Stroke: 

Challenges, Progress, 

and Promise

February 2009

National Institute of 

Neurological Disorders 

and Stroke

National Institutes of Health
Contents

Introduction ___________________________________________________________________________________________________________1

 

1

 Stroke Basics __________________________________________________________________________________________________3

Ischemic Stroke and Transient Ischemic Attack _____________________________________________________3

Hemorrhagic Stroke ____________________________________________________________________________________________5

Vascular Cognitive Impairment ____________________________________________________________________________6

 

2

 Stroke Diagnostics and Brain Imaging ___________________________________________________ 7

3

 Stroke Risk Factors_______________________________________________________________________________________9

Unmodifiable Risk Factors ___________________________________________________________________________________9 

Modifiable Risk Factors______________________________________________________________________________________ 10

 

4

 Current Stroke Treatment and Prevention __________________________________________ 14

Medications ______________________________________________________________________________________________________ 14

Surgeries and Other Procedures ________________________________________________________________________ 17

Rehabilitation ___________________________________________________________________________________________________ 19

 

5

 Research and Hope for the Future ________________________________________________________20

Prevention ________________________________________________________________________________________________________20

Acute Stroke and Post-Stroke Therapy ________________________________________________________________ 23

Neuroprotection _______________________________________________________________________________________________ 25

 

6

 Changing Stroke’s Impact by Changing Attitudes _____________________________ 32

Introduction

Chances are

that nearly everyone... 

 ...reading this has already had an unwelcome 

introduction to stroke, perhaps through 

firsthand experience or by witnessing its effects 

on a relative. Research sponsored by the National 

Institutes of Health (NIH) shows that about one 

in six Americans will experience a stroke at some 

point after age 65. Stroke is fatal in about 10 to 

20 percent of cases and, among survivors, it can 

cause a host of disabilities, including loss of mobility, 

impaired speech, and cognitive problems. These 

trends have made stroke the third leading cause 

of death in the U.S. (behind heart disease and 

cancer) and a major cause of disability. 

A stroke is a sudden event affecting the brain’s 

blood supply. In an ischemic stroke, a blood 

vessel that supplies the brain becomes blocked. 

In a hemorrhagic stroke, a blood vessel in the 

brain bursts. Although stroke is most common in 

older people, it can occur in individuals of any age, 

including young adults, children, infants, and 

fetuses in the womb.

Fortunately, the prospects for preventing and 

treating stroke are far better than they were just 

a few decades ago, thanks in part to research 

supported by the NIH’s National Institute of 

Neurological Disorders and Stroke (NINDS). 

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. 

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 

within three hours of stroke onset, the drug significantly 

reduces the likelihood of long-term disability. 

Current NINDS priorities in stroke research are set 

by its Stroke Progress Review Group (SPRG), 

an advisory body made up of scientists, clinicians, 

patient advocates, and industry representatives. 

One such priority is to develop new and more 

effective treatments for acute stroke. NINDS is 

supporting research on novel ways to restore 

blood flow to the ischemic brain, as well as 

treatments that would act directly on brain cells to 

protect them from the effects of stroke. 

Another priority is to improve post-stroke recovery 

by tapping into the brain’s capacity to repair 

itself; for example, by using drugs to stimulate 

the growth of new brain cells or physical therapy 

regimens to stimulate the re-wiring of existing cells. 

Finally, stroke prevention and the identification of 

stroke risk factors remain important parts of the 

NINDS portfolio.

Stroke: Challenges, Progress, and Promise 1
2

An ischemic stroke occurs when a blood ve

supplying the brain becomes blocked, as by a c

2 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise3

sel A hemorrhagic stroke occurs when a blood vessel lot. bursts, leaking blood into the brain.

NINDS supports several complementary 

networks of research centers aimed at 

improving treatment and care for individuals 

with acute stroke. The Specialized Program 

of Translational Research in Acute Stroke 

(SPOTRIAS) helps move experimental therapies 

for acute stroke from the lab into early-phase 

clinical studies. SPOTRIAS sites are located 

at major academic medical centers across 

the country, where scientists studying the 

molecular and cellular mechanisms of stroke 

can work closely with clinicians who have 

expertise in acute stroke care. The Neurological 

Emergencies Treatment Trials (NETT) network 

creates a similar collaborative framework among 

neurologists, neurosurgeons, and emergency 

medicine physicians to facilitate clinical trials 

on stroke in the emergency room. Meanwhile, 

through the Stroke Preclinical Trials Consortia, 

NINDS is forging collaboration among 

investigators who are testing potential stroke 

treatments in animal models. Finally, NINDS 

outreach programs help bridge research and 

practice by educating individuals, their loved 

ones, and healthcare providers about the latest 

advances in treatment and prevention.

NINDS is supporting 

research on novel ways to 

restore blood flow to the 

ischemic brain, as well as 

treatments that would act directly 

on brain cells to protect them 

from the effects of stroke.

1. Stroke 

basics

The effects of stroke manifest themselves rapidly. 

 The five most common symptoms of stroke are: n Sudden weakness or numbness of the face or 

limbs, especially on one side of the body.

n S udden confusion or difficulty speaking or 

understanding speech.

n Sudden trouble seeing in one or both eyes. n Sudden trouble walking, dizziness, or loss of 

balance or coordination.

n S udden severe headache with no known cause.

The exact symptoms depend on where in the 

brain’s vascular system the blockage or rupture 

has occurred. Strokes that predominantly affect 

one hemisphere of the brain are common. Since 

each hemisphere controls the opposite side of 

the body, a stroke in the left hemisphere will 

cause motor and sensory deficits on the right side 

of the body, and vice versa.

The long-term outcomes after a stroke vary 

considerably and depend partly on the type 

of stroke and the age of the affected person. 

Although most stroke survivors regain their 

functional independence, 15 to 30 percent will 

have a permanent physical disability. Some will 

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.

Ischemic Stroke and 

Transient Ischemic Attack

Ischemic strokes make up about 80 percent 

of all strokes. Just as a heart attack occurs 

when there is insufficient blood flow to the 

heart, an ischemic stroke (sometimes called 

a “brain attack”) occurs when there is a sudden 

interruption in blood flow to one or more 

regions of the brain. Like all cells in the body, 

neurons and other brain cells require oxygen 

and glucose delivered through the blood in 

order to function and survive. A few minutes of 

oxygen deprivation—called ischemia—is enough 

to kill millions of neurons. Moreover, ischemia 

can provoke inflammation, swelling (edema), 

and other processes that can continue to cause 

damage for hours to days after the initial insult.

Obstructive blood clots are the most common 

cause of ischemic stroke. Clotting (or coagulation) 

is a vital function that helps prevent bleeding 

when a blood vessel is damaged, but clots can 

also obstruct normal blood flow. When a clot 

forms in association with the wall of a blood 
Medical Terms for Common 

Stroke Symptoms and Disabilities 

Hemiplegia: paralysis on one side of the body.

Hemiparesis: weakness on one side of the body.

Hemineglect: lack of awareness of one side of 

the body or one side of the visual field. 

Dysphagia: difficulty swallowing. 

Dysarthria: difficulty talking, caused by 

facial weakness. 

Aphasia: difficulty speaking or understanding speech, 

caused by damage to the brain’s language centers.

vessel and grows large enough to impair blood 

flow, it is called a thrombus; a clot that breaks 

off the vessel wall and travels through the blood 

is an embolus. A cardioembolic stroke is 

caused by a clot that originates in the heart. 

Cardiac emboli are most likely to form in people 

with heart conditions such as atrial fibrillation 

(AF, an irregular heartbeat), heart failure, stenosis, 

or infections within the valves of the heart. 

They may also occur post-heart attack.

Another contributor to ischemic stroke is chronic 

atherosclerosis, which is a buildup of fatty deposits 

and cellular debris (plaque) on the inside of the 

blood vessel wall. As atherosclerotic plaques 

grow, they cause narrowing of the blood vessel 

(a condition called stenosis). Atherosclerosis can also 

activate cells involved in clotting.

Immediately after an ischemic stroke, the brain 

usually contains an irreversibly damaged core 

of tissue and an area of viable but at-risk tissue 

called the ischemic penumbra. Restoring 

normal blood flow—a process known as 

reperfusion—is essential to rescuing the 

penumbra. The longer reperfusion is delayed, 

the more cells in the penumbra will die. The 

region of brain tissue that is finally damaged is 

called an infarct.

If a stroke were a storm, a transient ischemic 

attack (TIA), or “mini-stroke,” would be an 

ominous thunderclap. Symptoms of a TIA 

are similar to those of a full-blown stroke but 

resolve within 24 hours, typically in less than one 

hour. Still, the short-lived nature of TIAs does 

not mean that they leave the brain unharmed. 

In about 40 to 50 percent of people who have 

experienced a TIA, a tiny dot of infarct can be 

seen by brain imaging.

Even when there is no sign of brain infarction, 

a TIA is both a warning and an opportunity 

for intervention. While someone who has 

experienced a full-blown stroke has a two to 

seven percent risk of having another stroke 

within the next 90 days; the 90-day risk of stroke 

following a TIA is 10 to 20 percent. In many 

cases, TIAs may be caused by an unstable clot 

that could create a more permanent blockage 

within the brain’s blood supply at any moment. 

Fortunately, there are a variety of treatments 

that can reduce the risk of stroke following 

a TIA, including medications to lower blood 

pressure and inhibit blood clotting. If necessary, 

surgical procedures can clear away plaque in the 

arteries that supply the brain, or a procedure 

called stenting can be used to widen the arteries. 

Severe strokes could be avoided if more people 

sought medical attention after a TIA. (For more 

about these treatments, see the chart on p. 10 

and “Current Stroke Treatment and Prevention” 

on p. 14.)

Hemorrhagic Stroke

An intracerebral hemorrhage occurs when 

a blood vessel ruptures within the brain. 

Several conditions can render blood vessels 

in the brain prone to rupture and bleeding. 

Chronic hypertension and a condition known 

as cerebral amyloid angiopathy can weaken the 

blood vessel wall. Poor blood clotting ability 

due to blood disorders or blood-thinning 

medications like warfarin further increase 

the risk of bleeding. Finally, structural 

abnormalities that can form in blood vessels 

during brain development also a play a role. 

For instance, an arteriovenous malformation 

(AVM) is a tangled mass of thin-walled cerebral 

blood vessels in the brain. AVMs are thought to 

be present from birth in one percent or less of 

the population. 

aneurysm

arteriovenous

malformation

An aneurysm is a bulge in a blood vessel and an 

arteriovenous malformation is a tangled mass 

of thin-walled vessels. Both of these structures 

are associated with a risk of hemorrhagic stroke.

Cerebral Amyloid 

Angiopathy

4 Curing Epilepsy: The Promise of Research Stroke: Challenges Curing Epilepsy: The Pro , Progress, and Promise mise of Research5

Cerebral amyloid angiopathy (CAA) refers to a 

buildup of protein deposits known as amyloid 

on the inside wall of blood vessels. It is a major 

contributing factor to intracerebral hemorrhage 

in older people and is sometimes associated with 

small ischemic infarctions and vascular cognitive 

impairment.

CAA is regarded as a disease of aging. It is rarely 

observed in individuals under age 50, but is 

seen in about 50 percent of individuals over age 

90. The proportion of intracerebral hemorrhage 

cases in older people that are causally linked to 

CAA is unclear, but recent estimates place that 

number as high as 50 percent.

The buildup of amyloid inside blood vessels 

weakens the vessel wall and may lead to 

blood vessel rupture. In recent years, a 

poorly understood connection has emerged 

between CAA and Alzheimer’s disease. 

Beta-amyloid—the toxic protein fragment that 

accumulates in clumps (called plaques) within 

the brain tissue of people with Alzheimer’s 

disease—is a component of the amyloid 

deposits found in people with CAA. Moreover, 

Alzheimer’s disease and CAA share similar 

genetic risk factors, such as the gene encoding 

apolipoprotein E (APOE). A variant of this 

gene known as e4 increases the risk of 

Alzheimer’s disease and the risk of recurrent 

intracerebral hemorrhage.
Stroke: Challenges, Progress, and Promise

7

A subarachnoid hemorrhage is the rupture of 

a blood vessel located within the subarachnoid 

space—a fluid-filled space between layers of 

connective tissue (meninges) that surround 

the brain. The first sign of a subarachnoid 

hemorrhage is typically a severe headache 

with a split-second onset and no known cause. 

Neurologists call this a thunderclap headache 

and it demands immediate medical attention. 

The rupture may occur in an AVM, but typically 

it occurs at a site where a blood vessel has 

weakened and bulged, called an aneurysm. 

Aneurysms affect as much as one percent of 

the population, and are sometimes hereditary. 

NINDS-funded studies have shown that the risk 

that an aneurysm will rupture is related to its 

size and shape, its location, and the person’s age. 

The risk is increased by smoking. Information about 

these risks helps doctors advise individuals on whether 

an asymptomatic aneurysm should be treated.

Immediately after an ischemic stroke (top left), a core 

of irreversibly damaged brain tissue (red) is surrounded 

by an area of viable but at-risk tissue called the 

penumbra (green). Unless blood flow is restored quickly, 

the tissue within the penumbra will be lost (bottom right).

Unlike other tissues in the body, neural tissue 

normally is shielded from direct contact 

with blood by the blood-brain barrier, which 

is a tightly sealed network of cellular and 

extracellular components that lines blood 

vessels in the brain. The blood-brain barrier 

is permeable to oxygen and other nutrients in 

the blood, but generally impermeable to red 

and white blood cells, and large molecules. 

During a hemorrhagic stroke, these cells and 

molecules are released en masse into the 

delicate environment that surrounds neurons. 

Meanwhile, the accumulation of blood, known 

as a hematoma, can cause an increase in 

intracranial pressure that further impairs 

normal blood flow and damages the brain 

by compression.

Vascular Cognitive 

Impairment

Even in the absence of a clinically obvious stroke 

or TIA, impaired blood flow in the brain may 

eventually lead to vascular cognitive impairment 

(VCI). At one extreme, VCI includes vascular 

dementia, but it also refers to a gradual decline 

in mental function caused by multiple strokes, 

some silent, over time. It is often associated 

with a more diffuse small vessel disease, caused 

by narrowing of small-diameter blood vessels 

that supply limited territories within the brain. 

Clinically, VCI may resemble Alzheimer’s 

disease (AD) and many older individuals with 

dementia meet the diagnostic criteria for both 

diseases. However, while AD primarily affects 

memory, VCI appears to primarily affect the 

brain’s executive function—the ability to plan 

activities from getting dressed in the morning to 

negotiating a business deal.

2. Stroke 

Diagnostics 

and brain 

Imaging

6 Stroke: Challenges, Progress, and Promise

W

 hen a stroke is suspected, a physician 

 will carry out a detailed assessment of the 

individual’s signs and symptoms. One common 

assessment tool is the NIH Stroke Scale, 

developed by NINDS. This is a checklist of 

questions and tasks that scores an individual’s 

level of alertness and ability to communicate and 

perform simple movements. Other common 

diagnostic procedures include blood tests and an 

electrocardiogram to check for cardiac abnormalities 

that might have contributed to the stroke.

Brain imaging techniques play an important 

role in stroke diagnosis, in the evaluation of 

individuals with stroke for clinical trials, and, 

to a growing extent, assessment of stroke risk. 

Several imaging techniques can be used to 

generate visual “slices” of the brain or even 

three-dimensional reconstructions. This in-depth 

look at the brain helps to: rule out other potential 

neurological conditions such as a brain tumor, 

differentiate ischemic from hemorrhagic stroke, 

identify which blood vessels have been damaged, 

and determine the extent and location of the infarct.

Computed tomography (CT) and magnetic 

resonance imaging (MRI) are the two most 

common imaging techniques used to identify 

infarctions caused by stroke. CT uses X-ray 

beams passed through the head at multiple angles 

to generate high-resolution brain images. It is 

faster, more widely available, and less expensive 

than MRI.

MRI, which does not involve X-rays, exposes the 

brain to a magnetic field in combination with a 

radio wave pulse. The brain’s absorption of this 

pulse and the rate at which energy is released 

when the pulse ends varies in different brain 

tissues and yields an image. Diffusion-weighted 

imaging (DWI) is a highly sensitive type of MRI 

that measures the diffusion of water in brain 

tissue, which changes during an ischemic stroke. 

DWI is especially useful for detecting small 

infarcts and is superior to CT for diagnosing 

ischemic stroke. Research studies suggest that 

DWI in combination with a brain blood perfusion 

study can be used to help identify the ischemic 

penumbra—brain tissue that is blood-starved, but 

salvageable if blood flow can be restored quickly. 

In many individuals, the extent of ischemic 

penumbra is related to the degree of diffusionperfusion mismatch, which is a DWI signal that 

occurs in brain tissue with normal water diffusion 

but abnormal blood flow.

Several imaging techniques are used to examine 

cerebral blood vessels. These techniques can 

reveal the site of blockage in an ischemic stroke 

or detect stenosis or vascular malformations (such 

as an aneurysm or AVM) that put a person at risk 

for stroke. Angiography of the brain involves 
8 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 9

MRI scans are commonly used to check for damage to the brain and the brain’s vasculature in people suspected of having a stroke.

 Brain imaging 

techniques play an important 

role in stroke diagnosis...and 

to a growing extent, in the 

assessment of stroke risk. Several 

imaging techniques can be used 

to generate visual “slices” of the 

brain or even three-dimensional 

reconstructions.

imaging after a contrast agent that shows up dark 

on a scan has been injected into a vein in the arm 

or leg, which yields a map of the brain’s blood vessels. 

A procedurally similar technique called perfusion 

imaging is sensitive for detecting abnormal 

blood flow in the brain. Doppler ultrasound 

involves passing high-frequency, inaudible sound 

waves into the neck or head. These sound waves 

bounce off of cells moving through the blood, 

producing an image and providing information 

on how fast the blood is traveling. In general, 

blood cells speed up as they move through a 

narrow vessel.

3. Stroke risk 

Factors

G

 iven that stroke is caused by blockage or 

 rupture of a blood vessel, it should be no 

surprise that similar modifiable risk factors 

contribute to stroke and cardiovascular disease, 

including hypertension, smoking, diabetes, 

high cholesterol, and lack of physical activity. It 

is possible to dramatically reduce these risks 

through healthier lifestyle choices or medications 

(such as blood pressure-lowering drugs). In fact, 

since 1950, there has been about a 60 percent 

decline in the mortality rate from stroke and a 

smaller but significant decline in the age-adjusted 

annual incidence of stroke—the number of 

people who have a stroke each year, adjusted to 

account for the increasing age of the population. 

Many experts attribute these trends to increasing 

awareness and control of stroke risk factors. 

(For quick facts about the most potent modifiable 

stroke risk factors and ways to counteract them, 

see “Modifiable Risk Factors ” on p. 10.)

Unmodifiable Risk Factors

The risk of stroke varies by age, sex, race, and 

even where we live. Although these risk factors 

are considered unmodifiable, they help inform 

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. 

The study, which receives primary support from 

NIH’s National Heart, Lung, and Blood Institute 

(NHLBI) and support for its stroke component 

from NINDS, has shown that the risk of stroke 

doubles for each decade between the ages 

of 55 and 85.

Stroke in young adults is relatively infrequent, 

but it does happen. The Northern Manhattan 

Study, supported by NINDS, found that, among 

people living in that area in the mid-1990s, the 

annual incidence of stroke was about two per 

10,000 among people age 20 to 44, and about 

56 per 10,000 among people ages 45 and older. 

This study and others in the U.S. have found that 

hemorrhagic and ischemic strokes tend to occur 

in roughly equal proportion in young people. 

The increased risk of stroke that occurs with age 

therefore appears to be mostly an increased risk 

of ischemic stroke. (Also see “Stroke in Infants 

and Children” on p. 11.)
10 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 11

Modifiable Risk Factors

Risk factor How much it affects stroke risk Why it affects stroke risk What you can do

Hypertension Hypertension causes a two- to 

four-fold increase in the risk of 

stroke before age 80. after age 

80, the impact of hypertension 

declines and other risk factors 

become more important.

Hypertension promotes 

atherosclerosis and causes mechanical 

damage to the walls of blood vessels. 

blood pressure medications, 

such as thiazide diuretics and 

angiotensin-converting enzyme 

(aCe) inhibitors, can reduce the 

risk of stroke by 30 to 40 percent. 

early treatment is essential. 

among older people with 

normal blood pressure, prior 

mid-life hypertension increases 

stroke risk up to 92 percent. 

Guidelines from the Centers for 

Disease Control and Prevention 

recommend a target blood pressure 

of less than 140/90 mm Hg. 

Cigarette smoking Smoking causes about a two-fold 

increase in the risk of ischemic 

stroke and up to a four-fold increase 

in the risk of hemorrhagic stroke. 

Smoking promotes atherosclerosis 

and aneurysm formation, and 

stimulates blood clotting factors. 

Stroke risk decreases significantly 

two years after quitting smoking 

and is at the level of nonsmokers 

by five years. 

Diabetes In terms of stroke and cardiovascular 

disease risk, having diabetes is the 

equivalent of aging 15 years.

In diabetes, glucose is not 

efficiently taken up by the body’s 

cells and accumulates in the blood 

instead, where it can damage the 

vascular system. Hypertension 

is common among diabetics 

and accounts for much of their 

increased stroke risk. 

blood pressure medications, 

dietary changes, and weight loss 

can lower stroke risk. Controlling 

blood sugar appears to reduce the 

risk of recurrent stroke. 

Physical 

obesity

inactivity and Waist-to-hip ratio equal to or 

above the median (mid-value 

the population) increases the 

of ischemic stroke three-fold.

for 

risk 

Obesity is associated with 

hypertension, diabetes, 

and heart disease.

While no clinical studies have 

tested the effects of exercise or 

weight loss on stroke risk, both 

tend to reduce hypertension and 

boost cardiovascular health. 

atrial fibrillation (aF) aF affects fewer than one percent 

of people under age 60, but is 

more prevalent in older people. 

It is responsible for one in four 

strokes after age 80, and is associated 

with high mortality and disability. 

aF refers to irregular contraction 

the atrium—the chamber where 

blood enters the heart. aF can 

lead to blood stagnation and 

increased clotting.

of Warfarin, a blood-thinning 

medication, can reduce the risk of 

stroke in people with aF. People 

under age 60 with aF and no other 

stroke risk factors may benefit from 

aspirin. Importantly, pacemakers 

have no effect on the risk of stroke 

associated with aF.

Cholesterol imbalance High-density lipoprotein (HDL) 

cholesterol is generally considered 

protective against ischemic stroke. 

Low-density lipoprotein (LDL) 

cholesterol, when present in excess, 

is considered harmful. 

LDL and HDL are needed to carry 

cholesterol (a fatty substance) 

through the blood (made up 

mostly of water), and deliver it 

to cells. because LDL delivers 

cholesterol to cells throughout 

the body, excess LDL can cause 

cholesterol to build up in blood 

vessels, leading to atherosclerosis. 

HDL sends cholesterol to the liver 

to be eliminated. 

Clinical trials have shown that 

cholesterol-lowering drugs known 

as statins reduce the risk of stroke. 

However, some studies point to 

only a weak association between 

stroke and cholesterol, and there 

is speculation that statins reduce 

stroke risk by acting through some 

unknown mechanism. 

Stroke in Infants and Children

Compared to stroke in the adult brain, stroke 

in the young, growing brain is associated with 

unique symptoms, risk factors, and outcomes—

and with more uncertainty in all three of these 

areas. Although stroke is often considered a 

disease of aging, the risk of stroke in childhood 

is actually highest during the perinatal period, 

which encompasses the last few months of fetal 

life and the first few weeks after birth.

As in adults, the symptoms of stroke in infants 

and children include headache, hemiplegia, and 

hemiparesis. But very young children with stroke 

are more likely than adults to experience other 

symptoms, such as seizures, breathing problems, 

or loss of consciousness. Because the incidence 

of childhood stroke is relatively low, parents 

and doctors often mistakenly attribute these 

symptoms to other causes, leading to delays in 

diagnosis. Moreover, the time of onset is usually 

unknown for strokes during the perinatal period.

Investigators know less about the risk of 

childhood stroke than they know about the 

risk of adult stroke. However, well-documented 

risk factors include congenital (inborn) heart 

abnormalities, head trauma, and bloodclotting disorders. An important risk factor 

for African American children is sickle cell 

disease. Although sickle cell disease is known 

for its effect on red blood cells—causing them 

to take on a sickle shape—it can also cause a 

narrowing of cerebral arteries. A 1998 study of 

some 3,000 people with sickle cell disease found 

that 11 percent experienced a stroke before age 

20. Fortunately, that same year, a study funded 

by NHLBI showed that repeated transfusions to 

replace sickled blood cells with normal blood 

cells reduced the risk of stroke by 92 percent. 

Yearly Doppler ultrasound imaging is recommended 

for young children with sickle cell disease and, 

if stenosis is found, repeated transfusions can 

be used as a means of stroke prevention.

Strokes during the perinatal period have been 

associated with premature birth, maternal 

infections, maternal drug abuse, prior infertility 

treatments, and maternal health conditions such 

as autoimmune disease and preeclampsia (a 

potentially serious combination of hypertension 

and kidney problems that affects about six 

percent of pregnant women).

The outcome of stroke in the very young is 

difficult to predict. A stroke during fetal 

development may lead to cerebral palsy—a 

permanent problem with body movement and 

muscle coordination that appears in infancy or 

early childhood. A stroke that occurs during 

infancy or childhood can also cause permanent 

disability. Generally, outcomes are worse in 

children under age one and in those who 

experience decreased consciousness or seizures. 

Fortunately, the developing brain is also known 

for its remarkable capacity to replace lost nerve 

cells and fix damaged connections between them. 

Healthy areas of the brain are often still pliable 

enough to compensate for damaged areas. 
12 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 13

A child with serious deficits immediately after a 

stroke can make an impressive recovery.

Treatment of stroke in children presents unique 

challenges. Delays in diagnosis, which can be 

especially prolonged in cases of perinatal stroke, 

mean that valuable time is lost. Moreover, most 

treatments for acute stroke were developed 

based on studies in adults and the guidelines for 

their use in children are still being refined. To 

address some of these issues, NINDS and NIH’s 

National Institute of Child Health and Human 

Development (NICHD) sponsored a workshop 

on perinatal stroke in August 2006 that brought 

together experts in pediatrics, neurology, 

cardiology, and public health. Goals set by this 

group include the development and testing 

of new therapies for perinatal stroke, a better 

understanding of the risk factors for it, and 

improved brain imaging methods to diagnose it. 

Stroke in Adults

From ages 55 to 75, the annual incidence and 

short-term risk of stroke are higher in men than 

in women. However, because women generally 

live longer than men, their lifetime risk of stroke 

is higher and they account for a larger fraction 

(about 61 percent) of stroke deaths each year.

Women have unique stroke risks associated 

with pregnancy and menopause. In women of 

childbearing age, the risk of stroke is relatively 

low (with an annual incidence of one in 10,000), 

but a recent study estimates that pregnancy 

increases that risk three-fold.

Several factors contribute to the increased risk of 

stroke during pregnancy. The activity of blood 

clotting proteins is naturally amplified during 

pregnancy, increasing the chances of ischemic 

stroke for the mother (and perhaps contributing 

to perinatal stroke). Most maternal strokes 

occur during the first several weeks after delivery, 

suggesting that the drop in blood volume or the 

rapid hormonal changes following childbirth 

also play a role. Pregnancy-related stroke is 

more likely to occur in women who experience 

certain complications, such as infections or 

preeclampsia, or who have other risk factors for 

stroke, such as hypertension or diabetes.

Hormone replacement therapy (HRT) may 

ease the discomfort and the loss of bone 

density associated with menopause. It was once 

considered a possible means of stroke prevention 

in post-menopausal women. However, a series 

of placebo-controlled clinical trials sponsored 

by NINDS and NHLBI has shown that HRT 

increases the risk of stroke. NHLBI’s Women’s 

Health Initiative showed that treatment with the 

hormones estrogen and progestin increased the 

risk of stroke by 31 percent in women with an 

intact uterus. In women who had undergone 

a hysterectomy, treatment with estrogen alone 

increased the risk of stroke by 39 percent. 

The NINDS Women’s Estrogen for Stroke Trial 

(WEST) found that women who had experienced 

a prior ischemic stroke and received estrogen 

were more likely to have a fatal recurrent stroke. 

Stroke Across Races and Regions

People from certain ethnic groups have a higher 

risk of stroke. Many studies show that the 

age-adjusted incidence of stroke is about twice 

as high in African Americans and Hispanic 

Americans as in Caucasians. Moreover, several 

studies have found that, on average, African and 

Hispanic Americans tend to experience stroke 

at younger ages than Caucasians. The stroke 

mortality rate is higher in African Americans 

than in Caucasians or Hispanics. The incidence 

of the various stroke subtypes also varies 

considerably in different ethnic groups.

In the U.S., stroke mortality is unusually high in a cluster 

of Southeastern states known as the Stroke Belt. In the 

Belt’s “buckle” (gold), stroke mortality may be double the 

national average.

Stroke is a global health problem. In some 

Eastern European countries and in the Far East, 

stroke rates are much higher than in the U.S. 

Within the U.S., stroke mortality is unusually 

high in people living in a cluster of Southeastern 

states—Alabama, Arkansas, Georgia, Louisiana, 

Mississippi, North Carolina, South Carolina, 

and Tennessee—known as the “Stroke Belt.” A 

recent study funded by NIH’s National Institute 

on Aging suggests that the “belt” is worn from 

childhood. That is, people who lived in the 

Stroke Belt during grade school but later moved 

away had the elevated stroke risk characteristic of 

the area, while people who moved to the Stroke 

Belt as adults did not have an elevated stroke risk. 

Although clearly influenced by differences in 

the prevalence of known stroke risk factors, the 

basis for these ethnic and geographic trends 

is not fully understood. For example, higher 

rates of hypertension and diabetes explain some, 

but not all, of the increased stroke risk among 

African Americans and residents of the Stroke 

Belt. Socioeconomic disadvantages in income 

and education level also appear to play a role. 

However, within a given geographic area, the 

most disadvantaged groups do not necessarily 

have the highest stroke risk. Finally, the 

relatively high percentage of African Americans 

living in Stroke Belt states does not explain the 

Stroke Belt’s existence, since Caucasians living 

there also have an increased risk of stroke.

With an eye toward improving stroke prevention 

in high-risk communities, NINDS is supporting 

two studies to confront these issues: the Reasons 

for Geographic and Racial Differences in Stroke 

(REGARDS) study and the Northern Manhattan 

Study (NOMAS). Launched in 2003, REGARDS 

has enrolled more than 30,000 participants 

(including 12,000 African Americans), with 

half of the participants coming from the Stroke 

Belt and half from the 40 other mainland states. 

REGARDS investigators have found that, in 

individuals with hypertension, awareness and 

treatment of it is more common in African 

Americans, but that effective treatment—lowering 

blood pressure to the normal range—is more 

common in Caucasians. They have also found 

evidence that strokes are more likely to occur 

without diagnosis in African Americans than in 

Caucasians, and in Stroke Belt residents than in 

non-residents. Thus, a lack of awareness about 

stroke and a failure to intervene at the first signs 

of disease may explain the high stroke mortality 

of certain groups.

Launched in 1990, the NOMAS study has been 

tracking stroke incidence, risk factors, and 

outcomes in Northern Manhattan, where about 

60 percent of residents now identify themselves 

as Hispanic and 15 percent identify as African 

American. NOMAS investigators have found 

that AF has an especially high impact on 

stroke risk in Caucasians, while a trend for 

hypertension and diabetes has a higher impact 

in Hispanics and African Americans. Physical 

inactivity appears to be a strong risk factor in all 

three ethnic groups.
14 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 15

4. Current 

Stroke 

Treatment 

and 

Prevention

T

 oday, there is a small but growing arsenal 

of treatments that can markedly improve

 the chances of recovering from a stroke. There is 

also a wealth of knowledge about what causes stroke 

and how to reduce the chances of having one.

Medications

As described in the chart on p. 10 (Modifiable 

Risk Factors), medicines that lower blood 

pressure and cholesterol can protect against 

atherosclerosis and reduce a person’s risk of 

stroke. Aspirin and other blood-thinning 

medications have been used for years to reduce 

the risk of ischemic stroke in individuals with 

AF or prior stroke. Recent studies have helped 

refine the use of these drugs to maximize safety 

and efficacy. This section, however, begins with a 

discussion of what happens when prevention fails 

and a person requires emergency treatment for 

an acute ischemic stroke. 

Thrombolytic Drugs

In treating acute ischemic stroke (acute meaning 

that the stroke has occurred within the past few 

hours), the immediate goal is to break apart the 

offending clot, a process known as thrombolysis. 

The body produces its own thrombolytic proteins, 

and some of these have been engineered into 

drugs. One, called tissue plasminogen activator 

(tPA), had a proven track record for treating 

heart attacks. In the late 1980s, NINDS-funded 

investigators laid the plans for the first placebocontrolled trial of tPA to treat acute ischemic 

stroke. They knew from animal studies that 

irreversible brain injury is likely to occur if blood 

flow is not restored within the first few hours after 

ischemic stroke. Therefore, the NINDS tPA Study 

Group tested the drug within a three-hour time 

window. Compared to individuals given placebo, 

those given intravenous tPA were more likely to 

have minimal or no disability three months after 

treatment—a finding that persuaded the U.S. 

Food and Drug Administration to approve tPA 

for use against acute stroke. Trials in Europe and 

the U.S. subsequently confirmed those results. 

Recent studies attempt to identify individuals who 

may benefit even after three hours of stroke onset. 

In any case, more brain tissue will be saved the 

earlier the treatment is delivered.

A 1998 follow-up analysis of the NINDS trial 

found that, after their initial hospitalization, 

people who received tPA were less likely to 

require inpatient rehabilitation or nursing home 

care. The authors estimated that this lower 

dependency on long-term care would translate 

into a savings to the healthcare system of more 

than $4 million for every 1,000 individuals 

treated with tPA.

Because treatment with tPA interferes with blood 

clotting and has also been shown to increase 

leaking along the blood-brain barrier, it carries 

a risk of intracerebral hemorrhage. Therefore, 

it is not recommended for some people, such 

as those with a history of brain hemorrhage or 

significantly elevated blood pressure (greater 

than 185/110 mm Hg). The risk of tPA-induced 

hemorrhage increases over time from stroke 

onset, which has limited its use to the first three 

hours after stroke (where benefit was most clearly 

established in the U.S. trials). 

Antiplatelet Drugs and Anticoagulants

Blood-thinning medications fall into two 

classes: antiplatelet drugs and anticoagulants. 

Antiplatelet drugs inhibit the activity of cells 

called platelets, which stick to damaged areas 

inside blood vessels and lay the foundation for 

blood clots. The most common antiplatelet 

drug is aspirin. Anticoagulants, such as heparin 

(produced by inflammatory cells in the body) and 

warfarin (found in plants and also known by the 

trade name Coumadin©), inhibit proteins in the 

blood that stimulate clotting.

Antiplatelet drugs and anticoagulants can help 

prevent a variety of potentially life-threatening 

conditions for which individuals with stroke are 

at risk, such as myocardial infarction, pulmonary 

embolism, and deep vein thrombosis—which are 

caused by clots in the heart, lungs and deep veins 

of the legs, respectively. In recent years, the value 

of these drugs in treating and preventing stroke 

itself has been more closely scrutinized. 

One focus of this research has been to determine 

if there is any benefit in giving antiplatelet 

drugs or anticoagulants during an acute 

ischemic stroke, as an adjunct to tPA, or as 

an alternative for people ineligible to receive 

tPA. In an international trial coordinated by 

researchers in the United Kingdom in the late 

1990s, individuals received aspirin, subcutaneous 

heparin injections, or neither treatment within 48 

hours of an ischemic stroke. Aspirin significantly 

reduced the risk of a recurrent ischemic stroke 

at two weeks. A similar benefit from heparin 

was offset by an increased risk of hemorrhagic 

stroke. Around the same time, NINDS-funded 

researchers tested whether acute stroke could 

be treated with intravenous Org 10172, a form of 

heparin considered less likely to cause bleeding. 

This study, Trial of Org 10172 in Acute Stroke 

Treatment (TOAST), found that Org 10172 

produced no significant benefit. The study authors 

also developed the TOAST criteria, a set of guidelines 

for classifying different subtypes of ischemic 

stroke that are now widely used in other studies.

Another issue is whether individuals at risk 

for ischemic stroke should be placed on a 

daily maintenance program of aspirin or 

anticoagulants. For many years, aspirin and 

warfarin were used as a means of stroke 

prevention in individuals with AF, but until 

recently, this practice was based more on 

anecdotal evidence than on scientific data. 

A systematic analysis of warfarin’s benefits was 

especially important since it is an expensive drug 

Platelets (magnified here thousands of times) home to 

damaged areas of blood vessels and contribute to the 

formation of clots. Antiplatelet drugs can help reduce 

the risk of ischemic stroke.
Robert, 

a 74 year-old retiree...

16 Stroke: Challenges, Progress, and Promise

 ...had just stepped inside after watering the lawn 

when he suddenly felt odd. He tried to speak to 

his wife, Alma, but realized that he couldn’t. He held 

her hand and stared at her. He didn’t know what 

was happening to him, but fortunately, she did.

As an avid reader of health information, Alma 

immediately recognized that Robert was having 

a stroke. She dialed 911, and about 30 minutes 

later, Robert was in an emergency room. Doctors 

quickly took pictures of Robert’s brain using a CT 

scan and determined that his stroke was ischemic in 

nature. In other words, a clot was blocking the flow 

of blood to vital brain areas, including the speech 

center. They also determined that Robert was a 

good candidate for tPA, a clot-busting drug that 

had been approved for use against acute ischemic 

stroke by the Food and Drug Administration in 1996, 

just four years earlier.

While the doctors administered tPA intravenously, 

they asked Robert a series of simple questions to 

test his ability to think and speak – questions like 

 “Do you know where you are?” and “Can you name 

your wife and children? Your grandchildren?” 

At first, his speech continued to fail him, but after 

a few minutes, he was answering every question. 

He was released from the hospital 6 days later, and 

after some speech therapy, he was soon reading to 

his grandchildren again.

During Robert’s treatment and evaluation at the 

hospital, doctors discovered that he had atrial 

fibrillation (AF), which is an abnormal heart rhythm 

and a risk factor for stroke. He now takes warfarin, 

a medication that inhibits blood clotting and has 

proven effective for reducing the risk of stroke in 

people with AF and other stroke risk factors. He 

hasn’t experienced any more strokes.

Robert and Alma have seven grandchildren and one 

great-granddaughter. Robert continues to enjoy 

reading to the youngest ones.

and, like heparin, is associated with an increased 

risk of hemorrhagic stroke. The NINDS Boston 

Area Anticoagulation Trial for Atrial Fibrillation 

(BAATAF) and the Stroke Prevention in Atrial 

Fibrillation (SPAF) trials showed that daily 

warfarin is best for people with AF who are 

over age 65 or who have additional vascular 

risk factors. Daily aspirin provides adequate 

protection against stroke among young people 

with AF.

Two other NINDS-sponsored trials compared 

the effectiveness of daily warfarin and aspirin 

for individuals who did not have AF, but who 

had experienced a prior stroke—and thus were 

at risk for another. The Warfarin vs. Aspirin 

Recurrent Stroke Study (WARSS) showed that 

aspirin was as effective as warfarin in preventing 

recurrent stroke in people with no history of AF 

or other cardioembolic causes of stroke. The 

Warfarin-Aspirin Symptomatic Intracranial 

Disease (WASID) trial focused more narrowly on 

individuals with stenosis of arteries in the brain 

and was terminated early because of a high rate 

of adverse events in participants treated with 

warfarin. Both trials concluded that aspirin is 

equivalent to warfarin for reducing the risk of 

stroke in people without AF.

Medication for Subarachnoid 

Hemorrhage

The drug nimodipine is used to treat cerebral 

vasospasm, a complication that sometimes follows 

subarachnoid hemorrhage. This refers to a 

constriction of blood vessels in the brain that 

can significantly reduce blood flow, leading to 

ischemia and infarction. Although its precise 

origins are unclear, cerebral vasospasm is thought 

to be triggered in part by an influx of calcium 

into the smooth muscles that control blood vessel 

diameter. Nimodipine is a calcium antagonist, 

meaning that it works by blocking the entry of calcium into cells. Nimodipine has been shown 

to reduce infarction and improve outcome in 

individuals with subarachnoid hemorrhage.

Surgeries and Other 

Procedures

Surgery is sometimes used to clear the congested 

blood vessels that cause ischemic stroke or to 

repair the vascular abnormalities that contribute 

to hemorrhagic stroke.

A surgery called carotid endarterectomy involves 

removing plaque to widen the carotids, a pair of 

arteries that ascend each side of the neck and are 

the main suppliers of blood to the brain. Stenosis 

that narrows a carotid artery by more than 50 

percent is considered clinically significant. In 

some cases, carotid stenosis is first detected after 

a person experiences a stroke or other symptoms, 

such as a TIA. It is also sometimes detected in 

the absence of symptoms, as when a physician 

presses a stethoscope to the neck and hears a 

bruit—a sound made by blood flowing past an 

obstruction. The presence of carotid stenosis 

can be confirmed by angiography or Doppler 

ultrasound.

Data from NINDS-funded research show that the 

risk of ischemic stroke from clinically significant 

asymptomatic carotid stenosis is about two to 

three percent per year (meaning that out of 100 

individuals with this condition, two or three will 

have a stroke each year). The risk of ischemic 

stroke from clinically significant symptomatic 

carotid stenosis is much higher—about 25 

percent during the first two years following the 

appearance of symptoms. 

Jim, a 58 year-old 

businessman...

Stroke: Challenges, Progress, and Promise 17

 ...was spending a Saturday morning preparing for 

a church retreat, when he was struck by a headache 

and a strange feeling in his throat. Thinking maybe 

he had strep throat, he asked his wife Judy to drive 

him to an urgent care center. He felt too drained to 

drive himself.

The urgent care doctor quickly recognized that Jim 

was having a stroke, and sent the couple to the 

nearest emergency department. On the way, Jim’s 

speech slurred, the right side of his face drooped, 

and the limbs on his right side grew heavy.

At the hospital, a CT scan indicated damage to the 

left side of Jim’s brainstem. This is the part of the 

brain that connects to the spinal cord, so the CT 

findings fit with the weakness Jim had on the right 

side of his body. The stroke was caused by a blood 

clot, but for medical reasons, Jim was not eligible 

for the clot-busting drug tPA.

Jim stayed under observation in intensive care for 

3 days. When he was released, he could not walk 

or use his right hand, so he spent a month at an 

inpatient rehabilitation center, where he received 

physical and occupational therapy. When he left 

the center, he had little function in his right hand, 

but he was able to walk with a four-pronged cane.

It has been more than 7 years since Jim’s stroke. 

He exercises regularly and can walk unassisted, 

but he still has trouble with his right hand. By 

participating in clinical research, he is receiving an 

experimental treatment called constraint-induced 

movement therapy. This involves wearing a large 

mitt that limits movement of his left hand, forcing 

him to use his right hand for daily activities. 

Researchers expect the therapy to be most effective 

within the first year after a stroke, but Jim has 

noticed some improvement. Although writing and 

eating remain easier with his left hand, he can do 

both with his right. He continues to be very active 

at church and in his community.
NINDS-supported research has compared the 

benefits of standard medical therapy alone 

(treatment with aspirin, blood pressure-lowering 

drugs, and cholesterol-lowering drugs) with 

standard medical therapy plus endarterectomy 

for both types of carotid stenosis. The 

Asymptomatic Carotid Atherosclerosis Study 

(ACAS) found that endarterectomy cut the 

risk of stroke in half among individuals with 

asymptomatic carotid stenosis of 60 percent 

or greater. The NINDS North American 

Symptomatic Carotid Endarterectomy Trial 

(NASCET) found major benefits for individuals 

with symptomatic carotid stenosis of 70 percent 

or greater. Their risk of stroke over a two-year 

period was cut to less than 10 percent.

Endarterectomy itself is associated with a small 

risk of stroke because the disruption of plaque 

during the procedure can send emboli into 

the bloodstream, or cause a clot at the site of 

surgery. NINDS supports the investigation of an 

alternative procedure known as carotid artery 

stenting, which involves inserting a stent (a tubelike device that is made of mesh-like material) 

into the carotid artery. The stent is compressed 

until the radiologist threads it into position, and 

is then expanded to mechanically widen the 

artery. It is also equipped with a downstream 

 “umbrella” to catch dislodged plaque. The 

Carotid Revascularization Endarterectomy vs. 

Stenting Trial (CREST) is designed to compare 

these two procedures in individuals with 

symptomatic carotid stenosis.

Several techniques are used to eliminate the 

vascular abnormalities linked to hemorrhagic 

stroke, or at least to reduce the risk that they 

will rupture. Arteriovenous malformations 

(AVMs) can be surgically removed through a 

procedure known as surgical resection. They 

can also be treated non-invasively (without the 

need to cut into the skull) using radiosurgery 

or embolization. Radiosurgery involves 

directing a beam of radiation at the AVM, while 

embolization involves injecting artificial emboli 

(usually made of foam) into the AVM to block it 

off from its parent vessel. 

Clipping and coiling are procedures used to 

treat intracerebral aneurysms. Clipping involves 

opening the skull and placing a clip near the 

aneurysm, to separate it from its parent blood 

vessel. In endovascular coiling, a wire topped 

with a detachable coil is inserted into a leg artery 

and threaded into the aneurysm. Once in place, 

the coil is released into the aneurysm, where it 

stimulates blood clotting and strengthens the 

blood vessel wall. Stents are also used in some 

cases to divert blood flow away from an aneurysm.

The carotid and vertebral arteries ascend through 

the neck and divide into branches that supply blood 

to different parts of the brain.

Rehabilitation 

Stroke rehabilitation includes physical therapy 

and other approaches intended to help 

individuals achieve long-term recovery from 

stroke. Physical therapy involves using exercises 

to restore movement and coordination. Many 

people also receive occupational therapy, which 

focuses on improving daily activities such as 

eating, drinking, dressing, bathing, reading, and 

writing. Speech therapy may help people who 

have problems producing or understanding 

speech. Finally, since depression, anxiety, and 

social isolation are common among individuals 

who have had a stroke, the potential benefits of 

psychological or psychiatric treatment should be 

considered.

Importantly, the goal of rehabilitation is not 

simply for the individual to cope with disability, 

but to relearn skills that have been lost. This 

relearning is made possible by the brain’s 

plasticity—its ability to reorganize itself by 

forming new connections between neurons. 

Plasticity soars in the developing brain and wanes 

as the brain matures, but even the aged brain 

appears to retain some plasticity and thus some 

capacity to repair itself after a stroke.

Basic research on the brain has shown that the 

most active neural connections tend to become 

stronger while the quietest connections tend 

to weaken until they disappear. Inspired by 

these findings, researchers are testing a few 

innovative techniques that follow a “use it or lose 

it” approach to stroke rehabilitation. 

One technique, called constraint-induced 

movement therapy (CIMT), focuses on improving 

upper limb function in people with stroke 

who are affected by hemiparesis (weakening 

on one side of the body). It involves constant 

restraint of the unaffected hand and arm with 

a mitt shaped like a boxing glove, so that the 

person is forced to use the affected hand and 

arm for daily activities. Meanwhile, the person 

receives regular training sessions to exercise 

the weakened arm. In the Extremity Constraint 

Induced Therapy Evaluation (EXCITE) trial, 

funded by NINDS and NICHD, individuals who 

experienced a hemiparetic stroke in the prior 

three to nine months received either CIMT 

for just two weeks or customary care, ranging 

from no treatment to standard physical therapy. 

Those who received CIMT were more likely to 

show improvement after one year, and much of 

this improvement was sustained even after two 

years. The Interdisciplinary Comprehensive 

Arm Rehabilitation Evaluation (I-CARE) trial 

is testing the efficacy of CIMT combined with 

task-specific training and 30 hours of one-on-one 

therapy within one to three months after a stroke.

Another technique involves using a body weightsupported treadmill (BWST) to help people 

who have trouble walking. Individuals walk on a 

treadmill while being supported by an overhead 

harness, which protects them from falling and 

allows them to concentrate on coordination 

and speed. Recently, investigators have begun 

to combine BWST training with “overground” 

training, where individuals immediately practice 

what they have learned on the treadmill by 

walking with assistance and encouragement 

from a physical therapist. In the Locomotor 

Experience Applied Post-Stroke (LEAPS) trial, 

NINDS-funded investigators will compare 

outcomes at one year in people who receive either 

standard physical therapy or a program of BWST 

training plus overground training. 

18 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 19
20 Stroke: Challenges, Progress, and Promise

5. research 

and Hope 

for the 

Future

S

 cientists continue to investigate ways to 

 better understand, diagnose, and treat stroke. 

Much of this research is conducted by the stroke 

community at the NIH or through research grants 

to academic centers throughout the United States.

Prevention

Genetic Risk Factors

In an effort to make stroke prevention more 

effective and more personalized, NINDS is 

supporting research to identify additional risk 

factors (including genetic factors) involved in 

stroke. Several rare inherited disorders cause an 

unusual predisposition toward stroke. With an 

eye toward finding disease-specific treatments 

and gaining general insights into stroke, scientists 

have begun to hunt down the responsible genes.

For instance, a rare disorder called cerebral 

autosomal dominant arteriopathy with 

subcortical infarcts and leukoencephalopathy 

(CADASIL) may offer clues to the mechanisms 

behind ischemic stroke. Younger individuals 

with CADASIL typically experience migraine 

that is accompanied by an increased sensitivity 

to light or sound, while older people experience 

TIAs and ischemic strokes. Researchers have 

traced the disease to mutations in the Notch3 

gene, which encodes a protein on the surface of 

the smooth muscle cells that line blood vessels. 

Notch proteins, of which there are many, are 

also receptors for signals that guide cellular 

movements during embryonic development. 

Several researchers supported by NINDS are 

studying Notch function in the adult brain.

An alternative to studying rare genetic diseases 

that dramatically affect stroke risk is to search for 

common genetic variations that have more subtle 

effects—typically single-letter changes in the 

DNA code (or genome) called single nucleotide 

polymorphisms (SNPs). In a genome-wide 

association study, researchers scan the genome of thousands of individuals, some who have a 

disease and some who do not, to determine if 

any SNPs are more common in people with 

the disease. 

In 2003, researchers completed a genome-wide 

association study of stroke in Iceland, where 

extensive genealogical records make it easier 

to trace genetic inheritance patterns. They 

reported that ischemic stroke was associated with 

variation in the phosphodiesterase-4D (PDE4D) 

gene. A recent study of about 500 American 

women (funded in part by NINDS) found that 

some variations in PDE4D increase the risk of 

ischemic stroke in women ages 15-49, and that 

the risk is further magnified by cigarette smoking. 

In other populations, researchers have failed to 

find a link between PDE4D and stroke.

More recently, researchers supported by NINDS 

found an association between intracranial 

aneurysms and SNPs located near genes on 

chromosomes 2, 8, and 9. The chromosome 9 

gene, Sox 17, was already known to be required 

for proper development of blood vessels in 

laboratory animals, so it makes sense that this 

gene appears to affect the risk of aneurysm formation. 

Clinical tests for variations in Sox 17 and other 

genes might be used to predict a person’s risk of 

developing an intracranial aneurysm.

There is evidence that clinical testing for SNPs 

might be useful for guiding preventative care 

in people who are already known to be at risk 

for stroke. For example, although it is known 

that children and adults with sickle cell disease 

are at high risk for stroke, it is not clear why 

some people with the disease experience strokes 

at an earlier age and with greater frequency. 

Researchers supported in part by NINDS have 

NIH-Supported Resources for 

Human Genetic Research

n The International HapMap is creating a catalog 

of SNPs and haplotypes (sets of associated 

SNPs) in different populations. This catalog is 

expected to contain up to 10 million SNPs upon 

completion, and is used by researchers to design 

genome-wide association studies.

n The NINDS Human Genetics Repository houses 

samples of DNA and cells that have been 

donated by individuals for use in genetic studies.

n 

The NIH Neuroscience Microarray Consortium 

provides researchers with services such as SNP 

genotyping and gene expression profiling 

(examining when and where specific genes are 

active in the body). It is funded by the NIH 

Neuroscience Blueprint, a joint effort among 

16 subdivisions of NIH, including NINDS.

Stroke: Challenges, Progress, and Promise 21
Stroke Therapy 

Gets Cooler

Stroke: Challenges, Progress, and Promise 23

Fever is a frequent complication of stroke and 

a predictor of poor outcome, so measures to 

bring body temperature to a normal level (about 

37.5°C) are common in acute stroke care. Recently 

though, scientists have begun to explore whether 

hypothermia (cooling the body below its normal 

temperature) might have neuroprotective effects 

against stroke.

Many people have heard stories of children who 

drowned in icy cold water and recovered with 

surprisingly little neurological impairment. This 

recovery is possible (at least in part) in hypothermia 

because the brain slows its metabolic rate and 

consumes less energy. In the 1950s, scientists began 

investigating whether controlled hypothermia 

could prevent the neurological damage associated 

with severe cardiac arrest. Unfortunately, these 

early studies tested extreme reductions in body 

temperature and found a high rate of dangerous 

side effects. In 2002, however, two studies showed 

that mild to moderate hypothermia (32-36°C), which 

was induced with a cooling blanket in one study and 

ice packs in the other, led to improved neurological 

outcome after cardiac arrest.

Animal studies suggest that hypothermia not only 

helps the brain resist ischemia, but may directly 

inhibit other harmful reactions that occur during 

stroke, including excitotoxicity and reperfusion 

injury. A trial supported by the NINDS SPOTRIAS 

program will test whether hypothermia offers 

enough protection against stroke to extend tPA’s 

effective time window to six hours after onset.

Several rare 

inherited disorders cause an 

unusual predisposition toward 

stroke. With an eye toward 

finding disease-specific 

treatments and gaining general 

insights into stroke, scientists 

have begun to hunt down the 

responsible genes. 

found several SNPs in different genes that modify 

the risk of stroke associated with sickle cell 

disease. Thus, testing for these SNPs could be 

used to identify people with sickle cell disease 

who are at highest risk for stroke, and to provide 

them with early therapeutic intervention. 

Finally, genetic testing might be useful for 

predicting how different people will respond to 

different stroke therapies. For example, because 

people metabolize warfarin at different rates, it 

is difficult to determine optimal dosing of the 

drug, which could cause severe bleeding if given 

in excess. Traditionally, physicians have had to 

estimate the initial dose based on a formula that 

includes the individual’s age, blood pressure, and 

other factors, and then adjust the dose through 

trial and error. It is now known that certain 

variants in two genes, CYP2C9 and VKORC1, 

cause increased sensitivity to warfarin. Taking 

these variations into account and plugging them 

into the traditional formula appear to predict an 

optimal warfarin dosage with greater accuracy. 

Biomarkers

In recent years, other risk factors have emerged 

that might be more appropriately called 

biomarkers. These are changes in the body (for 

example, changes in blood chemistry or gene 

expression) that indicate an ongoing disease 

process or a risk of disease but do not necessarily 

play causative roles in the disease.

In the late 1990s, for example, many studies 

(including the Framingham study) found 

an association between stroke and elevated 

blood levels of homocysteine, a relative of the 

amino acids the body uses to make proteins. 

Homocysteine levels tend to rise in people who 

consume inadequate amounts of the vitamins B12 and B9

 (folate), which are needed to convert 

homocysteine into useful amino acids. It is 

unclear whether elevated homocysteine plays 

a causative role in stroke or is just an innocent 

bystander. The NINDS Vitamin Intervention for 

Stroke Prevention (VISP) trial found that vitamin 

supplementation leading to modest reductions in 

homocysteine did not reduce the risk of recurrent 

stroke over a two-year period. It remains possible 

that B vitamin supplements are beneficial over a 

longer period or in people with no history of stroke.

Researchers also have discovered several 

biomarkers of advanced atherosclerosis that could 

be used to identify people in danger of stroke. 

For example, elevated levels of two proteins in the 

blood, C-reactive protein and phospholipase A

2

, 

are associated with atherosclerosis and increased 

risk of stroke. Irregularities in the appearance 

of atherosclerotic plaques, observed by highresolution ultrasound, are also tied to higher 

stroke risk.

Combination Therapies for 

Stroke Prevention

Many people at risk for stroke take multiple 

preventative medications, including antiplatelet 

drugs, ACE inhibitors, and/or statins. In 2006, 

NINDS-supported researchers completed the 

first study to explore whether using these three 

drugs in combination is more beneficial than 

using just one or two of them. The researchers 

examined the medication history and tracked 

the outcomes of more than 200 individuals 

who sought care within 24 hours of an ischemic 

stroke. Individuals taking all three drugs had 

strokes that were less severe, based on symptoms 

measured by the NIH Stroke Scale and on 

MRI scans showing they had less at-risk tissue 

surrounding the damaged regions of their brains. 

Individuals on triple therapy also had shorter 

hospital stays and better function at hospital 

discharge. Although these data are preliminary, 

they highlight the possibility of improving stroke 

outcomes by targeting multiple risk factors.

Acute Stroke and 

Post-Stroke Therapy

Better Thrombolysis in 

Ischemic Stroke

Although tens of thousands of people benefit 

from tPA each year, this represents only a small 

fraction of people affected by ischemic stroke. 

The use of tPA is limited by concerns that it 

could cause hemorrhage and many hospitals lack 

the infrastructure required to treat individuals 

within tPA’s short window of efficacy. NINDS’ 

professional outreach efforts are helping 

hospitals establish coordinated stroke care 

teams capable of rapidly delivering treatments, 

including tPA if warranted (see “Changing 

Stroke’s Impact by Changing Attitudes,” p. 32).

22 Stroke: Challenges, Progress, and Promise
24 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 25

 

Meanwhile, research efforts are underway to 

reduce the risk of hemorrhage from tPA. For 

example, NINDS-funded investigators are testing 

derivatives of tPA that may carry less risk of 

hemorrhage. Another strategy is to tease apart 

tPA’s destructive effect on the blood-brain barrier 

and identify drugs that block this effect. Along 

those lines, NINDS-funded studies have shown 

that proteins called matrix metalloproteinases 

(MMPs) degrade the blood-brain barrier during 

an acute stroke, and that treatment with tPA 

appears to enhance MMP activity. NINDSfunded investigators have found that tPA also 

increases blood-brain barrier permeability by 

acting through a protein called platelet-derived 

growth factor-CC (PDGF-CC). They showed that 

Gleevec©, a drug already approved for treating 

certain cancers, blocked PDGF-CC signaling and 

reduced hemorrhage in mice treated with tPA 

after ischemic stroke.

Research is also underway to enhance tPA’s clotbusting effects and extend its window of efficacy 

beyond three hours. To that end, many clinical 

trials now include brain imaging protocols to 

evaluate the extent of salvageable penumbra 

in each individual. Researchers suspect that 

individuals with larger areas of salvageable brain 

tissue might have a better chance of benefiting 

from therapy delivered after the three-hour mark.

A strategy known as bridging therapy involves 

supplementing intravenous tPA (the standard 

means of tPA delivery) with intra-arterial 

tPA injected directly at the site of the clot. 

The NINDS Interventional Management of 

Stroke (IMS) study is comparing the effects 

of bridging therapy and standard intravenous 

tPA for ischemic stroke. Another strategy is to 

combine intravenous tPA with new generation 

anticoagulants and antiplatelet drugs. Clinical 

studies coordinated by the NINDS SPOTRIAS 

network are testing tPA in combination with 

argatroban (which inhibits the blood clotting 

protein thrombin) and eptifibatide (which inhibits 

adhesion proteins on the surface of platelets).

Innovative strategies include mechanically 

disrupting the clot as either a supplement or 

an alternative to tPA. Doppler ultrasound, the 

same technique used to image blood vessels 

and locate a clot, is being tested as a means 

of delivering sound waves capable of breaking 

apart the clot. The NINDS Combined Lysis of 

Thrombus in Brain Ischemia with Transcranial 

Ultrasound and Systemic TPA (CLOTBUST) 

study was a small trial that compared tPA plus 

ultrasound to tPA plus placebo. Results showed 

that individuals who received tPA plus continuous 

ultrasound were more likely to experience 

complete restoration of blood flow by two hours 

after the start of the procedure. In addition to 

sound energy, researchers have also tested light 

energy against acute ischemic stroke. In the 

placebo-controlled NeuroThera Effectiveness and 

Safety Trial (NEST-1), people who were ineligible 

to receive tPA received infrared laser light 

applied over the scalp. Although its mechanism 

is unclear, the treatment improved functional 

outcome when given within 24 hours of stroke onset.

Recently, the FDA approved two clot-removal 

devices for use in treating acute ischemic stroke. 

The Penumbra System involves threading a 

catheter through cerebral blood vessels to 

the site of blockage and vacuuming out the 

clot. Meanwhile, MERCI (Mechanical Embolus 

Removal in Cerebral Ischemia) is a corkscrewlike device that can be extended from the tip of 

a catheter and used to snare the clot and pull 

it out. Although both devices are effective at 

restoring blood flow when used within 8 hours of 

stroke onset, no data yet exists to indicate if their 

use improves outcome. The NINDS Magnetic 

Resonance and Recanalization of Stroke Clots 

Using Embolectomy (MR RESCUE) trial is 

comparing MERCI to standard care within this 

time window.

An interruption 

in the brain’s blood supply leads 

to a cascade of harmful reactions 

that may continue for hours to 

days, even after blood flow has 

been restored.

Controlling Blood Pressure and 

Blood Flow in Hemorrhagic Stroke

Hemorrhagic stroke is usually accompanied by 

acute hypertension. Aggressive lowering of blood 

pressure is sometimes used in an attempt to 

reduce bleeding and hematoma volume, but its 

value is unclear. In the NINDS Antihypertensive 

Treatment in Acute Cerebral Hemorrhage 

(ATACH) trial, investigators are using the 

drug nicardipine to lower blood pressure in 

individuals with acute intracerebral hemorrhage 

and acute hypertension. These individuals are 

being divided into three groups in order to test 

three target blood pressure levels.

Just as anticoagulants are under study for 

treating acute ischemic stroke, drugs that 

promote coagulation are being eyed for their 

potential benefits against hemorrhagic stroke. 

Recombinant activated factor VII (rFVIIa), a 

modified version of a blood clotting factor, is 

FDA-approved to treat excessive bleeding in 

hemophilia. In two industry-sponsored trials, 

rFVIIa significantly reduced hematoma volume 

24 hours after hemorrhagic stroke, but in one trial

it failed to significantly reduce mortality at 90 days.

Neuroprotection

While some stroke treatments are aimed at 

correcting the vascular problems that cause 

stroke, another strategy, called neuroprotection, 

aims to shield neurons from the effects of stroke. 

An interruption in the brain’s blood supply leads 

to a cascade of harmful reactions—mostly in 

the ischemic penumbra—that may continue for 

hours to days, even after blood flow has been 

restored. The most important reactions are 

excitotoxicity, reperfusion injury, and breakdown 
26 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 27

of the blood-brain barrier. In recent years, 

thanks to an improved understanding of how 

these reactions unfold, researchers have begun to 

develop and test many neuroprotectant drugs.

Still, research on neuroprotectant drugs 

remains at a relatively early stage. Studies using 

animal models of stroke (mostly rodents) are 

essential to this research, just as they were for 

the development of tPA. In two common animal 

models of ischemic stroke, a string or suture 

is used to occlude either the carotid artery or 

the middle cerebral artery (a branch off of the 

carotid). These techniques allow researchers 

to carefully monitor the timing of post-stroke 

changes in the brain and to carefully plan the 

timing of therapeutic intervention. Several 

possible neuroprotectants have shown positive 

results when tested in an animal model, only to 

yield negative results in clinical trials. With each 

disappointment, however, investigators learn 

things that help them refine the development 

of candidate drugs; for example, by taking steps 

Mitochondria are cellular factories that use oxygen 

and glucose to produce energy. When mitochondria 

run out of oxygen during a stroke, a chain reaction 

of damaging events can ensue.

to eliminate drug side effects or changing the 

protocol for drug delivery. As in the case of tPA, 

there are strong indications that timing could 

mean everything for many neuroprotectant drugs.

Excitotoxicity and Reperfusion Injury

To understand how just a few moments of 

ischemia can lead to a cascade of damaging 

events in the brain, it is necessary to know 

something about how neurons extract 

energy from oxygen and glucose. Essential 

to energy production in all our cells are the 

mitochondria—cellular factories that use oxygen 

to break down glucose and convert it into the energy 

molecule ATP. During ischemia, mitochondrial 

production of ATP runs down and neurons lose 

control over the internal machinery that allows 

them to generate electrical and chemical signals.

Ischemic neurons release excessive amounts 

of glutamate, a chemical signal (or neurotransmitter) 

that excites neighboring neurons. As these 

neurons become active and release their own 

glutamate, excitation builds upon itself and 

spreads through the brain. Inside each neuron, 

this wave of excitation triggers a variety of 

responses. It activates enzymes capable of 

remodeling a neuron’s internal skeleton and 

outer membrane, and stimulates the production 

of oxygen-containing molecules that are 

capable of diffusing freely across the membrane 

and acting as short-lived, short-distance 

neurotransmitters. Although these processes are 

otherwise normal, the ramped-up excitation—or 

excitotoxicity—that accompanies stroke sends 

them into overdrive and causes neuronal 

damage. The over-excited neuron’s skeleton and 

membrane begin to break down. Perhaps worst 

of all, the neuron churns out oxygen-containing 

free radicals, compounds that can degrade 

proteins, lipids, and DNA.

Meanwhile, if blood flow is successfully restored 

after an acute stroke, the reintroduction of 

oxygen to energy-starved tissues can lead 

to reperfusion injury. This refers to a burst 

in oxygen-containing free radicals that are 

produced when damaged mitochondria suddenly 

resume taking up oxygen to produce ATP.

Antioxidants, which neutralize oxygen-based 

free radicals, may have beneficial effects against 

both excitotoxicity and reperfusion injury. 

NINDS is supporting research to determine if 

individuals with acute ischemic stroke benefit 

from intravenous albumin, a blood protein with 

antioxidant properties. A pilot trial involving 

80 individuals showed that albumin is safe when 

given within 16 hours of stroke. Results also 

showed that individuals treated with tPA tended 

to have better outcomes if they also received highdose albumin. The Albumin in Acute Stroke 

(ALIAS) trial, a NETT-supported trial, has a 

target enrollment of nearly 900 individuals and 

will test the efficacy of albumin given within

5 hours of stroke, with or without tPA.

Glutamate antagonists have attracted considerable 

attention as a possible treatment for excitotoxicity. 

Most of these drugs work by blocking the 

interaction between glutamate and the NMDA 

receptor, which is a type of pore, or ion channel,

which opens when glutamate attaches to it. 

Unfortunately, while these drugs have shown 

promise in the middle cerebral artery occlusion 

(MCAO) model of stroke, they have not been effective 

in individuals who have had a stroke. The likely 

reason is that the glutamate antagonists tested so 

far do not specifically target abnormal glutamate 

signaling. It is important to remember that while 

glutamate is pathologically elevated in ischemic 

brain tissue, it is also required for normal function in 

non-ischemic brain tissue. Thus, non-specific 

glutamate antagonists can cause serious side 

effects—such as hallucinations, extreme sedation, 

and respiratory depression—and the tolerated doses 

are apparently too low to suppress excitotoxicity.

To address this problem, NINDS is supporting 

research on a glutamate receptor blockade that 

is matched to the level of glutamate signaling. 

For example, the drug memantine is an openchannel blocker that slips into the NMDA 

receptor only after the receptor has already 

been opened by glutamate. Other glutamate 

antagonists under development would become 

active only when exposed to the slight increase 

in acidity that occurs in ischemic brain tissue. 

Finally, an innovative trial is testing if individuals 

who have experienced a stroke might benefit 

from intravenous magnesium sulfate delivered 

in the ambulance before they get to the hospital. 

Magnesium is abundant in the brain and 
28 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 29

acts as a natural open-channel blocker of the 

NMDA receptor. In the Field Administration of 

Stroke Therapy-Magnesium (FAST-MAG) trial, 

investigators hope to boost this natural blockade 

during the first few hours after stroke. A pilot 

trial showed that paramedics were able to deliver 

magnesium sulfate to 70 percent of individuals 

within two hours of onset, a finding that has positive 

implications for emergency stroke care in general. 

Breakdown of the Blood-Brain Barrier

A hemorrhagic stroke necessarily tears open 

the blood-barrier barrier. But even an ischemic 

stroke can damage the blood-brain barrier, 

through reperfusion injury or other reactions. 

The barrier is composed of tightly interlocked 

endothelial cells within the blood vessel wall, 

surrounded by a dense meshwork of proteins, 

known as an extracellular matrix. During acute 

stroke, endothelial cells appear to release MMPs, 

which are protein-degrading enzymes that eat 

away at this extracellular matrix. (For more

 information, see “Better Thrombolysis in 

Ischemic Stroke” on p. 23.)

NINDS-funded research has led to an evolving 

view about the role of MMPs in stroke. Early 

studies on animal models confirmed that MMPs 

help destroy the blood-brain barrier during acute 

stroke, but more recent studies show that by several 

days after a stroke, the activity of MMPs might 

actually help repair damaged neurons and blood 

vessels. In this late phase, MMPs appear to 

liberate growth factors that are trapped in the 

extracellular matrix. Thus, researchers envision 

drugs that could be used to carefully adjust 

the activity of MMPs—first downward and then 

upward—in order to improve recovery from stroke.

Other Targets for Neuroprotection

Inflammation

Inflammation occurs when immune cells, or 

leukocytes, mobilize to an injured part of the 

body to clean up dead and dying cells. When 

a blood clot or hemorrhage occurs somewhere 

in the brain’s vascular system, leukocytes 

accumulate at that site and invade the brain 

through openings in the blood-brain barrier. 

The first leukocytes to arrive release cytokines, 

which are chemicals that modulate the activity 

of other inflammatory cells. Some of these 

cytokines attract cells called macrophages 

(literally “big eaters”), which engulf and break 

down cellular debris.

How much inflammation contributes to longterm damage after stroke is an open question; 

like other responses to stroke, certain types of 

inflammatory responses at the right time might 

even be beneficial. Still, one study showed that 

the anti-inflammatory cytokine interferon-beta 

stabilized the blood-brain barrier and reduced 

the size of the infarct when given to rats up to 

6 hours following MCAO. Interferon-beta is 

already an FDA-approved treatment for multiple 

sclerosis. NINDS is supporting a clinical trial to 

assess the drug’s safety in individuals with acute 

ischemic stroke.

Apoptosis and the Alzheimer’s Connection

As neurons in the core of an ischemic infarct 

lose their ability to produce ATP, they undergo 

necrosis, the cellular equivalent of accidental 

death. In the ischemic penumbra, however, the 

buildup of free radicals may trigger a form of 

cell suicide known as apoptosis. An apoptotic 

cell activates protein-cutting enzymes called 

caspases that disassemble the cell’s working parts. 

NINDS-funded investigators have shown that in 

the MCAO model of ischemic stroke, caspases 

become activated within 9 hours, and caspase 

inhibitors reduce the spread of ischemic injury 

during this time.

Apoptosis and the activation of caspases have 

also been implicated in Alzheimer’s disease (AD). 

As researchers learn more about the role of 

apoptosis in AD, they are finding other connections 

between AD and stroke. Apoptosis is associated 

with increased activity of two enzymes known to 

generate beta-amyloid, which is the toxic protein 

fragment that accumulates in the brain during 

AD. Recent studies show that these enzymes, 

called beta- and gamma-secretase, are also activated 

after MCAO in rodents. These findings have led 

to the idea that abnormal blood flow might be a 

precipitating event for AD.

Astrocytes and the Neurovascular Unit

Neurons may be the workhorses of the brain, 

but they are far outnumbered by glia. While 

these cells once were considered mere structural 

support in the brain (glia is Greek for “glue”), 

they actually serve important functions. 

Oligodendrocytes, for example, form sheaths 

that insulate the electrical signals relayed by 

neurons. Astrocytes, so named because they 

form branches that give them a star-like shape, 

are perhaps the most versatile type of glia and 

In a process known as excitotoxicity, neurons become 

damaged when nearby cells release excess levels of 

the chemical signal glutamate.

The neurovascular unit consists of neurons (yellow), 

the blood vessels that supply them (pink), astrocytes 

(blue) and possibly other types of glial cells (green). 

By virtue of their contacts with neurons and blood vessels, 

astrocytes help match cerebral blood flow to neuronal 

energy demands.

Researchers envision

someday using drugs that 

could be used to carefully 

adjust the activity of matrix 

metalloproteinases (MMPs) 

in order to improve recovery 

from stroke.
30 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 31

the most relevant to stroke. The branches of 

astrocytes make contact with neurons and with 

the endothelial cells of blood vessels. Together, 

these cell types form a structure recently named 

the neurovascular unit.

Stroke researchers have begun to direct more 

attention toward astrocytes and how they interact 

with other parts of the neurovascular unit. 

Thanks to their close contact with blood vessels, 

astrocytes appear able to regulate cerebral blood 

flow, helping match the delivery of blood to the 

activity and energy demands of different brain 

regions. Scientists hypothesize that a breakdown 

of cerebral blood flow regulation not only 

increases the risk of stroke, but might increase the 

risk of AD by impairing the clearance of betaamyloid from the brain.

Astrocytes are able to store glucose, which 

probably allows them to serve as a reserve energy 

source for neurons. They are also capable of 

taking up glutamate and potentially “buffering” 

the effects of excitotoxicity. Finally, after stroke 

and other injuries to the brain, astrocytes 

enlarge, undergo shape changes, and begin 

producing signals that stimulate inflammation, a 

response called reactive astrocytosis. All of these 

properties have researchers looking at astrocytes 

as a possible target for neuroprotective drugs.

Neural Stem Cells

adult brain could not generate new neurons. It 

is now known that neural stem cells—the cells 

that build the embryonic brain—persist in 

pockets deep within the adult brain. Following 

stroke and other injuries, these cells make a weak 

attempt to replace neurons that have been lost. 

In rodents, stroke by MCAO leads to the birth 

of new neurons (called neurogenesis) and their 

migration to damaged brain regions, although 

most of the newly born neurons fail to survive 

long-term. Fortunately, as scientists learn more 

about this repair response, they are discovering 

possible ways to enhance it. For example, 

investigators funded by NINDS have found that 

astrocytes and endothelial cells provide neurons 

with a physical scaffold for migration, and that 

they release proteins that stimulate neuronal 

birth, migration, and survival. Delivering these 

neurotrophic proteins in the right combination 

at the right time might boost the survival of 

newborn neurons and of mature, damaged 

neurons that are struggling to stay alive.

After a stroke, neurons may undergo a type of cell 

suicide known as apoptosis, dismantling their internal 

machinery and even breaking down their DNA.

Transplantation of neural stem cells themselves 

also offers the possibility to repair damage 

caused by stroke. A few studies supported by 

NINDS have explored stem cell transplantation 

in rodent models of stroke, each using distinct 

strategies to increase the likelihood that the 

transplanted cells would reach the damaged parts 

of the brain and become functional neurons. 

In one study, mouse embryonic stem cells were 

primed to become neurons using genetic 

engineering, and then injected directly into 

the mouse brain one day after stroke. In another

study, stem cells were isolated from the 

developing mouse brain, pre-sorted for a cell 

surface protein that helps them migrate through 

the extracellular matrix, and then injected into 

the carotid artery two days after stroke. A third 

study involved injecting human bone marrow stem 

cells into the rat carotid artery one day after stroke. 

In all three studies, some of the injected stem 

cells migrated to damaged parts of the brain 

and took on characteristics of neurons or glia. 

Moreover, all three studies found functional 

improvements in the treated rodents, some even 

lasting up to one year in the bone marrow study. 

Many issues remain to be resolved before stem 

cell transplants can move to clinical trials in 

individuals with acute stroke, including the site 

and timing of injection, how to track the fate of 

the cells after injection, and the type of cell most 

likely to yield benefit. Ever-present are concerns 

that transplanted stem cells could be destroyed by 

the body’s immune defenses, or that they could 

divide uncontrollably and form tumors. 
32 Stroke: Challenges, Progress, and Promise Stroke: Challenges, Progress, and Promise 33

6. Changing 

Stroke’s 

Impact by 

Changing 

attitudes

As late as the 1950s, stroke treatment and 

 prevention were almost non-existent. 

There were no medications for acute stroke 

and surgeries were still very experimental. 

Moreover, with very little knowledge about stroke 

risk factors, there was no basis for primary or 

secondary prevention. Mary Lasker, a health 

advocate and a powerful force behind the 

establishment of NINDS in 1950, once said that 

at the time, “Whether you recovered or not was 

really largely by chance.”

NINDS has supported a variety of outreach 

efforts since the early 1990s to translate gains 

in research into gains in public health. In 

1995, a NINDS-funded survey of about 20,000 

households in and around Cincinnati, Ohio 

found that 68 percent of respondents could 

name one modifiable stroke risk factor and that 

25 percent could name two (where the correct 

responses included hypertension, smoking, heart 

disease, diabetes, high cholesterol, and prior 

stroke or TIA). When the survey was repeated in 2000, 72 percent of respondents could name one 

risk factor and 32 percent could name two—a 

small but significant improvement.

Results from those surveys also suggest that 

people are getting better at recognizing the five 

common symptoms of stroke (see “Stroke Basics,” 

p. 3), knowledge that could help save lives by 

reducing delays in treatment. In 1995, 57 percent 

of respondents could name at least one stroke 

warning sign, but by 2000, that number had 

increased to 70 percent.

Recognizing that lack of awareness about stroke 

remains a barrier to effective treatment, in May 

2001, NINDS launched its Know Stroke campaign 

(www.stroke.nih.gov) to educate the public about 

stroke symptoms and risk factors, and emphasize 

the importance of treating stroke as a medical 

emergency. The campaign has produced a stroke 

education kit and multiple publications that are 

available in both English and Spanish. The Know 

Stroke in the Community campaign, launched in 

partnership between NINDS and the Centers for 

Disease Control and Prevention in 2004, recruits 

 “Stroke Champions” who are trained to use these 

educational materials within their communities.

NINDS recognizes that providing resources 

and education for the medical profession is just 

as important as reaching out to the public at 

large. Although NINDS originally developed the 

NIH Stroke Scale in the early 1990s as a tool for 

evaluating people with stroke in clinical trials, 

the Scale’s utility in clinical practice quickly 

became apparent. (For more information, see 

 “Stroke Diagnostics and Brain Imaging,” p. 7.) 

NINDS now links to an online version of the Scale, 

and offers an interactive DVD that provides simple 

instructions and case studies illustrating its use.

NINDS also supports efforts to provide hospitals 

with the organization they need to rapidly 

triage and treat people who have experienced 

a stroke. One lesson learned from tPA is that 

hospitals cannot put the best stroke treatments 

into practice unless they are capable of rapid 

case management. When tPA was approved in 

1996, most hospitals were not equipped to utilize 

it within its short window of efficacy and, by 2000, 

only about one to two percent of individuals with 

acute ischemic stroke were receiving it nationwide.

That same year, the Brain Attack Coalition 

(BAC), a partnership that includes NINDS, 

several medical societies, and patient advocacy 

groups, developed a set of recommendations for 

establishing primary stroke centers. These are 

hospitals that are capable of providing emergency 

care for individuals with acute stroke. The 

recommendations emphasize creating an acute 

stroke team that is available around the clock 

and includes physicians, nurses, paramedics, and 

emergency department staff, with at least one 

physician who is an expert in cerebrovascular 

disease. The recommendations also call for 

rapid access to blood tests, brain imaging, and 

neurosurgery. The Joint Commission and 

many state health departments now use the 

recommendations to certify and evaluate primary 

stroke centers across the country.

Meanwhile, the SPOTRIAS and NETT programs 

create an infrastructure for acute stroke care 

at participating medical centers by supporting 

clinical testing of acute stroke therapies.

The number of individuals with ischemic stroke 

who receive tPA nationally remains at one to two 

percent. However, the experience at certified 

stroke centers and SPOTRIAS centers has shown 

that it is possible to improve an individual’s 

access to tPA with a coordinated stroke team in 

place. Stroke centers designated by the state 

of New York (using BAC guidelines) treat more 

individuals with ischemic stroke with tPA and 

deliver it faster than nondesignated hospitals in 

the state. Similarly, Joint Commission-certified 

primary stroke centers have reported higher 

rates of tPA use after their certification. Finally, 

NINDS SPOTRIAS centers have reported that up 

to 15 percent of individuals with ischemic stroke 

are treated with tPA.

As more stroke therapies emerge from the research 

pipeline, NINDS will continue to support efforts 

to ensure that clinicians are well-equipped to 

implement them.

CREDITS:

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New England Journal of Medicine 2007;356:2704-12. Copyright © 2007 

Massachusetts Medical Society. All Rights Reserved; Page 6: van der 

Worp, H Bart and van Gijn, Jan. Acute Ischemic Stroke. New England

Journal of Medicine 2007; 357:572-9. Copyright © 2007 Massachusetts 

Medical Society. All Rights Reserved; Page 8: John Crawford, MedArts, 

NIH; Page 13: George Howard, School of Public Health at the 

University of Alabama at Birmingham; Page 15: Martin, Mathew J., 

et al. Enhanced Detection of Thromboemboli with the Use of Targeted 

Microbubbles. Stroke 2007; 358:2726-2732. Copyright © 2007 American 

Heart Association; Page 21: National Institute of General Medical 

Sciences, NIH; Page 29: del Zoppo, Gregory J. Stroke and Neurovascular 

Protection. New England Journal of Medicine 2006; 354:553-555. 

Copyright © 2006 Massachusetts Medical Society. All Rights Reserved.
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