New treatments, philosophies extend time in which acute strokes can be stopped



By Pohla Smith, Pittsburgh Post-Gazette
Darrell Sapp/Post-Gazette
Dr. Andrew Ku adjusts CT equipment at Allegheny General Hospital. A CT scan finds the "penumbra" in the brain that is affected, but survives, after a stroke.



It was about noon last June 15, just another day at work as a supervisor for Armstrong World Industries, when John Janczura of Beaver Falls went into the office to look up a number in a phone book.

"[I] noticed the numbers looked fuzzy and that was it," said Mr. Janczura. "Next thing I remember was when paramedics came in."

Mr. Janczura, then 58, was having an acute ischemic stroke. That means a clot -- in medical terms an occlusive lesion -- was blocking a blood vessel in his brain, causing tissue damage that could result in permanent disability or even death if it were not quickly broken up and blood flow restored to the area.

Fortunately, a colleague also in the office recognized other symptoms of stroke: Mr. Janczura was unresponsive and the right side of his face was drooping. The colleague called 911.

Also fortunately, Mr. Janczura awoke in time to slurringly respond "Allegheny General Hospital" when the EMTs asked where he wanted to be taken. His cardiologist and other doctors he and his wife use are there and, he said, "I knew it was a good hospital to be at."
Symptoms of a Stroke

"The signs and symptoms of stroke are variable," says Dr. Ashis Tayal, medical director of the Comprehensive Stroke Center at Allegheny General Hospital. They include:

• Speech disturbances such as slurring or aphasia, a term which means use of wrong words, speech that is not fluent or an inability to understand speech.

• Vision disturbances such as abrupt loss of vision or blurred, double, or decreased sight.

• Drooping of one side of the face.

• Weakness of the extremities, typically on one side or the other.

• A loss of sensation or development of numbness.

• Sudden headaches that may be accompanied by stiff neck, facial pain, pain between the eyes, or vomiting.

• Altered consciousness.

• Confusion or problems with memory, spacial orientation or perception.

If you or someone you know experience any or several of these symptoms, seek immediate medical help. Time in which strokes can be stopped and permanent disability restricted is limited.

AGH is one of three Pittsburgh hospitals designated as Primary Stroke Centers by the Joint Commission. The others are UPMC Presbyterian and UPMC Mercy. There are about 600 such centers nationwide.

The Pittsburgh hospitals specialize in the use of cutting-edge technology involving catheter-delivered, mechanical clot-removal devices that allow neurologists to intervene up to eight hours from stroke onset. When a variety of factors, including a new one called "mismatch," permits, they also push the envelope on that time frame.

Mr. Janczura ended up benefitting from both the use of a clot-removal device called the Concentric Retrieval System, or a MERCI device, and a decision by his family to allow neurologists to begin the catheter-based intervention some 18 hours after the onset of his first symptoms.

"Once the clot was removed there were no physical or mental limitations at all," Mr. Janczura said, crediting skilled neurologists, the new technology and "answered prayers" for the outcome. "If they hadn't done it, I don't know what the possibilities might have been. I probably would have been in a nursing care facility. Instead, within four days I left the hospital. ... I went back to work four weeks after my stroke. I'm responsible for 40 people's actions. ... I can still golf. There are no limitations."

To understand how Mr. Janczura's outcome came about it helps to learn the evolution of stroke treatment.

"Back in '91, when I first started treating patients with strokes, the only thing we had was urokinase, which was a clot-dissolving drug that worked pretty well," said Dr. Andrew Ku, the neuro-interventional radiologist at AGH who did the stroke intervention on Mr. Janczura. "It's still used today, [but] usually we use tPA." Formally called Activase, tPA has been around since 1995.

If the patient arrives within three hours of onset, tPA is delivered intravenously, which means it courses through the entire body.

"The original trials that resulted in the approval [by the Food and Drug Administration] ... showed that tPA was effective and the benefits of it were larger than the risks if more people were treated within three hours," explained Dr. Ashis Tayal, medical director of the Comprehensive Stroke Center at AGH. "The longer you wait beyond three hours, the higher the risk of complications such as bleeding and, No. 2, the drug may be less effective."

A recent trial showed that tPA can be effective up to 4 1/2 hours from onset. "However," Dr. Tayal said, "the drug is not approved for that kind of use currently."

Even within three hours, he added, "the drug doesn't work for every patient and it doesn't open up all clots." The intravenous delivery cannot be used on patients taking blood thinners or those with bleeding problems.

But some 10 years ago, he added, neurologists began using a micro-catheter introduced through the groin -- in the same fashion as a heart catherization -- to inject a much smaller amount of tPA directly into the clot.

The advantages: "[It] can be done up to six hours from the onset of symptoms ... and it included many people who couldn't get tPA, like, for example, if you were on Coumadin. a blood thinner, for atrial fibrillation ... or if you arrive late or say you had major recent surgery for which injecting tPA into a vein was not indicated," Dr. Tayal said.

The risks: Bleeding can occur in the brain in 6 percent of the patients and worsen as a result.

Mr. Janczura has two heart valves and atrial fibrillation and takes an anticoagulant, or blood thinner, so he was not a candidate for tPA therapy.

He was, however, a good candidate for the MERCI catheter, which was approved by the FDA in 2005 and has gone through several design improvements since. The MERCI looks like a tiny corkscrew and works like one, too, albeit with added features to keep pieces of the clot from breaking off and floating off into the bloodstream.

"What you do is put in a larger tube, like for a main blood vessel, and then you put a small tube with the retriever through that larger tube," AGH's Dr. Ku said. The small catheter and MERCI device are sent on to the blood clot, while a balloon is inflated around the larger tube to briefly shut off blood flow. That's done to prevent the clot from being washed downstream as the interventionalist is retrieving the coil and blood clot back into the catheter, he added.

"It's approved for up to eight hours after the onset of stroke," Dr. Tayal said, and these specialized catheters continue to be revised and changed and modernized with increasing experience. Trials have shown using this catheter is effective in opening up arteries about 60 percent of the time. The risk again is bleeding.
New device

In January of this year, the FDA approved another catheter-delivered clot buster called the Penumbra System. "Penumbra" is the medical term used to describe the area of brain that has diminished blood flow because of the clot and is still alive but is threatened to die and result in permanent damage if blood flow is not quickly restored.

The Penumbra device works like a microscopic vacuum cleaner sucking the clot onto the catheter.

AGH's Penumbra device was delivered about two months ago, and Dr. Ku and the hospital's other neuro-interventionalist, Dr. Robert Williams, had at the time this article was printed used it four times, Dr. Tayal said. Presbyterian has purchased its Penumbra and was anxiously awaiting for delivery, said interventional neurologist Dr. Tudor Jovin, co-director of the UPMC Stroke Institute.

"Perhaps mechanical devices do a better job than lytic [clot-dissolving] drugs administered directly into the clot," Dr. Jovin said. "Those [drugs] tend to have a lower recanalization [vessel-clearing] rate, but it's still in the 60 percent range. In mechanical devices, it goes up to 70 to 80."

The Penumbra, like the MERCI, has a standard window of opportunity of eight hours.

"It's great that we now have more treatments available," Dr. Jovin added. "The challenge will be to see which clot is suited to which device."

Still, he said, "I think the most important aspect of acute stroke intervention is not what we treat with but whom we treat. What I mean by that is how do we select patients for these interventions. Right now most are done by time [of onset] ... [but] it turns out that perhaps time is not the best way to select patients."

The reason: "Within some currently used time frames, some may have major [permanent] damage in the brain and opening up the vessel won't help much," Dr. Jovin said. "But other patients within the same time frame or same blockage or occlusion [clot] can have very little permanent damage and these are very good patients for intervention. So we have taken the approach at UPMC Presbyterian that physiology [whether brain tissue at risk is damaged or salvageable] should be the most important factor in determining who gets treated."

In other words, he explained, "the larger the penumbra, the higher the benefit of opening up the vessel." That area is measured by one of two sophisticated imaging techniques called CT and MRI perfusion. Also measured is the area of brain tissue already dead, which is referred to as the "ischemic core."
Mismatch concept

Delineating the area of ischemic core from the area of the penumbra results in an entity called a "mismatch," and the larger the mismatch "the higher the likelihood of good outcome," regardless the time of onset, Dr. Jovin said.

"These are very revolutionary concepts in stroke interventions," Dr. Jovin added. "I think we have been leaders in that regard." This past spring, at a stroke meeting in Europe his department presented 47 cases of patients treated beyond eight hours of onset.

In a second category, he added, "We looked at these patients and compared them with about 150 in the database of acute stroke intervention that were treated within eight hours. ...

"The bottom line, the conclusion, is it's not more dangerous to treat after eight hours. The other conclusion is if you open the vessels, there was a strong prediction of a good outcome."

Dr. Jovin acknowledged that mismatch is, for now, not the only factor UPMC Presbyterian takes into consideration in deciding whether to intervene.

"It's a great hope there will be a time when this will be the only factor, but right now we do take a few other factors into consideration," he said. For example, patients with high blood sugar values don't do well with interventions so the surgeons tend to be conservative; similarly, thin and/or debilitated patients don't benefit from intervention because their condition can lead to poor recovery.

"We are aware of time, but more and more we're detaching ourselves from the concept of time," Dr. Jovin added.

At AGH, however, Dr. Tayal said, "it is rare for us to recommend intervening beyond eight hours [of onset]," but, on the other hand, "mismatch is a consideration in almost all interventional therapies.

"Other factors considered are younger age, an arterial clot in a location that can be treated with a catheter, [and] a large area of the brain at risk by perfusion."

A fluctuating course of stroke symptoms and a number of other factors went into the decision to intervene in John Janczura's stroke nearly 18 hours after onset of the symptoms.

"He had dramatically improved [following his arrival at AGH]," Dr. Tayal said. "His symptoms resolved in the emergency room, so we stopped the intervention and waited another 12 hours. He worsened again, so then we treated him with the catheter-based MERCI."

Dr. Tayal added, "Mismatch was a major factor in the decision. In fact, we demonstrated mismatch two times by CT perfusion, both at the time he came in, and just prior to treatment when he deteriorated for the second time."

Also considered were the facts that "he was young, had a clotted artery, had fluctuating and worsening neurological symptoms and a large area of brain tissue at risk."
Pohla Smith can be reached at psmith@post-gazette.com or 412-263-1228.

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