Journal of Neurology

, Volume 264, Issue 8, pp 1634–1641 | Cite as

Iron, dopamine, genetics, and hormones in the pathophysiology of restless legs syndrome

  • Farhan H. Khan
  • Caitlyn D. Ahlberg
  • Christopher A. Chow
  • Divya R. Shah
  • Brian B. KooEmail author


Restless legs syndrome (RLS) is a common, chronic neurologic condition, which causes a persistent urge to move the legs in the evening that interferes with sleep. Human and animal studies have been used to study the pathophysiologic state of RLS and much has been learned about the iron and dopamine systems in relation to RLS. Human neuropathologic and imaging studies have consistently shown decreased iron in different brain regions including substantia nigra and thalamus. These same areas also demonstrate a state of relative dopamine excess. While it is not known how these changes in dopamine or iron produce the symptoms of RLS, genetic and hormone studies of RLS have identified other biologic systems or genes, such as the endogenous opioid and melanocortin systems and BTBD9 and MEIS1, that may explain some of the iron or dopamine changes in relation to RLS. This manuscript will review what is known about the pathophysiology of RLS, especially as it relates to changes in iron, dopamine, genetics, and hormonal systems.


Restless legs syndrome Pathophysiology Dopamine Iron Genetics 



This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with ethical standards

Conflicts of interest

The authors have no conflicts of interest to report.


  1. 1.
    Earley CJ, Silber MH (2010) Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med 11:807–815CrossRefPubMedGoogle Scholar
  2. 2.
    Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, Ferini-Strambi L (2005) Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 165:1286–1292CrossRefPubMedGoogle Scholar
  3. 3.
    Ghorayeb I, Tison F (2009) Epidemiology of restless legs syndrome. Rev Neurol 165:641–649CrossRefPubMedGoogle Scholar
  4. 4.
    Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, Zucconi M, Ferri R, Trenkwalder C, Lee HB (2014) 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 15:860–873CrossRefPubMedGoogle Scholar
  5. 5.
    Whittom S, Dauvilliers Y, Pennestri MH, Vercauteren F, Molinari N, Petit D, Montplaisir J (2007) Age-at-onset in restless legs syndrome: a clinical and polysomnographic study. Sleep Med 9:54–59CrossRefPubMedGoogle Scholar
  6. 6.
    Winkelmann J, Polo O, Provini F, Nevsimalova S, Kemlink D, Sonka K, Hogl B, Poewe W, Stiasny-Kolster K, Oertel W, de Weerd A, Strambi LF, Zucconi M, Pramstaller PP, Arnulf I, Trenkwalder C, Klein C, Hadjigeorgiou GM, Happe S, Rye D, Montagna P (2007) Genetics of restless legs syndrome (RLS): state-of-the-art and future directions. Mov Disord 22(Suppl 18):S449–S458CrossRefPubMedGoogle Scholar
  7. 7.
    Moccia M, Erro R, Picillo M, Santangelo G, Spina E, Allocca R, Longo K, Amboni M, Palladino R, Assante R, Pappata S, Pellecchia MT, Barone P, Vitale C (2016) A four-year longitudinal study on restless legs syndrome in Parkinson disease. Sleep 39:405–412CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Trenkwalder C, Winkelmann J, Inoue Y, Paulus W (2015) Restless legs syndrome-current therapies and management of augmentation. Nat Rev Neurol 11:434–445CrossRefPubMedGoogle Scholar
  9. 9.
    Nordlander NB (1953) Therapy in restless legs. Acta Med Scand 145:453–457PubMedGoogle Scholar
  10. 10.
    Beard J (2003) Iron deficiency alters brain development and functioning. J Nutr 133:1468s–1472sPubMedGoogle Scholar
  11. 11.
    Sadrzadeh SM, Saffari Y (2004) Iron and brain disorders. Am J Clin Pathol 121(Suppl):S64–S70PubMedGoogle Scholar
  12. 12.
    Manconi M, Govoni V, De Vito A, Economou NT, Cesnik E, Casetta I, Mollica G, Ferini-Strambi L, Granieri E (2004) Restless legs syndrome and pregnancy. Neurology 63:1065–1069CrossRefPubMedGoogle Scholar
  13. 13.
    Winkelman JW, Chertow GM, Lazarus JM (1996) Restless legs syndrome in end-stage renal disease. Am J Kidney Dis 28:372–378CrossRefPubMedGoogle Scholar
  14. 14.
    Allen RP, Auerbach S, Bahrain H, Auerbach M, Earley CJ (2013) The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 88:261–264CrossRefPubMedGoogle Scholar
  15. 15.
    Frauscher B, Gschliesser V, Brandauer E, El-Demerdash E, Kaneider M, Rucker L, Poewe W, Hogl B (2009) The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: association with ferritin levels. Sleep Med 10:611–615CrossRefPubMedGoogle Scholar
  16. 16.
    Allen RP, Barker PB, Wehrl FW, Song HK, Earley CJ (2001) MRI measurement of brain iron in patients with restless legs syndrome. Neurology 56:263–265CrossRefPubMedGoogle Scholar
  17. 17.
    Earley CJ, Barker PB, Horská A, Allen RP (2006) MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome. Sleep Med 7:458–461CrossRefPubMedGoogle Scholar
  18. 18.
    Godau J, Klose U, Di Santo A, Schweitzer K, Berg D (2008) Multiregional brain iron deficiency in restless legs syndrome. Mov Disord 23:1184–1187CrossRefPubMedGoogle Scholar
  19. 19.
    Nie G, Sheftel AD, Kim SF, Ponka P (2005) Overexpression of mitochondrial ferritin causes cytosolic iron depletion and changes cellular iron homeostasis. Blood 105:2161–2167CrossRefPubMedGoogle Scholar
  20. 20.
    Connor JR, Boyer PJ, Menzies SL, Dellinger B, Allen RP, Ondo WG, Earley CJ (2003) Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 61:304–309CrossRefPubMedGoogle Scholar
  21. 21.
    Connor JR, Wang XS, Patton SM, Menzies SL, Troncoso JC, Earley CJ, Allen RP (2004) Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology 62:1563–1567CrossRefPubMedGoogle Scholar
  22. 22.
    Clardy SL, Earley CJ, Allen RP, Beard JL, Connor JR (2006) Ferritin subunits in CSF are decreased in restless legs syndrome. J Lab Clin Med 147:67–73CrossRefPubMedGoogle Scholar
  23. 23.
    Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DK, Allen RP (2000) Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 54:1698–1700CrossRefPubMedGoogle Scholar
  24. 24.
    Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J (2005) CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res 14:43–47CrossRefPubMedGoogle Scholar
  25. 25.
    Dean T Jr, Allen RP, O’Donnell CP, Earley CJ (2006) The effects of dietary iron deprivation on murine circadian sleep architecture. Sleep Med 7:634–640CrossRefPubMedGoogle Scholar
  26. 26.
    Unger EL, Earley CJ, Beard JL (2009) Diurnal cycle influences peripheral and brain iron levels in mice. J Appl Physiol (Bethesda, Md: 1985) 106:187–193CrossRefGoogle Scholar
  27. 27.
    Patton SM, Ponnuru P, Snyder AM, Podskalny GD, Connor JR (2011) Hypoxia-inducible factor pathway activation in restless legs syndrome patients. Eur J Neurol 18:1329–1335CrossRefPubMedGoogle Scholar
  28. 28.
    Bunn HF, Poyton RO (1996) Oxygen sensing and molecular adaptation to hypoxia. Physiol Rev 76:839–885PubMedGoogle Scholar
  29. 29.
    Lok CN, Ponka P (1999) Identification of a hypoxia response element in the transferrin receptor gene. J Biol Chem 274:24147–24152CrossRefPubMedGoogle Scholar
  30. 30.
    Connor JR, Ponnuru P, Lee BY, Podskalny GD, Alam S, Allen RP, Earley CJ, Yang QX (2011) Postmortem and imaging based analyses reveal CNS decreased myelination in restless legs syndrome. Sleep Med 12:614–619CrossRefPubMedPubMedCentralGoogle Scholar
  31. 31.
    Connor JR, Ponnuru P, Wang XS, Patton SM, Allen RP, Earley CJ (2011) Profile of altered brain iron acquisition in restless legs syndrome. Brain 134:959–968CrossRefPubMedPubMedCentralGoogle Scholar
  32. 32.
    Earley CJ, Ponnuru P, Wang X, Patton SM, Conner JR, Beard JL, Taub DD, Allen RP (2008) Altered iron metabolism in lymphocytes from subjects with restless legs syndrome. Sleep 31:847–852CrossRefPubMedPubMedCentralGoogle Scholar
  33. 33.
    Erikson KM, Jones BC, Beard JL (2000) Iron deficiency alters dopamine transporter functioning in rat striatum. J Nutr 130:2831–2837PubMedGoogle Scholar
  34. 34.
    Bruenger FW, Stover BJ, Atherton DR (1967) The incorporation of various metal ions into in vivo- and in vitro-produced melanin. Radiat Res 32:1–12CrossRefPubMedGoogle Scholar
  35. 35.
    Sofic E, Riederer P, Heinsen H, Beckmann H, Reynolds GP, Hebenstreit G, Youdim MB (1988) Increased iron (III) and total iron content in post mortem substantia nigra of parkinsonian brain. J Neural Transm 74:199–205CrossRefPubMedGoogle Scholar
  36. 36.
    Dowling P, Klinker F, Stadelmann C, Hasan K, Paulus W, Liebetanz D (2011) Dopamine D3 receptor specifically modulates motor and sensory symptoms in iron-deficient mice. J Neurosci 31:70–77CrossRefPubMedGoogle Scholar
  37. 37.
    Connor JR, Wang XS, Allen RP, Beard JL, Wiesinger JA, Felt BT, Earley CJ (2009) Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain 132:2403–2412CrossRefPubMedPubMedCentralGoogle Scholar
  38. 38.
    Beard JL, Chen Q, Connor J, Jones BC (1994) Altered monamine metabolism in caudate-putamen of iron-deficient rats. Pharmacol Biochem Behav 48:621–624CrossRefPubMedGoogle Scholar
  39. 39.
    Bianco LE, Wiesinger J, Earley CJ, Jones BC, Beard JL (2008) Iron deficiency alters dopamine uptake and response to L-DOPA injection in Sprague-Dawley rats. J Neurochem 106:205–215CrossRefPubMedGoogle Scholar
  40. 40.
    Ashkenazi R, Ben-Shachar D, Youdim MB (1982) Nutritional iron and dopamine binding sites in the rat brain. Pharmacol Biochem Behav 17(Suppl 1):43–47CrossRefPubMedGoogle Scholar
  41. 41.
    Erikson KM, Jones BC, Hess EJ, Zhang Q, Beard JL (2001) Iron deficiency decreases dopamine D1 and D2 receptors in rat brain. Pharmacol Biochem Behav 69:409–418CrossRefPubMedGoogle Scholar
  42. 42.
    Unger EL, Wiesinger JA, Hao L, Beard JL (2008) Dopamine D2 receptor expression is altered by changes in cellular iron levels in PC12 cells and rat brain tissue. J Nutr 138:2487–2494CrossRefPubMedPubMedCentralGoogle Scholar
  43. 43.
    Unger EL, Bianco LE, Jones BC, Allen RP, Earley CJ (2014) Low brain iron effects and reversibility on striatal dopamine dynamics. Exp Neurol 261:462–468CrossRefPubMedPubMedCentralGoogle Scholar
  44. 44.
    Montplaisir J, Godbout R, Boghen D, DeChamplain J, Young SN, Lapierre G (1985) Familial restless legs with periodic movements in sleep: electrophysiologic, biochemical, and pharmacologic study. Neurology 35:130–134CrossRefPubMedGoogle Scholar
  45. 45.
    Allen RP, Connor JR, Hyland K, Earley CJ (2009) 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 10:123–128CrossRefPubMedGoogle Scholar
  46. 46.
    Earley CJ, Hyland K, Allen RP (2006) Circadian changes in CSF dopaminergic measures in restless legs syndrome. Sleep Med 7:263–268CrossRefPubMedGoogle Scholar
  47. 47.
    Allen RP (2015) Restless leg syndrome/Willis-Ekbom disease pathophysiology. Sleep Med Clin 10:207–214CrossRefPubMedPubMedCentralGoogle Scholar
  48. 48.
    Earley CJ, Connor J, Garcia-Borreguero D, Jenner P, Winkelman J, Zee PC, Allen R (2014) Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom disease). Sleep Med 15:1288–1301CrossRefPubMedGoogle Scholar
  49. 49.
    Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J (2003) 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 4:101–119CrossRefPubMedGoogle Scholar
  50. 50.
    Rye DB, Trotti LM (2012) Restless legs syndrome and periodic leg movements of sleep. Neurol Clin 30:1137–1166CrossRefPubMedGoogle Scholar
  51. 51.
    Winkelman JW (2007) Periodic limb movements in sleep–endophenotype for restless legs syndrome? N Engl J Med 357:703–705CrossRefPubMedGoogle Scholar
  52. 52.
    Lazzarini A, Walters AS, Hickey K, Coccagna G, Lugaresi E, Ehrenberg BL, Picchietti DL, Brin MF, Stenroos ES, Verrico T, Johnson WG (1999) Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees. Mov Disord 14:111–116CrossRefPubMedGoogle Scholar
  53. 53.
    Trenkwalder C, Seidel VC, Gasser T, Oertel WH (1996) Clinical symptoms and possible anticipation in a large kindred of familial restless legs syndrome. Mov Disord 11:389–394CrossRefPubMedGoogle Scholar
  54. 54.
    Pichler I, Hicks AA, Pramstaller PP (2008) Restless legs syndrome: an update on genetics and future perspectives. Clin Genet 73:297–305CrossRefPubMedGoogle Scholar
  55. 55.
    Winkelmann J (2008) Genetics of restless legs syndrome. Curr Neurol Neurosci Rep 8:211–216CrossRefPubMedGoogle Scholar
  56. 56.
    Ht Moore, Winkelmann J, Lin L, Finn L, Peppard P, Mignot E (2014) Periodic leg movements during sleep are associated with polymorphisms in BTBD9, TOX3/BC034767, MEIS1, MAP2K5/SKOR1, and PTPRD. Sleep 37:1535–1542CrossRefGoogle Scholar
  57. 57.
    Schormair B, Kemlink D, Roeske D, Eckstein G, Xiong L, Lichtner P, Ripke S, Trenkwalder C, Zimprich A, Stiasny-Kolster K, Oertel W, Bachmann CG, Paulus W, Hogl B, Frauscher B, Gschliesser V, Poewe W, Peglau I, Vodicka P, Vavrova J, Sonka K, Nevsimalova S, Montplaisir J, Turecki G, Rouleau G, Gieger C, Illig T, Wichmann HE, Holsboer F, Muller-Myhsok B, Meitinger T, Winkelmann J (2008) PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet 40:946–948CrossRefPubMedGoogle Scholar
  58. 58.
    Stefansson H, Rye DB, Hicks A, Petursson H, Ingason A, Thorgeirsson TE, Palsson S, Sigmundsson T, Sigurdsson AP, Eiriksdottir I, Soebech E, Bliwise D, Beck JM, Rosen A, Waddy S, Trotti LM, Iranzo A, Thambisetty M, Hardarson GA, Kristjansson K, Gudmundsson LJ, Thorsteinsdottir U, Kong A, Gulcher JR, Gudbjartsson D, Stefansson K (2007) A genetic risk factor for periodic limb movements in sleep. N Engl J Med 357:639–647CrossRefPubMedGoogle Scholar
  59. 59.
    Winkelmann J, Schormair B, Lichtner P, Ripke S, Xiong L, Jalilzadeh S, Fulda S, Putz B, Eckstein G, Hauk S, Trenkwalder C, Zimprich A, Stiasny-Kolster K, Oertel W, Bachmann CG, Paulus W, Peglau I, Eisensehr I, Montplaisir J, Turecki G, Rouleau G, Gieger C, Illig T, Wichmann HE, Holsboer F, Muller-Myhsok B, Meitinger T (2007) Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 39:1000–1006CrossRefPubMedGoogle Scholar
  60. 60.
    Yang Q, Li L, Chen Q, Foldvary-Schaefer N, Ondo WG, Wang QK (2011) Association studies of variants in MEIS1, BTBD9, and MAP2K5/SKOR1 with restless legs syndrome in a US population. Sleep Med 12:800–804CrossRefPubMedPubMedCentralGoogle Scholar
  61. 61.
    Birinyi PV, Allen RP, Hening W, Washburn T, Lesage S, Earley CJ (2006) Undiagnosed individuals with first-degree relatives with restless legs syndrome have increased periodic limb movements. Sleep Med 7:480–485CrossRefPubMedGoogle Scholar
  62. 62.
    Kemlink D, Polo O, Frauscher B, Gschliesser V, Hogl B, Poewe W, Vodicka P, Vavrova J, Sonka K, Nevsimalova S, Schormair B, Lichtner P, Silander K, Peltonen L, Gieger C, Wichmann HE, Zimprich A, Roeske D, Muller-Myhsok B, Meitinger T, Winkelmann J (2009) Replication of restless legs syndrome loci in three European populations. J Med Genet 46:315–318CrossRefPubMedPubMedCentralGoogle Scholar
  63. 63.
    Stogios PJ, Downs GS, Jauhal JJ, Nandra SK, Prive GG (2005) Sequence and structural analysis of BTB domain proteins. Genome Biol 6:R82CrossRefPubMedPubMedCentralGoogle Scholar
  64. 64.
    DeAndrade MP, Johnson RL Jr, Unger EL, Zhang L, van Groen T, Gamble KL, Li Y (2012) Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice. Hum Mol Genet 21:3984–3992CrossRefPubMedPubMedCentralGoogle Scholar
  65. 65.
    Freeman A, Pranski E, Miller RD, Radmard S, Bernhard D, Jinnah HA, Betarbet R, Rye DB, Sanyal S (2012) Sleep fragmentation and motor restlessness in a Drosophila model of restless legs syndrome. Curr Biol 22:1142–1148CrossRefPubMedPubMedCentralGoogle Scholar
  66. 66.
    Hashimoto Y, Muramatsu K, Kunii M, Yoshimura S, Yamada M, Sato T, Ishida Y, Harada R, Harada A (2012) Uncovering genes required for neuronal morphology by morphology-based gene trap screening with a revertible retrovirus vector. FASEB J 26:4662–4674CrossRefPubMedPubMedCentralGoogle Scholar
  67. 67.
    Rye DB (2015) The molecular genetics of restless legs syndrome. Sleep Med Clin 10:227–233CrossRefPubMedGoogle Scholar
  68. 68.
    Argiropoulos B, Yung E, Humphries RK (2007) Unraveling the crucial roles of Meis1 in leukemogenesis and normal hematopoiesis. Genes Dev 21:2845–2849CrossRefPubMedGoogle Scholar
  69. 69.
    Azcoitia V, Aracil M, Martinez AC, Torres M (2005) The homeodomain protein Meis1 is essential for definitive hematopoiesis and vascular patterning in the mouse embryo. Dev Biol 280:307–320CrossRefPubMedGoogle Scholar
  70. 70.
    Minehata K, Kawahara A, Suzuki T (2008) meis1 regulates the development of endothelial cells in zebrafish. Biochem Biophys Res Commun 374:647–652CrossRefPubMedGoogle Scholar
  71. 71.
    Davidson S, Miller KA, Dowell A, Gildea A, Mackenzie A (2006) A remote and highly conserved enhancer supports amygdala specific expression of the gene encoding the anxiogenic neuropeptide substance-P. Mol Psychiatry 11(323):410CrossRefGoogle Scholar
  72. 72.
    Catoire H, Dion PA, Xiong L, Amari M, Gaudet R, Girard SL, Noreau A, Gaspar C, Turecki G, Montplaisir JY, Parker JA, Rouleau GA (2011) Restless legs syndrome-associated MEIS1 risk variant influences iron homeostasis. Ann Neurol 70:170–175CrossRefPubMedGoogle Scholar
  73. 73.
    Dinev D, Jordan BW, Neufeld B, Lee JD, Lindemann D, Rapp UR, Ludwig S (2001) Extracellular signal regulated kinase 5 (ERK5) is required for the differentiation of muscle cells. EMBO Rep 2:829–834CrossRefPubMedPubMedCentralGoogle Scholar
  74. 74.
    Cavanaugh JE, Jaumotte JD, Lakoski JM, Zigmond MJ (2006) Neuroprotective role of ERK1/2 and ERK5 in a dopaminergic cell line under basal conditions and in response to oxidative stress. J Neurosci Res 84:1367–1375CrossRefPubMedGoogle Scholar
  75. 75.
    Arndt S, Poser I, Moser M, Bosserhoff AK (2007) Fussel-15, a novel Ski/Sno homolog protein, antagonizes BMP signaling. Mol Cell Neurosci 34:603–611CrossRefPubMedGoogle Scholar
  76. 76.
    Pulido R, Krueger NX, Serra-Pages C, Saito H, Streuli M (1995) Molecular characterization of the human transmembrane protein-tyrosine phosphatase delta. Evidence for tissue-specific expression of alternative human transmembrane protein-tyrosine phosphatase delta isoforms. J Biol Chem 270:6722–6728CrossRefPubMedGoogle Scholar
  77. 77.
    O’Flaherty E, Kaye J (2003) TOX defines a conserved subfamily of HMG-box proteins. BMC Genom 4:13CrossRefGoogle Scholar
  78. 78.
    Dauvilliers Y, Winkelmann J (2013) Restless legs syndrome: update on pathogenesis. Curr Opin Pulm Med 19:594–600CrossRefPubMedGoogle Scholar
  79. 79.
    Wetter TC, Collado-Seidel V, Oertel H, Uhr M, Yassouridis A, Trenkwalder C (2002) Endocrine rhythms in patients with restless legs syndrome. J Neurol 249:146–151CrossRefPubMedGoogle Scholar
  80. 80.
    Garcia-Borreguero D, Larrosa O, Granizo JJ, de la Llave Y, Hening WA (2004) Circadian variation in neuroendocrine response to L-dopa in patients with restless legs syndrome. Sleep 27:669–673PubMedGoogle Scholar
  81. 81.
    Lee KA, Zaffke ME, Baratte-Beebe K (2001) Restless legs syndrome and sleep disturbance during pregnancy: the role of folate and iron. J Womens Health Gend-Based Med 10:335–341CrossRefPubMedGoogle Scholar
  82. 82.
    Dzaja A, Wehrle R, Lancel M, Pollmacher T (2009) Elevated estradiol plasma levels in women with restless legs during pregnancy. Sleep 32:169–174CrossRefPubMedPubMedCentralGoogle Scholar
  83. 83.
    Budhiraja P, Budhiraja R, Goodwin JL, Allen RP, Newman AB, Koo BB, Quan SF (2012) Incidence of restless legs syndrome and its correlates. J Clin Sleep Med 8:119–124PubMedPubMedCentralGoogle Scholar
  84. 84.
    Lattova Z, Keckeis M, Maurovich-Horvat E, Wetter TC, Wilde-Frenz J, Schuld A, Pollmacher T (2011) The stress hormone system in various sleep disorders. J Psychiatr Res 45:1223–1228PubMedGoogle Scholar
  85. 85.
    Hornyak M, Rupp A, Riemann D, Feige B, Berger M, Voderholzer U (2008) Low-dose hydrocortisone in the evening modulates symptom severity in restless legs syndrome. Neurology 70:1620–1622CrossRefPubMedGoogle Scholar
  86. 86.
    Koo BB, Feng P, Dostal J, Strohl KP (2008) Alpha-melanocyte stimulating hormone and adrenocorticotropic hormone: an alternative approach when thinking about restless legs syndrome? Mov Disord 23:1234–1242CrossRefPubMedGoogle Scholar
  87. 87.
    Walters AS, Ondo WG, Zhu W, Le W (2009) Does the endogenous opiate system play a role in the restless legs syndrome? A pilot post-mortem study. J Neurol Sci 279:62–65CrossRefPubMedGoogle Scholar
  88. 88.
    von Spiczak S, Whone AL, Hammers A, Asselin MC, Turkheimer F, Tings T, Happe S, Paulus W, Trenkwalder C, Brooks DJ (2005) The role of opioids in restless legs syndrome: an [11C]diprenorphine PET study. Brain 128:906–917CrossRefGoogle Scholar
  89. 89.
    Dutia R, Meece K, Dighe S, Kim AJ, Wardlaw SL (2012) Beta-endorphin antagonizes the effects of alpha-MSH on food intake and body weight. Endocrinology 153:4246–4255CrossRefPubMedPubMedCentralGoogle Scholar
  90. 90.
    Ukai M, Kameyama T (1984) Nonopiate effects of alpha-neo-endorphin on mouse behavior using multi-dimensional behavioral analyses. Peptides 5:129–131CrossRefPubMedGoogle Scholar
  91. 91.
    Williams DW Jr, Lipton JM, Giesecke AH Jr (1986) Influence of centrally administered peptides on ear withdrawal from heat in the rabbit. Peptides 7:1095–1100CrossRefPubMedGoogle Scholar
  92. 92.
    Kastin AJ, Schally AV, Kostrzewa RM (1980) Possible aminergic mediation of MSH release and of the CNS effects of MSH and MIF-I. Fed Proc 39:2931–2936PubMedGoogle Scholar
  93. 93.
    Sharp B, Ross R, Levin E, Sowers J (1982) Dopamine regulates canine plasma beta-endorphin-immunoreactivity levels. Endocrinology 110:1828–1830CrossRefPubMedGoogle Scholar

Copyright information

© Springer-Verlag Berlin Heidelberg 2017

Authors and Affiliations

  • Farhan H. Khan
    • 1
  • Caitlyn D. Ahlberg
    • 2
  • Christopher A. Chow
    • 1
  • Divya R. Shah
    • 1
  • Brian B. Koo
    • 1
    • 3
    Email author
  1. 1.Lippard Laboratory of Clinical Investigation, Division of Movement Disorders, Department of NeurologyYale University School of MedicineWest HavenUSA
  2. 2.Case Western Reserve University School of MedicineClevelandUSA
  3. 3.Connecticut Veterans Affairs Medical CenterWest HavenUSA

Personalised recommendations