para>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: ’ Ό50%
- 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)
DIAGNOSIS
- Depends on history, yet often "difficult to describe "
- May go undiagnosed for years by multiple doctors
HISTORY
- Signs/symptoms (see also "Description " ) (1)[A]
- Limited to evening, night
- Example descriptions: burning, achy, itching, antsy, "can 't get comfortable "
- Painful in ~35% of patients
- Discomfort associated with overwhelming urge to move and relieved by movement
- Urge to move may be the only "discomfort. "
- Movement frequency every 10 to 90 seconds (mean ~25 seconds)
- Some patients must get up and walk.
- May involve arms or, rarely, whole body
- Periodic movements in sleep in ’ Ό80% of patients.
- Insomnia, fatigue, anxiety
- Severity range: from rare, minor problem to daily severe impact on quality of life
- Early-onset RLS (before age 45 years) progresses slowly.
- Late-onset RLS (1)[A]
- Sometimes secondary to other factors
- Tends to progress more rapidly
- May resolve to extent that cause(s) resolve
Pediatric Considerations
Consider child 's own words in describing symptoms and these additional supportive findings (1)[A]:
Insomnia or sleep disturbance
RLS in immediate biologic relative
Periodic limb movements during sleep
Geriatric Considerations
For diagnosis in the cognitively impaired
Rubbing or kneading the legs in evening
Evening hyperactivity (foot tapping, pacing, fidgeting, tossing/turning in bed)
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%.
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].
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 hour 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
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.
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
COMPLICATIONS
- Vicious cycle between sleep loss from RLS and exacerbation of RLS by sleep loss
- Augmentation of symptoms from prolonged dopaminergic therapy
- Symptoms increase in severity, occur earlier, and/or spread.
- Higher doses increase risk.
- Highest risk from daily levodopa or Sinemet
- Iron deficiency increases risk.
- Add alternative medication then slowly down-titrate dopamine agonist.
- Obsessive-compulsive or impulse-control disorders from dopamine agonists
- Iatrogenic RLS (from antidepressants, etc.)
REFERENCES
11 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 " 873.22 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 " 307.33 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.44 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 " 1062.55 Ferini-Strambi L, Marelli S. Pharmacotherapy for restless legs syndrome. Expert Opin Pharmacother. 2014;15(8):1127 " 1138.66 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
- 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
- Periodic Limb Movement Disorder
- Algorithm: Restless Legs Syndrome
CODES
ICD10
G25.81 Restless legs syndrome
ICD9
333.94 Restless legs syndrome (RLS)
SNOMED
32914008 Restless legs (disorder)
CLINICAL PEARLS
- 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.