Question: RLS and blood markers

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Frunobulax
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Question: RLS and blood markers

Postby Frunobulax » Fri Oct 11, 2019 4:31 pm

As I have dug deep into biochemistry recently, I learned about a lot of stuff that may or may not be relate to RLS. I'm thinking along the lines of silent inflammation. As last discussed here http://bb.rls.org/viewtopic.php?f=21&t=10564&p=100113#p100112 (which went OT to some degree) I am not at all sure that BID is actually the cause of RLS, because a correlation doesn't imply causation and it could be the other way around (BID is a symptom but not the cause) or BID and RLS could have the same reason.

Inspired from Dave Feldman (https://cholesterolcode.com/, https://www.youtube.com/watch?v=jZu52duIqno, https://www.youtube.com/watch?v=kDOHw0qhT0A) I was wondering if someone has tried to observe basic biomarkers and correlate them with RLS severity. For example, has anyone tried to correlate blood sugar, insulin, triglycerides, cholesterol with RLS severity? Do we know if RLS patients tend to have high uric acid? I was wondering about that because one of the talks above mentions coffee sensitivity for some people where drinking coffee has dramatic effect on their blood triglycerides, which immediately reminded me that some RLS sufferers will activate their symptoms with coffee.

Basically, has anyone used a portable device that can measure trigycerides and blood glucose and found some correlation with RLS severity? I guess I'll purchase one of these babies myself, the cheapest devices that can measure triglycerides start around $150. As Feldman notes, of course no one can derive any useful information from sample size one, but the beauty of sample size one is that if 1000 people do the same experiment, it becomes sample size 1000 very quickly.

I can't elaborate on my ideas because most of them are only a gut feeling that there might be a connection. Maybe this: There has been a lot of research recently on consequences of insulin resistence, mechanics of silent inflammation and the role of carbohydrates (which we eat a lot more than 50 years ago) and polyunsaturated fats (the vegetable oils that are now omnipresent in kitchens). Could RLS be caused along the same mechanisms? Alzheimer is "diabetes of the brain", maybe RLS is something similar? Consider the connections:
  • We know that diabetics have a fairly high RLS prevalence (https://www.ncbi.nlm.nih.gov/pubmed/30213520), and almost most of us (all people not a low carb diet) have some degree of insulin resistence (IR), that is, most of us are in early stages of diabetes. (Do make sure you are familiar with insulin resistence and the metabolic syndrome, basically we need more and more insulin to process the same amount of carbs over the decades, and diabetes type 2 is just the breaking point where the pancreas breaks down. But that process goes on for everybody on a high-carb diet, and it depends on individual factors whether the pancreas reaches that breaking point or not in the lifetime of the patient).
  • Diabetes and IR are driven by carb consumption. Many RLS sufferers report that they get relief from staying away from carbs, especially refined sugar.
  • Fructose drives uric acid (not the purine, there are tribes like some Inuit and Masai that used to eat nothing but meat, and they have no gout or diabetes). Uric acid inhibits some reactions in the body which in turn increases inflammation. Inflammation in the brain is assumed to be the main reason for neurologic diseases like Alzheimer, Parkinson, Multiple Sclerosis and others.
  • Inflammation is driven by reactive oxygen species (ROS), which do affect the iron metabolism even though many details are fairly unclear (https://www.ncbi.nlm.nih.gov/pmc/articles/PMC1221947/pdf/11415455.pdf). But we do know that inflammation raises ferritin values, and it is possible that iron stores are depleted by ROS (after all, iron does react with those ROS like H2O2). Thus, we may have a pathway inflammation/oxydative stress -> low iron stores, but I'm very unsure about this.

As an addendum to the other thread, there is another possibility: Maybe we got it wrong just as we did in Alzheimer research? Maybe BID is a protective mechanism of the brain, as the amyloid plaques in Alzheimer (which appear to protect the brain from further damage, instead of causing the damage as we thought)? Maybe our brain is fighting inflammation and the depletion of the iron stores is just a side effect of that? In that case, iron IVs would solve the visible problem (RLS) but may cause damage because it exacarbates the original problem, possibly a silent inflammation?

ViewsAskew
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Re: Question: RLS and blood markers

Postby ViewsAskew » Tue Oct 15, 2019 7:05 am

My personal thoughts - and I am a social scientist, so NO experience with this - is that there is likely a difference in RLS based on when and how you get it.

I have had PLMS since I was 2 or 3 years old. I have had RLS/WED since I was a child. I never had any indicators of inflammation until I hit my 50s. I have had no diseases throughout the many years of this hellish disease - I am not diabetic, my triglycerides are normal, and my blood glucose is fine (my husband IS diabetic and I have tested myself many times). I eat some processed food, but mostly make all our own food from scratch. I have grown my own vegetable for years and currently buy mostly organic fruits and veggies, free-range dairy and meats, and so on. I use only "good" oils, and I have been on a sugar free, dairy free, soy free, gluten free, corn free diet in the past. I eat primarily gluten-free now as my husband is celiac. I do eat some sugar - a 1/2 tsp in my coffee sometimes, as well as some sweets now and then.

I still have RLS/WED and PLMS. As many of us with hereditary RLS do. My sister has none of these issues, nor does my mother. Or my brother or my nieces or one of my uncles. My other uncle has many of these things now that he is older, but had none of them as a teen when his RLS manifested - he always ate well and took excellent care of himself as he was a US Marine and an amateur boxer. All of us had RLS as children. Increasing iron for me DOES improve my symptoms. Just as it does for up to 80% of people in the Johns Hopkins studies.

More interesting is that in the last two years, my body is clearly unhappy in some way - I have eczema, I have become hypothyroid and there are indicators of another autoimmune problem. For the first time, I do have inflammation. Yet my RLS is not any worse. I have introduced fermented foods that I am making and I will soon go back to a stricter diet, seeing if I can impact the eczema and other problems. I haven't decided which protocol to follow, but my guess is that as my RLS did not worsen when these things happened, this will not make it better. I hope that it will help the other problems, though.

For those who have secondary RLS/WED or acquire it later in life, inflammation may indeed play a role. But, given my history and that of my entire family, there is no evidence at all that inflammation is involved in our RLS and PLMS.

It is possible that all of these factors cause changes in the gut and that the gut is involved in iron in some way, hence creating RLS through microbiome changes. That is just one theory that sort of pulls these together. If diet helps my RLS in the next few months, my bet is on the microbiome. It is clear that the ferritin goes somewhere for many of us - me included. We just don't know how or where. But, the gut makes a lot of sense, especially as it also could be involved in inflammation and the issues you have discussed.
Ann - Take what you need, leave the rest

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Frunobulax
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Re: Question: RLS and blood markers

Postby Frunobulax » Wed Oct 16, 2019 3:37 pm

ViewsAskew wrote:My personal thoughts - and I am a social scientist, so NO experience with this - is that there is likely a difference in RLS based on when and how you get it.

I have had PLMS since I was 2 or 3 years old. I have had RLS/WED since I was a child. I never had any indicators of inflammation until I hit my 50s.
[...]
More interesting is that in the last two years, my body is clearly unhappy in some way - I have eczema, I have become hypothyroid and there are indicators of another autoimmune problem. For the first time, I do have inflammation. Yet my RLS is not any worse.


The thing about inflammation is: It doesn't show up, and once you realize that you have it there are decades of buildup. Alzheimer is believed to be inflammation in the brain, yet there are no symptoms except a plaque buildup that shows up on brain imagery.

Gary Fettke did a beautiful talk on PUFA-driven inflammation (https://www.youtube.com/watch?v=iCQmfRMwHfA, a bit technical though). It's only a theory, but it's a good one. The cliff notes are as follows, or rather how I understand it.
  • Polyunsaturated fats (PUFAs) cause inflammation due to the unstable "unsaturated" bindings that allow oxidization (unlike saturated fats).
  • Due to a high carb diet, most people develop insulin resistence. Diagnosed diabetes is just the last step of the process. Think of insulin resistence like a car where you put a pebble in every day. After a few decades you'll realize that the car gets slower, shows signs of degrading (that is, if it's a car that doesn't age otherwise). After a few more decades the car will break down. It might take a few decades more or less, but it's invevitable. This is what happens to our pancreas if we eat high carb. (Any form of fasting or low-carb diet would be the equivalent of taking a few pebbles out again.) It has to produce more and more insulin, as the cells become more and more insulin resistent. At some point it breaks down and it can't produce enough insulin, but up to this point your blood sugar looks perfectly normal, unless you measure insulin and HOMA-IR too.
  • High insulin (the more insulin resistent you are, the higher your insulin at all times) puts fat cells in storage mode, and will transport some of the PUFAs into your fat cells. Also PUFAs become embedded into your cell membranes and mitochondria membranes, due to the normal process of repairing cell membranes via cholesterol.
  • As a result, the longer you have eaten PUFAs (again we're talking decades), the more of the stuff is in your body. (One study measured over 20% PUFAs in body fat, as opposed to a third of these values 50 years ago).
  • Fructose is metabolized to uric acid, and some glucose too (as some part of glucose is converted to fructose). Uric acid and the presence of UFAs cause inflammation.
  • Inflammation is kept in check by vitamin C, vitamin D, lipoic acid and other antioxidants, which get used up in the process.
  • Also Omega-3 is antiinflammatory, but instead of a 1:1 relation between PUFAs and omega-3 fatty acids (as it used to be when we were hunters and gatherers) we're up to 20:1 or so because industrial meat contains little omega 3 (compared to grass fed animals), and we consume less meat, butter and fish anyway. That's another factor that drives inflammation.
  • Usually around our 50s we start to become deficient in these antioxidants, because the process starts to kick in more and more. The more deficient we are, the more silent inflammation builds up. Might be at younger age if people grow up with PUFAs and high carb diet, or later if people grow up with saturated fats and/or control their carb intake.
  • At some point the inflammation can't be controlled anymore by the antioxidants, we start to get visible symptoms. If the inflammation is in the brain, we get various unspecific symptoms (dementia, multiple sclerosis, ME/CFS and stuff like this). We get arthritis and arteriosclerosis.

It's a theory, but it explains a lot. Even that some inuit or african tribes (Masai) that used to eat only fat meat (before they became contaminated with our carb-based diet in the middle of the last century) didn't need any antioxidants. They would literally eat vegetables only if they were starving, so they didn't get any vitamin C or whatever in their body, but they didn't need it because they had no inflammation and the vitamin C didn't get used up. That also explains why doctors like Steven Gundry report that 100% of his autoimmmune patients are severely deficient in vitamin C. And the process of insulin resistence explains why the process takes decades and is highly individual (obviously we also have different capacities of how durable our pancreas is).

Also I don't claim that this mechanism is in place for ALL RLS patients. Inflammation can have a lot of sources, but this is process that could drive inflammation. And again, maybe inflammation is only one factor that can lead to RLS, but I think it's at least a plausible enough theory that it''s worth thinking about it.

Frunobulax
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Re: Question: RLS and blood markers

Postby Frunobulax » Wed Oct 16, 2019 7:08 pm

Frunobulax wrote:That also explains why doctors like Steven Gundry report that 100% of his autoimmmune patients are severely deficient in vitamin C.


Vitamin D, not vitamin C. (Sometimes it's quite unnerving that I can't edit my own posts after an hour or so.)
Also coenzyme Q10 is in the same boat, antioxidant that we become deficient in with age. Vitamin C OTOH is something that we consume in generous amounts, but it seems we need the other ones too.

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Re: Question: RLS and blood markers

Postby ViewsAskew » Wed Oct 16, 2019 8:22 pm

Seems that we are mostly agreeing.
Ann - Take what you need, leave the rest



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Frunobulax
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Re: Question: RLS and blood markers

Postby Frunobulax » Thu Oct 17, 2019 12:07 pm

Oh, one more thing. I've heard from several patients with RLS that cortisone gave them complete relief from RLS. As cortisol is one of the most potent anti-inflammatory agents, that's another clue to an inflammation connection (for some patients at least). Also stress highly correlates with RLS, and stress messes with your cortisol (despite higher cortisol blood levels under stress, chronic stress is assumed to cause inflammation).

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Re: Question: RLS and blood markers

Postby Rustsmith » Thu Oct 17, 2019 1:58 pm

As stated earlier, conclusions cannot be drawn from a single example. But in my case, my RLS before I retired was moderate at its worst. I only remember issues occurring during the frequent very long airline flights that I had to take. My job also involved a huge amount of stress. My RLS went to very severe a few months after I retired and my stress levels dropped to that of a full retiree enjoying life.
Steve

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Frunobulax
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Re: Question: RLS and blood markers

Postby Frunobulax » Fri Oct 18, 2019 9:49 am

Rustsmith wrote:As stated earlier, conclusions cannot be drawn from a single example. But in my case, my RLS before I retired was moderate at its worst. I only remember issues occurring during the frequent very long airline flights that I had to take. My job also involved a huge amount of stress. My RLS went to very severe a few months after I retired and my stress levels dropped to that of a full retiree enjoying life.


Allow me to digress for a moment :)
The one thing about science (and medicine in particular) that we DON'T do well is that we often think like laywers and not like scientists. So basically, if you have a scientific theory and any data pops up that seem to contradict this theory, then the right thing to do is to analyze the data, and there are two basic possibilities: (a) the data fits the theory after all (because you found something that explains the difference) or (b) the theory is wrong. There is no middle ground. A laywer defending a theory on the other hand will present convincing data, but if anything pops up that contradicts his theory he will (a) try to ignore it or (b) point out that his data looks a lot more convincing. But this, as can be evidenced in the historical case of Galileo, can be quite wrong: There seemed to be very solid arguments that earth is flat and the sun revolves around the earth, and the brightest minds of their time firmly believed that, and yet when Galileo pointed out that there are some observations that don't fit the theory they dug in and acted like laywers.

Unfortunately, many medical researchers today adapt the laywers view too. This can be evidenced especially in nutritional science (I suggest to read the book by Nina Teichholz if you need convincing), but also in Alzheimer research (where we still spend billions on research to reduce plaques even though there is a lot of evidence that plaques are not the problem) and many other areas. We see correlation, find an explaination that looks plausible, and go full steam trying to find more supporting data (laywer approach) instead of looking closely at the contradictory data (scientist approach). Sometimes it works, sometimes it doesn't.

Let's not make that mistake too :) So no, your "size 1 sample" is important, especially if it doesn't fit the theory. If we can't find a way to fit it to the theory, then the theory is rubbish. Having said that, it's impossible to tell without doing a lot of diagnostic tests and knowing a lot more about you (and your stress/inflammation markers before retirement), but there are a number of reasons why inflammation could go up after retirement. I can name a few.
(1) We do not yet understand how stress drives inflammation, and which other factors drive inflammation. There is also a big difference between chronic stress and occasional stress, one is bad, the other beneficial. Maybe the stress in your workplace wasn't bad enough to constitute (bad) chronic stress but more of the beneficial kind. (2) It is possible that you changed your diet when you retired, or your lifestyle (less exercise/walks). (3) Or perhaps a factor is that you spent a lot more time in your own flat (or another location) than before that has some form of biotoxin, for example some forms of mould is known to cause inflammation (and mould is often invisible and will turn up only on specialized scans of air samples), or something that you are allergic to. (4) Or maybe you used to work a lot outside, and stayed mostly inside after retiring, causing your vitamin D levels to drop (vitamin D is anti-inflammatory). (5) Or you got more time outside, exposing you to something you're allergic to, which messed up your immune system. As a consequence your RLS got worse.

And again, I don't think there is satisfactory evidence for any theory in RLS. And in theory I mean pathogenesis, that is, we have a complete chain from a cause (or several different causes) to RLS that explains all the weirdness that we see. BID is only a part of a theory.
  • The BID theory (BID drives inflammation) is built on association, but we have little evidence for causation. It may be part of a pathogenesis, that is, (1) something causes BID (but what?) and (2) BID may cause RLS symptoms. There is some biochemic reasoning for (2), that is, we have an idea why iron deficiency would mess with dopamine production. But on the other hands, here are some facts that we need to explain, which I think cast doubt on the BID theory.
    1. The fact that only 50% of RLS patients respond to iron IVs. If BID is really the (only) cause, shouldn't the rate of responders be higher?
    2. Do we know that BID is mandatory for RLS, that is, patients that have NO BID also have no RLS?
    3. How does BID explain the high variability in RLS symptoms? That is, iron levels in our body do not change quickly (even after an IV it takes weeks to settle in), how can we explain day-to-day variation in our symptoms? How can we explain that for some patients (a minor fraction), stuff like amino acids and/or vitamin B12 relieves the symptoms reliably?
    4. As for the "what causes BID", it's easy to say "genetics". But I've seen many cases where we thought something was genetic (for example the tendency to become obese) but we found out that there are other major factors. For example in obesity/diabetes, there seems to be some genetic influence as to how quickly the pancreas throws in the towel and how sensitive your fat cells are to insulin (putting them in storage mode), but clearly diabetes/insulin resistence/obesity can be avoided with a low-carb diet.

    Saying "the data doesn't fully support the theory" is never as sexy as saying "I have a cool theory", but in this case I'll still opt for "we need more data". I'd consider it very likely that there is at least a secondary mechanism, that is, BID may be one factor but there may be other factors driving RLS.
  • The theory that inflammation drives RLS is not new, but there is even less evidence (to be fair). Still, the only way to test a theory is to throw it out and see what evidence we have, for and against it. (And I have no problem whatsoever to scrap a theory if it turns out to be implausible.) I'm not making a case that inflammation is the only thing that causes RLS, I am making a case that we should look at this theory. I think inflammation has the potential to explain some things that the BID does not explain (yet), namely:
    • Inflammation symptoms can change quickly if we introduce anti-inflammatory agents like cortisol.
    • There is a good explaination why inflammation would become more pronounced with age (long-term dietary effect as explained in my earlier post).
    • It also explains why it's so hard to determine why there are long-term changes in symptoms (for better or worse). We haven't understood silent inflammation yet, but we know that we can influence it with lifestyle and diet changes, and these changes take months to years to make a difference. For example, we know that the gut microbiom plays an important role to manufacture anti-inflammatory components used by our immune system. Kill the good bacteria in the gut microbiom, and a few years later you may see severe consequences.
    • Inflammation in the brain is linked to a lot of diseases like MS and ME/CFS, that are in some ways similar to RLS: It seems hard to identify even risk factors, and we have no clear idea why symptoms get better or worse. We might have a full blown war between the immune system and inflammation in our brain going on without noticing anything except unspecific symptoms (short term memory, depression and so on).
    • We know that some things used to treat RLS will also lower inflammation, for example vitamin B12 and even opioids are known to lower inflammation.
    • And maybe most importantly, the inflammation theory does not contradict the BID theory. It is clearly possible that inflammation in the brain may lead to low iron levels.

    As for "against", that's a hard one because we don't understand silent inflammation (yet). Maybe the fact that pregnant women sometimes get RLS that goes away after pregnancy, I have a hard time explaining this with inflammation, but on the other hand I have no clue what exactly happens in pregnancy. Well, I know about the bees and rabbits and all this, but I don't know the biochemisty ;) The little evidence that a quick google search turned up was that pregnancy is associated with elevated stress and sometimes poor diet, so maybe it's less "against" the inflammation theory, more "we've got to check it out to see if it's for or against".

So basically, if I had control over research, this is what I would do. It would quickly tell us if the inflammation theory is worth checking out. More precisely, the first step is to see if there is correlation (which I find highly probable), and the second step is to see if there is causation (and this one is wide open).
  1. Do SPECT scans of brains of serious RLS cases. See if we can find indications for brain inflammation, if there are clear patterns, if the regions are consistent (and we can distinguish the patterns from other diseases like Alzheimer, MS, ME/CFS).
  2. Try to correlate RLS symptoms with typical inflammation markers (TNF-alpha, IL6 and so on). See if symptoms change long-term with time if these markers go up or down.
  3. Try to do systematic, long-term experiments with diet. Get 2 groups, put one group on a low carb high fat diet with mostly saturated fats and no polyunsaturated fats, and see if it makes a difference for 2 years. Possibly get a third and fourth group that do the same with intermittent fasting, which is supposed to lower inflammation too. Unfortunately it takes years to reverse insulin resistence , so if RLS is an insulin resistence driven (or related) effect then we'll need good, long-term studies where we make sure that the participants follow the protocol. An intention-to-treat study will not suffice at all.

Sorry that this one got so long. But I love writing about these ideas, as it greatly helps me to think them through.

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Re: Question: RLS and blood markers

Postby Frunobulax » Fri Oct 18, 2019 1:01 pm

Frunobulax wrote:
  • The BID theory (BID drives inflammation)


should be BID drives RLS of course.

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Re: Question: RLS and blood markers

Postby badnights » Fri Nov 08, 2019 10:03 am

Just getting around to reading this Topic now, fascinating as always. I have limited energy this time of night so kind of point-form notes on some of the things you covered, just as the thoughts came into my head as I was reading.

I was wondering if someone has tried to observe basic biomarkers and correlate them with RLS severity. For example, has anyone tried to correlate blood sugar, insulin, triglycerides, cholesterol with RLS severity? Do we know if RLS patients tend to have high uric acid?

Not to my knowledge, but it would be good to have something basic like that done.

consequences of insulin resistence, mechanics of silent inflammation and the role of carbohydrates (which we eat a lot more than 50 years ago) and polyunsaturated fats (the vegetable oils that are now omnipresent in kitchens). Could RLS be caused along the same mechanisms?

one route could be thru changes to gut microbe population (carbs = bad bugs = bad bug poop (sorry, metabolic by-products) that gets in your blood = problems in potentially any system, including neurological e.g. WED/RLS).
The polyun fats would cause the problem via a different route - sucking up our bodily resources to deal with the resulting [ouch I forget what nasty things oxidized oils cause in our bodies] nasty things, I guess I'll say. And our bodily resources - by which I mean here the molecules that do our cellular metabolism - are limited by diets lacking in micronutrients.

Inflammation is driven by reactive oxygen species (ROS), which do affect the iron metabolism even though many details are fairly unclear (https://www.ncbi.nlm.nih.gov/pmc/articl ... 415455.pdf). But we do know that inflammation raises ferritin values, and it is possible that iron stores are depleted by ROS (after all, iron does react with those ROS like H2O2). Thus, we may have a pathway inflammation/oxydative stress -> low iron stores, but I'm very unsure about this.

Nice line of reasoning. Does not account for the iron deficiency being localized to the brain, though.

iron IVs would solve the visible problem (RLS) but may cause damage because it exacarbates the original problem, possibly a silent inflammation?

I have thought often that I might be causing a bigger problem down the road! haha. But I don't think BID is a protective response (I haven't thought thru why). Maybe partly because of the awesome restoration of refreshing sleep I've had since my infusion took effect, and my general sense of well-being; even if I knew that the BID was a protective response, I probably would choose to get the infusion - I'd rather live well now and die sooner than live like I did for the past 12 years.

lso Omega-3 is antiinflammatory, but instead of a 1:1 relation between PUFAs and omega-3 fatty acids (as it used to be when we were hunters and gatherers) we're up to 20:1 or so
I think you mean "between omega-6's and omega-3's". They're both polyunsaturated.

They would literally eat vegetables only if they were starving, so they didn't get any vitamin C or whatever in their body,

I'm not an expert but I'm not sure about this. The Inuit made various teas from local plants, some of which are rich in vitamin C. Also, the Dene ("Indians" who live in northern Canada) would eat the stomach and small intestine contents of the caribou they caught; Inuit may have done the same. Also, I've had Inuit people show which little tundra plants were edible. I didn't ask about the lifesyles of their great-grandparents, but the fact that they showed me such things implies a cultural use for the plants.

I'm totally on board with your general thesis, that inflammation might be invovled in WED/RLS, and that diet can have huge effects over time, negative or positive.

Unfortunately, many medical researchers today adapt the laywers view too. This can be evidenced especially in nutritional science.., but also in Alzheimer research...

Too true! Not just today, unfortunately. Even Mendel is suspected of bias (perhaps subconscious) in his classic experiment with pea plants that helped establish his theory of genetic inheritance - his data are too perfect. But modern nutritional "science" has been full of it! The guy who started the saturated-fat scare comes to mind, and the whole

(2) BID may cause RLS symptoms. There is some biochemic reasoning for (2), that is, we have an idea why iron deficiency would mess with dopamine production.

I don't know if you have these two papers from various of Arthur Walter's colleagues:
Ye-Ming J. Sun and others, 2011, Opioids protect against substantia nigra cell degeneration under conditions of iron deprivation: A mechanism of possible relevance to the Restless Legs Syndrome (RLS) and Parkinson's Disease. Journal of the Neurological Sciences v. 304, p. 93-101.
Shangru Lyu and others, 2019. Hyperactivity, dopaminergic abnormalities, iron deficiency and anemia in an in vivo opioid-receptors knockout mouse: Implications for the restless legs syndrome. Behavioural Brain Research v. 374, p.1-9.
These papers take it back a step further and suggest that an opioid deficiency might underlie the iron deficiency (2019 paper) and that opioids protect dopaminergic cells from iron deficiency (2011 paper). (very overimplified. They were dealing with mice (2019) and with cultered cells from a rat brain (2011).

The general thinking out there is that BID is part of WED/RLS. I don't think anyone has pretended to have determined cause and effect yet. But people are poking away at it. I like the opioid research, because it needs to be a part of the picture. The fact that opioids work to resolve symptoms can't be ignored without compromising the search for causes and mechanisms.

I'm not making a case that inflammation is the only thing that causes RLS, I am making a case that we should look at this theory.

You're in the same boat as with BID - if inflammation is the "cause", what caused the inflammation? There is a bigger picture here.

The rapid fluctuation of WED/RLS symptoms could be caused by the interaction of various bodily states with the low brain-iron state, including inflammation.

the first step is to see if there is correlation (which I find highly probable)

If WED/RLS is correlated with inflammation, why aren't ferritin concentrations high in all of us? Though I suppose an answer could be that not all forms of inflammation drive ferritin to increase.

Try to do systematic, long-term experiments with diet. Get 2 groups, put one group on a low carb high fat diet with mostly saturated fats and no polyunsaturated fats, and see if it makes a difference for 2 years. Possibly get a third and fourth group that do the same with intermittent fasting,

This needs to go farther. Micronutrients are essential to the smooth functioning of every cell - of every mitochondrion in every cell, and our bodies can;t carry out the processes of life without an adequate supply of them. For example, our bodies need micronutrients to eliminate toxins that we eat or breathe, or that get created by metabolic processes that have to use an inefficient pathway for lack of an essential nutirient required to make a molecule needed on the efficient pathway.
The diet experiments (excepting the controls) should include a healthy variety of micronutrient source foods, and eliminate all foods that cause stress in the body.
Beth - Wishing you a restful sleep tonight
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Frunobulax
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Re: Question: RLS and blood markers

Postby Frunobulax » Sat Nov 09, 2019 1:17 pm

(somehow quotes got mixed up in my first post. I tried to repair it, but it's still possible that I got some text shifted to the wrong quotes.)

badnights wrote:
consequences of insulin resistence, mechanics of silent inflammation and the role of carbohydrates (which we eat a lot more than 50 years ago) and polyunsaturated fats (the vegetable oils that are now omnipresent in kitchens). Could RLS be caused along the same mechanisms?

one route could be thru changes to gut microbe population (carbs = bad bugs = bad bug poop (sorry, metabolic by-products) that gets in your blood = problems in potentially any system, including neurological e.g. WED/RLS).
The polyun fats would cause the problem via a different route - sucking up our bodily resources to deal with the resulting [ouch I forget what nasty things oxidized oils cause in our bodies] nasty things, I guess I'll say. And our bodily resources - by which I mean here the molecules that do our cellular metabolism - are limited by diets lacking in micronutrients.


Oh, absolutely. I wrote something about the microbiome a short while ago. But I'm not yet sure if the microbiome is 90% or 10% of the mechanism here.
The mechanism via omega-6 is fairly direct: Insulin resistence leads to high uptake of omega-6 (high insulin means fatty acids are stored and not used for energy), omega-6 is metabolized to arachidonic acid which in turn activates the immune system producing ROS. That is, omega 6 -> high oxydative stress. The process is sped up by high insulin levels (food with high glycemic index and/or insulin resistence), as this increases the amount of omega-6 in the body.

It's really horrible how much misinformation is out there. If you google arachidonic acid you'll find websites advising to keep it low (sure), so you should avoid meat and stuff (which is nonsense, mostly the "healthy" polyunsaturated fats in the diet cause high arachidonic acid in the body).

badnights wrote:
Inflammation is driven by reactive oxygen species (ROS), which do affect the iron metabolism even though many details are fairly unclear (https://www.ncbi.nlm.nih.gov/pmc/articl ... 415455.pdf). But we do know that inflammation raises ferritin values, and it is possible that iron stores are depleted by ROS (after all, iron does react with those ROS like H2O2). Thus, we may have a pathway inflammation/oxydative stress -> low iron stores, but I'm very unsure about this.

Nice line of reasoning. Does not account for the iron deficiency being localized to the brain, though.

Perhaps the brain needs more iron to produce the neurotransmitters/dopamine. I'm also not sure about how well iron crosses the blood-brain-barrier. But then, this is all speculation. I'd love to have a few solid facts on my hands here :)


badnights wrote:I have thought often that I might be causing a bigger problem down the road! haha. But I don't think BID is a protective response (I haven't thought thru why). Maybe partly because of the awesome restoration of refreshing sleep I've had since my infusion took effect, and my general sense of well-being; even if I knew that the BID was a protective response, I probably would choose to get the infusion - I'd rather live well now and die sooner than live like I did for the past 12 years.

Well, iron IVs didn't do anything for me :-\

But again, this is just a theory. I have no trouble creating several contradictory theories. Those that aren't plausible we can eliminate quickly. But this procedure makes sure that we don't miss anything. I don't believe that BID is a protective response, but I can't rule it out so I would look into that.


badnights wrote:I think you mean "between omega-6's and omega-3's". They're both polyunsaturated.

Correct.

badnights wrote:[about Inuit diet]
I'm not an expert but I'm not sure about this. The Inuit made various teas from local plants, some of which are rich in vitamin C.


Oh, there are a lot of contradictory reports on that. And the diet of the various inuit groups will have a lot of variety. And undoubtedly their food included some vitamin C, but probably a lot less than we are getting. I am referring mainly to Stefansson http://www.comby.org/documents/documents_in_english/stefansson-diet-adventures.htm, who later did a meat-only experiment in a controlled environment https://doi.org/10.1001/jama.1929.02710010026005. Also the diet of the Inuit changed quickly, and there were later studies claiming that Stefansson got it wrong, but they disregarded the fact that those Inuit started to eat carbs in the meantime https://www.ncbi.nlm.nih.gov/pubmed/30018773. Similar results exist for the Masai (Mann 1964), but they are equally contested.

Ah, I didn't know them, I will have a look. Recently my focus shifted away from RLS and towards general inflammation, as my RLS is reasonably well controlled but my ME/CFS isn't, so...


badnights wrote:
I'm not making a case that inflammation is the only thing that causes RLS, I am making a case that we should look at this theory.


You're in the same boat as with BID - if inflammation is the "cause", what caused the inflammation? There is a bigger picture here.



Oh, but there are a lot of known causes for inflammation.
  • Toxins of all kind. Heavy metals, mould spores, pesticides, insecticides, all the chemistry in our furniture, clothing, cars, whatever. The thing is, we are highly individual in our detox abilities. I guess 99% of the people can live with small amount of mercury from amalgam fillings, but 1% get severe symptoms as their mercury detox is hindered (due to gene defects/variants). Other people will react to mould, and so on.
  • The omega-6 pathway mentioned before (oxydative stress).
  • Leaky gut causes inflammation, as stuff like LPS get in the blood and cause an immune reaction.
  • Deficiencies in micronutrients, which may be caused by inflammation but also by genetic issues (COMT or MTHFR mutations are common).

But there is no general pattern here. Causes for inflammation must be determined for each patient individually (partly through an interview about past and present lifestyle/diet).

badnights wrote:
the first step is to see if there is correlation (which I find highly probable)

If WED/RLS is correlated with inflammation, why aren't ferritin concentrations high in all of us? Though I suppose an answer could be that not all forms of inflammation drive ferritin to increase.


We measure blood ferritin, and brain iron status can be independent (as we know since the BID hypothesis). If RLS is inflammation in the brain, it's not immediately clear whether blood ferritin would rise too. So we could have RLS patients with inflammation predominantly in the brain (low ferritin) and patients with inflammation throughout their body (high ferritin). Or maybe at some point ferritin stores become depleted eventually, that is, after a few years or decades of inflammation the blood ferritin goes down eventually. That's an area where we need a LOT more research, all this is 100% speculation.


badnights wrote:
Try to do systematic, long-term experiments with diet. Get 2 groups, put one group on a low carb high fat diet with mostly saturated fats and no polyunsaturated fats, and see if it makes a difference for 2 years. Possibly get a third and fourth group that do the same with intermittent fasting,

This needs to go farther. Micronutrients are essential to the smooth functioning of every cell - of every mitochondrion in every cell, and our bodies can;t carry out the processes of life without an adequate supply of them. For example, our bodies need micronutrients to eliminate toxins that we eat or breathe, or that get created by metabolic processes that have to use an inefficient pathway for lack of an essential nutirient required to make a molecule needed on the efficient pathway.
The diet experiments (excepting the controls) should include a healthy variety of micronutrient source foods, and eliminate all foods that cause stress in the body.



Absolutely. The simplification here is basically due to the Pareto principle, I tried to pick the one factpr that would have the greatest impact. I would expect that certain micronutrients, say Vitamin D (I am a fan of vitamin D, as this is an antioxidant) reduce inflammation and relieve RLS symptoms, but we've got to find the most important factors. It's very hard to get rid of inflammation, omega-6 fatty acids get stored in our body fat cells (25% average of linoleic acid in body fat cells in a recent US survey), so for those of us (like me) carrying a bit more weight than necessary it might be necessary to slim down considerably before we see any effect, as we need to flush out most the omega-6 out of our body. My size-1 experiment continues, I'm down 26 pounds since January or so, and I have 30-40 more pounds to go (target BMI 23-25).

Ketogenic diet is associated with less blood glucose (-> less inflammation), lower fat storage in liver and pancreas (-> less inflammation), a healthier gut microbiome (-> more fatty acids that help our immune system), high ketones (beta-Hydroxybutyric acid) may have some antiinflammatory components too. And keto diet usually contains more micronutrients than high-carb diet, although this can't be generalized (concerns are potassium and calcium, while low-fat is horrible for omega-3 and vitamin D).

Disclaimer: I have no financial ties to the meat industry :) (or any other food industries, my employer is in the software industry).

BTW, my preferred "keto" contains some meat but also a lot of fiber, nuts and the like. Many people equate keto to carnivore, which is not true, you can do vegetarian keto without problems. Bottom line is that I eat pretty much the same amount of meat as I did before I went keto, maybe slightly more.


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