The Relationship Between Inflammation and RLS

For everything and anything else not covered in the other RLS sections.
inflammatory_rls
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The Relationship Between Inflammation and RLS

Post by inflammatory_rls »

I was intrigued davew’s assertion on this board (viewtopic.php?f=20&t=7129) that RLS is caused by inflammation, and decided to research the issue. I have no connection to davew, nor have I tried the purported “absolute cure” on RLCure. As a disclaimer, I have no background in science or medicine.

As asserted by davew, there is evidence that RLS is caused by general bodily inflammation (1, 2, 3). However, after researching the topic, I believe RLS is more plausibly caused by one specific type of inflammation: that of the Central Nervous System (CNS).

There isn’t any hard proof that CNS inflammation causes RLS (if there was, I wouldn’t need to spend my time writing this), but there is a considerable amount of incidental evidence. The purpose of this post is to demonstrate a correlative, and perhaps causative, link between CNS inflammation and RLS. I will present three arguments: first, that my inflammatory-RLS theory is consistent with what we know about RLS pathology; second, that my theory is consistent with what we know about RLS treatment; and third, that my theory is consistent with what we know about other related diseases.

RLS Pathology

RLS patients have irregularities in a variety of biological systems. Problems with these same systems can sometimes be caused by inflammation. Consider the following facts:
  • RLS has been linked to decreased iron levels in the CNS, even when RLS patients have normal blood iron levels (4). Iron deficiency is associated with inflammation (5).
  • RLS has been linked to dysfunction in patients’ dopaminergic circuitry (6). Abnormalities in mesolimbic and mesostriatal dopamine is associated with inflammation (7).
  • RLS has been linked to impairment of patients’ endogenous opioid systems (8). Debility of the opioid system is associated with inflammation (9).
  • RLS has been linked to elevated glutamate levels in the brain. Heightened glutamate levels may worsen sleep quality without a proportional increase in daytime sleepiness, symptoms which present in many RLS patients (10). Elevated glutamate levels are associated with inflammation (11).
  • RLS has been linked to dysregulation of serotonergic neurotransmission (12). Serotonergic imbalance is associated with inflammation (13).
As a response to inflammation, the brain produces quinolinic acid (14), a neurotoxin that acts as an N-methyl-D-aspartate (NMDA) receptor agonist. Artificially-induced in vivo CNS inflammation has caused a 246-fold increase in the level of quinolinic acid in brain homogenate (15). The effects of elevated quinolinic acid levels are consistent with RLS pathology, as demonstrated by the following points:
  • Injecting rabbits with quinolinic acid has precipitated seizures and disturbed sleep (16).
  • Injecting quinolinic acid into the brains of mice has precipitated seizures (17, 18).
  • Quinolinic acid “can increase glutamate release by neurons, inhibit its uptake by astrocytes and inhibit astroglial glutamine synthetase leading to excessive microenvironment glutamate concentrations and neurotoxicity” (14).
  • Other neurological diseases, including multiple sclerosis and Parkinson’s disease, are associated with quinolinic acid (19, 20). I discuss the connection of RLS to multiple sclerosis and Parkinson’s disease below.
RLS Treatment

Just as a variety of biological systems are implicated in RLS symptoms, a variety of treatments are used to soothe those symptoms. These same treatments are used to fight inflammation.
  • Hydrocortisone, which fights inflammation, has been used as an effective treatment for RLS (21, 22).
  • Vitamin D and folate can reduce RLS symptoms (23, 24). Both substances can also be used to treat inflammation (25, 26).
  • Magnesium is effective in treating some RLS patients (27). Magnesium has been shown to block NMDA receptors (28), tempering the effects of high quinolinic acid caused by neuroinflammation.
  • The drug ketamine has shown promising results in RLS case studies (29). Ketamine has anti-inflammatory properties and is a powerful NMDA antagonist (30).
Related Diseases

RLS has comorbidity with other diseases that affect the CNS. Our knowledge of most neurological diseases is in an embryonic state, but research ties some of these diseases to inflammation.
  • RLS has well-documented comorbidity with multiple sclerosis (31). Of particular interest is the fact that RLS can either precede or proceed the onset of multiple sclerosis (32), suggesting that neither disease causes the other, but that they are caused by the same lurking condition. The current scientific consensus is that multiple sclerosis is caused by immune-mediated inflammation of the CNS (33), which is consistent with my theory that CNS inflammation also causes RLS. Additionally, atrophy of the corpus callosum (found in both RLS (34) and multiple sclerosis (35) patients) has been associated with inflammation (36).
  • RLS has comorbidity with Parkinson’s disease. As is the case in multiple sclerosis, RLS may either precede or proceed the outbreak of Parkinson’s disease symptoms (37). The cause of Parkinson’s disease has not yet been fully elucidated, but CNS inflammation is thought to be an important component (38).
  • RLS has comorbidity with epilepsy (39), which research indicates is caused in part by inflammation (40).

The theory that CNS inflammation causes RLS is consistent with our knowledge of RLS pathology, treatment, and related diseases. I am unaware of any significant research refuting this hypothesis.

Thank you for taking the time to read this meandering, dilettante post. I welcome all critiques of this inflammatory-RLS theory, especially those from persons with scientific or medical backgrounds. It seems to me that any competing theory would have difficulty collating and justifying the available RLS pathology and treatment data, especially in offering explanations for the effectiveness of hydrocortisone and the non-causal RLS comorbidity with multiple sclerosis.


1. Restless Legs Syndrome--Theoretical Roles of Inflammatory and Immune Mechanisms, https://pubmed.ncbi.nlm.nih.gov/22258033/
2. Elevated C-reactive Protein Is Associated With Severe Periodic Leg Movements of Sleep in Patients With Restless Legs Syndrome, https://pubmed.ncbi.nlm.nih.gov/22750520/
3. Polymorphisms of Interleukin-1 Beta and Interleukin-17Alpha Genes Are Associated With Restless Legs Syndrome, https://journals.sagepub.com/doi/abs/10 ... 8827?rss=1
4. Causes of Restless Legs Syndrome, https://www.hopkinsmedicine.org/neurolo ... auses.html
5. Iron Homeostasis and the Inflammatory Response, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3108097
6. Restless Legs Syndrome: Current Concepts about Disease Pathophysiology, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4961894/
7. Inflammation Effects on Motivation and Motor Activity: Role of Dopamine, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5143486/
8. Does the Endogenous Opiate System Play a Role in the Restless Legs Syndrome? A Pilot Post-Mortem Study, https://pubmed.ncbi.nlm.nih.gov/19167016/
9. Alteration in Endogenous Opioid Systems Due to Chronic Inflammatory Pain Conditions, https://pubmed.ncbi.nlm.nih.gov/11821033/
10. Thalamic glutamate/glutamine in restless legs syndrome, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3716406/
11. Inflammation-induced changes in peripheral glutamate receptor populations, https://www.sciencedirect.com/science/a ... 9398013286
12. Availability of Brain Serotonin Transporters in Patients With Restless Legs Syndrome, https://pubmed.ncbi.nlm.nih.gov/20142619/
13. The immune-mediated alteration of serotonin and glutamate: towards an integrated view of depression, https://www.nature.com/articles/4002006
14. Quinolinic Acid, the Inescapable Neurotoxin, https://febs.onlinelibrary.wiley.com/do ... 12.08485.x
15. Quinolinic Acid in Vivo Synthesis Rates, Extracellular Concentrations, and Intercompartmental Distributions in Normal and Immune-Activated Brain as Determined by Multiple-Isotope Microdialysis, https://pubmed.ncbi.nlm.nih.gov/9422373/
16. Effect of Quinolinic Acid on Wakefulness and Sleep in the Rabbit, https://pubmed.ncbi.nlm.nih.gov/2144974/
17. Stimulant and Convulsive Effects of Kynurenines Injected Into Brain Ventricles in Mice, https://pubmed.ncbi.nlm.nih.gov/641543/
18. Quinolinic Acid Promotes Seizures and Decreases Glutamate Uptake in Young Rats: Reversal by Orally Administered Guanosine, https://pubmed.ncbi.nlm.nih.gov/15262204/
19. Kynurenine pathway metabolomics predicts and provides mechanistic insight into multiple sclerosis progression, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5290739/
20. Alternations of Metabolic Profile and Kynurenine Metabolism in the Plasma of Parkinson's Disease, https://pubmed.ncbi.nlm.nih.gov/29294246/
21. Low-dose Hydrocortisone in the Evening Modulates Symptom Severity in Restless Legs Syndrome, https://pubmed.ncbi.nlm.nih.gov/18443313/
22. Oral glucocorticosteroids: Effective in a case of restless legs syndrome resistant to other therapies, https://www.sciencedirect.com/science/a ... via%3Dihub
23. The Effect of Vitamin D Supplements on the Severity of Restless Legs Syndrome, https://pubmed.ncbi.nlm.nih.gov/25148866/
24. Restless Legs Syndrome: Pathophysiology and the Role of Iron and Folate, https://pubmed.ncbi.nlm.nih.gov/17604457/
25. Vitamin D and inflammatory diseases, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4070857/
26. Folic Acid Is Able to Polarize the Inflammatory Response in LPS Activated Microglia by Regulating Multiple Signaling Pathways, https://www.hindawi.com/journals/mi/2016/5240127/
27. Magnesium Therapy for Periodic Leg Movements-Related Insomnia and Restless Legs Syndrome: An Open Pilot Study, https://pubmed.ncbi.nlm.nih.gov/9703590/
28. The mechanism of magnesium block of NMDA receptors, https://www.sciencedirect.com/science/a ... 6584710128
29. Oral Ketamine: A Promising Treatment for Restless Legs Syndrome, https://journals.lww.com/anesthesia-ana ... ss.34.aspx
30. The Anti-Inflammatory Effects of Ketamine: State of the Art, https://pubmed.ncbi.nlm.nih.gov/21612145/
31. Association of multiple sclerosis with restless legs syndrome and other sleep disorders in women, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3345617/
32. High Prevalence of Restless Legs Syndrome in Multiple Sclerosis, https://pubmed.ncbi.nlm.nih.gov/17437613/
33. Chronic inflammation in multiple sclerosis — seeing what was always there, https://www.nature.com/articles/s41582-019-0240-y
34. Involvement of the Central Somatosensory System in Restless Legs Syndrome: A Neuroimaging Study, https://pubmed.ncbi.nlm.nih.gov/29695597/
35. Corpus Callosum Atrophy May Be an Effective MRI Marker for Long-Term Disease Progression in MS, https://www.mdedge.com/multiplesclerosi ... ective-mri
36. Inflammation Is Related to Corpus Callosum Integrity and Executive Functions in Healthy Older Adults, https://n.neurology.org/content/78/1_Su ... /IN4-1.006
37. Restless Legs Syndrome and Parkinson Disease: A Causal Relationship Between the Two Disorders?, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6066514/
38. Inflammation in Parkinson's Disease, https://pubmed.ncbi.nlm.nih.gov/22814707/
39. Epilepsy and Restless Legs Syndrome, https://pubmed.ncbi.nlm.nih.gov/28109988/
40. The role of inflammation in the development of epilepsy, https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5952578/

stjohnh
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Re: The Relationship Between Inflammation and RLS

Post by stjohnh »

Wow, Thanks for the very interesting and well researched discussion. It will be interesting to see how much future research supports this idea.
Blessings,
Holland


badnights
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Re: The Relationship Between Inflammation and RLS

Post by badnights »

@ inflammatory_rls I read through your post quickly a few days ago, and was intrigued ; I thought "I need to think about this more and check the research". I did check your hydrocortisone mention; I was not previously aware that hydrocortisone had helped WED/RLS symptoms. But I have not had time=energy to do more. If I did read it critically (meaning in the sense of a scientific review), I would look out for confusion of correlation with causation, for awareness that facts being compatible with a theory is not the same as facts supporting a theory, etc. I say that now because I don't know if I'm going to get around to reading it critically. :(
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ViewsAskew
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Re: The Relationship Between Inflammation and RLS

Post by ViewsAskew »

I had a similar thought as Beth. I am just not in a place that I can look at all of this and check each article/research critically - how large was the sample, how long did the research take place, was it a double blind, did they find causation or correlation, and so on.

My background is in the soft sciences - while I've done minor research studies and understand the method, I just don't have the background in biology and chemistry -and I think that is where others with would pick up things I would miss. I may be relatively well-read, but my expertise is elsewhere.

I have long had a somewhat fundamental concern with this theory - and that is for those of us with hereditary RLS/WED who have it from the time we are children. it's possible that there is some gut connection that creates inflammation and could be passed from mother to infant. But, seems odd that those of us with childhood RLS would have inflammation. In my case, I didn't have any that I know of or that showed up on tests until I was in my late forties/early fifties. I have had PLMS since I was a toddler and RLS/WED since I was in middle school.

About 17 or 18 years ago, for other reasons, I did many of the things one does to reduce inflammation from going gluten and sugar free to eating extremely clean to taking many supplements one would associate with reducing inflammation. At the time, my RLS/WED stayed the same as did my PLMS. I would awake upwards of 30 times a night from the movements and never felt rested.

There are other things - pregnancy and sex, for example - that can increase/cause RLS/WED. Women have it more often than men, particularly during child-bearing years. Do they have more inflammation? I don't know. Pregnancy commonly brings it on. It often leaves after delivery, but not always. I am unaware of pregnancy causing inflammation in the body.

People on dialysis have higher rates of RLS/WED, as do people with celiac disease. The only thing, as far as I know, that all of these have in common is the iron issue. And, that seems more likely, to me, to be the link. If inflammation causes iron dysregulation in some way, as does pregnancy, as does celiac as do hormones, then the lack of iron is the root cause, and the inflammation, pregnancy, and so on are what create the iron issue. That would mean that inflammation COULD be a cause for some people. Just as heredity, pregnancy, hormones, and other things are causes. One doctor hypothesizes that the gut microbiome can cause iron dysregulation - maybe inflammation does, also. Or maybe the elimination of things, such as sugar, allow the gut to function better, so that it isn't really the inflammation, but food that fuels the inflammation that also impacts iron. So many unknowns, seems to me.

It's 1 AM where I am, so could be holes in my logic here - as well as missing critical knowledge. Either way, I really believe in science - all of this would have to be rigorously tested.
Ann - Take what you need, leave the rest

Managing Your RLS

Opinions presented by Discussion Board Moderators are personal in nature and do not, in any way, represent the opinion of the RLS Foundation, and are not medical advice.

Frunobulax
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Re: The Relationship Between Inflammation and RLS

Post by Frunobulax »

ViewsAskew wrote:
Wed Jun 03, 2020 8:20 am
People on dialysis have higher rates of RLS/WED, as do people with celiac disease. The only thing, as far as I know, that all of these have in common is the iron issue. And, that seems more likely, to me, to be the link. If inflammation causes iron dysregulation in some way, as does pregnancy, as does celiac as do hormones, then the lack of iron is the root cause, and the inflammation, pregnancy, and so on are what create the iron issue. That would mean that inflammation COULD be a cause for some people. Just as heredity, pregnancy, hormones, and other things are causes. One doctor hypothesizes that the gut microbiome can cause iron dysregulation - maybe inflammation does, also. Or maybe the elimination of things, such as sugar, allow the gut to function better, so that it isn't really the inflammation, but food that fuels the inflammation that also impacts iron. So many unknowns, seems to me.
Reactive oxygen species (ROS), the main marker of systemic inflammation, have a dual purpose: They act as signalling, but in higher concentrations as "chemical warfare" as they destroy the DNA of invading cells (bacteria etc.). Therefore a side effect of inflammation is that some signalling pathways are chronically activated or deactivated.
There is the theory that the body will shift iron from "important" cells to the blood, causing higher ferritin in the blood and lower ferritin where it could help invaders. Thus, an iron deficiency can be caused by the immune system even though iron levels overall are good.

Considering that half of us don't respond to iron IVs, I'm not so sure that lack of iron is the root cause. Something blocks the iron from getting where it needs to be. and I have conjectured in the past that inflammation could be a cause of RLS. Maybe it's not the only reason, that is, maybe inflammation is the cause for people that don't respond to iron IVs, but iron deficiency can be an independent factor.

@inflammatory_rls I will need time to digest this, as I tend to really read linked studies (because so many studies are flawed). Still, maybe a word or two regarding your person would help - do you usually post under a different username, do you have RLS yourself, what's your connection? I find it surprising that someone who apparently has never posted here before writes such a big theory. It raises some doubts if you are familiar with the opinions and "unofficial" consensus here in the forum. As you may know (or not), there is plenty of knowledge here that hasn't made it into the scientific literature. Inflammation has been discussed before, though not in as much depth as you present here.

inflammatory_rls
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Re: The Relationship Between Inflammation and RLS

Post by inflammatory_rls »

@sbunter Thank you for that link. I'm sure I missed other important studies too. There was no real methodology to my research - I just googled a few dozen things.


@badnights I would greatly appreciate it if would review the studies, when you have the time of course. I am aware that correlation does not imply causation, as I have some background in statistics. Not all the evidence I presented is compelling. But I think it is important to note that there does not seem to be any evidence against this theory, and the connection between MS and RLS seems pretty convincing to me.


@ViewsAskew I'm sorry to hear that you developed PLMS and RLS symptoms at such an early age. Intuitively, it doesn't strike me as being more likely that you would develop an iron deficiency at a young age rather than developing CNS inflammation - at a random guess, I would say that both seem roughly as rare.

Regarding your point on diet and supplements, I have not yet had the chance to review studies regarding diet and inflammation, but is it possible that you may have been taking the wrong anti-inflammation supplements? Over the past few days I reviewed quite a few studies regarding the effects of various supplements on inflammation, and one of the main impressions I walked away with was that most supplements are only effective for certain people and circumstances. Very few supplements touted as being anti-inflammatory actually have robust evidence supporting their use.

The role of the immune system during pregnancy seems to be an area of active research, but there is evidence that pregnancy causes inflammation. This study has the most understandable Abstract on the topic, but unfortunately I can't find the full text version for free:
https://pubmed.ncbi.nlm.nih.gov/16843067/

Celiac's disease is an "inflammatory condition," as stated here:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3347005/

And "chronic inflammation is very common among dialysis patients," as stated here:
https://academic.oup.com/ndt/article/28/4/770/1854131


@Frunobulax Thank you for the information regarding iron. I read similar things while researching this topic, but you explained the idea very concisely.

I do not post under a different name, and only discovered this forum a couple weeks ago. I have had RLS for about a decade. While my symptoms are not as bad as those of many people on this board, they would still be considered severe. To give a general idea, once (before I figured out what was wrong and started seeking treatment) I was awake for about 60 hours straight.

I enjoy researching things, and over the years have spent a significant amount of time researching RLS. But my symptoms have worsened dramatically in the past few weeks and my recent research was driven by a fit of urgency rather than interest.

After starting this thread, I came across the thread where you attribute RLS to brain inflammation and recommend a diet-focused treatment approach. I referenced that post in the thread I started about anti-inflammation treatments a couple days ago:
viewtopic.php?p=102598#p102598

Frunobulax
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Re: The Relationship Between Inflammation and RLS

Post by Frunobulax »

inflammatory_rls wrote:
Wed Jun 03, 2020 11:46 pm
@Frunobulax Thank you for the information regarding iron. I read similar things while researching this topic, but you explained the idea very concisely.

I do not post under a different name, and only discovered this forum a couple weeks ago. I have had RLS for about a decade. While my symptoms are not as bad as those of many people on this board, they would still be considered severe. To give a general idea, once (before I figured out what was wrong and started seeking treatment) I was awake for about 60 hours straight.

I enjoy researching things, and over the years have spent a significant amount of time researching RLS. But my symptoms have worsened dramatically in the past few weeks and my recent research was driven by a fit of urgency rather than interest.

After starting this thread, I came across the thread where you attribute RLS to brain inflammation and recommend a diet-focused treatment approach. I referenced that post in the thread I started about anti-inflammation treatments a couple days ago:
viewtopic.php?p=102598#p102598
Thanks for elaborating. You pointed out in that other thread that you're a bit surprised by the lack of reaction. We do approach most theories with caution, as most of us have researched RLS for many years, and we all have been down a few dead ends. :)

Personally I find your theory intriguing. It has caused me to finally write something that I've been mulling over for some time, it's in a separate thread (viewtopic.php?p=102633#p102633). I will dig into the studies you mentioned eventually, but probably not in the next days/weeks as I have some spare time coming up in a couple of months where I can give this the attention it needs. (As you mention, it's always a matter of urgency -- my RLS is pretty well under control but I'm fighting ME/CFS, so I have to juggle different topics with limited energy.)

badnights
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Re: The Relationship Between Inflammation and RLS

Post by badnights »

Frunobulax wrote:Reactive oxygen species (ROS), the main marker of systemic inflammation,
It's misleading to say that ROS are "the main marker" of systemic inflammation. Although ROS are involved in the immune response, they are not routinely measured to detect inflammation.
Beth - Wishing you a restful sleep tonight
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Frunobulax
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Re: The Relationship Between Inflammation and RLS

Post by Frunobulax »

badnights wrote:
Fri Jun 05, 2020 7:45 am
Frunobulax wrote:Reactive oxygen species (ROS), the main marker of systemic inflammation,
It's misleading to say that ROS are "the main marker" of systemic inflammation. Although ROS are involved in the immune response, they are not routinely measured to detect inflammation.
True. I should have been more specific: ROS are main driver in many "silent" inflammations with unknown cause (autoimmune conditions), where we often have no antibodies and only slightly increased values of T-Cells etc. And these are the conditions that interest me the most.

But ROS are eliminated by antioxidants. So as long as a patient has sufficient antioxidants, there will be little oxidative stress (and it's hard to measure them directly, because many of them are very unstable and highly reactive). But low levels of antioxidants are an indirect marker of high ROS, and very typical for autoimmune conditions.

Rustsmith
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Re: The Relationship Between Inflammation and RLS

Post by Rustsmith »

Several days ago I wrote a response to this thread and now I find that it isn't here. I guess that with my poor sleep I never actually hit the Submit button before I hit the Home button on my browser.

As for my background, I was trained as a metallurgical engineer and my specialty is a branch of chemical thermodynamics, which I use when advising my PhD candidate students. I am also fortunate to have online access to the full copy of most medical journals through the university library. This is important since the abstracts can often be somewhat misleading, of which I admit that the abstract of some of my journal publications are not always crystal clear when it comes to the conclusions.

Like others, I have not had a chance to dig through all of the references provided in the original post by inflammatory_rls. However, when I wrote the missing post, I did get a full copy of the first reference to review. This paper is an example of why it is often important to be able to read the full paper and not just the abstract. The paper is what I call a paper study and is something that I see much more frequently in medical journals than in the journals in my field of study. The paper reports on a review of a number of other publications and does not present any new findings. I believe that there are several reasons why these papers are rather common within the field of medicine. One reason (and I suspect the justification for this paper) is to pull together a review of existing literature in the form of a publication so that it can be attached to a request for research funding. I know that my own physician and her co-author did exactly this a couple of years ago. There was a clinical trial at Stanford looking at SIBO and RLS at the time that the paper was published and I suspect that the authors were hoping to build upon Standford's results. Whether they were successful with their proposal is something that we will need to wait to see their future publications.

Another reason for this type of study is for a graduate student or post-doc to publish the results of their literature search. This serves as a record of their work for future students and also helps to pad the student's credentials by adding a publication prior to graduation or a post-doc's resume in hopes of getting a tenure track position at a university.

These papers can be very useful for other researchers, but only if one knows the qualifications and reputation of the authors. In this case, Dr Walters, the second author is well published in the field of RLS work. Without doing some digging, my guess is that the primary author was either a graduate student (who has since left Vanderbilt) or was a post-doc who moved on to the next position.

Regardless, the paper does not present any new ideas and the conclusions presented are all suggestions for future research. Maybe the authors have some ongoing work that came as a result of funding from this paper and maybe it was a dead end. Either way, the paper can serve as a source of bibliographical material that points to the work of others that the authors felt was valid research but does not serve as a source of data to prove or disprove one's theories.

PS - this time I checked to make certain that this actually got posted :lol:
Steve

https://www.mayoclinicproceedings.org/a ... 0/fulltext
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inflammatory_rls
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Re: The Relationship Between Inflammation and RLS

Post by inflammatory_rls »

This is important since the abstracts can often be somewhat misleading
A number of the studies I referenced have only the Abstract freely available. This is mostly because I don't understand enough science to make reading the full study valuable for me, so I have to rely on the Abstract being representative of the rest of the paper.

However, I did make an effort to reference reasonably high-quality publications. I did this by trying to find studies that were referenced by other studies a decent number of times - say at least 20 times. I assume that if a study is being used as a reference, it must meet a certain threshold of usefulness (unless it is being referenced as an example of a poorly-designed study).
Either way, the paper can serve as a source of bibliographical material that points to the work of others that the authors felt was valid research but does not serve as a source of data to prove or disprove one's theories.
Although I may be mistaken, I had thought that review articles were generally seen as valuable contributions to scientific knowledge.

The review article in question states "42 of the 47 RLS-associated conditions (89%) have also been associated with inflammatory and/or immune changes." It seems that the alternative to referencing this review article would have been tracking down the 47+ studies and redoing the work of the article by effectively rewriting it. I will admit that I am unfamiliar with the work of Dr. Walters, but the fact that the article has been referenced 96 times indicates to me that it is of pretty high quality.

In referencing the review article, I was trying to make the point that "there is evidence that RLS is caused by general bodily inflammation." I felt that the review article provided valuable context correlating RLS with inflammation before I delved into my main points.

I fear that this reply is overly aggressive, but I struggled to adopt the proper tone. I hope that you do not believe me ungrateful for your feedback.

badnights
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Re: The Relationship Between Inflammation and RLS

Post by badnights »

Steve wrote: Without doing some digging, my guess is that the primary author was either a graduate student (who has since left Vanderbilt) or was a post-doc who moved on to the next position. Without doing some digging, my guess is that the primary author was either a graduate student (who has since left Vanderbilt) or was a post-doc who moved on to the next position.
Weinstock is pretty well-known in his own right. He's a prof and researcher specializing in gastroenterology who more recently became interested in RLS/WED.

I agree with your view on the flood of pointless review papers in the medical literature - I think there's so much pressure to publish that students whip up literature reviews that aren't even very good, and there's so little oversight in some journals that all sorts of useless and incomplete stuff gets published - but I don't think this review is one of them. I haven't accessed the full paper, though. (I'm lucky that I can get full papers thru my work; I will miss that so much when I retire!)

For everyone's amusement: a medical researcher "discovered" a way to calculate the area under a curve and published the method in 1994, naming it after himself. But the method has been known since the 1800s (maybe earlier?) and is one of the most basic things taught in every high-school calculus course. A grand chunk of the medical community was oblivious to this, because not only was the paper accepted for publication, but by early 2007, it had garnered 75 citations (in the medical literature, of course). For an amusing and bemused commentary on this:
https://fliptomato.wordpress.com/2007/0 ... citations/
EDIT: I found this "Note that it has been cited 180 times, several in 2013, and many of those appear to be legitimate citations, not criticisms." at https://academia.stackexchange.com/ques ... that-paper
Beth - Wishing you a restful sleep tonight
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Frunobulax
Posts: 430
Joined: Mon Jun 02, 2014 7:41 pm

Re: The Relationship Between Inflammation and RLS

Post by Frunobulax »

Rustsmith wrote:
Fri Jun 05, 2020 8:04 pm
Like others, I have not had a chance to dig through all of the references provided in the original post by inflammatory_rls. However, when I wrote the missing post, I did get a full copy of the first reference to review. This paper is an example of why it is often important to be able to read the full paper and not just the abstract. The paper is what I call a paper study and is something that I see much more frequently in medical journals than in the journals in my field of study. The paper reports on a review of a number of other publications and does not present any new findings. I believe that there are several reasons why these papers are rather common within the field of medicine. One reason (and I suspect the justification for this paper) is to pull together a review of existing literature in the form of a publication so that it can be attached to a request for research funding. I know that my own physician and her co-author did exactly this a couple of years ago. There was a clinical trial at Stanford looking at SIBO and RLS at the time that the paper was published and I suspect that the authors were hoping to build upon Standford's results. Whether they were successful with their proposal is something that we will need to wait to see their future publications.
I encourage you to check out this video from Richard Feinman, who hits the nail on the head with what's wrong in medical research.
Quote: The 4 horsemen of statistical apocalypse: (a) intention-to-treat, (b) group statistics, (c) relative risk and (4) meta-analysis.
https://www.youtube.com/watch?v=J9v3YqS9iP4

So many studies are deeply flawed, often coming from a very minor issue (say a wrong assumption) that has major consequences. And you have to read the full text, especially the methods and statistical details, to get an idea if a study is sound or flawed.
inflammatory_rls wrote:
Fri Jun 05, 2020 11:56 pm
A number of the studies I referenced have only the Abstract freely available. This is mostly because I don't understand enough science to make reading the full study valuable for me, so I have to rely on the Abstract being representative of the rest of the paper.

However, I did make an effort to reference reasonably high-quality publications. I did this by trying to find studies that were referenced by other studies a decent number of times - say at least 20 times. I assume that if a study is being used as a reference, it must meet a certain threshold of usefulness (unless it is being referenced as an example of a poorly-designed study).
I'm afraid that's not enough. Sometimes there are factions that cross-review and cross-quote. You always, always have to read the full paper. With time you'll learn which areas are more contested. For my experience, nutritional research is the worst. Completely contradictory results, and no attempts to consolidate them. Instead loads of flawed papers referencing other flawed papers. Feinman wrote a book on this, which is a really good read ("Nutrition in crisis"). He talks a lot about statistics, and which mistakes are often made that lead to wrong conclusions.

inflammatory_rls
Posts: 14
Joined: Fri May 29, 2020 8:20 pm

Re: The Relationship Between Inflammation and RLS

Post by inflammatory_rls »

A grand chunk of the medical community was oblivious to this, because not only was the paper accepted for publication, but by early 2007, it had garnered 75 citations (in the medical literature, of course).
I'm afraid that's not enough. Sometimes there are factions that cross-review and cross-quote. You always, always have to read the full paper. With time you'll learn which areas are more contested. For my experience, nutritional research is the worst. Completely contradictory results, and no attempts to consolidate them. Instead loads of flawed papers referencing other flawed papers. Feinman wrote a book on this, which is a really good read ("Nutrition in crisis"). He talks a lot about statistics, and which mistakes are often made that lead to wrong conclusions.
I had not known that there was such a wide gap between the idea of science and its actual, imperfect application.

I'm not sure what to do. It seems clear now that I really had no business proposing any kind of theory and that I have made a fool of myself. I guess that's why it takes so long to earn a doctorate!

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