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Restless Legs Syndrome

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  • Restless legs syndrome

Alinda Coleman   ●   8 min read  


Restless legs syndrome (RLS) also known as Willis-Ekbom disease (WED) is a common neurological sensorimotor disorder. Its misdiagnosis is due in part to a lack of definitive diagnostic testing, and the condition’s wide clinical variability which may mistakenly lead to its symptoms being attributed to other conditions such as peripheral neuropathy, leg cramps and anxiety.[1] While there is no cure, RLS can be managed, and patient’s symptoms and quality of life improved, with herbal and nutritional interventions playing an important role.

Clinical Features

RLS affects approximately 5-10% of the population (in North America and Europe), making it a relatively common disorder that most practitioners are likely to come across in clinical practice.[1] It is more common in women than men, with the prevalence increasing with age. RLS is characterised by the following symptoms:

  • an uncomfortable urge to move the legs
  • an uncomfortable and unpleasant sensation in the legs
  • periodic limb movements during sleep
  • disturbed sleep
  • associated daytime fatigue, reduced concentration and mood changes.[1]

The symptoms of RLS, which follow a circadian rhythm, are worse for rest and in the evening and night, while movement and activity provide relief. While the legs are most commonly affected, some patients also experience symptoms in their arms or trunk.

What Causes RLS?

While theories surrounding the exact aetiology of RLS are still being explored, the pathophysiology behind RLS includes dopaminergic dysfunction, iron dysregulation and possible dysbiosis.

Dopaminergic dysfunction
The neurotransmitter dopamine is involved in motor control and the coordination of body movements.

Pharmacological studies and clinical findings have revealed dopaminergic system dysfunction in RLS patients. Specifically, brain dopamine signalling appears insufficient, with inadequate dopaminergic stimulation due to a reduction in dopamine receptors and transporters.[2,3] Dopaminergic agents are commonly prescribed for the management of RLS, however the risk of augmentation (a worsening of symptoms that exceeds the initial symptoms) increases with prolonged use.[1,4]

Iron dysregulation
Iron dysregulation is a significant finding in RLS. Low brain iron levels, despite normal peripheral iron distribution, has been described as the best-established neurobiological abnormality in RLS.[5] The current research points to a decreased acquisition of iron by cells in the brain, but whether this is due to genetics or activation of pathways in the brain (e.g. hypoxia) that are designed to limit cellular uptake is unclear.[5] It is important to remember that it is not the iron deficiency alone that accounts for RLS, but the interaction of the iron deficiency with other possibly genetic or epigenetic factors.[5]

Iron is a cofactor for tyrosine hydroxylase, the enzyme involved in the conversion of tyrosine to levodopa (L-DOPA), which is then converted to dopamine. Iron deficiency may decrease extracellular dopamine and affect brain dopaminergic transmission.[4] Mitochondrial iron deficiency and associated impairment of mitochondrial function may also play a role in RLS.[6]

Studies have shown that RLS occurs about five times more frequently in patients with iron deficiency anaemia (IDA) than in the general population.[5] One study involving 343 patients with IDA found that they were nine times more likely to have RLS than the general population.[1]

Dysbiosis and gut inflammation
An emerging theory suggests dysbiosis as an underlying factor in the development of RLS. Rates of gastrointestinal conditions such as irritable bowel syndrome (IBS), small intestinal bacterial overgrowth (SIBO), inflammatory bowel disease (IBD) and Helicobactor pylori infection have been found to be higher in patients with RLS than controls.[7-10]

Researchers hypothesise that the inflammation associated with these gastrointestinal conditions may increase hepcidin expression, thereby reducing gut iron absorption leading to central nervous system (CNS) iron deficiency.[7]

Other factors
Increased glutaminergic activity, peripheral hypoxia or a hypoadenosinergic state have also been postulated as potential contributors to RLS.[2,3]

Treatment Options

Treatment strategies for RLS include correcting iron deficiency, supporting dopamine synthesis and improving relaxation and quality of sleep. Core treatment options include valerian, lavender, iron, magnesium and tyrosine.

Valeriana officinalis (valerian)
With a history of use extending over 2000 years, valerian is one of the most well-known and utilised herbal medicines for the treatment of insomnia, anxiety and related disorders including restlessness. Various extracts of valerian root have been shown to improve sleep quality, with some extracts showing comparable efficacy to benzodiazepines.[11,12] Recent in vivo and in vitro studies show that valerian acts on a specific binding site on gamma-aminobutyric acid (GABA)A receptors that have an affinity for valerenic acid, one of the main active constituents of valerian, inducing relaxation.[13]

In a clinical trial involving RLS patients, an 800mg extract of valerian was shown to improve symptoms of RLS including sleep and reduce daytime sleepiness over an eight-week period compared to placebo.[14]

Lavandula angustifolia (lavender)
Traditionally, essential oils have derived their benefit through inhalation or via topical application. However, the internal use of specific essential oils such as lavender has become the focus of research. In clinical trials, oral supplementation with lavender essential oil has been shown to improve the symptoms of anxiety and improve parameters of sleep including perceived sleep latency, sleep duration, sleep quality, restlessness, and agitation associated with disturbed sleep.[15]

When administered intraperitoneally, lavender oil was shown to increase dopamine receptor expression in mice.[16] In humans, dopamine agonists (often prescribed for RLS) target these same receptors.[17] Whether this means oral lavender oil could target these same receptors in RLS patients is unknown – future research in this area would be welcomed.

Iron
Due to its role in the pathophysiology of RLS, both oral and intravenous iron supplementation has been used in the treatment of this condition. A recent Cochrane review found that iron therapy probably improves restlessness and the severity of RLS symptoms compared to placebo.[18]

While serum ferritin levels are a marker for bone marrow stores, they are not indicative of brain iron stores. So, while peripheral iron concentrations may be corrected, regional brain iron concentrations may still be insufficient.[19] This may explain why some patients do not respond to iron and RLS remains after the iron deficiency is corrected, with researchers postulating that brain iron transport and acquisition may be altered.[5]

Tyrosine
Low levels of the amino acid tyrosine have been associated with RLS.[11] Tyrosine is used in the synthesis of neurotransmitters including dopamine. Tyrosine is hydroxylated to L-DOPA via the iron-dependant enzyme tyrosine hydroxylase. From here, L-DOPA is converted to dopamine, which requires adequate amounts of pyridoxal-5-phosphate (active vitamin B6) as a coenzyme. Although no clinical studies have investigated the use of tyrosine in RLS, practitioners and patients may find it beneficial due to its key role in dopamine production.

Magnesium
Magnesium is vital for the conduction of nerve impulses and muscle contraction, and is often prescribed by practitioners for restlessness, insomnia and muscle cramps. Researchers have used both oral and intramuscular magnesium with success in alleviating RLS symptoms, although the sample sizes have been small.[20,21]

Patients with Parkinson’s disease, which is characterised by a loss of dopaminergic neurons, often have low magnesium concentrations in the brain.[21] Rats with low magnesium intakes have also been shown to exhibit a significant loss of dopaminergic neurons.[21] Whether these same findings of low magnesium levels apply to patients with RLS (and dopamine dysregulation) is unknown.

Other considerations for RLS patients include B vitamins, vitamin C, zinc, prebiotics and probiotics, which are required for neurotransmitter synthesis, nervous system health and optimal gastrointestinal function. Relaxation techniques, acupuncture, exercise, yoga, compression garments, hot/cold packs, proper sleep hygiene and abstinence from alcohol, tobacco and caffeinated drinks may be recommended to provide relief from symptoms.

Restless legs syndrome is a common, but often poorly managed, condition that responds well to herbal and nutritional interventions that target the underlying pathophysiology and aim to improve both the symptoms and patient’s quality of life.

References

  1. Kwatra V, Khan MA, Quadri SA, et al. Differential diagnosis and treatment of restless legs syndrome: a literature review. Cureus 2018;10(9):e3297. [Full text]
     
  2. Bollu PC, Yelam A, Thakkar MM. Sleep medicine: restless legs syndrome. Mo Med 2018;115(4):380-387. [Full text]
     
  3. Mitchell UH, Obray JD, Hunsaker E, et al. Peripheral dopamine in restless legs syndrome. Front Neurol 2018;15;9:155. [Full text]
     
  4. Guo S, Huang J, Jiang H, et al. Restless legs syndrome: from pathophysiology to clinical diagnosis and management. Front Aging Neurosci 2017;9:171. [Full text]
     
  5. Connor JR, Patton SM, Oexle K, et al. Iron and restless legs syndrome: treatment, genetics and pathophysiology. Sleep Med 2017;31:61-70. [Full text]
     
  6. Haschka D, Volani C, Stefani A, et al. Association of mitochondrial iron deficiency and dysfunction with idiopathic restless legs syndrome. Mov Disord 2019;34(1):114-123. [Abstract]
     
  7. Weinstock LB, Walters AS. Restless legs syndrome is associated with irritable bowel syndrome and small intestinal bacterial overgrowth. Sleep Med 2011;12(6):610-613. [Abstract]
     
  8. Rezvani F, Sayadnasiri M, Rezaei O. Restless legs syndrome in patients infected with Helicobacter pylori. Neurol Res 2018 Jul;40(7):581-585. [Abstract]
     
  9. Hoek PD, Smits MG, de Roos NM, et al. Increased prevalence of restless legs syndrome in patients with Crohn's disease. Eur J Gastroenterol Hepatol 2015 Aug;27(8):951-955. [Abstract]
     
  10. Takahara I, Takeshima F, Ichikawa T, et al. Prevalence of restless legs syndrome in patients with inflammatory bowel disease. Dig Dis Sci 2017 Mar;62(3):761-767. [Abstract]
     
  11. Braun L, Cohen M. Herbs and natural supplements: an evidence-based guide, 3rd ed. Sydney: Churchill Livingstone Elsevier, 2010. [Source]
     
  12. Ziegler G, Ploch M, Miettinen-Baumann A, et al. Efficacy and tolerability of valerian extract LI 156 compared with oxazepam in the treatment of non-organic insomnia - a randomized, double-blind, comparative clinical study. Eur J Med Res 2002;7(11):480-486. [Abstract]
     
  13. Palmieri G, Contaldi P, Fogliame G. Evaluation of effectiveness and safety of a herbal compound in primary insomnia symptoms and sleep disturbances not related to medical or psychiatric causes. Nat Sci Sleep 2017;9:163-169. [Full text]
     
  14. Cuellar NG, Ratcliffe SJ. Does valerian improve sleepiness and symptom severity in people with restless legs syndrome? Altern Ther Health Med 2009;15(2):22-28. [Abstract]
     
  15. Malcolm BJ, Tallian K. Essential oil of lavender in anxiety disorders: ready for prime time? Ment Health Clin 2017;7(4):147-155. [Full text]
     
  16. Kim Y, Kim M, Kim H, et al. Effect of lavender oil on motor function and dopamine receptor expression in the olfactory bulb of mice. J Ethnopharmacol 2009;125(1):31-35. [Abstract]
     
  17. Manconi M, Ferri R, Zucconi M, et al. Preferential D2 or preferential D3 dopamine agonists in restless legs syndrome. Neurology 2011;77(2):110-117. [Abstract]
     
  18. Trotti LM, Becker LA. Iron for the treatment of restless legs syndrome. Cochrane Database Syst Rev 2019;1:CD007834. [Full text]
     
  19. Bang YR, Jeon HJ, Park HY, et al. Symptom persistence after iron normalization in women with restless legs syndrome. Psychiatry Investig 2018;15(4):390-395. [Full text]
     
  20. Bartell S, Zallek S. Intravenous magnesium sulfate may relieve restless legs syndrome in pregnancy. J Clin Sleep Med 2006;2(2):187-188. [Abstract]
     
  21. Hornyak M, Voderholzer U, Hohagen F, et al. Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study. Sleep 1998;21(5):501-505. [Abstract]
     
  22. de Baaij JH, Hoenderop JG, Bindels RJ. Magnesium in man: implications for health and disease. Physiol Rev 2015;95(1):1-46. [Full text]

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Alinda Coleman B.Nat.