Stroke - a race against the clock

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Every 17 minutes someone in Sweden suffers a stroke. The consequences for the victim can be anything from death to a virtually full recovery, depending on the severity of the attack and how quickly treatment can be administered. Researchers are now trying to find new ways to reduce the damage caused by stroke and improve the odds of making a recovery. It is first and foremost a race against time.

For every minute that a blood vessel is blocked during a clot-induced stroke, two million brain cells die and the brain ages by three weeks. And the longer it takes for the clot to be treated, the greater the damage will be. Since the extent of the damage in brain tissue is directly related to how well patients do afterwards, it is absolutely essential to limit the damage as much as possible.

"The research relates to how we can reduce the acute damage of stroke," says Nils Wahlgren, Professor of Neurology at the Department of Clinical Neuroscience at Karolinska Institutet.

Every year, more than 30 000 people in Sweden suffer a stroke, which is one every 17 minutes, around the clock. Stroke is by far Sweden's most expensive physical disease because it leads to more days under hospital and nursing home care than any other physical disease. The annual cost weighs in at just over 16 billion kronor.

A stroke can be caused by two completely different problems in the brain. The most common cause is a blood clot that clogs a blood vessel in the brain and prevents the blood from supplying oxygen and energy to the parts of the brain beyond the blockage. About 85 per cent of all stroke victims have a stroke because of a clot. The remainder are instead caused by bleeding in which a blood vessel ruptures and blood flows into the brain. This can both damage brain tissue directly and stop the blood from supplying oxygen and energy, just as in the case of a clot. Despite these completely different causes, the symptoms of stroke are often very similar. The national stroke campaign has launched the AKUT test to make it easier to recognise a stroke.

The effect of a stroke on the victim varies greatly. Studies have shown that about 20 per cent die and 30 per cent become functionally dependent, which means they need the help of another person for basic things like going to the toilet. And as many as 50 per cent are functionally independent. But Nils Wahlgren says there are many distinctions that this picture fails to make.

"Half being functionally independent sounds like a very good figure, but a lot of problems lurk underneath. Patients can have various degrees of disruption to neurological functions that might present a major intrusion on their daily lives; they may no longer be able to work, drive a car or engage in previous hobbies, like playing the piano. There are many things that can have a huge impact on their lives, even if they are not dependent on someone else's help for basic needs," he says.

In addition, a stroke involves a higher risk of depression several months after the acute phase, as well as an increased risk of developing dementia in later life. But according to Nils Wahlgren, there are also those who will make a full recovery, but there are unfortunately no definite figures for this as it is not quite certain what is meant by a full recovery.

"Perhaps you are back and look fine, but there are still some small details that affect you. I think that if you have suffered a stroke, it always leaves its mark on you in some way," he says.

So the best thing, of course, is to avoid being hit by stroke. But there is no preventive treatment to protect otherwise healthy people against stroke. It is rather a matter of managing risk factors. Two important risk factors for stroke are high blood pressure and diabetes. These should be treated so that they stay within the threshold values for each condition. Also, the risk can always be reduced by healthy living, exercise and not becoming too overweight. Another very important risk factor is untreated cardiac fibrillation, which increases the risk of blood inside the heart forming a clot that can then be torn loose and become lodged once it reaches the brain.

"Going around with untreated cardiac fibrillation is a very great risk, except in young, otherwise completely healthy individuals," says Nils Wahlgren.

New treatment being tested

Nils Wahlgren and several of his colleagues at Karolinska Institutet are world leaders in a number of areas of stroke research. One example is research on improving thrombolysis - the clot-busting treatment used for the majority of patients whose stroke was caused by a blood clot (or thrombus). Doctors use medication called "tissue plasminogen activator", tPA, to dissolve clots in the brain. The disadvantage of this medication is that it is typically only possible to use it up to 4.5 hours after the first stroke symptoms. After this time, its effect is reduced, increasing the chances of symptomatic bleeding due to the risk of the blood-brain barrier, which normally protects the brain from foreign substances, being opened in an uncontrolled manner.

But Ulf Eriksson, Professor of Vascular Biochemistry at the Department of Medical Biochemistry and Biophysics, Karolinska Institutet, might have found an unusually successful solution to this problem. Ulf Eriksson's research focuses primarily on identifying and functionally describing the body's own signalling molecules. Just over ten years ago, he was working on the production of new growth factors and discovered a factor that turned out to be activated by tPA. He asked himself whether it might have something to do with the risk of bleeding in the case of late tPA treatment. And indeed it did.

"It turned out that the tPA-activated growth factor we had identified could single-handedly open the blood-brain barrier in a way almost identical to that during a stroke," says Ulf Eriksson.

Together with colleagues from the United States, he charted the mechanism at the receptor level and as luck would have it, he found that there was already an approved drug that blocked that very receptor. Imatinib, or Glivec as the drug is called at the chemist's, is currently used to treat quite a rare form of blood cancer known as chronic myeloid leukaemia, CML. In animal experiments, Ulf Eriksson was able to show that imatinib administered to mice with stroke caused by a blood clot in the brain reduced both the blood-brain barrier's permeability and the problems of bleeding in the case of late tPA treatment.

"By administering imatinib, we were able to extend this treatment window. You might say that we separate the good effect of tPA, that is to dissolve blood clots in the brain, from the harmful effects," says Ulf Eriksson.

Thanks to a major grant, researchers have now been able to set up their own clinical trials on an academic basis.

"If we get indications that the treatment reduces bleeding or fluid inflow, we hope to garner interest from industry. This has the potential to be a very important treatment," says Nils Wahlgren, who is leading the study.

But there they are not yet. The study will be carried out during 2013 and be concluded towards the end of the year. But even if the pharmaceutical industry's interest in paying for further clinical development is not aroused immediately, Nils Wahlgren believes that there are opportunities for further development. This is because he is also coordinator of the world's largest database for the treatment of stroke called SITS, "Safe Implementation of Treatments in Stroke", which currently encompasses over 80 000 stroke patients from 1 300 centres in 60 countries. By means of the contact network from the database, he can do research that would otherwise be financially impossible in an academic environment.

"We can turn to our 1 300 centres around the world and ask who would be interested in participating in a clinical trial. In this way, we can carry out a pretty economical academic study," he says.

And using the contact network in the database is something that already enables a study of an entirely different method, which is used to remove blood clots so large that it takes a long time to dissolve them with tPA. This involves something called thrombectomy, which simply put means the mechanical removal of the blood clot that is blocking the vessel like pulling a cork out of a bottle - though it is slightly more complicated. A sort of telescopic catheter is inserted in the patient's groin and can then be navigated up through the aorta via the neck vessels, continuing up to the vessels in the brain while the patient is awake. Using contrast fluid and x-rays, the doctor can see the clot's precise location in the brain, navigate to it and with a special instrument withdraw it all the way down and out through the groin.

"Important factors are the time until the clot is removed and the patient's capacity for a back-up supply to the brain," says Staffan Holmin, Professor of Clinical Neuroimaging at the Department of Clinical Neuroscience at Karolinska Institutet.

If the vessel is opened in time, the patient can often improve very quickly.

Staffan Holmin is one of the four interventional neuroradiologists who perform the mechanical clot removal and is also vice chairman of the department of neuroradiology at the Karolinska University Hospital, which for several years has been among the world's leading exponents of this technique.

But despite good experiences, the technique must be proven scientifically in international studies if it is to gain a greater user base. And the positive patient cases give rise to an ethical dilemma.

"With the experience we've had at our hospital, we can't really be drawing lots to see which half of the patients won't be treated. This view is shared by many other leading hospitals," says Nils Wahlgren.

Instead, he has used the database to recruit 30 hospitals around the world that have extensive experience of thrombectomy and 30 hospitals that are highly skilled in dissolving clots with tPA, but that do not have the opportunity to withdraw them. The research study then involves comparing how patients do at the various hospitals and seeing if it can be shown which method is best. If everything goes to plan, there will be an answer in 2014.

Recently, new results were published in the New England Journal of Medicine which showed that recovery after a blood clot in the brain was not better if the clot was removed mechanically. But Nils Wahlgren does not think these results will be of great significance because the techniques used today have been refined.

"The studies were done with an older technique, and most subjects were only given drugs and not mechanical treatment. The studies don't actually say anything about the modern thrombectomy procedure," says Nils Wahlgren.

Staffan Holmin also uses the technique with the telescopic catheter in experimental research projects whereby he has succeeded in creating a new, better and more clinically relevant means of inducing stroke in laboratory animals. This method makes it easier to obtain answers about the condition of brain tissue during the acute phase, which can then be used to tailor treatment for different stroke patients. He has also developed new microcatheter-based methods for delivering stem cells for transplantation or other types of substance locally to the brain or to other organ systems.

Because all stroke treatment is a race against time, Nils Wahlgren is also running a study to see how much it is possible to shorten what is known as the "door to needle time".

"We have seen that in Stockholm, as well as internationally, it takes about 60 minutes from door to needle. For a year now, we have been leading an international study whose goal is to get down to under 40 minutes," he says.

The possibility of shortening the times has been shown by his colleagues in Helsinki, where they have gone from 55-60 minutes all the way down to 25 minutes. Another interesting line of research that has not come as far relates to elevated blood sugar levels in the acute stroke phase. It has been shown that elevated blood sugar increases the risk of death, bleeding and becoming functionally dependent. And this applies to all patients, not just those who have diabetes.

"We are beginning to suspect that there are some very, very important things to study here," says Nils Wahlgren.

The brain can be repaired

But regardless of how good emergency treatment is in the future, there will always be a great need for rehabilitation following a stroke. Brain tissue dies and essential functions disappear, but not necessarily forever. There is the possibility of re-learning and of learning new things because the brain is plastic, which means that the brain's functional networks can be rebuilt throughout life. Most people have been taught that we are born with a certain number of brain cells, a number that can only go down. Think again, for that is not the case at all.

"No, that's what all the old textbooks say, and it is a truth that has had to be revised. We now know that there are stem cells, we know they are capable of developing into new neurons in the brain, but we still do not know what this means with respect to regaining functions after an injury," says Jörgen Borg, Professor of Rehabilitation Medicine at the Department of Clinical Sciences, Karolinska Institutet, whose research is about improving the rehabilitation process after acquired brain injuries in adults.

But re-learning demands hard work immediately after the stroke, in which training is used to try to push brain network activity to become functional again.

"It is known that training that starts early and is intensive makes a difference to the pace of recovery, and there is support for the end result being better," says Jörgen Borg.

The realisation that the brain is plastic and that the connections between neurons can be rebuilt throughout life in order to re-learn and to learn new things became an established truth in scientific circles in the 1960s and 1970s and is fundamental to today's rehabilitation programmes. Now, research has a lot to do with understanding what is going on inside the brain so as to individualise rehabilitation.

"Modern brain imaging has meant a great deal to our understanding of the brain's plasticity and adaptability after an injury. What appears to be the same clinically can have different explanations, and we believe understanding this is one of the keys to being able to design individualised treatment programmes," says Jörgen Borg.

But it is also a matter of completely new aids. At present, Jörgen Borg and his team are conducting a small pilot study with the robot suit HAL, "Hybrid Assisted Limb", from the Japanese company Cyberdyne. It is a kind of Robocop-like supportive skeleton that attaches to the outside of the leg and helps patients to start training to walk more quickly.

"It is an expression of the ambition to find new ways to intensify early training," says Jörgen Borg.

What then does the future have in store for the field of stroke? The proportion of patients who become functionally dependent after a stroke is slowly decreasing, something which may indicate both better treatment and better rehabilitation. At the same time, there is an increasing tendency of stroke in the slightly younger age groups, which could be caused by an increased incidence of diabetes and obesity. But the greatest difference in the future will probably be due to demographic change.

"In 2000, 13 per cent of the population was over 70 years of age. In 2050, 20 per cent will be. We can expect an increase in the number of stroke cases because of this factor," says Nils Wahlgren.

Text: Fredrik Hedlund, Published in Medical Science nr 1 2013.