Spring 1996 Volume 5, Number 3

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BY WALTER J. KOROSHETZ, M.D.

To be suddenly struck down by a major ischemic stroke is an unusually cruel fate: it can affect the core of the individual's being -- memories, communication, reasoning, and the neurologic basis of personality. In a sense, the tragedy of this type of sudden brain injury is rivaled only by death itself: Serious brain injury is akin to the selective death of one or more personal characteristics. As they have for death itself, most physicians have considered stroke irreversible, a "fait accompli," and have learned to quickly shift their attention to after-stroke issues that they consider treatable.

Ischemic stroke is caused when circulation in the brain is blocked by a blood clot (a "thrombus") or fragment (an "embolus"). The nerve cells deprived of blood flow begin to die and may go on dying even after blood is restored ("reperfused"). To make matters worse, reperfusion itself is risky if blood vessels in the brain were damaged during the blockage.

A nihilistic therapeutic philosophy used to be realistic, but neuroscientific research now offers a much more hopeful scenario for stroke. In a sense, the old nihilism is now the worst enemy of the stroke patient, because it is now possible to take action to limit stroke.

Studies with animal stroke models have yielded a half dozen strategies with proven benefit. These include dozens of drugs now in clinical trials -- ranging from neuroprotective drugs that uniquely protect brain tissue from ischemic injury, to drugs that promote recovery of function after stroke by enhancing biologic mechanisms. Also, lowered brain temperature (hypothermia), a reduction of even 3 to 4 degrees centigrade, has shown clear protective effects against ischemic damage in the brain and other organs.

The most important new development for stroke treatment is the advent of thrombolytic drugs (so-called "clot-busters," already used for heart disease). These drugs promote dissolution of blockage in cerebral arteries, improve blood flow to the ischemic zone, and can salvage ischemic brain tissue from infarction (dying locally). However, the strategy is inherently risky: When blood flow returns to ischemic, damaged, "leaky" blood vessels, serious or fatal hemorrhage into the brain can occur. This is more likely with thrombolytic agents, as they inhibit the normal clotting that would limit the problem.

Last year, investigators for the National Institute for Neurological Disorders and Stroke (NINDS) demonstrated conclusively that very early treatment with a thrombolytic agent improved the probability of a good outcome in selected ischemic stroke patients. And in early June, a landmark was passed when the FDA approved the treatment -- intravenous, recombinant tissue plasminogen activator (rt-PA) -- for use with stroke patients within 3 hours of onset of their symptoms.

Though the study also showed a tenfold increase in occurrence of brain hemorrhage, it was not enough to offset the benefit from rt-PA seen in the treated group as a whole. Perhaps most important, the findings were tied to rapid, hyperacute treatment: Half of the patients in the NINDS study were treated within 90 minutes of onset of their stroke. All were treated within 3 hours. In community practice, rt-PA's success rate may differ from the study rate, because accurate diagnosis and timeliness count above all.

The drug's entrance on the scene will be the first of a series of advances in the care of the stroke patient. It compels the institution of a medical system with emergency procedures for the stroke patient similar to those for heart attack -- including emergency stroke response teams and acute stroke units akin to cardiac care units. Only a few centers now have such stroke response capability. The use of rt-PA in the absence of the necessary structure may be disastrous, not because the strategy is flawed but because the system is unready. The widespread institution of structured acute stroke care now will hasten further improvements in acute stroke therapy.

The old patterns of practice based on therapeutic nihilism need to change. Stroke should no longer be cataloged subconsciously as "a tragedy that can't be helped." Instead, some core principles of the new age -- stroke as "brain attack" -- must be incorporated into general medical practice:

1. Time is brain! Early treatment, within hours of stroke onset, is the single most critical factor likely improve outcome with modern treatments. For rt-PA and almost all the other treatments in clinical trials, a short interval between stroke onset and treatment is critical. This requires a greater public information effort to make the signs of stroke and need for emergency treatment common public knowledge.

2. Refine the strategy. Researchers must redouble their efforts to develop methods for safe, timely reperfusion of the ischemic brain, as this offers the greatest potential for major recovery in stroke patients. The problem of brain hemorrhage after thrombolytic therapy for stroke needs to be overcome, though this will require much imaginative science in coming decades.

3. Master the weapons. Ischemic brain tissue passes through several stages on its way to cell death. Each stage has a most appropriate therapy. The stroke treatment of the future will combine agents tailored to the course of damage at a given time in an individual patient -- duration of ischemia, severity of ischemia, brain region involved and occurrence of reperfusion. Including a specific therapy in a patient's regimen will require knowing the place and stage of ischemic injury and balancing the benefits vs. the risks of the new therapy.

4. Deploy the resources. Major advances in community stroke treatment will require readjustment of medical resources. Real advances will come when physicians are empowered to duplicate the acute cardiac care experience. The shift in resources that occurred to care for patients with heart attack decades ago must now take place for patients with brain infarction: careful incorporation of new agents, improved diagnostic and brain monitoring techniques, and careful outcome monitoring at each stage.

5. Reduce the impediments. Will the current climate of cost containment and anti-specialization retard progress for stroke patients? Currently, government covers most of the cost of long term stroke disability. This insulates managed care providers from the true financial cost of stroke. If managed care providers were forced to share long term care costs, they would have adequate incentive to reimburse treatments that can prevent acute ischmic brain injury.