- 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
- 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]
- 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
- 10–30% prevalence; exacerbates existing RLS (4)
- May be secondary to iron or folate deficiency
- Family history (2,3)[A]
- Chronic inactivity
- Inadequate sleep
- Associated conditions (see below)
- 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
- Regular physical activity/exercise (6)[B]
- Adequate sleep
- Avoid evening caffeine, alcohol, tobacco
- Avoid causes of secondary RLS.
- CNS iron or dopamine deficiency or dysmetabolism
- Chronic extremity tissue pathology/inflammation
- Primary RLS: Subcortical dopamine deficiency (2,5)[B]
- Secondary RLS:
- Iron deficiency and associated conditions
- Chronic extremity tissue irritation
- Most antidepressants (exceptions: Bupropion and desipramine)
- Dopamine-blocking antiemetics (e.g., metoclopramide)
- Some antiepileptic agents (e.g., phenytoin)
- Phenothiazine antipsychotics; donepezil
- 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
- Relies on history, yet often “difficult to describe”
- May go undiagnosed for years and by multiple doctors
- 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
- 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
- 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)
Patient may be fidgety, unable to sit still.
Diagnostic Tests & Interpretation
Serum ferritin to assess for iron deficiency
- 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
- Serum ferritin: <50 ng/mL
- Transferrin saturation: <16%
- 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].
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.
- 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.
- 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.
- 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
- 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.
- 1st-line treatment: Nonpharmacologic (3)[C]
- Low-dose clonidine, clonazepam, or gabapentin may be considered.
- 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].
- 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
- Vitamin, mineral supplements: Ca, Mg, B12, folate
- Clonidine: 0.1–0.7 mg/d
- Baclofen: 20–80 mg/d
- OTC sleep aids p.r.n. for mild, intermittent RLS
Complementary and Alternative Medicine
- Sequential pneumatic leg compression
- Enhanced external counterpulsation
- MicroVas therapy
For orthopedic, neuropathic, or leg vascular disease (laser ablation, sclerotherapy, etc.)
- 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
- Iron infusion when Fe replacement fails
- When n.p.o., consider IV opiates
- Evening walks, hot baths, leg massage and warming
- Sleep interruption risks prolonged wakefulness.
- At 2-week intervals until stable, then annually
- If taking iron, remeasure ferritin.
- If treatment status changes, assess for associated conditions and medications.
Avoid evening caffeine and alcohol.
- Restless Legs Syndrome Foundation http://www.rls.org; e-mail: firstname.lastname@example.org; Tel: 507-287-6465; Fax: 507-287-6312
- WE MOVE (Worldwide Education & Awareness for Movement Disorders); http://www.wemove.org; e-mail: email@example.com; Tel: 212-875-8312; Fax: 212-875-8389
- National Sleep Foundation http://www.sleepfoundation.org; e-mail: firstname.lastname@example.org; Tel: 202-347-3471
- 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.
- 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.)
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See Also (Topic, Algorithm, Electronic Media Element)
Periodic Limb Movement Disorder
Algorithm: Restless Leg Syndrome (RLS)
333.94 Restless legs syndrome (RLS)
32914008 Restless legs (disorder)
- 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.