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Brain Attack: A Personal Reflection

Don B. Smith, MD

This is a refreshing article using a unique style of personal reflection to shed insights into how new technological advances in medicine take place. This article relates a personal reflection of the technologies of using intravenous or intra-arterial thrombolytics in treating acute strokes.

Some patients one can’t forget. Mr B is one of them. I met him in the fall of 1986. Only a few weeks earlier he was a robust 24-year-old, but he caught a cold and things were never the same. He became weak, fatigued, and short of breath. He saw his family doctor. He saw a cardiologist. He was admitted to the hospital with a diagnosis of viral cardiomyopathy. His heart began to fail, to dilate, to beat irregularly. He was placed on bed rest, and precautions were taken to prevent the formation of blood clots in the heart. For all this, he was neurologically intact.

On his second hospital day another disaster struck, literally before his nurse’s eyes. He suddenly became speechless and paralyzed. His right side was motionless. His left side, deprived of the reasoning of language, moved restlessly as he struggled to right himself in his bed.

Neurologic consultation was obtained immediately, but it was obvious to everyone what had happened. A clot had embolized to his left middle cerebral artery. His CT scan was normal, but that was no comfort. We all knew that on tomorrow’s scan two-thirds of his left hemisphere would be dark and dead. He would be disabled for the rest of his life. His future was shattered.

Still, it was still only an hour since his symptoms began. Was there nothing we could do? In the preceding several years it had become clear that cardiologists were on to something in treating heart attacks with clot busters. Dissolving clots that block the coronary arteries saved myocardium and saved lives. This was a desperate situation. I reached for a straw. I sought out a radiologic colleague and asked, “Why don’t we arteriogram this man and give him intra-arterial thrombolytic therapy?” My colleague looked at me as if I had lost my mind. He knew, as did I, that thrombolytic medications were contraindicated in patients with a stroke. Doctors tried this approach at least a couple of decades earlier and it proved disastrous, killing many people with intracerebral hemorrhage and benefitting almost no one. Was I looking for a malpractice case to call my own? Reluctantly and with sorrow, I agreed that he was right. We had no treatment.

We had seen hundreds of strokes. We knew that despite all of medicine’s late twentieth century progress, we might as well have been in the dark ages. There was nothing, at least nothing definitive, that we could do. It wasn’t that no one had tried. It just seemed that nothing worked. The literature was filled with reports of failed treatments for acute stroke: corticosteroids, osmotic agents, barbiturates, vasodilators, hyperbaric oxygen, hemodilution. Like many neurological disorders, stroke was an untreatable disease.

A few years passed, and my middle-of-the-night suggestion began to seem less heretical. Further research suggested that thrombolytic treatment for stroke did not necessarily lead to disaster and might even benefit some people. In the early 1990’s clinical trials were organized to investigate this issue. As the director of the CNI Stroke Program, I was delighted to have to opportunity to participate in such a trial, a double blind, placebo controlled study of intravenous r-tPA in acute ischemic stroke.

CNI was a leader. The first Colorado stroke patients to be treated with intravenous r-tPA were ours. The very first patient in our study was a woman in her 70’s with a pure motor deficit on her left side. She had a history of hypertension, but her blood pressure on that day was within the acceptable range. She seemed to meet all inclusion and exclusion criteria. I recall that we held our collective breath while giving a medication that years of conditioning had taught us was expressly verboten in this setting.

Remarkably, nothing terrible happened. Nothing wonderful happened either, but by the next day she was back to normal. Was this the work of the medicine or was it the natural history her illness? To this day, I don’t know for sure, but the fact that she didn’t drop dead from cerebral hemorrhage began to gradually boost our confidence. Fortunately for us, none of our early patients had a serious complication and several of them made gratifying recoveries. First impressions can be so compelling that they are hard to change.

Had we seen disaster early in our experience, it is likely that enrollment of additional patients at CNI would have been impossible, so strong was the bias against thrombolysis for stroke within the medical community at that time.

Our early experience with intravenous r-tPA gave us confidence in subsequent patients to try exactly the sort of treatment we were too fearful to offer Mr B: intra-arterial thrombolysis. We offered this on a compassionate basis in desperately ill patients who were not candidates for intravenous r-tPA. Again we were fortunate in our early experience. Our first case was a young woman with basilar artery thrombosis, typically a fatal syndrome. I watched in amazement as her clot disappeared before my eyes while my neuroradiologic colleagues infused urokinase under fluoroscopy. She began to improve immediately, and by discharge her only neurologic deficit was mildly disconjugate eye movement.

Our overall experience with intra-arterial thrombolysis was favorable, so much so that we reported out results at the North American Stroke Meeting. Subsequently, we were invited to join the Proact II study of intra-arterial pro-urokinase in acute middle cerebral artery thrombosis. With this, we had come almost full circle, back to the situation we faced in Mr B, but by this time we had something to offer: aggressive treatment of critically ill stroke patients in a scientifically sound way.

Gradually, from our center and from centers around the world, evidence accumulated to show that intravenous thrombolysis for acute stroke has unequivocal benefit in selected patients. I have no doubt that intra-arterial therapy will also be of value, though at present the FDA remains unconvinced, despite the positive result from the Proact-II trial, reported earlier this year.

As exciting as it is, thrombolysis for stroke is hardly a panacea. Intracerebral hemorrhage remains a significant risk and the vast majority of stroke patients are not appropriate candidates for treatment. In the 1990’s acute stroke treatment trials seem to have led us 2 steps forward and one-and-a-half steps back. For each report of progress there are several reports of failure. Some thrombolytic trials have shown convincingly that it is entirely possible to do more harm than good with clot-busters. The story for non-thrombolytic agents has been almost always disappointing.

CNI has been an active participant in several neuroprotective drug trials. We had great hopes that lubeluzole would widen the window of treatment opportunity, but like many other promising agents, it failed to deliver. The list of failed acute stroke treatments has mushroomed in the 1990’s. Despite impressive benefits in animal models, it has been hard to find any advantage for humans with these agents. A partial list of failures includes: dextrorphan; MK801; baclofen; naloxone; selfotel; aptiganel; eliprodil; piracetam; pentoxyfylline; nimodipine; danaproid; enlimobab; and trilazad. The results are mixed for several agents, such as citicoline and clomethiazole. The jury is still out on dozens of compounds which are still in various phases of development, but the optimism about neuroprotective agents has clearly faded in the last few years. We must not dwell on disappointment, however. We are clearly in a more favorable position than we were in 1986. Acute stroke today really is a “brain attack,” a true medical emergency.

The future has a way of being hard to predict, but from here it looks as if thrombolysis will continue to be of major importance. Newer, better thrombolytics will doubtless replace r-tPA. Candidates include TNK, pro-urokinase, and combined treatment with IIb/IIIa antagonists. Ancrod, a fibrinolytic agent derived from viper venom proved beneficial in a clinical trial reported this spring. Trials of mechanical clot disruption with innovative catheters are eagerly anticipated, as are trials of angioplasty and stenting. Retrograde trans-venous perfusion has shown promise in a small series of patients. Hypothermia will likely be of benefit, if we can find a practical means of achieving it.

Finally, for those patients who have a stroke despite our best efforts, we are beginning to see efforts at restorative treatment. Neuronal cell implants are being tried in selected patients. A variety of growth factors, anti-apoptotic factors, and genomic factors in stroke will be better understood and better utilized in the coming decade. The future of stroke treatment won’t get here as fast as we would like, but it is a bright future, indeed. We may reasonably hope that the helplessness we felt in Mr B’s case will become a rare emotion within our lifetimes.

Don B. Smith, MD, is a board-certified neurologist and a fellow of the American College of Physicians, the Stroke Council of the American Heart Association, and The American Academy of Neurology. He serves as director of the CNI Stroke Program and is a member of CNI. Back to top

Address comments and questions to: Don B. Smith, MD 701 East Hampden Avenue, Suite 540 Englewood, CO 80113

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