Published Research - General Sleep and RLS (WED)

[Oozz]

New paper by ferre on adenosine. Can anyone translate?

https://www.sciencedirect.com/science/ ... 0822003884

[Rustsmith]

It took me about three times through to mostly understand his first paper. This one may require five or six times even after reading his previous work.

After a quick scan, I suspect that this is mostly a summary paper that summarizes both his past work, the work of others and some work since his original publication. I didn't see much that seemed new news, except that this time he also mentions the role of endocabinoids along with dopamine, glutamate and adenosine. I had heard that he was working to understand how opioids help with RLS, so maybe this is an offshoot of that work.

I will continue reading this new work and will let you know if there is something new (if and/or when I find it).

[stockton2malone2]

https://n.neurology.org/content/82/21/e185
"The investigators showed that reduced leg oxygen levels were strongly associated with RLS symptom severity in untreated patients. They also showed that leg oxygen levels partially improved after dopamine medicine was restarted.3 Reduced leg oxygen levels improved when pramipexole treatment was restarted, similar to the effects of leg movement. This suggests that pramipexole may have a treatment effect on leg blood vessels in addition to its actions on brain and spinal cord nerve receptors.
This study by Salminen and colleagues has helped us better understand the problems, but more studies are needed. Low leg oxygen levels in RLS/WED need to be studied. It is possible that improving low leg oxygen levels could be a helpful treatment. This study did not prove that lower leg oxygen actually causes RLS/WED symptoms; it is also possible that lower leg oxygen instead results from the symptoms of RLS/WED. Further research is needed to clarify the direction of this association. Future research will need to determine what causes reduced leg oxygen levels in RLS/WED at a molecular level. One possible cause may involve nitric oxide (NO), a relaxer of blood vessel walls that may improve blood flow. If it can be shown that problems in NO function occur in RLS/WED, then treatments targeting such problems could potentially improve RLS/WED symptoms. Future laboratory and human studies are also necessary to understand how, when, and where dopamine therapies act in RLS/WED. This could lead to new treatments focused on leg blood vessels that could reduce some of the side effects of RLS medications."

[XenMan]

This study did not prove that lower leg oxygen actually causes RLS/WED symptoms; it is also possible that lower leg oxygen instead results from the symptoms of RLS/WED.

Peripheral hypoxia in restless legs syndrome (Willis-Ekbom disease)

" 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."

You can't have any discussion or research in this area because it suggests that there is a physical element to RLS, which is against the 'Iron Cult', the purely neurological dogma and rock star doctors, one of which published a paper on RLS that is biased, lacking and frankly irresponsible. That is why there are only two papers on this, cricket sounds following and nothing since.

If physical was researched, and accepted, it would change and solve many of the mysteries. Thankfully, I'm a science sceptic, in that I read the whole paper and conflicting papers to have a balanced view on everything.

I'm also glad that my RLS seems to be coming to an end, which wouldn't have happened if I followed the groupthink and taken the drugs.

[badnights]

https://n.neurology.org/content/82/21/e185
"The investigators showed that reduced leg oxygen levels were strongly associated with RLS symptom severity in untreated patients. They also showed that leg oxygen levels partially improved after dopamine medicine was restarted.3 Reduced leg oxygen levels improved when pramipexole treatment was restarted, similar to the effects of leg movement. This suggests that pramipexole may have a treatment effect on leg blood vessels in addition to its actions on brain and spinal cord nerve receptors.
This study by Salminen and colleagues has helped us better understand the problems, but more studies are needed. Low leg oxygen levels in RLS/WED need to be studied. It is possible that improving low leg oxygen levels could be a helpful treatment. This study did not prove that lower leg oxygen actually causes RLS/WED symptoms; it is also possible that lower leg oxygen instead results from the symptoms of RLS/WED. Further research is needed to clarify the direction of this association. Future research will need to determine what causes reduced leg oxygen levels in RLS/WED at a molecular level. One possible cause may involve nitric oxide (NO), a relaxer of blood vessel walls that may improve blood flow. If it can be shown that problems in NO function occur in RLS/WED, then treatments targeting such problems could potentially improve RLS/WED symptoms. Future laboratory and human studies are also necessary to understand how, when, and where dopamine therapies act in RLS/WED. This could lead to new treatments focused on leg blood vessels that could reduce some of the side effects of RLS medications."

Nitric oxide levels are increased by beta-endorphins. These and other endorphins are known to be low in WED/RLS from brain autopsies (sorry I don't have the references).
(You can also increase endorphins by laughing, even if it's fake laughter. And even by using the muscles that turn up the corners of your mouth (fake smiling). )

[badnights]

The glymphatic system is involved in WED. Ya, that's what I said, too: The What?

The article about it being involved in WED:
https://academic.oup.com/sleep/advance- ... ogin=false

An article that explains what it is (too bad we have to buy these but at least the abstracts are free):
https://link.springer.com/article/10.10 ... 015-1581-6

Wikipedia's harder-to-understand version of what it is:
https://en.wikipedia.org/wiki/Glymphatic_system

[Oozz]

Interesting case report study for treating augmentation. Any thoughts?

Article title: Aripiprazole, a Novel Option in the Management of Restless Legs Syndrome (RLS) Patients with Augmentation and/or Severe RLS Symptoms: A Report of 4 Cases

https://www.researchgate.net/publicati ... of_4_Cases

On a separate but related note, I’ve long theorized that an ultra low dose dopamine antagonist could be used to sensitize the dopamine receptor in augmentation. There are studies showing this for Parkinson’s.

[Rustsmith]

After reading through the case histories of the four patients involved in this study, I am not very impressed. There was little consistency between the backgrounds of the individuals and the authors admitted that the aripirazole could make RLS worse in some patients.

I find more hope in the use of Ecopipan for the treatment of augmentation, but larger scale trials are needed (if they are not already underway). Ecopipan works on the D1/D5 receptors in the spine and the theory is that augmentation results when there an imbalance between the D2/D4 and D1/D5 receptors develops.

If this new theory works, it would allow dopamine agonists to be "safely" used with far less chance of developing augmentation.

Here are two brief descriptions of work done to day, but there is more available if you dig:
https://www.tandfonline.com/doi/abs/10. ... 20.1838515
http://rlsfoundation.blogspot.com/2022/ ... erapy.html

[Rustsmith]

Below is the abstract of a paper written by David Rye at Emory that looked at RLS, PLMS and cardiovascular disease (CVD). They did not find a correlation between RLS and sub-clincial CVD but may have seen a correlation between PLMS and CVC.

Restless legs syndrome (RLS) and periodic limb movements of sleep (PLMS) have been variably implicated in risk for cardiovascular disease (CVD), but there is lack of consensus on these relationships. We sought to assess subclinical CVD measures and RLS/PLMS in a large cohort to further evaluate these associations. The Emory Center for Health Discovery and Well Being cohort is composed of employed adults, with subclinical CVD measures including endothelial function (flow-mediated vasodilation), microvascular function (reactive hyperemia index, RHI), arterial stiffness (pulse wave velocity and augmentation index), and carotid intima-media thickness (cIMT). Participants were grouped based on presence (N = 50) or absence (N = 376) of RLS and subclinical CVD measures compared between groups. A subset of participants (n = 40) underwent ambulatory monitoring for PLMS and obstructive sleep apnea. PLMS association with subclinical CVD measures was assessed. RLS status was significantly associated with flow-mediated dilation in univariate analyses but not after controlling for potential confounders; RLS was not associated with other subclinical CVD measures. PLMS were significantly correlated with the RHI, augmentation index, and cIMT in univariate analyses; only the association between PLMS and cIMT remained significant (p = 0.04) after controlling for RLS status, age, apnea–hypopnea index, hyperlipidemia, and hypertension. The observed association between higher PLMS and greater cIMT suggests that PLMS may be a marker of subclinical CVD. Further work is needed to determine the relationship between PLMS and CVD risk.

[Oozz]

https://www.forbes.com/sites/williamhas ... ivery/amp/

I saw this on 60 minutes as well. They are using ultrasound to temporarily increase the porosity of the BBb to deliver medicine to certain areas of the brain. I’m sure there is a lot more to this that I am missing but it seems promising.