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Iron Replacement Therapy in Restless Legs Syndrome

  • Sleep Disorders (A Iranzo, Section Editor)
  • Published:
Current Treatment Options in Neurology Aims and scope Submit manuscript

Abstract

Purpose of review

The main purpose of this manuscript is to review the existing clinical evidence about when iron replacement therapy should be initiated for RLS/WED, and how it should be administered (oral vs. intravenous).

Recent findings

Our knowledge of the pathophysiology of restless legs syndrome/Willis-Ekbom (RLS/WED) continues to grow, revealing the existence of brain iron deficiency as the most well-known biological alteration behind this disorder. Since iron replacement therapy in RLS/WED is one of the first-line available treatments, its indication should be considered periodically, at both the beginning and during the follow-up.

Summary

There is more and more evidence sustaining that the proper use of iron replacement therapy may lead to a reduction in symptomatic drug requirements, and therefore minimize the risk of complications that may result from their long-term use. For all the above, treatment paradigms for RLS/WED, previously based on symptomatic drugs, are changing, giving iron replacement therapy the importance it merits. Thus, it is essential for neurologists to be updated on why, when, and how to use iron in RLS/WED.

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Abbreviations

BID:

Brain iron deficiency

DA:

Dopaminergic agonists

FCM:

Ferric carboxymaltose

IV:

Intravenous

MRI:

Magnetic resonance imaging

RLS/WED:

Restless legs syndrome/Willis-Ekbom disease

SIP:

Systemic iron parameters

SN:

Substantia nigra

TCS:

Transcranial sonography

TIBC:

Total iron-binding capacity

TSAT:

Transferrin saturation

References and Recommended Reading

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

  1. Ohayon MM, O’Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. 2012;16:283–95.

    PubMed  Google Scholar 

  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;15:860–73.

    PubMed  Google Scholar 

  3. Earley CJ, Silber MH. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med. 2010;11:807–15.

    PubMed  Google Scholar 

  4. Ferri R, Koo BB, Picchietti DLFS. Periodic leg movements during sleep: phenotype, neurophysiology, and clinical significance. Sleep Med. 2017;31:29–38.

    PubMed  Google Scholar 

  5. Winkelman JW, Shahar E, Sharief IGD. Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study. Neurology. 2008;70:35–42.

    PubMed  Google Scholar 

  6. Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J. Restless legs syndrome associated with major diseases. Neurology. 2016;86:1336–43.

    PubMed  PubMed Central  CAS  Google Scholar 

  7. Pantaleo NP, Hening WA, Allen RP, et al. Pregnancy accounts for most of the gender difference in prevalence of familial RLS. Sleep Med. 2010;11:310–3.

    PubMed  Google Scholar 

  8. Wanner V, Garcia Malo C, Romero S, Cano-Pumarega I, García-Borreguero D. Non-dopaminergic vs. dopaminergic treatment options in restless legs syndrome. Adv Pharmacol. 2019;84:187–205.

    PubMed  Google Scholar 

  9. Garcia-Borreguero D, Silber MH, Winkelman JW, Högl B, Bainbridge J, Buchfuhrer M, et al. Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation. Sleep Med. 2016;21:1–11.

    PubMed  Google Scholar 

  10. Allen RP, Picchietti DL, Auerbach M, Cho YW, Connor JR, Earley CJ, et al. Evidence-based and consensus clinical practice guidelines for the iron treatment of restless legs syndrome/Willis-Ekbom disease in adults and children: an IRLSSG task force report. Sleep Med. 2018;41:27–44 These are the current guidelines made by the International RLS Study Group regarding iron replacement therapy, including several useful algorithms.

  11. Allen RP, Adler CH, Du W, et al. Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred, placebo-controlled preliminary clinical trial. Sleep Med. 2011;12:906–13.

    PubMed  Google Scholar 

  12. Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and the restless legs syndrome. Sleep. 1998;21:371–7.

    PubMed  CAS  Google Scholar 

  13. Rizzo G, Li X, Galantucci S, Filippi M, Cho YW. Brain imaging and networks in restless legs syndrome. Sleep Med. 2017;31:39–48.

    PubMed  Google Scholar 

  14. Earley CJ, Barker BP, Horská A, et al. MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome. Sleep Med. 2006;7:458–61.

    PubMed  Google Scholar 

  15. Provini F, Chiaro G. Neuroimaging in restless legs syndrome. Sleep Med Clin. 2015;10:215–26.

    PubMed  Google Scholar 

  16. Godau J, Sojer M. Transcranial sonography in restless legs syndrome. Int Rev Neurobiol. 2010;90:199–215.

    PubMed  Google Scholar 

  17. Connor J, Boyer P, Menzies S, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology. 2003;61:304–9.

    PubMed  CAS  Google Scholar 

  18. 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;54:1698–700.

    PubMed  CAS  Google Scholar 

  19. Mizuno S, Mihara T, Miyaoka T, Inagaki T, Horiguchi J. CSF iron, ferritin and transferrin levels in restless legs syndrome. J Sleep Res. 2005;14:43–7.

    PubMed  Google Scholar 

  20. Winkelmann J, Schormair B, Xiong L, Dion PA, Rye DB, Rouleau GA. Genetics of restless legs syndrome. Sleep Med. 2017;31:18–22.

    PubMed  Google Scholar 

  21. Ferré S, Quiroz C, Guitart X, et al. Pivotal role of adenosine neurotransmission in restless legs syndrome. Front Neurosci. 2018;11:1–14.

    Google Scholar 

  22. Yepes G, Guitart X, Rea W, Newman AH, Allen RP, Earley CJ, et al. Targeting hypersensitive corticostriatal terminals in restless legs syndrome. Ann Neurol. 2017;82:951–60.

    PubMed  PubMed Central  CAS  Google Scholar 

  23. 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;28:1886–90.

    PubMed  Google Scholar 

  24. Allen RP, Barker PB, Wehrl FW, Song HKEC. MRI measurement of brain iron in patients with restless legs syndrome. Neurology. 2001;56:263–5.

    PubMed  CAS  Google Scholar 

  25. Lanza G, Ferri R. The neurophysiology of hyperarousal in RLS: hints for a role of glutamate/GABA. Advances in Pharmacology. 2019;84:101–119. https://doi.org/10.1016/bs.apha.2018.12.002

  26. Ferré S, García-Borreguero D, Allen RPEC. New insights into the neurobiology of restless legs syndrome. Neuroscientist. 2019;25:113–25.

    PubMed  Google Scholar 

  27. Becker G, Berg D. Neuroimaging in basal ganglia disorders: perspectives for transcranial ultrasound. Mov Disord. 2001;16:23–32.

    PubMed  CAS  Google Scholar 

  28. Vivó-Orti MN, Tembl JI, Sastre-Bataller I, et al. Evaluación de la sustancia negra mediante ultrasonografía transcraneal. Rev Neurol. 2013;56:268–74.

    PubMed  Google Scholar 

  29. Sanzaro E, Iemolo F. Transcranial sonography in movement disorders: an interesting tool for diagnostic perspectives. Neurol Sci. 2016;37:373–6.

    PubMed  CAS  Google Scholar 

  30. Berg D. In vivo detection of iron and neuromelanin by transcranial sonography - a new approach for early detection of substantia nigra damage. J Neural Transm. 2006;113:775–80.

    PubMed  CAS  Google Scholar 

  31. Schmidauer C, Sojer M, Seppi K, et al. Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome. Ann Neurol. 2005;54:630–4.

    Google Scholar 

  32. Godau J, Schweitzer KJ, Liepelt I, Gerloff CBD. Substantia nigra hypoechogenicity: definition and findings in restless legs syndrome. Mov Disord. 2007;22:187–92.

    PubMed  Google Scholar 

  33. Godau J, Wevers AK, Gaenslen A, di Santo A, Liepelt I, Gasser T, et al. Sonographic abnormalities of brainstem structures in restless legs syndrome. Sleep Med. 2008;9:782–9.

    PubMed  Google Scholar 

  34. Garcia-Malo C, Wanner V, Miranda C, Romero Peralta S, Agudelo L, Cano-Pumarega I, et al. Quantitative transcranial sonography of the substantia nigra as a predictor of therapeutic response to intravenous iron therapy in restless legs syndrome. Sleep Med. 2019;66:123–9 This study found that transcranial sonography is a useful tool that helps in selecting which patients could benefit most from IV iron.

    PubMed  Google Scholar 

  35. Ganz T. Anemia of inflammation. N Engl J Med. 2019;381:1148–57.

    PubMed  Google Scholar 

  36. Waldvogel-Abramowski S, Waeber G, Gassner C, Buser A, Frey BM, Favrat BTJ. Physiology of iron metabolism. Transfus Med Hemother. 2014;41:213–21.

    PubMed  PubMed Central  Google Scholar 

  37. Singh N, Haldar S, Tripathi AK, Horback K, Wong J, Sharma D, et al. Brain iron homeostasis: from molecular mechanisms to clinical significance and therapeutic opportunities. Antioxid Redox Signal. 2014;20:1324–63.

    PubMed  PubMed Central  CAS  Google Scholar 

  38. Muckenthaler MU. Fine tuning of hepcidin expression by positive and negative regulators. Cell Metab. 2008;8:1–3.

    PubMed  CAS  Google Scholar 

  39. Watson J, Round AHW. Raised inflammatory markers. BMJ. 2012;344:e454.

    PubMed  Google Scholar 

  40. LA Pfeiffer CM. Laboratory methodologies for indicators of iron status: strengths, limitations, and analytical challenges. Am J Clin Nutr. 2017;106:1606S–14S.

    PubMed  PubMed Central  Google Scholar 

  41. Ridefelt P, Larsson A, Rehman JUAJ. Influences of sleep and the circadian rhythm on iron-status indices. Clin Biochem. 2010;43:323–8.

    Google Scholar 

  42. Earley CJ, Connor J, Garcia-Borreguero D, Jenner P, Winkelman J, Zee PC, et al. Altered brain iron homeostasis and dopaminergic function in restless legs syndrome (Willis-Ekbom disease). Sleep Med. 2014;15:1288–301.

    PubMed  Google Scholar 

  43. Powell LW. Diagnosis of hemochromatosis. Semin Gastrointest Dis. 2002;13:80–8.

    PubMed  Google Scholar 

  44. Steinberg KK, Cogswell ME, Chang JC, Caudill SP, McQuillan GM, Bowman BA, et al. Prevalence of C282Y and H63D mutations in the hemochromatosis (HFE) gene in the United States. JAMA. 2001;285:2216–22.

    PubMed  CAS  Google Scholar 

  45. Garcia-Borreguero D, Kohnen R, Silber MH, Winkelman JW, Earley CJ, Högl B, et al. The long-term treatment of restless legs syndrome/Willis-Ekbom disease: evidence-based guidelines and clinical consensus best practice guidance: a report from the International Restless Legs Syndrome Study Group. Sleep Med. 2013;14:675–84.

    PubMed  Google Scholar 

  46. Cho YW, Allen RP, Earley CJ. Clinical efficacy of ferric carboxymaltose treatment in patients with restless legs syndrome. Sleep Med. 2016;25:16–23.

    PubMed  Google Scholar 

  47. Tolkien Z, Stecher L, Mander AP, et al. Ferrous sulfate supplementation causes significant gastrointestinal side-effects in adults: a systematic review and meta-analysis. PLoS One. 2015;10:e0117383.

    PubMed  PubMed Central  Google Scholar 

  48. Davis BJ, Rajput A, Rajput ML, et al. A randomized, double-blind placebo-controlled trial of iron in restless legs syndrome. Eur Neurol. 2000;43:70–5.

    PubMed  CAS  Google Scholar 

  49. Wang J, O’Reilly B, Venkataraman R, et al. 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;10:973–5.

    PubMed  Google Scholar 

  50. Lee CS, Lee SD, Kang SH, Park HY, Yoon IY. Comparison of the efficacies of oral iron and pramipexole for the treatment of restless legs syndrome patients with low serum ferritin. Eur J Neurol. 2014;21:260–6.

    PubMed  CAS  Google Scholar 

  51. Stoffel N, Cercamondi C, Brittenham G, Zeder C, Geurts-Moespot AJ, Swinkels DW, et al. Iron absorption from oral iron supplements given on consecutive versus alternate days and as single morning doses versus twice-daily split dosing in iron-depleted women: two open-label, randomised controlled trials. Lancet Haematol. 2017;4:e524–33.

    PubMed  Google Scholar 

  52. Moretti D, Goede JS, Zeder C, et al. Oral iron supplements increase hepcidin and decrease iron absorption from daily or twice-daily doses in iron-depleted young women. Blood. 2015;126:1981–9.

    PubMed  CAS  Google Scholar 

  53. Wang C, Graham DJ, Kane RC, Xie D, Wernecke M, Levenson M, et al. Comparative risk of anaphylactic reactions associated with intravenous iron products. JAMA. 2015;314:2062–8.

    CAS  Google Scholar 

  54. Tomer A, Amir B, Alon G, et al. The safety of intravenous iron preparations: systematic review and meta-analysis. Mayo Clin Proc. 2015;90:12–23.

    CAS  Google Scholar 

  55. DeLoughery TG. Safety of oral and intravenous iron. Acta Haematol. 2019;142:8–12.

    PubMed  CAS  Google Scholar 

  56. Trenkwalder C, Winkelmann J, Oertel W, Virgin G, Roubert B, Mezzacasa A, et al. Ferric carboxymaltose in patients with restless legs syndrome and nonanemic iron deficiency: a randomized trial. Mov Disord. 2017;32:1478–82 This is to date the study with the highest number of RLS patients comparing IV iron (FCM) vs. placebo.

    PubMed  PubMed Central  CAS  Google Scholar 

  57. Cho YW, Allen RP, Earley CJ. Efficacy of ferric carboxymaltose (FCM) 500 mg dose for the treatment of restless legs syndrome. Sleep Med. 2018;42:7–12.

    PubMed  Google Scholar 

  58. Mehmood T, Auerbach M, Earley CJ, Allen RP. Response to intravenous iron in patients with iron deficiency anemia (IDA) and restless leg syndrome (Willis-Ekbom disease). Sleep Med. 2014;15:1473–6.

    PubMed  Google Scholar 

  59. 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;24:1445–52.

    PubMed  Google Scholar 

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Acknowledgments

We would like to thank Anne-Marie Williams for reviewing our work.

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Correspondence to Celia Garcia-Malo MD.

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Conflict of Interest

Dr. Garcia-Malo has received educational support from Accord.

Dr. Miranda declares that she has no conflict of interest.

Dr. Romero Peralta declares that she has no conflict of interest.

Dr. Cano-Pumarega declares that she has no conflict of interest.

Dr. Novo Ponte has received unrestricted educational support from AbbVie, Zambon, Novartis.

Over the last 2 years, Dr. Garcia-Borreguero has participated in consulting activities for American Regent, Corp., and has received a research grant from MSD.

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Garcia-Malo, C., Miranda, C., Romero Peralta, S. et al. Iron Replacement Therapy in Restless Legs Syndrome. Curr Treat Options Neurol 22, 11 (2020). https://doi.org/10.1007/s11940-020-0617-7

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