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:
  • Begin or worsen during rest or inactivity
  • Are relieved by movement but recur with inactivity. Relief by movement may not be noticeable but has been previously reported.
  • Occur preferentially in the evening/night. Circadian aspect may not be noticeable but must have been previously reported.
  • Are not solely accounted for by “mimics” or another medical or behavioral condition
    • Mimics include leg cramps, positional discomfort, habitual foot tapping, arthralgias/arthritis, myalgias, leg edema, peripheral neuropathy, radiculopathy; even though some may coexist
  • Cause concern, distress, sleep disturbance
• Patient may also report involuntary leg jerks during wake or 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 symptoms
  • 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 are twice more affected than males.
• Temperature (cold weather) and other environmental factors may increase incidence or trigger symptoms.

• 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)

Etiology and Pathophysiology

• Brain iron deficiency, impaired into brain iron transport
  • Iron deficiency and associated conditions
• CNS dopamine regulation:
  • Fast dopamine turnover consistent with increased dopamine production
  • Circadian changes in dopamine (increases in the evening)
  • Decreased dopamine transporter
• Genetics: heterogeneous
  • Susceptibility loci: 2p14, 2q, 6p21.2, 9p, 12q, 14q, 15q23, and 20p
  • Genes: MEIS1, MAP2K5/LBXCOR1, BTBD9
• Changes in substantia nigra, striatum, putamen (reduced iron, less myelin, less D₂ receptors)
• Sensorimotor pathways abnormalities:
  • Bilateral activation of the cerebellum and contralateral activation of the thalamus
  • Increased activation of the prefrontal and anterior cingulate cortex
  • Decreased gray matter volume which correlates with disease severity and duration
• Cortical excitability: increased thalamic glutamate
• Increased endogenous opioids, possibly
• Triggering and exacerbating factors:
  • Prolonged immobility, such hospitalizations
  • Medications:
    • Most antidepressants (except bupropion)
    • Dopamine-blocking antiemetics (e.g., metoclopramide, prochlorperazine)
    • Some antiepileptic agents (e.g., phenytoin)
    • Phenothiazine antipsychotics (risperidone, clozapine, olanzapine, quetiapine) possible exception: aripiprazole (partial D₂ agonist)
    • Cognition-enhancing medication: donepezil
    • Theophylline and other xanthines
    • Antihistamines/over-the-counter (OTC) cold preparations (e.g., pseudoephedrine)
    • Adrenergics, stimulants
    • Anti-inflammatory medications

Risk Factors

• Iron deficiency
• Family history
• Increased with every pregnancy
• Chronic renal failure—11–58% affecting dialysis compliance
• Sleep deprivation, alcohol, caffeine—limited data

General Prevention

• Regular physical activity/exercise during the day, low impact such as stretches, leisure walks in the evening
• Adequate sleep; delay wake time if possible.
• Avoid caffeine, alcohol, nicotine mainly in the evening.
• Avoid use of medications that trigger RLS (4)[C].

Commonly Associated Conditions

• Periodic limb movements during sleep (PLMS), 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, including coronary artery disease and stroke
• Venous insufficiency/peripheral vascular disease
• Pulmonary hypertension, lung transplantation, chronic obstructive pulmonary disease (COPD)
• Orthopedic problems, arthritis, fibromyalgia