases.

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

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

In children with stroke the underlying conditions that led to the stroke should be determined andmanaged to prevent future strokes. For example, a recent clinical study sponsored by the

National Heart, Lung, and Blood Institute found that giving blood transfusions to young childrenwith sickle cell anemia greatly reduces the risk of stroke. The Institute even suggests attemptingto prevent stroke in high-risk children by giving them blood transfusions before they experiencea stroke.

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

Intracerebral Hemorrhage: Discovery of novel risk loci

Three major NIH-funded efforts in this area have resulted in several genetic discoveries. These results are consistent with earlier epidemiologic and pathologic observations supporting thehypothesis that differences in anatomical location of ICH reflect differences in pathobiology. The apolipoprotein E (APOE) e2 and e4 alleles are risk factors for ICH in lobar brain regions; APOEe2 is a risk factor for more severe bleeding in lobar ICH; and CR-1 is a risk factor for lobar ICH.

Intracranial Aneurysms

Completion of two large genome wide association (GWA) studies and a follow-up study discovered 8 independent chromosomal regions that increase risk of intracranial aneurysms. Thesestudies identified risk variants common in the population but conferring modest risk. The 5 published risk loci explain ~10% of genetic risk. Extrapolating from other common diseases in whichcommon variants typically explain 30-40% of the risk, it is hypothesized that there are as yet unidentified loci containing common risk variants, potentially with lower odds ratios. Although thedisease-causing variants in identified intervals need to be determined, some of these intervals contain only one gene. Identification of these genes generates unique biological insights andideas for potentially novel biologically-based treatments.

Cerebrovascular Malformations

The major advance in cerebrovascular malformations has been the generation of animal models of cerebral cavernous malformations (CCMs). These models are aimed at examining thebiology of genes implicated in familial forms of CCMs and biochemical, structural and proteomic studies of their encoded proteins. Studies in model organisms demonstrated that the genesinvolved in familial CCM syndromes are essential for vascular development. The three CCM proteins appear to interact; each also has distinct interacting partners. Studies are ongoing inunderstanding the genetic basis of other malformations such as arteriovenous malformations (AVMs) and moyamoya variants.

Mitochon drial genetics

The identification of the disorder Mitochondrial myopathy, Encephalopathy, Lactic Acidosis with Stroke-like episodes (MELAS) associated with a number of point mutations in the mtDNAconfirmed the role of genetic variation in stroke phenotypes. About 80% of patients carry an A-to-G transition at position 3243 in the tRNALeu (UUR) gene. This variant is associated withOXPHOS Complex I deficiency. Two studies suggest that mtDNA variation can alter the individual susceptibility to sporadic ischemic stroke. It is suggested that variation forming one of thelarger mtDNA haplogroups (K) protected against the development of an ischemic stroke. Subsequent work has suggested that rather than a specific haplogroup, an overall score of commonvariation in the mtDNA genome increased the risk of stroke.

Single gene/familial disorders

Stroke is the sole or major clinical phenotypic expression of several monogenetic disorders. Pivotal trials funded by the NINDS established the striking efficacy of transfusion therapy inpreventing stroke in high-risk patients with sickle cell disease. The ongoing Silent Cerebral Infarct Transfusion (SIT) trial will test in children with sickle cell disease and MRI-detected silentinfarcts the efficacy of transfusion therapy in preventing silent and overt incident infarcts. Most single-gene disorders that predispose to ischemic or hemorrhagic stroke remain without aneffective treatment.

CADASIL is the leading cause of inherited vascular dementia. New mouse models suggest that Notch3 signaling relates to small vessel ischemic disease in CADASIL. A multicenterrandomized trial showed that donepezil can improve measures of cognitive performance in CADASIL. This trial provides insight into the effectiveness of cholinesterase inhibitors for sporadicvascular dementia, because CADASIL-associated dementia presents at an age where coexistent Alzheimer pathology is expected to be minimal.

Epidemiological studies support a strong genetic component in risk of stroke, a systematic review of the familial studies generated quantitative estimates of risks suggesting that first degreerelatives of stroke patients have increased risk of stroke (odds ratio of 1.76). With the advent of next-generation sequencing, identification of new genes is possible without large expandedpedigrees, which can take many years to assemble. A concerted effort is now required to establish independent cohorts of patients with familial forms of cerebrovascular disease.

Pharmacogenomics

Response to drug therapy varies among individuals, and genetic polymorph isms contribute to this variability. More than 10% of the 69 drugs currently with pharmacogenomic tests included intheir labeling are commonly used to prevent stroke directly or indirectly through treatment of vascular risk factors. Two mainstays of secondary stroke prevention, warfarin and clopidogrel, havehad identified pharmacogenomic modifiers of treatment response or dosing. Pharmacogenomic variation may account for one of the most common treatment-limiting adverse reactions to HMG-coA reductase inhibitors (statins). The Clinical Pharmacogenomics Implementation Consortium of the Pharmacogenomics Research Network has begun to develop and evaluate user-friendly,evidence-based algorithms to facilitate clinical adoption of pharmacogenomics.

Gene variants influence response to warfarin therapy.

The relabeling of warfarin in 2007 represents one of the earliest examples of FDA labeling that included pharmacogenomic data, and the DNA-based drug sensitivity test for both the CYP2C9(cytochrome P450 2C9) and VKORC1 (vitamin K epoxide reductase complex subunit 1) variants was the first ever approved. More recent clinical trial data demonstrate reductions inhospitalization, bleeding and thromboembolic events in those using genotypic information at the time of warfarin initiation compared to those using standard of care. The significance of warfarinpharmacogenomics has been muted somewhat with the arrival of several direct thrombin inhibitors and anti-Xa inhibitors.

Gene variants influence response to clopidogrel.

The evidence supporting adding pharmacogenomics data regarding the CYP2C19 (cytochrome P450 2C19) polymorphism to the labeling for clopidogrel came from a range of data and sourcesincluding post hoc analyses of clinical trials, cohort studies from academic centers, and large-scale epidemiological data using both biomarker and clinical endpoints. A secondpharmacogenomic variant due to polymorphisms in ABCB1 (the ATP-Binding Cassette, Subfamily B, Member 1) is also associated with decreased antiplatelet responses and increasedischemic events. Collectively, almost 50% of the clinical population harbors one or more genotypes associated with increased risk vascular events on standard dosing schedules for clopidogrel.

An algorithm for using pharmacogenomic information to guide therapy in treatment of interventional cardiology patients has recently been published. To date, no studies have focused primarilyon the effect on ischemic stroke. CYP2C19 variants appear not to influence other thienopyridines. However, neither of the newer agents has been specifically tested in ischemic stroke andprasugrel carries a black box warning against use in patients with a history of stroke. Ticlopidine has demonstrated efficacy in preventing stroke but carries risk of thrombotic thrombocytopenicpurpura and other blood dyscrasias.

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Genetic variation influences tolerance to statin medications.

Although HMG-coA reductase inhibitors (statins) reduce ischemic stroke risk, many individuals cannot tolerate them because of myalgias and myopathy. Individuals harboring variants inSLCO1B1 (the solute carrier organic anion transporter family member 1B1) gene that encodes the hepatic drug transporter have a 4.5-fold increase in the odds of myopathy per copy of theSLCO1B1*5 allele.

II. Key Challenges

Intracerebral Hemorrhage

Like ischemic stroke, ICH appears to be more than one disease, and available sample sizes for genetic study are inadequate. Identification of all of the genetic contribution to disease risk isessential in order to identify all the novel biological pathways that could become drug targets. Additional well characterized samples are needed for replication and studies of molecularmechanisms. These new collections should have more biobanking with not only DNA but also RNA, serum, plasma and, when available, tissue samples.

GWAS studies probe associations of common variants with stroke; future studies are needed to address the rare variant hypothesis, including exome sequencing and whole genomesequencing studies of extremely well-phenotyped ischemic stroke subtypes, intracerebral hemorrhage and subarachnoid hemorrhage.

Pediatric Stroke and Genetics

There are many obstacles to understanding childhood stroke genetics primarily related to small numbers of pediatric stroke cases. Initially it seemed that genes were an important cause ofstroke because of the obvious stroke association with monogenetic disorders such as sickle cell disease. However it soon became apparent that not all patients with genetic diseases, whichpredispose to stroke actually develop cerebral vasculopathy and most children with stroke do not have obvious monogenetic disorders. In other words, the genetic association is morecomplicated than first assumed.

Today there are challenges and opportunities. First, there are obvious synergies with the adult stroke studies. There is ongoing work at standardizing stoke phenotype which will make inclusionof pediatric stroke in large studies possible. For example SVD is now recognized in pediatric stoke and ischemic stroke is better characterized in a reproducible and reliable fashion allowing forpediatric stroke to be included in the NINDS Genetic Stroke network. This should be an initial priority.

A current focus in pediatric stroke research involves understanding patients with cerebral vasculopathy since such patients seem at highest risk for secondary stroke recurrence. Developingstandardized protocols for looking at genetics in this population with vasculopathies might be a fruitful approach. These disorders include moyamoya and other vasculopathies. The impact ofthe NF-1 mutation on vasculopathy including a recently described genetic inflammatory interplay may, for example, be a model for some of the vasculopathy seen in childhood. Here, as inmany genetic conditions, a clinical diagnosis is often difficult. As such a standard protocol for looking at the genetics of disorders that result in vasculopathy would be helpful to apply to allchildren with vasculopathy and stroke even if they do not have an obvious genetic disorder. A standardized genetic approach in pediatric research trials is needed.

Pharmacogenomics

Incorporating genetics at the design stage of clinical trials. Defining the type and levels of evidence required to change clinical practice by using genetic variant information to alter d rug or dose choice. Developing ways to obtain a patients genotypic information at the point of care. Integrating genetic information into practical treatment algorithms into the electronic medical record and practice guidelines.

Stroke in underrepresented populations

The burden of stroke varies greatly across racial and ethnic groups in the US. Both stroke incidence and mortality in African Americans are nearly twice that of non-Hispanic whites. In

Hispanics, stroke incidence and risk of recurrent stroke are also higher than in non-Hispanic whites. In addition, stroke tends to occur at younger ages in African Americans and Hispanics,resulting in greater disability and expense. Diverse populations remain underrepresented in stroke population genetics research. In 2008, the NIH Center for Research on Genomics and GlobalHealth was established to explore the relationship between human genetic variation and population differences in disease with the goal of understanding health inequalities. Similarly, the SNPHealth Association Resource (SHARe) was established to pursue genome-wide data collection and analyses in several multi-ethnic NHLBI cohort studies to identify genes underlyingcardiovascular and lung disease and other disorders.

Mitochon drial genetics

There has been a scarcity of studies focusing on stroke-related research; analysis of mitochondrial genetics should be built in to studies powered to understand the complex genetic nature ofstroke.

UNREALIZED OPPORTUNITIES

Intracerebral Hemorrhage

NIH-funded (ATACH-2) and international (INTERACT-2) clinical trials for acute ICH will enroll thousands of ICH patients, whose genetic material could be useful for further study. Studies of Alzheimer Disease (AD) have been leveraged to identify risk factors for cerebral amyloid angiopathy (CAA). Similar leveraging of acute trials would be fruitful.

Intracranial Aneurysm and cerebrovascular malformation s

The studies aimed at discovering genetic risk for intracranial aneurysms must account for the complex genetic architecture, which includes contribution of common, rare and possibly Mendelianalleles to aneurysm risk. Discovery of Mendelian disease genes will be very useful in understanding the disease biology. Disease-causing variants need to be identified within the associationintervals discovered by genome-wide studies. Rare variants with higher effect sizes appear to contribute significantly to intracranial aneurysm risk. Next generation sequencing technologiesalso offer the greatest opportunity for understanding the genetic basis of the sporadic forms of the cerebrovascular malformations.

Identification of cerebrovascular malformation genes, especially in genes causing CCMs, has already formed the basis of other studies aimed at dissecting the biology of these malformations.Studies that focus on downstream signaling pathways of each of the genes will lead to new insights into mechanisms of disease pathogenesis.

Opportunit ies in Translational Applications

The discovery of the genetic risk variants will provide insights into pathophysiology of IA formation and rupture and, when considered in combination with environmental and other risk factorssuch as smoking, hypertension and cerebral architecture, will lead to genotype-phenotype studies aimed at identifying at risk individuals in a cost effective way prior to catastrophic problemssuch as rupture. Although this clinical application relies on obtaining a comprehensive catalog of most (rare + common) variants, the ones that have already been identified significantly

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contributed to our thinking regarding the mechanisms underlying aneurysm formation and rupture, forming the basis for future biology based treatments. Further understanding of the geneticbasis of cerebrovascular malformations, especially the sporadic ones, will lead to similar genotype-phenotype studies, assisting the clinical treatment decision making process in the future.

Stroke in underrepresented populations

Recent studies suggest that it is not only the higher prevalence of risk factors, but also the overall lower socioeconomic status and health care system challenges that contribute e to strokehealth disparities seen among US racial/ethnic groups. It is likely that new methods and study designs will be necessary to d isentangle these complex relationships that create health disparitiesfor stroke and diseases that are important risk factors for stroke, like hypertension and diabetes mellitus. A key area of research will be the investigation of the biological (age, sex and genetics)and behavioral (environmental) bases of stroke and stroke risk factor differences in multi-ethnic populations, as well as their potential interactions contributing to stroke outcomes. As thepopulation genetics field shifts its focus from investigating common variants to rare variants, inclusion of minority populations will be critical for exploring disease biology.

Genetic analysis

Large epidemiological studies focusing on meta-analytic and Mendelian randomization analyses of both clinical risk factors combined with genetic factors have shown possible therapeutictargets for stroke prevention. Recent studies have incorporated genetic data in interventions to determine optimal therapeutic patterns that enhance risk reduction with improved efficacy. Thesestudies represent one application of genomics to personalized medicine.

Mitochon drial genetics

Next-generation technologies provide a potential avenue of investigation through whole mtDNA genome sequencing. In addition, identification and quantification of levels of mtDNA deletionsand heteroplasmy within disease-related tissue is yet to be performed. A concerted collaborative effort to generate large datasets of mtDNA variation is required, including the parametersmentioned above.

Functional understanding of etiology

Top priorities for the future include studies with greater focus on defining the cell-specific impact of genetic factors in SVD. The need for development and use of models that better mimic thehuman condition, including better incorporation of risk factors and issues related to gender and aging, remain. Models that incorporate newer advances in human genetics will be critical inunraveling the pathogenesis and impact of SVD. One area that remains unresolved is the etiological relevance of the MCAO model to the various types of stroke seen in humans. Although thisis a robust model and has been used to develop some therapies that have moved forward into clinical use, how well it can be leveraged to address genetic risk factors is unclear.

GWAS and other studies provide identified loci that may alter risk for stroke or of differences in outcome between people. However, identifying a locus does not a priori identify a mechanism.One way to address the proximal effect of gene variation is to look at the effects of nominated SNPs on gene expression. This has been done in a series of eQTL (expression quantitative traitloci) mapping experiments, including in brain. Some of these datasets are publically available and can be mined to nominate c andidates for functional effects of risk, which may be helpful indesigning animal experiments and in identifying new targets for therapy. However, in the context of stroke, the ongoing pathological process in the brain may modulate genetically controlledgene expression. One missing element is to look at genotype: gene expression relationships in the context of subtypes of stroke and of stroke outcomes.

Pharmacogenomics

Research on prevention of first and recurrent stroke

Investigation of group and individual responses to therapies has the potential to both improve mechanistic understanding of drug response and develop individualized treatment for strokeprevention. Regardless of a trials outcome, pharmacogenomic and bioma rker data that provide insight into mechanism of effect, differential treatment response, and identification of susceptibleand resistant subpopulations have the potential to amortize the NINDS investment in testing of specific agents. Incorporating genetic and biomarker analyses into every clinical trial would takeadvantage of the rich phenotypic data captured in the trial and would be an efficient use of scarce resources by compounding the return on investment. Furthermore, critical determinants ofdrug action are often poorly defined when a drug reaches market. Thus, having incorporated sample collection in the clinical trial populations provides an efficient and scientifically soundopportunity to test new theories, assess the impact of genetic factors (using Mendelian randomization), and compare in vitro surrogates to the gold standard clinical outcome.

Research on improving outcomes from stroke

Little is currently known about pharmacogenomics of rehabilitative therapies. Similar to investigation of acute treatments, studies of agents that ameliorate the devastating consequences ofstroke or enhance recovery should also include collection of genetic and biomarker data.

Research on reducing the burden of stroke among underrepresented populations

The differential responses across racial and ethnic groups to drugs used to prevent and treat stroke warrant further investigation. T he recent NIH initiatives partnering with African investigatorsmay provide unique opportunities to investigate genetic and environmental determinants of stroke risk in ancestral and Diaspora populations and allow meaningful intra- and inter-racialinvestigation of pharmacogenomics.

EPIDEMIOLOGY AND RISK FACTORS

Co-Chairs : Ralph Sacco, Lynda Lisabeth, Brett Kissela

Members : Heather Fullerton, Philip Gorelick, George Howard, Steve Kittner, Judith Lichtman, Matthew Reeves, Philip Wolf, Dan Woo

NINDS Liaisons : Claudia Moy, Salina Waddy

STROKE PRG 2011 REVIEW REPORT SUMMARY

Epidemiologic research is critical for understanding the public health burden of stroke. Through epidemiologic research, population subgroups at the greatest risk of stroke are id entifiedallowing for the prioritization of future research and funding. High quality observational epidemiologic studies are critical in identifying new associations and relationships which can be translatedinto the development of interventions to reduce the public health impact of stroke through clinical and behavioral intervention trials. Some of the observed reduction in stroke i ncidence andmortality, as well as improved outcomes in recent stroke clinical trials, has been attributed to more intensive control of risk factors. A great deal of progress has been made in strokeepidemiology since the last SPRG. Staff identified at least 35 grant awards (23 NINDS, 12 non-NINDS) since 2007 that were related to stroke epidemiology. Advances are summarized in avariety of areas:

Common Data Elements (Previous Priority #1) NINDS initiated a Common Data Element (CDE) project to facilitate the combining of epidemiologic data from multiplesources and studies

Linkage between Epidemiological Data and Administrative Data (Previous Priority #1) - Several NIH funded grants are linking population-based epidemiologic studies toMedicare data, allowing for the identification of strokes

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Stroke Trends (Previous Priority #2) New epidemiologic data on temporal trends in stroke incidence have been published from the Framingham Heart Study, the GreaterCincinnati-Northern Kentucky Stroke Study, and the Brain Attack Surveillance in Corpus Christi (BASIC)

Epidemiologic Training (Previous Priority #3) - Increase in training opportunities in clinical research methodology and epidemiology: at least 6 NINDS T32 programs, 19 K23s,2 K24s, 4 K02s, and 1 F31 have been funded. SPOTRIAS and R25s have also increased research training.

Other advances in areas are outlined including: Stroke Geography, Stroke in Women, Pediatric Stroke, Disparities in Stroke Care, Novel Risk Factors, Vascular CognitiveImpairment, Stroke Genetic Epidemiology, and Translational Epidemiology

New stroke research opportunities, emerging topics, and unresolved areas since 2007 are summarized across a variety of topic areas : Race-ethnic and Geographic Disparities,Eliminating stroke health disparities, Post-stroke Outcomes including Cognition, Stroke in Women including HRT, Pediatric Stroke, Stroke Trends, Novel Risk Factors including Socioculturalfactors and subclinical disease, and Epidemiologic Training

Three priorities for future directions of stroke epidemiology research:

1. Improve the Understanding of Race and Ethnic Stroke Disparities (TOP PRIORITY)

Despite recent successes from NIH-funded studies providing some insights into the causes of these disparities, the understanding of the contributors to these disparities remains insufficient toguide development of interventions. Epidemiologic studies need to focus on specific gaps in our understanding of the risk, de terminants and outcomes of stroke in special populations includingwomen, racial and ethnic subgroups, and children, as well as explanation for geographic variability.

2. Evaluate the usefulness of health IT as a tool for epidemiology research

There has been an explosion of electronic health-related data, including large administrative data sets and data collected in electronic medical records, which will become increasingly availablefor research studies. A major priority in the next 5 years will be to evaluate the validity and effectiveness of these data sources in providing added value to stroke epidemiology and surveillancestudies.

3. Translate Knowledge from Epidemiological Studies into Improved Health

Continued support of epidemiologic stroke studies that monitor trends in stroke burden, fill gaps in knowledge, and discover new associations should be a high priority. Critically, we need toaccelerate the translation of the results from epidemiology studies into improved health by informing evidence-based practice recommendations and clinical care, translating findings intobehavioral interventions, and providing the fundamental preliminary data needed for randomized clinical trials. ?

TOP STROKE EPIDEMIOLOGY RESEARCH ADVANCES SINCE 2007

Epidemiologic research is critical for understanding the public health burden of stroke including the distribution of stroke in the population as well as its determinants. Through epidemiologicresearch, population subgroups at the greatest risk of stroke are identified allowing for the prioritization of future research and funding. Epidemiologic research is essential for examining trendsin stroke over time, including changes in disease burden such as risk and outcomes, as well as prevalence and control of risk factors, data that are pivotal to identify emerging problems, butalso to document our successes in the f ield. Finally, high quality observational epidemiologic studies are critical in identifying new associations and relationships which can be translated into thedevelopment of interventions to reduce the public health impact of stroke through clinical and behavioral intervention trials. A great deal of progress has been made in stroke epidemiologyduring the interval since the last Stroke Progress Review Group report. Staff identified at least 35 grant awards (23 NINDS, 12 non-NINDS) since 2007 that were related to stroke epidemiology.Some of these advances are described below.

Common Data Elements (Previous Priority #1)

To facilitate the combining of epidemiologic data from multiple sources and studies for more powerful analyses, there is a need for common data elements and definitions. As part of its effort tofacilitate high quality research and streamline clinical trial data collection, NINDS initiated a Common Data Element (CDE) project. A stroke CDE working group was assembled and datastandards that include recommended CDEs as well as case report forms, which could be used by epidemiologic studies, were developed. The National Human Genome Research Institute

(NHGRI) has also developed the PhenX Toolkit, which provides standard measures related to complex diseases, phenotypic traits and environmental exposures relevant to epidemiologicalstudies of stroke.

Linkage between Epidemiological Data and Admin istrative Data (Previous Priority #1)

Several NIH funded grants are linking population-based epidemiologic studies to Medicare data, allowing for the identification of strokes without the logistical difficulty and expense of medicallyverified stroke events. As examples the NIH-funded Chicago Health and Aging Project has been linked to Medicare data and is being used to study psychosocial risk factors for stroke in abiracial population. The Health and Retirement Study has been linked to Medicare and is being used to study factors related to functional and cognitive outcome following stroke. The GWTG-Stroke registry has also been linked with Medicare files. This linkage will provide important opportunities to measure longer term post-discharge outcomes such as 30-day and 1-year mortalityand readmission rates.

Stroke Trends (Previous Priority #2)

New epidemiologic data on temporal trends in stroke incidence have been published. The Framingham Heart Study (FHS) reported trends in incidence data showing a significant decline instroke incidence over the 50-year span of the study. Data from the Greater Cincinnati/Northern Kentucky Stroke Study (GCNKSS) also showed a decline in stroke incidence for whites but notfor blacks over the time period 1993-94 through 2005. Importantly, GCNKSS has been funded to continue to examine trends over time. In addition, the Brain Attack Surveillance in CorpusChristi (BASIC) Project has been funded to examine trends in stroke incidence in Mexican Americans, an understudied population with increased stroke risk.

Epidemiologic Trainin g (Previous Priority #3)

An increase in training opportunities in clinical research methodology and epidemiology has occurred since 2007. At least 6 NINDS T32 programs exist that include training opportunities forclinical research methods. At least 19 K23 awards and 2 K24s have been awarded to encourage further clinical research training and mentorship. At least 4 K02 grants support investigators instroke epidemiology. At least 1 F31 award has also supported a pre-doctoral student investigating stroke epidemiology. The CTSAs at multiple institutions have improved the infrastructure forclinical research and have interfaced with K30 and K12 programs to support more training opportunities. The SPOTRIAS program included a training core in several of the awards. The R25program was launched to allow residents to enter research training in the PGY4 year and accelerate a more rapid transition into research. A number of workshops/training courses haveemphasized clinical trial methodology training, but few have been specifically directed towards observational epidemiology: NIMHD Translational Health DisparitiesCours e http://www.nimhd.nih.gov/hdss/NIMHD_thdc.html , Clinical Trial Methods Course in Neurolog yhttp://www.neurologytrials.org/CourseInformation.aspx , The Science of Small ClinicalTrial s http://small-trials.keenminds.org/ .

Stroke Geography

The Reasons for Geographic and Racial Disparities in Stroke (REGARDS) Study published its first stroke incidence results. Consistent with previous studies, this study found higher strokerates for blacks versus whites, especially at younger ages. The study further showed that the geographic variation in stroke mortality (with highest mortality in the southeastern US, the "strokebelt") is due in part to higher incidence rates in blacks versus whites.

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Stroke in Women

New epidemiologic data illustrating the public health impact of stroke in women have emerged. Data from the FHS have demonstrated that women have greater lifetime risk of stroke than men.Data from several population-based studies, including the FHS, have reported on the reversal of the association between sex and stroke with advanced age such that women have anincreased risk compared with men in the oldest ages. Several papers have been published documenting worse post-stroke outcomes in women than men, particularly functional outcomes andinstitutionalization.

Hormone Replacement Therapy and Stroke

New observational epidemiologic data from Europe have emerged suggesting that current use of low dose transdermal estrogen may not increase stroke risk among post-menopausal women.

Pediatric Stroke

New epidemiologic data regarding disparities, risk factors and cost in pediatric stroke have been published. A previously documented race disparity in US childhood ischemic stroke mortality(black>white) has largely resolved, likely due to the implementation of transfusion therapy as per the NINDS funded STOP trial. A UK study demonstrated higher pediatric stroke mortality inboys than girls, consistent with previously documented findings from the US. The International Pediatric Stroke Study also demonstrated a male predominance in childhood ischemic strokeincidence. Elevated testosterone levels were associated with childhood ischemic stroke in a case-control study, suggesting a possible mechanism for sex differences. Recent minor acuteinfections and head or neck trauma have emerged as risk factors for childhood arterial ischemic stroke. The same case-control study suggested that traditional atherosclerotic risk factors mayplay a role in stroke in adolescents. A study using ad ministrative data suggested that atherosclerotic risk factors are prevalent in adolescents and young adults admitted for stroke. Direct costsof neonatal and childhood stroke (acute and 5 -year costs) have been published and exceed reported costs for adult stroke.

Disparities in Stroke Care

The Get With the Guidelines (GWTG)-Stroke program has grown immensely, with data from over 1.6 million stroke admissions from more than 1,400 US hospitals. The GWTG data haveprovided important insights into disparities in the quality of stroke care. GWTG-Stroke data on race/ethnic differences in care among ischemic stroke patients found that compared to non-Hispanic white (NHW) patients, black patients had modest but consistently poorer care for several performance measures including tPA use, DVT prophylaxis, lipid therapy, antithrombotictherapy at discharge, anticoagulation therapy among atrial fibrillation patients, and smoking cessation. The quality of care was similar between Hispanic and NHW patients. GWTG-Stroke dataexamining sex differences among ischemic stroke patients have documented that women were less likely than men to receive defect free care (66% vs. 71%).

Novel Risk Factors

As control of traditional risk factors improves, the importance of novel risk factors may increase. Epidemiologic research from a variety studies including REGARDS and NOMAS has identifiedseveral novel stroke risk factors as independent predictors of stroke including obstructive sleep apnea, metabolic syndrome, chronic kidney disease, insulin resistance, high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A2, lipoprotein (a), and infectious burden. Subclinical measures such as carotid plaque area, distensibility, white matter hyperintensities,and silent strokes are related to traditional and novel vascular risk factors and are determinants of stroke and cognitive impairment.

Epidemiologic research has begun to explore the role of the environment in stroke. Ecologic studies have suggested links between neighborhood disadvantage and density of fast foodrestaurants and stroke risk. Neighborhood-level social cohesion was recently found to be protective against stroke mortality in a prospective study after accounting for sociodemographics andrisk factors. New evidence regarding the association between air pollution and stroke has also emerged.

Vascular Cognitive Impairment

As reviewed in detail in the Vascular Cognitive Impairment section, epidemiologic research has demonstrated that vascular risk factors are increasingly recognized as contributing to cognitivedecline and dementia. Data from FHS, Northern Manhattan Study (NOMAS), and Rotterdam have shown that vascular risk factors are associated with subclinical microvascular disease therebycontributing to cognitive impairment associated with aging. Covert cerebral infarcts and microvascular changes predispose to cognitive decline, depression and gait disturbance and to overtbrain infarcts and are more frequent in African Americans. It is now known that cerebrovascular disease frequently co- exists with Alzheimers Disease pathology and appears to exacerbate thecognitive impairment in patients with Alzheimers dementia. Incident cognitive decline occurred more commonly in the stroke b elt compared to other geographic regions, possibly related tosubclinical strokes and/or precursor or concomitant risk factors for both stroke and cognitive impairment. Neuroimaging studies have identified a markedly increased rate of microhemorrhagesamong African-American ICH cases.

Stroke Genetic Epidemiology

As explicated in detail in the Genetics section, several advances in stroke genetics have been made. Specific to genetic epidemiology, familial aggregation studies based on confirmedoccurrence of stroke in both parents and offspring have more firmly established family history as an independent risk factor for ischemic stroke. In the FHS, parental ischemic stroke by the ageof 65 was associated with a 300% increase in ischemic stroke risk in the offspring, even after adjustment for other vascular risk factors. Increased risk conferred by family history was greatest inthe subgroup with other established stroke risk factors. Case-control and prospective studies have identified family history of ruptured intracranial aneurysm and smoking as risk factors forrupture of intracranial aneurysm, with important implications for screening and patient management. Meta-analysis of intracerebral hemorrhage studies has shown that Apo-E genotypes are notonly associated with lobar intracerebral hemorrhage but also with deep intracerebral hemorrhage. Large GWA studies of non-stroke conditions such as myocardial infarction and atrial fibrillationhave led to replicated ischemic stroke subtype-specific genetic associations with atherosclerotic at chromosome 4q25 and cardioembolic stroke at chromosome 16q22, respectively. LargeGWA studies of subarachnoid hemorrhage have identified replicated associations at new candidate genes. Precursor subclinical traits such as carotid IMT, carotid plaque, left ventricular mass,and left atrial size have been found to have high heritability and preliminary regions of linkage identified in the Family Study Of Stroke Risk and Carotid Atherosclerosis.

New projects have been initiated to address the genetics of stroke including the NINDS Stroke Genetics Network Study (SiGN), Risk Assessment of Cerebrovascular Events Study (RACE),Ethnic/Racial Variation in Intracerebral Hemorrhage (ERICH), Genetics of Intracerebral Hemorrhage in Anticoagulation (GOCHA), Familial Intracranial Aneurysm Study II (FIA II), and Predictorsof Spontaneous Cerebral AVM Hemorrhage.

Translational Epidemiology

Epidemiologic studies have identified key stroke risk factors, led to intervention trials, and provided evidence for guidelines. There are several recent examples that illustrate how epidemiology

has informed intervention trials and clinical practice. A few relevant examples are provided. Epidemiologic study from NOMAS and others has demonstrated that patients taking statins at thetime of stroke have decreased mortality and improved outcomes. This coupled with the pre-clinical data on the potential neuroprotective properties of statins have led to NINDS funded phase 1and 2 trials. Observational data on the variation in outcomes for mild and rapidly improving stroke patients who are not treated with IV rtPA have led to the design of proposed trials. Data fromthe BASIC Project have identified increased stroke risk in Mexican Americans driven in part by increased prevalence of risk factors. This research has been translated into an NINDS fundedculturally-sensitive, church-based, multicomponent, behavioral intervention for Mexican Americans and non-Hispanic whites to reduce important behavioral and biological stroke risk factors.Epidemiologic data demonstrating the independent association of obstructive sleep apnea with stroke and cardiovascular disease endpoints have resulted in a clinical trial of sleep apneatreatment among patients with TIA.

In summary, epidemiologic research has made significant progress since the last SPRG report. Research funded by NINDS and other NIH Institutes has resulted in a clearer understanding ofthe public health burden of stroke in high risk groups, including African Americans, women, children, and those residing in the southeast US. A significant decline in stroke incidence in whiteshas been reported but a similar trend in African Americans is not apparent. Novel stroke risk factors have been identified, a nd knowledge gained has been transformed into interventions thatmay improve the health of the US population.

NEW STROKE RESEARCH OPPORTUNITIES, EMERGING TOPICS, AND UNRESOLVED AREAS SINCE 2007

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Race-ethnic and Geographic Disparities

Although one of the two primary goals of the Healthy People 2010 report was the elimination of health disparities, the magnitude of racial and geographic stroke disparities substantiallyincreased between 2000 and 2010. The understanding of the contributors to these disparities remains insufficient to guide the development of interventions to reduce the disparities. Forexample, traditional risk factors have been shown to contribute less than half of the black-to-white racial disparities in stroke, where the unexplained additional risk may potentially beattributable to sources only now beginning to be investigated.

Eliminating Stroke Health Disparities

Eliminating stroke health disparities will likely require multi-level interventions that address not only the individual factors that are associated with stroke but also the structural conditions thatdisproportionately expose race-ethnic minorities to elevated risk. Research regarding the role of the environment in stroke has lagged substantially behind progress in heart disease. Researchis needed to identify specific features of the social and physical environment, both positive and negative, that influence stroke risk. Understanding the pathways by which env ironmentsinfluence stroke risk could inform the development of novel multi-level interventions to reduce stroke risk and to reduce race-ethnic disparities.

Post-stroke Outcomes including Cognition

Better epidemiologic data regarding post-stroke outcomes, including functional, cognitive, neurologic and quality of life outcomes, are needed. In particular, there i s a lack of information onlong-term stroke outcomes in representative populations, and there is very limited information about stroke outcomes in race-ethnic minorities. The lack of outcome data in race-ethnicminorities is particularly important given the considerably younger average age at stroke onset in African and Hispanic Americans. The limited availability of stroke outcome data is partiallydriven by the difficulty in collecting outcome measures 90-days or greater post-stroke.

The number of stroke survivors will increase dramatically with the aging US population. Post-acute rehabilitation care will play an increasingly important role in our health care system. Thereare significant gaps in our understanding of the use and effectiveness of post-acute care for stroke largely due to difficulty obtaining longitudinal outcome data on survivors treated acrossdifferent post-acute care settings. There is a need to develop better measures and determinants of long term outcomes post-stroke. The development of proxy measures collected at or soonafter discharge that accurately reflect later recovery would assist in research aimed at assessing disparities in outcomes as well as research aimed at evaluating the impact of hospital-basedstroke care or post-acute care.

Comparative effectiveness research that identifies post-acute care settings and patterns associated with better post-stroke outcomes could guide future intervention studies designed to developmore effective, equitable and cost-effective approaches to post-acute care in stroke survivors.

Stroke in Women

The stroke burden in women is higher than for men, including an increased lifetime risk and less favorable outcomes after stroke, particularly functional outcomes. This disparity has receivedlittle attention compared to other health disparities. The lack of information on the reasons why women have poorer outcomes post-stroke has prohibited the design of interventions aimed atreducing the high burden of stroke disability in women.

Hormone Replacement Therapy and Stroke

Clinical trial data indicate that use of standard dose estrogen plus progestin, as well as estrogen alone, increases stroke risk in healthy post-menopausal women. It is unknown how thesefindings have influenced use of hormone therapy over time and the subsequent impact on stroke risk in women. In addition, more epidemiologic research is needed to understand the safestand most effective formulation, dose, and duration of hormone therapy that will treat vasomotor symptoms without increasing risk for stroke.

Pediatric Stroke

The NINDS-funded Vascular effects of Infection in Pediatric Stroke (VIPS) study will explore the role of infection in childhood arterial ischemic stroke, particularly cerebral arteriopathy. Studiesof the genetics of childhood arteriopathies including genetic susceptibility to the vascular effects of infection are needed. Trauma has emerged as an important risk factor for stroke in the young.Because boys sustain more trauma than girls, and black children more than white children, this risk factor may partly explain observed sex and race disparities in childhood stroke risk butadditional research is needed. Clinical prediction rules for stroke after trauma are not available, yet could be useful in identifying a subgroup of high risk trauma victims that could be targeted forprophylactic anti-thrombotic therapy. Recent data suggest that atherosclerotic risk factors may play a role in adolescent stroke. A better understanding of these associations is important forpublic health measures; it may be that detection and management of these risk factors should start in childhood. Data on rates of recurrent stroke in children are limited, yet critical for thedesign of secondary stroke prevention studies. The VIPS study will measure recurrence rates, and predictors of recurrence, in a prospective cohort. There are no published utilities for pediatricstroke; hence, cost-utility analyses for pediatric stroke treatments cannot be performed. The majority of childhood stroke research has focused on ischemic stroke. The most common cause ofa childhood hemorrhagic stroke is a structural vascular lesion: arteriovenous malformation, cavernous malformation, or aneurysm. Although there are NIH-funded studies on vascularmalformations, risk factors for cerebral aneurysms in children have not been studied.

Stroke Trends

The US population is changing rapidly with respect to demographic composition and risk factor prevalence. In addition, our ability to prevent and treat strokes is changing. For these reasons, itis imperative that there is continued funding for epidemiologic studies to collect data on secular and temporal trends in stroke incidence, recurrence, mortality, and functional and cognitiveoutcomes. Currently, limited data are available to evaluate long term trends in minority populations and less so for hemorrhagic stroke compared to ischemic stroke. Temporal trends ofhemorrhagic stroke in high risk populations are also needed to identify high impact areas for potential intervention.

Novel Risk Factors includi ng Sociocultural factors and subclinical disease

Traditional risk factors explain a large proportion of stroke risk, but further studies of novel stroke risk factors including sociocultural and environmental factors and subclinical disease may helprefine risk prediction and lead to new prevention and/or intervention approaches. Studies on the progression of subclinical diseases also can aid in defining surrogate measures for potential riskmodifying therapies.

Epidemiologic Training

Metrics are needed to measure the success of previously instituted training programs on launching research careers. There is a need to accelerate training in clinical research andepidemiologic methods during residency and fellowship with more training grants (including R25s). Further expansion of short courses to help clinical investigators become more competitive inclinical and translational study design, including courses for observational epidemiology, are needed. Training programs to encourage pre-doctoral students in epidemiology and biostatistics toengage in stroke research are needed.

THREE PRIORITIES FOR FUTURE DIRECTIONS OF STROKE EPIDEMIOLOGY RESEARCH:

1. Improve the Understanding of Race and Ethnic Stroke Disparities

Although rates of stroke and mortality are dropping across many population groups, significant disparities continue to exist. The persistence of these disparities has led to high-level goals in theHHS Action Plan to Reduce Racial and Ethnic Health Dispari ties to increase the availability, quality, and use of data to improve the health of minority populations and underscoring the need to

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implement a multifaceted health disparities data collection strategy across HHS. Likewise, the Institute of Medicine statement on the surveillance of cardiovascular and chronic lung diseasesstated that Untangling the effects of environment, income, education, race, ethnicity, and genetic