November 13, 1998
Studies Widen 'Therapeutic Window,' Shed Light on Disease Targets
"Cancers are very different. That's exactly the model you should have for stroke. Stroke is not just one diseaseit's actually a bunch of different diseases that may have some similar manifestations," says Schwamm, above left with colleagues Walter Koroshetz (center) and Guy Rordorf.
Stroke researchers at Massachusetts General Hospital report good news this month: the chances of preventing brain damage and enhancing recovery after a stroke may be greater than previously thought.
Until recently, doctors believed little could be done after 24 hours to limit the spread of tissue damage. In the November Stroke, Walter Koroshetz, Lee Schwamm, and colleagues announce a more generous estimate. Using imaging methods that reveal the state of brain tissue at various stages in 14 stroke patients, they found damage continued for an average of 32.7 hours. In one patient, damage progressed for 61 hours.
"What this means is that the window of opportunity for therapies designed to prevent the growth of stroke is much greater than we thought, maybe 24 to 48 hours," says Schwamm, assistant professor of neurology. The same imaging techniques can be used to diagnose the nature of a stroke and refine treatments.
Like his fellow researchers, Ferdinando Buonanno (right) is using new technologies to not only assess but arrest the spread of damage in stroke patients. “Almost every way you devise to kill cells, growth factor can save them,” says Seth Finklestein (left). He and his colleagues are using growth factors to limit the spread of stroke and enhance recovery.
MGH colleague Seth Finklestein, associate professor of neurology, delivered a similar message at the 28th annual meeting of the Society for Neuroscience, held this month in Los Angeles. By blocking a tiny artery on the right side of the brain of rats, he and his colleagues were able to create a stroke with a very specific behavioral consequence: an inability to place the left paw on a table. Finklestein reported that he and his colleagues were able to restore the lost paw function by injecting a growth factor into rats three days after a stroke. Their previous studies had shown function could be restored by giving growth factor 24 hours after a stroke.
"So we have extended the therapeutic window for recovery from stroke in a rat from 24 hours to 3 days at a minimum," says Finklestein, adding, "But rats are rats."
Schwamm agrees. "Ten to 15 years ago if you developed a drug that could reduce the size of a stroke in an animal model, that would be big news. Now, 30 to 40 compounds do that. It's not big news to prove it in a rat. You have to prove it in a person."
The bad news is that despite the horde of promising new compounds designed to prevent the spread of stroke, only one drug has passed clinical trials. One problem is that human strokes are much more complex and variable than those induced in lab animals. They have many causes--blood clots can form in the heart or in the brain, and they can occur in large or tiny vessels in many different regions.
"It's not just like tying up a blood vessel in a specific place and that's it," says Schwamm. "It's very dynamic--a clot may be expanding and contracting. Blood may be flowing in from neighboring collateral vessels to support the region in some patients but not in others."
All of these factors will affect how a patient responds to a particular therapy. "If you just say a stroke is a stroke, your chance of developing the right therapy goes right through the window. There's just not going to be a magic bullet that makes all strokes better," Schwamm says.
Similarly, many drugs fail clinical trials not because they do not work but because the researchers do not take into account who is most likely to benefit from them. "A lot of potentially good drugs have been put six feet under by a bad trial design," says Schwamm. "The key to stroke therapy and trials is to carefully pick your patients, ones that you think will benefit," says Finklestein.
The good news, once again, is that the imaging techniques used by Schwamm and his colleagues make it possible to do just that. By revealing the distribution and rate of blood flow and the amount of tissue already damaged, they can help doctors decide whether and how to treat a patient. "For example, if we see there's all this territory that is vulnerable and that might die if we don't do something, but on the picture of what's died already, there is almost nothing--those are the people we have a real chance to save," Schwamm says.
Still, few people make it to the hospital within the first day after a stroke--mostly because they do not know the signs of stroke. Koroshetz, associate professor of neurology, is currently heading a project to increase public awareness. Schwamm has designed a Web site that doctors and nurses at satellite clinics can use to identify and refer stroke patients who are eligible for new protective treatments.
Finklestein and Schwamm and his colleagues are currently working with pharmaceutical companies to test promising new drugs. "New molecular techniques are going to revolutionize stroke treatment as long as the pharmaceutical companies get smart and stay smart about the way they design clinical trials," Schwamm says.
One thing they may have to realize is that human clinical trials are all too human. "We don't always get them right--we may choose the wrong dose or regimen. But that does not mean the drug is not effective," Finklestein says. "For me this is not a one shot deal. This is a field we want to bring to fruition."