Published Research - General Sleep and RLS (WED)

[Rustsmith]

I do have access to the full paper, which is very interesting. As Holland said, this is very preliminary work and the sample size for their part of the work was very small (71 total subjects between RLS and controls). But then they compared their results with other studies and post-mortem brain tissue and got good correlations. They were able to predict RLS with 90% accuracy using serum samples, which would be great if a GP could run a "simple" blood test to get reasonable predictions of RLS, especially for patients who cannot answer the current diagnostic questions, like children and those suffering from dementia.

The authors point out a large number of limitations to their work beyond just the sample size, including the fact that there is currently no way to tie their procedure results back to any of the known physical aspects of RLS. Perhaps a bit surprising was that none of the normal genes that usually correlate with RLS (MEIS1, BTBD9 and PTPRD) were involved in their results. But then they point out the very limited size of their sample cohort and so they suggested that replicating their study on a much larger group would quite possible introduce these 3 genes.

What was interesting is that the genes that were involved in their results touch upon a number of other diseases, including a couple that often have significant correlations to RLS, like Parkinsons and ADHD.

All in all, a very interesting first step but one that will require a number of followup studies.

[Oozz]

https://jcsm.aasm.org/doi/10.5664/jcsm.9404

These results suggest that NPNS could be a promising alternative to pharmacological therapies for RLS and could provide a solution for medication-resistant RLS patients and for medication-naïve RLS patients who are unwilling or unable to take medication.

[ViewsAskew]

Very interesting!

[debbluebird]

I don't understand. What is it? How does it work?

[Rustsmith]

This is an important new update to the recommended ways of managing RLS. It addresses some important new treatments as well as new ways of classifying RLS, especially for those of us with the more severe form of the disease.

https://www.mayoclinicproceedings.org/a ... 0/fulltext

EDIT:
The article can now be found at:
https://www.sciencedirect.com/science/a ... 9620314890

[ViewsAskew]

I don't understand. What is it? How does it work?

If you go to the link to the study, it gives a bit more info. Not a lot, but it tells you the device they used. How it works? No idea! My guess is that it's similar to a TENS in its delivery, but is doing something else.

https://clinicaltrials.gov/ct2/show/NCT04700683

Device: Noctrix Health NPNS device v1.0 - Active
Wearable device programmed to deliver electrical stimulation to peripheral nerves of the lower limbs.

[Oozz]

I’m wondering if it is a TENS or NMES, the electrical current I believe is different as is the rhythm. A proprietary rhythm of the stimulations could make this uniquely effective for RLS. Also they are focusing on a nerve near the calf. I’m very interested to see what the actual protocol is.

[Oozz]

https://scholar.google.com/scholar?as_y ... P3lxn9K-cJ

Conclusions

Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep. Our findings confirm the efficacy of dipyridamole in restless legs syndrome predicted from preclinical studies and support a key role of adenosine in restless legs syndrome. © 2021 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society

[stjohnh]

Conclusions

Dipyridamole has significant therapeutic effects on both sensory and motor symptoms of restless legs syndrome and on sleep.

This is a very helpful development in RLS treatment. The authors include people who worked on the much more theoretical article published a couple of years ago outlining the possible roles of adenosine and glutamate pathway dysfunction (resulting from brain iron deficiency) in RLS. This article shows, at least, that dipyridamole could be used as initial treatment for mild/moderate RLS. It adds another step to better meds for treating more severe patients.

I continue to have some sleep issues, even though my urge-to-move is well controlled with iv iron (Injectafer) about once yearly. I tried dipyridamole a couple of years ago while I was still using pramipexole and noticed a distinct improvement. I am currently using THC to help with sleep, but don't like the stoned feeling or balance problems that the THC produces. I have considered trying dipyridamole in conjunction with the iv iron, and am more strongly considering it after reading this article.

This information should make it much easier for people who want to try dipyridamole to get it from their doctors.

[badnights]

An interesting case report of treatment of WED/RLS with Chinese herbs. An interesting read, despite their use of the adjective "psychosomatic".

Successful treatment of restless leg syndrome with the traditional herbal medicines Dangguijakyak-san and Shihogyeji-tang - A case report

"The patient was treated with extracts of the traditional herbal medicines Dangguijakyak-san (DS) and Shihogyeji-tang (ST). After 47 days of therapy, all herbal medicines were discontinued, and symptoms had not returned by the last follow-up 244 days after the initial treatment."

"DS and ST have a number of pharmacological effects. A previous study suggested that DS has a synergistic effect on the synthesis of acetylcholine and norepinephrine in the cerebral cortex and hippocampus.[22] This pharmacological action is assumed to have a positive effect on climacteric disorder models.[22] ST is a combination of Soshihotang and Gyejitang, and Soshihotang is known to exhibit antidepressant effects by increasing the levels of monoamine neurotransmitters.[23] Therefore, we predicted that combining DS and ST would have a positive effect on RLS, as revealed by psychosomatic symptoms. In particular, we focused on Paeoniae Radix, which is a common component of DS and ST. A systematic review and meta-analysis reported that herbal medicine prescriptions containing Paeoniae Radix were helpful for alleviating symptoms of RLS.[13] Paeoniflorin, the major component of Paeoniae Radix, is known to act as an activator of the adenosine A1 receptor (A1R), which plays a role in stabilizing brain metabolism by lowering synaptic secretions.[24,25] Iron deficiency has often been found in patients with RLS, and an experimental study suggested that an iron-deficient diet lowers the activity of the A1R and dopamine D2 receptors.[26] Based on these findings, we expected that the paeoniflorin in Paeoniae Radix could enhance dopamine activity through the activation of the A1R and recover the function of the dopaminergic A11 system to alleviate the symptoms of RLS.

These pharmacologic effects of DS and ST seem to be involved in the suppression of abnormal sensations related to RLS. Notably, in contrast to conventional pharmacological treatment, abnormal sensations did not recur for months following the discontinuation of DS and ST. Pharmacological treatment with dopamine agonists is known to cause dopamine agonist withdrawal syndrome[27] and RLS symptoms reappear as soon as treatment is discontinued.[28] This also suggests that the components of DS and ST, especially Paeoniae Radix, have a semi-permanent effect on the improvement of A1R function in RLS patients. However, additional clinical and experimental studies are required to further evaluate this potential effect."

Full article is here : https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8341247/

[Rustsmith]

Here is a link to the recent publication that reports on the double-blind study of dipyridamole. The results still look good, but the most severe case in the trial was an IRLSSG rating of only 24.

https://pubmed.ncbi.nlm.nih.gov/34137476/

[badnights]

Published in Sleep Medicine, October 2021
Abstract

Background and aims
The data on the prevalence of the Restless Legs Syndrome/Willis -Ekbom disease (RLS/WED) in the population of teenagers is scarce. The aim of this study was to determine RLS/WED occurrence in adolescents, its diagnostic accuracy, family history, clinical characteristics and impact on everyday functioning.
Material and methods

A group of 2379 pupils (aged 13-18 y.o.) from 6 randomly selected secondary schools in Gdańsk, Poland were screened for RLS/WED with the use of a questionnaire. In order to verify the diagnosis and perform additional tests (neurological examination, psychological evaluation, biochemical blood tests, demographic questionnaire, International RLS rating scale/IRLSS, Epworth daytime sleepiness scale). all of the respondents with RLS/WED suspicion and their parents were asked for a consultation by a child neurologist. Both children and parents with RLS/WED diagnosis were tested with actigraphy at home for at least two consecutive nights.

Results
Two thousand and ninety seven students (88,15%) filled the questionnaire correctly (1171 girls and 926 boys, 56% and 44%). Sixty four respondents were suspected of having RLS/WED (3,1%), however, 36 of them were diagnosed as RLS/WED-mimics (mainly positional discomfort). Finally, 21(1%) were diagnosed with definite idiopathic RLS/WED. The average age of symptom onset was 10. 96 years. The severity was moderate in the most of the cases (61. 9%) and the course of the disease was intermittent in all of them. Family history was positive in 80%. Abnormal actigraphy (PLMS index > 5/h) was present in 80%. Blood level of ferritin was low (<50ng/ml) in 85%. Excessive daytime sleepiness and school problems affected almost half of them. The presence of RLS/WED symptoms was associated with disrupted sleep, behavioral problems (irritability, aggression, hyperactivity), attention deficit and lowered mood. No correlation between RLS/WED and attention deficit hyperactivity disorder (ADHD), nocturnal enuresis or primary headaches was found. Thirty eight percent of the patients sought medical help, but none of them obtained proper diagnosis nor treatment of RLS/WED.

Conclusions
In this study restless legs syndrome affected 1% of Polish teenagers, in the majority of cases was idiopathic and associated with positive family history. It affected sleep and everyday functioning. Neurological consultation is essential to avoid false positive diagnoses of RLS/WED in teenagers.

Keywords
restless legs syndrome
Willis-Ekbom disease
adolescents

[ViewsAskew]

None got a diagnosis. Yeesh.

[badnights]

I just read a study, to be published in January 2022 but available online now. It is called Screening autonomic functions in patients with restless legs syndrome. The abstract is here: https://www.sciencedirect.com/science/a ... 0221001545. My summary follows.

The motive for the study was the thought that WED/RLS might be related to dysfunctions in the autonomic nervous system. That's the part of the nervous system that controls unconscious body functions: heart rate, blood pressure, digestion, temperature control, sweating, urination, sexual functions. The idea of a relationship arose because various autonomic changes have been associated with WED/RLS: blood pressure changes, heart-rate variability changes,and dysfunction in gastrointestinal, urinary and sexual functions. Also, autonomic changes are known to be associated with PLMS, which is common in WED/RLS. And certain dopaminergic neurons (possibly related to WED/RLS) project from the hypothalamus to parts of the spinal cord that mediate the autonomic nervous system.

So the study authors decided to use a questionnaire designed to detect signs of autonomic dysfunction, plus the Epworth Sleepiness Scale and the IRLSSG severity scale, on a group of 70 patients who had never taken medications for WED/RLS and a group of 85 healthy controls.

The results indicate that having WED/RLS is associated with having the following autonomic problems (note this is a statistical association - not everyone with WED has any or all of these problems):

swallowing/choking (gastrointestinal subscale)
sialorrhea (drooling) (gastrointestinal subscale)
urinary urgency (urinary subscale)
urinary incontinence (urinary subscale)
urinary frequency (urinary subscale)
nocturia (peeing at night) (urinary subscale)
light-headed standing up (cardiovascular subscale)
light-headed standing for some time (cardiovascular subscale)
cold intolerance (thermoregulatory subscale)
over-sensitivity to bright light (pupillomotor subscale)
women: vaginal lubrication problems (sexual subscale)
women: problem with orgasm (sexual subscale)

Two other studies showed that male patients with severe WED/RLS have an increased risk of erectile dysfunction. This study did not show that, but probably only because the number of males in the study was small (18 patients, 20 controls).

(The authors of this study say that both the heat intolerance and cold intolerance scores are higher in WED/RLS patients than in controls, but the numbers in their table actually say that controls have more of a problem with heat intolerance than WED patients. Maybe they mixed the numbers up. If so, then heat intolerance should be added to the above list.)

The authors also found positive correlations between WED/RLS severity and total autonomic dysfunction score, as well as the gastrointestinal, cardiovascular, and thermoregulatory subscale scores; and between Epworth Sleepiness score and total autonomic dysfunction score, as well urinary, cardiovascular, and pupillomotor subscale scores. No relationship was found among age, body mass index, disease duration, age at disease onset, and autonomic dysfunction scores.

The mechanisms underlying these dysfunctions are not clear. Cardiac issues could arise from disrupted sleep. Many autonomic issues could arise from the state of hyper-arousal caused by over-activity of glutamate in the WED brain.

[Frunobulax]

I just read a study, to be published in January 2022 but available online now. It is called Screening autonomic functions in patients with restless legs syndrome. The abstract is here: https://www.sciencedirect.com/science/a ... 0221001545.

For those of us reading a lot of studies, if you are asked for a christmas wish then there is a book that I can recommend very much: Stuart Ritchies "Science Fictions: Exposing Fraud, Bias, Negligence and Hype in Science". I knew quite a few things that could go wrong with studies, but this book taught me a few new tricks -- and things to look for. And unfortunately something in that book fits this study: There is something fundamentally wrong if the sample sizes (number of patients) are as small as in this study, which means that the study it will either show false results or greatly exxagerate results.

Mind you, I haven't read the full text of this study. And I can't say if the results are correct or not. But I do see a few red flags just from reading the abstract. I just thought this study would make a good example to share some of what I have learned, and explain the generic issues with small numbers

The researches took RLS sufferers and had them fill out a questionaire. Then they looked for statistical trends, and reported the one that had statistical significance. And you should never, ever do that. For one, questionnaires are notoriously unreliable. (Do all patients have the same understanding? One person may have a totally different concept of what severe pain is than the next person. Also bias is important, which is well known from nutritional science: Could you say how many eggs you ate in the last year? Do you count eggs used in bread/cake/convenience foods, and how many did you have? Note that if you think eggs are not healthy, for whatever reason, you will probably vastly underestimate the number of eggs you ate.) But let's assume for the rest of this post that all patients filled out the questionnaire perfectly. The reason why whatever result you see will be either wrong or exaggerated is purely mathematical and lies in the small numbers.

The problem is best explained with an example. Consider a 2-sided coin. If you do 1000 flips and head comes up say 60% of the time, we can be very sure that the coin isn't fair. But if we do 10 flips and head comes up 6 times there is a strong possibility that this is just random chance and the coin is fair. Studies use the concept of the p-value and statistical significance to express this. The quest in studies is to reach "statistical significance", which is defined as a p-value of at most 0.05 -- and you have a much better chance of getting your paper published if the p-value is at 0.049 compared to 0.051.

The definition of the p-value, if I remember correctly, is that this is the probabilty of seeing this exact data being just a random fluctuation.If you flip it 4 times and head comes up every time, you might assume that it's "loaded" and not a fair coin. However, the chance of getting 4 times head with a fair coin is 1 out of 16 (6.25%), so you write a research paper about it you'd write "this is not a fair coin, heads is more likely to come up than tails, p-value 0.0625 (not statistically significant)". The "not statistically significant" means that there is at least a 5% chance that the result isn't really there -- it could be a fair coin and you just got unlucky. On the other hand, do 5 flips and if head comes up every time then the p-value is 0.03125.


(1) Take 1000 fair coins and flip them each 5 times. (Think 1000 different questions in your questionaire.) On average, 31 of these coins will show heads 5 times (1 out of 32 flips) and 31 will show tails 5 times. By your protocol, you would report that you have found 62 coins to be unfair (after all the p-value for each coin is 0.03125 that it is fair) -- even though all coins were fair!

(2) Now we do a second experiment. Take an unfair coin, that has a 60% probability of showing heads and 40% tails. The probability to roll heads 5 times in 5 flips is 7.78%. Now roll 1000 such coins 5 times each. You will find that (on average) 78 coins show heads 5 times, so you would conclude that 78 coins are unfair (correctly) and have a 100% chance to come up with heads (dead wrong), p=0.03125 again. (If it is a fair coin, the chance is still 3.125% to give this result.) You would also see "no statistically significant result" for the remaining 922 coins (again dead wrong).

And this illuminates what the problem with small numbers is. Because as in experiment (1), simply due to random chance some associations will show up that aren't really there. But even worse, as you see from experiment (2), you will miss most associations (we couldn't show anything for 922 coins) and the remaining associations are vastly exxagerated (we thought that 78 coins have a 100% chance to come up heads).

This is not a theoretical example. We had this in genetics when researchers looked for "critical genes", genes that would determine some major trait (intelligence, height or whatever). Researchers did small studies and identified a lot of "candidate" genes, claiming strong associations with some personality traits -- and all of them were wrong and couldn't be verified in followup studies with larger numbers.

The problem of course is the method. A good study lists all the effects it wants to check before the study is started, and then reports all results (regardless of the p-value). Looking for effects in data that you have already collected is the equivalent of the "Texas sharpshooter fallacity" (https://en.wikipedia.org/wiki/Texas_sha ... er_fallacy): Shoot 30 bullets randomly at a barn and you will find some bullet holes grouped close together. Then draw a bullseye around these bullet holes and claim that there was something that attracted the bullets to this spot, there has to be a relation there!

Now, you *can* see good results in small numbers, but then the p-value will be much lower than 0.05. Take smoking for example, which increases the risk of lung cancer by a factor 10 to 30 (depending on the study) -- if you take 100 lung cancer patients then 90 or more of them would have been smokers. However, if we talk about RLS, there is literally no hope of finding such a clear cut association

Anyway, do get the book. It's a fascinating read.