Mechanism that repairs brain after stroke discovered

 

October 10, 2014

Lund University

A previously unknown mechanism through which the brain produces new nerve cells after a stroke has been discovered by researchers. A stroke is caused by a blood clot blocking a blood vessel in the brain, which leads to an interruption of blood flow and therefore a shortage of oxygen. Many nerve cells die, resulting in motor, sensory and cognitive problems. The researchers have shown that following an induced stroke in mice, support cells, so-called astrocytes, start to form nerve cells in the injured part of the brain.

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A stroke is caused by a blood clot blocking a blood vessel in the brain, which leads to an interruption of blood flow and therefore a shortage of oxygen. Many nerve cells die, resulting in motor, sensory and cognitive problems.

A previously unknown mechanism through which the brain produces new nerve cells after a stroke has been discovered at Lund University and Karolinska Institutet in Sweden. The findings have been published in the journal Science.

A stroke is caused by a blood clot blocking a blood vessel in the brain, which leads to an interruption of blood flow and therefore a shortage of oxygen. Many nerve cells die, resulting in motor, sensory and cognitive problems.

The researchers have shown that following an induced stroke in mice, support cells, so-called astrocytes, start to form nerve cells in the injured part of the brain. Using genetic methods to map the fate of the cells, the scientists could demonstrate that astrocytes in this area formed immature nerve cells, which then developed into mature nerve cells.

"This is the first time that astrocytes have been shown to have the capacity to start a process that leads to the generation of new nerve cells after a stroke," says Zaal Kokaia, Professor of Experimental Medical Research at Lund University.

The scientists could also identify the signalling mechanism that regulates the conversion of the astrocytes to nerve cells. In a healthy brain, this signalling mechanism is active and inhibits the conversion, and, consequently, the astrocytes do not generate nerve cells. Following a stroke, the signalling mechanism is suppressed and astrocytes can start the process of generating new cells.

"Interestingly, even when we blocked the signalling mechanism in mice not subjected to a stroke, the astrocytes formed new nerve cells," says Zaal Kokaia.

"This indicates that it is not only a stroke that can activate the latent process in astrocytes. Therefore, the mechanism is a potentially useful target for the production of new nerve cells, when replacing dead cells following other brain diseases or damage."

The new nerve cells were found to form specialized contacts with other cells. It remains to be shown whether the nerve cells are functional and to what extent they contribute to the spontaneous recovery that is observed in a majority of experimental animals and patients after a stroke.

A decade ago, Kokaia's and Lindvall's research group was the first to show that stroke leads to the formation of new nerve cells from the adult brain's own neural stem cells. The new findings further underscore that when the adult brain suffers a major blow such as a stroke, it makes a strong effort to repair itself using a variety of mechanisms.

The major advancement with the new study is that it demonstrates for the first time that self-repair in the adult brain involves astrocytes entering a process by which they change their identity to nerve cells.

"One of the major tasks now is to explore whether astrocytes are also converted to neurons in the human brain following damage or disease. Interestingly, it is known that in the healthy human brain, new nerve cells are formed in the striatum. The new data raise the possibility that some of these nerve cells derive from local astrocytes. If the new mechanism also operates in the human brain and can be potentiated, this could become of clinical importance not only for stroke patients, but also for replacing neurons which have died, thus restoring function in patients with other disorders such as Parkinson's disease and Huntington's disease," says Olle Lindvall, Senior Professor of Neurology.

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Story Source:

The above story is based on materials provided by Lund University. Note: Materials may be edited for content and length.

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Journal Reference:

1. J. P. Magnusson, C. Goritz, J. Tatarishvili, D. O. Dias, E. M. K. Smith, O. Lindvall, Z. Kokaia, J. Frisen. A latent neurogenic program in astrocytes regulated by Notch signaling in the mouse. Science, 2014; 346 (6206): 237 DOI: 10.1126/science.346.6206.237

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Intracranial stents: More strokes than with drug treatment alone

 

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The risk of having another stroke is higher if patients, after dilation of their blood vessels in the brain, not only receive clot-inhibiting drugs, but also have small tubes called stents inserted. However, studies have provided no hint of a benefit from stenting, which is also referred to with the abbreviation "PTAS." This is the conclusion reached in the rapid report of the German Institute for Quality and Efficiency in Health Care (IQWiG), as published on 9 October 2014.

Stents are supposed to prevent restenosis

Blood vessels in the brain that are narrowed or blocked can cause stroke. If patients have already had a stroke or temporary ischaemia (transient ischaemic attack, TIA), there is a high risk that this occurs again. These patients therefore receive drugs that prevent blood clotting. Another option is to additionally widen the narrowed vessels.

Nowadays this is often done using a small balloon in a procedure known as percutaneous transluminal angioplasty (PTA). But even after PTA and simultaneous blood-thinning medication, vessels often remain narrow (stenosis) or new narrowing occurs (restenosis). The treatment has therefore been expanded to include stenting (percutaneous transluminal angioplasty and stenting, PTAS): Small wire mesh tubes are inserted to support the widened blood vessels and prevent restenosis. This stenting has been available for approximately 10 years.

Compare PTAS with treatment alternatives

The Federal Joint Committee (G-BA) had commissioned IQWiG to assess the benefit of PTAS for patients with symptoms of narrowed blood vessels in the brain (symptomatic intracranial stenosis). PTAS was to be compared with drug treatment with blood-thinning medications alone and with balloon dilatation without stenting (PTA). Like PTAS, PTA always involves administration of blood-thinning drugs.

Four studies identified

IQWiG identified a total of four randomized controlled trials (RCTs) that included patients with symptomatic intracranial stenosis. In three studies, PTAS was compared with drug treatment alone. One study tested PTAS versus PTA.

One relevant study on PTAS versus medication alone

The SAMMPRIS study was relevant for the assessment of PTAS in comparison with drug treatment alone. SAMMPRIS included a total of 451 participants and is the largest study currently available. It is also the only study to provide data both on mortality and side effects and on stroke in all areas of the brain.

The two other studies (Miao 2012 and Gao 2013) only reported strokes that occurred in the territory of the treated vessels. However, it is relevant for the patients whether strokes occur at all -- irrespective of their localization. Hence only data from the SAMMPRIS study were available for the outcome "stroke" as well.

Lack of data for important outcomes

Besides mortality (all-cause mortality and from stroke), the burden of disease in the form of stroke, TIA, and other physical or psychological impairments from ischaemia, the patient-relevant outcomes of this assessment also include side effects (e.g. bleeding events or myocardial infarction) and dependence on others or requiring care. However, these were not fully reported in any of the studies. None of the four studies provided results on further criteria that are important for patients such as health-related quality of life, hospitalization or physical endurance.

Considerably more strokes in temporal proximity to the intervention

As the SAMMPRIS data showed, a new stroke is considerably more common in patients who have received an intracranial stent than in patients who only received medication: This was the case in 59 participants (26.3%) in the PTAS group, and in only 42 participants (18.5%) in the comparator group.

Differentiated by type of stroke, these differences can be determined in haemorrhagic stroke, i.e. stroke caused by bleeding, but not in ischaemic stroke, which is caused by narrowing. The haemorrhagic strokes were often periprocedural events occurring within 30 days of the intervention. In many cases, these strokes were apparently caused by mechanical manipulation during the placement of the stent.

No differences in morbidity and revascularization

These disadvantages are not accompanied by advantages in other outcomes: There was no relevant difference between the treatment groups in mortality (all-cause mortality and cerebrovascular mortality). The IQWiG report came to the same conclusion with regard to repeated revascularization, i.e. the necessity to widen narrowed vessels again.

Results potentially biased

All the studies included by IQWiG were subject to uncertainty and their results might be biased. The main reasons were unclear issues regarding randomization and the premature unplanned termination of the studies.

This is also true for SAMMPRIS, which started in November 2008, but was ended prematurely in April 2011 because considerably more events (counting deaths and strokes) had occurred in the PTAS group. Even though this decision is comprehensible, the results can be biased because of the premature termination of the study.

Despite the uncertainty described, IQWiG overall considers there to be a hint of harm from PTAS in comparison with drug treatment alone.

Drugs were not used in compliance with their approval

The interpretation of the SAMMPRIS results was made more difficult because the drugs were not used according to the specifications in the Summary of Product Characteristics valid in Germany: The patients in both groups received a combination of two clot-inhibiting drugs, acetylsalicylic acid (ASA) and clopidogrel (dual antiplatelet therapy). This combination is used in Germany, but is not approved for stroke because it is known to increase the risk of bleeding. It can also not be excluded that there is an interaction between the drugs and stent placement (PTAS), which particularly might influence the occurrence of bleeding.

RCTs indispensable in medical devices as well

PTAS is another example that high-quality studies are needed for risk class III medical devices, which also include stents: In the United States, intracranial stents had at first been approved for treatment of a specific, relatively small group of fewer than 4000 patients affected. This approval was based on case series and on the Humanitarian Device Exemption. However, Medicare, an American health insurance for elderly and disabled people, then demanded an RCT as prerequisite for its reimbursement of stents.

So the SAMMPRIS study, funded by the National Institutes of Health, was initiated. Only this RCT, i.e. a study with a higher level of evidence, revealed that more strokes occurred under the new, allegedly innovative Treatment.

Product safety is not the same as patient safety

This confirmed the conclusion already drawn in the case of antibody-coated stents inserted in coronary vessels: Not only the medical device is decisive, but also its manner of application. "The entire application including its accompanying factors has to be investigated, and not only the stents themselves, to obtain reliable knowledge about the benefit stents have for patients," concludes Stefan Sauerland, Head of the IQWiG Department of Non-Drug Interventions.

Executive Summary of the Rapid Report is available at: https://www.iqwig.de/download/N14-01_Executive-summary_Intracranial-stents.pdf

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Story Source:

The above story is based on materials provided by Institute for Quality and Efficiency in Health Care. Note: Materials may be edited for content and length.

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7 Habits to Prevent a Stroke

 

RunPhoto/Stone/Getty Images

Updated September 24, 2014.
Written or reviewed by a board-certified physician. See About.com's Medical Review Board.

A stroke can be a devastating event with serious long-term consequences. Advances in stroke treatment have made the long term outcome for stroke patients better. However, there is often a short window of time for effective treatment. One important approach to stroke care includes prevention, especially for people who are at risk. Not every stroke is preventable but there are some known preventable risk factors that can be modified with lifestyle habits. It is helpful to know some of the controllable causes of stroke and to learn how to control them.

1. Lower high blood pressure

Hypertension is chronic high blood pressure. It raises the risk of stroke and it also contributes to the development of heart disease and cerebrovascular disease- 2 well-known stroke risk factors. The first step in effective management of hypertension requires diagnosis through regular blood pressure screenings. Treatment of hypertension can include a diet low in salt, weight management, regular exercise or stress control. Sometimes medication to lower blood pressure is required. Your doctor can advise you on the best approaches for you when it comes to maintaining a normal blood pressure.

2. Control heart disease

Heart disease can be present at birth. It may occur later in life due to hereditary. Heart disease can develop a result of hypertension, obesity, diabetes or high cholesterol. Heart disease can include coronary artery disease (disease of the blood vessels that supply the heart), heart valve problems, heart muscle problems, an enlarged heart or an irregular heartbeat. There are many effective ways to diagnose and treat heart disease, depending on the cause. As with hypertension, the best approach is to have regular check ups with your doctor to detect problems early before they progress.

3. Lower high cholesterol

High cholesterol contributes to heart disease and cerebrovascular disease. It is usually the result of a diet high in unhealthy kinds of fat. Lowering cholesterol requires a diet with moderate fat intake, moderate exercise and sometimes medication.

4. Control diabetes

Diabetes can contribute to cardiovascular disease and cerebrovascular disease. Diabetes is a disorder of blood sugar metabolism. Diabetes may be inborn or acquired. People with type 1 diabetes require close management of blood sugar levels, usually with insulin treatment. People with type 2 diabetes require management of food intake, weight management and sometimes medication to maintain desirable levels of blood sugar.

5. Manage obesity

Obesity is also a risk factor for stroke. It can contribute to hypertension and high cholesterol. Obesity is often managed by diet and exercise. Sometimes, weight loss supplements or surgical procedures for weight loss can help when it is difficult to lose weight with diet and exercise alone. Genetics play a role in obesity as some people are more predisposed to being overweight than others, making weight loss a bigger challenge.

6. Stop smoking

Smoking contributes to heart disease, cerebrovascular disease and hypertension. Smoking can be a difficult habit to break. Different approaches, including behavioral control, counseling, support groups, nicotine patches and smoking cessation programs can be used to help quit smoking. Research shows that many of the harmful effects of smoking can be reversed over time when smoking is discontinued. Often, smoking cessation is more successful when guided by a trained health care professional.

7. Manage stress

Stress can contribute to stroke risk by contributing to hypertension, heart disease, diabetes and cerebrovascular disease. Management of stress and anxiety often involves a comprehensive approach to behavior and emotional responses. Stress is not objectively measurable and requires a long term approach for optimal control

Other less common causes of stroke may be more complex such as autoimmune disease and blood clotting disorders. These medical problems require long-term close medical management by a physician.

Stroke Patients Lose Month for Each 15-Minute Delay

 

By Jason Gale Mar 14, 2014 1:38 AM GMT-0300

Photographer: Jason Gale/Bloomberg

Stroke survivor Diane Barbeler, left, with neurologist Atte Meretoja at the Royal Melbourne Hospital.

Diane Barbeler had a stroke on Monday last week. The next day, she walked out of the hospital with only minor sensory changes in her right hand and foot.

Barbeler owes her quick recovery to the tissue plasminogen activator, or tPA, that she received within 3 hours of losing strength and control in her lower limb, says Atte Meretoja, a neurologist who helped diagnose her stroke at Australia’s Royal Melbourne Hospital. Patients like Barbeler, 66, gain a month of disability-free life for every 15 minutes saved in getting the clot-busting drug, according to research by Meretoja and colleagues published today in the journal Stroke.

By quantifying the importance of speed, Meretoja and collaborators in Australia, Finland and the U.S. aim to inspire medical services to improve response time. The world’s fastest stroke services in Helsinki and Melbourne take an average of 20 minutes from the patient’s arrival at the hospital to start tPA treatment, Meretoja said. Most other centers in Australia, the U.S. and Europe take 70 to 80 minutes.

“The main delay in stroke is due to people not calling for help,” said Meretoja, the lead author of the study and an associate professor of medicine at the University of Melbourne. “We have now demonstrated that this is very harmful, and people lose on average a month of life for every 15 minutes they wait at home hoping that the symptoms will go away.”

 

Brain Death

Stroke is the fourth-most common cause of death in the U.S., and the leading cause of adult disability. It occurs when blood flow to the brain stops, according to the U.S. National Institutes of Health. Brain cells begin to die within minutes. Ischemic stroke, which accounts for about 87 percent of cases, is caused by a blood clot, while hemorrhagic stroke is caused by a blood vessel that breaks and bleeds into the brain.

Symptoms of stroke include sudden numbness of the leg, arm or face, confusion, problems with vision, abrupt severe headache, dizziness, loss of balance or trouble walking. The American Stroke Association advises people to call emergency medical services immediately if someone shows any of these symptoms.

Barbeler, who describes herself as a fit and active recent retiree, stood upright after leaning down to pick vegetables in her garden when she felt heaviness in her right foot, along with a loss of sensation and control, she said.

“I couldn’t tell my foot to move,” she said. “I could lift my foot, but I couldn’t tell where I was putting it. Then, my hand was a bit numb. ‘Have I pinched something in my neck?’ was my first thought.”

With help from her husband, Christopher, Barbeler returned to her house and finished a cup of tea while contemplating the cause of her sudden illness, she said. Meanwhile, Christopher called her family doctor’s office for advice.

 

Call For Ambulance

“The nurse told him to call for an ambulance immediately,” Barbeler recalled in an interview yesterday. She was taken directly to the Royal Melbourne Hospital, where doctors used computerized tomography, or CT, images of her brain to rule out causes other than stroke for her symptoms, which had worsened slightly en route from her home in Lauriston, a small town about 100 kilometers (62 miles) north of Melbourne.

Subsequent, more detailed images identified a small offending clot, Meretoja said.

“Because the symptoms were milder than usual, we had to make sure there was something to treat because the treatment isn’t risk-free,” he said. “A few percent of patients will get a bleed because of the treatment.”

 

Time Is Brain

TPA should be given within 4 1/2 hours of the onset of stroke symptoms, according to the American Stroke Association. Speeding treatment by just 1 minute means another 1.8 days of healthy life, today’s study found.

While it’s not possible to predict what the outcome would have been had Barbeler not received the tPA within hours of the onset of her stroke, it’s likely the damage caused by a lack of oxygen to a small part of her brain would have resulted in “trouble walking for a long time,” Meretoja said. There would have also been a risk that the clot could have progressed to cause a greater blood-oxygen deficit.

His research shows that, although all patients benefit from faster treatment, younger patients with longer life expectancies gained more than older patients. The average age of Meretoja’s stroke patients is 75 years.

Today’s study by scientists at the University of Melbourne’s Florey Institute of Neuroscience and Mental Health, Helsinki University Central Hospital and the University of California, Los Angeles Stroke Center, is based on evidence from trials of clot-busting drugs that was applied to 2,258 stroke patients in Australia and Finland to calculate what the patient outcomes would have been if they had been treated faster or slower.

 

Helsinki Model

“Until now, we have always known it’s important to treat the patients quickly, but we have never known how important it is,” said Meretoja, 38, who has been studying stroke and treating patients with the condition for 15 years, mostly in Helsinki, where treatment times are the shortest.

Ten days after her stroke, Barbeler says her hand has a “sense of feeling fatter” and her foot, which turns in slightly when she walks, feels as though its tendons are shorter. The symptoms should gradually fade as areas of her brain unaffected by the stroke begin to compensate, Meretoja said.

Relieved to have avoided weeks of rehabilitation and the possibility of permanent disability, the former professional opera singer and information technology consultant is keen to tell others to heed the signs of stroke, which don’t always include dizziness and pain -- symptoms she’d assumed were indicative of stroke.

“They’re the things I had no idea about,” she said. “I had no pain at any stage through this.”

To contact the reporter on this story: Jason Gale in Melbourne at j.gale@bloomberg.net

To contact the editors responsible for this story: Anjali Cordeiro at acordeiro2@bloomberg.net Terje Langeland, Jason Gale