restless legs syndrome; Willis-Ekbom disease (RLS)
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Introduction
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
- iron deficiency with low serum ferritin[10]
- folate deficiency
- end-stage renal disease, uremia
- venous or arterial insufficiency
- alterations in dopamine or endogenous opioid systems
- pharmaceutical agents
- tricyclic antidepressants can precipitate RLS
- SSRI & SNRI may exacerbate RLS
- sensory neuropathy[4]
- familial
- associated with pregnancy
- associated with hypertension in women (HR=1.41)[13]
- sleep disorder[5][19][20]
- idiopathic
Epidemiology
- overall prevalence is 9-24%[3][6], 3%[9]; 2-15%[23]
- very low prevalence in patients < 30 years of age
- higher prevalence in women than men (14% vs 6%)[7] (4% vs 2%)[9]
- prevalence increases up to age 79[9]
- higher incidence in patients with poor health (physical or mental)
- 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
- sensation bilateral, very disagreeable, but not painful
- prickling, tense or 'creepy-crawly'
- urge to rub or move legs is irresistable
- dyskinesias & myoclonic jerking may occur
- relief of symptoms with motor activation
- symptoms may worsen in the evening or at night
- often interferes with sleep
- ~85% if patients also have nocturnal myoclonus[10]
- anxiety, depression &/or poor mental health is common[7][23]
- physical examination is normal
Laboratory
Diagnostic procedures
- polysomnography*
- bilateral anterior tibialis EMG
* to evaluate associated disorder of nocturnal myoclonus
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]
Differential diagnosis
Management
- treat underlying etiology
- treat iron deficiency if serum ferritin < 50-75 ng/mL[10]
- reduce the associated dysesthesia
- dopaminergic agonists are 1st line for daily symptoms[5][10]
- pramipexole (Mirapex) 0.5 mg QHS[18] (max 1.5 mg)
- ropinirole (Requip)* 0.25 mg QHS
- rotigotine patch; start 1 mg/24 hours; max 3 mg/24 hours[10]
- pergolide (Permax) 0.1-0.65 mg QHS (2 hours prior to HS)
- average effective dose 0.34 mg QHS
- bromocriptine (Parlodel) 5 mg QHS (max 20 mg)
- anticonvulsants
- gabapentin enacarbil (Horizant)[27]
- FDA-approved for treatment of resless legs syndrome
- pregabalin (Lyrica) 300 mg QD[18]
- carbamazepine[5]
- gabapentin enacarbil (Horizant)[27]
- Sinemet 25/100-50/200 QHS
- effective in 70% of patients for years
- not FDA approved
- daytime rebound occurs in 30% of patients
- reserve for refractory cases & elderly patients
- benzodiazepines
- analgesics, opioids
- amantadine 100-300 mg PO QD
- clonidine is effective in some patients[5]
- for refractory symptoms
- switch to different dopamine agonist
- swith to an opioid or gabapentin if using a dopamine agonist
- add a second medication[10]
- 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]
- AVOID drugs & habits that may exacerbate symptoms[8]
- bupropion may be of benefit for patients with depression & RLS
- does not exacerbate RLS[22]
- sleep hygiene
- behavorial interventions
* Requip is the 1st drug FDA-approved for treatment of restless legs syndrome[8]
More general terms
Additional terms
References
- ↑ Saunders Manual of Medical Practice, Rakel (ed), WB Saunders, Philadelphia, 1996, pg 1017, 1039-40
- ↑ Internal Medicine News 31(17): 41, 1998
- ↑ 3.0 3.1 Journal Watch, Mass Med Soc 20(17):140 (Sept) 2000 Phillips et al, Arch Intern Med 160:2137, 2000
- ↑ 4.0 4.1 Movement Disorder Clinic, UCLA Medical Center, 2001
- ↑ 5.0 5.1 5.2 5.3 5.4 5.5 5.6 Geriatrics Review Syllabus, American Geriatrics Society, 5th edition, 2002-2004;
Geriatric Review Syllabus, 7th edition Parada JT et al (eds) American Geriatrics Society, 2010
Geriatric Review Syllabus, 8th edition (GRS8) Durso SC and Sullivan GN (eds) American Geriatrics Society, 2013
Geriatric Review Syllabus, 10th edition (GRS10) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2019
Geriatric Review Syllabus, 11th edition (GRS11) Harper GM, Lyons WL, Potter JF (eds) American Geriatrics Society, 2022 - ↑ 6.0 6.1 Journal Watch 23(24):195, 2003 Nichols DA et al, Arch Intern Med 163:2323, 2003 PMID: https://www.ncbi.nlm.nih.gov/pubmed/14581252
- ↑ 7.0 7.1 7.2 Alessi C In: Intensive Course in Geriatric Medicine & Board Review, Marina Del Ray, CA, Sept 29-Oct 2, 2004
- ↑ 8.0 8.1 8.2 Prescriber's Letter 12(6): 2005 Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=210606&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 9.0 9.1 9.2 9.3 Journal Watch 25(14):109, 2005 Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, Ferini-Strambi L. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med. 2005 Jun 13;165(11):1286-92. <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/15956009 <Internet> http://www.aasmnet.org/PDF/270328.pdf http://www.aasmnet.org/PDF/270329.pdf
- ↑ 10.0 10.1 10.2 10.3 10.4 10.5 10.6 Medical Knowledge Self Assessment Program (MKSAP) 14, 15, 16, 17, 18, 19. American College of Physicians, Philadelphia 2006, 2009, 2012, 2015, 2018, 2021
Medical Knowledge Self Assessment Program (MKSAP) 19 Board Basics. An Enhancement to MKSAP19. American College of Physicians, Philadelphia 2022 - ↑ OMIM https://mirror.omim.org/entry/611185
- ↑ Prescriber's Letter 18(7): 2011 Treatment of Restless Legs Syndrome Detail-Document#: http://prescribersletter.com/(5bhgn1a4ni4cyp2tvybwfh55)/pl/ArticleDD.aspx?li=1&st=1&cs=&s=PRL&pt=3&fpt=25&dd=270711&pb=PRL (subscription needed) http://www.prescribersletter.com
- ↑ 13.0 13.1 Batool-Anwar S et al Restless Legs Syndrome and Hypertension in Middle-Aged Women Hypertension October 10, 2011 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/21986505 <Internet> http://hyper.ahajournals.org/content/early/2011/10/09/HYPERTENSIONAHA.111.174037.abstract
- ↑ 14.0 14.1 Li Y, Wang W, Winkelman JW Prospective study of restless legs syndrome and mortality among men. Neurology. June 12, 2013 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/23761622 <Internet> http://www.neurology.org/content/early/2013/06/12/WNL.0b013e318297eee0.abstract
- ↑ Bayard M, Avonda T, Wadzinski J. Restless legs syndrome. Am Fam Physician. 2008 Jul 15;78(2):235-40. PMID: https://www.ncbi.nlm.nih.gov/pubmed/18697508
- ↑ Allen RP, Picchietti D, Hening WA et al Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003 Mar;4(2):101-19. PMID: https://www.ncbi.nlm.nih.gov/pubmed/14592341
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 Aug; 15:860 PMID: https://www.ncbi.nlm.nih.gov/pubmed/25023924 - ↑ Chesson AL Jr, Wise M, Davila D et al Practice parameters for the treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine Report. Standards of Practice Committee of the American Academy of Sleep Medicine. Sleep. 1999 Nov 1;22(7):961-8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/10566915
- ↑ 18.0 18.1 18.2 Allen RP et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014 Feb 13; 370:621 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24521108 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMoa1303646
Chokroverty S Therapeutic Dilemma for Restless Legs Syndrome. N Engl J Med 2014; 370:667-668February 13, 2014 <PubMed> PMID: https://www.ncbi.nlm.nih.gov/pubmed/24521115 <Internet> http://www.nejm.org/doi/full/10.1056/NEJMe1313155 - ↑ 19.0 19.1 Rose KM, Beck C, Tsai PF et al Sleep disturbances and nocturnal agitation behaviors in older adults with dementia. Sleep. 2011 Jun 1;34(6):779-86. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21629366
- ↑ 20.0 20.1 Bloom HG, Ahmed I, Alessi CA et al Evidence-based recommendations for the assessment and management of sleep disorders in older persons. J Am Geriatr Soc. 2009 May;57(5):761-89 PMID: https://www.ncbi.nlm.nih.gov/pubmed/19484833
- ↑ Scholz H, Trenkwalder C, Kohnen R et al Dopamine agonists for restless legs syndrome. Cochrane Database Syst Rev. 2011 Mar 16;(3):CD006009 PMID: https://www.ncbi.nlm.nih.gov/pubmed/21412893
- ↑ 22.0 22.1 Bayard M, Bailey B, Acharya D Bupropion and restless legs syndrome: a randomized controlled trial. J Am Board Fam Med. 2011 Jul-Aug;24(4):422-8. PMID: https://www.ncbi.nlm.nih.gov/pubmed/21737767
- ↑ 23.0 23.1 23.2 23.3 Ohayon MM, O'Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. 2012 Aug;16(4):283-95. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/ 21795081
- ↑ Garcia-Borreguero D, Kohnen R, Silber MH et al The long-term treatment of restless legs syndrome/Willis- Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med. 2013 Jul;14(7):675-84 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23859128
- ↑ 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 Aug 1;35(8):1039-62. Review. PMID: https://www.ncbi.nlm.nih.gov/pubmed/22851801 Free PMC Article (corresponding NGC guideline withdrawn Nov 2017)
- ↑ Bogan RK, Fry JM, Schmidt MH et al Ropinirole in the treatment of patients with restless legs syndrome: a US-based randomized, double-blind, placebo- controlled clinical trial. Mayo Clin Proc. 2006 Jan;81(1):17-27. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16438474
- ↑ 27.0 27.1 Bogan RK, Bornemann MA, Kushida CA et al Long-term maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study. Mayo Clin Proc. 2010 Jun;85(6):512-21. PMID: https://www.ncbi.nlm.nih.gov/pubmed/20511481 Free PMC Article
- ↑ Winkelman JW, Sethi KD, Kushida CA et al Efficacy and safety of pramipexole in restless legs syndrome. Neurology. 2006 Sep 26;67(6):1034-9. Epub 2006 Aug 23. PMID: https://www.ncbi.nlm.nih.gov/pubmed/16931507
- ↑ Bertisch S. In the Clinic. Restless legs syndrome. Ann Intern Med. 2015;163(9):ITC1-ITC11 PMID: https://www.ncbi.nlm.nih.gov/pubmed/26524584
- ↑ Silber MH, Becker PM, Earley C, Garcia-Borreguero D, Ondo WG; Medical Advisory Board of the Willis-Ekbom Disease Foundation. Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome. Mayo Clin Proc. 2013;88(9):977-986 PMID: https://www.ncbi.nlm.nih.gov/pubmed/24001490
- ↑ Allen RP, Auerbach S, Bahrain H, Auerbach M, Earley CJ. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 2013 Apr; 88:261 PMID: https://www.ncbi.nlm.nih.gov/pubmed/23494945 Free full text
- ↑ 32.0 32.1 Zhuang S, Na M, Winkelman JW et al Association of Restless Legs Syndrome With Risk of Suicide and Self-harm. JAMA Netw Open. 2019;2(8):e199966. PMID: https://www.ncbi.nlm.nih.gov/pubmed/31441941 https://jamanetwork.com/journals/jamanetworkopen/fullarticle/2748664
- ↑ 33.0 33.1 33.2 Winkelman JW, Wipper B, Zackon J Long-term Safety, Dose Stability, and Efficacy of Opioids for Patients With Restless Legs Syndrome in the National RLS Opioid Registry. Neurology. 2023. Jan 25 PMID: https://www.ncbi.nlm.nih.gov/pubmed/36697248 https://n.neurology.org/content/early/2023/01/25/WNL.0000000000206855
- ↑ 34.0 34.1 Short V et al. A randomized double-blind pilot study to evaluate the efficacy, safety, and tolerability of intravenous iron versus oral iron for the treatment of restless legs syndrome in patients with iron deficiency anemia. Am J Hematol 2024 Jun; 99:1077. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38476079 https://onlinelibrary.wiley.com/doi/10.1002/ajh.27290
- ↑ 35.0 35.1 35.2 35.3 35.4 Marshall Lisa Solving Restless Legs: Largest Genetic Study to Date May Help. Medscape. June 14, 2024 https://www.medscape.com/viewarticle/solving-restless-legs-largest-genetic-study-date-may-help-2024a1000b40
Schormair B, Zhao C, Bell S et al Genome-wide meta-analyses of restless legs syndrome yield insights into genetic architecture, disease biology and risk prediction. Nat Genet. 2024 Jun;56(6):1090-1099. PMID: https://www.ncbi.nlm.nih.gov/pubmed/38839884 PMCID: PMC11176086 Free PMC article. - ↑ 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
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