An update on restless legs syndrome (Willis-Ekbom disease): Clinical features, pathogenesis and treatment

Current Opinion in Neurology

Volumn 27, Issue 4, 2014, Pages 493-501

  Garcia Borreguero, Diego ^a   Williams, Anne Marie ^a  

^a SLEEP RESEARCH INSTITUTE   (Spain)

Author keywords

diagnosis and clinical features; pathophysiology; restless legs syndrome (Willis Ekbom disease); treatment guidelines

Indexed keywords

DOPAMINE RECEPTOR STIMULATING AGENT; BTBD9 PROTEIN, HUMAN; HOMEODOMAIN PROTEIN; MYELOID ECOTROPIC VIRAL INTEGRATION SITE 1 PROTEIN; PROTEIN TYROSINE PHOSPHATASE; TRANSCRIPTION FACTOR; TUMOR PROTEIN;

ACTIMETRY; CARDIOVASCULAR RISK; CLINICAL ASSESSMENT; CLINICAL EVALUATION; CLINICAL FEATURE; DISEASE ASSOCIATION; DISEASE SEVERITY; DOPAMINERGIC ACTIVITY; DOPAMINERGIC SYSTEM; FUNCTIONAL MAGNETIC RESONANCE IMAGING; GENETIC POLYMORPHISM; GENETIC RISK; HUMAN; IMMOBILIZATION; INCIDENCE; LONG TERM CARE; MORBIDITY; MOTOR DYSFUNCTION; NEUROLOGIC DISEASE; PATHOGENESIS; PATHOPHYSIOLOGY; PERIODIC LIMB MOVEMENT DISORDER; POLYSOMNOGRAPHY; POSITRON EMISSION TOMOGRAPHY; PRACTICE GUIDELINE; QUALITY OF LIFE; RESTLESS LEGS SYNDROME; REVIEW; SLEEP DISORDER; SLEEP PATTERN; TREATMENT INDICATION; TREATMENT RESPONSE; UNPLEASANT SENSATION; WAKEFULNESS; GENETICS; SINGLE NUCLEOTIDE POLYMORPHISM;

DOPAMINE AGONISTS; HOMEODOMAIN PROTEINS; HUMANS; NEOPLASM PROTEINS; POLYMORPHISM, SINGLE NUCLEOTIDE; PROTEIN TYROSINE PHOSPHATASES; RESTLESS LEGS SYNDROME; TRANSCRIPTION FACTORS;

EID: 84904059720     PISSN: 13507540     EISSN: 14736551     Source Type: Journal    
DOI: 10.1097/WCO.0000000000000117     Document Type: Review

References (107)

1. Hening WA, Allen RP, Washburn M, et al. The four diagnostic criteria for Restless Legs Syndrome are unable to exclude confounding conditions (''mimics''). Sleep Med 2009; 10:976-981.
2. 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. (in press).
3. Patel N, Jankovic J, Hallett M. Sensory aspects of movement disorders. Lancet Neurol 2014; 13:100-112.
4. Allen RP, Stillman P, Myers AJ. Physician-diagnosed restless legs syndrome in a large sample of primary medical care patients in western Europe: prevalence and characteristics. Sleep Med 2010; 11:31-37.
5. Bassetti CL, Mauerhofer D, Gugger M, et al. Restless legs syndrome: a clinical study of 55 patients. Eur Neurol 2001; 45:67-74.
6. Winkelman JW, Finn L, Young T. Prevalence and correlates of restless legs syndrome symptoms in the Wisconsin Sleep Cohort. Sleep Med 2006; 7:545-552.
7. Benediktsdottir B, Janson C, Lindberg E, et al. Prevalence of restless legs syndrome among adults in Iceland and Sweden: lung function, comorbidity, ferritin, biomarkers and quality of life. Sleep Med 2010; 11:1043-1048.
8. Winkelman JW, Redline S, Baldwin CM, et al. Polysomnographic and healthrelated quality of life correlates of restless legs syndrome in the Sleep Heart Health Study. Sleep 2009; 32:772-778.
9. Saletu B, Anderer P, Saletu M, et al. EEG mapping, psychometric, and polysomnographic studies in restless legs syndrome (RLS) and periodic limb movement disorder (PLMD) patients as compared with normal controls. Sleep Med 2002; 3 (Suppl):S35-S42.
10. Kerr S, McKinon W, Bentley A. Descriptors of restless legs syndrome sensations. Sleep Med 2012; 13:409-413.
11. Karroum EG, Golmard JL, Leu-Semenescu S, Arnulf I. Sensations in restless legs syndrome. Sleep Med 2012; 13:402-408.
12. Karroum EG, Leu-Semenescu S, Arnulf I. Topography of the sensations in primary restless legs syndrome. J Neurol Sci 2012; 320:26-31.
13. Montplaisir J, Boucher S, Nicolas A, et al. Immobilization tests and periodic leg movements in sleep for the diagnosis of restless leg syndrome. Mov Disord 1998; 13:324-329.
14. Bombois S, Derambure P, Pasquier F, Monaca C. Sleep disorders in aging and dementia. J Nutr Health Aging 2010; 14:212-217.
15. Dauvilliers Y, Rompre S, Gagnon JF, et al. REM sleep characteristics in narcolepsy and REM sleep behavior disorder. Sleep 2007; 30:844-849.
16. Pedroso JL, Braga-Neto P, Felicio AC, et al. Sleep disorders in cerebellar ataxias. Arq Neuropsiquiatr 2011; 69:253-257.
17. Fulda S, Rusakova I, Ferri R, et al. P6. Leg movements during sleep in patients with obstructive sleep apnea. Clin Neurophysiol 2012; 123:e104.
18. Manconi M, Ferri R, Zucconi M, et al. Dissociation of periodic leg movements from arousals in restless legs syndrome. Ann Neurol 2012; 71:834-844.
19. Yumino D, Wang H, Floras JS, et al. Relation of periodic leg movements during sleep and mortality in patients with systolic heart failure. Am J Cardiol 2011; 107:447-451.
20. Koo BB, Blackwell T, Ancoli-Israel S, et al. Association of incident cardiovascular disease with periodic limb movements during sleep in older men: outcomes of sleep disorders in older men (MrOS) study. Circulation 2011; 124:1223-1231.
21. Walters AS, Rye DB. Evidence continues to mount on the relationship of restless legs syndrome/periodic limb movements in sleep to hypertension, cardiovascular disease, and stroke. Sleep 2010; 33:287.
22. Walters AS, LeBrocq C, Dhar A, et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med 2003; 4:121-132.
23. Allen R, Becker PM, Bogan R, et al. Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome. Sleep 2004; 27:907-914.
24. Fulda S, Wetter TC. Where dopamine meets opioids: a meta-analysis of the placebo effect in restless legs syndrome treatment studies. Brain 2008; 131:902-917.
25. Allen RP. Improving RLS diagnosis and severity assessment: polysomnography, actigraphy and RLS-sleep log. Sleep Med 2007; 8 (Suppl 2):S13-S18.
26. Tzonova D, Larrosa O, Calvo E, et al. Breakthrough symptoms during the daytime in patients with restless legs syndrome (Willis-Ekbom disease). Sleep Med 2012; 13:151-155.
27. Michaud M, Dumont M, Paquet J, et al. Circadian variation of the effects of immobility on symptoms of restless legs syndrome. Sleep 2005; 28:843-846.
28. Michaud M, Paquet J, Lavigne G, et al. Sleep laboratory diagnosis of restless legs syndrome. Eur Neurol 2002; 48:108-113.
29. Garcia-Borreguero D, Kohnen R, Boothby L, et al. Validation of the multiple suggested immobilization test (m-SIT): a test for the assessment of severity of restless legs syndrome (Willis-Ekbom disease). Sleep 2013; 36:1101-1109.
30. Allen RP, Walters AS, Montplaisir J, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005; 165:1286-1292.
31. Earley CJ, Heckler D, Allen RP. Repeated IV doses of iron provides effective supplemental treatment of restless legs syndrome. Sleep Med 2005; 6: 301-305.
32. Nomura T, Inoue Y, KusumiM, et al. Prevalence of restless legs syndrome in a rural community in Japan. Mov Disord 2008; 23:2363-2369.
33. Chen NH, Chuang LP, Yang CT, et al. The prevalence of restless legs syndrome in Taiwanese adults. Psychiatry Clin Neurosci 2010; 64:170-178.
34. Cho SJ, Hong JP, Hahm BJ, et al. Restless legs syndrome in a community sample of Korean adults: prevalence, impact on quality of life, and association with DSM-IV psychiatric disorders. Sleep 2009; 32:1069-1076.
35. Castillo PR, Kaplan J, Lin SC, et al. Prevalence of restless legs syndrome among native South Americans residing in coastal and mountainous areas. Mayo Clin Proc 2006; 81:1345-1347.
36. Szentkiralyi A, Fendrich K, Hoffmann W, et al. Incidence of restless legs syndrome in two population-based cohort studies in Germany. Sleep Med 2011; 12:815-820.
37. Kagimura T, Nomura T, Kusumi M, et al. Prospective survey on the natural course of restless legs syndrome over two years in a closed cohort. Sleep Med 2011; 12:821-826.
38. Budhiraja P, Budhiraja R, Goodwin JL, et al. Incidence of restless legs syndrome and its correlates. J Clin Sleep Med 2012; 8:119-124.
39. Manconi M, Ulfberg J, Berger K, et al. When gender matters: restless legs syndrome. Report of the ''RLS and woman'' workshop endorsed by the European RLS Study Group. Sleep Med Rev 2012; 16:297-307.
40. Cesnik E, Casetta I, Turri M, et al. Transient RLS during pregnancy is a risk factor for the chronic idiopathic form. Neurology 2010; 75:2117-2120.
41. Zhang C, Li Y, Malhotra A, et al. Restless legs syndrome status as a predictor for lower physical function. Neurology 2014; 82:1212-1218.
42. Allen RP, Bharmal M, Calloway M. Prevalence and disease burden of primary restless legs syndrome: results of a general population survey in the United States. Mov Disord 2011; 26:114-120.
43. Lee HB, Ramsey CM, Spira AP, et al. Comparison of cognitive functioning among individuals with treated restless legs syndrome (RLS), untreated RLS, and no RLS. J Neuropsychiatry Clin Neurosci 2014; 26:87-91.
44. Szentkiralyi A, Volzke H, Hoffmann W, et al. The relationship between depressive symptoms and restless legs syndrome in two prospective cohort studies. Psychosom Med 2013; 75:359-365.
45. Salas RE, Kwan AB. The real burden of restless legs syndrome: clinical and economic outcomes. Am J Manag Care 2012; 18:S207-S212.
46. Meyers J, Candrilli S, Allen R, et al. Healthcare resource utilization and costs associated with restless legs syndrome among managed care enrollees treated with dopamine agonists. Manag Care 2012; 21:44-51.
47. Dodel R, Happe S, Peglau I, et al. Health economic burden of patients with restless legs syndrome in a German ambulatory setting. Pharmacoeconomics 2010; 28:381-393.
48. Reinhold T, Muller-Riemenschneider F, Willich SN, Bruggenjurgen B. Economic and human costs of restless legs syndrome. Pharmacoeconomics 2009; 27:267-279.
49. Phillips B, Hening W, Britz P, Mannino D. Prevalence and correlates of restless legs syndrome: results from the 2005 National Sleep Foundation Poll. Chest 2006; 129:76-80.
50. Giannini G, Zanigni S, Melotti R, et al. Association between restless legs syndrome and hypertension: a preliminary population-based study in South Tyrol, Italy. Eur J Neurol 2014; 21:72-78.
51. Winter AC, Schurks M, Glynn RJ, et al. Restless legs syndrome and risk of incident cardiovascular disease in women and men: prospective cohort study. BMJ Open 2012; 2:e000866.
52. Mirza M, Shen WK, Sofi A, et al. Frequent periodic leg movement during sleep is associated with left ventricular hypertrophy and adverse cardiovascular outcomes. J Am Soc Echocardiogr 2013; 26:783-790.
53. Giannaki CD, Zigoulis P, Karatzaferi C, 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; 9:147-153.
54. Pennestri MH, Montplaisir J, Fradette L, et al. Blood pressure changes associated with periodic leg movements during sleep in healthy subjects. Sleep Med 2013; 14:555-561.
55. Sas AM, Di Fonzo A, Bakker SL, et al. Autosomal dominant restless legs syndrome maps to chromosome 20p13 (RLS-5) in a Dutch kindred. Mov Disord 2010; 25:1715-1722.
56. Xiong L, Jang K, Montplaisir J, et al. Canadian restless legs syndrome twin study. Neurology 2007; 68:1631-1633.
57. Schormair B, Kemlink D, Roeske D, et al. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat Genet 2008; 40:946-948.
58. 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; 39:1000-1006.
59. Stefansson H, Rye DB, Hicks A, et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007; 357:639-647.
60. Berger K, von Eckardstein A, Trenkwalder C, et al. Iron metabolism and the risk of restless legs syndrome in an elderly general population-the MEMOStudy. J Neurol 2002; 249:1195-1199.
61. Hogl B, Kiechl S, Willeit J, et al. Restless legs syndrome: a community-based study of prevalence, severity, and risk factors. Neurology 2005; 64:1920-1924.
62. Allen RP, Auerbach S, Bahrain H, et al. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 2013; 88:261-264.
63. 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; 24:592-603.
64. Winkelmann J, Schadrack J, Wetter TC, et al. Opioid and dopamine antagonist drug challenges in untreated restless legs syndrome patients. Sleep Med 2001; 2:57-61.
65. Paulus W, Trenkwalder C. Less is more: pathophysiology of dopaminergictherapy-related augmentation in restless legs syndrome. Lancet Neurol 2006; 5:878-886.
66. Oboshi Y, Ouchi Y, Yagi S, et al. In vivo mesolimbic D2/3 receptor binding predicts posttherapeutic clinical responses in restless legs syndrome: a positron emission tomography study. J Cereb Blood Flow Metab 2012; 32:654-662.
67. Rizzo G, Tonon C, Testa C, et al. Abnormal medial thalamic metabolism in patients with idiopathic restless legs syndrome. Brain 2012; 135:3712-3720.
68. Ku J, Cho YW, Lee YS, et al. Functional connectivity alternation of the thalamus in restless legs syndrome patients during the asymptomatic period: a resting-state connectivity study using functional magnetic resonance imaging. Sleep Med 2014; 15:289-294.
69. Earley CJ, Connor J, Garcia-Borreguero D, et al. Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom disease). Sleep Med 2014. (in press).
70. Oexle K, Schormair B, Ried JS, et al. Dilution of candidates: the case of ironrelated genes in restless legs syndrome. Eur J Hum Genet 2013; 21:410-414.
71. Freeman A, Pranski E, Miller RD, et al. Sleep fragmentation and motor restlessness in a Drosophila model of restless legs syndrome. Curr Biol 2012; 22:1142-1148.
72. 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; 304:93-101.
73. 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; 28:1886-1890.
74. Jellen LC, Lu L,Wang X, et al. Iron deficiency alters expression of dopaminerelated genes in the ventralmidbrain inmice. Neuroscience 2013; 252:13-23.
75. 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; 14:675-684.
76. Scholz H, Trenkwalder C, Kohnen R, et al. Dopamine agonists for restless legs syndrome. Cochrane Database Syst Rev 2011; CD006009.
77. Hornyak M, Scholz H, Kohnen R, et al. What treatment works best for restless legs syndrome? Meta-analyses of dopaminergic and nondopaminergic medications. Sleep Med Rev 2014; 18:153-164.
78. Garcia-Borreguero D, Patrick J, DuBrava S, et al. Pregabalin versus pramipexole: effects on sleep disturbance in restless legs syndrome. Sleep 2014; 37:635-643.
79. Allen RP, Chen C, Garcia-Borreguero D, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med 2014; 370:621-631.
80. Allen R, Chen C, Soaita A, et al. A randomized, double-blind, 6-week, doseranging study of pregabalin in patients with restless legs syndrome. Sleep Med 2010; 11:512-519.
81. Trenkwalder C, Benes H, Grote L, et al. Prolonged release oxycodonenaloxone 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; 12:1141-1150.
82. Garcia-Borreguero D, Ferini-Strambi L,Kohnen R, 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; 19:1385-1396.
83. Trenkwalder C, Hening WA, Montagna P, et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov Disord 2008; 23:2267-2302.
84. Zanettini R, Antonini A, Gatto G, et al. Valvular heart disease and the use of dopamine agonists for Parkinson's disease. N Engl J Med 2007; 356:39-46.
85. Moller JC, Korner Y, Cassel W, et al. Sudden onset of sleep and dopaminergic therapy in patients with restless legs syndrome. SleepMed 2006; 7:333-339.
86. Trotti LM, Bhadriraju S, Becker LA. Iron for restless legs syndrome. Cochrane Database Syst Rev 2012; 5:CD007834.
87. Ondo WG, Jankovic J, Simpson R, Jimenez-Shahed J. Globus pallidus deep brain stimulation for refractory idiopathic restless legs syndrome. Sleep Med 2012; 13:1202-1204.
88. 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 multicenter study. J Neurol 2010; 257:230-237.
89. 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; 12:440-444.
90. Garcia-Borreguero D, Hogl B, Ferini-Strambi L, 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; 27:277-283.
91. Oertel W, Trenkwalder C, Benes H, et al. Long-term safety and efficacy of rotigotine transdermal patch for moderate-to-severe idiopathic restless legs syndrome: a 5-year open-label extension study. Lancet Neurol 2011; 10:710-720.
92. Trenkwalder C, Benes H, Grote L, et al. Cabergoline compared to levodopa in the treatment of patients with severe restless legs syndrome: results from a multicenter, randomized, active controlled trial. Mov Disord 2007; 22:696-703.
93. Earley CJ, Allen RP. Restless legs syndrome augmentation associated with tramadol. Sleep Med 2006; 7:592-593.
94. 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; 4:101-119.
95. Garcia-Borreguero D, Allen RP, Kohnen R, et al. Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute. Sleep Med 2007; 8:520-530.
96. Garcia-Borreguero D, Allen R, Kohnen R, et al. Loss of response during longterm treatment of restless legs syndrome: guidelines approved by the International Restless Legs Syndrome Study Group for use in clinical trials. Sleep Med 2010; 11:956-957.
97. Bayard S, Yu H, Langenier MC, et al. Decision making in restless legs syndrome. Mov Disord 2010; 25:2634-2640.
98. Cornelius JR, Tippmann-Peikert M, Slocumb NL, et al. Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: a case-control study. Sleep 2010; 33:81-87.
99. Dang D, Cunnington D, Swieca J. The emergence of devastating impulse control disorders during dopamine agonist therapy of the restless legs syndrome. Clin Neuropharmacol 2011; 34:66-70.
100. Earley CJ, Silber MH. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med 2010; 11:807-815.
101. Gahr M, Connemann BJ, Schonfeldt-Lecuona CJ. [Pathological gambling induced by dopamine agonists]. Fortschr Neurol Psychiatr 2011; 79:470-474.
102. Kolla BP, Mansukhani MP, Barraza R, Bostwick JM. Impact of dopamine agonists on compulsive behaviors: a case series of pramipexole-induced pathological gambling. Psychosomatics 2010; 51:271-273.
103. Leu-Semenescu S, Karroum E, Brion A, et al. Dopamine dysregulation syndrome in a patient with restless legs syndrome. Sleep Med 2009; 10:494-496.
104. Pourcher E, Remillard S, Cohen H. Compulsive habits in restless legs syndrome patients under dopaminergic treatment. J Neurol Sci 2010; 290: 52-56.
105. Salas RE, Allen RP, Earley CJ, Gamaldo CE. A case of compulsive behaviors observed in a restless legs syndrome patient treated with a dopamine agonist. Sleep 2009; 32:587-588.
106. Schreglmann SR, Gantenbein AR, Eisele G, Baumann CR. Transdermal rotigotine causes impulse control disorders in patients with restless legs syndrome. Parkinsonism Relat Disord 2012; 18:207-209.
107. Voon V, Schoerling A, Wenzel S, et al. Frequency of impulse control behaviours associated with dopaminergic therapy in restless legs syndrome. BMC Neurol 2011; 11:117.