Exercise for Restless Legs Syndrome

There is not a lot known if doing exercises is really that beneficial for restless legs syndrome and if it is useful, just what sort and type of exercises should be used.

Three people walking in a park, getting some exercise

I just came across this clinical trial in which they are going to study exercise in restless legs syndrome. I look forward to see the results of the study.

Summary of the study:

Restless leg syndrome (RLS) is a very common neurological condition characterized by an uncontrollable desire to move the legs. Due to the traumatic effect of RLS on morbidity, the patient is negatively affected in many different directions. The duration and quality of sleep of the patients decrease, and their cognitive functions change. The prevalence or risk of anxiety and depression increases in this population. At the same time, the quality of life of patients is significantly reduced. Among the different pharmacological agents used in RLS, dopamine agonists are the most widely used. However, the reporting of serious and common side effects related to this treatment has led to non-pharmacological approaches in the treatment of RLS and the effectiveness of many different approaches has been investigated. The exercise approach, which is determined to be effective in the treatment of the disease, is a subject that has been little studied. The type, duration and frequency of optimal exercise could not be standardized. In addition, the effect of exercise on RLS patients has been investigated in limited subjects. For this reason, the aim of our study is to examine the effect of different exercise programs on symptoms, sleep, cognitive functions, quality of life, psychological status and fatigue in patients with RLS.

Novel Treatment Method for Restless Legs

Clemens, along with associate professor Kori Brewer, examine a mouse’s spinal column in their lab at the Brody School of Medicine. Clemens’ work with mouse models was essential in helping him develop his Restless Legs Syndrome treatment.

Media Release:

An East Carolina University faculty member’s latest patent may change the way Restless Legs Syndrome (RLS) is treated, leading to more effective care over a longer period of time for patients.

Stefan Clemens, an associate professor in the Brody School of Medicine’s Department of Physiology, was awarded U.S. Patent 10,751,327 on Aug. 25 for his novel treatment method for the treatment of RLS.

Restless Legs Syndrome is a nervous system disorder that affects between 5% and 8% of the population in the United States. Those suffering from RLS experience an uncontrollable urge to move their legs caused by an unpleasant sensation. While the exact cause of RLS is still unknown, the syndrome is typically treated with dopaminergic drugs — medications that replace or prevent the loss of dopamine — that have a high initial effect but over time lose their effectiveness.

“The problem is that patients on these dopaminergics eventually develop a side effect called augmentation,” Clemens said. “Their symptoms get worse while taking the current medication used for treatment.”

Classic RLS treatments act on a dopamine receptor known as D3 that has a suppressive effect in the nervous system. However, Clemens’ lab has shown in animal models that over time this medication leads to an increase of a different, excitatory receptor subtype, D1. This increase of the D1 receptor might be the cause of augmentation.

Clemens’ patent proposes a new treatment method that targets the increased D1 receptor levels in RLS patients suffering from augmentation, leading to reduced activation of D1 receptors while providing traditional therapy relief from RLS.

“Our lab postulates that this new compound will maintain long-term efficacy for RLS,” Clemens said. “If augmentation begins, we predict that we can reduce D1 receptor activation in patients and balance things back out, keeping the treatment effective.”

Clemens was awarded a grant from the North Carolina Biotechnology Center to run a small pilot study with a collaborator from the University of Houston using this new treatment method.

This work has gained the attention of a company that has interest in establishing a partnership where ECU’s patent rights may be used in combination with its existing drug formulation to bring relief to RLS patients suffering from augmentation.

Clemens added that the idea to apply for a patent came from ECU’s Office of Licensing and Commercialization.

“They not only brought the idea of patenting our research to my attention, but they also helped me through the process and handled all of the legal and technical aspects of filing a patent,” he said. “The patent would not have been issued without their help. I now know that it can be very beneficial to have experts in other areas come from different angles that make us think of other ways to use our work.”

Marti Van Scott, director of licensing and commercialization, said that finding commercialization opportunities for faculty research is an important bridge that brings science into the communities the university serves.

“It is a pleasure to work alongside our faculty to identify translational research opportunities that have potential to make a meaningful impact,” Van Scott said. “Licensing and commercialization works hard to identify skilled development partners to offer essential guidance for these translational activities. Whether it’s a new therapeutic or medical device, teaching or training method, or research tool, we are available to support the campus research and innovation ecosystem.”

While Clemens’ lab continues to work on its RLS treatment, Clemens said he’s also continuing to work on other medical treatments, including care for opioid pain tolerance.

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Suicide and self-harm risk nearly triple in people with restless leg syndrome

Press release

Restless legs syndrome was associated with a nearly tripled risk of suicide and self-harm in a new study led by Penn State researchers.

Using Big Data, the researchers found that people with restless legs syndrome (RLS) had a 2.7- fold higher risk of suicide or self-harm, even when the researchers controlled for such conditions as depression, insomnia, diabetes and others.

The study was published today (Aug. 23) in the Journal of the American Medical Association (JAMA) Network Open.

Xiang Gao, associate professor of nutritional sciences and director of the Nutritional Epidemiology Lab at Penn State, said that as suicide rates rise in the United States, the findings suggest that physicians should pay special attention to the mental health of patients with RLS.

“Our study suggests that restless legs syndrome isn’t just connected to physical conditions, but to mental health, as well,” Gao said. “And, with RLS being under-diagnosed and suicide rates rising, this connection is going to be more and more important. Clinicians may want to be careful when they’re screening patients both for RLS and suicide risk.”

According to the researchers, RLS affects approximately five percent of the U.S. population, causing an uncomfortable feeling in a person’s legs resulting in the urge to move them, often during the night. While the exact cause of RLS is unknown, previous research has found an association between RLS and iron deficiency, as well as low levels of dopamine in the brain.

Gao said that while RLS has been linked with a higher chance of mortality in the past, scientists do not know why. Previous research has found associations between RLS and a greater risk for hypertension or heart attack, suggesting a possible cardiovascular component. But, some studies have also found links between RLS and depression and thoughts of suicide.

“I’ve wanted to explore a potential connection between RLS and suicide for more than 10 years, but because both RLS and suicide rates are low from a data perspective, it wasn’t possible,” Gao said. “But, when I moved here to Penn State, I gained access to a data set with more than 200 million people, so it gave us power to finally test this hypothesis.”

The researchers used data from the Truven Health MarketScan national claims from 2006 to 2014, including 24,179 people who had been diagnosed with RLS and 145,194 people who did not have RLS. All participants were free of suicide and self-harm at the baseline of the study.

After analyzing the data, the researchers found that people who had restless leg syndrome had a 270 percent higher chance of suicide or self-harm than people who did not. The risk did not decrease even when the researchers controlled for such factors as depression, sleep disorders and common chronic diseases.

“After controlling for these factors, we still didn’t see the association decrease, meaning RLS could still be an independent variable contributing to suicide and self-harm,” said Muzi Na, Broadhurst Career Development Professor for the Study of Health Promotion and Disease Prevention at Penn State. “We still don’t know the exact reason, but our results can help shape future research to learn more about the mechanism.”

In the future, the researchers said additional studies will need to be done to replicate and confirm the findings.

Breakthrough in treatment of restless legs syndrome

Press release:

New research published in the Journal of Physiology presents a breakthrough in the treatment of Restless Legs Syndrome (RLS).

RLS is a common condition of the nervous system that causes an overwhelming irresistible urge to move the legs. Patients complain of unpleasant symptoms such as tingling, burning and painful cramping sensations in the leg. More than 80% of people with RLS experience their legs jerking or twitching uncontrollably, usually at night.

Until now it was thought that RLS is caused by genetic, metabolic and central nervous system mechanisms. For the first time the researchers show that, in fact, it is not only the central nervous system but also the nerve cells targeting the muscles themselves that are responsible.

This new research indicates that the involuntary leg movements in RLS are caused by increased excitability of the nerve cells that supply the muscles in the leg, which results in an increased number of signals being sent between nerve cells.

Targeting the way messages are sent between nerve cells to reduce the number of messages to normal levels may help prevent the symptoms of RLS occurring. This could be achieved by new drugs that block the ion channels that are essential for the communication between nerve cells.

The research conducted by the University of Gottingen in conjunction with the University of Sydney and Vanderbilt University involved measuring the nerve excitability of motor nerve cells of patients suffering with RLS and healthy subjects.

The next step is to investigate the effect of different medications in patients and the effect on RLS.

Dirk Czesnik, corresponding author of the study, commented on the findings:

‘Patients who suffer from Restless legs syndrome complain of painful symptoms in the legs leading to sleep disturbances. The mechanisms for RLS are still not completely understood. We have shown that also the nerve cells supplying muscles in the leg are responsible and hereby additional drug treatments may be ahead targeting these nerve cells.’

Restless legs syndrome brain stimulation study supports motor cortex ‘excitability’ as a cause

Press release:

Johns Hopkins Medicine researchers say new experiments using magnetic pulse brain stimulation on people with moderate to severe restless legs syndrome (RLS) have added to evidence that the condition is due to excitability and hyperarousal in the part of the brain’s motor cortex responsible for leg movement.

The researchers say their findings, published online in Sleep Medicine on May 31, may help devise safer, more effective ways to treat RLS and the chronic sleep deprivation it causes, using electrical or magnetic pulses to calm or interrupt the hyperarousal. Some 10 percent of adults in the U.S. experience RLS at one time or another, and about 1 in 500 report that the condition is severe and chronic enough to interfere with their quality of life, work productivity or mental health, according to the National Sleep Foundation.

People with severe RLS describe symptoms of the condition as an overwhelming urge to move their legs when they are at rest. They may feel pain, or the sensation of soda bubbles in their veins or worms crawling in their legs, with relief coming only when standing or deliberately moving their legs. Long-term effects include fatigue, anxiety and depression, much of it linked to repeated interruption of sound sleep. Standard treatments, which may carry significant side effects, include medications that behave like the neurotransmitter dopamine, opioids and anti-seizure drugs.

Although many conditions, such as kidney disease and diabetes, have been associated with RLS, the neurological roots of the condition have been subject to much debate.

The new study, the Johns Hopkins researchers say, supports the idea that the underlying mechanism for RLS rests in the brain’s “move my legs” center and makes even more sense of the relief those with RLS experience when they get up and move them.

“Essentially the brain sends the signal when it’s preparing to move a limb, even when you aren’t planning to move, so your body is ready and amped up,” says Richard Allen, Ph.D., professor of neurology at the Johns Hopkins University School of Medicine. “The only way to alleviate the feeling is to move.”

In the new study, the researchers identified 32 adults with a moderate to severe RLS diagnosis from patients and asked them to stop their treatments for 12 days. They recruited 31 adult matched controls with no history of RLS or other sleep disorders and healthy sleeping patterns as controls. Participants in both groups were an average age of 58, and 59 percent were women.

For the experiments, the researchers used transcranial magnetic stimulation (TMS) to apply safe pulses able to selectively stimulate various regions of the brain that control movement of the muscles in the hand or the leg. They then used electrodes attached to the hand or leg to measure muscle responses in that hand or leg during such stimulations in those with RLS and in the control group.

Pairing two pulses as a stimulus can either cause a reaction or suppress/inhibit a reaction in a muscle depending on the timing between the two pulses. The researchers looked at one type of excitatory paired pulses and two types of inhibitory pulses¾short- and long-interval ones.

For each analysis, the researchers took the ratio of the responses. The ratios were greater in the leg for those with RLS, at 0.36 compared with 0.07 for those people without RLS, when looking at the inhibitory long-interval pulses, but not with the short-interval pulses. They said they didn’t see a difference in excitatory pulses in the legs.

“This basically means that inhibition is reduced or weakened in people with restless legs syndrome compared to people without the condition,” says Rachel Salas, M.D., associate professor of neurology at Johns Hopkins. “The reduced response means that the region of the brain controlling the legs shows increased cortical excitability in the motor cortex.”

In a separate set of experiments measuring the effect of paired pulses given to the brain in the region that controls the hand, they found no real differences in the ratios of either of the inhibitory pulses¾short- or long-interval ones¾between people with RLS and those without the condition.

But the researchers say they did find that the ratios picked up from the hand muscles using excitatory pulses were lower, at 1.01 compared with controls with a ratio of 1.85.

“The measurements from the hand muscles show that the activity in the brain is reduced in the region that controls the hand in people with restless legs syndrome compared to controls,” says Salas.

Salas says that previous research shows that inhibitory pulses are associated with the action of the neurotransmitter GABA, a brain chemical typically known for tamping down activity in the brain’s neurons. The researchers say that since there is hyperactivity in the leg-controlling portion of the brain, it’s possible that cells and tissues there are lacking enough GABA to prevent hyperactivity.

“Other studies with TMS have been done on people with RLS, but they didn’t look at people with severe forms of the condition or at the long-interval paired pulses in the leg,” says Salas. “We are fortunate to have access to such individuals because the Johns Hopkins Sleep Center attracts people worldwide and many who have exhausted treatment options available elsewhere,” she adds.

Salas notes that medications that act like the neurotransmitter dopamine, such as ropinirole or pramipexole, work in the short term but can exacerbate the condition over time. Opioids are effective, but not ideal due to their risk for dependency. With the results of this new study, the researchers are hoping to use electrical stimulation to suppress the brain’s activity, and planning of these studies is in the works.

High levels of rare gut bacteria may be linked to restless legs syndrome

Press release:

SAN ANTONIO – Small intestine bacterial overgrowth (SIBO) may be more prevalent among patients with restless legs syndrome (RLS), according to preliminary findings from a small, new study.

Results show that SIBO was found in all seven participants who have RLS. In contrast, the prevalence of SIBO in the general population is estimated to be no more than 15%.

“We’ve observed extremely high rates of small intestinal bacterial overgrowth in the RLS group,” said lead author Daniel Jin Blum, Ph.D., D.B.S.M., an adjunct clinical instructor at Stanford Center for Sleep Sciences and Medicine in Redwood City, California. “Exploring the relationship between RLS and gut microbial health has the potential to open novel avenues for possible detection, prevention and treatment for RLS and other sleep disorders.”

SIBO is a condition in which rare gut-residing bacteria are over-represented in the gut. RLS is a sensorimotor disorder characterized by a complaint of a strong, nearly irresistible urge to move the limbs that is often accompanied by other uncomfortable sensations. These symptoms begin or worsen during periods of rest or inactivity such as lying down or sitting, are partially or totally relieved by movement such as walking or stretching, and occur exclusively or predominantly in the evening or at night.

Low iron in the brain is a key risk factor for RLS. According to the authors, this brain iron deficiency may be secondary to dietary iron deficiency or, potentially, gut inflammation.

Study participants completed questionnaires concerning sleep and SIBO symptoms and took home a fecal collection kit and a SIBO breath test kit. Fecal samples were examined by the University of Minnesota Genomics Center, and SIBO breath samples were evaluated by Aerodiagnostics for hydrogen and methane abnormalities.

Additional study participants continue to be recruited at the Stanford Sleep Center. Further analyses will examine fecal microbial composition, subtypes of RLS iron deficiency, and comparisons with insomnia.

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The research abstract was published recently in an online supplement of the journal Sleep and will be presented Sunday, June 9, in San Antonio at SLEEP 2019, the 33rd annual meeting of the Associated Professional Sleep Societies LLC (APSS), which is a joint venture of the American Academy of Sleep Medicine and the Sleep Research Society.

This study was funded by a Pau Innovation Gift Fund Seed Grant.

Abstract Title: Restless Leg Syndrome: Does It Start With A Gut Feeling?

Brain structure linked to symptoms of restless legs syndrome

Press release:

MINNEAPOLIS – People with restless legs syndrome may have changes in a portion of the brain that processes sensory information, according to a study published in the April 25, 2018, online issue of Neurology®, the medical journal of the American Academy of Neurology.

Restless legs syndrome is a disorder that causes uncomfortable sensations in the legs, accompanied by an irresistible urge to move them. It often occurs in the evening and at night, sometimes affecting a person’s ability to sleep. In some cases, exercise may reduce symptoms. Iron supplements may also be prescribed if there is an iron deficiency. For more serious cases, there are also medications, but many have serious side effects if taken too long.

“Our study, which we believe is the first to show changes in the sensory system with restless legs syndrome, found evidence of structural changes in the brain’s somatosensory cortex, the area where sensations are processed,” said study author Byeong-Yeul Lee, PhD, of the University of Minnesota in Minneapolis. “It is likely that symptoms may be related to the pathological changes in this area of the brain.”

The brain’s somatosensory cortex is part of the body’s somatosensory system, which is made up of nerves and pathways that react to changes either inside or outside the body. This system helps a person perceive touch, temperature, pain, movement and position.

The study involved 28 people with severe restless legs symptoms who had the disorder for an average of 13 years. They were compared to 51 people of the same age without the disorder. Each participant had a brain scan with magnetic resonance imaging (MRI).

Researchers found that people with restless legs syndrome had a 7.5 percent decrease in the average thickness of brain tissue in the area of the brain that processes sensations compared to the healthy participants. They also found a substantial decrease in the area of the brain where nerve fibers connect one side of the brain to the other.

Lee said, “These structural changes make it even more convincing that RLS symptoms are stemming from unique changes in the brain and provide a new area of focus to understand the syndrome and possibly develop new therapies.”

He said while the study shows a possible link between symptoms and the areas of the brain that process sensory information, it is possible that symptoms may instead be linked to impaired function in other parts of the sensory system.

Restless sleep may be an early sign of Parkinson’s disease

Press release:

Researchers from Aarhus University have discovered that patients with the RBD sleep behaviour disorder lack dopamine and have a form of inflammation of the brain. This means that they are at risk of developing Parkinson’s disease or dementia when they grow older.

Do you sleep restlessly and hit out and kick in your sleep? This could be a sign of a disorder associated with diseases of the brain. Researchers from Aarhus University have studied the condition of the dopamine producing nerve cells in the brain and cells that participate in the brain’s immune system in people suffering from the sleep disorder Rapid eye movement sleep behaviour disorder, RBD.

The study shows that patients suffering from RBD have a risk of developing Parkinson’s disease or dementia in the future, because they already suffer from a lack of dopamine in the brain. Parkinson’s disease occurs precisely because the group of nerve cells in the brain that produce dopamine stop working.

The RBD sleep disorder is characterised by disturbances in the part of sleep where dreams take place. Healthy people are relaxed and lie still during dream sleep, while people suffering from RBD live out their dreams so that while sleeping they can hit out, kick and shout.

“These patients have an inflammation of the brain in the area where the dopamine-producing nerve cells are found,” says one of the researchers behind the study, Morten Gersel Stokholm from Aarhus University and the PET Centre at Aarhus University Hospital.

The findings have just been published in the neurological journal The Lancet Neurology.

This is completely new knowledge, as researchers have not previously demonstrated that there is a form of inflammation of the brain in patients who are at risk of developing Parkinson’s disease.

“With this study, we have gained new knowledge about the disease processes in the brain in the early initial stages of the disease development. The idea is for this knowledge to be used to determine which patients with the sleep disorder will later develop Parkinson’s disease. At the same time, this is also knowledge that can help to develop drugs which can stop or slow the development of the diseases,” explains Morten Gersel Stokholm about the sleep disorder which most often affects persons aged 50-70, and more frequently men than women.

Parkinson’s disease

There are 7,300 Parkinson’s disease patients in Denmark. Symptoms are slow movements, often with shaking, together with muscular rigidity. Parkinson’s disease is a chronic condition that continues to worsen over time. The disease is somewhat more common in men than in women. Parkinson’s disease occurs because the brain lacks dopamine. It is primarily adults who are affected, and the first signs most often appear between the ages of 50-70.

Background for the results:

The study is a case-control study.

The people behind the project are Medical Doctor and PhD student Morten Gersel Stokholm and Associate Professor, MD, Nicola Pavese in collaboration with medical doctors from the Department of Neurology and the Sleep Clinic, Aarhus University Hospital and medical doctors from the University Hospital Clinic de Barcelona.

Restless legs syndrome study identifies 13 new genetic risk variants

Press release:

A new study into the genetics underlying restless legs syndrome has identified 13 previously-unknown genetic risk variants, while helping inform potential new treatment options for the condition.

As many as one in ten people of European ancestry is affected by restless legs syndrome, in which sufferers feel an overwhelming urge to move, often in conjunction with unpleasant sensations, usually in the legs. Rest and inactivity provoke the symptoms, whereas movement can lead to temporary relief. The condition is chronic and can get progressively worse, with long-lasting effects on patients’ mental and physical health. People with restless legs syndrome have substantially impaired sleep, reduced overall quality of life, and increased risk of depression, anxiety disorders, hypertension, and, possibly, cardiovascular disease.

For around one in 50 people, the condition can be severe enough to require chronic medication, which may in turn have potentially serious side effects.

Studies of families and twins have shown that there is a strong genetic component to the disorder and led to the discovery of six genetic variants that increased the risk of developing the condition.

“We have studied the genetics of restless legs syndrome for more than 10 years and the current study is the largest conducted so far,” says Dr Barbara Schormair from the Institute of Neurogenomics at the Helmholtz Zentrum München, first author of the study. “We are convinced that the newly discovered risk loci will contribute substantially to our understanding of the causal biology of the disease.”

Now, an international team of researchers has compared the genetic data from over 15,000 patients with more than 95,000 controls, and identified a further 13 genetic risk variants. The findings were then replicated in a sample of 31,000 patients and 287,000 controls. The results are published in Lancet Neurology.

“Restless legs syndrome is surprisingly common, but despite this, we know little about what causes it – and hence how to treat it,” says Dr Steven Bell from the Department of Public Health and Primary Care at the University of Cambridge, also one of the first authors on the study. “We already know that it has a strong genetic link, and this was something we wanted to explore in more detail.”

Several of the genetic variants have previously been linked to the growth and development of nerve cells – a process known as neurogenesis – and to changes in the formation of neuronal circuits. These findings strengthen the case for restless legs syndrome being a neurodevelopmental disorder whose origins may go back to development in the womb as well as impaired nerve cell growth in later life.

“The genetic risk variants that we’ve discovered add more weight to the idea that this condition is related to the development of our nervous system,” says Dr Emanuele Di Angelantonio, also from the Department of Public Health and Primary Care. “It also gives us some clues to how we may treat patients affected by the condition.”

Prof Juliane Winkelmann, who heads the Institute of Neurogenomics at the Helmholtz Zentrum as well as a restless legs syndrome outpatient clinic at the Klinikum Rechts der Isar in Munich, adds: “Our genetic findings are an important step towards developing new and improved treatment options for our patients.”

One particular biological pathway implicated by the findings is known to be a target for the drug thalidomide. While the drug has a controversial reputation due to its previous use when treating pregnant women that led to serious birth defects in their offspring, it is now used to treat some cancers. The researchers suggest that thalidomide or similar drugs may offer potential treatment options for male patients with restless leg syndrome and female patients beyond reproductive age, but they stress the necessity of rigorous clinical testing for efficacy and side-effects before any such use.