Restless legs syndrome (RLS) is a complex neurological disorder that presents with a blend of sensory and motor disturbances. Characterized by an irresistible urge to move the legs accompanied by uncomfortable sensations, RLS presents a unique challenge in both diagnosis and management. This disorder disrupts restorative sleep and significantly impacts the quality of life of those afflicted. As our understanding of the underlying mechanisms of RLS deepens, so does our ability to tailor effective treatment strategies. This article will explore genetic underpinnings, neurological complexities, and the evolving array of therapeutic approaches to provide relief to those who experience it.
What is Restless Legs Syndrome?
Restless legs syndrome (RLS), also known as Willis-Ekbom disease, is a neurological disorder characterized by an irresistible urge to move the legs, often accompanied by uncomfortable sensations in the legs. This typically occurs when a person is at rest, especially during the evening or nighttime hours, and is temporarily relieved with movement. The symptoms of RLS can lead to difficulty falling and staying asleep, resulting in daytime fatigue.
RLS affects up to 15% of the population. It can occur in men and women of all ages; however, women are more commonly affected than men. People of any age, including children, can develop RLS. However, the risk of developing the syndrome increases with age. (15, 19)
Restless Legs Syndrome Signs and Symptoms
People with RLS experience a bilateral, irresistible urge to move their legs with uncomfortable sensations often described as aching, throbbing, pulling, itching, crawling, or creeping. Rarely, these sensations also affect the arms, chest, or head. (18)
Common characteristics of RLS include (18):
- Sensations typically occur during periods of inactivity
- Sensations are relieved with movement
- Symptoms are worse at night
RLS is categorized as a sleep disorder because symptoms typically disrupt being able to fall or stay asleep easily. Symptoms of insomnia include daytime sleepiness, changes in mood, impaired memory and difficulty concentrating, depression, and anxiety. (19)
More than 80% of people with RLS also experience periodic limb movement of sleep (PLMS), characterized by involuntary leg twitching or jerking movements during sleep (18).
What Are the Possible Causes of Restless Legs Syndrome?
RLS may occur as a primary condition ("primary RLS") or due to another underlying disease or factor ("secondary RLS"). The underlying cause of primary and secondary RLS is unknown; however, research suggests that dysfunction of the dopaminergic system and low iron stores in the central nervous system are involved.
While the exact genetic basis of the disorder isn't fully understood, the familial tendency of RLS suggests an autosomal dominant pattern of inheritance in up to 75% of patients (15). Variants of the PPRD, BTBD9, and MEIS1 genes, which are involved in nervous system signaling and functioning, have been most strongly associated with RLS risk.
- Iron deficiency (with or without anemia)
- Kidney failure
- Parkinson's disease
- Peripheral neuropathy
- Rheumatoid arthritis
Additionally, antipsychotic, antidepressant, and antinausea medications can cause and aggravate RLS symptoms (20).
Acknowledging the theories surrounding iron deficiency and dopamine imbalance as causative factors for disease development and recognizing the gut's role in neurotransmitter synthesis, nutrient absorption, and systemic inflammation, emerging research focuses on the connection between RLS and gastrointestinal disorders. An estimated 25-30% of patients with irritable bowel syndrome (IBS) have RLS. Other research has noted an increased prevalence of RLS in patients with celiac disease, small intestinal bacterial overgrowth, and Crohn's disease (5).
Functional Medicine Labs to Test for Root Cause of Restless Legs Syndrome
Labs help to uncover underlying and contributing factors to symptomology and disease pathology. A functional medicine doctor may recommend ordering the following labs to help them better understand an individual's disease state and make informed and effective treatment decisions and recommendations.
A complete blood count (CBC) and iron panel, which should include ferritin, serum iron, total iron binding capacity, and transferrin saturation, screens for anemia and iron deficiency. Including a complete iron panel, instead of just ferritin - the standard lab marker for iron status - gives a more complete picture of iron metabolism and distribution throughout the body.
A complete thyroid panel is used to screen thyroid function, measure circulating thyroid hormones, and diagnose/monitor thyroid conditions that can be associated with and exacerbate RLS symptoms.
Comprehensive Gut Assessment
A variety of testing options are available to assess gut health and function. A comprehensive stool test, which measures intestinal markers related to the large intestinal microbiome, digestion and absorption, inflammation, and immunology, is a popular panel amongst functional doctors to screen for intestinal inflammation, dysbiosis, and maldigestion that can contribute to systemic pathologies.
Serum testing, such as the Celiac, IBS, and Crohn's Assay (CICA) is also available to measure immune and genetic markers that can indicate celiac disease and inflammatory bowel disease. Positive results warrant a referral to gastroenterology for diagnostic endoscopy/colonoscopy.
An organic acids test (OAT) is a urine test that provides an in-depth snapshot of metabolic health and function. Many markers included on this panel are used to screen for dysbiosis, nutrient deficiencies, and neurotransmitter imbalances - making it a relevant test for evaluating gut health and RLS.
Studies have observed a higher prevalence of vitamin D deficiency in people with RLS than in the general population. Additionally, there appears to be a negative association between RLS severity and serum vitamin D levels (i.e., higher RLS severity correlates with lower vitamin D). Vitamin D can be measured with a simple blood test to rule out deficiency and ensure that serum levels are within an optimal range. (3)
Conventional Treatment for Restless Legs Syndrome
Since RLS is a chronic condition, conventional treatment generally focuses on symptom management rather than a complete cure. However, treating underlying medical conditions may result in the improvement of secondary RLS. The treatment strategy for RLS depends on the severity of symptoms, underlying causes, and individual patient characteristics. It generally encompasses avoiding triggers (e.g., caffeine, alcohol, and nicotine), regular exercise, and maintaining a consistent sleep schedule. In more severe cases, medications may be prescribed, including dopaminergic agents, opioids, anticonvulsants, and other medications that help manage the symptoms of RLS. Many of these medications come with warnings of adverse side effects and the potential for worsening of RLS symptoms. (2)
Integrative Medicine Protocol for Restless Legs Syndrome
In addition to the therapeutic diet and nutritional supplements discussed below, an integrative approach to treating RLS combines various modalities to relieve RLS symptoms. Promising evidence supports non-pharmacologic interventions to reduce RLS symptoms, including warm baths, yoga, acupuncture, infrared light therapy, massage therapy, and topical essential oils (8).
Therapeutic Diet for Restless Legs Syndrome
Due to the stimulating effects caffeine exerts on the nervous system and muscle tissue, increased caffeine consumption has been linked to RLS. Patients, therefore, should be counseled on limiting or eliminating caffeinated beverages from their diet.
In one study of 131 patients with reactive hypoglycemia, 45% had RLS with spontaneous leg cramps. Symptoms improved when patients adhered to a diet designed to improve blood sugar control. The Mediterranean diet is a well-documented nutritional strategy to manage high and low blood sugar.
Given the association between iron deficiency and RLS, patients should also be encouraged to incorporate iron-rich foods into their diet. These include red meat, oysters, liver, chicken, dark leafy greens, legumes, molasses, and tofu.
Best Supplements for Managing Restless Legs Syndrome
Nutritional supplements can be used to correct nutrient deficiencies identified on lab work, help palliate uncomfortable symptoms, and promote restful sleep.
Among many other things, iron is required to convert tyrosine to dopamine; roughly one-quarter of people with RLS are deficient in this essential mineral. A 2019 Cochrane review including ten studies and over 400 participants with RLS concluded that iron supplementation was more effective than placebo in improving restlessness and RLS severity.
Dose: iron as ferrous sulfate 325 mg twice daily
Duration 4-12 weeks
As discussed above, evidence suggests that vitamin D deficiency can cause or exacerbate RLS. Therefore, if vitamin D deficiency is identified during laboratory evaluation, supplemental vitamin D should be administered to the patient. In a small study, vitamin D supplementation for 3-8 months to normalize deficient serum vitamin D levels improved RLS by 62%.
Dose and Duration: will vary depending on the degree of deficiency; doses may range from 1,000-10,000 IU daily to optimize and maintain vitamin D status
St. John's Wort
St. John's Wort is an herb that contains constituents that act on messengers in the nervous system to upregulate neurotransmitter levels and regulate mood. Studies have found that St. John's Wort can be used to treat depression, insomnia, and symptoms of RLS effectively.
Dose: 300 mg 1-3 times daily
Duration 1-3 months
When to Retest Labs
Retesting labs to monitor treatment will depend on each patient's circumstances. For example, those with secondary RLS due to hypothyroidism may require labwork every 4-6 weeks as thyroid hormone therapy is optimized and adjusted. Alternatively, hemoglobin A1c may be monitored every three months in diabetics until blood sugar goals are achieved. Frequent lab work may not be necessary for patients without underlying medical conditions, and clinical observation alone may be sufficient for monitoring treatment efficacy.
By acknowledging the intricate interplay of RLS's genetics, lifestyle, environment, and underlying biochemical imbalances, a functional medicine approach unveils a comprehensive strategy to alleviate the burden of RLS. Personalized interventions, encompassing nutrient optimization, lifestyle modification, and stress modulation, support the body's innate healing capacities to restore biological and physiologic balance to the system, offering hope for RLS symptom relief.
Lab Tests in This Article
1. Apaydin, E. A., Maher, A. R., Shanman, R., et al. (2016). A systematic review of St. John's wort for major depressive disorder. Systematic Reviews, 5(1). https://doi.org/10.1186/s13643-016-0325-2
2. Bayard, M., Avonda, T., & Wadzinski, J. (2008). Restless Legs Syndrome. American Family Physician, 78(2), 235–240. https://www.aafp.org/pubs/afp/issues/2008/0715/p235.html
3. Cederberg, K. L. J., Silvestri, R., & Walters, A. S. (2023). Vitamin D and Restless Legs Syndrome: A Review of Current Literature. Tremor and Other Hyperkinetic Movements, 13(1). https://doi.org/10.5334/tohm.741
4. Cloyd, J. (2023, February 2). Top Lab Test to Run on Your Iron Deficiency Anemia Patients. Rupa Health. https://www.rupahealth.com/post/top-lab-test-to-run-on-your-iron-deficiency-anemia-patients
5. Cloyd, J. (2023, August 14). Top Labs To Run Bi-Annually On Your Patients Who Suffer From Restless Legs Syndrome. Rupa Health. https://www.rupahealth.com/post/top-labs-to-run-bi-annually-on-your-patients-who-suffer-from-restless-legs-syndrome
6. Connor, J. R., Patton, S. M., Oexle, K., et al. (2017). Iron and restless legs syndrome: treatment, genetics and pathophysiology. Sleep Medicine, 31(1), 61–70. https://doi.org/10.1016/j.sleep.2016.07.028
7. Creedon, K. (2022, August 4). 6 Speciality Labs That Get To The Root Cause Of Insomnia. Www.rupahealth.com. https://www.rupahealth.com/post/6-speciality-labs-that-get-to-the-root-cause-of-insomnia
8. DePorto, T. (2022, November 30). Restless Leg Syndrome: Causes, Symptoms, and Treatment. Rupa Health. https://www.rupahealth.com/post/restless-leg-syndrome-causes-symptoms-and-treatment
9. Dichtl, S., Haschka, D., Nairz, M., et al. (2018). Dopamine promotes cellular iron accumulation and oxidative stress responses in macrophages. Biochemical Pharmacology, 148, 193–201. https://doi.org/10.1016/j.bcp.2017.12.001
10. Jiménez-Jiménez, F. J., Alonso-Navarro, H., García-Martín, E., et al. (2018). Genetics of restless legs syndrome: An update. Sleep Medicine Reviews, 39, 108–121. https://doi.org/10.1016/j.smrv.2017.08.002
11. Lazzell, K. (2023, January 23). How Alison Fixed Her Restless Leg Syndrome With Functional Medicine: A Case Study. Rupa Health. https://www.rupahealth.com/post/how-allison-fixed-her-restless-leg-syndrome-with-functional-medicine-a-case-study
12. Lutz, E. G. (1978). Restless legs, anxiety and caffeinism. The Journal of Clinical Psychiatry, 39(9), 693–698. https://pubmed.ncbi.nlm.nih.gov/690085/
13. MacNeill, S. (2020, August 31). What You Need to Know About St. John's Wort. Fullscript. https://fullscript.com/blog/st-johns-wort
14. Maholy, N. (2023, May 26). Integrative Nutrition Approaches to Managing Blood Sugar Levels. Rupa Health. https://www.rupahealth.com/post/integrative-nutrition-approaches-to-managing-blood-sugar-levels
15. Mansur, A., Castillo, P. R., Rocha Cabrero, F., et al. (2020). Restless Legs Syndrome. PubMed; StatPearls Publishing. https://www.ncbi.nlm.nih.gov/books/NBK430878/
16. Pereira Jr, J., Pradella-Hallinan, M., & Alves, R. (2013). Saint John's wort, an herbal inducer of the cytochrome P4503A4 isoform, may alleviate symptoms of Willis-Ekbom's disease. Clinics, 68(4), 469–474. https://doi.org/10.6061/clinics/2013(04)06
17. Preston, J. (2023, May 18). Complementary and Integrative Medicine Treatment for Pediatric Sleep Disorders: Testing, Supplements, and Therapies. Rupa Health. https://www.rupahealth.com/post/complementary-and-integrative-medicine-treatment-for-pediatric-sleep-disorders-testing-supplements-and-therapies
18. Restless Legs Syndrome. National Institute of Neurological Disorders and Stroke. https://www.ninds.nih.gov/health-information/disorders/restless-legs-syndrome#1
19. Restless Legs Syndrome. (2020, January 24). Cleveland Clinic. https://my.clevelandclinic.org/health/diseases/9497-restless-legs-syndrome
20. Restless Legs Syndrome. (2023, April 24). National Organization for Rare Disorders. https://rarediseases.org/rare-diseases/restless-legs-syndrome/#causes
21. Roberts, H. J. (1973). Spontaneous leg cramps and "restless legs" due to diabetogenic (functional) hyperinsulinism. A basis for rational therapy. JFMA, the Journal of the Florida Medical Association. Florida Medical Association, 60(5), 29–31. https://pubmed.ncbi.nlm.nih.gov/4695820/
22. Schulz, H., & Jobert, M. (1994). Effects of hypericum extract on the sleep EEG in older volunteers. Journal of Geriatric Psychiatry and Neurology, 7(1), S39-43. https://doi.org/10.1177/089198879400700111
23. Vazquez, K. (2022, August 22). How Gut Dysbiosis Negatively Affects Hormone Regulation, Immune System Activation, and Neurotransmitter Production. Rupa Health. https://www.rupahealth.com/post/how-gut-dysbiosis-negatively-affects-hormone-regulation-immune-system-activation-and-neurotransmitter-production
24. Wali, S., Shukr, A., Boudal, A., et al. (2014). The effect of vitamin D supplements on the severity of restless legs syndrome. Sleep and Breathing, 19(2), 579–583. https://doi.org/10.1007/s11325-014-1049-y
25. Weinberg, J. L. (2022, November 16). What Is the Mediterranean Diet? Rupa Health. https://www.rupahealth.com/post/4-science-backed-health-benefits-of-the-mediterranean-diet