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Restless Legs Syndrome: Pathophysiology and Treatment

  • Sleep Disorders (S Chokroverty, Section Editor)
  • Published:
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Opinion statement

Restless legs syndrome (RLS) is a complicated sensory-motor syndrome. The pathology is increasingly understood, but a clear physiologic understanding still remains elusive. The most robust findings remain reduced central nervous system (CNS) iron and some perturbation in dopaminergic systems. Other neurotransmitter systems are also like involved, and the phenotype may result from distinct pathophysiologic processes. Treatment of RLS is often very successful, and treatment goals should be high. Dopamine agonists may most robustly improve pure urge to move and certainly periodic limb movements. They do not directly improve sleep, and long-term use is limited by augmentation. Alpha-2-delta ligand drugs such as gabapentin enacarbil and pregabalin improve RLS, presumably in a less specific manner. These drugs increase slow wave sleep and improve pain, but have less impact on leg movements. Mu specific opioids also robustly improve RLS and are probably underutilized in severe cases. Intravenous iron inconsistently but sometimes considerably improves RLS and can be considered in refractory cases.

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References and Recommended Reading

Papers of particular interest, published recently, have been highlighted as: • Of importance

  1. Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. 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;4(2):101–19. Most accepted definition of RLS.

  2. Montplaisir J, Boucher S, Poirier G, Lavigne G, Lapierre O, Lesperance P. Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov Disord. 1997;12(1):61–5.

    PubMed  CAS  Google Scholar 

  3. Giannaki CD, Zigoulis P, Karatzaferi C, Hadjigeorgiou GM, George KP, Gourgoulianis K, et al. Periodic limb movements in sleep contribute to further cardiac structure abnormalities in hemodialysis patients with restless legs syndrome. J Clin Sleep Med. 2013;9(2):147–53.

    PubMed  PubMed Central  Google Scholar 

  4. Li Y, Walters AS, Chiuve SE, Rimm EB, Winkelman JW, Gao X. Prospective study of restless legs syndrome and coronary heart disease among women. Circulation. 2012;126(14):1689–94.

  5. Walters AS, Moussouttas M, Siddiqui F, Silveira DC, Fuentes K, Wang L, et al. Prevalence of stroke in restless legs syndrome: initial results point to the need for more sophisticated studies. Open Neurol J. 2010;4:73–7.

    PubMed  PubMed Central  Google Scholar 

  6. Winkelman JW, Shahar E, Sharief I, Gottlieb DJ. Association of restless legs syndrome and cardiovascular disease in the sleep heart health study. Neurology. 2008;70(1):35–42.

    PubMed  Google Scholar 

  7. Winter AC, Schurks M, Glynn RJ, Buring JE, Gaziano JM, Berger K, et al. Vascular risk factors, cardiovascular disease, and restless legs syndrome in women. Am J Med. 2013;126(3):220–7. 227 e221-222.

    PubMed  PubMed Central  Google Scholar 

  8. Szentkiralyi A, Volzke H, Hoffmann W, Happe S, Berger K. A time sequence analysis of the relationship between cardiovascular risk factors, vascular diseases and restless legs syndrome in the general population. J Sleep Res. 2013;22(4):434–42.

    PubMed  Google Scholar 

  9. Manconi M, Ferri R, Zucconi M, Clemens S, Rundo F, Oldani A, et al. Effects of acute dopamine-agonist treatment in restless legs syndrome on heart rate variability during sleep. Sleep Med. 2011;12(1):47–55.

    PubMed  Google Scholar 

  10. Manconi M, Ferri R, Zucconi M, Bassetti CL, Fulda S, Arico D, et al. Dissociation of periodic leg movements from arousals in restless legs syndrome. Ann Neurol. 2012;71(6):834–44.

    PubMed  Google Scholar 

  11. Ekbom KA. Growing pains and restless legs. Acta Paediatr Scand. 1975;64(2):264–6.

    PubMed  CAS  Google Scholar 

  12. Rajaram SS, Walters AS, England SJ, Mehta D, Nizam F. Some children with growing pains may actually have restless legs syndrome. Sleep. 2004;27(4):767–73.

    PubMed  Google Scholar 

  13. Picchietti DL, Bruni O, de Weerd A, Durmer JS, Kotagal S, Owens JA, et al. Pediatric restless legs syndrome diagnostic criteria: an update by the international restless legs syndrome study group. Sleep Med. 2013;14(12):1253–9.

    PubMed  Google Scholar 

  14. Yeh P, Walters AS, Tsuang JW. Restless legs syndrome: a comprehensive overview on its epidemiology, risk factors, and treatment. Sleep Breath. 2012;16(4):987–1007.

    PubMed  Google Scholar 

  15. Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. Sex and the risk of restless legs syndrome in the general population. Arch Intern Med. 2004;164(2):196–202.

    PubMed  Google Scholar 

  16. Pantaleo NP, Hening WA, Allen RP, Earley CJ. Pregnancy accounts for most of the gender difference in prevalence of familial RLS. Sleep Med. 2010;11(3):310–3.

    PubMed  PubMed Central  Google Scholar 

  17. Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP. Abnormalities in csf concentrations of ferritin and transferrin in restless legs syndrome. Neurology. 2000;54(8):1698–700.

    PubMed  CAS  Google Scholar 

  18. Allen RP, Barker PB, Wehrl F, Song HK, Earley CJ. Mri measurement of brain iron in patients with restless legs syndrome. Neurology. 2001;56(2):263–5.

    PubMed  CAS  Google Scholar 

  19. Astrakas LG, Konitsiotis S, Margariti P, Tsouli S, Tzarouhi L, Argyropoulou MI. T2 relaxometry and fmri of the brain in late-onset restless legs syndrome. Neurology. 2008;71(12):911–6.

    PubMed  CAS  Google Scholar 

  20. Schmidauer C, Sojer M, Stocckner H, Hogel B, Wenning W, Poewe W. Brain parenchyma sonography differentiates rls patients from normal controls and patients with parkinson's disease. Mov Disord. 2005;20(supple10):S43.

    Google Scholar 

  21. Godau J, Klose U, Di Santo A, Schweitzer K, Berg D. Multiregional brain iron deficiency in restless legs syndrome. Mov Disord. 2008;23(8):1184–7.

    PubMed  Google Scholar 

  22. Connor JR, Wang XS, Patton SM, Menzies SL, Troncoso JC, Earley CJ, et al. Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology. 2004;62(9):1563–7.

    PubMed  CAS  Google Scholar 

  23. Snyder AM, Wang X, Patton SM, Arosio P, Levi S, Earley CJ, et al. Mitochondrial ferritin in the substantia nigra in restless legs syndrome. J Neuropathol Exp Neurol. 2009;68(11):1193–9.

    PubMed  CAS  PubMed Central  Google Scholar 

  24. Garcia-Borreguero D, Larrosa O, Granizo JJ, de la Llave Y, Hening WA. Circadian variation in neuroendocrine response to l-dopa in patients with restless legs syndrome. Sleep. 2004;27(4):669–73.

    PubMed  Google Scholar 

  25. Earley CJ, Hyland K, Allen RP. Circadian changes in csf dopaminergic measures in restless legs syndrome. Sleep Med. 2006;7(3):263–8.

    PubMed  Google Scholar 

  26. Walters AS, Ondo WG, Zhu W, Le W. Does the endogenous opiate system play a role in the restless legs syndrome? A pilot post-mortem study. J Neurol Sci. 2009;279(1–2):62–5.

    PubMed  CAS  Google Scholar 

  27. Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology. 2003;61(3):304–9.

    PubMed  CAS  Google Scholar 

  28. Pittock SJ, Parrett T, Adler CH, Parisi JE, Dickson DW, Ahlskog JE. Neuropathology of primary restless leg syndrome: absence of specific tau- and alpha-synuclein pathology. Mov Disord. 2004;19(6):695–9.

    PubMed  Google Scholar 

  29. Connor JR, Wang XS, Allen RP, Beard JL, Wiesinger JA, Felt BT, et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain. 2009;132(Pt 9):2403–12.

    PubMed  PubMed Central  Google Scholar 

  30. Staedt J, Stoppe G, Kogler A, Riemann H, Hajak G, Munz DL, et al. Nocturnal myoclonus syndrome (periodic movements in sleep) related to central dopamine d2-receptor alteration. Eur Arch Psychiatry Clin Neurosci. 1995;245(1):8–10.

    PubMed  CAS  Google Scholar 

  31. Trenkwalder C, Walters AS, Hening WA, Chokroverty S, Antonini A, Dhawan V, et al. Positron emission tomographic studies in restless legs syndrome. Mov Disord. 1999;14(1):141–5.

    PubMed  CAS  Google Scholar 

  32. Turjanski N, Lees AJ, Brooks DJ. Striatal dopaminergic function in restless legs syndrome: 18f-dopa and 11c-raclopride pet studies. Neurology. 1999;52(5):932–7.

    PubMed  CAS  Google Scholar 

  33. Tribl GG, Asenbaum S, Happe S, Bonelli RM, Zeitlhofer J, Auff E. Normal striatal d2 receptor binding in idiopathic restless legs syndrome with periodic leg movements in sleep. Nucl Med Commun. 2004;25(1):55–60.

    PubMed  CAS  Google Scholar 

  34. Earley CJ, Kuwabara H, Wong DF, Gamaldo C, Salas RE, Brasic JR, et al. Increased synaptic dopamine in the putamen in restless legs syndrome. Sleep. 2013;36(1):51–7.

    PubMed  PubMed Central  Google Scholar 

  35. Allen RP, Connor JR, Hyland K, Earley CJ. Abnormally increased csf 3-ortho-methyldopa (3-omd) in untreated restless legs syndrome (rls) patients indicates more severe disease and possibly abnormally increased dopamine synthesis. Sleep Med. 2009;10(1):123–8.

    PubMed  PubMed Central  Google Scholar 

  36. Lee SJ, Kim JS, Song IU, An JY, Kim YI, Lee KS. Poststroke restless legs syndrome and lesion location: anatomical considerations. Mov Disord. 2009;24(1):77–84.

    PubMed  Google Scholar 

  37. Ondo WG, He Y, Rajasekaran S, Le WD. Clinical correlates of 6-hydroxydopamine injections into a11 dopaminergic neurons in rats: a possible model for restless legs syndrome. Mov Disord. 2000;15(1):154–8.

    PubMed  CAS  Google Scholar 

  38. Qu S, Le W, Zhang X, Xie W, Zhang A, Ondo WG. Locomotion is increased in a11-lesioned mice with iron deprivation: a possible animal model for restless legs syndrome. J Neuropathol Exp Neurol. 2007;66(5):383–8.

    PubMed  CAS  Google Scholar 

  39. Earley CJ, Allen RP, Connor JR, Ferrucci L, Troncoso J. The dopaminergic neurons of the a11 system in rls autopsy brains appear normal. Sleep Med. 2009;10(10):1155–7.

    PubMed  PubMed Central  Google Scholar 

  40. Ben-Shachar D, Finberg JP, Youdim MB. Effect of iron chelators on dopamine d2 receptors. J Neurochem. 1985;45(4):999–1005.

    PubMed  CAS  Google Scholar 

  41. Zhao H, Zhu W, Pan T, Xie W, Zhang A, Ondo WG, et al. Spinal cord dopamine receptor expression and function in mice with 6-ohda lesion of the a11 nucleus and dietary iron deprivation. J Neurosci Res. 2007;85(5):1065–76.

    PubMed  CAS  Google Scholar 

  42. Ye Z, Connor JR. Identification of iron responsive genes by screening cdna libraries from suppression subtractive hybridization with antisense probes from three iron conditions. Nucleic Acids Res. 2000;28(8):1802–7.

    PubMed  CAS  PubMed Central  Google Scholar 

  43. Wang X, Wiesinger J, Beard J, Felt B, Menzies S, Earley C, et al. Thy1 expression in the brain is affected by iron and is decreased in restless legs syndrome. J Neurol Sci. 2004;220(1–2):59–66.

    PubMed  CAS  Google Scholar 

  44. Jeng CJ, McCarroll SA, Martin TF, Floor E, Adams J, Krantz D, et al. Thy-1 is a component common to multiple populations of synaptic vesicles. J Cell Biol. 1998;140(3):685–98.

    PubMed  CAS  PubMed Central  Google Scholar 

  45. Shults CW, Kimber TA. Thy-1 immunoreactivity distinguishes patches/striosomes from matrix in the early postnatal striatum of the rat. Brain Res Dev Brain Res. 1993;75(1):136–40.

    PubMed  CAS  Google Scholar 

  46. von Spiczak S, Whone AL, Hammers A, Asselin MC, Turkheimer F, Tings T, et al. The role of opioids in restless legs syndrome: an [11c] diprenorphine pet study. Brain. 2005;128(Pt 4):906–17.

    Google Scholar 

  47. Stiasny-Kolster K, Magerl W, Oertel WH, Moller JC, Treede RD. Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome. Brain. 2004;127(Pt 4):773–82.

    PubMed  CAS  Google Scholar 

  48. Stiasny-Kolster K, Pfau DB, Oertel WH, Treede RD, Magerl W. Hyperalgesia and functional sensory loss in restless legs syndrome. Pain. 2013;154(8):1457–63.

    PubMed  Google Scholar 

  49. Allen RP, Barker PB, Horska A, Earley CJ. Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep. Neurology. 2013;80(22):2028–34.

    PubMed  CAS  PubMed Central  Google Scholar 

  50. Winkelman JW, Schoerning L, Platt S, Jensen J. Restless legs syndrome and central nervous system gamma-aminobutyric acid: preliminary associations with periodic limb movements in sleep and restless leg syndrome symptom severity. Sleep Med (2014).

  51. Patton SM, Cho YW, Clardy TW, Allen RP, Earley CJ, Connor JR. Proteomic analysis of the cerebrospinal fluid of patients with restless legs syndrome/willis-ekbom disease. Fluids Barriers CNS. 2013;10(1):20.

    PubMed  CAS  PubMed Central  Google Scholar 

  52. Bucher SF, Seelos KC, Oertel WH, Reiser M, Trenkwalder C. Cerebral generators involved in the pathogenesis of the restless legs syndrome. Ann Neurol. 1997;41(5):639–45.

    PubMed  CAS  Google Scholar 

  53. Etgen T, Draganski B, Ilg C, Schroder M, Geisler P, Hajak G, et al. Bilateral thalamic gray matter changes in patients with restless legs syndrome. Neuroimage. 2005;24(4):1242–7.

    PubMed  Google Scholar 

  54. Ondo W, Jankovic J. Restless legs syndrome: clinicoetiologic correlates. Neurology. 1996;47(6):1435–41.

    PubMed  CAS  Google Scholar 

  55. Ondo WG, Vuong KD, Wang Q. Restless legs syndrome in monozygotic twins: clinical correlates. Neurology. 2000;55(9):1404–6.

    PubMed  CAS  Google Scholar 

  56. Xiong L, Jang K, Montplaisir J, Levchenko A, Thibodeau P, Gaspar C, et al. Canadian restless legs syndrome twin study. Neurology. 2007;68(19):1631–3.

    PubMed  CAS  Google Scholar 

  57. Winkelmann J, Muller-Myhsok B, Wittchen HU, Hock B, Prager M, Pfister H, et al. Complex segregation analysis of restless legs syndrome provides evidence for an autosomal dominant mode of inheritance in early age at onset families. Ann Neurol. 2002;52(3):297–302.

    PubMed  Google Scholar 

  58. Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirsson TE, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med. 2007;357(7):639–47.

    PubMed  CAS  Google Scholar 

  59. Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L, Jalilzadeh S, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007;39(8):1000–6.

    PubMed  CAS  Google Scholar 

  60. Schormair B, Kemlink D, Roeske D, Eckstein G, Xiong L, Lichtner P, et al. Ptprd (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet. 2008;40(8):946–8.

    PubMed  CAS  Google Scholar 

  61. Desautels A, Turecki G, Montplaisir J, Brisebois K, Sequeira A, Adam B, et al. Evidence for a genetic association between monoamine oxidase a and restless legs syndrome. Neurology. 2002;59(2):215–9.

    PubMed  CAS  Google Scholar 

  62. Winkelmann J, Lichtner P, Schormair B, Uhr M, Hauk S, Stiasny-Kolster K, et al. Variants in the neuronal nitric oxide synthase (nnos, nos1) gene are associated with restless legs syndrome. Mov Disord. 2008;23(3):350–8.

    PubMed  Google Scholar 

  63. Desautels A, Turecki G, Montplaisir J, Xiong L, Walters AS, Ehrenberg BL, et al. Restless legs syndrome: confirmation of linkage to chromosome 12q, genetic heterogeneity, and evidence of complexity. Arch Neurol. 2005;62(4):591–6.

    PubMed  Google Scholar 

  64. Bonati MT, Ferini-Strambi L, Aridon P, Oldani A, Zucconi M, Casari G. Autosomal dominant restless legs syndrome maps on chromosome 14q. Brain. 2003;126(Pt 6):1485–92.

    PubMed  Google Scholar 

  65. Chen S, Ondo WG, Rao S, Li L, Chen Q, Wang Q. Genomewide linkage scan identifies a novel susceptibility locus for restless legs syndrome on chromosome 9p. Am J Hum Genet. 2004;74(5):876–85.

    PubMed  CAS  PubMed Central  Google Scholar 

  66. Pichler I, Schwienbacher C, Zanon A, Fuchsberger C, Serafin A, Facheris MF, et al. Fine-mapping of restless legs locus 4 (rls4) identifies a haplotype over the spats2l and kctd18 genes. J Mol Neurosci. 2012;49(3):600–5.

    PubMed  Google Scholar 

  67. Levchenko A, Provost S, Montplaisir JY, Xiong L, St-Onge J, Thibodeau P, et al. A novel autosomal dominant restless legs syndrome locus maps to chromosome 20p13. Neurology. 2006;67(5):900–1.

    PubMed  CAS  Google Scholar 

  68. Sas AM, Di Fonzo A, Bakker SL, Simons EJ, Oostra BA, Maat-Kievit AJ, et al. Autosomal dominant restless legs syndrome maps to chromosome 20p13 (rls-5) in a dutch kindred. Mov Disord. 2010;25(11):1715–22.

    PubMed  Google Scholar 

  69. Lohmann-Hedrich K, Neumann A, Kleensang A, Lohnau T, Muhle H, Djarmati A, et al. Evidence for linkage of restless legs syndrome to chromosome 9p: are there two distinct loci?[see comment]. Neurology. 2008;70(9):686–94.

    PubMed  CAS  Google Scholar 

  70. Levchenko A, Montplaisir JY, Asselin G, Provost S, Girard SL, Xiong L, et al. Autosomal-dominant locus for restless legs syndrome in french-canadians on chromosome 16p12.1. Mov Disord. 2009;24(1):40–50.

    PubMed  Google Scholar 

  71. Skehan EB, Abdulrahim MM, Parfrey NA, Hand CK. A novel locus for restless legs syndrome maps to chromosome 19p in an irish pedigree. Neurogenetics. 2012;13(2):125–32.

    PubMed  CAS  Google Scholar 

  72. Balaban H, Bayrakli F, Kartal U, Pinarbasi E, Topaktas S, Kars HZ. A novel locus for restless legs syndrome on chromosome 13q. Eur Neurol. 2012;68(2):111–6.

    PubMed  CAS  Google Scholar 

  73. Weissbach A, Siegesmund K, Bruggemann N, Schmidt A, Kasten M, Pichler I, et al. Exome sequencing in a family with restless legs syndrome. Mov Disord. 2012;27(13):1686–9.

    PubMed  CAS  Google Scholar 

  74. Vilarino-Guell C, Soto AI, Young JE, Lin SC, Uitti RJ, Wszolek ZK, et al. Susceptibility genes for restless legs syndrome are not associated with parkinson disease. Neurology. 2008;71(3):222–3.

    PubMed  CAS  Google Scholar 

  75. Lin CH, Chen ML, Wu VC, Li WY, Sy HN, Wu SL, et al. Association of candidate genetic variants with restless legs syndrome in end stage renal disease: a multicenter case-control study in taiwan. Eur J Neurol. 2014;21(3):492–8.

    PubMed  CAS  Google Scholar 

  76. Huiqi Q, Shan L, Mingcai Q. Restless legs syndrome (rls) in uremic patients is related to the frequency of hemodialysis sessions. Nephron. 2000;86(4):540.

    PubMed  CAS  Google Scholar 

  77. Yasuda T, Nishimura A, Katsuki Y, Tsuji Y. Restless legs syndrome treated successfully by kidney transplantation--a case report. Clin Transpl (1986) 138.

  78. Winkelmann J, Stautner A, Samtleben W, Trenkwalder C. Long-term course of restless legs syndrome in dialysis patients after kidney transplantation. Mov Disord. 2002;17(5):1072–6.

    PubMed  Google Scholar 

  79. Azar SA, Hatefi R, Talebi M. Evaluation of effect of renal transplantation in treatment of restless legs syndrome. Transplant Proc. 2007;39(4):1132–3.

    PubMed  CAS  Google Scholar 

  80. Manconi M, Govoni V, De Vito A, Economou NT, Cesnik E, Casetta I, et al. Restless legs syndrome and pregnancy. Neurology. 2004;63(6):1065–9. Largest study of RLS during pregnancy.

    PubMed  CAS  Google Scholar 

  81. Tunc T, Karadag YS, Dogulu F, Inan LE. Predisposing factors of restless legs syndrome in pregnancy. Mov Disord. 2007;22(5):627–31.

    PubMed  Google Scholar 

  82. Ondo WG, Vuong KD, Jankovic J. Exploring the relationship between parkinson disease and restless legs syndrome. Arch Neurol. 2002;59(3):421–4.

    PubMed  Google Scholar 

  83. Ondo W, Chen S, Dragan E. Does idiopathic restless legs syndrome delay onset and reduce severity of parkinson’s disease. Mov Disord. 2014;29(Supple1):S303.

    Google Scholar 

  84. Ondo WG, Jia JJ. Effect of tetrabenazine use on restless legs syndrome. Sleep Med. 2010;11(9):958–9.

    PubMed  Google Scholar 

  85. Jagota P, Asawavichienjinda T, Bhidayasiri R. Prevalence of neuroleptic-induced restless legs syndrome in patients taking neuroleptic drugs. J Neurol Sci. 2012;314(1–2):158–60.

    PubMed  Google Scholar 

  86. Garcia-Borreguero D, Ferini-Strambi L, Kohnen R, O'Keeffe S, Trenkwalder C, Hogl B, et al. European guidelines on management of restless legs syndrome: report of a joint task force by the European federation of neurological societies, the European neurological society and the European sleep research society. Eur J Neurol. 2012;19(11):1385–96.

    PubMed  Google Scholar 

  87. Garcia-Borreguero D, Kohnen R, Silber MH, Winkelman JW, Earley CJ, Hogl B, 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;14(7):675–84. Only review of long-term management of disease.

    PubMed  Google Scholar 

  88. Silber MH, Becker PM, Earley C, Garcia-Borreguero D, Ondo WG. Willis-ekbom disease foundation revised consensus statement on the management of restless legs syndrome. Mayo Clin Proc. 2013;88(9):977–86. Recent review of treatment options.

    PubMed  Google Scholar 

  89. Hornyak M, Scholz H, Kohnen R, Bengel J, Kassubek J, Trenkwalder C. What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and non-dopaminergic medications. Sleep Med Rev. 2014;18(2):153–64.

    PubMed  Google Scholar 

  90. Ondo WG, Hossain MM, Gordon MF, Reess J. Predictors of placebo response in restless legs syndrome studies. Neurology. 2013;81(2):193–4.

    PubMed  Google Scholar 

  91. Trenkwalder C, Garcia-Borreguero D, Montagna P, Lainey E, de Weerd AW, Tidswell P, et al. Ropinirole in the treatment of restless legs syndrome: results from the treat rls 1 study, a 12 week, randomised, placebo controlled study in 10 European countries. J Neurol Neurosurg Psychiatry. 2004;75(1):92–7.

    PubMed  CAS  PubMed Central  Google Scholar 

  92. Walters AS, Ondo WG, Dreykluft T, Grunstein R, Lee D, Sethi K. Ropinirole is effective in the treatment of restless legs syndrome. Treat rls 2: a 12-week, double-blind, randomized, parallel-group, placebo-controlled study. Mov Disord. 2004;19(12):1414–23.

    PubMed  Google Scholar 

  93. Bogan R, Connolly G, Rederich G. Ropinirole is effective, well tolerated treatment for moderate-to-severe rls: results of a u.S. Study. Mov Disord. 2005;20(supple10):S61.

    Google Scholar 

  94. Oertel WH, Stiasny-Kolster K, Bergtholdt B, Hallstrom Y, Albo J, Leissner L, et al. Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-rls study). Mov Disord. 2007;22(2):213–9.

    PubMed  Google Scholar 

  95. Trenkwalder C, Stiasny-Kolster K, Kupsch A, Oertel WH, Koester J, Reess J. Controlled withdrawal of pramipexole after 6 months of open-label treatment in patients with restless legs syndrome. Mov Disord. 2006;21(9):1404–10.

    PubMed  Google Scholar 

  96. Partinen M, Hirvonen K, Jama L, Alakuijala A, Hublin C, Tamminen I, et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study-the prelude study. Sleep Med. 2006;7(5):407–17.

    PubMed  Google Scholar 

  97. Trenkwalder C, Benes H, Poewe W, Oertel WH, Garcia-Borreguero D, de Weerd AW, et al. Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 2008;7(7):595–604.

    PubMed  CAS  Google Scholar 

  98. Oertel WH, Benes H, Garcia-Borreguero D, Geisler P, Hogl B, Saletu B, et al. Efficacy of rotigotine transdermal system in severe restless legs syndrome: a randomized, double-blind, placebo-controlled, six-week dose-finding trial in europe. Sleep Med. 2008;9(3):228–39.

    PubMed  Google Scholar 

  99. Earley CJ, Yaffee JB, Allen RP. Randomized, double-blind, placebo-controlled trial of pergolide in restless legs syndrome. Neurology. 1998;51(6):1599–602.

    PubMed  CAS  Google Scholar 

  100. Staedt J, Wassmuth F, Ziemann U, Hajak G, Ruther E, Stoppe G. Pergolide: Treatment of choice in restless legs syndrome (rls) and nocturnal myoclonus syndrome (nms). A double-blind randomized crossover trial of pergolide versus l-dopa. J Neural Transm (Budapest). 1997;104(4-5):461–8.

    CAS  Google Scholar 

  101. Trenkwalder C, Brandenburg U, Hundemer H, Lledo A, Quail D. A randomized long-term placebo controlled multicenter trial of pergolide in the treatment of restless legs syndrome with central evaluation of polysomnographic data. Neurology. 2001;56(Supple 3):A5.

    Google Scholar 

  102. Wetter TC, Stiasny K, Winkelmann J, Buhlinger A, Brandenburg U, Penzel T, et al. A randomized controlled study of pergolide in patients with restless legs syndrome. Neurology. 1999;52(5):944–50.

    PubMed  CAS  Google Scholar 

  103. Walters AS, Hening WA, Kavey N, Chokroverty S, Gidro-Frank S. A double-blind randomized crossover trial of bromocriptine and placebo in restless legs syndrome. Ann Neurol. 1988;24(3):455–8.

    PubMed  CAS  Google Scholar 

  104. Reuter I, Ellis CM, Ray Chaudhuri K. Nocturnal subcutaneous apomorphine infusion in parkinson's disease and restless legs syndrome. Acta Neurol Scand. 1999;100(3):163–7.

    PubMed  CAS  Google Scholar 

  105. Happe S, Trenkwalder C. Role of dopamine receptor agonists in the treatment of restless legs syndrome. CNS Drugs. 2004;18(1):27–36.

    PubMed  CAS  Google Scholar 

  106. Benes H. Transdermal lisuride: short-term efficacy and tolerability study in patients with severe restless legs syndrome. Sleep Med. 2006;7(1):31–5.

    PubMed  Google Scholar 

  107. Benes H, Kurella B, Kummer J, Kazenwadel J, Selzer R, Kohnen R. Rapid onset of action of levodopa in restless legs syndrome: a double-blind, randomized, multicenter, crossover trial. Sleep. 1999;22(8):1073–81.

    PubMed  CAS  Google Scholar 

  108. Saletu M, Anderer P, Hogl B, Saletu-Zyhlarz G, Kunz A, Poewe W, et al. Acute double-blind, placebo-controlled sleep laboratory and clinical follow-up studies with a combination treatment of rr-l-dopa and sr-l-dopa in restless legs syndrome. J Neural Transm. 2003;110(6):611–26.

    PubMed  CAS  Google Scholar 

  109. Trenkwalder C, Benes H, Grote L, Happe S, Hogl B, Mathis J, et al. Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: results from a multi-center, randomized, active controlled trial. Mov Disord. 2007;22(5):696–703.

    PubMed  Google Scholar 

  110. Pellecchia MT, Vitale C, Sabatini M, Longo K, Amboni M, Bonavita V, et al. Ropinirole as a treatment of restless legs syndrome in patients on chronic hemodialysis: an open randomized crossover trial versus levodopa sustained release. Clin Neuropharmacol. 2004;27(4):178–81.

    PubMed  CAS  Google Scholar 

  111. Garcia-Borreguero D, Kohnen R, Hogl B, Ferini-Strambi L, Hadjigeorgiou GM, Hornyak M, et al. Validation of the augmentation severity rating scale (asrs): a multicentric, prospective study with levodopa on restless legs syndrome. Sleep Med. 2007;8(5):455–63.

    PubMed  Google Scholar 

  112. Hogl B, Garcia-Borreguero D, Kohnen R, Ferini-Strambi L, Hadjigeorgiou G, Hornyak M, et al. Progressive development of augmentation during long-term treatment with levodopa in restless legs syndrome: results of a prospective multi-center study. J Neurol. 2010;257(2):230–7.

    PubMed  PubMed Central  Google Scholar 

  113. Allen RP, Chen C, Garcia-Borreguero D, Polo O, DuBrava S, Miceli J, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med. 2014;370(7):621–31.

    PubMed  CAS  Google Scholar 

  114. Garcia-Borreguero D, Hogl B, Ferini-Strambi L, Winkelman J, Hill-Zabala C, Asgharian A, et al. Systematic evaluation of augmentation during treatment with ropinirole in restless legs syndrome (willis-ekbom disease): results from a prospective, multicenter study over 66 weeks. Mov Disord. 2012;27(2):277–83.

    PubMed  CAS  Google Scholar 

  115. Benes H, Garcia-Borreguero D, Ferini-Strambi L, Schollmayer E, Fichtner A, Kohnen R. Augmentation in the treatment of restless legs syndrome with transdermal rotigotine. Sleep Med. 2012;13(6):589–97.

    PubMed  Google Scholar 

  116. Inoue Y, Hirata K, Hayashida K, Hattori N, Tomida T, Garcia-Borreguero D. Efficacy, safety and risk of augmentation of rotigotine for treating restless legs syndrome. Prog Neuropsychopharmacol Biol Psychiatry. 2013;40:326–33.

    PubMed  CAS  Google Scholar 

  117. Ondo W, Romanyshyn J, Vuong KD, Lai D. Long-term treatment of restless legs syndrome with dopamine agonists. Arch Neurol. 2004;61(9):1393–7.

    PubMed  Google Scholar 

  118. Silber MH, Girish M, Izurieta R. Pramipexole in the management of restless legs syndrome: an extended study. Sleep. 2003;26(7):819–21.

    PubMed  Google Scholar 

  119. Yaltho TC, Ondo WG. The use of gabapentin enacarbil in the treatment of restless legs syndrome. Ther Adv Neurol Disord. 2010;3(5):269–75.

    PubMed  CAS  PubMed Central  Google Scholar 

  120. Merlino G, Serafini A, Young JJ, Robiony F, Gigli GL, Valente M. Gabapentin enacarbil, a gabapentin prodrug for the treatment of the neurological symptoms associated with disorders such as restless legs syndrome. Curr Opin Investig Drugs. 2009;10(1):91–102.

    PubMed  CAS  Google Scholar 

  121. Allen R, Chen C, Soaita A, Wohlberg C, Knapp L, Peterson BT, et al. A randomized, double-blind, 6-week, dose-ranging study of pregabalin in patients with restless legs syndrome. Sleep Med. 2010;11(6):512–9.

    PubMed  Google Scholar 

  122. Garcia-Borreguero D, Larrosa O, Williams AM, Albares J, Pascual M, Palacios JC, et al. Treatment of restless legs syndrome with pregabalin: a double-blind, placebo-controlled study. Neurology. 2010;74(23):1897–904.

    PubMed  CAS  Google Scholar 

  123. Lee DO, Ziman RB, Perkins AT, Poceta JS, Walters AS, Barrett RW. A randomized, double-blind, placebo-controlled study to assess the efficacy and tolerability of gabapentin enacarbil in subjects with restless legs syndrome. J Clin Sleep Med. 2011;7(3):282–92.

    PubMed  PubMed Central  Google Scholar 

  124. VanMeter SA, Kavanagh ST, Warren S, Barrett RW. Dose response of gabapentin enacarbil versus placebo in subjects with moderate-to-severe primary restless legs syndrome: an integrated analysis of three 12-week studies. CNS Drugs. 2012;26(9):773–80.

    PubMed  CAS  Google Scholar 

  125. Inoue Y, Hirata K, Uchimura N, Kuroda K, Hattori N, Takeuchi M. Gabapentin enacarbil in japanese patients with restless legs syndrome: a 12-week, randomized, double-blind, placebo-controlled, parallel-group study. Curr Med Res Opin. 2013;29(1):13–21.

    PubMed  CAS  Google Scholar 

  126. Garcia-Borreguero D, Larrosa O, de la Llave Y, Verger K, Masramon X, Hernandez G. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology. 2002;59(10):1573–9.

    PubMed  CAS  Google Scholar 

  127. Walters AS, Winkelmann J, Trenkwalder C, Fry JM, Kataria V, Wagner M, et al. Long-term follow-up on restless legs syndrome patients treated with opioids. Mov Disord. 2001;16(6):1105–9.

    PubMed  CAS  Google Scholar 

  128. Walters AS, Wagner ML, Hening WA, Grasing K, Mills R, Chokroverty S, et al. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep. 1993;16(4):327–32.

    PubMed  CAS  Google Scholar 

  129. Kaplan PW, Allen RP, Buchholz DW, Walters JK. A double-blind, placebo-controlled study of the treatment of periodic limb movements in sleep using carbidopa/levodopa and propoxyphene. Sleep. 1993;16(8):717–23.

    PubMed  CAS  Google Scholar 

  130. Trenkwalder C, Benes H, Grote L, Garcia-Borreguero D, Hogl B, Hopp M, et al. Prolonged release oxycodone-naloxone for treatment of severe restless legs syndrome after failure of previous treatment: a double-blind, randomised, placebo-controlled trial with an open-label extension. Lancet Neurol. 2013;12(12):1141–50.

    PubMed  CAS  Google Scholar 

  131. Lindvall P, Hariz GM, Blomstedt P. Overall self-perceived health in restless legs treated with intrathecal morphine. Acta Neurol Scand. 2012;127(4):268–73.

    PubMed  Google Scholar 

  132. Ondo WG. Methadone for refractory restless legs syndrome. Mov Disord. 2005;20(3):345–8.

    PubMed  Google Scholar 

  133. Silver N, Allen RP, Senerth J, Earley CJ. A 10-year, longitudinal assessment of dopamine agonists and methadone in the treatment of restless legs syndrome. Sleep Med. 2011;12(5):440–4.

    PubMed  Google Scholar 

  134. Walters AS. Review of receptor agonist and antagonist studies relevant to the opiate system in restless legs syndrome. Sleep Med. 2002;3(4):301–4.

    PubMed  Google Scholar 

  135. Di Chiara G, Imperato A. Opposite effects of mu and kappa opiate agonists on dopamine release in the nucleus accumbens and in the dorsal caudate of freely moving rats. J Pharmacol Exp Ther. 1988;244(3):1067–80.

    PubMed  Google Scholar 

  136. Trotti LM, Bhadriraju S, Becker LA. Iron for restless legs syndrome. Cochrane Database Syst Rev. 2012;5:CD007834.

    PubMed  PubMed Central  Google Scholar 

  137. Lee CS, Lee SD, Kang SH, Park HY, Yoon IY. Comparison of the efficacies of oral iron and pramipexole for the treatment of restless legs syndrome patients with low serum ferritin. Eur J Neurol. 2013;21(2):260–6.

    PubMed  Google Scholar 

  138. Cho YW, Allen RP, Earley CJ. Lower molecular weight intravenous iron dextran for restless legs syndrome. Sleep Med. 2013;14(3):274–7.

    PubMed  Google Scholar 

  139. Earley CJ, Horska A, Mohamed MA, Barker PB, Beard JL, Allen RP. A randomized, double-blind, placebo-controlled trial of intravenous iron sucrose in restless legs syndrome. Sleep Med. 2009;10(2):206–11.

    PubMed  PubMed Central  Google Scholar 

  140. Lettieri CJ, Eliasson AH. Pneumatic compression devices are an effective therapy for restless legs syndrome: a prospective, randomized, double-blinded, sham-controlled trial. Chest. 2009;135(1):74–80.

    PubMed  Google Scholar 

  141. Nahab FB, Peckham EL, Hallett M. Double-blind, placebo-controlled, pilot trial of botulinum toxin a in restless legs syndrome. Neurology. 2008;71(12):950–1.

    PubMed  PubMed Central  Google Scholar 

  142. Ondo W. Vim deep brain stimulation does not improve pre-existing restless legs syndrome in patients with essential tremor. Parkinsonism Relat Disord. 2006;12(2):113–4.

    PubMed  Google Scholar 

  143. Ondo WG, Jankovic J, Simpson R, Jimenez-Shahed J. Globus pallidus deep brain stimulation for refractory idiopathic restless legs syndrome. Sleep Med. 2012;13(9):1202–4.

    PubMed  Google Scholar 

  144. Tilma J, Tilma K, Norregaard O, Ostergaard JR. Early childhood-onset restless legs syndrome: symptoms and effect of oral iron treatment. Acta Paediatr. 2013;102(5):e221–6.

    PubMed  Google Scholar 

  145. Grim K, Lee B, Sung AY, Kotagal S. Treatment of childhood-onset restless legs syndrome and periodic limb movement disorder using intravenous iron sucrose. Sleep Med. 2013;14(11):1100–4.

    PubMed  Google Scholar 

  146. Mohri I, Kato-Nishimura K, Kagitani-Shimono K, Kimura-Ohba S, Ozono K, Tachibana N, et al. Evaluation of oral iron treatment in pediatric restless legs syndrome (rls). Sleep Med. 2012;13(4):429–32.

    PubMed  Google Scholar 

  147. Amos LB, Grekowicz ML, Kuhn EM, Olstad JD, Collins MM, Norins NA, et al. Treatment of pediatric restless legs syndrome. Clin Pediatr (Phila). 2013;53(4):331–6.

    Google Scholar 

  148. England SJ, Picchietti DL, Couvadelli BV, Fisher BC, Siddiqui F, Wagner ML, et al. L-dopa improves restless legs syndrome and periodic limb movements in sleep but not attention-deficit-hyperactivity disorder in a double-blind trial in children. Sleep Med. 2011;12(5):471–7.

    PubMed  PubMed Central  Google Scholar 

  149. de Oliveira MM, Conti CF, Valbuza JS, de Carvalho LB, do Prado GF. The pharmacological treatment for uremic restless legs syndrome: Evidence-based review. Mov Disord. 2010;25(10):1335–42.

    PubMed  Google Scholar 

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William G. Ondo reports grants and personal fees from Lundbeck, USWorld Meds, and Merz, as well as personal fees from Avanir, TEVA, UCBPharma, and Xenoport, outside the submitted work.

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    William G. Ondo MD

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Ondo, W.G. Restless Legs Syndrome: Pathophysiology and Treatment. Curr Treat Options Neurol 16, 317 (2014). https://doi.org/10.1007/s11940-014-0317-2

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