Hope Through Research
Table of Contents
What is Stroke?
Transient Ischemic Attacks
How Do You Recognize Stroke?
How is the Cause of Stroke Determined?
Imaging for the Diagnosis of Acute Stroke
Who is at Risk for Stroke?
Unmodifiable Risk Factors
The "Stroke Belt"
Other Risk Factors
Blood Cholesterol Levels
Modifiable Lifestyle Risk Factors
Head and Neck Injuries
Genetic Risk Factors
What Stroke Therapies are Available?
What Disabilities Can Result From a Stroke?
What Special Risks do Women Face?
Are Children at Risk For Stroke?
What Research is Being Done by the NINDS?
NINDS-Sponsored Stroke Clinical Trials: April 2004
Findings From Recently Completed Clinical Trials
Ongoing Clinical Trials
Where can I get more information?
More than 2,400 years ago the father of medicine, Hippocrates,
recognized and described stroke-the sudden onset of paralysis. Until
recently, modern medicine has had very little power over this
disease, but the world of stroke medicine is changing and new and
better therapies are being developed every day. Today, some people
who have a stroke can walk away from the attack with no or few
disabilities if they are treated promptly. Doctors can
finally offer stroke patients and their families the one thing that
until now has been so hard to give: hope.
In ancient times stroke was called apoplexy,*
a general term that physicians applied to anyone suddenly struck
down with paralysis. Because many conditions can lead to sudden
paralysis, the term apoplexy did not indicate a specific diagnosis
or cause. Physicians knew very little about the cause of stroke and
the only established therapy was to feed and care for the patient
until the attack ran its course.
The first person to investigate the pathological signs of
apoplexy was Johann Jacob Wepfer. Born in Schaffhausen, Switzerland,
in 1620, Wepfer studied medicine and was the first to identify
postmortem signs of bleeding in the brains of patients who died of
apoplexy. From autopsy studies he gained knowledge of the
carotid and vertebral arteries that supply the brain
with blood. He also was the first person to suggest that apoplexy,
in addition to being caused by bleeding in the brain, could be
caused by a blockage of one of the main arteries supplying blood to
the brain; thus stroke became known as a cerebrovascular
disease ("cerebro" refers to a part of the brain; "vascular"
refers to the blood vessels and arteries).
Medical science would eventually confirm Wepfer's hypotheses, but
until very recently doctors could offer little in the area of
therapy. Over the last two decades basic and clinical investigators,
many of them sponsored and funded in part by the National Institute
of Neurological Disorders and Stroke (NINDS), have learned a great
deal about stroke. They have identified major risk factors for the
disease and have developed surgical techniques and drug treatments
for the prevention of stroke. But perhaps the most exciting new
development in the field of stroke research is the recent approval
of a drug treatment that can reverse the course of stroke if given
during the first few hours after the onset of symptoms.
Studies with animals have shown that brain injury occurs within
minutes of a stroke and can become irreversible within as little as
an hour. In humans, brain damage begins from the moment the stroke
starts and often continues for days afterward. Scientists now know
that there is a very short window of opportunity for treatment of
the most common form of stroke. Because of these and other advances
in the field of cerebrovascular disease stroke patients now have a
chance for survival and recovery.
*Terms in Italics are defined in the glossary.
Cost of Stroke to the United
- total cost of stroke to the United States: estimated at
about $43 billion / year
- direct costs for medical care and therapy: estimated at
about $28 billion / year
- indirect costs from lost productivity and other factors:
estimated at about $15 million / year
- average cost of care for a patient up to 90 days after a
- for 10% of patients, cost of care for the first 90 days
after a stroke: $35,000*
- percentage of direct cost of care for the first 90 days*:
initial hospitalization = 43%
physician costs = 14%
hospital readmission =
medications and other expenses = 13%
* From "The Stroke/Brain
Attack Reporter's Handbook," National Stroke Association, Englewood,
What is Stroke?
A stroke occurs when the blood supply to part of the brain is
suddenly interrupted or when a blood vessel in the brain bursts,
spilling blood into the spaces surrounding brain cells. In the same
way that a person suffering a loss of blood flow to the heart is
said to be having a heart attack, a person with a loss of blood flow
to the brain or sudden bleeding in the brain can be said to be
having a "brain attack."
Brain cells die when they no longer receive oxygen and nutrients
from the blood or when they are damaged by sudden bleeding into or
around the brain. Ischemia is the term used to describe the
loss of oxygen and nutrients for brain cells when there is
inadequate blood flow. Ischemia ultimately leads to
infarction, the death of brain cells which are eventually
replaced by a fluid-filled cavity (or infarct) in the injured
When blood flow to the brain is interrupted, some brain cells die
immediately, while others remain at risk for death. These damaged
cells make up the ischemic penumbra and can linger in
a compromised state for several hours. With timely treatment these
cells can be saved. The ischemic penumbra is discussed in more
detail in the Appendix.
Even though a stroke occurs in the unseen reaches of the brain,
the symptoms of a stroke are easy to spot. They include sudden
numbness or weakness, especially on one side of the body; sudden
confusion or trouble speaking or understanding speech; sudden
trouble seeing in one or both eyes; sudden trouble walking,
dizziness, or loss of balance or coordination; or sudden severe
headache with no known cause. All of the symptoms of stroke appear
suddenly, and often there is more than one symptom at the
same time. Therefore stroke can usually be distinguished from other
causes of dizziness or headache. These symptoms may indicate that a
stroke has occurred and that medical attention is needed
There are two forms of stroke: ischemic - blockage of a
blood vessel supplying the brain, and hemorrhagic - bleeding
into or around the brain. The following sections describe these
forms in detail.
An ischemic stroke occurs when an artery supplying the brain with
blood becomes blocked, suddenly decreasing or stopping blood flow
and ultimately causing a brain infarction. This type of stroke
accounts for approximately 80 percent of all strokes. Blood clots
are the most common cause of artery blockage and brain infarction.
The process of clotting is necessary and beneficial throughout the
body because it stops bleeding and allows repair of damaged areas of
arteries or veins. However, when blood clots develop in the wrong
place within an artery they can cause devastating injury by
interfering with the normal flow of blood. Problems with clotting
become more frequent as people age.
Blood clots can cause ischemia and infarction in two ways. A clot
that forms in a part of the body other than the brain can travel
through blood vessels and become wedged in a brain artery. This
free-roaming clot is called an embolus and often forms in the
heart. A stroke caused by an embolus is called an embolic
stroke. The second kind of ischemic stroke, called a
thrombotic stroke, is caused by thrombosis, the
formation of a blood clot in one of the cerebral arteries that stays
attached to the artery wall until it grows large enough to block
Ischemic strokes can also be caused by stenosis, or a
narrowing of the artery due to the buildup of plaque (a
mixture of fatty substances, including cholesterol and other
lipids) and blood clots along the artery wall. Stenosis can occur in
large arteries and small arteries and is therefore called large
vessel disease or small vessel disease, respectively.
When a stroke occurs due to small vessel disease, a very small
infarction results, sometimes called a lacunar infarction,
from the French word "lacune" meaning "gap" or "cavity."
The most common blood vessel disease that causes stenosis is
atherosclerosis. In atherosclerosis, deposits of plaque build
up along the inner walls of large and medium-sized arteries, causing
thickening, hardening, and loss of elasticity of artery walls and
decreased blood flow. The role of cholesterol and blood lipids with
respect to stroke risk is discussed in the section on cholesterol
under "Who is at Risk for Stroke?".
In a healthy, functioning brain, neurons do not come into direct
contact with blood. The vital oxygen and nutrients the neurons need
from the blood come to the neurons across the thin walls of the
cerebral capillaries. The glia (nervous system cells that support
and protect neurons) form a blood-brain barrier, an elaborate
meshwork that surrounds blood vessels and capillaries and regulates
which elements of the blood can pass through to the neurons.
When an artery in the brain bursts, blood spews out into the
surrounding tissue and upsets not only the blood supply but the
delicate chemical balance neurons require to function. This is
called a hemorrhagic stroke. Such strokes account for approximately
20 percent of all strokes.
Hemorrhage can occur in several ways. One common cause is a
bleeding aneurysm, a weak or thin spot on an artery wall.
Over time, these weak spots stretch or balloon out under high
arterial pressure. The thin walls of these ballooning aneurysms can
rupture and spill blood into the space surrounding brain cells.
Hemorrhage also occurs when arterial walls break open.
Plaque-encrusted artery walls eventually lose their elasticity and
become brittle and thin, prone to cracking. Hypertension, or
high blood pressure, increases the risk that a brittle artery
wall will give way and release blood into the surrounding brain
A person with an arteriovenous malformation (AVM) also has
an increased risk of hemorrhagic stroke. AVMs are a tangle of
defective blood vessels and capillaries within the brain that have
thin walls and can therefore rupture.
Bleeding from ruptured brain arteries can either go into the
substance of the brain or into the various spaces surrounding the
brain. Intracerebral hemorrhage occurs when a vessel within
the brain leaks blood into the brain itself. Subarachnoid
hemorrhage is bleeding under the meninges, or outer membranes,
of the brain into the thin fluid-filled space that surrounds the
The subarachnoid space separates the arachnoid membrane from the
underlying pia mater membrane. It contains a clear fluid
(cerebrospinal fluid or CSF) as well as the small
blood vessels that supply the outer surface of the brain. In a
subarachnoid hemorrhage, one of the small arteries within the
subarachnoid space bursts, flooding the area with blood and
contaminating the cerebrospinal fluid. Since the CSF flows
throughout the cranium, within the spaces of the brain, subarachnoid
hemorrhage can lead to extensive damage throughout the brain. In
fact, subarachnoid hemorrhage is the most deadly of all strokes.
Transient Ischemic Attacks
A transient ischemic attack (TIA), sometimes called a
mini-stroke, starts just like a stroke but then resolves leaving no
noticeable symptoms or deficits. The occurrence of a TIA is a
warning that the person is at risk for a more serious and
debilitating stroke. Of the approximately 50,000 Americans who have
a TIA each year, about one-third will have an acute stroke
sometime in the future. The addition of other risk factors compounds
a person's risk for a recurrent stroke. The average duration of a
TIA is a few minutes. For almost all TIAs, the symptoms go away
within an hour. There is no way to tell whether symptoms will be
just a TIA or persist and lead to death or disability. The patient
should assume that all stroke symptoms signal an emergency and
should not wait to see if they go away.
Recurrent stroke is frequent; about 25 percent of people who
recover from their first stroke will have another stroke within 5
years. Recurrent stroke is a major contributor to stroke disability
and death, with the risk of severe disability or death from stroke
increasing with each stroke recurrence. The risk of a recurrent
stroke is greatest right after a stroke, with the risk decreasing
with time. About 3 percent of stroke patients will have another
stroke within 30 days of their first stroke and one-third of
recurrent strokes take place within 2 years of the first stroke.
How Do You Recognize Stroke?
Symptoms of stroke appear suddenly. Watch for these symptoms and
be prepared to act quickly for yourself or on behalf of someone you
- Sudden numbness or weakness of the face, arm, or leg, especially on one side of the body.
- Sudden confusion, trouble talking, or understanding speech.
- Sudden trouble seeing in one or both eyes.
- Sudden trouble walking, dizziness, or loss of balance or coordination.
- Sudden severe headache with no known cause.
If you suspect you or someone you know is experiencing any of
these symptoms indicative of a stroke, do not wait. Call 911
emergency immediately. There are now effective therapies for
stroke that must be administered at a hospital, but they lose their
effectiveness if not given within the first 3 hours after stroke
symptoms appear. Every minute
is the Cause of Stroke Determined?
Physicians have several diagnostic techniques and imaging tools
to help diagnose the cause of stroke quickly and accurately. The
first step in diagnosis is a short neurological examination. When a
possible stroke patient arrives at a hospital, a health care
professional, usually a doctor or nurse, will ask the patient or a
companion what happened and when the symptoms began. Blood tests, an
electrocardiogram, and CT scans will often be done. One test that
helps doctors judge the severity of a stroke is the standardized NIH
Stroke Scale, developed by the NINDS. Health care professionals use
the NIH Stroke Scale to measure a patient's neurological deficits by
asking the patient to answer questions and to perform several
physical and mental tests. Other scales include the Glasgow Coma
Scale, the Hunt and Hess Scale, the Modified Rankin Scale, and the
Imaging for the Diagnosis of Acute Stroke
Health care professionals also use a variety of imaging devices
to evaluate stroke patients. The most widely used imaging procedure
is the computed tomography (CT) scan. Also known as a CAT
scan or computed axial tomography, CT creates a series of
cross-sectional images of the head and brain. Because it is readily
available at all hours at most major hospitals and produces images
quickly, CT is the preferred diagnostic technique for acute stroke.
CT also has unique diagnostic benefits. It will quickly rule out a
hemorrhage, can occasionally show a tumor that might mimic a stroke,
and may even show evidence of early infarction. Infarctions
generally show up on a CT scan about 6 to 8 hours after the start of
If a stroke is caused by hemorrhage, a CT can show evidence of
bleeding into the brain almost immediately after stroke symptoms
appear. Hemorrhage is the primary reason for avoiding certain drug
treatments for stroke, such as thrombolytic therapy, the only proven
acute stroke therapy for ischemic stroke (see section on
"What Stroke Therapies are Available?"). Thrombolytic therapy cannot
be used until the doctor can confidently diagnose the patient as
suffering from an ischemic stroke because this treatment might
increase bleeding and could make a hemorrhagic stroke worse.
Another imaging device used for stroke patients is the
magnetic resonance imaging (MRI) scan. MRI uses magnetic
fields to detect subtle changes in brain tissue content. One effect
of stroke is an increase of water content in the cells of brain
tissue, a condition called cytotoxic edema. MRI can detect
edema as soon as a few hours after the onset of stroke. The benefit
of MRI over CT imaging is that MRI is better able to detect small
infarcts soon after stroke onset. Unfortunately, not every hospital
has access to an MRI device and the procedure is time-consuming and
expensive. It also is not as accurate in determining when hemorrhage
is present. Finally, because MRI takes longer to perform than CT, it
should not be used if it delays treatment.
Other types of MRI scans, often used for the diagnosis of
cerebrovascular disease and to predict the risk of stroke, are
magnetic resonance angiography (MRA) and functional
magnetic resonance imaging (fMRI). Neurosurgeons use MRA to
detect stenosis (blockage) of the brain arteries inside the skull by
mapping flowing blood. Functional MRI uses a magnet to pick up
signals from oxygenated blood and can show brain activity through
increases in local blood flow. Duplex Doppler ultrasound and
arteriography are two diagnostic imaging techniques used to
decide if an individual would benefit from a surgical procedure
called carotid endarterectomy. This surgery is used to remove
fatty deposits from the carotid arteries and can help prevent stroke
(see information on carotid endarterectomy.
Doppler ultrasound is a painless, noninvasive test in which sound
waves above the range of human hearing are sent into the neck.
Echoes bounce off the moving blood and the tissue in the artery and
can be formed into an image. Ultrasound is fast, painless,
risk-free, and relatively inexpensive compared to MRA and
arteriography, but it is not considered to be as accurate as
arteriography. Arteriography is an X-ray of the carotid artery taken
when a special dye is injected into the artery. The procedure
carries its own small risk of causing a stroke and is costly to
perform. The benefits of arteriography over MR techniques and
ultrasound are that it is extremely reliable and still the best way
to measure stenosis of the carotid arteries. Even so, significant
advances are being made every day involving noninvasive imaging
techniques such as fMRI.
Who is at Risk for Stroke?
Some people are at a higher risk for stroke than others.
Unmodifiable risk factors include age, gender, race/ethnicity, and
stroke family history. In contrast, other risk factors for stroke,
like high blood pressure or cigarette smoking, can be changed or
controlled by the person at risk.
Unmodifiable Risk Factors
It is a myth that stroke occurs only in elderly adults. In
actuality, stroke strikes all age groups, from fetuses still in the
womb to centenarians. It is true, however, that older people have a
higher risk for stroke than the general population and that the risk
for stroke increases with age. For every decade after the age of 55,
the risk of stroke doubles, and two-thirds of all strokes occur in
people over 65 years old. People over 65 also have a seven-fold
greater risk of dying from stroke than the general population. And
the incidence of stroke is increasing proportionately with
the increase in the elderly population. When the baby boomers move
into the over-65 age group, stroke and other diseases will take on
even greater significance in the health care field.
Gender also plays a role in risk for stroke. Men have a higher
risk for stroke, but more women die from stroke. The stroke risk for
men is 1.25 times that for women. But men do not live as long as
women, so men are usually younger when they have their strokes and
therefore have a higher rate of survival than women. In other words,
even though women have fewer strokes than men, women are generally
older when they have their strokes and are more likely to die from
Stroke seems to run in some families. Several factors might
contribute to familial stroke risk. Members of a family might have a
genetic tendency for stroke risk factors, such as an inherited
predisposition for hypertension or diabetes. The influence of a
common lifestyle among family members could also contribute to
The risk for stroke varies among different ethnic and racial
groups. The incidence of stroke among African-Americans is almost
double that of white Americans, and twice as many African-Americans
who have a stroke die from the event compared to white Americans.
African-Americans between the ages of 45 and 55 have four to five
times the stroke death rate of whites. After age 55 the stroke
mortality rate for whites increases and is equal to that of
Compared to white Americans, African-Americans have a higher
incidence of stroke risk factors, including high blood pressure and
cigarette smoking. African-Americans also have a higher incidence
and prevalence of some genetic diseases, such as diabetes and
sickle cell anemia, that predispose them to stroke.
Hispanics and Native Americans have stroke incidence and
mortality rates more similar to those of white Americans. In
Asian-Americans stroke incidence and mortality rates are also
similar to those in white Americans, even though Asians in Japan,
China, and other countries of the Far East have significantly higher
stroke incidence and mortality rates than white Americans. This
suggests that environment and lifestyle factors play a large role in
The "Stroke Belt"
Several decades ago, scientists and statisticians noticed that
people in the southeastern United States had the highest stroke
mortality rate in the country. They named this region the stroke
belt. For many years, researchers believed that the increased
risk was due to the higher percentage of African-Americans and an
overall lower socioeconomic status (SES) in the southern states. A
low SES is associated with an overall lower standard of living,
leading to a lower standard of health care and therefore an
increased risk of stroke. But researchers now know that the higher
percentage of African-Americans and the overall lower SES in the
southern states does not adequately account for the higher incidence
of, and mortality from, stroke in those states. This means that
other factors must be contributing to the higher incidence of and
mortality from stroke in this region.
Recent studies have also shown that there is a stroke
buckle in the stroke belt. Three southeastern states, North
Carolina, South Carolina, and Georgia, have an extremely high stroke
mortality rate, higher than the rate in other stroke belt states and
up to two times the stroke mortality rate of the United States
overall. The increased risk could be due to geographic or
environmental factors or to regional differences in lifestyle,
including higher rates of cigarette smoking and a regional
preference for salty, high-fat foods.
Other Risk Factors
The most important risk factors for stroke are hypertension,
heart disease, diabetes, and cigarette smoking. Others include heavy
alcohol consumption, high blood cholesterol levels, illicit drug
use, and genetic or congenital conditions, particularly vascular
abnormalities. People with more than one risk factor have what is
called "amplification of risk." This means that the multiple risk
factors compound their destructive effects and create an overall
risk greater than the simple cumulative effect of the individual
Of all the risk factors that contribute to stroke, the most
powerful is hypertension, or high blood pressure. People with
hypertension have a risk for stroke that is four to six times higher
than the risk for those without hypertension. One-third of the adult
U.S. population, about 50 million people (including 40-70 percent of
those over age 65) have high blood pressure. Forty to 90 percent of
stroke patients have high blood pressure before their stroke event.
A systolic pressure of 120 mm of Hg over a diastolic pressure of
80 mm of Hg*
is generally considered normal. Persistently high blood pressure
greater than 140 over 90 leads to the diagnosis of the disease
called hypertension. The impact of hypertension on the total risk
for stroke decreases with increasing age, therefore factors other
than hypertension play a greater role in the overall stroke risk in
elderly adults. For people without hypertension, the absolute risk
of stroke increases over time until around the age of 90, when the
absolute risk becomes the same as that for people with hypertension.
Like stroke, there is a gender difference in the prevalence of
hypertension. In younger people, hypertension is more common among
men than among women. With increasing age, however, more women than
men have hypertension. This hypertension gender-age difference
probably has an impact on the incidence and prevalence of stroke in
Antihypertensive medication can decrease a person's risk for
stroke. Recent studies suggest that treatment can decrease the
stroke incidence rate by 38 percent and decrease the stroke fatality
rate by 40 percent. Common hypertensive agents include adrenergic
agents, beta-blockers, angiotensin converting enzyme inhibitors,
calcium channel blockers, diuretics, and vasodilators.
After hypertension, the second most powerful risk factor for
stroke is heart disease, especially a condition known as atrial
fibrillation. Atrial fibrillation is irregular beating of the
left atrium, or left upper chamber, of the heart. In people with
atrial fibrillation, the left atrium beats up to four times faster
than the rest of the heart. This leads to an irregular flow of blood
and the occasional formation of blood clots that can leave the heart
and travel to the brain, causing a stroke.
Atrial fibrillation, which affects as many as 2.2 million
Americans, increases an individual's risk of stroke by 4 to 6
percent, and about 15 percent of stroke patients have atrial
fibrillation before they experience a stroke. The condition is more
prevalent in the upper age groups, which means that the prevalence
of atrial fibrillation in the United States will increase
proportionately with the growth of the elderly population. Unlike
hypertension and other risk factors that have a lesser impact on the
ever-rising absolute risk of stroke that comes with advancing age,
the influence of atrial fibrillation on total risk for stroke
increases powerfully with age. In people over 80 years old, atrial
fibrillation is the direct cause of one in four strokes.
Other forms of heart disease that increase stroke risk include
malformations of the heart valves or the heart muscle. Some valve
diseases, like mitral valve stenosis or mitral annular
calcification, can double the risk for stroke, independent of
other risk factors.
Heart muscle malformations can also increase the risk for
stroke. Patent foramen ovale (PFO) is a passage or a hole
(sometimes called a "shunt") in the heart wall separating the two
atria, or upper chambers, of the heart. Clots in the blood are
usually filtered out by the lungs, but PFO could allow emboli or
blood clots to bypass the lungs and go directly through the arteries
to the brain, potentially causing a stroke. Research is currently
under way to determine how important PFO is as a cause for stroke.
Atrial septal aneurysm (ASA), a congenital (present from birth)
malformation of the heart tissue, is a bulging of the septum or
heart wall into one of the atria of the heart. Researchers do not
know why this malformation increases the risk for stroke. PFO and
ASA frequently occur together and therefore amplify the risk for
stroke. Two other heart malformations that seem to increase the risk
for stroke for unknown reasons are left atrial enlargement and left
ventricular hypertrophy. People with left atrial enlargement have a
larger than normal left atrium of the heart; those with left
ventricular hypertrophy have a thickening of the wall of the left
Another risk factor for stroke is cardiac surgery to correct
heart malformations or reverse the effects of heart disease. Strokes
occurring in this situation are usually the result of surgically
dislodged plaques from the aorta that travel through the bloodstream
to the arteries in the neck and head, causing stroke. Cardiac
surgery increases a person's risk of stroke by about 1 percent.
Other types of surgery can also increase the risk of stroke.
Blood Cholesterol Levels
Most people know that high cholesterol levels contribute to heart
disease. But many don't realize that a high cholesterol level also
contributes to stroke risk. Cholesterol, a waxy substance produced
by the liver, is a vital body product. It contributes to the
production of hormones and vitamin D and is an integral component of
cell membranes. The liver makes enough cholesterol to fuel the
body's needs and this natural production of cholesterol alone is not
a large contributing factor to atherosclerosis, heart disease, and
stroke. Research has shown that the danger from cholesterol comes
from a dietary intake of foods that contain high levels of
cholesterol. Foods high in saturated fat and cholesterol, like
meats, eggs, and dairy products, can increase the amount of total
cholesterol in the body to alarming levels, contributing to the risk
of atherosclerosis and thickening of the arteries.
Cholesterol is classified as a lipid, meaning that it is
fat-soluble rather than water-soluble. Other lipids include fatty
acids, glycerides, alcohol, waxes, steroids, and fat-soluble
vitamins A, D, and E. Lipids and water, like oil and water, do not
mix. Blood is a water-based liquid, therefore cholesterol does not
mix with blood. In order to travel through the blood without
clumping together, cholesterol needs to be covered by a layer of
protein. The cholesterol and protein together are called a
There are two kinds of cholesterol, commonly called the "good"
and the "bad." Good cholesterol is high-density lipoprotein,
or HDL; bad cholesterol is low-density lipoprotein, or
LDL. Together, these two forms of cholesterol make up a
person's total serum cholesterol level. Most cholesterol
tests measure the level of total cholesterol in the blood and don't
distinguish between good and bad cholesterol. For these total serum
cholesterol tests, a level of less than 200 mg/dL**
is considered safe, while a level of more than 240 is considered
dangerous and places a person at risk for heart disease and stroke.
Most cholesterol in the body is in the form of LDL. LDLs
circulate through the bloodstream, picking up excess cholesterol and
depositing cholesterol where it is needed (for example, for the
production and maintenance of cell membranes). But when too much
cholesterol starts circulating in the blood, the body cannot handle
the excessive LDLs, which build up along the inside of the arterial
walls. The buildup of LDL coating on the inside of the artery walls
hardens and turns into arterial plaque, leading to stenosis and
atherosclerosis. This plaque blocks blood vessels and contributes to
the formation of blood clots. A person's LDL level should be less
than 130 mg/dL to be safe. LDL levels between 130 and 159 put a
person at a slightly higher risk for atherosclerosis, heart disease,
and stroke. A score over 160 puts a person at great risk for a heart
attack or stroke.
The other form of cholesterol, HDL, is beneficial and contributes
to stroke prevention. HDL carries a small percentage of the
cholesterol in the blood, but instead of depositing its cholesterol
on the inside of artery walls, HDL returns to the liver to unload
its cholesterol. The liver then eliminates the excess cholesterol by
passing it along to the kidneys. Currently, any HDL score higher
than 35 is considered desirable. Recent studies have shown that high
levels of HDL are associated with a reduced risk for heart disease
and stroke and that low levels (less than 35 mg/dL), even in people
with normal levels of LDL, lead to an increased risk for heart
disease and stroke.
A person may lower his risk for atherosclerosis and stroke by
improving his cholesterol levels. A healthy diet and regular
exercise are the best ways to lower total cholesterol levels. In
some cases, physicians may prescribe cholesterol-lowering
medication, and recent studies have shown that the newest types of
these drugs, called reductase inhibitors or statin drugs,
significantly reduce the risk for stroke in most patients with high
cholesterol. Scientists believe that statins may work by reducing
the amount of bad cholesterol the body produces and by reducing the
body's inflammatory immune reaction to cholesterol plaque associated
with atherosclerosis and stroke.
*mm of Hg-or millimeters of mercury-is the standard means of
expressing blood pressure, which is measured using an instrument
called a sphygmomanometer. Using a stethoscope and a cuff that is
wrapped around the patient's upper arm, a health professional
listens to the sounds of blood rushing through an artery. The first
sound registered on the instrument gauge (which measures the
pressure of the blood in millimeters on a column of mercury) is
called the systolic pressure. This is the maximum pressure produced
as the left ventricle of the heart contracts and the blood begins to
flow through the artery. The second sound is the diastolic pressure
and is the lowest pressure in the artery when the left ventricle is
describes the weight of cholesterol in milligrams in a deciliter of
blood. This is the standard way of measuring blood cholesterol
Diabetes is another disease that increases a person's risk for
stroke. People with diabetes have three times the risk of stroke
compared to people without diabetes. The relative risk of stroke
from diabetes is highest in the fifth and sixth decades of life and
decreases after that. Like hypertension, the relative risk of stroke
from diabetes is highest for men at an earlier age and highest for
women at an older age. People with diabetes may also have other
contributing risk factors that can amplify the overall risk for
stroke. For example, the prevalence of hypertension is 40 percent
higher in the diabetic population compared to the general
Modifiable Lifestyle Risk Factors
Cigarette smoking is the most powerful modifiable stroke risk
factor. Smoking almost doubles a person's risk for ischemic stroke,
independent of other risk factors, and it increases a person's risk
for subarachnoid hemorrhage by up to 3.5 percent. Smoking is
directly responsible for a greater percentage of the total number of
strokes in young adults than in older adults. Risk factors other
than smoking - like hypertension, heart disease, and diabetes -
account for more of the total number of strokes in older adults.
Heavy smokers are at greater risk for stroke than light smokers.
The relative risk of stroke decreases immediately after quitting
smoking, with a major reduction of risk seen after 2 to 4 years.
Unfortunately, it may take several decades for a former smoker's
risk to drop to the level of someone who never smoked.
Smoking increases the risk of stroke by promoting atherosclerosis
and increasing the levels of blood-clotting factors, such as
fibrinogen. In addition to promoting conditions linked to stroke,
smoking also increases the damage that results from stroke by
weakening the endothelial wall of the cerebrovascular
system. This leads to greater damage to the brain from events that
occur in the secondary stage of stroke. (The secondary effects of
stroke are discussed in greater detail in the Appendix.)
High alcohol consumption is another modifiable risk factor for
stroke. Generally, an increase in alcohol consumption leads to an
increase in blood pressure. While scientists agree that heavy
drinking is a risk for both hemorrhagic and ischemic stroke, in
several research studies daily consumption of smaller amounts of
alcohol has been found to provide a protective influence against
ischemic stroke, perhaps because alcohol decreases the clotting
ability of platelets in the blood. Moderate alcohol
consumption may act in the same way as aspirin to decrease blood
clotting and prevent ischemic stroke. Heavy alcohol consumption,
though, may seriously deplete platelet numbers and compromise blood
clotting and blood viscosity, leading to hemorrhage. In addition,
heavy drinking or binge drinking can lead to a rebound effect after
the alcohol is purged from the body. The consequences of this
rebound effect are that blood viscosity (thickness) and platelet
levels skyrocket after heavy drinking, increasing the risk for
The use of illicit drugs, such as cocaine and crack cocaine, can
cause stroke. Cocaine may act on other risk factors, such as
hypertension, heart disease, and vascular disease, to trigger a
stroke. It decreases relative cerebrovascular blood flow by up to 30
percent, causes vascular constriction, and inhibits vascular
relaxation, leading to narrowing of the arteries. Cocaine also
affects the heart, causing arrhythmias and rapid heart rate that can
lead to the formation of blood clots.
Marijuana smoking may also be a risk factor for stroke. Marijuana
decreases blood pressure and may interact with other risk factors,
such as hypertension and cigarette smoking, to cause rapidly
fluctuating blood pressure levels, damaging blood vessels.
Other drugs of abuse, such as amphetamines, heroin, and anabolic
steroids (and even some common, legal drugs, such as caffeine and
L-asparaginase and pseudoephedrine found in over-the-counter
decongestants), have been suspected of increasing stroke risk. Many
of these drugs are vasoconstrictors, meaning that they cause blood
vessels to constrict and blood pressure to rise.
Head and Neck Injuries
Injuries to the head or neck may damage the cerebrovascular
system and cause a small number of strokes. Head injury or traumatic
brain injury may cause bleeding within the brain leading to damage
akin to that caused by a hemorrhagic stroke. Neck injury, when
associated with spontaneous tearing of the vertebral or carotid
arteries caused by sudden and severe extension of the neck, neck
rotation, or pressure on the artery, is a contributing cause of
stroke, especially in young adults. This type of stroke is often
called "beauty-parlor syndrome," which refers to the practice of
extending the neck backwards over a sink for hair-washing in beauty
parlors. Neck calisthenics, "bottoms-up" drinking, and improperly
performed chiropractic manipulation of the neck can also put strain
on the vertebral and carotid arteries, possibly leading to ischemic
Recent viral and bacterial infections may act with other risk
factors to add a small risk for stroke. The immune system responds
to infection by increasing inflammation and increasing the
infection-fighting properties of the blood. Unfortunately, this
immune response increases the number of clotting factors in the
blood, leading to an increased risk of embolic-ischemic stroke.
Genetic Risk Factors
Although there may not be a single genetic factor associated with
stroke, genes do play a large role in the expression of stroke risk
factors such as hypertension, heart disease, diabetes, and vascular
malformations. It is also possible that an increased risk for stroke
within a family is due to environmental factors, such as a common
sedentary lifestyle or poor eating habits, rather than hereditary
Vascular malformations that cause stroke may have the strongest
genetic link of all stroke risk factors. A vascular malformation is
an abnormally formed blood vessel or group of blood vessels. One
genetic vascular disease called CADASIL, which stands for cerebral
autosomal dominant arteriopathy with subcortical infarcts and
leukoencephalopathy. CADASIL is a rare, genetically inherited,
congenital vascular disease of the brain that causes strokes,
subcortical dementia, migraine-like headaches, and psychiatric
disturbances. CADASIL is very debilitating and symptoms usually
surface around the age of 45. Although CADASIL can be treated with
surgery to repair the defective blood vessels, patients often die by
the age of 65. The exact incidence of CADASIL in the United States
What Stroke Therapies are Available?
Physicians have a wide range of therapies to choose from when
determining a stroke patient's best therapeutic plan. The type of
stroke therapy a patient should receive depends upon the stage of
disease. Generally there are three treatment stages for stroke:
prevention, therapy immediately after stroke, and post-stroke
rehabilitation. Therapies to prevent a first or recurrent stroke are
based on treating an individual's underlying risk factors for
stroke, such as hypertension, atrial fibrillation, and diabetes, or
preventing the widespread formation of blood clots that can cause
ischemic stroke in everyone, whether or not risk factors are
present. Acute stroke therapies try to stop a stroke while it is
happening by quickly dissolving a blood clot causing the stroke or
by stopping the bleeding of a hemorrhagic stroke. The purpose of
post-stroke rehabilitation is to overcome disabilities that result
from stroke damage.
Therapies for stroke include medications, surgery, or
Medication or drug therapy is the most common treatment for
stroke. The most popular classes of drugs used to prevent or treat
stroke are antithrombotics (antiplatelet agents and
anticoagulants), thrombolytics, and neuroprotective
Antithrombotics prevent the formation of blood clots that can
become lodged in a cerebral artery and cause strokes. Antiplatelet
drugs prevent clotting by decreasing the activity of platelets,
blood cells that contribute to the clotting property of blood. These
drugs reduce the risk of blood-clot formation, thus reducing the
risk of ischemic stroke. In the context of stroke, physicians
prescribe antiplatelet drugs mainly for prevention. The most widely
known and used antiplatelet drug is aspirin. Other antiplatelet
drugs include clopidogrel and ticlopidine. The NINDS sponsors a wide
range of clinical trials to determine the effectiveness of
antiplatelet drugs for stroke prevention.
Anticoagulants reduce stroke risk by reducing the clotting
property of the blood. The most commonly used anticoagulants include
warfarin (also known as Coumadin<ฎ ) and heparin. The NINDS has
sponsored several trials to test the efficacy of anticoagulants
versus antiplatelet drugs. The Stroke Prevention in Atrial
Fibrillation (SPAF) trial found that, although aspirin is an
effective therapy for the prevention of a second stroke in most
patients with atrial fibrillation, some patients with additional
risk factors do better on warfarin therapy. Another study, the Trial
of Org 10127 in Acute Stroke Treatment (TOAST), tested the
effectiveness of low-molecular weight heparin (Org 10172) in stroke
prevention. TOAST showed that heparin anticoagulants are not
generally effective in preventing recurrent stroke or improving
Thrombolytic agents are used to treat an ongoing, acute ischemic
stroke caused by an artery blockage. These drugs halt the stroke by
dissolving the blood clot that is blocking blood flow to the brain.
Recombinant tissue plasminogen activator (rt-PA) is a
genetically engineered form of t-PA, a thombolytic substance made
naturally by the body. It can be effective if given intravenously
within 3 hours of stroke symptom onset, but it should be used only
after a physician has confirmed that the patient has suffered an
ischemic stroke. Thrombolytic agents can increase bleeding and
therefore must be used only after careful patient screening. The
NINDS rt-PA Stroke Study showed the efficacy of t-PA and in 1996 led
to the first FDA-approved treatment for acute ischemic stroke. Other
thrombolytics are currently being tested in clinical trials.
Neuroprotectants are medications that protect the brain from
secondary injury caused by stroke (see Appendix).
Although only a few neuroprotectants are FDA-approved for use at
this time, many are in clinical trials. There are several different
classes of neuroprotectants that show promise for future therapy,
including calcium antagonists, glutamate antagonists, opiate
antagonists, antioxidants, apoptosis inhibitors, and many others.
One of the calcium antagonists, nimodipine, also called a calcium
channel blocker, has been shown to decrease the risk of the
neurological damage that results from subarachnoid hemorrhage.
Calcium channel blockers, such as nimodipine, act by reducing the
risk of cerebral vasospasm, a dangerous side effect of
subarachnoid hemorrhage in which the blood vessels in the
subarachnoid space constrict erratically, cutting off blood flow.
Surgery can be used to prevent stroke, to treat acute stroke, or
to repair vascular damage or malformations in and around the brain.
There are two prominent types of surgery for stroke prevention and
treatment: carotid endarterectomy and extracranial/intracranial
Carotid endarterectomy is a surgical procedure in which a doctor
removes fatty deposits (plaque) from the inside of one of the
carotid arteries, which are located in the neck and are the main
suppliers of blood to the brain. As mentioned earlier, the disease
atherosclerosis is characterized by the buildup of plaque on the
inside of large arteries, and the blockage of an artery by this
fatty material is called stenosis. The NINDS has sponsored two large
clinical trials to test the efficacy of carotid endarterectomy: the
North American Symptomatic Carotid Endarterectomy Trial (NASCET) and
the Asymptomatic Carotid Atherosclerosis Trial (ACAS). These trials
showed that carotid endarterectomy is a safe and effective stroke
prevention therapy for most people with greater than 50 percent
stenosis of the carotid arteries when performed by a qualified and
experienced neurosurgeon or vascular surgeon.
Currently, the NINDS is sponsoring the Carotid Revascularization
Endarterectomy vs. Stenting Trial (CREST), a large clinical trial
designed to test the effectiveness of carotid endarterectomy versus
a newer surgical procedure for carotid stenosis called stenting. The
procedure involves inserting a long, thin catheter tube into an
artery in the leg and threading the catheter through the vascular
system into the narrow stenosis of the carotid artery in the neck.
Once the catheter is in place in the carotid artery, the radiologist
expands the stent with a balloon on the tip of the catheter. The
CREST trial will test the effectiveness of the new surgical
technique versus the established standard technique of carotid
EC/IC bypass surgery is a procedure that restores blood flow to a
blood-deprived area of brain tissue by rerouting a healthy artery in
the scalp to the area of brain tissue affected by a blocked artery.
The NINDS-sponsored EC/IC Bypass Study tested the ability of this
surgery to prevent recurrent strokes in stroke patients with
atherosclerosis. The study showed that, in the long run, EC/IC does
not seem to benefit these patients. The surgery is still performed
occasionally for patients with aneurysms, some types of small artery
disease, and certain vascular abnormalities.
One useful surgical procedure for treatment of brain aneurysms
that cause subarachnoid hemorrhage is a technique called
"clipping." Clipping involves clamping off the aneurysm from
the blood vessel, which reduces the chance that it will burst and
A new therapy that is gaining wide attention is the detachable
coil technique for the treatment of high-risk intracranial
aneurysms. A small platinum coil is inserted through an artery in
the thigh and threaded through the arteries to the site of the
aneurysm. The coil is then released into the aneurysm, where it
evokes an immune response from the body. The body produces a blood
clot inside the aneurysm, strengthening the artery walls and
reducing the risk of rupture. Once the aneurysm is stabilized, a
neurosurgeon can clip the aneurysm with less risk of hemorrhage and
death to the patient.
|Physical Therapy (PT)
||Relearn walking, sitting, lying
down, switching from one type of movement to another|
|Occupational Therapy (OT)
||Relearn eating, drinking,
swallowing, dressing, bathing, cooking, reading, writing,
||Relearn language and communications
||Alleviate some mental and emotional
Stroke is the number one cause of serious adult disability in the
United States. Stroke disability is devastating to the stroke
patient and family, but therapies are available to help rehabilitate
For most stroke patients, physical therapy (PT) is the
cornerstone of the rehabilitation process. A physical therapist uses
training, exercises, and physical manipulation of the stroke
patient's body with the intent of restoring movement, balance, and
coordination. The aim of PT is to have the stroke patient relearn
simple motor activities such as walking, sitting, standing, lying
down, and the process of switching from one type of movement to
Another type of therapy involving relearning daily activities is
occupational therapy (OT). OT also involves exercise and training to
help the stroke patient relearn everyday activities such as eating,
drinking and swallowing, dressing, bathing, cooking, reading and
writing, and toileting. The goal of OT is to help the patient become
independent or semi-independent.
Speech and language problems arise when brain damage occurs in
the language centers of the brain. Due to the brain's great ability
to learn and change (called brain plasticity), other areas
can adapt to take over some of the lost functions. Speech therapy
helps stroke patients relearn language and speaking skills, or learn
other forms of communication. Speech therapy is appropriate for
patients who have no deficits in cognition or thinking, but have
problems understanding speech or written words, or problems forming
speech. A speech therapist helps stroke patients help themselves by
working to improve language skills, develop alternative ways of
communicating, and develop coping skills to deal with the
frustration of not being able to communicate fully. With time and
patience, a stroke survivor should be able to regain some, and
sometimes all, language and speaking abilities.
Many stroke patients require psychological or psychiatric help
after a stroke. Psychological problems, such as depression, anxiety,
frustration, and anger, are common post-stroke disabilities. Talk
therapy, along with appropriate medication, can help alleviate some
of the mental and emotional problems that result from stroke.
Sometimes it is also beneficial for family members of the stroke
patient to seek psychological help as well.
For more information on rehabilitation, contact the National
Rehabilitation Information Center , a service of the National
Institute on Disability and Rehabilitation Research (see Where
I can get more information).
What Disabilities Can Result From a Stroke?
Although stroke is a disease of the brain, it can affect the
entire body. Some of the disabilities that can result from a stroke
include paralysis, cognitive deficits, speech problems, emotional
difficulties, daily living problems, and pain.
A common disability that results from stroke is paralysis on
one side of the body, called hemiplegia. A related disability
that is not as debilitating as paralysis is one-sided weakness or
hemiparesis. The paralysis or weakness may affect only the
face, an arm, or a leg or may affect one entire side of the body and
face. A person who suffers a stroke in the left hemisphere of the
brain will show right-sided paralysis or paresis. Conversely, a
person with a stroke in the right hemisphere of the brain will show
deficits on the left side of the body. A stroke patient may have
problems with the simplest of daily activities, such as walking,
dressing, eating, and using the bathroom. Motor deficits can result
from damage to the motor cortex in the frontal lobes of the brain or
from damage to the lower parts of the brain, such as the cerebellum,
which controls balance and coordination. Some stroke patients also
have trouble eating and swallowing, called dysphagia.
Stroke may cause problems with thinking, awareness, attention,
learning, judgment, and memory. If the cognitive problems are
severe, the stroke patient may be said to have apraxia,
agnosia, or "neglect." In the context of stroke, neglect
means that a stroke patient has no knowledge of one side of his or
her body, or one side of the visual field, and is unaware of the
deficit. A stroke patient may be unaware of his or her surroundings,
or may be unaware of the mental deficits that resulted from the
Stroke victims often have problems understanding or forming
speech. A deficit in understanding speech is called aphasia.
Trouble speaking or forming words is called dysarthria.
Language problems usually result from damage to the left temporal
and parietal lobes of the brain.
A stroke can lead to emotional problems. Stroke patients may have
difficulty controlling their emotions or may express inappropriate
emotions in certain situations. One common disability that occurs
with many stroke patients is depression. Post-stroke depression may
be more than a general sadness resulting from the stroke incident.
It is a clinical behavioral problem that can hamper recovery and
rehabilitation and may even lead to suicide. Post-stroke depression
is treated as any depression is treated, with antidepressant
medications and therapy.
Stroke patients may experience pain, uncomfortable numbness, or
strange sensations after a stroke. These sensations may be due to
many factors including damage to the sensory regions of the brain,
stiff joints, or a disabled limb. An uncommon type of pain resulting
from stroke is called central stroke pain or central pain
syndrome (CPS). CPS results from damage to an area in the
mid-brain called the thalamus. The pain is a mixture of sensations,
including heat and cold, burning, tingling, numbness, and sharp
stabbing and underlying aching pain. The pain is often worse in the
extremities - the hands and feet - and is made worse by movement and
temperature changes, especially cold temperatures. Unfortunately,
since most pain medications provide little relief from these
sensations, very few treatments or therapies exist to combat CPS.
What Special Risks do Women Face?
Some risk factors for stroke apply only to women. Primary among
these are pregnancy, childbirth, and menopause. These risk factors
are tied to hormonal fluctuations and changes that affect a woman in
different stages of life. Research in the past few decades has shown
that high-dose oral contraceptives, the kind used in the 1960s and
1970s, can increase the risk of stroke in women. Fortunately, oral
contraceptives with high doses of estrogen are no longer used and
have been replaced with safer and more effective oral contraceptives
with lower doses of estrogen. Some studies have shown the newer
low-dose oral contraceptives may not significantly increase the risk
of stroke in women.
Other studies have demonstrated that pregnancy and childbirth can
put a woman at an increased risk for stroke. Pregnancy increases the
risk of stroke as much as three to 13 times. Of course, the risk of
stroke in young women of childbearing years is very small to begin
with, so a moderate increase in risk during pregnancy is still a
relatively small risk. Pregnancy and childbirth cause strokes in
approximately eight in 100,000 women. Unfortunately, 25 percent of
strokes during pregnancy end in death, and hemorrhagic strokes,
although rare, are still the leading cause of maternal death in the
United States. Subarachnoid hemorrhage, in particular, causes one to
five maternal deaths per 10,000 pregnancies.
A study sponsored by the NINDS showed that the risk of stroke
during pregnancy is greatest in the post-partum period - the 6 weeks
following childbirth. The risk of ischemic stroke after pregnancy is
about nine times higher and the risk of hemorrhagic stroke is more
than 28 times higher for post-partum women than for women who are
not pregnant or post-partum. The cause is unknown.
In the same way that the hormonal changes during pregnancy and
childbirth are associated with increased risk of stroke, hormonal
changes at the end of the childbearing years can increase the risk
of stroke. Several studies have shown that menopause, the end of a
woman's reproductive ability marked by the termination of her
menstrual cycle, can increase a woman's risk of stroke. Fortunately,
some studies have suggested that hormone replacement therapy can
reduce some of the effects of menopause and decrease stroke risk.
Currently, the NINDS is sponsoring the Women's Estrogen for Stroke
Trial (WEST), a randomized, placebo-controlled, double-blind trial,
to determine whether estrogen therapy can reduce the risk of death
or recurrent stroke in postmenopausal women who have a history of a
recent TIA or non-disabling stroke. The mechanism by which estrogen
can prove beneficial to postmenopausal women could include its role
in cholesterol control. Studies have shown that estrogen acts to
increase levels of HDL while decreasing LDL levels.
Are Children at Risk For Stroke?
The young have several risk factors unique to them. Young people
seem to suffer from hemorrhagic strokes more than ischemic strokes,
a significant difference from older age groups where ischemic
strokes make up the majority of stroke cases. Hemorrhagic strokes
represent 20 percent of all strokes in the United States and young
people account for many of these.
Clinicians often separate the "young" into two categories: those
younger than 15 years of age, and those 15 to 44 years of age.
People 15 to 44 years of age are generally considered young adults
and have many of the risk factors mentioned above, such as drug use,
alcohol abuse, pregnancy, head and neck injuries, heart disease or
heart malformations, and infections. Some other causes of stroke in
the young are linked to genetic diseases.
Medical complications that can lead to stroke in children include
intracranial infection, brain injury, vascular malformations such as
moyamoya syndrome, occlusive vascular disease, and genetic disorders
such as sickle cell anemia, tuberous sclerosis, and Marfan's
The symptoms of stroke in children are different from those in
adults and young adults. A child experiencing a stroke may have
seizures, a sudden loss of speech, a loss of expressive language
(including body language and gestures), hemiparesis (weakness on one
side of the body), hemiplegia (paralysis on one side of the body),
dysarthria (impairment of speech), convulsions, headache, or fever.
It is a medical emergency when a child shows any of these symptoms.
In children with stroke the underlying conditions that led to the
stroke should be determined and managed to prevent future strokes.
For example, a recent clinical study sponsored by the National
Heart, Lung, and Blood Institute found that giving blood
transfusions to young children with sickle cell anemia greatly
reduces the risk of stroke. The Institute even suggests attempting
to prevent stroke in high-risk children by giving them blood
transfusions before they experience a stroke.
Most children who experience a stroke will do better than most
adults after treatment and rehabilitation. This is due in part to
the immature brain's great plasticity, the ability to adapt to
deficits and injury. Children who experience seizures along with
stroke do not recover as well as children who do not have seizures.
Some children may experience residual hemiplegia, though most will
eventually learn how to walk.
Research is Being Done by the NINDS?
The NINDS is the leading supporter of stroke research in the
United States and sponsors a wide range of experimental research
studies, from investigations of basic biological mechanisms to
studies with animal models and clinical trials.
Currently, NINDS researchers are studying the mechanisms of
stroke risk factors and the process of brain damage that results
from stroke. Some of this brain damage may be secondary to the
initial death of brain cells caused by the lack of blood flow to the
brain tissue. This secondary wave of brain injury is a result of a
toxic reaction to the primary damage and mainly involves the
excitatory neurochemical, glutamate. Glutamate in the normal
brain functions as a chemical messenger between brain cells,
allowing them to communicate. But an excess amount of glutamate in
the brain causes too much activity and brain cells quickly "burn
out" from too much excitement, releasing more toxic chemicals, such
as caspases, cytokines, monocytes, and oxygen-free radicals. These
substances poison the chemical environment of surrounding cells,
initiating a cascade of degeneration and programmed cell death,
called apoptosis. NINDS researchers are studying the
mechanisms underlying this secondary insult, which consists mainly
of inflammation, toxicity, and a breakdown of the blood vessels that
provide blood to the brain. Researchers are also looking for
ways to prevent secondary injury to the brain by providing different
types of neuroprotection for salvagable cells that prevent
inflammation and block some of the toxic chemicals created by dying
brain cells. From this research, scientists hope to develop
neuroprotective agents to prevent secondary damage. For more
information on excitotoxicity, neuroprotection, and the ischemic
cascade, please refer to the Appendix.
Another area of research involves experiments with
vasodilators, medications that expand or dilate blood vessels
and thus increase blood flow to the brain. Vasodilators have long
been used to treat many disorders, including heart disease.
Researchers hope that vasodilators may aid in the rehabilitation of
stroke victims by increasing blood flow to the brain. So far,
unfortunately, they have shown limited success, possibly because
they have not been given soon enough after the onset of stroke.
Basic research has also focused on the genetics of stroke and
stroke risk factors. One area of research involving genetics is gene
therapy. Gene therapy involves putting a gene for a desired protein
in certain cells of the body. The inserted gene will then "program"
the cell to produce the desired protein. If enough cells in the
right areas produce enough protein, then the protein could be
therapeutic. Scientists must find ways to deliver the therapeutic
DNA to the appropriate cells and must learn how to deliver enough
DNA to enough cells so that the tissues produce a therapeutic amount
of protein. Gene therapy is in the very early stages of development
and there are many problems to overcome, including learning how to
penetrate the highly impermeable blood-brain barrier and how
to halt the host's immune reaction to the virus that carries the
gene to the cells. Some of the proteins used for stroke therapy
could include neuroprotective proteins, anti-inflammatory proteins,
and DNA/cellular repair proteins, among others.
The NINDS supports and conducts a wide variety of studies in
animals, from genetics research on zebrafish to rehabilitation
research on primates. Much of the Institute's animal research
involves rodents, specifically mice and rats. For example, one study
of hypertension and stroke uses rats that have been bred to be
hypertensive and therefore stroke-prone. By studying stroke in rats,
scientists hope to get a better picture of what might be happening
in human stroke patients. Scientists can also use animal models to
test promising therapeutic interventions for stroke. If a therapy
proves to be beneficial to animals, then scientists can consider
testing the therapy in human subjects.
One promising area of stroke animal research involves
hibernation. The dramatic decrease of blood flow to the brain in
hibernating animals is extensive - extensive enough that it would
kill a non-hibernating animal. During hibernation, an animal's
metabolism slows down, body temperature drops, and energy and oxygen
requirements of brain cells decrease. If scientists can discover how
animals hibernate without experiencing brain damage, then maybe they
can discover ways to stop the brain damage associated with decreased
blood flow in stroke patients. Other studies are looking at the role
of hypothermia, or decreased body temperature, on metabolism and
Both hibernation and hypothermia have a relationship to
hypoxia and edema. Hypoxia, or anoxia, occurs
when there is not enough oxygen available for brain cells to
function properly. Since brain cells require large amounts of oxygen
for energy requirements, they are especially vulnerable to hypoxia.
Edema occurs when the chemical balance of brain tissue is disturbed
and water or fluids flow into the brain cells, making them swell and
burst, releasing their toxic contents into the surrounding tissues.
Edema is one cause of general brain tissue swelling and contributes
to the secondary injury associated with stroke.
The basic and animal studies discussed above do not involve
people and fall under the category of preclinical research; clinical
research involves people. One area of investigation that has made
the transition from animal models to clinical research is the study
of the mechanisms underlying brain plasticity and the neuronal
rewiring that occurs after a stroke.
New advances in imaging and rehabilitation have shown that the
brain can compensate for function lost as a result of stroke. When
cells in an area of the brain responsible for a particular function
die after a stroke, the patient becomes unable to perform that
function. For example, a stroke patient with an infarct in the area
of the brain responsible for facial recognition becomes unable to
recognize faces, a syndrome called facial agnosia. But, in time, the
person may come to recognize faces again, even though the area of
the brain originally programmed to perform that function remains
dead. The plasticity of the brain and the rewiring of the neural
connections make it possible for one part of the brain to change
functions and take up the more important functions of a disabled
part. This rewiring of the brain and restoration of function, which
the brain tries to do automatically, can be helped with therapy.
Scientists are working to develop new and better ways to help the
brain repair itself to restore important functions to the stroke
One example of a therapy resulting from this research is the use
of transcranial magnetic stimulation (TMS) in stroke
rehabilitation. Some evidence suggests that TMS, in which a small
magnetic current is delivered to an area of the brain, may possibly
increase brain plasticity and speed up recovery of function after a
stroke. The TMS device is a small coil which is held outside of the
head, over the part of the brain needing stimulation. Currently,
several studies at the NINDS are testing whether TMS has any value
in increasing motor function and improving functional recovery.
Clinical research is usually conducted in a series of trials that
become progressively larger. A phase I clinical trial is directly
built upon the lessons learned from basic and animal research and is
used to test the safety of therapy for a particular disease and to
estimate possible efficacy in a few human subjects. A phase II
clinical trial usually involves many subjects at several different
centers and is used to test safety and possible efficacy on a
broader scale, to test different dosing for medications or to
perfect techniques for surgery, and to determine the best
methodology and outcome measures for the bigger phase III clinical
trial to come.
A phase III clinical trial is the largest endeavor in clinical
research. This type of trial often involves many centers and many
subjects. The trial usually has two patient groups who receive
different treatments, but all other standard care is the same and
represents the best care available. The trial may compare two
treatments, or, if there is only one treatment to test, patients who
do not receive the test therapy receive instead a placebo. The
patients are told that the additional treatment they are receiving
may be either the active treatment or a placebo. Many phase III
trials are called double-blind, randomized clinical trials.
Double-blind means that neither the subjects nor the doctors and
nurses who are treating the subjects and determining the response to
the therapy know which treatment a subject receives. Randomization
refers to the placing of subjects into one of the treatment groups
in a way that can't be predicted by the patients or investigators.
These clinical trials usually involve many investigators and take
many years to complete. The hypothesis and methods of the trial are
very precise and well thought out. Clinical trial designs, as well
as the concepts of blinding and randomization, have developed over
years of experimentation, trial, and error. At the present time,
researchers are developing new designs to maximize the opportunity
for all subjects to receive therapy.
Most treatments for general use come out of phase III clinical
trials. After one or more phase III trials are finished, and if the
results are positive for the treatment, the investigators can
petition the FDA for government approval to use the drug or
procedure to treat patients. Once the treatment is approved by the
FDA, it can be used by qualified doctors throughout the country. The
back packet of this brochure contains cards with information on some
of the many stroke clinical trials the NINDS supports or has
NINDS-Sponsored Stroke Clinical Trials: April 2004
Clinical trials give researchers a way to test new
treatments in human subjects. Clinical trials test surgical devices
and procedures, medications, rehabilitation therapies, and lifestyle
and psychosocial interventions to determine how safe and effective
they are and to establish the proper amount or level of treatment.
Because of their scope and the need for careful analysis of data and
outcomes, clinical trials are usually conducted in three phases and
can take several years or more to complete.
- Phase I clinical trials are small (involving
fewer than 100 people) and are designed to define side effects and
tolerance of the medication or therapy.
- Phase II trials are conducted with a larger
group of subjects and seek to measure the effects of a therapy and
establish its proper dosage or level of treatment.
- Phase III trials often involve hundreds
(sometimes thousands) of volunteer patients who are assigned to
treatment and non-treatment groups to test how well the treatment
works and how safe it is at the recommended dosage or level of
therapy. Many of these trials use a controlled, randomized,
double-blind study design. This means that patients are randomly
assigned to groups and neither the subject nor the study staff
knows to which group a patient belongs. Phase III randomized
clinical trials are often called the gold standard of clinical
NINDS conducts clinical trials at the NIH Clinical Center and
also provides funding for clinical trials at hospitals and
universities across the United States and Canada. Below are findings
from some of the largest and most significant recent clinical
trials, as well as summaries of some of the most promising clinical
trials in progress.
Findings From Recently Completed Clinical Trials
Warfarin vs. Aspirin Recurrent Stroke Study (WARSS)
WARSS was a 7-year double-blind randomized clinical trial that
enrolled more than 200 patients at 48 participating centers. It was
the largest clinical trial ever to compare the benefits of aspirin
to warfarin for the prevention of recurrent stroke. Findings from
the study were published in the The New England Journal of Medicine
(November 15, 2001), which showed that aspirin works as well as
warfarin in helping to prevent recurrent strokes in most patients.
Whether warfarin was superior to aspirin for stroke prevention was
unclear prior to WARSS. Most clinicians believed that warfarin was a
better blood thinner than aspirin, although it had three drawbacks:
it was more expensive, it required monthly blood tests for proper
monitoring, and it had a greater risk for side effects. The WARSS
trial demonstrated that aspirin was not only cheaper and safer than
warfarin for preventing stroke, it was just as effective without
the additional costs of monthly monitoring.
African-American Antiplatelet Stroke Prevention Study (AAASPS)
Womens Estrogen for Stroke Trial (WEST)
The AAASPS study was a randomized double-blind trial that
enrolled 1,800 African-American stroke patients at more than 60
sites to compare the benefits of ticlopidine to aspirin in
preventing recurrent stroke. A previous clinical trial of
ticlopidine had indicated that the antiplatelet drug might be
particularly effective for stroke reduction among non-whites,
primarily African-Americans. The trial ended early when data
analysis suggested that there was less than a 1 percent chance that
ticlopidine would be shown to be superior to aspirin if the study
were carried to completion. Results showed that 650 mg of aspirin
per day is just as effective as ticlopidine in preventing recurrent
stroke and has the added benefit of easy availability, lower cost,
and less risk for side effects. The findings were published in the
Journal of the American Medical Association (June 11, 2003).
WEST was the first clinical trial to test the benefits of
estrogen therapy for prevention of recurrent cerebrovascular disease
in women. The randomized double-blind placebo-controlled trial
recruited 664 postmenopausal women from 21 hospitals across the
United States. Findings from the study, published in The New England
Journal of Medicine (October 2001), demonstrated that hormone
replacement therapy with estrogen did not reduce the risk of stroke
or death in postmenopausal women who had already had one stroke or
transient ischemic attack (TIA, also called mini-stroke). The data
also suggested that women who received estrogen were more likely to
have a fatal stroke during the first 6 months of treatment, and that
their non-fatal strokes were more severe. Based on these findings,
the WEST investigators recommended against prescribing estrogen
therapy for the purpose of preventing future recurrent stroke in
Ongoing Clinical Trials
The Family Intervention in Recovery from Stroke Trial (FIRST)
This study is testing whether or not the daily involvement and
support of family, friends, and neighbors can improve the functional
abilities of elderly stroke patients. An intervention has been
designed to mobilize the social networks of stroke patients to
provide effective emotional and practical support. Close to 300
patients from two large city hospitals have been randomly assigned
to two groups: one that receives the intervention, and one that
receives the usual care. At 3 months and 6 months, members of each
group are being assessed for functional ability based both on how
well they think they are doing as well as their performance on tests
that measure functional abilities. A number of previous studies have
indicated that psychosocial interventions can improve emotional
adjustment in stroke patients and promote longer survival rates in
patients with chronic illnesses. This is the first study to focus
specifically on the impact of such psychosocial interventions on
physical function in stroke survivors.
The Carotid Revascularization Endarterectomy vs. Stenting Trial (CREST)
Carotid Occlusion Surgery Study (COSS)
The use of dilation and stenting techniques similar to those used
to unclog and open heart arteries has been proposed as a less
invasive alternative to carotid endarterectomy (a surgical procedure
that opens and widens blocked carotid arteries on either side of the
neck). This trial is comparing the two techniques for safety and
effectiveness. The standard carotid endarterectomy surgical
procedure is being used on one set of patients. A procedure that
inserts an expanding metal scaffold (stent) into the neck artery
after widening it with balloon dilation is being tested on another
group. If stenting is shown to be safe, effective, and durable, this
less invasive procedure is likely to have a wider application in
medical practice. A small add-on study to CREST is using genetic
sampling and screening techniques to identify specific genes that
could increase the risk for stroke.
The goal of this multicenter randomized clinical trial is to
determine if extracranial bypass surgery can reduce the risk of
subsequent stroke for a subgroup of people who have a blocked
carotid artery and an increased oxygen extraction fraction (OEF,
which indicates how hard the brain has to work to pull oxygen out of
the blood supply). An increased OEF has been shown to be a powerful
and independent risk factor for subsequent stroke increasing the
odds by 25 to 50 percent. Participants have been randomly assigned
to medical care with antiplatelet therapy, or antiplatelet therapy
in combination with extracranial bypass surgery, which increases
blood flow to the brain by using a healthy blood vessel to bypass
the blocked artery. The participants are being followed for an
average of 2 years to monitor incidence of stroke.
Warfarin vs. Aspirin for Intracranial Arterial Stenosis (WASID)
Intraoperative Hypothermia for Aneurysm Surgery Trial (IHAST)
The goal of this trial is to compare the effectiveness of
warfarin to aspirin in preventing subsequent strokes or other
vascular-related events, such as heart attacks, in patients with
clogged arteries in the brain (intracranial arterial stenosis). This
is a randomized multicenter trial that is following two groups of
patients who have had a transient ischemic attack (TIA, commonly
called a mini-stroke), or a minor stroke caused by blocked or
narrowed arteries in the brain. One group is receiving warfarin; the
other is taking aspirin. Patients are being followed for 4 years to
compare the rates of death due to stroke and vascular-related
diseases. This study hopes to show which treatment is better for
patients with intracranial arterial stenosis.
Aneurysmal subarachnoid hemorrhage (SAH), in which a bulging
artery ruptures and bleeds into the area between the skull and the
brain, accounts for only 5 percent of all strokes but has a high
rate of mortality and high levels of disability in those who
survive. The usual course of treatment is to clip and seal the area
around the ruptured artery to end the bleeding and establish normal
circulation. The trial investigators believe that this surgical
procedure often causes additional neurological damage that can lead
to death or substantial disability after surgery. IHAST is a
randomized clinical trial designed to evaluate the safety and
effectiveness of hypothermia (lowering body temperature to 33
degrees centigrade) to prevent neurological damage during surgery.
Patients are being tested 3 months following surgery to establish
whether or not there is an improvement in neurological outcome if
hypothermia is used during surgery.
Extremity Constraint-Induced Therapy Evaluation (EXCITE)
Warfarin vs. Aspirin in Reduced Cardiac Ejection Fraction (WARCEF)
Impaired movement in the arms and legs is a major consequence of
stroke. Therapeutic interventions to improve motor function and
promote independent use of arms and hands are limited. One technique
that has been shown to be successful in basic research studies with
animal and human subjects is constraint-induced (CI) movement
therapy (also called forced use). The CI technique involves
restriction of the less affected arm, while the more affected arm is
forced to perform repetitive motions. This trial has randomized
stroke patients with at least minimal ability in their arms to two
groups one that receives customary care and one that receives CI
therapy. A year after the trial begins, the customary care group
will cross over to also receive CI therapy, in order to test whether
or not delayed therapy can be effective. Changes in both groups in
terms of increased motor function and psychosocial function will be
The purpose of this study is to determine which of two treatments
warfarin or aspirin is better for preventing death from stroke
in patients with low ejection fraction (EF) and heart failure. EF is
a measurement that indicates the amount of blood pumped (ejected)
from the heart with each beat. Low EF is a known risk factor for
stroke in people with heart failure, because the lower the EF, the
less blood is being pumped out of the heart. This multicenter (70
sites) study has enrolled thousands of patients with low EF and
randomly assigned them to be treated with warfarin or aspirin.
Telephone reports and physical exams every 4 months over the course
of 3 years have been recording their health status and the
occurrence of stroke or other cardiovascular events. Data is also
being analyzed for differences in therapy response among men and
women, and African-Americans and other racial groups. The study will
define the optimal stroke prevention therapy for patients with
cardiac failure and low EF.
Secondary Prevention of Small Subcortical Strokes (SPS3)
Field Administration of Stroke Therapy Magnesium Trial (FAST-MAG)
This trial is testing the benefits of combined antiplatelet
therapy (aspirin and clopidogrel) compared to intensive blood
pressure control to prevent recurring stroke in people who have
small subcortical strokes (S3). S3, in which the thread-like
arteries within cerebral tissue become blocked and halt blood flow
to the brain, is the most frequent type of stroke in Hispanic
Americans. For those who survive S3, there is a high risk for
additional strokes, vascular dementia, and cognitive decline. The
trial is enrolling 2,500 patients (20 percent of whom will be
Hispanic Americans) who will then be assigned to two interventions:
treatment with aspirin and clopidogrel, or intensive blood pressure
control. Patients are being followed every 3 months for 3 years.
There have been no previous clinical trials focused on the use of
combined antiplatelet therapy after S3, on optimal target levels of
blood pressure control after stroke, or on prevention of stroke and
dementia in Hispanic Americans. The results of this trial will help
establish optimal stroke prevention treatment levels for those with
S3 and determine if those levels are different for Hispanic
This is a three-phase trial to develop and test methods that can
quickly deliver neuroprotective therapies to prevent further damage
to brain tissue after stroke. While a number of neuroprotective
drugs have been shown to reduce stroke damage to brain tissue in
animals, there have been no Phase III clinical trials in humans,
mostly because of difficulties in administering the drugs quickly
enough. In the first phase of this project, paramedics will
immediately administer a neuroprotective agent (magnesium sulfate)
to patients with symptoms of acute stroke and the outcomes will be
evaluated for safety, practicality, and timesaving over hospital
treatment. The second phase is a standard, Phase III clinical trial
that randomizes patients to receive either treatment with magnesium
sulfate or placebo. The last phase will test differences in outcomes
between early treatment before patients reach the hospital versus
later treatment in the hospital. If early treatment is shown to be
practical as well as more beneficial, a larger multicenter trial can
be launched to demonstrate the advantages of administering therapy
before patients arrive at the hospital. The results from such a
trial could potentially set a new standard of care.
Where can I get more information?
For more information on neurological disorders or research
programs funded by the National Institute of Neurological Disorders
and Stroke, contact the Institute's Brain Resources and Information
Network (BRAIN) at:
P.O. Box 5801
Bethesda, MD 20824
Information also is available from the following
American Health Assistance
22512 Gateway Center
Clarksburg, MD 20871
301-948-3244 800-437-AHAF (2423)
Non-profit charitable organization dedicated
to funding research and educating the public on Alzheimer's
disease, glaucoma, macular degeneration, heart disease, and
stroke. Provides emergency financial assistance to Alzheimer's
disease patients and their
American Stroke Association: A Division
of American Heart Association
Dallas, TX 75231-4596
Offers a wide
array of programs, products, and services, from patient
education materials to scientific statements with cutting-edge
information for healthcare professionals.
12 Clarendon Street
Information and support
organization for brain aneurysm patients, their families, and
the medical community.
Children's Hemiplegia and Stroke
4101 West Green Oaks Blvd., Ste.
Arlington, TX 76016
Non-profit 501(c)(3) corporation that offers
support and information for families of children who have
hemiplegia due to stroke or other causes. Also provides
information regarding research and causes of any type of
Hazel K. Goddess Fund for Stroke
Research in Women
785 Park Avenue
New York, NY
that focuses on critical issues specific to stroke in women,
including research, prevention, treatment, education, and
29 John Street
York, NY 10038
212-267-2814 800-922-4NAA (4622)
Promotes the care, welfare, and rehabilitation
of people with aphasia through public education and support of
research. Offers printed materials, a toll-free information
hotline, a newsletter, and a listing of support
9707 East Easter Lane
303-649-9299 800-STROKES (787-6537)
National non-profit organization that offers
education, services and community-based activities in
prevention, treatment, rehabilitation and recovery. Serves the
public and professional communities: people at risk, patients
and their health care providers, stroke survivors, and their
families and caregivers.
805 12th Street
Offers mutual support, education, social and
recreational programs and activities to people who have
experienced strokes, their families, and
acute stroke-a stage of stroke starting
at the onset of symptoms and last for a few hours thereafter.
agnosia-a cognitive disability
characterized by ignorance of or inability to acknowledge one side
of the body or one side of the visual field.
aneurysm -a weak or thin spot on an
artery wall that has stretched or ballooned out from the wall and
filled with blood, or damage to an artery leading to pooling of
blood between the layers of the blood vessel walls.
anoxia-a state of almost no oxygen
delivery to a cell, resulting in low energy production and possible
death of the cell; see hypoxia.
anticoagulants-a drug therapy used to
prevent the formation of blood clots that can become lodged in
cerebral arteries and cause strokes.
antiplatelet agents-a type of
anticoagulant drug therapy that prevents the formation of blood
clots by preventing the accumulation of platelets that form the
basis of blood clots; some common antiplatelets include aspirin and
ticlopidine; see anticoagulants.
antithrombotics-a type of anticoagulant
drug therapy that prevents the formation of blood clots by
inhibiting the coagulating actions of the blood protein thrombin;
some common antithrombotics include warfarin and heparin; see
aphasia-the inability to understand or
create speech, writing, or language in general due to damage to the
speech centers of the brain.
apoplexy-a historical, but obsolete
term for a cerebral stroke, most often intracerebral hemorrhage,
that was applied to any condition that involved disorientation
apoptosis- a form of cell death
involving shrinking of the cell and eventual disposal of the
internal elements of the cell by the body's immune system. Apoptosis
is an active, non-toxic form of cell suicide that does not induce an
inflammatory response. It is often called programmed cell death
because it is triggered by a genetic signal, involves specific cell
mechanisms, and is irreversible once initiated.
apraxia-a movement disorder
characterized by the inability to perform skilled or purposeful
voluntary movements, generally caused by damage to the areas of the
brain responsible for voluntary movement.
arteriography-an X-ray of the carotid
artery taken when a special dye is injected into the artery.
arteriovenous malformation (AVM)-a
congenital disorder characterized by a complex tangled web of
arteries and veins.
atherosclerosis-a blood vessel disease
characterized by deposits of lipid material on the inside of the
walls of large to medium-sized arteries which make the artery walls
thick, hard, brittle, and prone to breaking.
atrial fibrillation-irregular beating
of the left atrium, or left upper chamber, of the heart.
blood-brain barrier-an elaborate
network of supportive brain cells, called glia, that surrounds blood
vessels and protects neurons from the toxic effects of direct
exposure to blood.
carotid artery-an artery, located on
either side of the neck, that supplies the brain with blood.
carotid endarterectomy-surgery used to
remove fatty deposits from the carotid arteries.
central stroke pain (central pain
syndrome)-pain caused by damage to an area in the
thalamus. The pain is a mixture of sensations, including heat and
cold, burning, tingling, numbness, and sharp stabbing and underlying
cerebral blood flow (CBF)-the flow of
blood through the arteries that lead to the brain, called the
cerebrospinal fluid (CSF)-clear fluid that bathes the
brain and spinal cord.
cerebrovascular disease-a reduction in
the supply of blood to the brain either by narrowing of the arteries
through the buildup of plaque on the inside walls of the arteries,
called stenosis, or through blockage of an artery due to a blood
cholesterol-a waxy substance, produced
naturally by the liver and also found in foods, that circulates in
the blood and helps maintain tissues and cell membranes. Excess
cholesterol in the body can contribute to atherosclerosis and high
"clipping"-surgical procedure for
treatment of brain aneurysms, involving clamping an aneurysm from a
blood vessel, surgically removing this ballooned part of the blood
vessel, and closing the opening in the artery wall.
computed tomography (CT) scan-a series
of cross-sectional X-rays of the brain and head; also called
computerized axial tomography or CAT scan.
Coumadinฎ-a commonly used
anticoagulant, also known as warfarin.
cytokines-small, hormone-like proteins
released by leukocytes, endothelial cells, and other cells to
promote an inflammatory immune response to an injury.
cytotoxic edema-a state of cell
compromise involving influx of fluids and toxic chemicals into a
cell causing subsequent swelling of the cell.
detachable coil-a platinum coil that is
inserted into an artery in the thigh and strung through the arteries
to the site of an aneurysm. The coil is released into the aneurysm
creating an immune response from the body. The body produces a blood
clot inside the aneurysm, strengthening the artery walls and
reducing the risk of rupture.
duplex Doppler ultrasound-a diagnostic
imaging technique in which an image of an artery can be formed by
bouncing sound waves off the moving blood in the artery and
measuring the frequency changes of the echoes.
dysarthria-a language disorder
characterized by difficulty with speaking or forming words.
dysphagia-trouble eating and
edema-the swelling of a cell that
results from the influx of large amounts of water or fluid into the
embolic stroke-a stroke caused by an
embolus-a free-roaming clot that
usually forms in the heart.
endothelial wall-a flat layer of cells
that make up the innermost lining of a blood vessel.
excitatory amino acids-a subset of
neurotransmitters; proteins released by one neuron into the space
between two neurons to promote an excitatory state in the other
bypass-a type of surgery that restores blood flow to a
blood-deprived area of brain tissue by rerouting a healthy artery in
the scalp to the area of brain tissue affected by a blocked artery.
functional magnetic resonance imaging
(fMRI)-a type of imaging that measures increases in
blood flow within the brain.
glia-also called neuroglia; supportive
cells of the nervous system that make up the blood-brain barrier,
provide nutrients and oxygen to the vital neurons, and protect the
neurons from infection, toxicity, and trauma. Some examples of glia
are oligodendroglia, astrocytes, and microglia.
glutamate-also known as glutamic acid,
an amino acid that acts as an excitatory neurotransmitter in the
hemiparesis-weakness on one side of the
hemiplegia-paralysis on one side of the
hemorrhagic stroke-sudden bleeding into
or around the brain.
heparin-a type of anticoagulant.
high-density lipoprotein (HDL)-also
known as the good cholesterol; a compound consisting of a lipid and
a protein that carries a small percentage of the total cholesterol
in the blood and deposits it in the liver.
homeostasis-a state of equilibrium or
balance among various fluids and chemicals in a cell, in tissues, or
in the body as a whole.
hypertension (high blood
pressure)-characterized by persistently high arterial
blood pressure defined as a measurement greater than or equal to 140
mm/Hg systolic pressure over 90 mm/Hg diastolic pressure.
hypoxia-a state of decreased oxygen
delivery to a cell so that the oxygen falls below normal levels;
incidence-the extent or frequency of an
occurrence; the number of specific new events in a given period of
infarct-an area of tissue that is dead
or dying because of a loss of blood supply.
infarction-a sudden loss of blood
supply to tissue, causing the formation of an infarct.
interleukins-a group of
cytokine-related proteins secreted by leukocytes and involved in the
inflammatory immune response of the ischemic cascade.
intracerebral hemorrhage-occurs when a
vessel within the brain leaks blood into the brain.
ischemia-a loss of blood flow to
tissue, caused by an obstruction of the blood vessel, usually in the
form of plaque stenosis or a blood clot.
ischemic cascade-a series of events
lasting for several hours to several days following initial ischemia
that results in extensive cell death and tissue damage beyond the
area of tissue originally affected by the initial lack of blood
ischemic penumbra-areas of damaged, but
still living, brain cells arranged in a patchwork pattern around
areas of dead brain cells.
ischemic stroke-ischemia in the tissues
of the brain.
lacunar infarction-occlusion of a small
artery in the brain resulting in a small area of dead brain tissue,
called a lacunar infarct; often caused by stenosis of the small
arteries, called small vessel disease.
large vessel disease-stenosis in large
arteries of the cerebrovascular system.
leukocytes-blood proteins involved in
the inflammatory immune response of the ischemic cascade.
lipoprotein-small globules of
cholesterol covered by a layer of protein; produced by the liver.
low-density lipoprotein (LDL)-also
known as the bad cholesterol; a compound consisting of a lipid and a
protein that carries the majority of the total cholesterol in the
blood and deposits the excess along the inside of arterial walls.
magnetic resonance angiography (MRA)-an
imaging technique involving injection of a contrast dye into a blood
vessel and using magnetic resonance techniques to create an image of
the flowing blood through the vessel; often used to detect stenosis
of the brain arteries inside the skull.
magnetic resonance imaging (MRI) scan-a
type of imaging involving the use of magnetic fields to detect
subtle changes in the water content of tissues.
mitochondria-the energy producing
organelles of the cell.
mitral annular calcification-a disease
of the mitral valve of the heart.
mitral valve stenosis-a disease of the
mitral heart valve involving the buildup of plaque-like material on
and around the valve.
necrosis-a form of cell death resulting
from anoxia, trauma, or any other form of irreversible damage to the
cell; involves the release of toxic cellular material into the
intercellular space, poisoning surrounding cells.
neuron-the main functional cell of the
brain and nervous system, consisting of a cell body, an axon, and
neuroprotective agents-medications that
protect the brain from secondary injury caused by stroke.
oxygen-free radicals-toxic chemicals
released during the process of cellular respiration and released in
excessive amounts during necrosis of a cell; involved in secondary
cell death associated with the ischemic cascade.
plaque-fatty cholesterol deposits found
along the inside of artery walls that lead to atherosclerosis and
stenosis of the arteries.
plasticity-the ability to be formed or
molded; in reference to the brain, the ability to adapt to deficits
platelets-structures found in blood
that are known primarily for their role in blood coagulation.
prevalence-the number of cases of a
disease in a population at any given point in time.
recombinant tissue plasminogen activator
(rt-PA)-a genetically engineered form of t-PA, a
thrombolytic, anti-clotting substance made naturally by the body.
small vessel disease-a cerebrovascular
disease defined by stenosis in small arteries of the brain.
stenosis-narrowing of an artery due to
the buildup of plaque on the inside wall of the artery.
stroke belt-an area of the southeastern
United States with the highest stroke mortality rate in the country.
stroke buckle-three southeastern
states, North Carolina, South Carolina, and Georgia, that have an
extremely high stroke mortality rate.
subarachnoid hemorrhage-bleeding within
the meninges, or outer membranes, of the brain into the clear fluid
that surrounds the brain.
thrombolytics-drugs used to treat an
ongoing, acute ischemic stroke by dissolving the blood clot causing
the stroke and thereby restoring blood flow through the artery.
thrombosis-the formation of a blood
clot in one of the cerebral arteries of the head or neck that stays
attached to the artery wall until it grows large enough to block
thrombotic stroke-a stroke caused by
tissue necrosis factors-chemicals
released by leukocytes and other cells that cause secondary cell
death during the inflammatory immune response associated with the
total serum cholesterol-a combined
measurement of a person's high-density lipoprotein (HDL) and
low-density lipoprotein (LDL).
t-PA-see recombinant tissue plasminogen
transcranial magnetic stimulation
(TMS)-a small magnetic current delivered to an area of
the brain to promote plasticity and healing.
transient ischemic attack (TIA)-a
short-lived stroke that lasts from a few minutes up to 24 hours;
often called a mini-stroke.
vasodilators-medications that increase
blood flow to the brain by expanding or dilating blood vessels.
vasospasm-a dangerous side effect of
subarachnoid hemorrhage in which the blood vessels in the
subarachnoid space constrict erratically, cutting off blood flow.
vertebral artery-an artery on either
side of the neck; see carotid artery.
warfarin-a commonly used anticoagulant,
also known as Coumadinฎ.
The Ischemic Cascade
The brain is the most complex organ in the human body. It
contains hundreds of billions of cells that interconnect to form a
complex network of communication. The brain has several different
types of cells, the most important of which are neurons. The
organization of neurons in the brain and the communication that
occurs among them lead to thought, memory, cognition, and awareness.
Other types of brain cells are generally called glia (from
the Greek word meaning "glue"). These supportive cells of the
nervous system provide scaffolding and support for the vital
neurons, protecting them from infection, toxins, and trauma. Glia
make up the blood-brain barrier between blood vessels and the
substance of the brain.
Stroke is the sudden onset of paralysis caused by injury to brain
cells from disruption in blood flow. The injury caused by a blocked
blood vessel can occur within several minutes and progress for hours
as the result of a chain of chemical reactions that is set off after
the start of stroke symptoms. Physicians and researchers often call
this chain of chemical reactions that lead to the permanent brain
injury of stroke the ischemic cascade.
Primary Cell Death
In the first stage of the ischemic cascade, blood flow is cut off
from a part of the brain (ischemia). This leads to a lack of oxygen
(anoxia) and lack of nutrients in the cells of this core area. When
the lack of oxygen becomes extreme, the mitochondria, the
energy-producing structures within the cell, can no longer produce
enough energy to keep the cell functioning. The mitochondria break
down, releasing toxic chemicals called oxygen-free radicals
into the cytoplasm of the cell. These toxins poison the cell from
the inside-out, causing destruction of other cell structures,
including the nucleus.
The lack of energy in the cell causes the gated channels of the
cell membrane that normally maintain homeostasis to open and
allow toxic amounts of calcium, sodium, and potassium ions to flow
into the cell. At the same time, the injured ischemic cell releases
excitatory amino acids, such as glutamate, into the space
between neurons, leading to overexcitation and injury to nearby
cells. With the loss of homeostasis, water rushes into the cell
making it swell (called cytotoxic edema) until the cell membrane
bursts under the internal pressure. At this point the nerve cell is
essentially permanently injured and for all purposes dead
(necrosis and infarction). After a stroke starts, the
first cells that are going to die may die within 4 to 5 minutes. The
response to the treatment that restores blood flow as late as 2
hours after stroke onset would suggest that, in most cases, the
process is not over for at least 2 to 3 hours. After that, with rare
exceptions, most of the injury that has occurred is essentially
Secondary Cell Death
Due to exposure to excessive amounts of glutamate, nitric oxide,
free radicals, and excitatory amino acids released into the
intercellular space by necrotic cells, nearby cells have a more
difficult time surviving. They are receiving just enough oxygen from
cerebral blood flow (CBF) to stay alive. A compromised cell
can survive for several hours in a low-energy state. If blood flow
is restored within this narrow window of opportunity, at present
thought to be about 2 hours, then some of these cells can be
salvaged and become functional again. Researchers funded by the
NINDS have learned that restoring blood flow to these cells can be
achieved by administrating the clot-dissolving thrombolytic agent
t-PA within 3 hours of the start of the stroke.
Inflammation and the Immune Response
While anoxic and necrotic brain cells are doing damage to still
viable brain tissue the immune system of the body is injuring the
brain through an inflammatory reaction mediated by the vascular
system. Damage to the blood vessel at the site of a blood clot or
hemorrhage attracts inflammatory blood elements to that site. Among
the first blood elements to arrive are leukocytes, white
blood cells that are covered with immune system proteins that attach
to the blood vessel wall at the site of the injury. After they
attach, the leukocytes penetrate the endothelial wall, move through
the blood-brain barrier, and invade the substance of the brain
causing further injury and brain cell death. Leukocytes called
monocytes and macrophages release inflammatory chemicals
(cytokines, interleukins, and tissue necrosis
factors) at the site of the injury. These chemicals make it
harder for the body to naturally dissolve a clot that has caused a
stroke by inactivating anti-clotting factors and inhibiting the
release of natural tissue plasminogen activator. NINDS researchers
are currently working to create interventional therapies that will
inhibit the effects of cytokines and other chemicals in the
inflammatory process during stroke.
These brain cells that survive the loss of blood flow (ischemia)
but are not able to function make up the ischemic penumbra. These
areas of still-viable brain cells exist in a patchwork pattern
within and around the area of dead brain tissue (also called an
"Stroke: Hope Through Research", NINDS. Publication date July 2004.
Office of Communications and Public
National Institute of Neurological Disorders
National Institutes of Health
Bethesda, MD 20892
NINDS health-related material is provided for information
purposes only and does not necessarily represent endorsement by or
an official position of the National Institute of Neurological
Disorders and Stroke or any other Federal agency. Advice on the
treatment or care of an individual patient should be obtained
through consultation with a physician who has examined that patient
or is familiar with that patient's medical history.
Last updated December 13, 2004