Restless Legs Syndrome

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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 (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

Incidence
  • 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.

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/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

Genetics

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

-- To view the remaining sections of this topic, please or --

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 (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

Incidence
  • 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.

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/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

Genetics

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

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