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Restless Legs Syndrome
Donald E. Watenpaugh, PhD
John R. Burk, MD
image BASICS
DESCRIPTION
  • Sensorimotor disorder consisting of a strong urge to move the legs, usually with paresthesia (1)[A]
  • Symptoms emerge during inactivity.
  • Movement relieves symptoms, but they soon recur with inactivity.
  • Symptoms occur preferentially in the evening/night.
  • Symptoms may involve the arms or be more generalized.
  • Patient may also report involuntary leg jerks (1)[A].
  • Associated with insomnia and/or functional impairment(s)
  • Not solely accounted for by another disorder
  • System(s) affected: musculoskeletal; nervous
  • Synonym(s): Willis-Ekbom disease
EPIDEMIOLOGY
Incidence
  • Onset at any age; increases with age
  • Predominant sex: male = female (nulliparous); female (parous) two times > male (2)[B]
  • May increase in summer (warm) months
Prevalence
  • 4-15% of Caucasian adults; underdiagnosed
  • 1-3% in children and adolescents
  • Increases with age
  • Lower in non-Caucasians
Pregnancy Considerations
10-30% prevalence; exacerbates existing restless legs syndrome (RLS)
ETIOLOGY AND PATHOPHYSIOLOGY
  • Primary (early-onset) RLS: subcortical dopamine deficiency/dysmetabolism
  • Late-onset (often secondary) RLS:
    • Iron deficiency and associated conditions
    • Chronic extremity tissue pathology/inflammation
    • Medications
      • Most antidepressants (exceptions: bupropion and desipramine)
      • Dopamine-blocking antiemetics (e.g., metoclopramide, prochlorperazine)
      • Some antiepileptic agents (e.g., phenytoin)
      • Phenothiazine antipsychotics; donepezil
      • Theophylline and other xanthines
      • Antihistamines/over-the-counter (OTC) cold preparations (e.g., pseudoephedrine)
      • Adrenergics, stimulants
Genetics
  • Early-onset RLS heritability: ˜50%
  • Genetically heterogenous
    • Susceptibility loci: 2p14, 2q, 6p21.2, 9p, 12q, 14q, 15q23, and 20p
    • Genes: MEIS1, MAP2K5/LBXCOR1, and BTBD9
RISK FACTORS
  • Family history (3,4)
  • Aging
  • Chronic inactivity
  • Inadequate sleep
  • Associated conditions (see “Commonly Associated Conditions”)
  • Certain medications (see “Etiology”)
GENERAL PREVENTION
  • Regular physical activity/exercise
  • Adequate sleep
  • Avoid evening caffeine, alcohol, tobacco.
  • Avoid late-day use of medications that cause RLS.
COMMONLY ASSOCIATED CONDITIONS
  • Periodic limb movements of sleep, insomnia, sleep walking, other parasomnias, delayed sleep phase
  • Iron deficiency, renal disease/uremia/dialysis, gastric surgery, liver disease
  • Parkinson disease, multiple sclerosis, peripheral neuropathy, migraine
  • Orthopedic problems, arthritis, fibromyalgia
  • Venous insufficiency/peripheral vascular disease, erectile dysfunction
  • Pulmonary hypertension, lung transplantation, chronic obstructive pulmonary disease (COPD)
  • ADHD, anxiety/depression, “sundowning”
  • Pregnancy (especially if Fe- or folate-deficient)
image DIAGNOSIS
  • Depends on history, yet often “difficult to describe”
  • May go undiagnosed for years by multiple doctors
DIFFERENTIAL DIAGNOSIS
  • Claudication: Movement does not relieve pain and may worsen it.
  • Motor neuron disease fasciculation/tremor: no discomfort or circadian pattern
  • Peripheral neuropathy: usually no circadian pattern; unresponsive to dopamine agonists
  • Dermatitis/pruritus: movement only to scratch; no circadian pattern
  • Sleep-related leg cramps: isolated and very painful muscle contracture
  • Periodic limb movement disorder: no wakeful movements
  • Sleep starts: isolated involuntary events
  • Rhythmic movement sleep disorder: movement periodicity faster than RLS
  • Growing pains: no urge to move or relief by movement; circadian pattern opposite RLS
  • ADHD: no sleep disorders or complaints in diagnostic criteria
DIAGNOSTIC TESTS & INTERPRETATION
Serum ferritin to assess for iron deficiency
Diagnostic Procedures/Other
  • Sleep study helpful but not required
    • Frequent, periodic movements during wake
  • Suggested immobilization test
    • Conducted before nocturnal polysomnography
    • Patient attempts to sit still in bed for 1 hour
    • >40 movements per hour suggests RLS.
  • Ankle actigraphy for in-home use
  • Electromyography, nerve conduction studies for peripheral neuropathy, radiculopathy
Test Interpretation
  • Serum ferritin should be >75 ng/mL.
  • Transferrin saturation should be >16%.
image TREATMENT
First-line treatments
  • Prescribed daily exercise (3)[B]; adequate sleep
  • Correct iron deficiency.
  • Dopaminergic medications
  • For secondary RLS, treat cause(s).
  • Multiple possible causes are not mutually exclusive.
GENERAL MEASURES
  • If iron deficient, supplement:
    • 325 mg FeSO4 TID
    • Repletion requires months.
  • Daily exercise. However, avoid unusual activity that may exacerbate symptoms.
  • Regular and replete sleep
  • Hot bath and leg massage
  • Warm the legs (long heavy socks, electric blanket).
  • Intense mental activity (games, puzzles, etc.)
  • Avoid exacerbating factors.
MEDICATION
  • Use minimum effective dose.
  • Preferentially use longer-acting/extended-release options.
  • Daytime sleepiness unusual with doses and timing for RLS
  • Severe/refractory RLS may require combination therapy (4,5)[A].
P.911

First Line
  • Dopamine agonists (4,5)[A]; titrate every 3 days to minimum dose necessary to fully control symptoms:
    • Pramipexole (Mirapex): 0.125 to 0.5 mg 1 hour before symptoms; titrate by 0.125 mg
    • Ropinirole (Requip): 0.25 to 4 mg 1 hour before symptoms; titrate by 0.25 mg
    • Divide dose for evening and bedtime symptoms.
    • Transdermal rotigotine (Neupro): 1 to 3 mg/24 hours patch; initiate with 1 mg/day; titrate by 1 mg weekly
    • Avoid dopamine agonists in psychotic patients, particularly if taking dopamine antagonists.
    • Add a different class of medication before exceeding dopamine agonist recommended dose.
  • Gabapentin enacarbil (Horizant): 600 mg every day ˜5:00 PM (4,5)[A]
  • All other medications off-label
Second Line
  • Anticonvulsants (for comorbid neuropathy).
    • Pregabalin (Lyrica): 50 to 300 mg/day
    • Carbamazepine: 200 to 800 mg/day
  • Opioids (low risk of tolerance/addiction at bedtime)
    • Hydrocodone: 5 to 20 mg/day
    • Tramadol: 50 mg/day
    • Oxycodone: 2.5 to 20 mg/day
  • Benzodiazepines and agonists (for associated insomnia or anxiety)
    • Clonazepam (Klonopin): 0.5 to 3 mg/day
    • Temazepam, triazolam, alprazolam, zaleplon, zolpidem, and diazepam
  • Dopamine agonists
    • Carbidopa-levodopa (Sinemet or Sinemet CR): 10/100 to 25/250; PRN for sporadic symptoms
Pregnancy Considerations
  • Initial approach: nonpharmacologic therapies, assess/correct iron deficiency
  • Avoid medications class C or D.
  • In 3rd trimester, may consider low-dose clonazepam or opioids (6)[B].
Pediatric Considerations
  • First-line treatment: nonpharmacologic therapies, assess/correct iron deficiency
  • Low-dose clonidine or clonazepam may be considered.
Geriatric Considerations
  • Avoid medications that cause dizziness or unsteadiness.
  • Many medications given to elderly cause/exacerbate RLS.
ISSUES FOR REFERRAL
  • Severe, intractable symptoms
  • Augmentation response to dopaminergic therapy
  • Peripheral neuropathy; orthopedic problems
  • Peripheral vascular disease; intransigent iron deficiency
ADDITIONAL THERAPIES
  • Vitamin, mineral supplements: Ca, Mg, B12, folate
  • Clonidine: 0.05 to 0.1 mg/day
  • Baclofen: 20 to 80 mg/day
  • Methadone: 5 to 10 mg/day
  • Oxycodone PR-Naloxone PR: 10 or 5 mg/day
  • Prescription or OTC hypnotics
SURGERY/OTHER PROCEDURES
For orthopedic, neuropathic, or leg vascular disease (laser ablation, sclerotherapy, etc.)
COMPLEMENTARY & ALTERNATIVE MEDICINE
  • Relaxis leg vibration device (FDA approved; see http://www.sensorymedical.com)
  • Sequential pneumatic leg compression
  • Enhanced external counterpulsation
  • Compression stockings
  • Acupuncture
  • MicroVas therapy
  • Near-infrared light (3)[B]
INPATIENT CONSIDERATIONS
  • Control RLS after orthopedic procedures.
  • Addition/withdrawal of medications affecting RLS (e.g., narcotics)
  • Changes in medical status may require medication changes (e.g., Mirapex contraindicated in renal failure and Requip contraindicated in liver disease).
IV Fluids
  • Iron infusion when oral Fe fails or contraindicated.
  • When NPO, consider IV opiates.
Nursing
  • Evening walks, hot baths, leg massage, and warming
  • Sleep interruption risks prolonged wakefulness.
image ONGOING CARE
FOLLOW-UP RECOMMENDATIONS
Patient Monitoring
  • At 2-week intervals until stable, then annually
  • If taking iron, remeasure ferritin.
  • If status changes, assess for associated conditions and medications.
DIET
Avoid evening caffeine and alcohol.
PATIENT EDUCATION
  • Willis-Ekbom Disease Foundation: www.rls.org
  • National Sleep Foundation: sleepfoundation.org
  • American Academy of Sleep Medicine: http://sleepeducation.com/
PROGNOSIS
  • Early-onset: lifelong condition with no current cure
  • Late-onset/secondary: may subside with resolution of precipitating factors
  • Current therapies usually control symptoms
REFERENCES
1. Allen RP, Picchietti DL, Garcia-Borreguero D, et al. Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria—history, rationale, description, and significance. Sleep Med. 2014;15(8):860-873.
2. Manconi M, Ulfberg J, Berger K, et al. When gender matters: restless legs syndrome. Report of the “RLS and woman” workshop endorsed by the European RLS Study Group. Sleep Med Rev. 2012;16(4):297-307.
3. Wilt TJ, MacDonald R, Ouellette J, et al. Treatment for Restless Legs Syndrome. Agency for Healthcare Research and Quality Comparative Effectiveness Reviews (US). 2012; Report No.: 12(13)-EHC147-EF.
4. Aurora RN, Kristo DA, Bista SR, et al. The treatment of restless legs syndrome and periodic limb movement disorder in adults—an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses: an American Academy of Sleep Medicine Clinical Practice Guideline. Sleep. 2012;35(8):1039-1062.
5. Ferini-Strambi L, Marelli S. Pharmacotherapy for restless legs syndrome. Expert Opin Pharmacother. 2014;15(8):1127-1138.
6. Picchietti DL, Hensley JG, Bainbridge JL, et al. Consensus clinical practice guidelines for the diagnosis and treatment of restless legs syndrome/Willis-Ekbom disease during pregnancy and lactation. Sleep Med Rev. 2015;22:64-77.
Additional Reading
&NA;
  • Amos LB, Grekowicz ML, Kuhn EM, et al. Treatment of pediatric restless legs syndrome. Clin Pediatr (Phila). 2014;53(4):331-336.
  • Garcia-Borreguero D, Benitez A, Kohnen R, et al. Augmentation of restless leg syndrome (Willis-Ekbom disease) during long-term dopaminergic treatment. Postgrad Med. 2014;127(7):716-725.
See Also
&NA;
  • Periodic Limb Movement Disorder
  • Algorithm: Restless Legs Syndrome
Codes
&NA;
ICD10
G25.81 Restless legs syndrome
Clinical Pearls
&NA;
  • Insomnia with frequent tossing/turning and difficulty “getting comfortable” is often RLS.
  • Many antidepressants, antipsychotics, antiemetics, and antihistamines cause or exacerbate RLS.
  • Titrate medication for RLS, especially dopaminergics, only up to the minimum dose necessary to control symptoms.
  • RLS may interfere with use of positive airway pressure to treat obstructive sleep apnea.
  • RLS and other sleep disorders may cause ADHD.