Description

• Sensorimotor disorder consisting of a strong, nearly irresistible urge to move the limbs (1)[A]
• The urge usually affects the legs at least initially but may involve arms or other body parts (2)[C].
• The urge might be accompanied by uncomfortable and unpleasant sensations.
• The symptoms (Sx):
  • Begin or worsen during rest or inactivity
  • Are relieved by movement but recur with inactivity. If not present, previous relief by movement
  • Occur preferentially in the evening/night. If not present, previously reported circadian aspect
• Involuntary leg jerks reported during wake/sleep (1)[A].
• System(s) affected: nervous; musculoskeletal
• Early <45 years versus late >45 years onset (1)[A]
  • 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

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

• 4–15% in Caucasian adults, underdiagnosed
• 2–3% are clinically significant.
• 1–3% in children and adolescents
• Increases with age up to 70s
• 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 (3)[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, ID and associated conditions
• BID leads to central nervous system dopamine dysregulation:
  • Higher than normal dopamine levels in the morning and lower than normal dopamine at night leading to downregulation of dopamine D₂ receptors
  • Decreased dopamine transporter
• BID results in increased glutamate and decreased adenosine leading to hyperarousal and insomnia.
• Changes in substantia nigra, striatum, putamen: reduced iron, less myelin, fewer D₂ receptors
• Sensorimotor pathways: abnormalities and increased motor excitability
• Increased endogenous opioids, possibly
• Triggering and exacerbating factors:
  • Prolonged immobility, such hospitalizations
  • Medications (meds):
    • Most antidepressants (except bupropion)
    • Dopamine-blocking antiemetics (e.g., metoclopramide, prochlorperazine)
    • Phenothiazine antipsychotics (e.g., risperidone, clozapine, olanzapine quetiapine). Possible exception: aripiprazole (partial D₂ agonist)
    • Cognition-enhancing meds: memantine
    • Theophylline and other xanthines
    • Sedating antihistamines, OTC cold preparations

Heterogeneous:

• 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 Tsat<16
• Family Gx
• Increased with every pregnancy
• Chronic renal failure: 11–58% affects dialysis compliance
• Sleep deprivation (including untreated OSA)
• 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 meds that may trigger RLS (4)[C].

Commonly Associated Conditions

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