GOOD HEALTH MAGAZINE : MEDICINE : STROKE: THE SUDDEN, SILENT SCOURGE

Every year, nearly 149,000 Americans die from stroke, the third leading cause of death. But there is good news: The mortality rate has been dropping sharply, and researchers may be on the brink of a revolution in prevention and therapy.

Every year, nearly 149,000 Americans die from stroke. But there is good news: The mortality rate has been dropping sharply, and researchers may be on the brink of a revolution in prevention and therapy.

he old man sits alone in his wheelchair, watching his beloved Kansas City Royals struggle through another televised spring training game, or simply staring out the window at the squirrels emerging from their winter doldrums.

At 77 years of age, he is an enigma. His right side is paralyzed and virtually useless. His speech is limited to yeses and noes that often don’t seem to make sense. But his eyes burn with a pride that reflects the intelligence that was once there--and may still be.

What is he thinking about in his mental prison? Does he relive the AAU basketball games he played as a young man or the years he worked on the Union Pacific Railroad during World War II? Is he once more whiling away the early-morning hours in his vegetable garden, or is he remembering the spring days he spent fishing for crappie in nearby Pony Express Lake? Or are his thoughts a jumble of confusion and fear, sadness and regret? We don’t know. Perhaps science will never know the answer to such questions. That is what makes stroke--a sudden interruption of blood flow that causes brain cells to die--so devastating to its victims and their families.

My father had a stroke on July 17, 1985. At 5:30 in the morning, he arose, exhaled sharply and collapsed to the floor. In the briefest of seconds, a black wall descended across his mind, muting his communication with the outside world, severing control of the right side of his body, and irrevocably changing the lives of his family.

His--our--experience is not uncommon. Every year, about a half-million Americans have a stroke and nearly 149,000 die from it, making stroke the third leading cause of death behind heart disease and cancer.

In 1987, the most recent year for which figures are available, there were more than 2 million stroke survivors alive, according to the American Heart Assn. In 1989, the cost of caring for these survivors was an estimated $11.2 billion, plus another $2.3 billion for lost productivity.

But there is good news mixed in with these grim statistics. According to the AHA, the death rate for stroke has been dropping sharply. In the 1940s and 1950s, U.S. stroke mortality declined at a rate of about 1% a year. Since 1973, however, the death rate has dropped by an average of 5.5% a year.

In 1950, 89 of every 100,000 people in the United States died from stroke. By 1987, according to the AHA, the rate had shrunk to 30 per 100,000. These decreases are generally attributed to efforts to lower the risk factors for stroke and to modest improvements in therapy for individuals who have suffered a stroke.

More important, researchers may be on the brink of a revolution in approaches to stroke prevention and therapy. At present, there is little that can be done on a routine basis for stroke victims. “We can put you in bed and tuck you in but, in truth, we don’t have any effective therapy,” says Dr. Roger Simon, a neurologist at UC San Francisco Medical Center. “But very shortly, we probably will.”

In the past two years, neurologists have begun conducting clinical trials with a number of new drugs and therapies that can reduce the risk of having a stroke, minimize the damage to brain cells during a stroke and--if given early enough--reverse the conditions that produced it in the first place, such as by dissolving the blood clots that impede the flow of life-giving blood to the brain.

These techniques will be of no use to people such as my father, for whom it is too late. Rather, they are meant to be used before a stroke occurs or within one to eight hours after a stroke--a period researchers are coming to call the “window of opportunity” because of the possibility of intervention.

“We’re working with things that weren’t even conceived of as recently as 1984,” says Simon. “There’s an enormous amount of excitement.” Echos Dr. Michael A. Sloan, a neurologist at the University of Maryland Medical Center in Baltimore: “This is a promising time, a very exciting time to be in clinical stroke work. We can’t say which of the new drugs will work out best, but the therapeutic knowledge of the past is dead.”

Strokes occur when a blood vessel bringing oxygen and nutrients to the brain either becomes clogged by a blood clot or bursts open. In either case, the area of the brain served by the blood vessel no longer receives the flow of blood it needs. Deprived of oxygen, the brain cells in the area die.

When they do, the parts of the body they control can’t function. The devastating effects are usually permanent because dead brain cells aren’t replaced--although in some cases, through intensive therapy such as that undergone by actress Patricia Neal, other parts of the brain can be trained to take over the functions of the dead cells. After three years of therapy in the mid-1960s, Neal, 64, is still making movies.

Stroke is a disease of aging. Only 29% of strokes occur in individuals under the age of 65. The incidence of stroke doubles in each successive decade for people over 55. Men are about 30% more likely than women to have a stroke and blacks are about 60% more subject to stroke than whites.

There are four main types of stroke: two caused by clots, accounting for about 83% of all strokes, and two caused by hemorrhaging.

In a thrombosis, a blood clot forms in the brain itself, usually as a result of the buildup of fatty atherosclerotic plaques on the inside of blood vessels. Such strokes tend to occur during the night or first thing in the morning.

Thrombotic strokes are frequently preceded by precursors called mini-strokes, or what are known as transient ischemic attacks, which occur when small clots briefly block a blood vessel. Such mini-strokes, which last less than 24 hours, cause sudden weakness or numbness of the face and limbs on one side of the body, temporary loss of speech, dimness of vision and dizziness.

Individuals who have mini-strokes are nearly 10 times as likely to have a stroke as are healthy people of the same age and sex. My father apparently had two mini-strokes--getting weak one afternoon walking uphill from the garden, getting dizzy one morning in the yard--without recognizing their significance.

In a cerebral embolism, the damaging blood clot forms elsewhere in the body, most often in the carotid arteries in the neck or in the heart itself, and is carried to the brain by the normal flow of blood.

The most common cause of embolisms is atrial fibrillation, which is shared by an estimated 1 million Americans. In this condition, the two upper chambers of the heart (the atria) quiver instead of beating effectively. The result is that not all the blood they hold is pumped out of them; when blood pools, it tends to clot.

Less commonly, strokes are caused by the rupture of a weak spot, called an aneurysm, on a blood vessel in the brain. When the aneurysm ruptures, blood flow is interrupted. If the blood vessel is on the surface of the brain (subarachnoid hemorrhaging), the blood leaks into the fluid surrounding the brain. If the vessel is within the brain (cerebral hemorrhaging), the blood accumulates within the brain. In addition to injury caused by loss of circulation, the pooled blood can damage brain cells by putting pressure on them.

Aside from the use of aspirin to prevent clot formation, the most common approach to preventing strokes is a surgical procedure called carotid endarterectomy, in which the fat deposits that clog the carotid arteries in the neck are surgically cleaned out so that clots are less likely to form.

The operation has been around for at least 30 years and is now performed on as many as 100,000 Americans each year, but questions have arisen recently about both its safety and efficacy. Critics have charged that it is not sufficiently effective at reducing stroke to justify the risk associated with the procedure: Between 2% and 8% of those undergoing the procedure die or suffer severe complications.

The National Institute of Neurological Diseases and Stroke is sponsoring two large clinical trials. One, organized by Dr. James Toole, a neurosurgeon at Wake Forest University in Winston-Salem, N.C., involves 1,500 patients at 18 medical centers. All the patients--none of whom have previously had any symptoms of stroke but all of whom have clogging arteries--will receive aspirin, and half will also undergo carotid endarterectomies.

A separate study, organized by Dr. Henry J. M. Barnett, a neurosurgeon at Canada’s University of Western Ontario, will focus on patients who have already had transient ischemic attacks. All the patients will receive aspirin, treatment for high blood pressure, and counseling about diet and smoking. Half the 3,000 patients to be enrolled at 36 medical centers will also receive endarterectomies.

Researchers hope that these studies will finally provide definitive answers about the relative risks and efficacy of the surgical procedure. “Everybody in the world wants the answer,” Barnett says.

Surgery is also used to prevent strokes caused by aneurysms. If an aneurysm can be detected before it bursts, surgeons can go into the brain and clip out the weak section, eliminating the risk of stroke. This procedure was successfully used, for example, when Sen. Joseph Biden (D-Del.) was forced to drop out of the 1988 presidential race because of an aneurysm. Such operations are now performed about 15,000 times a year.

In many cases, however, the aneurysm is buried deep inside the brain in a spot surgeons cannot reach without damaging the brain. To treat those, a few researchers are now working with rice grain-sized microballoons that can be threaded through arteries to reach the inoperable site, then inflated and anchored in place.

In performing this procedure, Dr. Jafar Jafar, a neurosurgeon at the University of Illinois at Chicago Circle, slowly inflates the balloon near the site of the aneurysm to completely block the blood vessel. The operation is done using a local anesthetic so that the patient is conscious and Jafar can be sure that other vessels in the area are adjusting and carrying more blood to the brain.

The patient is monitored during the procedure to ensure that no damage is done by blocking the vessel. Once Jafar is satisfied that the patient is all right, the balloon is sealed off and anchored in place. Because no blood is then flowing past the aneurysm, there is no risk of it rupturing.

Dr. Randall Higashida, a radiologist at UC San Francisco, has developed a similar procedure, but he inflates one or more balloons in the aneurysm itself, thereby reinforcing the vessel wall without blocking blood flow. He has performed the procedure in more than 200 patients who could not be treated in any other fashion; the operation reduced the incidence of stroke in the group, but about 7% died or had serious complications, he recently reported.

Drugs also might be useful in preventing strokes among individuals who have suffered mini-strokes. Dr. William Hass, a neurologist at the New York University School of Medicine, recently completed a study with a new anti-clotting drug, ticlopidine hydrochloride, manufactured by Syntex Research of Palo Alto.

In the trial, 3,069 people throughout North America took aspirin or ticlopidine hydrochloride. After three years, 13% of those taking aspirin had suffered a stroke during the trial, compared to only 10% of those taking ticlopidine--a 21% reduction in risk. In women, the drug was 27% more effective than aspirin in reducing stroke risk.

“I’m excited, I never expected it to turn out this good,” Hass says. “We have a new drug . . . to prevent strokes.”

Texas researchers hope they can overcome another risk factor for stroke--the increased risk of clotting caused by atrial fibrillation in the upper chambers of the heart. Drs. Robert Hart and David Sherman, neurologists at the University of Texas Health Sciences Center in San Antonio, headed an NINDS-sponsored trial in which 1,244 people with the condition were given either aspirin, warfarin--a drug that is widely used to inhibit clotting--or a placebo. The risk of stroke was reduced by 81% among those who received either aspirin or warfarin, but the researchers could not determine which was best.

Once a clot has formed, the ideal solution to stroke would be to dissolve the clot before permanent damage can be done to brain cells in the area. To many researchers, the best hope for accomplishing this is a product of genetic engineering called tissue plasminogen activator or tPA.

This drug is already widely used for treating heart attacks caused by clots. Injected into the bloodstream shortly after an attack occurs, tPA dissolves fibrin in the clot, breaking the clot up and allowing circulation to be restored in the affected areas. The chief risk is that the drug will dissolve beneficial clots elsewhere in the body, such as a clot formed naturally to stop bleeding at a small leak in a blood vessel. That could allow potentially fatal, uncontrolled hemorrhaging.

Two major studies of tPA are being conducted. One, headed by Dr. Gregory del Zoppo, a neurologist at the Scripps Clinic at La Jolla, has already treated more than 100 stroke victims at 13 medical centers in the United States and two in West Germany. Patients in the study are subjected to an angiogram to determine which vessels are blocked and are then given an infusion of tPA as soon as possible, but within eight hours after a stroke occurs. An hour after the infusion, the patients undergo another angiogram to determine if the vessel has been reopened.

“The data analysis is not complete,” Del Zoppo says, “but it looks as though some patients have a definite reopening of arteries that were occluded . . . We have patients who have improved significantly.”

The second study, headed by Dr. Thomas Brott, a neurologist at the University of Cincinnati Medical Center, is designed to have patients receive tPA within 90 minutes after the onset of symptoms. Many patients in that study have also shown clinical improvement.

“The problem right now is that there are so few studies that (follow the course of patients) right after a stroke that we don’t know how many improve on their own,” Del Zoppo notes. Similarly, although some patients in both studies have developed hemorrhages, little data exists to indicate how many would have done so had the tPA not been administered.

The ongoing studies may clear up some of those dilemmas. “In a few months, we should have some answers,” Del Zoppo says.

Another promising way to dissolve clots is with a substance called ancrod, isolated from the venom of the Malayan pit viper. Ancrod stimulates the body to release its own tPA, according to Dr. Charles P. Olinger, a neurologist at the University of Cincinnati Medical Center. It also thins the blood to improve circulation and acts as an anticoagulant to prevent other clots from forming, apparently without any significant side effects.

In a preliminary study of 20 stroke victims, half of whom received ancrod and half of whom received a dummy shot, Olinger found that those who got ancrod scored three times better than the comparison group on a neurological scale used to measure stroke severity. “We’re not making any claims, but it looks promising,” Olinger says. “We think it has multiple actions, we think it is safe, and we know that it works fast.”

Olinger and Knoll Pharmaceutical Co., which makes the drug at a snake farm in West Germany, have now begun a larger study that will include 150 patients at seven medical centers in the United States and two in West Germany.

Now that physicians think they have realistic ways to unplug clogged vessels, some physicians are turning to a search for techniques to protect brain cells from damage until blood flow is restored.

“Although many cells in the brain stop functioning immediately after a stroke occurs,” says UCSF’s Simon, “it takes some time, on the order of minutes to a few hours, before cells in the brain actually die. It is this golden window of opportunity that we hope to exploit . . . Large numbers of drug companies are investing substantial funds because they see significance and hope as well.”

Many things happen to brain cells when they are cut off from oxygen. One of the most important is that a neurotransmitter--a chemical that carries messages from one cell to another--called glutamate leaks out of the oxygen-deprived cells. This excess glutamate causes the cells to continuously attempt to send messages on to other cells. In their overexcitement, they literally self-destruct.

Researchers have discovered several chemicals that seem to prevent such cell behavior by binding to the sites on cell surfaces where glutamate would normally bind without stimulating the cells to send on messages. Two of the most promising, MK-801 made by Merck & Co. and CGS-19755 by Ciba-Geigy Co., are close relatives of the street drug PCP, also known as “angel dust.”

Both drugs have been shown to reduce the number of damaged brain cells in animal models of stroke by 50% or more. “If it weren’t for the fact that FDA (the U.S. Food and Drug Administration) had recently gotten cold feet, one or both would be in patients right now,” Simon says.

The delay was a response to data produced by Dr. John W. Olney, a psychiatrist at Washington University in St. Louis. He reported in June that MK-801 and related drugs caused a brief swelling of brain cells in rats. The swelling was transient, apparently harmless and unrelated to the psychotropic effects of PCP, Simon says, but so far FDA has continued to refuse permission to begin human trials.

Another problem caused by lack of oxygen, ironically, is the combination of chemicals in cellular membranes with highly reactive compounds called oxygen-free radicals, which are generated at many sites in the body when ambient oxygen levels are low.

The Upjohn Co. of Kalamazoo, Mich., has developed a family of anti-oxidants that it calls “lazaroids” after the Biblical Lazarus who was resurrected from death. Research in animals has shown that one of the lazaroids, U-74006F, can sharply reduce the death of brain cells as a result of stroke, head injury, spinal injury and hemorrhage, according to neuropharmacologist Edward Hall of Upjohn.

Upjohn has recently begun human studies of the use of this lazaroid to minimize brain damage in moderate and severe head injuries. As many as 200 patients will be treated with the drug, four times a day for five days, at eight U.S. medical centers. The company will have to perform separate studies for stroke, “but much of the information developed should be applicable to stroke as well,” Hall says. They hope to complete the study this year.

Experts agree, however, that none of these new therapies will be very useful unless people begin to change their attitudes about stroke. “Heart attacks have symptoms that bring people to hospitals,” Del Zoppo says. “But with stroke, people say, ‘Maybe it’ll go away in the morning.’ If they don’t come to the hospital, there’s nothing we can do for them.”

My father got to the hospital in time. Unfortunately, none of these new treatments were available yet. Could things have worked out differently if the stroke had come a couple of years later? Would tPA have helped? Would he still be fishing and gardening instead of locked in his wheelchair? Those are questions that will haunt us--and thousands of other families--for the rest of our lives.

WHAT CAUSES A STROKE?

There are three primary causes of strokes. Thrombosis and embolism both cut off the brain’s blood supply, leading to tissue death. Rupture of a blood vessel in or near the brain is the cause of hemorrhage. Since any part of the brain can be affected by a stroke, symptoms vary considerably. Thrombosis is blockage by a clot ( thrombus ) that has gradually built up on the wall of a brain artery. Cerebral thrombosis causes 225,000 strokes a year. Embolism is the blocking of an artery in the brain by a clot ( embolus ) that has moved through the blood system to the brain. Embolism annually accounts for 190,000 strokes. Hemorrhage results from the rupture of a blood vessel and subsequent bleeding within the brain. Approximately 85,000 strokes a year are caused by hemorrhage.

Methods of treatment

(A) Surgery or balloons to block aneurysms. (B) Drugs to minimize damage to brain. (C) Snake venom and TPA to dissolve clots. (D) Surgery to clean out fat deposits in arteries.

STROKE SYMPTOMS

HEADACHE DIZZINESS, CONFUSION VISUAL DISTURBANCE SLURRING OR LOSS OF SPEECH DIFFICULTY IN SWALLOWING

Stroke symptoms can develop in minutes or hours or even over several days. Any of the above symptoms may appear, in varying severity. Symptoms of mild strokes can be hardly apparent, but others can result in severe physical or mental disorders, coma or death.