Description

• 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

Epidemiology

Incidence

• 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)

Prevalence

• 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

Genetics

• Susceptibility loci: 2p14, 2q, 6p21.2, 9p, 12q, 14q, 15q23, and 20p
• Genes: MEIS1, MAP2K5/LBXCOR1, BTBD9, PRPRD, TOX3

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