Published Research - General Sleep and RLS (WED)

For everything and anything else not covered in the other WED/RLS sections.
cornelia

Re: Published Research - General Sleep and WED (RLS)

Postby cornelia » Sat Jun 08, 2013 12:56 pm

Gosh, this is an important study I guess, done by some well known and great researchers.

I read the word 'imflammation' again in this study, but maybe this has nothing to do with what we usualy think of it.

Anyway, I am so thankful for having these great researchers doing their utmost to find better treatment or even a cure for RLS.

Corrie

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Re: Published Research - General Sleep and WED (RLS)

Postby badnights » Sat Jun 08, 2013 7:26 pm

lol I just same here to post it too.

Despite what the summary says in the first paragraph, I didn't think anyone had ever demonstrated low dopamine levels in RLS/WED, I thought the only indication of involvement was the effectiveness of dopamine drugs. Which would make this study a first in that regard. It would be nice to see the real study, they must refer to precedents.

It is fascinating to see the link with vitamin D again; the link between iron, inflammation, and RLS; the link with dopamine; with pain; with sleep disturbances; all revealed in a sample of CSF.

This would seem to mean there might be a clinically measureable indicator of RLS/WED? i.e. something measureable in a lab that could provide a diagnosis, independent of patient symptoms. (And something solid to convince naysayers that it's a real disease.)

I am sure the inflammation means what we think it means, which is a tissue response to injury. There was another recent (past 2 years?) indication that inflammation is or might be involved in RLS/WED, I forget if it was something I read elsewhere or something posted here - and now this one... I have begun to think we will have to readjust our thinking and accept that inflammation might be involved after all. To what extent, I wonder?

I would love to see the actual paper.
Beth - Wishing you a restful sleep tonight
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Re: Published Research - General Sleep and WED (RLS)

Postby badnights » Sat Jun 08, 2013 8:17 pm

The CME that views posted about in this Forum (North America: Email your Doctor! CME - July 10th, 2013) is going to discuss a review paper, and they provided a link to download the paper on the CME site. I have attached it here. The executive summary is good and is a few pages long, ending with Table D which lists recommendations for future research.

Remember this review is focused specifically on treatment studies, not studies of the causes of the disease, or its prevalence, or genetics.

They summarize the results ONLY of studies that meet stringent criteria for proper procedure. They included such studies that looked at the effectiveness of RLS medications, the harms of them, and characteristics of patients that affect disease outcome or treatment outcome. There are NO eligible studies on the benefits of using opioids. !! And almost none of the long-term harms of dopamine drugs.

Among their comments:
• Many classes of drugs used in clinical
practice such as opioids and sedative
hypnotics have not been evaluated in
clinical trials.
• Long-term durability of treatment
benefits remains unknown.
• Augmentation is a significant harm with
dopaminergic therapy and can lead to
treatment discontinuation; yet, little is
known about patient characteristics
that may lead to augmentation.
• Most clinical trials were of short
duration (typically 12 weeks) yet RLS
patients whose symptoms are severe
confront a chronic, progressive disease
that may require lifelong treatment.

Among their recommendations:
• Randomized trials of nonpharmacologic treatments
including herbal therapy, mind-body medicine, and
manipulative treatments.
• Randomized trials of classes of drugs other than
dopamine agonists, such as opioids and sedative
hypnotics.
• Randomized trials of effectiveness of drugs in specific
patient subgroups such as children, older adults, and
individuals with secondary RLS.
• Long-term studies of augmentation with dopaminergic
therapy. Potential study designs could include RCTs,
prospective observational studies, and retrospective
observational studies, including case-control studies..
• Studies that evaluate specific patient characteristics such
as iron status and disease severity that may make
patients susceptible to augmentation with dopaminergic
therapy.
• Assess augmentation with different dopaminergic drugs
using standard criteria and methods of assessment.
Attachments
2012 AHRQ Comparative Effectiveness Review No. 86 Treatment of RLS.pdf
(1.63 MiB) Downloaded 72 times
Beth - Wishing you a restful sleep tonight
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Re: Published Research - General Sleep and WED (RLS)

Postby ViewsAskew » Sat Jun 08, 2013 9:47 pm

The only way some of those studies are going to happen is if the Sleep Foundation, a national health service, or the WED Foundation steps ups and pays for them, unfortunately. I suppose some Ph.D students could do a retrospective study, though. I hope that people pay attention to this and promote these studies among their students, in their practices, etc. Though....we could create our own non-profit and get grants (not sure from where) and pay ourselves to do some of these, Beth. :-).
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Re: Published Research - General Sleep and WED (RLS)

Postby badnights » Sat Jun 08, 2013 10:17 pm

I bought the WEDawareness.org domain name. My tentative idea is to create a site with information of some kind, videos, maybe let people post videos; interviews with clinicians and researchers; and a place for people to donate.

I suppoise there would have to be a holding organization to hold the donations til they reached a useable amount, then to pass the money along to an acceptable reaserch unit to do specific research; probably need prior arrangement with a single research unit, to simplify things; might be able to use the existing WEDF grant program somehow.

Then we would have a say in what research was done. But getting emnough funding is a trick I don;;t know how to solve. Heck, I can't evn type.
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Re: Published Research - General Sleep and WED (RLS)

Postby ViewsAskew » Sat Jun 08, 2013 10:24 pm

Yes, funding is difficult, unless it leads to a profitable drug!
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cornelia

Re: Published Research - General Sleep and WED (RLS)

Postby cornelia » Sun Jun 09, 2013 11:25 am

I think there must exist some research done a long time ago that suggested that RLS patients have low dopamine levels. At least dr B is mentioning that in his book, but I'm not 100% sure.

Beth, the inflammation study you mentioned is the Weinstock/Walters study.

Corrie

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Re: Published Research - General Sleep and WED (RLS)

Postby ViewsAskew » Sun Jun 09, 2013 7:55 pm

cornelia wrote:Gosh, this is an important study I guess, done by some well known and great researchers.

I read the word 'imflammation' again in this study, but maybe this has nothing to do with what we usualy think of it.

Anyway, I am so thankful for having these great researchers doing their utmost to find better treatment or even a cure for RLS.

Corrie


A year or so ago, we had a member here who believed WED was all about inflammation response. He suggested doing many things to reduce inflammation would reduce WED. I remember reading through the list of things and thinking that I'd tried most of them and they'd not helped. I've also read that some people believe inflammation is the root of ALL disease. It will be interesting to see where this goes with inflammation and how it's related. My guess is that we just don't know enough about inflammation, yet, either!

http://www.wellnessletter.com/ucberkele ... ammation/#
http://www.pnas.org/content/early/2012/ ... 9.abstract
http://online.wsj.com/article/SB1000142 ... 90070.html
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Re: Published Research - General Sleep and WED (RLS)

Postby badnights » Sun Jun 09, 2013 11:18 pm

Beth, the inflammation study you mentioned is the Weinstock/Walters study.

thanks
Beth - Wishing you a restful sleep tonight
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Re: Published Research - General Sleep and WED (RLS)

Postby ViewsAskew » Mon Jun 10, 2013 3:16 am

Not really research, but the results came from research....new criteria in diagnosing WED.

http://www.ajmc.com/conferences/sleep-2 ... Why-Change

Restless Legs Syndrome/Willis-Ekbom Disease Diagnostic Criteria: Why Change?
During this session, Daniel Picchietti, MD, described the need for changes in the criteria for the diagnosis of restless leg syndrome (RLS), which is also known as Willis-Ekbom disease (WED). Picchietti also discussed the methodology underlying the revision and the changes in the diagnostic criteria as of 2013, for example, the addition of specifiers of clinical significance, specifiers of clinical course, and pediatric criteria for RLS. Finally, he examined some of the controversy surrounding the changes in the criteria for RLS diagnosis.

A better understanding of the changes to guidelines for the diagnosis of WED/RLS, the rationale behind these changes, and the controversy surrounding discrepancies between guidelines published by different societies will help clinicians, healthcare professionals, and the managed care community to recognize cases of this potentially painful disease.

The 2003 diagnostic criteria published by the International Restless Legs Syndrome Study Group (IRLSSG) and National Institutes of Health (NIH) have been cited over 1100 times in peer-reviewed literature. Since 2003, investigators have published over 3000 new publications on the topic of RLS. Thus the IRLSSG/NIH criteria merited revision in light of recent advances in the understanding of RLS.

Examining the changes in diagnostic criteria, Picchietti spoke about 5 prior incarnations of the guidelines for diagnosis of RLS/WED dating back to 1960. The most recent revision to the diagnostic criteria was published after a 2008 IRLSSG meeting featuring a collaboration of over 50 experts.

The new guidelines include 4 major changes. Changes include specifiers for clinical significance, specifiers for clinical course, and addition of a fifth essential feature characteristic of RLS/WED, in addition to the 4 existing features. The fifth criterion involves recognition of conditions that might mimic RLS. For instance, leg cramps, positional discomfort, myalgia, leg edema, arthritis, and habitual foot tapping do not constitute RLS. This change may improve the sensitivity and specificity of diagnosis of RLS. RLS may still occur in patients with conditions that mimic RLS.

Dr Picchietti added that a mild, nuisance form of RLS also exists in the community. This mild form, which does not often lead to a consultation with a physician, has led to difficulty in quantifying the epidemiology of RLS.

Aware of this, the study group included a specifier that defines clinical significance of RLS/WED. In general, the impact of RLS on sleep quality differentiates mild RLS from other forms that may not require treatment.

Although this guideline applies in clinical treatment, this guideline may not apply to clinical studies identifying genetic disorders related to RLS. For instance, in recruiting subjects for a control group of patients without RLS in a genetic study, it might be desirable to exclude patients with even mild symptoms of RLS, even if the 2013 diagnostic criteria do not qualify those patients for a diagnosis.

The study group also added a specifier that differentiates patients based on the clinical course of RLS. The guidelines now divide RLS into chronic-persistent and intermittent forms. Dr Picchietti noted that chronic-persistent RLS might have a greater effect in terms of negative cardiovascular outcomes compared with intermittent forms of RLS.

Regarding the diagnosis of RLS in pediatric patients, Dr Picchietti explained that phrases such as “need to move,” “want to move,” “my legs want to kick,” and similar statements are typical ways that children express the symptoms of RLS. These differ from the way adults might express RLS symptoms. For instance, adults might say, “I have an urge to move my legs.”

The Diagnostic and Statistical Manual of Mental Disorders, 5th edition, diagnostic criteria for RLS/WED, in contrast to the IRLSSG/NIH criteria, includes a stipulation that severe RLS must include at least 3 instances of RLS per week. However, many physicians have noted that patients with extreme symptoms of RLS often experience fewer than 3 instances of RLS per week. During a question/answer session, an expert in RLS, Dr Allen, confirmed that the stipulation of 3 instances of RLS per week, as a diagnostic criterion, was inconsistent with clinical experience.
- See more at: http://www.ajmc.com/conferences/sleep-2 ... rGbUu.dpuf
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Re: Published Research - General Sleep and WED (RLS)

Postby ViewsAskew » Mon Jun 10, 2013 3:19 am

So, based on the above, the new criteria:
http://irlssg.org/diagnostic-criteria/



2011 Revised IRLSSG Diagnostic Criteria for RLS

Restless legs syndrome (RLS), a neurological sensorimotor disease often profoundly disturbing sleep and quality of life has variable expression influenced by genetic, environmental and medical factors. The symptoms vary considerably in frequency from less than once a month or year to daily and severity from mildly annoying to disabling. Symptoms may also remit for various periods of time. RLS is diagnosed by ascertaining symptom patterns that meet the following five essential criteria adding clinical specifiers where appropriate.

Essential Diagnostic Criteria (all must be met)

1. An urge to move the legs usually but not always accompanied by or felt to be caused by uncomfortable and unpleasant sensations in the legs.1, 2

2. The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting.

3. The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues. 3

4. The urge to move the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night than during the day.4

5. The occurrence of the above features are not solely accounted for as symptoms primary to another medical or a behavioral condition (e.g., myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping.) 5

Specifiers for Clinical Course of RLS
A. Chronic-persistent RLS: Symptoms when not treated would occur on average at least twice weekly for the past year.

B. Intermittent RLS: symptoms when not treated would occur on average < 2/week for the past year, with at least 5 lifetime events.

Specifier for Clinical Significance for RLS

The symptoms of RLS cause significant distress or impairment in social, occupational, educational or other important areas of functioning by the impact on sleep, energy/vitality, daily activities, behavior, cognition or mood.

_______________________________________________________________

Footnotes:

1. Sometimes the urge to move the legs is present without the uncomfortable sensations and sometimes the arms or other parts of the body are involved in addition to the legs.

2. For children, the description of these symptoms should be in the child’s own words.

3. When symptoms are very severe, relief by activity may not be noticeable but must have been previously present.

4. When symptoms are very severe, the worsening in the evening or night may not be noticeable but must have been previously present.

5. These conditions, often referred to as “RLS mimics”, have been commonly confused with RLS particularly in surveys because they produce symptoms that meet or at least come very close to meeting all of the above criteria. The list here gives some examples of this that have been noted as particularly significant in epidemiological studies and clinical practice. RLS may also occur with any of these conditions, but the RLS symptoms will then be more in degree, conditions of expression or character than those usually occurring as part of the other condition.

6.The clinical course criteria do not apply for pediatric cases nor for some special cases of provoked RLS such as pregnancy or drug induced RLS where the frequency may be high but limited to duration of the provocative condition.
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Re: Published Research - General Sleep and WED (RLS)

Postby ViewsAskew » Wed Jun 12, 2013 8:19 pm

More about the proteins identified in the new research study by Patton, et.al. There is a lengthy discussion of the methods at the following link:

http://www.fluidsbarrierscns.com/content/10/1/20

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
Abstract
Background

Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a sensorimotor disorder that causes patients to experience overwhelming and distressing sensations in the legs compelling the patient to move their legs to provide relief. The purpose of this study was to determine if biomarkers in the cerebrospinal fluid can distinguish RLS/WED patients from neurological controls.
Methods

We obtained CSF samples by lumbar puncture from 5 early-onset RLS/WED patients and 5 controls. We performed 2-dimensional difference in-gel electrophoresis (2D-DIGE). Proteins that were significantly altered were identified by Student’s t-test. Protein spots that were differentially expressed (p ≤ 0.05, Av. Ratio ≥ 2.0) between RLS/WED and control CSF samples were identified using MALDI-TOF-MS. Statistical analyses of the validation immunoblot assays were performed using Student’s t-test.
Results

In this discovery study we identified 6 candidate CSF protein markers for early-onset RLS/WED. Four proteins (Cystatin C, Lipocalin-type Prostaglandin D2 Synthase, Vitamin D binding Protein, and β-Hemoglobin) were increased and 2 proteins (Apolipoprotein A1 and α-1-acid Glycoprotein) were decreased in RLS/WED patients.
Conclusions

Our results reveal a protein profile in the RLS/WED CSF that is consistent with clinical findings of disruptive sleep, cardiovascular dysfunction and painful symptoms. Moreover, protein profiles are consistent with neuropathological findings of activation of hypoxia inducible factor (HIF) pathways and alterations in dopaminergic systems. These data indicate the CSF of RLS/WED patients may provide information relevant to biological basis for RLS/WED, treatment strategies and potential new treatment targets.
Keywords:
Sleep disorders; Restless legs syndrome/Willis-Ekbom disease; Nitric oxide; Hypoxia inducible factor; Pain

Background

Restless Legs Syndrome/Willis-Ekbom Disease (RLS/WED) is a sensorimotor disorder that affects between 5-10% of the population [1]. Patients who suffer with RLS/WED experience an overwhelming and distressing sensation that forces them to move their legs [2]. Those with moderate to severe symptoms report significant disability, chronically reduced sleep times, 20% reduction in their work productivity, diminished quality of life, and increased depression and anxiety [3]. RLS/WED has also been identified as a risk factor for cardiovascular disease [4-7]. RLS/WED prevalence increases with age and it affects women twice as frequently as men.

Iron dysregulation in the pathogenesis of RLS/WED is supported by a substantial volume of research including several studies reporting decreased ferritin in cerebrospinal fluid (CSF) and decreased brain iron particularly in the substantia nigra using MRI, ultrasound imaging and brain autopsy analysis [8]. A number of studies to date support the concept of diminished brain iron in RLS/WED, thus providing the basis for the hypothesis that RLS/WED occurs as a result of low brain iron content [8-10]. We still do not understand, however, the full consequences that low brain iron may have on neural systems in patients with RLS/WED. We performed proteomic analyses in order identify neural systems and pathways that are altered in those suffering with RLS/WED and possibly identify novel avenues for potential therapeutic intervention.

CSF was utilized for this biomarker study because it is most likely to reflect changes in CNS metabolic status due to its proximity to the brain. An advantage of CSF as the biological fluid for proteomic analyses over blood is that the CSF is sequestered behind both the blood–brain and brain-CSF barriers. This isolation permits the identification of biomarkers that are specific to CNS disease processes. Hence, our goal for this study was to identify CSF biomarkers for RLS/WED using two-dimensional difference-in-gel electrophoresis (2D-DIGE) together with tandem Mass Spectrometric (MS) analysis. To further validate the identified biomarkers, we used immunoblot analyses to quantify differences in protein levels between early-onset RLS/WED and age- and gender-matched control subjects. In this study, we identify six proteins whose levels are altered in early-onset RLS/WED subjects.

Conclusion

Our results reveal a protein profile in the RLS/WED CSF that is consistent with iron deficiency, dopamine dysregulation and inflammation. The APO-A1 finding may be of relevance outside of CNS given the recently reported increased risk of cardiovascular disease in patients with RLS and cardiovascular dysfunction and reports of painful symptoms. The profiles in the CSF are also consistent with neuropathological findings of activation of HIF pathways and alterations in dopaminergic systems. The data indicate that the CSF protein profile, if confirmed in larger sample sizes, may provide support for existing hypotheses about a biological basis for RLS/WED which could prove clinically meaningful in evaluating therapeutic strategies and identifying new targets.
Competing interests

Dr. Allen has in the last 2 years served as a consultant for Boehringer Ingelheim, GlaxoSmithKline, Luitpold Pharmaceuticals, Pfizer, EMD Serono, Pharmacosmos, Neurogen, Jazz Pharmaceuticals and UCB Pharma. He also received research support from GlaxoSmithKline, Pharmacosmos and the USA National Institutes of Health. Dr. Earley was a member of the Data Safety Committee for Phase III clinical trial by Merck. Dr. Connor discloses that he is a paid consultant for GlaxoSmithKline and the International Copper Association and has consulted for Neurogen. Drs. Patton and Cho, and Mr. Clardy report no disclosures.
Authors’ contributions

SMP carried out the 2D-DIGE analyses, identification of biomarker proteins, and drafted the manuscript, YWC recruited, diagnosed and obtained cerebrospinal fluid samples from RLS/WED and control subjects, TC performed the DeCyder-DIA proteein analyses of 2D-DIGE images, RPA participated in study design and coordination, and assisted in the draft of the manuscript, CE participated in study design and assisted in the draft of the manuscript, and JRC participated in the study design and assisted in the draft of the manuscript. All authors have read and approved the final version of the manuscript.
Acknowledgements

This work was supported by grants from GlaxoSmithKline (#109851) (JRC).
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Re: Published Research - General Sleep and WED (RLS)

Postby ViewsAskew » Sat Jun 15, 2013 8:21 am

Some of you may have seen this already. There is NO proof of linkage or causation, but in an 8 year study more men who had WED/RLS died than those who didn't - it translated into a 40% higher rate. Yikes.

http://www.nlm.nih.gov/medlineplus/vide ... 313-1.html
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Re: Published Research - General Sleep and WED (RLS)

Postby Polar Bear » Sat Jun 15, 2013 6:53 pm

There is no breakdown about cause of death but we have heard that in general we RLS/WED sufferers are more likely to have heart problems.
Betty
http://www.willis-ekbom.org/about-rls-wed/publications
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Re: Published Research - General Sleep and WED (RLS)

Postby badnights » Mon Jun 17, 2013 7:39 am

Causes of death I bet will include everything that is likely to fail in a stressed organism, including heart.
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