Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

Restless legs syndrome: pathophysiology, clinical presentation and management

Nature Reviews Neurology volume 6, pages 337–346 (2010)Cite this article

Subjects

Abstract

Restless legs syndrome (RLS) is a somatosensory network disorder that is clinically diagnosed according to four main criteria: an urge to move the legs, usually associated with unpleasant leg sensations; induction or exacerbation of symptoms by rest; symptom relief on activity; and diurnal fluctuations in symptoms with worsening in the evening and at night. Genetic variants in four chromosomal regions have been identified that increase the risk of RLS. In addition, various different lesions, ranging from peripheral neuropathies to spinal cord lesions or alterations of brain metabolism, are implicated in RLS. In most cases, sleep disorders with frequent sleep fragmentation and characteristic periodic limb movements during sleep can be identified during a polysomnographic recording. The first-line drugs for RLS are dopaminergic agents, which are effective in low to moderate doses. Alternative or additional treatments include opioids and anticonvulsants. Augmentation—paradoxical worsening of symptoms by dopaminergic treatment—is the main problem encountered in difficult-to-treat patients. Iron deficiency must be identified and treated by supplementation, both to improve RLS symptoms and to potentially lower the risk of augmentation. Here, we review the latest studies pertaining to the pathophysiology, clinical presentation and management of RLS.

Key Points

  • Restless legs syndrome (RLS) is a sleep–wake disorder, the key feature of which is an urge to move, mostly in the legs; the symptoms follow a circadian pattern

  • The key role of brain iron deficiency in both idiopathic and secondary RLS makes identification of patients with low serum ferritin levels essential

  • Whole genome association studies in patients with RLS compared with controls have identified four variants associated with an elevated risk of developing RLS symptoms

  • Whenever possible, any causes of secondary RLS associated with other comorbidities must be identified and treated

  • Three nonergot dopamine agonists, ropinirole, pramipexole and rotigotine, are licensed for the treatment of RLS in different countries

  • To help prevent augmentation—paradoxical worsening of RLS symptoms after initially successful treatment with dopaminergic agents—doses should be kept within the recommended ranges

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Nervous system regions involved in RLS.

Similar content being viewed by others

References

  1. Trenkwalder, C. & Paulus, W. Why do restless legs occur at rest?—pathophysiology of neuronal structures in RLS. Neurophysiology of RLS (part 2). Clin. Neurophysiol. 115, 1975–1988 (2004).

    Article  CAS  PubMed  Google Scholar 

  2. Allen, R. P. 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. 4, 101–119 (2003).

    Article  PubMed  Google Scholar 

  3. Walters, A. S. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov. Disord. 10, 634–642 (1995).

    Article  CAS  PubMed  Google Scholar 

  4. Hening, W. & Trenkwalder, C. Restless legs syndrome. In Movement Disorders (eds Schapira, A. et al.) 587–621 (Saunders Elsevier, Philadelphia, 2009).

    Google Scholar 

  5. Winkelmann, J. 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. 52, 297–302 (2002).

    Article  PubMed  Google Scholar 

  6. Allen, R. P. & Earley, C. J. Defining the phenotype of the restless legs syndrome (RLS) using age-of-symptom-onset. Sleep Med. 1, 11–19 (2000).

    Article  CAS  PubMed  Google Scholar 

  7. Benes, H. & Kohnen, R. Validation of an algorithm for the diagnosis of Restless Legs Syndrome: the Restless Legs Syndrome-Diagnostic Index (RLS-DI). Sleep Med. 10, 515–523 (2009).

    Article  PubMed  Google Scholar 

  8. Benes, H., von Eye, A. & Kohnen, R. Empirical evaluation of the accuracy of diagnostic criteria for Restless Legs Syndrome. Sleep Med. 10, 524–530 (2009).

    Article  PubMed  Google Scholar 

  9. Okura, K. et al. Comparison of sleep variables between chronic widespread musculoskeletal pain, insomnia, periodic leg movements syndrome and control subjects in a clinical sleep medicine practice. Sleep Med. 9, 352–361 (2008).

    Article  PubMed  Google Scholar 

  10. Hening, W., Allen, R., Washburn, M., Leasage, S. & Earley, C. Mimics of the restless legs syndrome can often satisfy the standard diagnostic criteria [abstract]. Sleep 27, A297 (2004).

    Article  Google Scholar 

  11. Benes, H., Walters, A. S., Allen, R. P., Hening, W. A. & Kohnen, R. Definition of restless legs syndrome, how to diagnose it, and how to differentiate it from RLS mimics. Mov. Disord. 22 (Suppl. 18), S401–S408 (2007).

    Article  PubMed  Google Scholar 

  12. Stiasny-Kolster, K., Kohnen, R., Möller, J. C., Trenkwalder, C. & Oertel, W. H. Validation of the “L-DOPA test” for diagnosis of restless legs syndrome. Mov. Disord. 21, 1333–1339 (2006).

    Article  PubMed  Google Scholar 

  13. Montplaisir, J. et al. Immobilization tests and periodic leg movements in sleep for the diagnosis of restless leg syndrome. Mov. Disord. 13, 324–329 (1998).

    Article  CAS  PubMed  Google Scholar 

  14. Brodeur, C., Montplaisir, J., Godbout, R. & Marinier, R. Treatment of restless legs syndrome and periodic movements during sleep with L-dopa: a double-blind, controlled study. Neurology 38, 1845–1848 (1988).

    Article  CAS  PubMed  Google Scholar 

  15. Michaud, M., Lavigne, G., Desautels, A., Poirier, G. & Montplaisir, J. Effects of immobility on sensory and motor symptoms of restless legs syndrome. Mov. Disord. 17, 112–115 (2002).

    Article  PubMed  Google Scholar 

  16. Michaud, M., Paquet, J., Lavigne, G., Desautels, A. & Montplaisir, J. Sleep laboratory diagnosis of restless legs syndrome. Eur. Neurol. 48, 108–113 (2002).

    Article  PubMed  Google Scholar 

  17. Aksu, M., Demirci, S. & Bara-Jimenez, W. Correlation between putative indicators of primary restless legs syndrome severity. Sleep Med. 8, 84–89 (2007).

    Article  PubMed  Google Scholar 

  18. Michaud, M. et al. Circadian variation of the effects of immobility on symptoms of restless legs syndrome. Sleep 28, 843–846 (2005).

    Article  PubMed  Google Scholar 

  19. Birinyi, P. V., Allen, R. P., Lesage, S., Dean, T. & Earley, C. J. Investigation into the correlation between sensation and leg movement in restless legs syndrome. Mov. Disord. 20, 1097–1103 (2005).

    Article  PubMed  Google Scholar 

  20. Hening, W. A. et al. Circadian rhythm of motor restlessness and sensory symptoms in the idiopathic restless legs syndrome. Sleep 22, 901–912 (1999).

    Article  CAS  PubMed  Google Scholar 

  21. Trenkwalder, C. et al. Circadian rhythm of periodic limb movements and sensory symptoms of restless legs syndrome. Mov. Disord. 14, 102–110 (1999).

    Article  CAS  PubMed  Google Scholar 

  22. Michaud, M. et al. Circadian rhythm of restless legs syndrome: relationship with biological markers. Ann. Neurol. 55, 372–380 (2004).

    Article  CAS  PubMed  Google Scholar 

  23. García-Borreguero, D. et al. Augmentation as a treatment complication of restless legs syndrome: concept and management. Mov. Disord. 22 (Suppl. 18), S476–S484 (2007).

    Article  PubMed  Google Scholar 

  24. Montplaisir, J. et al. Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: a study of 133 patients diagnosed with new standard criteria. Mov. Disord. 12, 61–65 (1997).

    Article  CAS  PubMed  Google Scholar 

  25. Hening, W. et al. Impact, diagnosis and treatment of restless legs syndrome (RLS) in a primary care population: the REST (RLS epidemiology, symptoms, and treatment) primary care study. Sleep Med. 5, 237–246 (2004).

    Article  PubMed  Google Scholar 

  26. Hornyak, M., Feige, B., Voderholzer, U., Philipsen, A. & Riemann, D. Polysomnography findings in patients with restless legs syndrome and in healthy controls: a comparative observational study. Sleep 30, 861–865 (2007).

    Article  PubMed  Google Scholar 

  27. Allen, R. P. & Earley, C. J. Validation of the Johns Hopkins restless legs severity scale. Sleep Med. 2, 239–242 (2001).

    Article  PubMed  Google Scholar 

  28. García-Borreguero, D., Larrosa, O., de la Llave, Y., Granizo, J. J. & Allen, R. Correlation between rating scales and sleep laboratory measurements in restless legs syndrome. Sleep Med. 5, 561–565 (2004).

    Article  PubMed  Google Scholar 

  29. Hornyak, M. et al. Relationship of periodic leg movements and severity of restless legs syndrome: a study in unmedicated and medicated patients. Clin. Neurophysiol. 118, 1532–1537 (2007).

    Article  PubMed  Google Scholar 

  30. Trenkwalder, C. et al. Efficacy of pergolide in treatment of restless legs syndrome: the PEARLS Study. Neurology 62, 1391–1397 (2004).

    Article  CAS  PubMed  Google Scholar 

  31. Allen, R. et al. Ropinirole decreases periodic leg movements and improves sleep parameters in patients with restless legs syndrome. Sleep 27, 907–914 (2004).

    Article  PubMed  Google Scholar 

  32. Hornyak, M., Feige, B., Riemann, D. & Voderholzer, U. Periodic leg movements in sleep and periodic limb movement disorder: prevalence, clinical significance and treatment. Sleep Med. Rev. 10, 169–177 (2006).

    Article  PubMed  Google Scholar 

  33. Bliwise, D. L., Petta, D., Seidel, W. & Dement, W. Periodic leg movements during sleep in the elderly. Arch. Gerontol. Geriatr. 4, 273–281 (1985).

    Article  CAS  PubMed  Google Scholar 

  34. Ancoli-Israel, S. et al. Periodic limb movements in sleep in community-dwelling elderly. Sleep 14, 496–500 (1991).

    Article  CAS  PubMed  Google Scholar 

  35. Coleman, R. M. Periodic movements in sleep (nocturnal myoclonus) and restless legs syndrome. In Sleeping and Waking Disorders: Indications and Techniques (ed. Guilleminault, C.) 265–295 (Addison-Wesley Pub. Co., Medical/Nursing Division, Menlo Park, CA, 1982).

    Google Scholar 

  36. Ferri, R., Gschliesser, V., Frauscher, B., Poewe, W. & Högl, B. Periodic leg movements during sleep and periodic limb movement disorder in patients presenting with unexplained insomnia. Clin. Neurophysiol. 120, 257–263 (2009).

    Article  PubMed  Google Scholar 

  37. Zucconi, M. et al. The official World Association of Sleep Medicine (WASM) standards for recording and scoring periodic leg movements in sleep (PLMS) and wakefulness (PLMW) developed in collaboration with a task force from the International Restless Legs Syndrome Study Group (IRLSSG). Sleep Med. 7, 175–183 (2006).

    Article  PubMed  Google Scholar 

  38. Boehm, G., Wetter, T. C. & Trenkwalder, C. Periodic leg movements in RLS patients as compared to controls: Are there differences beyond the PLM index? Sleep Med. 10, 566–571 (2009).

    Article  PubMed  Google Scholar 

  39. Ferri, R. et al. Computer-assisted detection of nocturnal leg motor activity in patients with restless legs syndrome and periodic leg movements during sleep. Sleep 28, 998–1004 (2005).

    Article  PubMed  Google Scholar 

  40. Kushida, C. A. et al. Practice parameters for the indications for polysomnography and related procedures: an update for 2005. Sleep 28, 499–521 (2005).

    Article  PubMed  Google Scholar 

  41. Hornyak, M. et al. Consensus statement from the German Sleep Society: indications for performing polysomnography in the diagnosis and treatment of restless leg syndrome. Sleep Med. 3, 457–458 (2002).

    Article  PubMed  Google Scholar 

  42. Gschliesser, V. et al. PLM detection by actigraphy compared to polysomnography: a validation and comparison of two actigraphs. Sleep Med. 10, 306–311 (2009).

    Article  PubMed  Google Scholar 

  43. Stefansson, H. et al. A genetic risk factor for periodic limb movements in sleep. N. Engl. J. Med. 357, 639–647 (2007).

    Article  CAS  PubMed  Google Scholar 

  44. Allen, R. P. Improving RLS diagnosis and severity assessment: polysomnography, actigraphy and RLS-sleep log. Sleep Med. 8 (Suppl. 2), S13–S18 (2007).

    Article  PubMed  Google Scholar 

  45. Hening, W. A., Allen, R. P., Washburn, M., Lesage, S. & Earley, C. J. Validation of the Hopkins telephone diagnostic interview for restless legs syndrome. Sleep Med. 9, 283–289 (2008).

    Article  PubMed  Google Scholar 

  46. Walters, A. S. et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 4, 121–132 (2003).

    Article  PubMed  Google Scholar 

  47. Abetz, L. et al. The reliability, validity and responsiveness of the International Restless Legs Syndrome Study Group rating scale and subscales in a clinical-trial setting. Sleep Med. 7, 340–349 (2006).

    Article  PubMed  Google Scholar 

  48. Atkinson, M. J. et al. Validation of the Restless Legs Syndrome Quality of Life Instrument (RLS-QLI): findings of a consortium of national experts and the RLS Foundation. Qual. Life Res. 13, 679–693 (2004).

    Article  CAS  PubMed  Google Scholar 

  49. Kell, D. B. Iron behaving badly: inappropriate iron chelation as a major contributor to the aetiology of vascular and other progressive inflammatory and degenerative diseases. BMC Med. Genomics 2, 2 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Paulus, W. & Schomburg, E. D. Dopamine and the spinal cord in restless legs syndrome: does spinal cord physiology reveal a basis for augmentation? Sleep Med. Rev. 10, 185–196 (2006).

    Article  PubMed  Google Scholar 

  51. Clemens, S., Rye, D. & Hochman, S. Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 67, 125–130 (2006).

    Article  PubMed  Google Scholar 

  52. Heckman, C. J., Mottram, C., Quinlan, K., Theiss, R. & Schuster, J. Motoneuron excitability: the importance of neuromodulatory inputs. Clin. Neurophysiol. 120, 2040–2054 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Monte-Silva, K. et al. Dose-dependent inverted U-shaped effect of dopamine (D2-like) receptor activation on focal and nonfocal plasticity in humans. J. Neurosci. 29, 6124–6131 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Nitsche, M. A. et al. Serotonin affects transcranial direct current-induced neuroplasticity in humans. Biol. Psychiatry 66, 503–508 (2009).

    Article  CAS  PubMed  Google Scholar 

  55. Rizzo, V. et al. Dopamine agonists restore cortical plasticity in patients with idiopathic restless legs syndrome. Mov. Disord. 24, 710–715 (2009).

    Article  PubMed  Google Scholar 

  56. Paulus, W. & Trenkwalder, C. Less is more: pathophysiology of dopaminergic-therapy-related augmentation in restless legs syndrome. Lancet Neurol. 5, 878–886 (2006).

    Article  CAS  PubMed  Google Scholar 

  57. Zhao, H. 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. 85, 1065–1076 (2007).

    Article  CAS  PubMed  Google Scholar 

  58. Paalzow, G. H. L-dopa induces opposing effects on pain in intact rats: (–)–sulpiride, SCH 23390 or alpha-methyl-DL-p-tyrosine methylester hydrochloride reveals profound hyperalgesia in large antinociceptive doses. J. Pharmacol. Exp. Ther. 263, 470–479 (1992).

    CAS  PubMed  Google Scholar 

  59. Shimizu, T., Iwata, S., Miyata, A., Fukuda, T. & Nomoto, M. Delayed L-DOPA-induced hyperalgesia. Pharmacol. Biochem. Behav. 85, 643–647 (2006).

    Article  CAS  PubMed  Google Scholar 

  60. McNab, F. et al. Changes in cortical dopamine D1 receptor binding associated with cognitive training. Science 323, 800–802 (2009).

    Article  CAS  PubMed  Google Scholar 

  61. Pappas, S. S., Behrouz, B., Janis, K. L., Goudreau, J. L. & Lookingland, K. J. Lack of D2 receptor mediated regulation of dopamine synthesis in A11 diencephalospinal neurons in male and female mice. Brain Res. 1214, 1–10 (2008).

    Article  CAS  PubMed  Google Scholar 

  62. Trenkwalder, C., Högl, B. & Winkelmann, J. Recent advances in the diagnosis, genetics and treatment of restless legs syndrome. J. Neurol. 256, 539–553 (2009).

    Article  CAS  PubMed  Google Scholar 

  63. Winkelmann, J. et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat. Genet. 39, 1000–1006 (2007).

    Article  CAS  PubMed  Google Scholar 

  64. Schormair, B. et al. PTPRD (protein tyrosine phosphatase receptor type delta) is associated with restless legs syndrome. Nat. Genet. 40, 946–948 (2008).

    Article  CAS  PubMed  Google Scholar 

  65. Bucher, S. F., Seelos, K. C., Oertel, W. H., Reiser, M. & Trenkwalder, C. Cerebral generators involved in the pathogenesis of the restless legs syndrome. Ann. Neurol. 41, 639–645 (1997).

    Article  CAS  PubMed  Google Scholar 

  66. Unrath, A., Juengling, F. D., Schork, M. & Kassubek, J. Cortical grey matter alterations in idiopathic restless legs syndrome: An optimized voxel-based morphometry study. Mov. Disord. 22, 1751–1756 (2007).

    Article  PubMed  Google Scholar 

  67. Unrath, A., Muller, H. P., Ludolph, A. C., Riecker, A. & Kassubek, J. Cerebral white matter alterations in idiopathic restless legs syndrome, as measured by diffusion tensor imaging. Mov. Disord. 23, 1250–1255 (2008).

    Article  PubMed  Google Scholar 

  68. Etgen, T. et al. Bilateral thalamic gray matter changes in patients with restless legs syndrome. Neuroimage 24, 1242–1247 (2005).

    Article  PubMed  Google Scholar 

  69. Celle, S. et al. Lack of specific gray matter alterations in restless legs syndrome in elderly subjects. J. Neurol. 257, 344–348 (2010).

    Article  PubMed  Google Scholar 

  70. Hornyak, M. et al. Voxel-based morphometry in unmedicated patients with restless legs syndrome. Sleep Med. 9, 22–26 (2007).

    Article  PubMed  Google Scholar 

  71. Cervenka, S. et al. Support for dopaminergic hypoactivity in restless legs syndrome: a PET study on D2-receptor binding. Brain 129, 2017–2028 (2006).

    Article  PubMed  Google Scholar 

  72. Turjanski, N., Lees, A. J. & Brooks, D. J. Striatal dopaminergic function in restless legs syndrome: 18F-dopa and 11C-raclopride PET studies. Neurology 52, 932–937 (1999).

    Article  CAS  PubMed  Google Scholar 

  73. Connor, J. R. et al. Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome. Brain 132, 2403–2412 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  74. Tergau, F., Wischer, S. & Paulus, W. Motor system excitability in patients with restless legs syndrome. Neurology 52, 1060–1063 (1999).

    Article  CAS  PubMed  Google Scholar 

  75. Gorsler, A. & Liepert, J. Influence of cabergoline on motor excitability in patients with restless legs syndrome. J. Clin. Neurophysiol. 24, 456–460 (2007).

    Article  CAS  PubMed  Google Scholar 

  76. Nardone, R. et al. Cabergoline reverses cortical hyperexcitability in patients with restless legs syndrome. Acta Neurol. Scand. 114, 244–249 (2006).

    Article  CAS  PubMed  Google Scholar 

  77. von Spiczak, S. et al. The role of opioids in restless legs syndrome: an [11C]diprenorphine PET study. Brain 128, 906–917 (2005).

    Article  PubMed  Google Scholar 

  78. Earley, C. J. et al. Abnormalities in CSF concentrations of ferritin and transferrin in restless legs syndrome. Neurology 54, 1698–1700 (2000).

    Article  CAS  PubMed  Google Scholar 

  79. Clardy, S. L., Earley, C. J., Allen, R. P., Beard, J. L. & Connor, J. R. Ferritin subunits in CSF are decreased in restless legs syndrome. J. Lab. Clin. Med. 147, 67–73 (2006).

    Article  CAS  PubMed  Google Scholar 

  80. Earley, C. J., Hyland, K. & Allen, R. P. Circadian changes in CSF dopaminergic measures in restless legs syndrome. Sleep Med. 7, 263–268 (2006).

    Article  PubMed  Google Scholar 

  81. Astrakas, L. G. et al. T2 relaxometry and fMRI of the brain in late-onset restless legs syndrome. Neurology 71, 911–916 (2008).

    Article  CAS  PubMed  Google Scholar 

  82. Allen, R. P. & Earley, C. J. The role of iron in restless legs syndrome. Mov. Disord. 22 (Suppl. 18), S440–S448 (2007).

    Article  PubMed  Google Scholar 

  83. Connor, J. R. Pathophysiology of restless legs syndrome: evidence for iron involvement. Curr. Neurol. Neurosci. Rep. 8, 162–166 (2008).

    Article  CAS  PubMed  Google Scholar 

  84. Allen, R. P., Barker, P. B., Wehrl, F., Song, H. K. & Earley, C. J. MRI measurement of brain iron in patients with restless legs syndrome. Neurology 56, 263–265 (2001).

    Article  CAS  PubMed  Google Scholar 

  85. Earley, C. J., Barker, B. P., Horská, A. & Allen, R. P. MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome. Sleep Med. 7, 458–461 (2006).

    Article  PubMed  Google Scholar 

  86. Schmidauer, C. et al. Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome. Ann. Neurol. 58, 630–634 (2005).

    Article  PubMed  Google Scholar 

  87. Godau, J., Schweitzer, K. J., Liepelt, I., Gerloff, C. & Berg, D. Substantia nigra hypoechogenicity: definition and findings in restless legs syndrome. Mov. Disord. 22, 187–192 (2007).

    Article  PubMed  Google Scholar 

  88. Berg, D. Disturbance of iron metabolism as a contributing factor to SN hyperechogenicity in Parkinson's disease: implications for idiopathic and monogenetic forms. Neurochem. Res. 32, 1646–1654 (2007).

    Article  CAS  PubMed  Google Scholar 

  89. Qu, S. et al. Locomotion is increased in A11-lesioned mice with iron deprivation: a possible animal model for restless legs syndrome. J. Neuropathol. Exp. Neurol. 66, 383–388 (2007).

    Article  CAS  PubMed  Google Scholar 

  90. Dowling, P., Klinker, F., Amaya, F., Paulus, W. & Liebetanz, D. Iron-deficiency sensitizes mice to acute pain stimuli and formalin-induced nociception. J. Nutr. 139, 2087–2092 (2009).

    Article  CAS  PubMed  Google Scholar 

  91. Ondo, W. G., He, Y., Rajasekaran, S. & Le, W. D. Clinical correlates of 6-hydroxydopamine injections into A11 dopaminergic neurons in rats: a possible model for restless legs syndrome. Mov. Disord. 15, 154–158 (2000).

    Article  CAS  PubMed  Google Scholar 

  92. Paulus, W. & Schomburg, E. D. Dopamine and the spinal cord in restless legs syndrome: does spinal cord physiology reveal a basis of augmentation? Sleep Med. Rev. 10, 185–196 (2006).

    Article  PubMed  Google Scholar 

  93. Qu, S. et al. Projections of diencephalic dopamine neurons into the spinal cord in mice. Exp. Brain Res. 168, 152–156 (2006).

    Article  CAS  PubMed  Google Scholar 

  94. Schöls, L., Haan, J., Riess, O., Amoiridis, G. & Przuntek, H. Sleep disturbance in spinocerebellar ataxias: is the SCA3 mutation a cause of restless legs syndrome? Neurology 51, 1603–1607 (1998).

    Article  PubMed  Google Scholar 

  95. Bara-Jimenez, W., Aksu, M., Graham, B., Sato, S. & Hallett, M. Periodic limb movements in sleep: state-dependent excitability of the spinal flexor reflex. Neurology 54, 1609–1616 (2000).

    Article  CAS  PubMed  Google Scholar 

  96. Rijsman, R. M., Stam, C. J. & de Weerd, A. W. Abnormal H-reflexes in periodic limb movement disorder; impact on understanding the pathophysiology of the disorder. Clin. Neurophysiol. 116, 204–210 (2005).

    Article  CAS  PubMed  Google Scholar 

  97. Stiasny-Kolster, K., Magerl, W., Oertel, W. H., Möller, J. C. & Treede, R. D. Static mechanical hyperalgesia without dynamic tactile allodynia in patients with restless legs syndrome. Brain 127, 773–782 (2004).

    Article  CAS  PubMed  Google Scholar 

  98. Schattschneider, J. et al. Idiopathic restless legs syndrome: Abnormalities in central somatosensory processing. J. Neurol. 251, 977–982 (2004).

    Article  PubMed  Google Scholar 

  99. Bachmann, C. G. et al. Thermal hypoesthesia differentiates secondary RLS associated with small fibre neuropathy from primary RLS. Brain (in press).

  100. Hornyak, M. et al. Cognitive behavioural group therapy to improve patients' strategies for coping with restless legs syndrome: a proof-of-concept trial. J. Neurol. Neurosurg. Psychiatry 79, 823–825 (2008).

    Article  CAS  PubMed  Google Scholar 

  101. Fulda, S. & Wetter, T. C. Where dopamine meets opioids: a meta-analysis of the placebo effect in restless legs syndrome treatment studies. Brain 131, 902–917 (2008).

    Article  PubMed  Google Scholar 

  102. Trenkwalder, C. et al. Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice. Mov. Disord. 23, 2267–2302 (2008).

    Article  PubMed  Google Scholar 

  103. O'Keeffe, S. T., Gavin, K. & Lavan, J. N. Iron status and restless legs syndrome in the elderly. Age Ageing 23, 200–203 (1994).

    Article  CAS  PubMed  Google Scholar 

  104. Trenkwalder, C., Högl, B., Benes, H. & Kohnen, R. Augmentation in restless legs syndrome is associated with low ferritin. Sleep Med. 9, 572–574 (2008).

    Article  PubMed  Google Scholar 

  105. Trenkwalder, C. et al. L-dopa therapy of uremic and idiopathic restless legs syndrome: a double-blind, crossover trial. Sleep 18, 681–688 (1995).

    Article  CAS  PubMed  Google Scholar 

  106. Walker, S. L., Fine, A. & Kryger, M. H. L-DOPA/carbidopa for nocturnal movement disorders in uremia. Sleep 19, 214–218 (1996).

    CAS  PubMed  Google Scholar 

  107. Staedt, J. et al. Pergolide: treatment of choice in restless legs syndrome (RLS) and nocturnal myoclonus syndrome (NMS). A double -blind randomized crosover trial of pergolide versus L-dopa. J. Neural Transm. 104, 461–468 (1997).

    Article  CAS  PubMed  Google Scholar 

  108. Collado-Seidel, V. et al. A controlled study of additional sr-L-dopa in L-dopa-responsive restless legs syndrome with late-night symptoms. Neurology 52, 285–290 (1999).

    Article  CAS  PubMed  Google Scholar 

  109. Benes, H. et al. Rapid onset of action of levodopa in restless legs syndrome: a double-blind, randomized, multicenter, crossover trial. Sleep 22, 1073–1081 (1999).

    Article  CAS  PubMed  Google Scholar 

  110. Eisensehr, I., Ehrenberg, B. L., Rogge Solti, S. & Noachtar, S. Treatment of idiopathic restless legs syndrome (RLS) with slow-release valproic acid compared with slow-release levodopa/benserazid. J. Neurol. 251, 579–583 (2004).

    Article  CAS  PubMed  Google Scholar 

  111. Trenkwalder, C. 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. 22, 696–703 (2007).

    Article  PubMed  Google Scholar 

  112. Allen, R. P. & Earley, C. J. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep 19, 205–213 (1996).

    Article  CAS  PubMed  Google Scholar 

  113. Trenkwalder, C. et al. One-year treatment with standard and sustained-release levodopa: appropriate long-term treatment of restless legs syndrome? Mov. Disord. 18, 1184–1189 (2003).

    Article  PubMed  Google Scholar 

  114. Partinen, M. et al. Efficacy and safety of pramipexole in idiopathic restless legs syndrome: a polysomnographic dose-finding study--the PRELUDE study. Sleep Med. 7, 407–417 (2006).

    Article  PubMed  Google Scholar 

  115. Oertel, W. H. et al. Efficacy of cabergoline in restless legs syndrome: a placebo-controlled study with polysomnography (CATOR). Neurology 67, 1040–1046 (2006).

    Article  CAS  PubMed  Google Scholar 

  116. Adler, C. H. et al. Ropinirole for restless legs syndrome: a placebo-controlled crossover trial. Neurology 62, 1405–1407 (2004).

    Article  CAS  PubMed  Google Scholar 

  117. Trenkwalder, C. et al. Ropinirole in the treatment of restless legs syndrome: results from a 12-week, randomised, placebo-controlled study in 10 European countries. J. Neurol. Neurosurg. Psychiatry 75, 92–97 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  118. Walters, A. S. et al. 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. 19, 1414–1423 (2004).

    Article  PubMed  Google Scholar 

  119. Bliwise, D. L. et al. Randomized, double-blind, placebo-controlled, short-term trial of ropinirole in restless legs syndrome. Sleep Med. 6, 141–147 (2005).

    Article  CAS  PubMed  Google Scholar 

  120. Bogan, R. K., Fry, J. M., Schmidt, M. H., Carson, S. W. & Ritchie, S. Y. Ropinirole in the treatment of patients with restless legs syndrome: a US-based randomized, double-blind, placebo-controlled clinical trial. Mayo Clin. Proc. 81, 17–27 (2006).

    Article  CAS  PubMed  Google Scholar 

  121. Happe, S., Sauter, C., Klösch, G., Saletu, B. & Zeitlhofer, J. Gabapentin versus ropinirole in the treatment of idiopathic restless legs syndrome. Neuropsychobiology 48, 82–86 (2003).

    Article  CAS  PubMed  Google Scholar 

  122. Hansen, R. A. et al. Effect of ropinirole on sleep outcomes in patients with restless legs syndrome: meta-analysis of pooled individual patient data from randomized controlled trials. Pharmacotherapy 29, 255–262 (2009).

    Article  CAS  PubMed  Google Scholar 

  123. Montplaisir, J., Karrasch, J., Haan, J. & Volc, D. Ropinirole is effective in the long-term management of restless legs syndrome: a randomized controlled trial. Mov. Disord. 21, 1627–1635 (2006).

    Article  PubMed  Google Scholar 

  124. Garcia-Borreguero, D. et al. A 52-week open-label study of the long-term safety of ropinirole in patients with restless legs syndrome. Sleep Med. 8, 742–752 (2007).

    Article  PubMed  Google Scholar 

  125. Montplaisir, J., Nicolas, A., Denesle, R. & Gomez-Mancilla, B. Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology 52, 938–943 (1999).

    Article  CAS  PubMed  Google Scholar 

  126. Winkelman, J. W. et al. Efficacy and safety of pramipexole in restless legs syndrome. Neurology 67, 1034–1039 (2006).

    Article  CAS  PubMed  Google Scholar 

  127. Trenkwalder, C. et al. Controlled withdrawal of pramipexole after 6 months of open-label treatment in patients with restless legs syndrome. Mov. Disord. 21, 1404–1410 (2006).

    Article  PubMed  Google Scholar 

  128. Oertel, W. H. et al. Efficacy of pramipexole in restless legs syndrome: a six-week, multicenter, randomized, double-blind study (effect-RLS study). Mov. Disord. 22, 213–219 (2007).

    Article  PubMed  Google Scholar 

  129. Ferini-Strambi, L. et al. Effect of pramipexole on RLS symptoms and sleep: a randomized, double-blind, placebo-controlled trial. Sleep Med. 9, 874–881 (2008).

    Article  PubMed  Google Scholar 

  130. Stiasny-Kolster, K., Kohnen, R., Schollmayer, E., Möller, J. C. & Oertel, W. H. Patch application of the dopamine agonist rotigotine to patients with moderate to advanced stages of restless legs syndrome: a double-blind, placebo-controlled pilot study. Mov. Disord. 19, 1432–1438 (2004).

    Article  PubMed  Google Scholar 

  131. Trenkwalder, C. et al. Efficacy of rotigotine for treatment of moderate-to-severe restless legs syndrome: a randomised, double-blind, placebo-controlled trial. Lancet Neurol. 7, 595–604 (2008).

    Article  CAS  PubMed  Google Scholar 

  132. Oertel, W. H. 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. 9, 228–239 (2008).

    Article  PubMed  Google Scholar 

  133. García-Borreguero, D. 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. 8, 520–530 (2007).

    Article  PubMed  Google Scholar 

  134. Earley, C. J. & Allen, R. P. Restless legs syndrome augmentation associated with tramadol. Sleep Med. 7, 592–593 (2006).

    Article  PubMed  Google Scholar 

  135. Vetrugno, R. et al. Augmentation of restless legs syndrome with long-term tramadol treatment. Mov. Disord. 22, 424–427 (2007).

    Article  PubMed  Google Scholar 

  136. García-Borreguero, D. et al. Validation of the Augmentation Severity Rating Scale (ASRS): A multicentric, prospective study with levodopa on restless legs syndrome. Sleep Med. 8, 455–463 (2007).

    Article  PubMed  Google Scholar 

  137. Högl, B., Garcia-Borreguero, D., Sohr, M. & Brenner, S. Similar incidences of augmentation during 26 weeks of double-blind pramipexole treatment for restless legs syndrome in comparison to placebo. Neurology 72 (Suppl. 3), A106 (2009).

    Google Scholar 

  138. Guilleminault, C., Cetel, M. & Philip, P. Dopaminergic treatment of restless legs and rebound phenomenon. Neurology 43, 445 (1993).

    Article  CAS  PubMed  Google Scholar 

  139. Walters, A. S. et al. Successful treatment of the idiopathic restless legs syndrome in a randomized double-blind trial of oxycodone versus placebo. Sleep 16, 327–332 (1993).

    Article  CAS  PubMed  Google Scholar 

  140. Kaplan, P. W., Allen, R. P., Buchholz, D. W. & Walters, J. K. A double-blind, placebo-controlled study of the treatment of periodic limb movements in sleep using carbidopa/levodopa and propoxyphene. Sleep 16, 717–723 (1993).

    Article  CAS  PubMed  Google Scholar 

  141. Walters, A. S. et al. Long-term follow-up on restless legs syndrome patients treated with opioids. Mov. Disord. 16, 1105–1109 (2001).

    Article  CAS  PubMed  Google Scholar 

  142. Sommer, M. et al. Pregabalin in restless legs syndrome with and without neuropathic pain. Acta Neurol. Scand. 115, 347–350 (2007).

    Article  CAS  PubMed  Google Scholar 

  143. Garcia-Borreguero, D. et al. Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study. Neurology 59, 1573–1579 (2002).

    Article  CAS  PubMed  Google Scholar 

  144. Thorp, M. L., Morris, C. D. & Bagby, S. P. A crossover study of gabapentin in treatment of restless legs syndrome among hemodialysis patients. Am. J. Kidney Dis. 38, 104–108 (2001).

    Article  CAS  PubMed  Google Scholar 

  145. Kushida, C. A., Becker, P. M., Ellenbogen, A. L., Canafax, D. M. & Barrett, R. W. Randomized, double-blind, placebo-controlled study of XP13512/GSK1838262 in patients with RLS. Neurology 72, 439–446 (2009).

    Article  CAS  PubMed  Google Scholar 

  146. Walters, A. S. et al. Gabapentin enacarbil in restless legs syndrome: a phase 2b, 2-week, randomized, double-blind, placebo-controlled trial. Clin. Neuropharmacol. 32, 311–320 (2009).

    Article  CAS  PubMed  Google Scholar 

  147. Bermejo, P. E. Restless legs syndrome induced by topiramate: two more cases. J. Neurol. 256, 662–663 (2009).

    Article  PubMed  Google Scholar 

  148. Montagna, P., Sassoli de Bianchi, L., Zucconi, M., Cirignotta, F. & Lugaresi, E. Clonazepam and vibration in restless leg syndrome. Acta Neurol. Scand. 69, 428–430 (1984).

    Article  CAS  PubMed  Google Scholar 

  149. Saletu, M. et al. Restless legs syndrome (RLS) and periodic limb movement disorder (PLMD): acute placebo-controlled sleep laboratory studies with clonazepam. Eur. Neuropsychopharmacol. 11, 153–161 (2001).

    Article  CAS  PubMed  Google Scholar 

  150. Peled, R. & Lavie, P. Double-blind evaluation of clonazepam on periodic leg movements in sleep. J. Neurol. Neurosurg. Psychiatry 50, 1679–1681 (1987).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  151. Horiguchi, J., Inami, Y., Sasaki, A., Nishimatsu, O. & Sukegawa, T. Periodic leg movements in sleep with restless legs syndrome: effect of clonazepam treatment. Jpn J. Psychiatry Neurol. 46, 727–732 (1992).

    CAS  PubMed  Google Scholar 

  152. Bonnet, M. H. & Arand, D. L. The use of triazolam in older patients with periodic leg movements, fragmented sleep, and daytime sleepiness. J. Gerontol. 45, M139–M144 (1990).

    Article  CAS  PubMed  Google Scholar 

  153. Bezerra, M. L. & Martínez, J. V. Zolpidem in restless legs syndrome. Eur. Neurol. 48, 180–181 (2002).

    Article  CAS  PubMed  Google Scholar 

  154. Davis, B. J., Rajput, A., Rajput, M. L., Aul, E. A. & Eichhorn, G. R. A randomized, double-blind placebo-controlled trial of iron in restless legs syndrome. Eur. Neurol. 43, 70–75 (2000).

    Article  CAS  PubMed  Google Scholar 

  155. Sloand, J. A., Shelly, M. A., Feigin, A., Bernstein, P. & Monk, R. D. A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome. Am. J. Kidney Dis. 43, 663–670 (2004).

    Article  CAS  PubMed  Google Scholar 

  156. Earley, C. J., Heckler, D. & Allen, R. P. Repeated IV doses of iron provides effective supplemental treatment of restless legs syndrome. Sleep Med. 6, 301–305 (2005).

    Article  PubMed  Google Scholar 

  157. 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. 24, 1445–1452 (2009).

    Article  PubMed  Google Scholar 

  158. Wagner, M. L. et al. Randomized, double-blind, placebo-controlled study of clonidine in restless legs syndrome. Sleep 19, 52–58 (1996).

    Article  CAS  PubMed  Google Scholar 

  159. Evidente, V. G., Adler, C. H., Caviness, J. N., Hentz, J. G. & Gwinn-Hardy, K. Amantadine is beneficial in restless legs syndrome. Mov. Disord. 15, 324–327 (2000).

    Article  CAS  PubMed  Google Scholar 

  160. Hornyak, M., Voderholzer, U., Hohagen, F., Berger, M. & Riemann, D. Magnesium therapy for periodic leg movements-related insomnia and restless legs syndrome: an open pilot study. Sleep 21, 501–505 (1998).

    Article  CAS  PubMed  Google Scholar 

  161. Walters, A. S. et al. Validation of the International Restless Legs Syndrome Study Group rating scale for restless legs syndrome. Sleep Med. 4, 121–132 (2003).

    Article  PubMed  Google Scholar 

  162. Kohnen, R., Oertel, W. H., Stiasny-Kolster, K., Benes, H. & Trenkwalder, C. Severity rating of restless legs syndrome: Review of ten years of experience with the RLS-6 scales in clinical trials [abstract]. Sleep 26, A342 (2003).

    Article  Google Scholar 

  163. Kohnen, R., Benes, H., Heinrich, C. R. & Kurella, B. Development of the disease-specific Restless Legs Syndrome Quality of Life (RLS-QoL) questionnaire [abstract]. Mov. Disord. 17, A232 (2002).

    Google Scholar 

  164. Ware, J. E. Jr & Sherbourne, C. D. The MOS 36-item short-form health survey (SF-36). I. Conceptual framework and item selection. Med. Care 30, 473–483 (1992).

    Article  PubMed  Google Scholar 

  165. Högl, B., Leissner, L. & Poewe, W. Clinical global impression-improvement (CGI-I) and patient global improvement (PGI) are equivalent and useful tools in measuring treatment effects in restless legs syndrome (RLS) patients [abstract]. Eur. J. Neurol. 12, 215 (2005).

    Google Scholar 

Download references

Acknowledgements

The authors would like to thank Anne-Marie Williams for her help in editing the manuscript.

Author information

Authors and Affiliations

  1. Paracelsus-Elena Hospital, Center of Parkinsonism and Movement Disorders, Klinikstrasse 16, 34128, Kassel, Germany

    Claudia Trenkwalder

  2. Department of Clinical Neurophysiology, University of Göttingen, Robert-Koch-Strasse 40, D37075, Göttingen, Germany

    Walter Paulus

Authors
  1. Claudia Trenkwalder
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Walter Paulus
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Claudia Trenkwalder.

Ethics declarations

Competing interests

C. Trenkwalder has received honoraria for consultancy from Boehringer Ingelheim, Novartis, Orion Pharma, Solvay and UCB. She has received honoraria as a speaker from Boehringer Ingelheim, GlaxoSmithKline, Hoffmann-La-Roche, Pfizer and UCB Schwarz Pharma. W. Paulus has received honoraria for consultancy from EBS Technologies, GlaxoSmithKline and Mundipharma Research. He has received honoraria as a speaker from Boehringer Ingelheim, Pfizer Pharma and UCB.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Trenkwalder, C., Paulus, W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 6, 337–346 (2010). https://doi.org/10.1038/nrneurol.2010.55

Download citation

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrneurol.2010.55

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing