Restless Legs Syndrome – Causes, Symptoms, Diagnosis, Treatment and Ongoing care

Basics

Description

  • Sensorimotor disorder defined by 4 criteria (1,2)[A]:
    • A strong urge to move the legs, usually accompanied by discomfort
    • The urge to move and discomfort occur during inactivity (seated or recumbent)
    • Movement immediately relieves symptoms, but they recur with subsequent inactivity.
    • Symptoms occur primarily in the evening/night.
  • Symptoms may instead or also involve the arms, or be more generalized.
  • Patient may also complain of involuntary leg jerks.
  • Systems affected: Musculoskeletal; Nervous
  • Synonym(s): Ekbom syndrome

Epidemiology

Incidence

  • Onset at any age; increases with age (1,3)[A]
  • Primary RLS presents early and progresses slowly.
  • Secondary RLS:
    • Precipitated by other conditions/medications
    • Tends to progress rapidly
    • Resolves to extent that cause(es) resolve
  • Predominant sex: Male = Female (nulliparous); Female (parous) 2 × > Male (4)[B]

Prevalence

  • 4–12% of Caucasian adults; underdiagnosed
  • >3% in children and adolescents
  • Increases with age
  • Lower with African American, Mediterranean, Middle Eastern, and East Asian descent

Pregnancy Considerations

  • 10–30% prevalence; exacerbates existing RLS (4)
  • May be secondary to iron or folate deficiency

Risk Factors

  • Family history (2,3)[A]
  • Aging
  • Chronic inactivity
  • Inadequate sleep
  • Associated conditions (see below)

Genetics

  • Primary RLS heritability: ∼50%
  • Genetically heterogenous (2,5)[B]:
    • Susceptibility loci: 2p14, 2q, 6p21.2, 9p, 12q, 14q, 15q23, and 20p
    • Genes: MEIS1, MAP2K5/LBXCOR1, and BTBD9

General Prevention

  • Regular physical activity/exercise (6)[B]
  • Adequate sleep
  • Avoid evening caffeine, alcohol, tobacco
  • Avoid causes of secondary RLS.

Pathophysiology

  • CNS iron or dopamine deficiency or dysmetabolism
  • Chronic extremity tissue pathology/inflammation

Etiology

  • Primary RLS: Subcortical dopamine deficiency (2,5)[B]
  • Secondary RLS:
    • Iron deficiency and associated conditions
    • Chronic extremity tissue irritation
    • Medications:
      • Most antidepressants (exceptions: Bupropion and desipramine)
      • Dopamine-blocking antiemetics (e.g., metoclopramide)
      • Some antiepileptic agents (e.g., phenytoin)
      • Phenothiazine antipsychotics; donepezil
      • Theophylline
      • Antihistamines/OTC cold preparations (pseudoephedrine, etc.)
      • Stimulants, particularly if taken later in day

Commonly Associated Conditions

  • Periodic limb movements of sleep; insomnia, sleep walking and other parasomnias; delayed sleep phase
  • Iron deficiency; renal disease/uremia/dialysis; gastric surgery; liver disease
  • Parkinson disease; peripheral neuropathy; ADHD; anxiety/depression; “sundowning”
  • Venous insufficiency/peripheral vascular disease; erectile dysfunction
  • Orthopedic problems, arthritis
  • Pulmonary hypertension; lung transplantation; COPD

Diagnosis

  • Relies on history, yet often “difficult to describe”
  • May go undiagnosed for years and by multiple doctors

History

  • Signs/symptoms (see also Description) (1,2)[A]:
    • Example paresthesia descriptions: Burning, achy, itching, antsy, “can’t get comfortable”
    • Symptoms 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 10–90 s (mean ∼25 s)
    • Some patients must get out of bed and walk.
    • May involve arms or, rarely, whole body
    • Periodic movements in sleep in ∼80% of patients
    • Insomnia, daytime fatigue, anxiety
  • Severity range: From rare, minor problem to daily severe impact on quality of life
  • Severe cases: Difficulty riding in cars or sitting still at events in afternoon/evening

Pediatric Considerations

  • If all 4 diagnostic criteria not met, apply 1st 3 along with 2 of these (1,3)[A]:
    • Insomnia or sleep disturbance
    • RLS in immediate biological relative
    • Periodic limb movements during sleep

Geriatric Considerations

  • For diagnosis in the cognitively impaired (2,7)[A]:
    • Rubbing or kneading the legs in evening
    • Evening hyperactivity (foot tapping, pacing, fidgeting, tossing/turning in bed)

Physical Exam

Patient may be fidgety, unable to sit still.

Diagnostic Tests & Interpretation

Lab

Serum ferritin to assess for iron deficiency

Diagnostic Procedures/Surgery

  • Sleep study not required, but can be helpful:
    • 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 can be used in the home.
  • Electromyography and nerve conduction studies to check for peripheral neuropathy and radiculopathy

Pathological Findings

  • Serum ferritin: <50 ng/mL
  • Transferrin saturation: <16%

Differential Diagnosis

  • Claudication: Movement does not relieve pain and may worsen it.
  • Motor neuron disease fasciculation/tremor: No discomfort or circadian pattern
  • Dermatitis/pruritus: Urge to move only to scratch; no circadian pattern
  • Sleep-related leg cramps: Isolated and very painful muscle contracture
  • Periodic limb movement disorder: No wakeful discomfort or movement
  • Sleep starts/hypnic jerks: Isolated involuntary events; no discomfort
  • 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 (8)[A].

Treatment

1st-line treatments (2,6,9,10)[A]:

  • Prescribed daily exercise, adequate sleep
  • Dopaminergic medications
  • Correction of iron deficiency
  • For secondary RLS, treat cause(s); multiple possible causes are not mutually exclusive.

Medication

  • Use minimum effective dose (2,9,10)[A].
  • Daytime sleepiness side effect is unusual with doses and timing for RLS.
  • Severe or refractory RLS and augmentation requires combination therapy.

First Line

  • FDA-approved dopamine agonists (11)[A]; titrate every 3 days to minimum necessary dose (2)[A]:
    • Pramipexole (Mirapex): 0.125–1.5 mg 1 hour before bed; titrate by 0.125 mg
    • Ropinirole (Requip): 0.25–4.0 mg 1 hour before bed; titrate by 0.25 mg
    • Divide dose for evening and bedtime symptoms.
    • Liver disease: Pramipexole due to renal clearance
    • Renal insufficiency: Ropinarole due to hepatic catabolism
  • Off-label dopamine agonists:
    • Cabergoline: 0.25–3.0 mg (warning: Valvulopathy)
    • Carbidopa-levodopa (Sinemet or Sinemet CR): 25/100–100/400; p.r.n. for sporadic symptoms
  • Avoid dopamine agonists in psychotic patients, particularly if taking dopamine antagonists.

Second Line

  • Anticonvulsants (for painful or neuropathic RLS):
    • Gabapentin (Neurontin): 300–1,800 mg/d
    • Carbamazepine: 200–800 mg/d
    • Pregabalin (Lyrica): 50–300 mg/d
  • Opioids (low risk of tolerance/addiction q.h.s.):
    • Hydrocodone: 5–20 mg/d
    • Tramadol: 50 mg/d
    • Oxycodone: 2.5–20 mg/d
  • Benzodiazepines and agonists (for associated insomnia and/or anxiety):
    • Temazepam, triazolam, alprazolam, zaleplon, zolpidem, and diazepam
    • Clonazepam (Klonopin): 0.5–3.0 mg/d

Pregnancy Considerations

  • Initial approach: Nonpharmacologic therapies, iron supplements (4)[C]
  • Most medications class C or D should not be used.
  • In 3rd trimester, low-dose opioids or clonazepam may be considered.

Pediatric Considerations

  • 1st-line treatment: Nonpharmacologic (3)[C]
  • Low-dose clonidine, clonazepam, or gabapentin may be considered.

Geriatric Considerations

  • In weak or frail patients, avoid medications that may cause dizziness or unsteadiness.
  • Many medications given to the elderly cause or exacerbate RLS (7)[B].

Additional Treatment

General Measures

  • If iron deficient, supplement:
    • 325 mg FeSO4 with vitamin C between meals
    • Repletion requires months, so symptoms continue.
  • Daily exercise is beneficial and sometimes curative (6)[B] (unusual activity may exacerbate symptoms).
  • Regular and replete sleep schedule
  • Hot bath and leg massage
  • Warm the legs (long heavy socks, electric blanket)
  • Intense mental activity (games, puzzles, etc.)

Issues for Referral

  • Severe symptoms/augmentation; Peripheral neuropathy; low back or leg orthopedic problems
  • Peripheral vascular disease; intransigent iron deficiency

Additional Therapies

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  • Vitamin, mineral supplements: Ca, Mg, B12, folate
  • Clonidine: 0.1–0.7 mg/d
  • Baclofen: 20–80 mg/d
  • Quinine
  • Methadone
  • OTC sleep aids p.r.n. for mild, intermittent RLS

Complementary and Alternative Medicine

  • Sequential pneumatic leg compression
  • Enhanced external counterpulsation
  • Acupuncture
  • MicroVas therapy

Surgery/Other Procedures

For orthopedic, neuropathic, or leg vascular disease (laser ablation, sclerotherapy, etc.)

In-Patient Considerations

  • Control RLS after orthopedic procedures.
  • Addition/withdrawal of medications affecting RLS
  • Procedures or new-onset disease that promote RLS
  • Changes in medical status may require medication changes. Examples:
    • Renal failure: Mirapex contraindicated
    • Liver disease: Requip contraindicated

IV Fluids

  • Iron infusion when Fe replacement fails
  • When n.p.o., 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 treatment status changes, assess for associated conditions and medications.

Diet

Avoid evening caffeine and alcohol.

Patient Education

  • Restless Legs Syndrome Foundation http://www.rls.org; e-mail: rlsfoundation@rls.org; Tel: 507-287-6465; Fax: 507-287-6312
  • WE MOVE (Worldwide Education & Awareness for Movement Disorders); http://www.wemove.org; e-mail: wemove@wemove.org; Tel: 212-875-8312; Fax: 212-875-8389
  • National Sleep Foundation http://www.sleepfoundation.org; e-mail: nsf@sleepfoundation.org; Tel: 202-347-3471

Prognosis

  • Primary RLS: Lifelong condition with no current cure
  • Secondary RLS: May partially or completely subside with resolution of precipitating factors
  • Current therapies usually control symptoms.

Complications

  • Augmentation of symptoms (severity increases, occurrence earlier, and/or spreading to arms or torso) from prolonged dopamine agonist use:
    • Highest risk from daily levodopa or Sinemet
    • Higher doses of any agonist increase risk.
    • Iron deficiency increases risk.
    • Detitrate dopamine agonist, concurrently add alternative medication (2,9,10)[B].
  • Development of obsessive-compulsive or impulse-control disorders from dopamine agonists
  • Vicious cycle between sleep loss from RLS and exacerbation of RLS symptoms by sleep loss
  • Coping with/correcting for iatrogenic RLS (as from antidepressants, etc.)

References

1. Sateia MJ. Restless legs syndrome. In: International Classification of Sleep Disorders Diagnostic & Coding Manual. 2nd ed. Westchester, IL: American Academy of Sleep Medicine; 2005:178–81.

2. Satija P, Ondo WG. Restless legs syndrome: pathophysiology, diagnosis and treatment. CNS Drugs. 2008;22:497–518.

3. Simakajornboon N, Kheirandish-Gozal L, Gozal D et al. Diagnosis and management of restless legs syndrome in children. Sleep Med Rev. 2009;13:149–56.

4. Thomas K, Watson CB. Restless legs syndrome in women: a review. J Womens Health (Larchmt). 2008;17:859–68.

5. Trotti LM, Bhadriraju S, Rye DB. An update on the pathophysiology and genetics of restless legs syndrome. Curr Neurol Neurosci Rep. 2008;8:281–7.

6. Aukerman MM, Aukerman D, Bayard M, et al. Exercise and restless legs syndrome: a randomized controlled trial. J Am Board Fam Med. 2006 Sep-Oct;19:487–93.

7. Spiegelhalder K, Hornyak M. Restless legs syndrome in older adults. Clin Geriatr Med. 2008;24:167–80.

8. Walters AS, Silvestri R, Zucconi M, et al. Review of the possible relationship and hypothetical links between attention deficit hyperactivity disorder (ADHD) and the simple sleep related movement disorders, parasomnias, hypersomnias, and circadian rhythm disorders. J Clin Sleep Med. 2008;4:591–600.

9. Ferini-Strambi L. Treatment options for restless legs syndrome. Expert Opin Pharmacother. 2009;10:545–54.

10. Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord. 2008;23:2267–302.

11. Zintzaras E, Kitsios GD, Papathanasiou AA, et al. Randomized trials of dopamine agonists in restless legs syndrome: a systematic review, quality assessment, and meta-analysis. Clin Ther. 2010;32:221–37.

Additional Reading

See Also (Topic, Algorithm, Electronic Media Element)

Periodic Limb Movement Disorder

Algorithm: Restless Leg Syndrome (RLS)

Codes

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.
  • RLS and other sleep disorders may cause ADHD (8)[B].
  • Many antidepressants, antipsychotics, antiemetics, and antihistamines cause or exacerbate RLS.
  • RLS may interfere with use of positive airway pressure to treat obstructive sleep apnea.

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