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restless legs syndrome; Willis-Ekbom disease (RLS)

An irresistable urge to move the legs, especially at night, due to uncomfortable, crawling, dull, tingling sensations in the lower 1/2 of the legs that occurs at rest. Etiology: 1) iron deficiency with low serum ferritin [10] 2) folate deficiency 3) end-stage renal disease, uremia 4) venous or arterial insufficiency 5) alterations in dopamine or endogenous opioid systems 6) pharmaceutical agents a) tricyclic antidepressants can precipitate RLS b) SSRI & SNRI may exacerbate RLS 7) sensory neuropathy [4] 8) familial 9) associated with pregnancy 10) associated with hypertension in women (HR=1.41) [13] 11) sleep disorder [5,19,20] 12) idiopathic Epidemiology: 1) overall prevalence is 9-24% [3,6], 3% [9]; 2-15% [23] 2) very low prevalence in patients < 30 years of age 3) higher prevalence in women than men (14% vs 6%) [7] (4% vs 2%) [9] 4) prevalence increases up to age 79 [9] - not in Asian countries [23] 5) higher incidence in patients with poor health (physical or mental) 6) 80-85% associated with nocturnal myoclonus [5] Genetics: - genetic variations in BTBD9 may be associated with susceptibility to restless legs syndrome (RLS) type 6 - MEIS1, PTPRD, SKOR1, NTNG1, CADM1, RANBP17 linked to susceptibility to RLS [35] - defects in MEIS1 could be a cause of susceptibility to RLS type 7 - RLS susceptibilty linked to GRIA1 & GRIA4, which encode subunits of the AMPA-type glutamate ionotropic receptors [35] - RLS susceptibilty linked to CCKBR encoding the predominant cholecystokinin receptor in the brain [35] Clinical manifestations: 1) sensation bilateral, very disagreeable, but not painful - prickling, tense or 'creepy-crawly' 2) urge to rub or move legs is irresistable 3) dyskinesias & myoclonic jerking may occur 4) relief of symptoms with motor activation 5) symptoms may worsen in the evening or at night 6) often interferes with sleep 7) ~85% if patients also have nocturnal myoclonus [10] 8) anxiety, depression &/or poor mental health is common [7,23] 9) physical examination is normal Laboratory: 1) complete blood count (CBC) 2) iron studies - serum iron, TIBC, serum ferritin 3) serum folate? 4) chemistry panel - serum urea nitrogen - serum creatinine - serum bicarbonate Special laboratory: 1) polysomnography* 2) bilateral anterior tibialis EMG * to evaluate associated disorder of nocturnal myoclonus Differential diagnosis: 1) hypnic jerks 2) neuropathic pain 3) akathisia Complications: - depression is common is patients with insomnia & RLS - increased risk of suicide or self-harm (RR=2.7) [32] - 2-fold increased risk of mortality in men [14] - may be associated with agitation in demented elderly - may be risk factor for diabetes mellitus type-2 [35] Management: 1) treat underlying etiology - treat iron deficiency if serum ferritin < 50-75 ng/mL [10] - a normal CBC rules out iron deficiency (GRS11) [5] - treatment with oral iron non inferior to IV iron [34] 2) reduce the associated dysesthesia 3) dopaminergic agonists are 1st line for daily symptoms [5,10] a) pramipexole (Mirapex) 0.5 mg QHS [18] (max 1.5 mg) b) ropinirole (Requip)* 0.25 mg QHS c) rotigotine patch; start 1 mg/24 hours; max 3 mg/24 hours [10] d) pergolide (Permax) 0.1-0.65 mg QHS (2 hours prior to HS) - average effective dose 0.34 mg QHS e) bromocriptine (Parlodel) 5 mg QHS (max 20 mg) 4) anticonvulsants a) gabapentin enacarbil (Horizant) [27] - FDA-approved for treatment of resless legs syndrome b) pregabalin (Lyrica) 300 mg QD [18] c) carbamazepine [5] 5) Sinemet 25/100-50/200 QHS a) effective in 70% of patients for years b) not FDA approved c) daytime rebound occurs in 30% of patients d) reserve for refractory cases & elderly patients 6) benzodiazepines a) clonazepam (Klonopin) 0.5-2.0 mg QHS b) temazepam (Restoril) 15-30 mg QHS c) tolerance may develop 7) analgesics, opioids a) tramadol b) hydrocodone c) oxycodone d) morphine (mean morphine milligram equivalents of 38.4 mg/day) [33] 8) amantadine 100-300 mg PO QD 9) clonidine is effective in some patients [5] 10) for refractory symptoms a) switch to different dopamine agonist b) swith to an opioid or gabapentin if using a dopamine agonist c) add a second medication [10] d) low-dose opioids (mean morphine equivalents = 38 mg/day) adequately control symptoms of refractory RLS over 2 year follow-up in the majority of patients [33] 11) AVOID drugs & habits that may exacerbate symptoms [8] a) SSRIs, tricyclic antidepressants, sedating antihistamines, lithium, neuroleptics, metoclopramide b) smoking, caffeine, alcohol 12) bupropion may be of benefit for patients with depression & RLS - does not exacerbate RLS [22] 13) sleep hygiene a) regular sleep & wake times b) restricting bed to sleep & sex c) avoiding anxiety-provoking activities before bed 14) behavorial interventions a) brief walks before bedtime b) hot baths or cold showers c) massaging of limbs * Requip is the 1st drug FDA-approved for treatment of restless legs syndrome [8]

Interactions

disease interactions

Related

nocturnal myoclonus (periodic limb movement disorder, PLMD, periodic limb movements of sleep, PLMS)

General

sleep-related movement disorder syndrome

Database Correlations

OMIM 611185

References

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  36. NINDS Restless Legs Syndrome Information Page https://www.ninds.nih.gov/disorders/All-Disorders/Restless-Legs-Syndrome-Information-Page - Restless Legs Syndrome Fact Sheet https://www.ninds.nih.gov/Disorders/Patient-Caregiver-Education/Fact-Sheets/Restless-Legs-Syndrome-Fact-Sheet - Facts About Restless Legs Syndrome (RLS) http://www.nhlbi.nih.gov/health/public/sleep/rls.htm