Restless Legs Syndrome
BASICS
DESCRIPTION
- Sensorimotor disorder consisting of a strong urge to move the limbs; legs are commonly affected initially but may involve arms/other body parts.
- Symptoms (Sx) begin/worsen during rest or inactivity; current or previous relief of symptoms by movement
- Occurs often in the evening; if not currently, previously reported circadian aspect
- Involuntary leg jerks reported during wake/sleep.
- Early onset phenotype: 40–92% familial, stable, slow progression of Sx.
- Late onset phenotype: more aggravating factors and rapid progression.
- Synonym(s): Willis-Ekbom disease
EPIDEMIOLOGY
Prevalence
Estimated 7.12% globally among adults 20 to 79 years old. Affects up to 10% of the elderly population in North American and Europe (1).Pregnancy Considerations
- 10–30% prevalence; triggers/exacerbates RLS
- Predictors: past history (Hx), family Hx, iron deficiency (ID), Hgb ≤11 g/dL (2)[ ]
- Peaks in 3rd trimester
- Most symptoms are relieved by 1-month postpartum.
ETIOLOGY AND PATHOPHYSIOLOGY
- Brain iron deficiency (BID), from low serum iron or impaired transport of iron into the brain, leading to CNS dopamine (DA) dysregulation:
- Higher than normal DA levels in the morning leading to DA D2 receptors downregulation.
- Lower than normal DA at night
- Increased glutamate and decreased adenosine leading to hyperarousal and insomnia
- Sensorimotor pathways abnormalities and increased motor excitability
- Triggered by prolonged immobility, such as hospitalizations
- Medication induced:
- Most antidepressants (except bupropion)
- DA-blocking antiemetics (e.g., metoclopramide, prochlorperazine).
- Phenothiazine antipsychotics (risperidone, clozapine, olanzapine, quetiapine, etc); possible exception: aripiprazole (partial D2 agonist)
- PPIs, H2 blockers (increase risk)
- Theophylline and other xanthines
- Sedating antihistamines
- Melatonin may exacerbate symptoms (3).
Genetics
- Susceptibility loci: 2p14, 2q, 6p21.2, 9p, 12q, 14q, 15q23, and 20p
- Genes: MEIS1, BTBD9, PTPRD, TOX3, MAP2K5/LBXCOR1
RISK FACTORS
- ID; vitamin D deficiency
- Family Hx
- Chronic renal failure
- Temperature (cold weather, other environmental factors may increase incidence/trigger Sx) (4)
GENERAL PREVENTION
- Regular physical activity during the day, low-impact activity at night such as stretches, walks
- Adequate sleep quality/quantity; delay wake time if possible.
- Avoid caffeine, alcohol, and nicotine mainly in the evening.
- Avoid meds that may trigger RLS (5)[ ].
COMMONLY ASSOCIATED CONDITIONS
- Insomnia, sleep walking, delayed sleep phase
- ID, renal disease/uremia/dialysis, gastric surgery, IBS
- Parkinson disease, multiple sclerosis, peripheral neuropathy, Machado-Joseph disease, migraines
- Anxiety, depression, ADHD
- Cardiovascular disease, diabetes mellitus, pulmonary hypertension, COPD
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Citation
Domino, Frank J., et al., editors. "Restless Legs Syndrome." 5-Minute Clinical Consult, 34th ed., Wolters Kluwer, 2026. Medicine Central, im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116907/all/Restless_Legs_Syndrome.
Restless Legs Syndrome. In: Domino FJF, Baldor RAR, Golding JJ, et al, eds. 5-Minute Clinical Consult. Wolters Kluwer; 2026. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116907/all/Restless_Legs_Syndrome. Accessed July 16, 2025.
Restless Legs Syndrome. (2026). In Domino, F. J., Baldor, R. A., Golding, J., & Stephens, M. B. (Eds.), 5-Minute Clinical Consult (34th ed.). Wolters Kluwer. https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116907/all/Restless_Legs_Syndrome
Restless Legs Syndrome [Internet]. In: Domino FJF, Baldor RAR, Golding JJ, Stephens MBM, editors. 5-Minute Clinical Consult. Wolters Kluwer; 2026. [cited 2025 July 16]. Available from: https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116907/all/Restless_Legs_Syndrome.
* Article titles in AMA citation format should be in sentence-case
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T1 - Restless Legs Syndrome
ID - 116907
ED - Domino,Frank J,
ED - Baldor,Robert A,
ED - Golding,Jeremy,
ED - Stephens,Mark B,
BT - 5-Minute Clinical Consult, Updating
UR - https://im.unboundmedicine.com/medicine/view/5-Minute-Clinical-Consult/116907/all/Restless_Legs_Syndrome
PB - Wolters Kluwer
ET - 34
DB - Medicine Central
DP - Unbound Medicine
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