UAB Explores Innovative Stroke Therapies

By Jo Lynn Orr

UAB neurologists are using ultrasound to help break up clots in the brain (above) and testing other new treatments to improve stroke care.

In 1947, as tension between Russia and the United States threatened to erupt into nuclear war, the Bulletin of the Atomic Scientists added a new element to its cover: a stylized clock face with the hands set at seven minutes to midnight. For the past 63 years, the clock’s minute hand has moved back and forth to reflect the imminence of nuclear holocaust.

In the world of stroke care, the countdown to doomsday begins as soon as the brain’s oxygen supply is disrupted, either through a blood clot (ischemic stroke—the cause of 80 percent of strokes) or by bursting blood vessels (hemorrhagic stroke, which accounts for the other 20 percent of cases). Stroke kills more people worldwide than any other disease. It is the third leading cause of death in the United States and the leading cause of serious, long-term disability.

For years, the stroke clock was set at three hours. Patients receiving emergency treatment before that time stood a good chance of recovering significant function; after the three-hour window closed, there wasn’t much hope. But new advances in stroke treatment are steadily pushing open the treatment window and adding precious time back onto the clock. Neurologist Andrei Alexandrov, M.D., and his team at the UAB Comprehensive Stroke Research Center are contributing many of those breakthroughs, developing and testing revolutionary therapies that are effective several hours, days, and even weeks after stroke onset.

Rescue Squad:
Time Since Stroke – Up to 4.5 Hours

Left to right: Damon Patterson, Andrei Alexandrov, and Anne Alexandrov. Andrei Alexandrov is leading a team of researchers and clinicians testing innovative new stroke therapies.

One of Alexandrov’s goals is to increase use of the powerful clot-busting drug tPA (tissue plasminogen activator)—and develop new ways to enhance its effects. In 2006, the year before Alexandrov arrived at UAB, four patients received tPA; in 2009, 106 UAB patients received the drug, with very few tPA-related complications, he notes.

Although tPA is very effective at dissolving blood clots and lowering a patient’s risk of permanent disability, many physicians are reluctant to use it. Determining if a stroke victim is a viable candidate for tPA requires specialized knowledge and experience; the drug also increases the risk of bleeding, and administering it requires constant patient monitoring. Then there is its strict timeframe: tPA must be used within three hours of stroke onset—or so many physicians think. But that last restriction is no longer accurate, Alexandrov says. The American Stroke Association now supports use of tPA up to 4.5 hours from stroke onset.

UAB’s stroke unit is testing several ways to enhance tPA administration. In 2009, 40 patients at UAB were treated with intra-arterial rescue therapies, which include direct delivery of tPA to the clot in the brain, as well as use of devices capable of retrieving blood clots and stents that can keep arteries open. While there are currently no studies that show this type of treatment to be superior to tPA, it does provide an ability to treat stroke beyond the 4.5-hour window, Alexandrov says.

Alexandrov and the UAB stroke team are also leaders in the use of ultrasound to enhance tPA’s clotbusting effects. Ultrasound itself may help to break up clots in the brain’s arteries, especially in combination with tPA. In fact, two recent independent meta-analyses of this therapy—which was developed by Alexandrov—have shown it to be superior to tPA alone.

Alexandrov is now testing tiny, gas-filled “microspheres” that are delivered to the clot, then agitated using a small beam of ultrasound waves. When the ultrasound beam intercepts the bubbles it causes them to explode into the clot. In combination with tPA, these bubbles may help to break up the clot even further. In clinical trials conducted at UAB, ultrasound therapy was able to break up clots with twice the success rate of tPA alone.

Typically, tPA works primarily by partially breaking up a clot so that blood flow is established to areas of the brain deprived of oxygen; but tPA only breaks up clots completely 13 percent of the time. Alexandrov says his goal is to refine the ultrasound combo therapy to the point where 50 percent of clots are completely broken up in the ER.

But ultrasound therapy faces a major obstacle before it can achieve widespread use: Only a handful of people in the world have enough training to administer it properly. “Most stroke neurologists don’t know how to do it,” Alexandrov says. “People are excited, but few of them can use the technology.” So Alexandrov has developed an automated treatment “helmet” that fits over a patient’s head and will allow emergency-room personnel to provide the therapy with only limited prior training. “It’s just like putting on a pair of glasses,” Alexandrov says. He has been tapped by the National Institutes of Health to lead a worldwide clinical trial to test the efficacy of the helmet; the trial will launch in 2011.

Saving the Brain:
Time Since Stroke – Up to 4.5 Days

UAB interventional stroke neurologists such as Damon Patterson use new techniques to remove clots deep in the brain up to several days post-stroke.

While tPA-based therapies attack clots chemically, UAB neurologists are also exploring new ways to remove clots physically—and in the process treat stroke patients who would have been written off as hopeless cases only a few years ago. Adapting innovations originally pioneered in cardiology, interventional stroke neurologists such as Damon Patterson, M.D., are reporting fascinating advances in the new field of endovascular therapy. Using advanced imaging techniques, they guide catheters deep into the brain to remove clots and restore blood flow.

UAB is a nationally recognized leader in endovascular therapy, and its physicians frequently receive calls from other hospitals about their stroke cases, says Patterson. “We listen to their report and advise administering tPA if it’s appropriate,” he explains. “Then we rush the patient here to our cath lab in order to extend the response time window and hopefully provide a good outcome.”

Seven to eight hours post-stroke is generally regarded as the effective limit for neuro-endovascular therapy, Patterson notes, but new imaging techniques are allowing physicians to widen that timeframe. “Each person’s brain is unique and responds to a stroke in its own way,” he says. “New ways of looking at the brain quickly, such as reperfusion, allow us to determine which parts of the brain are already damaged and which parts are at risk of becoming damaged. We then use that info to determine if there is enough brain to save and if it’s going to be safe to try to save it.”

This makes rigid treatment timelines obsolete, Patterson says. “With these newer devices, we can extend the time window almost indefinitely.” Those extra hours are especially useful when treating “wakeup strokes”—when people wake up in the morning with symptoms, Patterson explains. “You have to go back to when they were last seen normal, which most of the time is when they went to bed the night before. We don’t know at what point during the night that the stroke actually started. With perfusion imaging, we might see that there is a whole bunch of brain to save and very little has been permanently damaged. It’s also wonderful because we’re able to extend time windows so that rural hospitals without these imaging capabilities can get stroke victims to us.”

UAB neurologists recently used neuro-endovascular therapy to remove a clot from a patient an unheard-of four-and-a-half days after stroke onset.

Applying the CUFFS:
Time Since Stroke – Two Weeks

Anne Alexandrov (right) and her team with the ECP device, which uses inflatable cuffs to increase blood flow to the brains of patients who have suffered a stroke.

UAB stroke researchers are testing another new treatment that can benefit patients long after an ischemic stroke, when clotbusters and even catheter procedures may no longer be an option. The NIH-funded Counterpulsation to Upgrade Forward Flow in Stroke (CUFFS) trial is examining the external counterpulsation (ECP) device—a bed-sized apparatus with a system of inflatable cuffs that are placed around a patient’s lower legs and buttocks. The cuffs inflate and deflate rhythmically for a full hour in time with the patient’s heartbeat.

“We published two earlier studies involving ECP, which has been shown to significantly increase blood flow to the brain,” says Anne Alexandrov, Ph.D., R.N., C.C.R.N., a professor of acute and critical care in the UAB School of Nursing, and UAB Comprehensive Stroke Research Center, and Andrei Alexandrov’s wife. Although ECP patients should ideally start treatment within 48 hours of stroke onset, the patients in these studies "had a significant reduction in their neurologic disability despite being treated on average two weeks after the onset of their stroke,” she says. Alexandrov’s second paper also established that the ECP device was safe to use with these late-treatment patients, she explains.

The current generation of treatments is bringing about a revolution in stroke care, and “even more new therapies are on the horizon,” Patterson adds. “This is an amazing time for stroke treatment. And the next wave of devices that are coming out are simply remarkable.”