Uncovering Restless Leg Syndrome Root Causes

Thanks for joining us!  Check out the video and then dive into the rich detail below.  Find the deep dive on Sleep Interconnectedness I mention in the video here.

This is a sample entry from the SAFM Q&A Treasure Chest, a tool with hundreds of entries to support students with their client needs. Students get unlimited access as part of SAFM’s functional medicine training program.

A question from a Practitioner:

Hi Tracy!  I’m looking for some insight on potential root causes of restless leg syndrome, or what I believe to be restless leg syndrome.  This client has had it off and on for a few years.  In the past she thinks it was triggered when she ate very salty foods or drank alcohol.  She hasn’t had it in well over a year.  Now, however, she is 6 months pregnant, and it’s come back with a vengeance.  It generally acts up after she gets into bed and is trying to get to sleep.  From my research I know that iron or magnesium deficiency may be at play….and that both are “normal” during pregnancy.  She takes a magnesium glycinate supplement and uses magnesium oil on skin daily (she finds replenishing magnesium significantly helps with morning sickness!) and has increased meat consumption since learning she was pregnant.

I know there are multiple likely contributors to RLS.  I would appreciate your insight and recommendations of where to focus our investigation together.  Also, I want to be able to explain the root causes to her logically.  Thank you!

Tracy’s Response:

Oh, great question!  Let me share some general info on RLS and our current understanding of most likely drivers and root causes through the lens of functional medicine interconnectedness.

Restless Leg Syndrome (or RLS) is a neurological dynamic in which a person has a periodic compulsion or need to move their legs in order to relief a general feeling of discomfort.   We are more likely to be affected by RLS as we age, but it can occur at any age.  As you mention, it is also quite common in pregnancy.  This is a general article regarding our current understanding of  RLS causes.

Also, genetic connections may be at play, especially in those who experience RLS in childhood.

It’s common for symptoms to be pronounced in the evening or during the night.  Many of those with RLS may be unaware that it is the primary cause of their insomnia or frequent awakenings or disturbed sleep.  Of course the sleep partner usually is well aware of what’s actually going on!

As an aside…Keep in mind that people who complain of “restless legs” may actually be experiencing leg cramps.  A bad cramp can indeed cause someone to jerk awake suddenly in the night due to intense pain.  As we have discussed elsewhere in SAFM topics, cramps are very often caused by insufficient magnesium, insufficient potassium, dehydration, insufficient thiamine, or a combination of these elements.   So to your point, it’s important that all of these dynamics be addressed fully.  Alcohol and caffeine intake can exacerbate all of these drivers due to increased urination (especially if the intake is atypical and the body has had adjusted to the diuretic effect) and also alcohol’s possible depletion of thiamine.  I highly recommend RBC magnesium labs to ensure it is in the upper third of the reference range.  Our needs for daily supplementation can vary dramatically and may be quite high.  I have supported several clients who needed 1000+mg/day to fully relieve symptoms.

Research generally points to RLS being caused by imbalanced neurotransmitter action, most typically that of adenosine, dopamine, and glutamate, all potentiated by insufficient brain iron.  In looking for true root causes, however, I believe key drivers for RLS are usually both in the gut (affecting iron absorption and inflammation) and in the aggregate stress level (affecting glutamate overtly).

• RLS research has long implicated excessive activity of both glutamate and dopamine.  As a master stimulatory neurotransmitter, high glutamate would exacerbate dopamine further.  Hyperdominergic activity during the day (when its levels are highest) can lead to receptor desensitization which causes insufficient dopamine action at night, during the circadian low point.  The circadian gap between highest daytime and lowest night-time levels has been demonstrated to be much larger in RLS patients, up to 4X the gap found in normal patients.  This also explains why long-term use of dopamine agonists may result, over time, in much worse RLS than before treatment.
• More recent research has highlighted the additional, synergistic role of adenosine, an atypical neurotransmitter that is a powerful modulator of glutamate and dopamine action.  And brain iron level has a large impact on adenosine receptor behavior.
• In addition to low brain iron, many other factors can contribute to excessive glutamate activity e.g. mental/emotional stress, physiological stress, toxicity, intake of stimulatory foods, excess dietary glutamate (e.g. MSG). Stimulatory foods such as coffee, black tea, chocolate, and sugar may play a significant role here given the resulting increases in glutamate and are important to avoid for those struggling with RLS.   L-theanine is an amino acid (found naturally in green tea) which increases GABA levels and reduces glutamate receptor sensitivity and could help to calm the brain prior to sleep (~400mg+ dose).  Taurine also helps promote conversion of glutamate to GABA (1000mg+ dose).

• Low brain iron.  As often happens in the body, insufficient levels of a nutrient drive segmented behavior as the body prioritizes available supply to certain tissues/functions and allows more overt deficiency in lower priority tissues.  This selective iron storage and transport in the face of insufficient levels also happens in the brain (more here).   Iron deficiency also increases the activity of tyrosine hydroxylase (the enzyme which catalyzes dopamine synthesis) in key areas of the body.

• Certainly iron is necessary for the synthesis of dopamine.  True iron deficiency is common in those with RLS (~25%), with many more perhaps having suboptimal levels.  But there is a more esoteric issue here with regard to iron availability and action specifically in the brain and nervous systems.  Iron may be plentiful in the lower tissues but deficient in the cerebrospinal fluid or deficient in select tissues of the brain.   Severity of RLS symptoms does correlate with ferritin level when there is insufficient iron.  I recommend you check ferritin to ensure it’s ample and above at least 50 ng/ml; it may need to be higher to provide brain sufficiency (>70 ng/ml).

• Disease begins in the gut!  Keep in mind that iron is notoriously hard to absorb from the GI tract.   Inflammation is more likely to be generated from within the gut, as that is where 2/3+ of our immune system resides.  And that strong inflammation impairs iron absorption.  There are impressive connections between SIBO and RLS which likely have several roots, including impaired mineral absorption, increased intestinal permeability that impairs iron absorption from the gut, and increased inflammation.
  • In patients with both SIBO and RLS,  77% of patients treated with the nonabsorbed antibiotic rifaximin  had  ≥80% long-lasting improvement of RLS symptoms (post antibiotic therapy with probiotics was included).  This type of data goes beyond correlation and clearly reinforces a causal connection between RLS and gut microbial imbalance and its impact on nutrient absorption!
  • IBS was diagnosed in 28% of RLS patience (vs. 4% of controls) – a dramatic data point!  30% of IBS patients also have RLS.  Both Celiac and Crohns disease patients are several times more likely  to have RLS than the general populations (35%+).   Of course, GI disturbance or disease has to progress enough to cause sufficient malabsorption and inflammation to cause RLS to occur.
  • Keep in mind, however, that there is a reason the 5Rs have a logical order of priority.  You will want to address microbial imbalances/pathogens first!  – before supplementing with iron, to ensure that iron doesn’t exacerbate a gut infection.  In SAFM practitioner case examples, we often see the client’s primary care physician misstep of aggressively supplementing iron while also treating (or not even investigating) a notable pathogenic gut imbalance – and making no notable progress on either goal given the simultaneous timing.
  • And of course, having a fortified, balanced immune system is key to preventing a microbial infection or imbalance.  Checking key nutrients such as Vitamin A, Vitamin D, and Zinc (via RBC measure) would also be prudent.  Because of its immunosuppressive effects, high cortisol levels could also be a puzzle piece, and a focus on stress management is going to be key for any RLS case.

• Surges in certain inflammatory compounds (specific interleukins) cause the liver to secrete more of a protein called hepcidin (which controls iron absorption in the gut) and drive lower iron levels.   This is part of the how the body protects itself from excess iron to prevent fueling an infection.  Supplementing iron just once a day, in the morning, and only every other day may help increase iron replenishment (over more frequent intake) due to hepcidin suppression.

• Hypoglycemia.  Nearly 50% of patients with reactive hypoglycemia have RLS, so it’s important to ensure good blood sugar control. Cortisol levels are important overnight for maintaining optimal blood sugar, so low adrenal output of cortisol overnight may also be an issue in some people with RLS.

• Thyroid function. There may also be a connection between thyroid function and dopamine action in RLS as well.  Iron is a key co-factor for the conversion of T4 to T3 thyroid hormone.  Even in more recent research, there is an increased incidence of RLS in thyroid patients, but of course, this connection might also be via the gut.
• Folate status.  This is one I encourage you definitely to explore.  This is a write-up which will be quite interesting to you.  Studies generally show that RLS isolated to pregnancy is highly nutrient-dependent, that is very responsive to supplementation with missing nutrients, specifically iron and folate.  This clinical write-up will also be of interest. 
  • The need for both iron and folate is much higher during pregnancy (3-4X more for iron; 8-10X more for folate).  Individuals with other predisposing issues (e.g. pre-existing gut issues such as IBS or genetic impairments in folate such as from MTHFR SNPs) will likely have an even greater likelihood of these symptoms during pregnancy.  Blood work such as homocysteine (optimal 6-8 umol/L), RBC folate, and/or the organic acid formiminoglutamic acid (want lower half of reference range) will help to definitively identify if your prenatal supplement regimen is giving sufficient folate.  I would also make sure you are using a prenatal vitamin with methyl folate and not folic acid to help ensure maximum cellular folate.

For your client in particular, I would focus on the following at a minimum and then encourage you to explore further avenues among the above based on your client’s unique presentation:

• Stress relief and mindfulness.  Anticipating the birth of a baby and the sweeping life changes ahead can be fundamentally stressful.  Work with your client to acknowledge this stress and prioritize effective daily choices in self-care and quieting the mind.
• Labs. Check at least Ferritin, RBC magnesium, Vitamin D, and homocysteine to ensure all are optimal (not just “normal” within typical reference ranges).  If possible, also RBC folate, Vitamin A, and RBC Zinc.
  • If necessary, use an iron supplement, especially an amino acid chelate form such as iron bisglycinate, in the morning with food (esp. with high Vitamin C content), only every other day, and away from significant calcium intake.
• You’ve already put a focus on ensuring adequate protein intake which is key.  Emphasize good Eating Hygiene. 
• Ensure the prenatal multivitamin includes the activated form of Vitamin B6 (pyridoxal-5-phosphate) to ensure consistent availability for the formation of both dopamine and serotonin (key for making adequate melatonin).
• Review key principles of Sleep Hygiene to ensure other contributors to poor sleep are being addressed consistently.  A strong, balanced immune system requires regular, deep sleep.  This will help prevent infections (and downstream inflammation) and gut microbial imbalance (and downstream nutrient malabsorption).
• You mentioned a history of RLS prior to pregnancy, and triggered specifically by alcohol and salty foods, which points to a role for dehydration, insufficient magnesium, and perhaps insufficient thiamine in the past.  As basic as it seems, I have worked with many pregnant women who become dehydrated, especially in the late first or second trimester where there is a higher urination rate for these women.  Sipping on plain, clean water throughout the day is important.

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fatima

Perhaps also drawing on muscle calcification, from the aspect of boron deficiency? As I understand it, boron, in the presence of Vit D and Magnesium, allows for the interchange of Mg/Cal in the cells, thus reducing aches and pains in the tissues and can be helpful in reducing RLS pains.

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SAFM Team

Reply to  fatima

It is an interesting and possible point. Yes, boron has many functions in the body – this is a good summary of many of them:
https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4712861/
However, we couldn’t find any direct study that boron relieves RLS symptoms due to its action on preventing/reversing muscle calcification.

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Daniela Lafond

This was a great article, with many avenues to explore in resolving RLS! I did want to ask about calcium’s role. My (male) family member and myself have had RLS on and off through the years, like the patient in the question, and again like the patient, during my pregnancy, symptoms worsened. At that time, my midwife told me to take calcium, which resolved my pregnancy RLS. Could increased calcium needs during pregnancy be a cause of suddenly worsening RLS?

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Admin

SAFM Team

Reply to  Daniela Lafond

Thanks for sharing your experience! Actually one of the reason why magnesium can so often help with RLS is in part because it helps to balance/reduce the activity of calcium (so the opposite of what you propose). I do not know of any research that would tie calcium deficiency specifically to RLS. However, a common symptom of calcium deficiency is overall muscle twitching/cramping (vs. RLS specifically), and perhaps this is part of what you were experiencing. So, a contributing, exacerbating factor vs. a primary cause? Here’s a quick summary: https://www.medicalnewstoday.com/articles/321865 .

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CW

I love how comprehensive this is. It has been very informative. Thank you!

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