Restless Legs Syndrome



  • Sensorimotor disorder consisting of a strong, nearly irresistible urge to move the limbs. Legs are usually affected initially but may involve arms or other body parts.
  • The symptoms (Sx):
    • Begin or worsen during rest or inactivity
    • Are relieved by movement but recur with inactivity. If not current, previous relief by movement
    • Occur preferentially in the evening/night. If not current, previously reported circadian aspect
  • Involuntary leg jerks reported during wake/sleep.
  • Early (<45 years) versus late (>45 years) onset
    • Early onset phenotype: 40–92% familial, stable, slow progression of Sx
    • Late onset phenotype: more aggravating factors; rapid progression is common.
  • Synonym(s): Willis-Ekbom disease



  • 0.8–2.2% annually
  • Onset at any age
  • Parous females have twice the prevalence of males.
  • Temperature (cold weather, other environmental factors may increase incidence/trigger Sx)


  • 1–3% of Caucasians (likely underdiagnosed)
  • Increases with age
  • Lower in non-Caucasians (except Koreans)

Pregnancy Considerations

  • 10–30% prevalence; triggers/exacerbates RLS
  • Predictors: past history (Hx), family Hx , iron deficiency (ID), Hgb ≤11 g/dL (1)[C]
  • Peaks in 3rd trimester
  • Most are relieved by 1-month postpartum.

Etiology and Pathophysiology

  • Brain iron deficiency (BID), from either low serum iron or impaired transport of iron into the brain, leading to CNS dopamine dysregulation:
    • Higher than normal dopamine (DA) levels in the morning and lower than normal DA at night leading to downregulation of DA D2 receptors
    • Increased glutamate and decreased adenosine leading to hyperarousal and insomnia
  • Sensorimotor pathways abnormalities and increased motor excitability
  • Triggered by prolonged immobility, such 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)
    • Cognition-enhancing meds: memantine
    • Theophylline and other xanthines
    • Sedating antihistamines, OTC cold preparations


  • Susceptibility loci: 2p14, 2q, 6p21.2, 9p, 12q, 14q, 15q23, and 20p

Risk Factors

  • ID: ferritin <75 ng/mL or transferrin saturation (TSAT) <16
  • Family history
  • Chronic renal failure
  • Sleep deprivation
  • Alcohol, caffeine (limited data)

General Prevention

  • Regular physical activity/exercise during the day, low-impact activity at night such as stretches, walks
  • Adequate sleep; delay wake time if possible.
  • Avoid caffeine, alcohol, nicotine mainly in the evening.
  • Avoid use of medications that may trigger RLS (2)[C].

Commonly Associated Conditions

  • Insomnia, sleep walking, delayed sleep phase
  • Iron deficiency, renal disease/uremia/dialysis, gastric surgery, IBS, liver disease
  • Parkinson disease, multiple sclerosis, peripheral neuropathy, Machado-Joseph disease, migraine
  • Anxiety, depression, ADHD
  • Cardiovascular disease, coronary artery disease and stroke
  • Venous insufficiency/peripheral vascular disease
  • Pulmonary hypertension, lung transplantation, chronic obstructive pulmonary disease (COPD)
  • Orthopedic problems, arthritis, fibromyalgia

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