• 1
    Ekbom KA. Restless legs. Acta Med Scand 1945;158:1123.
  • 2
    Nordlander NB. Therapy in restless legs. Acta Med Scand 1953;145:453457.
  • 3
    Hentze MW, Muckenthaler MU, Galy B, Camaschella C. Two to tango: regulation of Mammalian iron metabolism. Cell 2010;142:2438. PubMed PMID: 20603012.
  • 4
    Andrews NC. Disorders of iron metabolism. N Engl J Med 1999;341:19861995. PubMed PMID: 10607817.
  • 5
    Conrad ME, Umbreit JN. Disorders of iron metabolism. N Engl J Med 2000;342:12931294. PubMed PMID: 10787338.
  • 6
    McKie AT, Barrow D, Latunde-Dada GO, et al. An iron-regulated ferric reductase associated with the absorption of dietary iron. Science 2001;291:17551759. PubMed PMID: 11230685.
  • 7
    Conrad ME, Umbreit JN, Moore EG. Iron absorption and transport. Am J Med Sci 1999;318:213229. PubMed PMID: 10522550.
  • 8
    Ganz T. Hepcidin, a key regulator of iron metabolism and mediator of anemia of inflammation. Blood 2003;102:783788. PubMed PMID: 12663437.
  • 9
    Uglane MT, Westad S, Backe B. Restless legs syndrome in pregnancy is a frequent disorder with a good prognosis. Acta Obstet Gynecol Scand 2011;90:10461048. PubMed PMID: 21504414.
  • 10
    Neau JP, Marion P, Mathis S, et al. Restless legs syndrome and pregnancy: follow-up of pregnant women before and after delivery. Eur Neurol 2010;64:361366. PubMed PMID: 21088424.
  • 11
    Manconi M, Govoni V, De Vito A, et al. Restless legs syndrome and pregnancy. Neurology 2004;63:10651069. PubMed PMID: 15452299.
  • 12
    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;88:261264. PubMed PMID: 23494945.
  • 13
    Bryant BJ, Yau YY, Arceo SM, Hopkins JA, Leitman SF. Ascertainment of iron deficiency and depletion in blood donors through screening questions for pica and restless legs syndrome. Transfusion 2013;53:16371644. Pubmed Central PMCID: 3691288.
  • 14
    Spencer BR, Kleinman S, Wright DJ, et al. Restless legs syndrome, pica, and iron status in blood donors. Transfusion 2013;53:16451652. PubMed PMID: 23763445.
  • 15
    Silber MH, Richardson JW. Multiple blood donations associated with iron deficiency in patients with restless legs syndrome. Mayo Clin Proc 2003;78:5254. PubMed PMID: 12528877.
  • 16
    Kryger MH, Shepertycky M, Foerster J, Manfreda J. Sleep disorders in repeat blood donors. Sleep 2003;26:625626. PubMed PMID: 12938819.
  • 17
    Ulfberg J, Nystrom B. Restless legs syndrome in blood donors. Sleep Med 2004;5:115118. PubMed PMID: 15033129.
  • 18
    Arunthari V, Kaplan J, Fredrickson PA, Lin SC, Castillo PR, Heckman MG. Prevalence of restless legs syndrome in blood donors. Movement disorders: official journal of the Movement Disorder Society. 2010;25:14511455. PubMed PMID: 20629149.
  • 19
    Burchell BJ, Allen RP, Miller JK, Hening WA, Earley CJ. RLS and blood donation. Sleep Med 2009;10:844849. PubMed PMID: 19157975.
  • 20
    Gamaldo CE, Benbrook AR, Allen RP, Scott JA, Henning WA, Earley CJ. Childhood and adult factors associated with restless legs syndrome (RLS) diagnosis. Sleep Med 2007;8:716722. PubMed PMID: 17512781.
  • 21
    Tunc T, Karadag YS, Dogulu F, Inan LE. Predisposing factors of restless legs syndrome in pregnancy. Movement disorders: official journal of the Movement Disorder Society. 2007;22:627631. PubMed PMID: 17285614.
  • 22
    Manchanda S, Davies CR, Picchietti D. Celiac disease as a possible cause for low serum ferritin in patients with restless legs syndrome. Sleep Med 2009;10:763765. PubMed PMID: 19138881.
  • 23
    Moccia M, Pellecchia MT, Erro R, et al. Restless legs syndrome is a common feature of adult celiac disease. Mov Disord 2010;25:877881. PubMed PMID: 20461805.
  • 24
    Weinstock LB, Walters AS, Mullin GE, Duntley SP. Celiac disease is associated with restless legs syndrome. Dig Dis Sci 2010;55:16671673. PubMed PMID: 19731029.
  • 25
    Weinstock LB, Bosworth BP, Scherl EJ, et al. Crohn's disease is associated with restless legs syndrome. Inflamm Bowel Dis 2010;16:275279. PubMed PMID: 19575360.
  • 26
    Smith HS, Dhingra R, Ryckewaert L, Bonner D. Proton pump inhibitors and pain. Pain Physician 2009;12:10131023. PubMed PMID: 19935988.
  • 27
    Cortese S, Konofal E, Lecendreux M, Mouren MC, Bernardina BD. Restless legs syndrome triggered by heart surgery. Pediatr Neurol 2006;35:223226. PubMed PMID: 16939866.
  • 28
    Tobiasson M, Alyass B, Soderlund S, Birgegard G. High prevalence of restless legs syndrome among patients with polycytemia vera treated with venesectio. Med Oncol 2010;27:105107. PubMed PMID: 19225914.
  • 29
    Curgunlu A, Doventas A, Karadeniz D, et al. Prevalence and characteristics of restless legs syndrome (RLS) in the elderly and the relation of serum ferritin levels with disease severity: hospital-based study from Istanbul, Turkey. Arch Gerontol Geriatr 2012;55:7376. PubMed PMID: 21722973.
  • 30
    Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and the restless legs syndrome. Sleep 1998;21:371377. PubMed PMID: 9646381.
  • 31
    O'Keeffe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age Ageing 1994;23:200203. PubMed PMID: 8085504.
  • 32
    Berger K, von Eckardstein A, Trenkwalder C, Rothdach A, Junker R, Weiland SK. Iron metabolism and the risk of restless legs syndrome in an elderly general population–the MEMO-Study. J Neurol 2002;249:11951199. PubMed PMID: 12242538.
  • 33
    Kim KW, Yoon IY, Chung S, et al. Prevalence, comorbidities and risk factors of restless legs syndrome in the Korean elderly population - results from the Korean Longitudinal Study on Health and Aging. J Sleep Res 2010;19(1 Pt 1):8792. PubMed PMID: 19686313.
  • 34
    Hogl B, Kiechl S, Willeit J, et al. Restless legs syndrome: a community-based study of prevalence, severity, and risk factors. Neurology 2005;64:19201924. PubMed PMID: 15955944.
  • 35
    Earley CJ, Ponnuru P, Wang X, et al. Altered iron metabolism in lymphocytes from subjects with restless legs syndrome. Sleep 2008;31:847852. PubMed PMID: 18548829. Pubmed Central PMCID: 2442411.
  • 36
    Dean T, Jr., Allen RP, O'Donnell CP, Earley CJ. The effects of dietary iron deprivation on murine circadian sleep architecture. Sleep Med 2006;7:634640. PubMed PMID: 17098470.
  • 37
    Dowling P, Klinker F, Stadelmann C, Hasan K, Paulus W, Liebetanz D. Dopamine D3 receptor specifically modulates motor and sensory symptoms in iron-deficient mice. J Neurosci 2011;31:7077. PubMed PMID: 21209191.
  • 38
    Sun YM, Hoang T, Neubauer JA, Walters AS. Opioids protect against substantia nigra cell degeneration under conditions of iron deprivation: a mechanism of possible relevance to the Restless Legs Syndrome (RLS) and Parkinson's disease. J Neurol Sci 2011;304:93101. PubMed PMID: 21376342.
  • 39
    Bianco LE, Unger EL, Earley CJ, Beard JL. Iron deficiency alters the day-night variation in monoamine levels in mice. Chronobiol Int 2009;26:447463. PubMed PMID: 19360489.
  • 40
    Unger EL, Earley CJ, Beard JL. Diurnal cycle influences peripheral and brain iron levels in mice. J Appl Physiol 2009;106:187193. PubMed PMID: 18988764. Pubmed Central PMCID: 2636939.
  • 41
    Dowling P, Klinker F, Amaya F, Paulus W, Liebetanz D. Iron-deficiency sensitizes mice to acute pain stimuli and formalin-induced nociception. J Nutr 2009;139:20872092. PubMed PMID: 19776188.
  • 42
    Zhao H, Zhu W, Pan T, 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;85:10651076. PubMed PMID: 17342757.
  • 43
    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;66:383388. PubMed PMID: 17483695.
  • 44
    Luo F, Li C, Ondo WG, Xu P, Xie W, Le W. The long-term effects of the dopamine agonist pramipexole in a proposed restless legs syndrome animal model. Sleep Med 2011;12:4146. PubMed PMID: 21044864.
  • 45
    Wang J, O'Reilly B, Venkataraman R, Mysliwiec V, Mysliwiec A. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: a randomized, double-blind, placebo-controlled study. Sleep Med 2009;10:973975. PubMed PMID: 19230757.
  • 46
    Xiong L, Dion P, Montplaisir J, et al. Molecular genetic studies of DMT1 on 12q in French-Canadian restless legs syndrome patients and families. Am J Med Genet B Neuropsychiatr Genet 2007;144B:911917. PubMed PMID: 17510944.
  • 47
    Castiglioni E, Finazzi D, Goldwurm S, et al. Sequence variations in mitochondrial ferritin: distribution in healthy controls and different types of patients. Genet Test Mol Biomarkers 2010;14:793796. PubMed PMID: 20939738.
  • 48
    Oexle K, Schormair B, Ried JS, et al. Dilution of candidates: the case of iron-related genes in restless legs syndrome. Eur J Human Genet 2013;21:410414. PubMed PMID: 22929029. Pubmed Central PMCID: 3598324.
  • 49
    Schormair B, Kemlink D, Roeske D, et al. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet 2008;40:946948. PubMed PMID: 18660810.
  • 50
    Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007;357:639647. PubMed PMID: 17634447
  • 51
    Winkelmann J, Czamara D, Schormair B, et al. Genome-wide association study identifies novel restless legs syndrome susceptibility loci on 2p14 and 16q12.1. PLoS Genet 2011;7:e1002171. PubMed PMID: 21779176. Pubmed Central PMCID: 3136436.
  • 52
    Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet 2007;39:10001006. PubMed PMID: 17637780.
  • 53
    McLaren CE, Garner CP, Constantine CC, et al. Genome-wide association study identifies genetic loci associated with iron deficiency. PLoS ONE 2011;6:e17390. PubMed PMID: 21483845. Pubmed Central PMCID: 3069025.
  • 54
    Oexle K, Ried JS, Hicks AA, et al. Novel association to the proprotein convertase PCSK7 gene locus revealed by analysing soluble transferrin receptor (sTfR) levels. Hum Mol Genet 2011;20:10421047. PubMed PMID: 21149283. Pubmed Central PMCID: 3033185.
  • 55
    Benyamin B, Ferreira MA, Willemsen G, et al. Common variants in TMPRSS6 are associated with iron status and erythrocyte volume. Nat Genet 2009;41:11731175. PubMed PMID: 19820699. Pubmed Central PMCID: 3135421.
  • 56
    Benyamin B, McRae AF, Zhu G, et al. Variants in TF and HFE explain approximately 40% of genetic variation in serum-transferrin levels. Am J Hum Genet 2009;84:6065. PubMed PMID: 19084217. Pubmed Central PMCID: 2668053.
  • 57
    Tanaka T, Roy CN, Yao W, et al. A genome-wide association analysis of serum iron concentrations. Blood 2010;115:9496. PubMed PMID: 19880490. Pubmed Central PMCID: 2803694.
  • 58
    Pichler I, Minelli C, Sanna S, et al. Identification of a common variant in the TFR2 gene implicated in the physiological regulation of serum iron levels. Hum Mol Genet 2011;20:12321240. PubMed PMID: 21208937. Pubmed Central PMCID: 3043660.
  • 59
    Catoire H, Dion PA, Xiong L, et al. Restless legs syndrome-associated MEIS1 risk variant influences iron homeostasis. Ann Neurol 2011;70:170175. PubMed PMID: 21710629.
  • 60
    Sorensen E, Grau K, Berg T, et al. A genetic risk factor for low serum ferritin levels in Danish blood donors. Transfusion 2012;52:25852589. PubMed PMID: 22486183.
  • 61
    DeAndrade MP, Johnson RL, Jr., Unger EL, et al. Motor restlessness, sleep disturbances, thermal sensory alterations and elevated serum iron levels in Btbd9 mutant mice. Hum Mol Genet 2012;21:39843992. PubMed PMID: 22678064. Pubmed Central PMCID: 3428151.
  • 62
    Freeman A, Pranski E, Miller RD, et al. Sleep fragmentation and motor restlessness in a Drosophila model of Restless Legs Syndrome. Curr Biol 2012;22:11421148. PubMed PMID: 22658601. Pubmed Central PMCID: 3381864.
  • 63
    Knake S, Heverhagen JT, Menzler K, Keil B, Oertel WH, Stiasny-Kolster K. Normal regional brain iron concentration in restless legs syndrome measured by MRI. Nat Sci Sleep 2010;2:1922. PubMed PMID: 23616694. Pubmed Central PMCID: 3630928.
  • 64
    Allen RP, Barker PB, Wehrl F, Song HK, Earley CJ. MRI measurement of brain iron in patients with restless legs syndrome. Neurology. 2001;56:263265. PubMed PMID: 11160969.
  • 65
    Earley CJ, B Barker P, Horska A, Allen RP. MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome. Sleep Med 2006;7:45861. PubMed PMID: 16740411.
  • 66
    Haba-Rubio J, Staner L, Petiau C, Erb G, Schunck T, Macher JP. Restless legs syndrome and low brain iron levels in patients with haemochromatosis. J Neurol Neurosurg Psychiatry 2005;76:10091010. PubMed PMID: 15965214. Pubmed Central PMCID: 1739708.
  • 67
    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;71:911916. PubMed PMID: 18794493.
  • 68
    Margariti PN, Astrakas LG, Tsouli SG, Hadjigeorgiou GM, Konitsiotis S, Argyropoulou MI. Investigation of unmedicated early onset restless legs syndrome by voxel-based morphometry, T2 relaxometry, and functional MR imaging during the night-time hours. AJNR Am J Neuroradiol 2012;33:667672. PubMed PMID: 22173758.
  • 69
    Godau J, Wevers AK, Gaenslen A, et al. Sonographic abnormalities of brainstem structures in restless legs syndrome. Sleep Med 2008;9:782789. PubMed PMID: 18024170.
  • 70
    Rizzo G, Manners D, Testa C, et al. Low brain iron content in idiopathic restless legs syndrome patients detected by phase imaging. Mov Disord 2013;28:18861890 PubMed PMID: 23780623.
  • 71
    Schmidauer C, Sojer M, Seppi K, et al. Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome. Ann Neurol 2005;58:630634. PubMed PMID: 16037973.
  • 72
    Godau J, Schweitzer KJ, Liepelt I, Gerloff C, Berg D. Substantia nigra hypoechogenicity: definition and findings in restless legs syndrome. Mov Disord 2007;22:187192. PubMed PMID: 17133515.
  • 73
    Pedroso JL, Bor-Seng-Shu E, Felicio AC, et al. Severity of restless legs syndrome is inversely correlated with echogenicity of the substantia nigra in different neurodegenerative movement disorders. a preliminary observation. J Neurol Sci 2012;319:5962. PubMed PMID: 22632781.
  • 74
    Kruer MC, Boddaert N, Schneider SA, et al. Neuroimaging features of neurodegeneration with brain iron accumulation. AJNR Am J Neuroradiol 2012;33:407414. PubMed PMID: 21920862.
  • 75
    Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology 2003;61:304309. PubMed PMID: 12913188.
  • 76
    Connor JR, Wang XS, Patton SM, et al. Decreased transferrin receptor expression by neuromelanin cells in restless legs syndrome. Neurology 2004;62:15631567. PubMed PMID: 15136682.
  • 77
    Clardy SL, Wang X, Boyer PJ, Earley CJ, Allen RP, Connor JR. Is ferroportin-hepcidin signaling altered in restless legs syndrome? J Neurol Sci 2006;247:173179. PubMed PMID: 16759669.
  • 78
    Snyder AM, Wang X, Patton SM, et al. Mitochondrial ferritin in the substantia nigra in restless legs syndrome. J Neuropathol Exp Neurol 2009;68:11931199. PubMed PMID: 19816198. Pubmed Central PMCID: 3024883.
  • 79
    Connor JR, Ponnuru P, Lee BY, et al. Postmortem and imaging based analyses reveal CNS decreased myelination in restless legs syndrome. Sleep Med 2011;12:614619. PubMed PMID: 21570342. Pubmed Central PMCID: 3110510.
  • 80
    Patton SM, Ponnuru P, Snyder AM, Podskalny GD, Connor JR. Hypoxia-inducible factor pathway activation in restless legs syndrome patients. Eur J Neurol 2011;18:13291335. PubMed PMID: 21985026.
  • 81
    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;54:16981700. PubMed PMID: 10762522.
  • 82
    Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J. CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res 2005;14:4347. PubMed PMID: 15743333.
  • 83
    Earley CJ, Heckler D, Allen RP. Repeated IV doses of iron provides effective supplemental treatment of restless legs syndrome. Sleep Med 2005;6:301305. PubMed PMID: 15978514.
  • 84
    Davis BJ, Rajput A, Rajput ML, Aul EA, Eichhorn GR. A randomized, double-blind placebo-controlled trial of iron in restless legs syndrome. Eur Neurol 2000;43:7075. PubMed PMID: 10686463.
  • 85
    Sloand JA, Shelly MA, Feigin A, Bernstein P, Monk RD. A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Am J Kidney Dis 2004;43:663670. PubMed PMID: 15042543.
  • 86
    Ondo WG. Intravenous iron dextran for severe refractory restless legs syndrome. Sleep Med 2010;11:494496. PubMed PMID: 20371212.
  • 87
    Cho YW, Allen RP, Earley CJ. Lower molecular weight intravenous iron dextran for restless legs syndrome. Sleep Med 2013;14:274277. PubMed PMID: 23333678.
  • 88
    Earley CJ, Heckler D, Allen RP. The treatment of restless legs syndrome with intravenous iron dextran. Sleep Med 2004;5:231235. PubMed PMID: 15165528.
  • 89
    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;10:206211. PubMed PMID: 18280205. Pubmed Central PMCID: 2703581.
  • 90
    Grote L, Leissner L, Hedner J, Ulfberg J. A randomized, double-blind, placebo controlled, multi-center study of intravenous iron sucrose and placebo in the treatment of restless legs syndrome. Mov Disord 2009;24:14451452. PubMed PMID: 19489063.
  • 91
    Allen RP, Adler CH, Du W, Butcher A, Bregman DB, Earley CJ. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred, placebo-controlled preliminary clinical trial. Sleep Med 2011;12:906913. PubMed PMID: 21978726.
  • 92
    Hornyak M, Scholz H, Kiemen A, Kassubek J. Investigating the response to intravenous iron in restless legs syndrome: an observational study. Sleep Med 2012;13:732735. PubMed PMID: 22503006.
  • 93
    Birgegard G, Schneider K, Ulfberg J. High incidence of iron depletion and restless leg syndrome (RLS) in regular blood donors: intravenous iron sucrose substitution more effective than oral iron. Vox Sang 2010;99:354361. PubMed PMID: 20598107.
  • 94
    Trotti LM, Bhadriraju S, Becker LA. Iron for restless legs syndrome. Cochrane Database Syst Rev. 2012;5:CD007834. PubMed PMID: 22592724.
  • 95
    Trenkwalder C, Hogl B, Benes H, Kohnen R. Augmentation in restless legs syndrome is associated with low ferritin. Sleep Med 2008;9:572574. PubMed PMID: 17921065.
  • 96
    Frauscher B, Gschliesser V, Brandauer E, et al. The severity range of restless legs syndrome (RLS) and augmentation in a prospective patient cohort: association with ferritin levels. Sleep Med 2009;10:611615. PubMed PMID: 19200780.
  • 97
    Hogl B, Garcia-Borreguero D, Kohnen R, 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;257:230237. PubMed PMID: 19756826. Pubmed Central PMCID: 3085743.
  • 98
    Spieler D, Kaffe M, Knauf F, et al. Restless Legs Syndrome-associated intronic common variant in Meis1 alters enhancer function in the developing telencephalon. Genome Res 2014;24:592603. PubMed PMID: 24642863.