Published Research - General Sleep and RLS (WED)

[Aiken]

Ooo, "dysesthesia," now I finally have a clinical term for why I can't bear to be touched late in the day. Great word.

[ViewsAskew]

Aha! Exercise linked to fewer PLMs



NEW YORK (Reuters Health) - Exercise may improve sleep patterns in people with insomnia or sleep disruptions related to periodic leg movements, according to study findings reported by Brazilian researchers.

Dr. Marco Tulio de Mello and colleagues at Federal University of Sao Paulo-UNIFESP assessed the effects of acute intensive exercise on sleep patterns in 22 volunteers with periodic leg movements, which are often associated with restless legs syndrome. Eleven subjects continued with 72 physical training sessions for roughly the next 6 months.

Reductions in periodic leg movements were observed after both intensive and regular physical exercise. Intensive exercise increased sleep efficiency (actual time asleep) and rapid eye movement (REM) sleep, and reduced wake time after sleep onset. Chronic physical exercise increased sleep efficiency and REM sleep and reduced sleep latency (time to takes to fall asleep). The release of beta-endorphins, opioid compounds that provide a feeling of well-being, after acute intensive exercise corresponded with reduced periodic leg movements levels.

The improvements were particularly pronounced in the patients with milder periodic leg movements, the authors in their report, published in the January issue of Medicine & Science in Sports & Medicine.

In a statement from the American College of Sports Medicine, the journal publisher, lead author Dr. Andrea Maculano Esteves comments, "The ability of have restful and uninterrupted sleep is often taken for granted, but not usually by people with periodic leg movements or restless leg syndrome."

"Exercise restores that ability, and quickly, too, as we see in the improvements in the acute exercise sessions. An added benefit here is that exercise is an alternative to a pharmacologic treatment, in terms of both outcome and cost."

Med Sci Sports Exerc 2009;41:237-242.

[ViewsAskew]

New Gene Identified

Wow, that makes 4. Very interesting info in this report. This is working out like many hypothesized - the gene variant seems likely to explain why some of us have pain and why we respond to different treatments.

http://insciences.org/article.php?article_id=1886

New risk gene for the restless legs syndrome discovered
Published on 2 February 2009, 03:50 Last Update: 22 hour(s) ago by Insciences
Tags: BTBD9 Genetics LBXCOR1 Medicine MEIS1 Restless legs syndrome

Restless legs syndrome (RLS) is one of the most common neurological diseases with an age-dependent prevalence of up to 10%. The symptoms are characterized by an urge to move and uncomfortable sensations in the lower limbs; they only occur while at rest in the evening or at night and are thus associated with problems of going to sleep and severe sleep disturbances. The disease picture has both a strongly genetic and environmental component. To the last category belong pregnancy, nutrition (e.g. iron deficiency) and changes in metabolism (e.g. dialysis).

A year ago, with the aid of a genome-wide study, scientists of the Institute of Human Genetics, together with colleagues of the Institute of Epidemiology as part of an international consortium were able to prove that frequent sequence variants in genes increase the risk for the disease. The already identified genes MEIS1, LBXCOR1 and BTBD9 provide the first clues to the molecular mechanisms underlying the development of the disease. Both MEIS1 and LBXCOR1 are described as transcription factors, which among other things play a role in the early development of the spinal marrow.

In studies of RLS families a gene locus was narrowed to the chromosome 9p. Now, in the current study, 2500 RLS patients and 4750 healthy test persons out of the population database KORA were investigated for frequent gene variants. The scientists succeeded in identifying PTPRD, a protein tyrosine phosphatase as new risk gene for RLS. That means that to date four RLS genes have been discovered through genome-wide studies. Carriers of risk sequence variants in these genes have a 40% higher risk of getting RLS.

PTPRD plays a role in the correct pathfinding of neural dendrites to the motor neurons. The neurons steer the muscles, directly or indirectly, for example the legs. Thus PTPRD, like the other three identified risk genes, is important for the embryonic development of the organism. This could be a clue as to why RLS is a very early development disorder of the central nervous system.

With the identified RLS risk genes, for the first time it has become possible to conduct targeted molecular-genetic causal research for RLS and to create a basis for the improvement of therapy.

[ViewsAskew]

Hormones ARE related to increased RLS risk....like we didn't know that!


http://www.medindia.net/news/Hormonal-C ... 7015-1.htm


A study in the Feb. 1 issue of the journal Sleep shows that the elevation in estradiol levels that occurs during pregnancy is more pronounced in pregnant women with restless legs syndrome (RLS) than in controls.


During the last trimester of pregnancy, levels of the estrogenic steroid hormone estradiol were 34,211 pg/mL in women with RLS and 25,475 pg/mL in healthy controls. At three months postpartum, estradiol levels had dropped to 30.73 pg/mL in the RLS group and 94.92 pg/mL in controls. Other hormone levels did not differ significantly between the study groups.

According to the authors the data strongly suggest that estrogens play an important role in RLS during pregnancy. The study also supports previous reports of high RLS incidence in the last trimester of pregnancy when estradiol is maximally elevated.

"Our findings strongly support the concept that neuroactive hormones play a relevant pathophysiological role in RLS," said principal investigator Thomas Pollmacher, MD, director of the Center for Medical Health at Klinikum Ingolstadt and professor of psychiatry at Ludwig Maximilians University in Munich, Germany. "This information will increase the understanding of RLS in pregnancy and will assist in the development of specific therapeutic approaches."

The American Academy of Sleep Medicine describes RLS as a sleep-related movement disorder that involves an almost irresistible urge to move the legs at night. This urge tends to be accompanied by unusual feelings or sensations, called "paresthesias," that occur deep in the legs. These uncomfortable sensations often are described as a burning, tingling, prickling or jittery feeling. RLS can profoundly disturb a person’s ability to go to sleep or return to sleep after an awakening.


The AASM reports that RLS occurs 1.5 to two times more often in women than in men. Eighty percent to 90 percent of people with RLS also experience periodic limb movements (PLMs) during sleep, which are involuntary jerking or twitching movements of the feet or legs.


According to the authors RLS symptoms
often occur for the first time during pregnancy
. Symptoms typically worsen during pregnancy and improve or even disappear after delivery. The risk of developing RLS increases gradually with the number of pregnancies.
The study also found that women with RLS had more PLMs than controls before and after delivery. PLMs decreased significantly after delivery in women with RLS and stayed low in women without RLS.

Only minor differences appeared between the two study groups in subjective sleep quality and objective sleep measures. One explanation suggested by the authors is that only RLS patients who did not need pharmacological treatment were selected for the study; RLS symptoms of participants were in the mild to moderate range.

The study involved nine healthy pregnant women (mean age 32.9 years) who were placed in a control group and 10 pregnant women (mean age 31.6 years) who fulfilled diagnostic criteria for RLS. Eight women from the RLS group reported symptoms previous to the present pregnancy, and all members of the RLS group described worsening of symptoms during pregnancy. The mean age of onset for RLS symptoms was 22.6 years.

Sleep data and leg movements were recorded during overnight polysomnography around the 36th week of gestation and again at 12 weeks postpartum. Blood samples were taken each morning after
the polysomnography and before breakfast. Accompanying questionnaires on sleep and RLS symptoms also were collected.

Source-Eurekalert
SRM

[ViewsAskew]

Not sure if this is related to the same gene research as upthread...but it's an interesting story...

http://www.newswise.com/articles/view/548730/

Newswise — In 2005, a woman who had trouble sleeping asked Siong-Chi Lin, M.D., for help. Dr. Lin, a sleep disorders specialist at the Mayo Clinic campus in Florida, diagnosed restless legs syndrome. This common neurologic disorder interrupts sleep because of unpleasant sensations in the legs at rest, especially in the evening, that are temporarily relieved by movement.

Restless legs syndrome affects between 5 and 11 percent of the population in North America and Europe, says Dr. Lin. The cause may be a number of clinical factors, such as iron deficiency, but it has a strong genetic component as well. “In most people, it is likely due to a number of different causes, but genes are very likely the most important factor in affected families,” he says.

Medications, especially agents that increase transmission of dopamine in brain neurons, are effective in many people and worked for his new patient, says Dr. Lin. “The syndrome may appear as a nuisance for most people, however it can also seriously affect some people’s quality of life,” he says.

Dr. Lin’s patient told him that many of her relatives also have the same trouble sleeping — difficulties she could trace back through her ancestry.

With the patient’s approval, that information was relayed to “gene hunters” in Mayo Clinic’s neurosciences department. These investigators have established an international reputation for their ability to find the genetic roots of rare, as well as common, neurological disorders. Dr. Lin accompanied investigators to Indiana, the hub of the extended family, which is believed to be of English descent, to interview dozens of individuals spanning multiple generations. They found that 30 relatives were affected by restless legs syndrome, and discovered that almost three times as many females had the condition compared to males.

Now, the researchers are reporting in the February issue of Mayo Clinic Proceedings that the restless legs syndrome found in this family is likely due to a gene mutation that has never been linked to the disorder.

To date, five loci, or areas on the genome, have been linked to restless legs syndrome in other families around the world, but this family does not have any of those mutations.

“That means this family likely has a novel gene that is causing the disease,” says the study’s lead investigator, Carles Vilariño-Güell, Ph.D., a neuroscientist at Mayo Clinic’s campus in Jacksonville. The researchers have not yet pinpointed the culprit gene, but say they are getting close.

This study is important, Dr. Vilariño-Güell says, because this family is one of the largest with restless legs syndrome ever studied, and the disorder spans multiple generations. Therefore, the gene linked to the syndrome is widespread among the affected relatives, increasing the chances that the researchers will soon zero in on the gene responsible.

“With so many people in this family affected by the syndrome, we have a lot of power to find the gene mutation causing disease,” he says.

Once a gene is discovered, researchers can investigate its normal function and the mutation’s effect, and then can “try to overcome that problem with drug therapy,” he says. They can also trace the molecular route from the gene mutation to the disorder, and see if the other loci linked to the syndrome lie along this pathway. So far, no one has found a definitive link between restless legs syndrome and a specific gene mutation, but large families hold the clues for these discoveries, says Dr. Vilariño-Güell.

Co-authors of the study include Matthew Farrer, Ph.D., and Zbigniew Wszolek, M.D.

The study was funded by The Mayo Foundation Research Committee, the National Institutes of Health, and the Pacific Alzheimer Research Foundation.

[ViewsAskew]

They have developed a new questionnaireto identify RLS that ALSO excludes other diseases that mimic RLS. Too bad the study results do not show the questionnaire!

A quick search only turned up more references to the study, alas. Hopefully someone will publish it online somewhere soon.

[SquirmingSusan]

Awesome. Can't wait to see it.

[ViewsAskew]

A link to RLS, pregnancy and high estrogen.

[ViewsAskew]

Another potential piece in the puzzle:

Cerebral white matter alterations in idiopathic restless legs syndrome, as measured by diffusion tensor imaging.

UNRATH A, MULLER HP, LUDOLPH AC, RIECKER A, KASSUBEK J.
Mov Disord 2008;23(9):1250-5.
Department of Neurology, University of Ulm, Ulm, Germany

Abstract:


In search for the pathoanatomical correlate of the restless legs syndrome (RLS), various neuroimaging and electrophysiological techniques have demonstrated partly conflicting results of cortical, subcortical, brainstem, and spinal alterations. In a novel approach, the delineation of potential cerebral white matter tract disruption was investigated by application of quantitative whole brain-based diffusion tensor imaging (DTI) to a well characterized group of 45 patients with idiopathic RLS.

The data of patients and 30 healthy controls were statistically compared including computation of regional fractional anisotropy (FA) as a quantitative marker of white matter integrity by use of the tensor imaging and fiber tracking software. In the patient group, multiple subcortical areas of significantly reduced FA were observed bihemispherically in close proximity to the primary and associate motor and somatosensory cortices, in the right-hemispheric thalamus (posterior ventral lateral nucleus), in motor projectional fibers and adjacent to the left anterior cingulum.

Together with the results of a recent study by use of an MRI-based gray matter analysis, which localized RLS-associated changes in the sensorimotor cortices, these findings gave support to an altered subcortical network, with the major component of altered cerebral sensorimotor pathways, within a hodological concept of the RLS pathoanatomy.

[Aiken]

Interesting. I'm inclined to wonder if the change in white matter is the chicken or the egg, though.

[ViewsAskew]

Possible...but, that's still a clue. Working backwards and all that...

[ViewsAskew]

Seems that the we now have and RLS phenotype that does NOT respond to L-Dopa (and doesn't have PLMs)...

From a PubMed search:

Karroum E, Konofal E, Arnulf I.

UF pathologies du sommeil, groupe hospitalier Pitié-Salpêtrière, Assistance publique-Hôpitaux de Paris, pavillon Marguerite-Bottard, Paris cedex, France. pr_karroum@hotmail.com

Restless-legs syndrome (RLS) is a sensorimotor disorder, characterized by an irresistible urge to move the legs usually accompanied or caused by uncomfortable and unpleasant sensations. It begins or worsens during periods of rest or inactivity, is partially or totally relieved by movements and is exacerbated or occurs at night and in the evening. RLS sufferers represent 2 to 3% of the general population in Western countries. Supportive criteria include a family history, the presence of periodic-leg movements (PLM) when awake or asleep and a positive response to dopaminergic treatment. The RLS phenotypes include an early onset form, usually idiopathic with a familial history and a late onset form, usually secondary to peripheral neuropathy. Recently, an atypical RLS phenotype without PLM and l-DOPA resistant has been characterized. RLS can occur in childhood and should be distinguished from attention deficit/hyperactivity disorder, growing pains and sleep complaints in childhood. RLS should be included in the diagnosis of all patients consulting for sleep complaints or discomfort in the lower limbs. It should be differentiated from akathisia, that is, an urge to move the whole body without uncomfortable sensations. Polysomnographic studies and the suggested immobilization test can detect PLM. Furthermore, an l-DOPA challenge has recently been validated to support the diagnosis of RLS. RLS may cause severe-sleep disturbances, poor quality of life, depressive and anxious symptoms and may be a risk factor for cardiovascular disease. In most cases, RLS is idiopathic. It may also be secondary to iron deficiency, end-stage renal disease, pregnancy, peripheral neuropathy and drugs, such as antipsychotics and antidepressants. The small-fiber neuropathy can mimic RLS or even trigger it. RLS is associated with many neurological and sleep disorders including Parkinson's disease, but does not predispose to these diseases. The pathophysiology of RLS includes an altered brain-iron metabolism, a dopaminergic dysfunction, a probable role of pain control systems and a genetic susceptibility with nine loci and three polymorphisms in genes serving developmental functions. RLS treatment begins with the elimination of triggering factors and iron supplementation when deficient. Mild or intermittent RLS is usually treated with low doses of l-DOPA or codeine; the first-line treatment for moderate to severe RLS is dopaminergic agonists (pramipexole, ropinirole, rotigotine). In severe, refractory or neuropathy-associated RLS, antiepileptic (gabapentin, pregabalin) or opioid (oxycodone, tramadol) drugs can be used.

[ViewsAskew]

Cool blog. The focus is on ADHD. In this post, they explore a bit about ADHD and RLS. I followed some other links to see other things they said about RLS.

Interesting stuff.

[ViewsAskew]

New studyshowing that men and women who are sleep deprived respond differently in terms of inflammatory response.

[ViewsAskew]

This research article isn't saying anything new, but good to know that they are trying to find out why. This article is simply exploring what the potential causes may be.