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.
Similar content being viewed by others
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
Ohayon MM, O’Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. 2012;16:283–95.
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.
Earley CJ, Silber MH. Restless legs syndrome: understanding its consequences and the need for better treatment. Sleep Med. 2010;11:807–15.
Ferri R, Koo BB, Picchietti DLFS. Periodic leg movements during sleep: phenotype, neurophysiology, and clinical significance. Sleep Med. 2017;31:29–38.
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.
Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J. Restless legs syndrome associated with major diseases. Neurology. 2016;86:1336–43.
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.
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.
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.
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.
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.
Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and the restless legs syndrome. Sleep. 1998;21:371–7.
Rizzo G, Li X, Galantucci S, Filippi M, Cho YW. Brain imaging and networks in restless legs syndrome. Sleep Med. 2017;31:39–48.
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.
Provini F, Chiaro G. Neuroimaging in restless legs syndrome. Sleep Med Clin. 2015;10:215–26.
Godau J, Sojer M. Transcranial sonography in restless legs syndrome. Int Rev Neurobiol. 2010;90:199–215.
Connor J, Boyer P, Menzies S, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology. 2003;61:304–9.
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.
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.
Winkelmann J, Schormair B, Xiong L, Dion PA, Rye DB, Rouleau GA. Genetics of restless legs syndrome. Sleep Med. 2017;31:18–22.
Ferré S, Quiroz C, Guitart X, et al. Pivotal role of adenosine neurotransmission in restless legs syndrome. Front Neurosci. 2018;11:1–14.
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.
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.
Allen RP, Barker PB, Wehrl FW, Song HKEC. MRI measurement of brain iron in patients with restless legs syndrome. Neurology. 2001;56:263–5.
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
Ferré S, García-Borreguero D, Allen RPEC. New insights into the neurobiology of restless legs syndrome. Neuroscientist. 2019;25:113–25.
Becker G, Berg D. Neuroimaging in basal ganglia disorders: perspectives for transcranial ultrasound. Mov Disord. 2001;16:23–32.
Vivó-Orti MN, Tembl JI, Sastre-Bataller I, et al. Evaluación de la sustancia negra mediante ultrasonografía transcraneal. Rev Neurol. 2013;56:268–74.
Sanzaro E, Iemolo F. Transcranial sonography in movement disorders: an interesting tool for diagnostic perspectives. Neurol Sci. 2016;37:373–6.
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.
Schmidauer C, Sojer M, Seppi K, et al. Transcranial ultrasound shows nigral hypoechogenicity in restless legs syndrome. Ann Neurol. 2005;54:630–4.
Godau J, Schweitzer KJ, Liepelt I, Gerloff CBD. Substantia nigra hypoechogenicity: definition and findings in restless legs syndrome. Mov Disord. 2007;22:187–92.
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.
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.
Ganz T. Anemia of inflammation. N Engl J Med. 2019;381:1148–57.
Waldvogel-Abramowski S, Waeber G, Gassner C, Buser A, Frey BM, Favrat BTJ. Physiology of iron metabolism. Transfus Med Hemother. 2014;41:213–21.
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.
Muckenthaler MU. Fine tuning of hepcidin expression by positive and negative regulators. Cell Metab. 2008;8:1–3.
Watson J, Round AHW. Raised inflammatory markers. BMJ. 2012;344:e454.
LA Pfeiffer CM. Laboratory methodologies for indicators of iron status: strengths, limitations, and analytical challenges. Am J Clin Nutr. 2017;106:1606S–14S.
Ridefelt P, Larsson A, Rehman JUAJ. Influences of sleep and the circadian rhythm on iron-status indices. Clin Biochem. 2010;43:323–8.
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.
Powell LW. Diagnosis of hemochromatosis. Semin Gastrointest Dis. 2002;13:80–8.
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.
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.
Cho YW, Allen RP, Earley CJ. Clinical efficacy of ferric carboxymaltose treatment in patients with restless legs syndrome. Sleep Med. 2016;25:16–23.
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.
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.
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.
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.
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.
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.
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.
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.
DeLoughery TG. Safety of oral and intravenous iron. Acta Haematol. 2019;142:8–12.
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.
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.
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.
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.
Acknowledgments
We would like to thank Anne-Marie Williams for reviewing our work.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
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.
Human and Animal Rights and Informed Consent
This article does not contain any studies with human or animal subjects performed by any of the authors.
Additional information
Publisher’s Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
This article is part of the Topical Collection on Sleep Disorders
Rights and permissions
About this article
Cite this article
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
Published:
DOI: https://doi.org/10.1007/s11940-020-0617-7