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Stroke Epidemic: New Therapeutic Strategies

Prof Guido Stoll (, Germany) spoke on the subject of strokes at the 23rd Meeting of the (ENS) in Barcelona: “Worldwide, one person dies every six seconds as the result of a stroke. Every year, 250 to 280 new cases are reported per 100,000 inhabitants in Europe, for a total of 600,000 strokes. It is a disease of epidemic proportions, which will continue to pose a host of problems for us.” About 3,000 experts are discussing current developments in their field at this congress right now. A special symposium is devoted to the subject of strokes. Participants critically explored the mechanical processes for reopening blocked arteries (recanalization) in the brain amongst other subjects.

Mechanical elimination of thrombi: innovation with two sides

An inadequate supply of blood to the brain due to thrombi (blood clots) accounts for 80 to 90% of strokes and the sudden neurological deficiency symptoms associated with them. The remaining 10 to 20% are attributable to cerebral haemorrhages. The only method that has thus far been proved effective is within 4.5 hours after the stroke. This IV-injected pharmacological treatment dissolves the clot. Additional mechanical interventions are the only chance for many patients, namely those who have thrombi over eight millimetres in diameter, which are usually resistant to dissolution. “Thrombectomy is a minimally invasive catheter-directed intervention to remove thrombi. In most cases, it restores the interrupted flow of blood immediately. It appears that specific conditions must be met for this type of intervention to be beneficial in the long term,” explained.

Penumbra as a promising neurological area

Researchers at the University of Bern analysed 1,200 sets of data from acute stroke interventions and found that 90% of the mechanical interventions were above average in effectiveness if two criteria were met. First, the thrombus has to be completely removed and not fragmented in the process. Second, the collaterals, that is, the laterally running side branches of the arteries, are not sealed by the intervention. They form a natural bypass for the blocked artery and supply the tissue immediately adjoining the destroyed area and still containing nerve cells capable of surviving. This penumbra around the area of necrosis is a promising neurological area of decisive importance. If the collaterals continue supplying it adequately, the patients have a good chance. Experts at the University of Bern criticise that the techniques and instruments selected for many of the current studies sacrificed the collaterals and penumbra so the success of the treatment was quite poor.

Studies discussed in the New England Journal of Medicine (March 2013) show that the mechanical methods yield no results if they are used even an hour later than the thrombolysis. The time loss can no longer be offset although the recanalization rate would be much better (SYNTHESIS Expansion Trial). A further study (IMS III Trial) concludes that endovascular methods have advantages if they are combined with thrombolysis in accordance with a strict timetable; otherwise they are detrimental. A third study (MR RESCUE) concluded that patients who are not treated until after the critical time window of 4.5 hours and who have a specific type of penumbra pattern appear to benefit. “For actual clinical practice that means intravenous thrombolysis remains the treatment of choice. Further clinical studies are urgently needed to determine which patients profit from an additional mechanical removal of thrombi. Unfortunately, 90% of all stroke patients come too late to the hospital and thrombolysis cannot be used. We therefore have to do everything we can to prevent strokes from happening in the first place and to improve the therapeutic possibilities,” Prof Stoll emphasised.

Major advances have been made in the last two years in the prevention of strokes for patients with atrial fibrillation. Prof Diener from Essen, Germany, presented them at the stroke symposium. The inhibition of plasmatic blood clotting with new oral thrombin and factor Xa inhibitors prevents at least as many emboli from the heart into the brain as the heretofore usual treatment with vitamin K antagonists but involves a substantial reduction in the cerebral haemorrhaging feared in connection with “blood thinning”.

Pharmaceuticals against life-endangering cerebral oedemas

Dangerous oedemas that form after brain infarcts are still puzzling for scientists. Prof Stoll explained: “The brain tissue with neurons and glial cells may be dead but complex, largely unknown molecular processes continue to occur in the infarct region. The infarct region swells up and cannot escape because of the spatial restriction imposed by the bony skull. It presses against areas of the brain not even affected by the stroke.” If substantial swelling occurs, cerebral death follows unless part of the skullcap is surgically removed in time in a decompression operation. Until now, there have been no other reliable therapeutic options. Prof Stoll: “Cortisone has no decongestive effect with strokes the way it does with many other cerebral diseases. That is certainly one reason the mortality rate in people with brain oedemas is as high as 80%.”

Research findings are now offering new hope. In experimental studies, a working group from Wurzburg, Germany, was able to show for the first time that steroid receptors undergo premature degradation. These receptors are indispensable for the effectiveness of cortisone. Pharmacological inhibition of this degradation resulted in the cortisone counteracting the formation of cerebral oedemas. The very latest studies have also shown that factors in the plasmatic clotting system, such as factor XII (FXII), are not only involved in the formation of blood clots during a stroke but also play an instrumental part in oedema formation in the brain. FXII activates, inter alia, the kinin system, which is responsible for the formation of oedemas in the body. In experimental studies, researchers actually succeeded in suppressing the development of cerebral oedemas in the experiment by blocking a key molecule of this thrombotic oedematous activation path, C1 esterase. Prof Stoll: “That might possibly open up a new therapy option for the treatment of cerebral oedemas, especially since BerinertR, the C1 esterase inhibitor used, is already approved for another indication. Extensive tests will be needed, however, before it can be used for stroke patients.”

Source

23rd Meeting of the European Society of Neurology (ENS) 2013.
ENS Abstract 121: Thrombolysis and endovascular recanalization in acute stroke;
ENS Abstract 124: Mechanisms and treatment of brain oedema formation;
New England Journal of Medicine; March 7, 2013, Chimowitz MI: Endovascular Treatment for Acute Ischemic Stroke – Still Unproven

European Neurological Society