Special Report: Ten Halting Steps Forward In Research On Stroke

A stroke patient at Spaulding Rehabilitation Hospital

Stroke eventually killed my biological father, But first it turned him from a successful doctor, author and professor into a Job-like figure who lost everything he loved.

He and my mother split up before I was born, and he went on to a second stormy divorce. He had finally found happiness in his third marriage, to a woman seventeen years his junior. But his youthful wife broke under the pressure of caring for him in his diminished, post-stroke form. She slit her own throat with a razor. He found her in the bedroom in a welter of blood and saved her life, pinching her artery closed to stop the spurting until the paramedics arrived. After she recovered, she divorced him, despite all his entreaties. Living on her own, she tried again to bleed to death, and there was no one there to save her.

My father had loved being a doctor. The stroke knocked out just enough of his memory and reasoning faculties to make him clearly unfit to practice. He had loved writing medical novels. The stroke left him unable to spell even the simplest words, and plotting that had once been complex and suspenseful now came out embarrassingly sophomoric, unpublishable. He had enjoyed public speaking and television appearances. Now he slurred his words. He was left, he said often, with nothing that he enjoyed in life except smoking — the very cigarettes that probably led to the stroke in the first place. Death had always been his nemesis, but when it finally came, four years after his stroke, I believe he welcomed it.

Stroke is the second-biggest killer worldwide, and the biggest disabler of American adults. It costs the American economy an estimated $74 billion each year. Among its surviving victims, 70% cannot work as they did before, and about one-third need help with basic self-care. Having seen its damage first-hand, I find myself always watching for word of progress on stroke as I scan the research news, and usually struck by how little there seems to be.

Why is there so very little good news, so few breakthroughs? What is so hard about stroke?

In answer, Dr. Randie M. Black-Schaffer, medical director of the stroke program at Spaulding Rehabilitation Hospital, offered this vivid analogy:

Say it’s wartime, and a bomb is dropped in a field. It’s relatively easy to fix, you just regrade the dirt and sprinkle some grass seed. That’s what happens when you get a skin wound. It’s not hard to get the cut to heal up almost as good as new.

World War Two bombing near Paris

Now say the bomb is dropped not on a field but on a town. A great many things have to happen for that town to start functioning again as a town. You start by clearing out the debris — which is like the inflammatory processes in the brain that clear out the cells killed by the stroke. Then you rebuild the buildings, but buildings alone do not make a town. You have to bring the people back, which is like bringing back the blood cells and the neurons. And then the town has to be connected to other towns, by road and by phone lines. And even then, the pattern of movements of goods and services to and from the town may never quite be the same.

In short, Dr. Black-Schaffer said, “It’s just so complex when you have damage in the brain. There are so many different components and systems involved in each functional area of the brain. They all have to be working right in order for the patient to be able to carry on the function.”

Given that image of a bombed town, it is amazing that researchers have made any progress at all. But they have. Lately there have been a couple of exciting findings, and they come against a longer-term background of growing, hard-won understanding of stroke’s effects in the brain. All in all, enough progress for a round-up of promising steps forward.

Herewith, ten relatively bright spots:

1. Overview: Treatment of stroke has advanced — though not as dramatically as hoped — and lab research has come a long way in recent years.

Experimenting in animal models and test tubes, scientists have come to understand far more about the biological cascade of events that kill or cripple people who have strokes. Dr. Michael A. Moskowitz of Massachusetts General Hospital, a leading stroke researcher, recently published an overarching look at the state of the science in the journal Neuron. Titled “The Science of Stroke: Mechanisms in Search of Treatments,” it covers an impressive array of recent research on how and why brain cells die in stroke, from inflammation to oxidative stress.

“Tremendous progress has been made in the understanding of fundamental mechanisms of neuronal cell death,” he writes.

“However,” he had to add, “the translation of these powerful molecular and cellular principles into clinically effective neuroprotective therapies in stroke has been challenging.”

Not that there have been no treatment advances. Dr. Black-Schaffer says: “We now have drugs that can be targeted, via sophisticated delivery devices and using our extraordinary imaging capability with MRI and CT scans, to dissolve, ensnare and retrieve blood clots in small cerebral arteries, enabling many patients to recover far more completely from a clot in the brain than was possible even 15 years ago.”

2. Prevent, prevent, prevent

The best stroke is still the one that never happens, and the research on preventing stroke is no less important than research on possible treatments.

Among the findings: About two-thirds of our risk for stroke can be affected by our own behavior. The American Stroke Association lists all the stroke risk factors here. They include: uncontrolled blood pressure, high cholesterol, (this was disputed for a while but is now backed by clear evidence) and smoking.

“You can’t emphasize enough the importance of that ounce of prevention,” Dr. Moskowitz said.

Dr. Lee Schwamm, director of telestroke and acute stroke services at Mass. General, says that systematic efforts to improve stroke care in hospitalized patients have been boosting the rates of stroke-prevention treatments, recent studies show. Many more patients are getting started early on prevention.

3. That first brief window — ‘clot-busters’ for the lucky few

It was an exciting advance when “clot-busters” such as Tissue Plasminogen Activator entered medical use over a decade ago. They can lessen or reverse the damage from a stroke, but must be given within about four-and-a-half hours of onset.

The nation has been developing a network of hospitals best equipped to treat stroke, in part so that specialists can administer clot-busters quickly enough. Mass. General, for example, reports that last year, 80% of its stroke patients received clot-busters within an hour of arrival at the emergency department.

The trouble is, the drugs cannot be used for all strokes; and researchers report that nationwide, only about 5 percent of stroke patients get treatment in time for clot-busting to be safely given by vein, though specialized centers can reach 20%.

Dr. Schwamm: “Many patients who aren’t eligible for intravenous clot-busting can be treated with special catheters that are advanced directly into brain arteries to remove blood clots and restore blood flow.” Also, newer clot-busting drugs are being tested to see whether they might do a better job or allow a longer window for treatment.

Bottom line: Time is of the essence, which mean we all need to know how to recognize a stroke and when to call for help. The American Stroke Association lists the warning signs here.
NPR offers a 2009 list of certified stroke-care hospitals here.

4. The longer, bigger window

Dr. Moskowitz says that the single greatest advance in the scientific understanding of stroke in recent years is the recognition that beyond that brief clot-busting window of several hours, “there are some very important events that shape the evolution of the stroke injury, and at the same time prepare the brain to repair itself.”

In the course of a stroke, he said, cells become “committed to die” — whether because of chemical signals they’ve received or their own injuries. “It’s very difficult to rescue cells in the process of cell death,” he said, “but we know more and more about what the mechanisms are that bring us to that point.” Now, that knowledge must be translated into treatment, he said.

(“Committed to die.” I can’t help thinking of my young stepmother. It remains a deep family mystery why she couldn’t just walk away. Guilt? Depression-induced psychosis? It was my father’s cells that were committed to die by the stroke. But it was as if, in her, an “I must die” switch were triggered, and that impulse, once unleashed, could not be turned off.)

“We used to think the stroke story was over in minutes or hours,” Dr. Moskowitz said, “so we would give some kind of clot-busting drug and that was it. But now we know that we can introduce certain types of drugs that target signaling mechanisms that work 24 hours later than that, even 48 hours, because there’s an evolution of tissue injury that gives us a handle for future therapy.”

Such treatments could target inflammation, for example, or “excitotoxicity,” in which an overabundance of the brain messenger glutamate kills cells.


5. Brain freeze

Studies clearly show that when a patient has a cardiac arrest and the brain is deprived of oxygen, cooling the brain to about 35 degrees somehow saves a lot of brain tissue, Dr. Moskowitz said.

Can this be used for the most common type of stroke, the ischemic form in which a clot cuts off blood from a part of the brain?

That’s tricky, because the rest of the brain is functioning and thus hard to cool. But techniques are developing. What’s clear is that lowering the brain’s temperature hinders all the signaling mechanisms that have been linked to cell damage, Dr. Moskowitz said. Hypothermia is not “ready for prime time” with ischemic strokes, but “it’s a potentially exciting therapeutic advance,” and clinical trials over the next several years should tell whether it will work out.

6. Not just neurons

Sometimes, it’s an important advance just to start thinking in a new way.

Stroke researchers used to think about blood vessels and brain cells rather separately.

“Now we’ve realized that there’s a tremendous amount of interdependence and integration, that the blood vessel is part and parcel of the brain, that there is a ‘neurovascular unit,’” Dr. Moskowitz said.

That new thinking may translate into a better understanding of how the brain fixes itself, how stem cells migrate from the blood into the stroke area to do repair work, Dr. Moskowitz said. “We don’t quite know how they’re doing that job, but the experimental data suggest they’re capable,” he said.

The new neurovascular thinking is also important for the growing understanding that stroke is powerfully connected to neurodegenerative diseases like Alzheimer’s and Parkinson’s. It has become ever clearer that stroke damage accelerates their deterioration.

7. Brain self-defense

The opposite of that deterioration is brain resilience. In “ischemic tolerance,” the brain “marshalls a whole series of defensive strategies to protect itself under conditions of lack of blood supply,” Dr. Moskowitz said.

Here’s an odd discovery: In some cases, after the brain is subjected to a stressful event — trauma, lack of oxygen — it becomes super-resilient over the next day or two or three. Hit it again with the same sort of stress, and the injury will be much less. Researchers are trying to understand how to reproduce that natural response.

“It would be nice to have that on all the time,” Dr. Moskowitz said, “and to identify a population who’s at very high risk and initiate these mechanisms. That’s very exciting.”

8. The Promise Of Prozac

Last month, researchers published some dramatic findings about the effects of the antidepressant Prozac on stroke patients. The study, funded by the French government and published by the journal Lancet Neurology, found that in a group of 118 patients, those given Prozac for three months improved 34 points on a 100-point scale, while those given a placebo improved only 24 points. That ten-point gap could make the difference between a patient being able to live independently or not.

Dr. Randie Black-Schaffer

Dr. Black-Schaffer:

“Fluoxetine (Prozac) has several effects that may benefit stroke patients.  It improves mood, and therefore motivation and energy level, which is very helpful in the recovery and rehabilitation phase after a stroke. Approximately half of stroke patients become depressed at some point after their stroke, so this is an important effect for this population. Second, there is some  data in animals and anecdotal data in humans that it can enhance muscle activation, which may improve the  speed and extent  of active movements. Third, there is animal data that if given at the time of the stroke it has neuroprotective effects and can limit the size of the stroke though this has not been tested in humans yet.

The current study is the largest to date to look at fluoxetine’s effects on stroke recovery, and their results are very positive.

My conclusion at present is that there is limited but promising evidence that it may be a useful drug for stroke patients fall of the reasons above.  I’m not ready to prescribe it for all of my patients, but am inclined to start it early in those who are becoming depressed.”

9. Better clinical trials

This one depresses me, so I’m going to make it short. Dr. Moskowitz says that one of the advances in stroke research of the last ten years is to learn how not to do clinical trials. The experiments to assess drugs have often been less than optimal, he said. When you target one aspect of the stroke cascade, other pathways may compensate, muddying the waters. Some drugs may thus have been wrongly judged ineffective.

But methods of assessing drugs are getting more sophisticated, including brain imaging techniques.

10. The biggest window of all — rewiring in the years after

Of course, the most burning question of all is whether anything more, anything at all, can be done to help the millions of people who have been living with the effects of stroke for years.

Dr. Moskowitz says that there is growing understanding that stroke involves not just cell death but the brain rewiring that comes later.

Researchers “realized that we knew an enormous amount of what was going on at the early stages, but we knew almost nothing about the later stages, and we’re recognizing that there may well be a therapeutic opportunity here,“ she said.

As the head of Spaulding’s stroke rehab program, Dr. Black-Schaffer faces the question of rewiring every day. She sums up: “Where we are now is that we have a number of interventions” — including various forms of physical therapy and some medications — “that seem to have modest effect sizes in improving people’s outcomes after a stroke, but we haven’t really figured out how best to combine them.”

The take-home message of the last 15 years, she said, is just that intensive physical activity, intensive practice at meaningful tasks by a motivated patient, “will result in significant improvement for years after a stroke.” It’s “the piano lessons model of stroke recovery: practice and practice and practice.”

So no magic bullet?

“I don’t see one,” she said. “I wish I could. The various lines of research that have been pursued in the last 20 years have not revealed the possibility of one to me. Once you have brain damage, reestablishing connections is a very daunting task. Preventing it might be a lot easier.”

A happier ending

I didn’t want to end on such a down-note, so I asked Drs. Schwamm and Black-Schaffer for a more upbeat finish.

Dr. Black-Schaffer: “Twenty years ago, our only goal was to help people adapt to the disability caused by the stroke. Now we know enough about the cellular and molecular mechanisms that we aim higher — to improve the neurological recovery after stroke, not just ease adaptation to permanent deficits. Our growing impatience as a clinical and research community derives from this higher goal that we have now set for ourselves and our patients. I am hopeful that the creative tension thus generated among “neuro-recovery” investigators will lead to significant advances in stroke recovery research in the next decade.”

Dr. Schwamm: “Exciting new research suggests that major advances may be on the way. Animal studies conclusively show that a stimulus-rich environment promotes the growth of new brain connections critical to repair. The use of telemedicine or novel computer interfaces to engage stroke patients in rehabilitation activities promises to provide this stimulus-rich environment. Preliminary data shows that something as simple as playing computer video games like the Nintendo Wii can improve cardiovascular fitness and stroke recovery.”

“While the future often looks bleak when viewed from the bedside of a newly diagnosed stroke patient, the natural history for many is one of recovery and return to independent living. For those who don’t recover spontaneously, some day — hopefully soon — a wider array of restorative treatments will be readily available.”

(A 2011 Favorite)

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