Published Research - General Sleep and RLS (WED)

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

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

Postby cornelia » Wed Apr 30, 2014 10:07 am

we have heard from the morphine pump on this board, but I'm not sure if this report on 7 swedish patients has been reported yet:

It is with great interest that we read the case report by Ross et al. (3) describing the successful treatment of refractory restless legs with intrathecal morphine. They are, however, wrong in their statement that this is the third published case of this particular treatment. In an article in the Swedish medical journal Lakartidningen, we previously accounted for 7 patients with refractory restless legs syndrome who were successfully treated with intrathecal morphine (2). An abstract in English is available through the official web site of this journal, and the article is indexed by PubMed. Our 7 patients were treated at 3 hospitals in the northern region of Sweden, which is covered by the neurosurgical department of Umeå University Hospital. The 2 patients previously reported by Jakobsson and Ruuth (1) are included in this retrospective study.A total of 10 patients were tested with bolus doses of intrathecal morphine administered via a lumbar catheter. Seven patients responded to treatment and received a permanent pump system for drug infusion. All 7 patients reported complete relief of symptoms after this procedure. Two of the 10 patients were tested with bolus doses of morphine and placebo doses of saline before implantation of a pump. None of the patients reported relief of symptoms after the administration of saline. Similar to Ross et al., we had 1 patient with a malfunctioning system, in this case attributable to low battery power in the pump. This patient experienced a recurrence of restless legs after being free of symptoms for 6 years. After replacement of the pump, the patient was again free of symptoms.The mean daily dose of intrathecal morphine in the 7 patients was 300 μg, and 4 patients needed less than 75 μg daily. No signs of tolerance were observed in 5 patients. The mean follow-up time was 48 months. In contrast to the patient described by Ross et al., we have not experienced exacerbation of restless legs symptoms or a combative behavior in the 3 patients who received a pump system under general anesthesia. Our experience is that intrathecal morphine may be an effective treatment for refractory restless legs syndrome, and we agree that a clinical trial should be performed for further evaluation of this treatment.Peter LindvallKrister Ruuth

Corrie

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

Postby ViewsAskew » Wed Apr 30, 2014 9:54 pm

It would be wonderful if they would do a clinical trial. I dearly hope that they do.
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Re: Published Research - General Sleep and WED (RLS)

Postby ViewsAskew » Fri May 02, 2014 6:08 am

AH! Back to vascular???? I cannot see the text, so not sure what it says, but I'm guessing (based on the title) that there is new evidence to support microvascular involvement. Whether this is in secondary WED, primary, or both, I suppose it remains to be seen. And, of course, all the other research results have to fit somewhere - unless, as hypothesized, there are literally different types of WED.


Article in Neurology:
Putting the legs back into restless legs syndrome
New evidence for the microvascular hypothesis

http://www.neurology.org/content/early/ ... 62.extract
Restless legs syndrome (RLS)/Willis-Ekbom disease (WED) affects 5% to 10% of the population and occurs more frequently in women, with a family history in half of patients. RLS/WED results in sleep disruption, impaired quality of life, and reduced daytime productivity; its hallmarks include an irresistible urge to move the legs at rest, temporary relief by movement, and evening worsening. In 1945, Ekbom1 postulated that leg microvascular alterations may cause RLS/WED. However, the therapeutic advent of dopaminergic drugs shifted research focus toward analyzing brain dopamine dysregulation.2
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Peripheral hypoxia in restless legs syndrome (Willis-Ekbom d

Postby ViewsAskew » Sat May 03, 2014 4:19 am

Another interesting finding:

This is the abstract:


Objective: A case-control study to measure oxygen and carbon dioxide partial pressures in the legs in order to assess the involvement of peripheral hypoxia or hypercapnia in the pathogenesis of restless legs syndrome (RLS).

Methods: RLS severity was assessed with a standard questionnaire. Suggested immobilization tests were performed twice in 15 patients with RLS and 14 healthy controls. Patients with RLS participated in the tests with and without pramipexole medication. During the tests, peripheral oxygen and carbon dioxide partial pressures were measured noninvasively on the skin of the legs and the chest.

Results: During immobilization, the patients with RLS had lower partial pressure of oxygen in their legs (5.54 vs 7.19 kPa, p < 0.01) but not on the chest (8.75 vs 8.20 kPa, p = 0.355). More severe RLS correlated with high chest-to-foot oxygen gradient (ρ = 0.692, p < 0.01). Carbon dioxide levels did not differ between the groups. Pramipexole corrected the peripheral hypoxia toward the levels observed in the controls (from 5.54 to 6.65 kPa, p < 0.05).

Conclusions: Peripheral hypoxia is associated with the appearance of RLS symptoms. Strong correlation with RLS severity suggests a close pathophysiologic link between peripheral hypoxia and the symptoms of RLS. This is further supported by the simultaneous reversal of hypoxia and discomfort by dopaminergic treatment.


http://www.neurology.org/content/early/ ... hort?rss=1
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cornelia

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

Postby cornelia » Sat May 03, 2014 9:30 am

It is all so interesting to read but I get tired from all this research which, to my feeling, doesn't seem to get an us anywhere. Of course I know this is not true but I guess I am getting impatient. I want to get a better life and I prefer NOW! Well,this is unreal and we have to wait patiently I guess.
Corrie

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

Postby jul2873 » Sun May 04, 2014 3:13 am

This research is so interesting, Ann. So, essentially, it's saying that we don't get enough oxygen to the cells in our legs? I wonder if that is why flying is such a problem for so many of us. Is the air thinner in a plane?

I share Cornelia's frustration, on the one hand. On the other hand, considering how common WED is, and the many problems with available treatments, I think there should be more research.

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

Postby ViewsAskew » Sun May 04, 2014 9:30 am

jul2873 wrote:This research is so interesting, Ann. So, essentially, it's saying that we don't get enough oxygen to the cells in our legs? I wonder if that is why flying is such a problem for so many of us. Is the air thinner in a plane?

I share Cornelia's frustration, on the one hand. On the other hand, considering how common WED is, and the many problems with available treatments, I think there should be more research.


Until I read the whole article, I'm not sure exactly what they are saying!

Well, the air is thinner at high altitudes, so I imagine it is thinner in a plane. I quick search shows this:
http://usatoday30.usatoday.com/news/nat ... oxygen.htm

Hypoxia is an issue in planes.

I saw this response from a doctor in answer to a question about hypoxia.

"Hypoxia refers to a decreased level of oxygen in the body. Many conditions can result in hypoxia including, but not limited to, lung conditions like acute asthma, COPD, pulmonary embolism, etc., cardiac conditions like congestive heart failure, acute MI, valve abnormalities, etc., musculoskeletal conditions like ALS, diaphragmatic paralysis, etc. Hypoxia can lead to anxiety!"

I thought it interesting that hypoxia can lead to anxiety.

Also found it interesting that the dopaminergic resolved the hypoxia....how weird is that?????
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Re: Published Research - General Sleep and WED (RLS)

Postby ViewsAskew » Wed May 28, 2014 3:19 am

This is a short and easy to read article that is a synopsis of the above study about oxygen: http://www.neurology.org/content/82/21/ ... 440a2e1c6f
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Re: Published Research - General Sleep and WED (RLS)

Postby ViewsAskew » Sat May 31, 2014 8:38 am

I found more about the above study - about hypoxia. This is from Medscape. Anyone can get an account there, I think. I've had mine for years.

Here are a few quotes that are important, I think.

'Salminen said their results, if confirmed, could have major implications for the treatment of RLS. "If we can identify the site of action of the dopaminergic drugs, new medications could be developed that could treat the symptoms much more specifically."'

'More severe RLS correlated with high chest-to-foot oxygen gradient. Carbon dioxide levels did not differ between the groups. ... Salminen commented: "Because we didn't see a difference in carbon dioxide levels, this suggests that the mechanism is not to do with peripheral blood flow. But there are probably other mechanisms at play — possibly iron-mediated oxygen transport."'

'While the study is exciting, he warned that it is very preliminary. "We believe that peripheral hypoxia is definitely involved in some way. But we haven't proven a causal effect in this study. We have just shown a correlation. And we only had small numbers — only 15 patients — so the results obviously need to be confirmed in further studies."'
Ann - Take what you need, leave the rest



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cornelia

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

Postby cornelia » Sat May 31, 2014 11:53 am

I just read the study and I think again; how promising and then immedately after that I read it is preliminary, which is understandable makes me feel that they need a lot more time to figure this part of research out. I respect all the research that is done A LOT but honestly the more I read the more I think it will take years and years before they find out what RLS is about and what can be done. I
Corrie

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

Postby ViewsAskew » Sat May 31, 2014 10:53 pm

cornelia wrote:I just read the study and I think again; how promising and then immedately after that I read it is preliminary, which is understandable makes me feel that they need a lot more time to figure this part of research out. I respect all the research that is done A LOT but honestly the more I read the more I think it will take years and years before they find out what RLS is about and what can be done. I
Corrie


Yes, I agree. Ten years ago, I was hoping for something significant in about ten to fifteen years. While we do know a lot more, it's all incidental info - we still know nothing about the actual mechanism.
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Re: Published Research - General Sleep and WED (RLS)

Postby Rustsmith » Fri Jun 06, 2014 3:19 pm

I don't know if this NIH report has been referenced already, but if not then some may find it interesting. The referenced site provides an executive summary of the entire report, which apparently is a book.

http://www.ncbi.nlm.nih.gov/books/NBK153154/

In reading through it, the main message that I got was that there is a LOT that is not known and has not been studied and that this extends well beyond the simple "what causes WED" and "how is it best treated".

Since this report was prepared for the NIH, hopefully this will result in some additional research and maybe some of the large scale studies that are recommended.

Also of note was their finding of no studies of opiates in the treatment of WED even though they admit that this is common practice.
Steve

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

Postby ViewsAskew » Fri Jun 06, 2014 7:49 pm

Thanks, Steve. I do not think I'd seen it.

They cited that no "eligible" studies cited the use of opioids. There are several studies. One was just done in 2013 (summer?), likely after this was written (Feb 2013), and it was done primarily so we'd have a decent study to cite, as I understand it. It was a German study, by Trenkwalder, IIRC. I was so pleased when it came out - many of us are on thin ice regarding opioid use. This legitimized it for us.

I once asked the doctors on the WEDF medical advisory board why no opioids were approved for treating WED. The cost to do a study is very high. Since all the opioids are already in generic form, there is no incentive for a drug company to run such a study. They told me opioids would never be "on label" in the US because of that.

I hope that this study was used by someone at the NIH to identify new funding and research options!
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Re: Published Research - General Sleep and WED (RLS)

Postby badnights » Wed Jun 11, 2014 3:01 pm

The first thing I thought of on reading of the relation between leg hypoxia and WED was iron, our oxygen carrier, already heavily implicated in WED. No idea what the mechanism might be; how does the body choose how to distribute iron when stores are low? are the legs the first to be sacrificed? But there is only one frustratingly incomplete speculation on this in the links and posts below, by Salminen that "...there are probably other mechanisms at play — possibly iron-mediated oxygen transport."
Beth - Wishing you all restful sleep tonight
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Chronic sleep loss increases permeability of bbb

Postby badnights » Wed Jul 02, 2014 6:05 am

Apparently, sleeplessness can cause an unhealthy permeability of the blood-brain barrier, allowing neurotoxins entry to the brain. The article is a poor translation from Spanish (I assume), and a lot of it is speculation, but it seems that they demonstrated degradation of the bbb in animal models, and increased permeability of the degraded bbb to 2nd-generation anti-histamines. I recall someone posting recently about worsening of WED when they took 2nd-generation anti-histamines, and this offers an explanation.

see also the post in this Topic called "Chronic sleep loss might cause long-term damage to brain cells" viewtopic.php?f=5&t=4749&p=74034&hilit=Chronic+sleep+loss+damage+to+brain+cells#p74034

Sleep loss causes brain vulnerability to toxic elements
10 June 2014 Investigación y Desarrollo

The longer the insomnia, junctions of cerebral blood vessels begin to degrade

In search of the answer to why do we sleep, research conducted at the Mexican Metropolitan Autonomous University (UAM) revealed that chronic sleep loss can cause certain neurotoxic molecules, which normally circulate in the blood, to be transported to the central nervous system and interfere with the function of neurons.

Beatriz Gómez González, professor and researcher at UAM and head of the scientific project, explained that this phenomenon arises due to an alteration in the central nervous system called blood-brain barrier, which is the component responsible for protecting the brain from potentially neurotoxic agents.

Through the induction of sleep loss on some animals, the specialist at UAM and his staff corroborated that the longer the period of insomnia, joints vessels in the blood-brain barrier began to degrade. "The blood vessels were found not so closely united, we observed that some elements could cross that barrier and reach the brain tissue itself," explained the researcher.

By entering the brain, some nerve agents could potentially affect neuronal function and even promote neuron death. For example, the specialist said, an agent called monosodium glutamate found in a wide range of processed foods may cause neuronal damage by overactivation of these cells (excitotoxicity), although the range of neurotoxic agents circulating in the blood is very extensive.

Furthermore, the research group at UAM studied the risks that could arise as a result of the administration of some drugs to the increased permeability of the blood-brain barrier induced by chronic sleep loss. Gómez González said that, based on some studies, it has been confirmed that some second-generation antihistamines permeate into the brain tissue when this phenomenon occurs.

"Although manufacturers of antibiotic drugs or second-generation antihistamines ensure that these do not affect brain function, there is evidence that these may impact on the central nervous system when there is an increase in the permeability of the blood-brain barrier," said the researcher. This phenomenon may cause some unwanted excitotoxicity effects in neurons, drowsiness, behavioral changes and even neuronal death.

Another phenomenon reported by researchers at UAM, with the induction of sleep loss in animals is the increased number of pinocytotic vesicles in cells. These relate to certain folds of a cell elements and capture materials found in the bloodstream; but this phenomenon may increase the risk of neurotoxic elements entering the brain tissue. "The animals that have been induced sleeplessness develop up to three times these vesicles compared to animals in natural state."
Beth - Wishing you all restful sleep tonight
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