Saving Brain
The Southeast's oldest stroke center is at the hub of pivotal studies with one common goal: protecting brain tissue under siege



Willie Harris, with neurologist Michael
Frankel, is living proof of the importance
of treating stroke symptoms quickly.


The impact of an experimental clot buster given within three to six hours of stroke is remarkable: many patients recovered completely or had minor disabilities from what otherwise would have been devastating brain injuries


by Pam Auchmutey

For three days straight, Willie Harris came home from work complaining of a bad headache and seeing red spots before his eyes. The worst was soon to come.

Early one morning, Willie woke up for work as usual. A few minutes later, he began to make a choking sound, and when he tried to get up he fell. When his wife, Addie, rushed to help him, she noticed he was drenched in sweat and his speech was garbled. Willie had suffered a stroke.

By the time the ambulance arrived at Grady Hospital, Willie was semiconscious, his body paralyzed on both sides. The Emory stroke team was ready. They determined he had suffered an acute ischemic stroke, the most common type, and that his basilar artery was 100% occluded. They told Addie that his chances for meaningful survival were slim. They also told her about a drug that could perhaps save his life and help minimize any disabling effects from his stroke. Within the hour, a neurointerventional radiology team was ready to administer the clot-buster t-PA (tissue plasminogen activator) through Willie's femoral artery, past the aorta, and up to the site of the clot in his brain.

Shortly after the procedure, Willie still lay completely paralyzed and unable to breathe on his own. As Addie walked down the corridor toward his room, her heart sank when she saw the group of doctors and nurses clustered around the doorway. "This is it," she thought. "This is the end of the line." Then she realized the doctors and nurses were smiling. Her husband of nearly 40 years was awake and able to move.

In the past, severe stroke patients like Willie had little hope. Most lived out their years in nursing homes or died. Fortunately, Willie's family recognized his stroke as a medical emergency, and the ambulance took him to the oldest and one of the best-known stroke treatment centers in the Southeast. Organized 10 years ago, the Emory stroke team at Grady (and now Emory Hospital) serves as a model for other hospitals in establishing stroke-ready treatment centers across the region.

During the early 1990s, Grady was one of 41 US hospitals to participate in the landmark study leading to FDA approval of t-PA as the only proven treatment for stroke. Funded by the National Institute of Neurological Disorders and Stroke (NINDS), the 1995 study showed that patients who received intravenous t-PA within three hours of stroke were more likely to recover normal physical and mental function. Approved by the FDA in 1996, t-PA has dramatically changed how stroke patients are treated once they hit the hospital door.

"The NINDS study was a pivotal moment in health care," says Michael Frankel, a member of Willie's stroke team and Emory chief of neurology at Grady. "It changed our whole view on treating stroke as a medical emergency. These patients have gone from the back to the front of the ER."

Today, Frankel and his colleagues are on a mission to save brain and educate the public on just how drastically stroke treatment has changed. Often, t-PA treatment is underused because patients don't get to the emergency room quickly enough.

"People tend to view stroke as a leisurely event," says neurologist Barney Stern. "Most strokes are painless, so there's no perceived urgency to seek care. It's not like the sudden onset of symptoms associated with a heart attack."

When patients do reach the hospital, doctors move quickly to determine where the brain has been damaged, whether there is bleeding in the brain, and when the patient last appeared to be normal. "That starts the clock ticking. It tells us whether we should walk, trot, or run," says Stern. "If symptom onset falls within a three-hour window, the patient may be eligible for IV t-PA. But it's a small minority -- perhaps 5% of patients with stroke. The major factor is time."

Stroke experts hope to expand that window of time through research. A new study under way at Grady, Emory, and 14 other stroke centers around the country aims to enhance t-PA's ability to open blocked vessels, particularly in the most severe strokes. Frankel is leading the Atlanta site for the $2.2 million NINDS project, which is looking at the effects of using t-PA in combination therapy. Patients in the interventional management of stroke (IMS) study will receive t-PA through an arm vein, followed by intra-arterial therapy to break up any residual clot. The incentive driving the combination therapy is time. Patients can begin intravenous t-PA therapy right away, while an interventional neuroradiology team is assembled for the intra-arterial procedure. "That can take an hour in the best of situations," says Frankel. "Every second counts."

He is optimistic that patients who receive combination therapy will be able to walk and speak after treatment. Thus far, about 100 patients across the country, including seven at Grady and Emory, have received the therapy, with encouraging results. At least 20 will undergo the therapy at Grady and Emory hospitals during the next two years.

Once the study is complete, investigators will compare data from 80 patients nationwide with results from the 1995 NINDS study, in which t-PA was given only intravenously. The studies are strikingly similar to ones from the mid-1980s, which led to FDA approval of t-PA for myocardial infarction.

"We're following in the footsteps of studies that have been done for the heart to see if we can find as much benefit for the brain," says Frankel. "We certainly have with intravenous t-PA, and we also think so with intra-arterial t-PA. But it's not perfect. We want to make t-PA treatment for stroke better. We're trying to build a better mousetrap."

Buying more time


There may be more than one way to build one for stroke. Grady and Emory will soon join more than 70 hospitals worldwide in a study that potentially could expand the time window for treating ischemic stroke. Patients in this study will receive intra-arterial r-proUK (recombinant prourokinase), an experimental clot buster, within three to six hours of their stroke. The study is a follow-up to PROACT (prourokinase for acute cerebral thromboembolism) II, in which Grady and Emory hospitals participated. Its purpose is to determine if r-proUK improves the outcome for ischemic stroke caused by blockage of the middle cerebral artery (MCA). PROACT II evaluated 180 patients nationally who received heparin or r-proUK plus heparin. An interventional neuroradiologist delivers the r-proUK by injecting it through a microcatheter into the MCA.

"Overall, the impact of this new therapy is remarkable," says Frankel. "Many patients recovered completely or had minor disabilities from what otherwise would have been devastating brain injuries. This study is the first to show that we can successfully intervene within six hours from the onset of stroke symptoms through direct delivery of a clot buster."

Expanding the window of opportunity for stroke treatment would be an added blessing for patients who live outside the vicinity of a stroke-ready center such as Grady or Emory. "If someone comes to us from a community hospital that is an hour or two away, intra-arterial r-proUK, with a six-hour window, would give them time to get here by ambulance or even helicopter," says Stern.

Warfarin versus aspirin

Neurologist Marc Chimowitz is leading a
50-site, $14.5 million study to compare
aspirin and warfarin in preventing stroke.


Once a patient has had a stroke, doctors rely on a variety of blood thinners to help prevent recurrence. Although these medications are used widely, no one has compared them in patients with atherosclerosis of an intracranial artery to determine which one works best -- until now. Neurologist Marc Chimowitz is head of a $14.5 million NIH study to compare outcomes for patients who take warfarin or aspirin. The study involves people who have had transient ischemic attacks (TIAs) or mild strokes caused by 50% or more narrowing of a major brain artery.

"We surveyed a number of neurologists before we entered the study, and many of them use warfarin to treat intracranial stenosis," explains Chimowitz. "That's the practice pattern that's evolved for this disease. Warfarin has been proven effective in treating atrial fibrillation. But it has yet to be proven in treating atherosclerosis of the major intracranial arteries."

Chimowitz oversees the daunting task of recruiting more than 800 patients for the WASID (warfarin-aspirin symptomatic intracranial disease) trial at 50 sites in this country and Canada. More than 200 patients are enrolled thus far; 45% are minorities. Of the 700,000 Americans who experience stroke each year, about 40,000 have symptomatic intracranial stenosis, which affects African Americans, Asians, and Hispanics in disproportionately large numbers.

WASID also provides a golden opportunity to collect data related to diagnosis. WASID patients will be evaluated using noninvasive tests (transcranial Doppler ultrasound and MR or CT angiography) in addition to standard angiography. This will make possible another study, SONIA (stroke outcomes and neuroimaging of intracranial atherosclerosis), led by researchers at Brown University and affiliated with WASID, to see which test more accurately detects the disease.

To qualify for WASID, patients must have at least 50% narrowing of the symptomatic brain artery. Investigators will compare the prognosis of patients with moderate stenosis (50% to 69%) with those with 70% or more. "It's possible that patients with more severe stenosis may not do well, regardless of medical therapy," says Chimowitz. "They may be appropriate to target with angioplasty or angioplasty and stenting. To determine that, it's important to have accurate measurements of stenosis, and you can't really do that without standard angiography.

"We see WASID as a stepping-stone to a follow-up study that looks at angioplasty and stenting of intracranial arteries versus best medical therapies," he adds. "It's commonplace in the heart, but it's new in the brain. One school of thought is that angioplasty and stenting will be the way to treat some of these patients."

Stenting and surgery

Rehab research director Steven Wolf uses
constraint-induced therapy, in which
patients wear a mitt on their "good" arm
to help them regain use of their impaired
arm. This therapy is the basis for a $7.5
million project funded by the National
Center for Medical Rehabilitation and
Research. Wolf estimates that at least
20% to 25% of the current stroke popula-
tion can benefit from this intervention.


Often, t-PA is underused because patients don't get to the emergency room quickly enough -- they tend to view stroke as a leisurely event

For the past five years, Emory has refined its expertise in angioplasty and stenting to treat symptomatic intracranial stenosis. Less invasive than surgery, the procedure is an appealing option for patients for whom medical therapy has failed or is unsuitable. Emory is one of five US medical centers evaluating the safety of the first intracranial stent in a pilot study funded by Guidant Corporation, the manufacturer.

"This is an exciting opportunity that shows great promise," says Stern. "As one of five sites with access to a device for intracranial stenting, our ability and proficiency with this procedure will increase. Our experience in selected patients shows they have benefited from it."

In conjunction with WASID, Stern has proposed a study with the CDC and with collaborators in SWISS (siblings with ischemic stroke study) to examine the genetics of symptomatic intracranial stenosis. This research would also focus on patients with narrowing of the blood vessels in the neck (symptomatic extracranial stenosis), who are part of CREST (carotid revascularization endarterectomy versus stent trial), a study comparing the effectiveness of carotid angioplasty and stenting versus endarterectomy.

After much controversy, research published in the mid-1990s showed that endarterectomy was highly beneficial to patients with 50% or more blockage of the extracranial carotid artery. About the time these and other study results were published, doctors began experimenting with carotid angioplasty. The initial results were less than encouraging; significant narrowing of the artery remained after the procedure. To solve the problem, endovascular stents were developed to keep the artery open after angioplasty. But the jury is still out regarding long-term effects.

"We don't know yet if these stents will cause scarring and thickening that could occlude the vessel," says Daniel Barrow, chair of neurological surgery at Emory. "It's been our practice to reserve angioplasty and stenting for patients who are at very high risk for endarterectomy. At this point, endarterectomy is still the gold standard until the two procedures can be compared."

Barrow also specializes in another type of surgery that is considered controversial. In the mid-1980s, a common procedure to restore blood flow was virtually halted when a major trial showed that extracranial-to-intracranial bypass provided no benefit to patients. Since then, new technology in measuring cerebral blood flow has enabled neurosurgeons like Barrow to better identify candidates for bypass surgery to prevent stroke. Emory will participate in the NINDS-funded carotid occlusion surgery study, which will use PET scanning to randomize patients for surgery or medical therapy.

"This study may redeem an operation that many of us feel is beneficial to patients," says Barrow. "The patients on whom we do this operation have giant aneurysms or aneurysms that are inoperable. We also do it on patients with carotid occlusion or carotid stenosis that's not amenable to endarterectomy. Once this study is completed, we hope to better identify the subgroup who have carotid occlusion and very low blood flow to the brain."

Clipping and coiling

Emory continues to build upon a successful track record in treating aneurysms as a major cause of hemorrhagic stroke. The traditional surgical method is to close off the aneurysm with a clip to restore blood flow through the artery. A newer option is endovascular coiling. Small coils made of soft platinum are placed in the aneurysm through a microcatheter. The devices "coil" up inside the aneurysm, filling it from the inside and cutting off blood flow. Like stenting, coiling is less invasive than surgery and, hence, more appealing to some patients. And, like stenting, the procedure isn't for everyone.

"When you clip an aneurysm, it's gone forever," says Barrow. "With coiling, it's essential that we follow up with an arteriogram at six months and then once a year to be sure the aneurysm doesn't recur. If it does, we may have to recoil it. More often, we go in surgically and clip it. In general, we reserve coiling for inoperable or difficult aneurysms, or for patients who are poor surgical candidates. Clipping is still the treatment of choice, but the indications for coiling are expanding and will likely continue to do so."

Broadest possible options

Expanding the window of opportunity for treatment would be an added blessing for patients who live outside the vicinity of a stroke-ready center such as Grady or Emory, says neurologist Barney Stern

About the time the t-PA revolution began, the seeds were planted for the Emory Stroke Center, a confederation of specialists in neurology, neurosurgery, vascular surgery, radiology, interventional neuroradiology, and rehab medicine whose alliance allows Emory to provide access to the latest innovations in stroke treatment.

"There's an old saying, if the only tool you have is a hammer, then everything looks like a nail," says Barrow. "If the only thing you can do at a hospital is clip aneurysms, you try to figure out how to clip it. The nice thing about Emory is we have huge experience in a lot of things. We can step back as a team to determine the best option for the patient and tailor treatment to the patient's needs."

Despite these advantages, Barrow and others face an uphill battle when it comes to stroke education and prevention. "Stroke exerts a wide effect on society because it's a disabler," says Frankel. "Most people survive strokes, and most of them remain disabled. Once stroke occurs, our job is to save brain. However, the best way to treat stroke is to prevent it from ever happening."

Frankel carries that message with him as co-chair of Operation Stroke for Atlanta, which works with the American Stroke Association to educate the public and enhance health professionals' knowledge about stroke treatment and prevention. The group has its work cut out for them. A random survey showed that two out of three Atlantans could not name even one of the warning signs of stroke.

In the meantime, Frankel has a new and powerful ally. Fifteen months after suffering his stroke, Willie Harris is back at Grady Hospital with Addie. They are talking with a local TV reporter, who is taping a segment about stroke treatment and prevention.

The reporter asks Willie how he's doing. Now retired at age 59, he walks 10 blocks each day with a cane, and shaves and showers himself. He washes dishes and rakes the yard. His peripheral vision and speech are impaired, and it's hard for him to write his name. But there's no mistaking the twinkle in his eye as he reveals the secret to surviving his stroke. "All of my friends were praying for me -- what goes up comes down," he says. "And there are good doctors at Emory."


Pam Auchmutey is associate director of Health Sciences Publications at Emory.

 


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