Restless Leg Syndrome

Aka: Restless Leg Syndrome, Restless Legs Syndrome, Ekboms Syndrome

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II. Epidemiology

  1. Fourth leading cause of Insomnia
  2. Family History of restless legs in 50-60%
  3. Incidence in adults: 6-10% (only 2 to 3% seek treatment)
  4. Incidence in adults over age 65 years: 10-28%
  5. More common in women
  6. Onset before age 18 in one third of patients

III. Risk Factors

  1. Family History of Restless Leg Syndrome (accounts for 50% of RLS patients)
  2. Iron Deficiency Anemia (especially if Serum Ferritin <50 ng/ml)
  3. Chronic Renal Failure (Chronic Kidney Disease)
  4. Antidepressant use (Akathisia)
  5. Pregnancy
  6. Neuropathy

IV. Pathophysiology: Possible etiologies

  1. Dopamine deficiency in Brainstem or spinal cord
  2. Endogenous Opiate deficiency
  3. Small fiber Peripheral Neuropathy

V. Causes

  1. Idiopathic in most cases
  2. Iron Deficiency Anemia
  3. Renal Dialysis
  4. Pregnancy (as high as 19%)
  5. Hypothyroidism
  6. Diabetes Mellitus
  7. Electrolyte disturbance
    1. Decreased Serum Magnesium
    2. Decreased Serum Folate
  8. Leg varicosities
    1. May be relieved with sclerotherapy
  9. Drug-induced causes
    1. See Akathisia
    2. Selective Serotonin Reuptake Inhibitors (common)
    3. Antihistamines (e.g. Benadryl)
    4. Antipsychotics
    5. Antiemetics
      1. Phenergan
      2. Metoclopramide
      3. Prochlorperazine
    6. Lithium
    7. Tricyclic Antidepressants (e.g. Elavil)
      1. Treat with Propranolol 40 mg PO tid
    8. Substances
      1. Caffeine
      2. Tobacco use

VI. Symptoms

  1. Timing
    1. Symptoms worsen in the afternoon, evening and bedtime
    2. Contrast with Periodic Limb Movement which occurs during sleep
  2. Overall urge to move legs due to uncomfortable leg Sensations (Akathisia)
    1. Creeping or crawling restlessness
    2. Wormy or boring Sensation
    3. Tingling, pins and needles, or prickly Sensation
    4. Pulling or drawing Sensation
  3. Severity
    1. Symptoms can cause very significant morbidity (to point of Suicidal Ideation)
  4. Palliative
    1. Movement (e.g. walking) temporarily relieves Sensation until sitting or lying back down again
  5. Provocative
    1. Prolonged period of inactivity (e.g. car travel)
    2. Prolonged sitting (e.g. classes or meetings)
    3. Lying down or sleeping

VII. Signs

  1. Periodic flexions
    1. Occur every 20-40 seconds during non-REM Sleep

VIII. Labs

  1. Serum Ferritin (<50 ng/ml associated with Restless Leg Syndrome)
  2. Serum Glucose
  3. Serum Creatinine
  4. Consider other lab testing to consider
    1. Thyroid Stimulating Hormone
    2. Serum Magnesium
    3. Serum Folate

IX. Differential Diagnosis

  1. See Akathisia
  2. Periodic Limb Movement
  3. Night Cramps (Leg Cramps)
  4. Peripheral Vascular Disease
  5. Anxiety Disorder
  6. Drug induced Akathisia
  7. Peripheral Neuropathy
  8. Tic Disorder

X. Diagnosis: Essential Features (4 criteria)

  1. Intense urge to move legs (typically asssociated with uncomfortable creeping or aching leg Sensations) AND
  2. Symptoms begin or worsen with rest or inactivity AND
  3. Symptoms are at least in part relieved with walking or Stretching AND
  4. Worse or limited to evening and overnight

XI. Management: General measures

  1. Discontinue provocative habits
    1. Discontinue Caffeine usage
    2. Tobacco Cessation
    3. Alcohol cessation
  2. Encourage relaxing bedtime routine
    1. Avoid vigorous Exercise 2 hours before bedtime
    2. Avoid sexual activity 2 hours before bedtime
    3. Adjust schedule to allow awakening later
  3. Correct Iron Deficiency Anemia
    1. Screen with Serum Ferritin in most if not all patients with Restless Leg Syndrome
    2. Consider Iron Supplementation for Serum Ferritin <75 mcg/L
  4. Local massage (leg massage)
  5. Moderate intensity Exercise (e.g. brisk walking) may also decrease symptoms longterm
  6. Cold compress application
  7. Consider adaptive changes at work or school
    1. Work at high desk with stool
    2. Sit in aisle seat on trips or meetings
  8. Consider sleep clinic referral for refractory symptoms

XII. Management: GABA Agents (preferred first line)

  1. First-line option for persistent restless legs
    1. Delayed onset of relief while starting and titrating medication
    2. Better tolerated longterm than the Dopaminergic agents (listed above)
    3. Similar efficacy to the Dopaminergic agents (50% symptom reduction with NNT 5)
  2. Gabapentin (Neurontin)
    1. Start: 300 mg orally at bedtime
    2. Increase: every 3-4 nights until symptoms controlled or at a maximum of 1800 mg
    3. Effective in RCT at 1800 mg/day (600 mg tid)
      1. Garcia-Borreguero (2002) Neurology 59:1573-9 [PubMed]
  3. Pregabalin (Lyrica)
    1. Start 300 mg orally at bedtime

XIII. Management: Non-Ergotamine Dopamine Agonists (preferred second line)

  1. Preferred for frequent or nightly restless legs symptoms
    1. Quick onset of improved symptoms
    2. Risk of sedation, Nausea, Hallucinations and Compulsive Gambling and other behaviors
    3. Augmentation (worsening symptoms) occurs in 6-7% of patient per year
      1. Switch to GABA Agent (Gabapentin or Pregabalin) - see below
  2. Pramipexole (Mirapex)
    1. Initial dose: 0.125 mg one tablet orally at bedtime
    2. Subsequent: Increase dose every third night until symptoms controlled or at a maximum of 4 tablets at bedtime
    3. See Mirapex for dosing strategy
  3. Ropinirole (Requip)
    1. Initial dose: 0.25 mg orally at bedtime
    2. Subsequent: Increase dose every third night until symptoms controlled or at a maximum of 4 tablets at bedtime
    3. See Requip for dosing strategy
  4. Rotigotine (Neupro) Transdermal
    1. Dopamine Agonist transdermal patch
    2. Indicated for moderate to severe symptoms refractory to Pramipexole or Ropinirole
    3. Dosing
      1. One patch applied daily to a new site
      2. Do not repeat the same site for 14 days
      3. Start at 1 mg/24 hours
      4. May increase weekly to a maximum of 3 mg/24 hours

XIV. Management: Other agents

  1. Analgesics at bedtime
    1. Acetaminophen (Tylenol)
    2. NSAIDS (e.g. Ibuprofen)
    3. Nighttime Opioid Analgesics (e.g. Oxycodone 5-10 mg at bedtime) may also be effective
  2. Dopamine Agonists
    1. Consider for occsional symptoms
    2. Carbidopa and Levodopa
      1. Sinemet 12.5/50 mg PO qhs prn
      2. Sinemet CR 25/100 mg PO qhs prn
  3. Ergotamine Dopamine Agonists
    1. Pergolide (Permax) 0.05 to 1 mg
      1. First dose at dinner
      2. Second dose one hour before bed
    2. Cabergoline (Dostinex)
      1. Initial dose: 0.5 mg PO at bedtime
  4. Benzodiazepines
    1. Not recommended
  5. Alpha Adrenergic Agonists
    1. Clonidine 0.1 mg PO qhs

XV. Course

  1. Symptoms progress with age

XVI. Resources

  1. Restless Legs Syndrome Foundation
    1. http://www.rls.org

XVII. References

  1. (2017) Presc Lett 24(4):20-1
  2. (2000) Am Fam Physician 62:108-14 [PubMed]
  3. Bayard (2008) Am Fam Physician 78(2): 235-43 [PubMed]
  4. Clark (2001) J Am Board Fam Pract 14:368-74 [PubMed]
  5. Henning (1999) Sleep 22:970-99 [PubMed]
  6. Holder (2022) Am Fam Physician 105(4): 397-405 [PubMed]
  7. Paulson (2000) Geriatrics 55:35-48 [PubMed]
  8. Ramar (2013) Am Fam Physician 88(4): 231-8 [PubMed]

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