Nine years ago the Food and Drug Administration approved tissue plasminogen activator (tPA) as the first, and still only, drug for treating ischemic strokes, which are caused by blood clots in the brain that starve neurons of oxygen. Yet only 3 percent of stroke victims receive this clot-busting thrombolytic, largely because they enter the emergency room within three hours of the onset of symptoms. After that, tPA's effectiveness in reducing death and disability sinks, while the relative risk of dangerous hemorrhaging rises. Recently scientists have discovered ways that could extend tPA's window of time, at least for some patients, and have found alternatives that may be both effective and safe beyond three hours.

A key to a bigger tPA window was the realization among researchers that not all neurons deprived of oxygen died after three hours, as was previously assumed. Restoring blood flow can revive enough neurons to significantly improve recovery. The trick is figuring out which patients can still benefit from treatment.

From the beginning, doctors used CT scans to triage patients, separating the many with ischemic stroke, who are candidates for tPA, from the few with hemorrhaging stroke, who are not. (About 80 percent of all strokes are ischemic.) But the images could not show how much of the ischemic tissue was already dead and how much was still salvageable. "We were treating patients blindly," remarks Steven Warach of the National Institutes of Health's Stroke Center. "We didn't know what was going on in the brain."

Today's MRI scans can distinguish between dead and dying cells, and newer CT scans seem able to as well. "It's been a big advance," says Warach, who described MRI's diagnostic effectiveness in the March 2005 American Journal of Neuroradiology. "We can push the time window for tPA to eight hours." Selecting patients for treatment on the basis of a "tissue clock" rather than the "ticking clock" gives many more patients a chance for a fuller recovery. As important, MRI and CT imaging may also identify those at risk for bleeding if given thrombolytics, a concern that keeps some physicians from administering tPA even within three hours.

Simple, nondrug measures may keep endangered neurons alive until they can be rescued with tPA, says Aneesh B. Singhal of Massachusetts General Hospital, where a small pilot study gave participants high-flow oxygen through a face mask. "It buys time," explains Singhal, who co-authored the paper on it in the April 2005 Stroke. "We can delay the progression of ischemic stroke by several hours. Because oxygen therapy is readily available in ambulances and the ER, it could make logical combination therapy" with tPA.

Meanwhile potentially safer drugs have entered late-stage clinical testing. Desmoteplase, which derives from the saliva of a vampire bat, chews up the fibrin holding a clot in place just as tPA does, but it is more potent and selective. "Even at nine hours, patients had significant long-term clinical benefits, in terms of better recovery after 90 days," says Warach of phase II results. The drug recently entered phase III trials.

Another drug in phase III testing protects neurons by way of a different method. Cerovive (NXY-059) works by scavenging up free radicals that break down the blood-brain barrier and worsen stroke outcome. Preliminary results from a global trial, known as SAINT I, suggest the chemical reduces the amount of disability after a stroke.

Even with the good news, many patients will not qualify for these therapies, because they may still arrive too late or have contraindications. A therapy that encourages brain cells to step up their own repair mechanisms might be the best solution, but that is still a long way off.