Restless Legs Syndrome

Restless Legs Syndrome is a topic covered in the 5-Minute Clinical Consult.

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Basics

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

Incidence
  • 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.

Prevalence
  • 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 or exacerbates RLS
  • Predictors: family history, past history, iron deficiency, Hgb ≤11 g/dL (3)[C]
  • Peaks in 3rd trimester
  • Most are relieved by 1-month postpartum.

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

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