Semin Neurol 2017; 37(04): 439-445
DOI: 10.1055/s-0037-1605342
Review Article
Thieme Medical Publishers 333 Seventh Avenue, New York, NY 10001, USA.

The Role of Iron in Pediatric Restless Legs Syndrome and Periodic Limb Movements in Sleep

Tiffany Munzer
1   Department of Developmental and Behavioral Pediatrics, University of Michigan, Ann Arbor, Michigan
,
Barbara Felt
1   Department of Developmental and Behavioral Pediatrics, University of Michigan, Ann Arbor, Michigan
› Author Affiliations
Further Information

Publication History

Publication Date:
24 August 2017 (online)

Abstract

Restless legs syndrome (RLS) is a common and treatable neurologic condition in pediatric patients, with a prevalence as high as 2 to 3%. The diagnosis of RLS is made clinically based on an urge to move the legs accompanied by lower extremity discomfort that occurs during rest usually later in the day and is relieved by movement. Periodic limb movements in sleep (PLMS) can overlap with RLS, although PLMS also exists as a separate entity characterized by stereotyped movements of lower extremities in sleep. Both conditions may be highly debilitating and interfere with daily function notably in the areas of educational attainment and behavioral regulation. Iron deficiency has been implicated in the pathophysiology of both RLS and PLMS. Current evidence suggests that treatment of ferritin levels < 50 µg/L may be beneficial in improving pediatric RLS symptoms and comorbid conditions or daytime dysfunction associated with RLS. Areas for future research include (1) clarifying the ferritin or other iron status measure level which predicts iron treatment will provide symptom improvement in pediatric patients, and (2) randomized clinical trials using iron therapy to determine the degree and duration of treatment.

 
  • References

  • 1 Picchietti MA, Picchietti DL. Restless legs syndrome and periodic limb movement disorder in children and adolescents. Semin Pediatr Neurol 2008; 15 (02) 91-99
  • 2 Allen RP, Picchietti DL, Garcia-Borreguero D. , et al; International Restless Legs Syndrome Study Group. 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 (08) 860-873
  • 3 Picchietti DL, Bruni O, de Weerd A. , et al; International Restless Legs Syndrome Study Group (IRLSSG). Pediatric restless legs syndrome diagnostic criteria: an update by the International Restless Legs Syndrome Study Group. Sleep Med 2013; 14 (12) 1253-1259
  • 4 Grim K, Lee B, Sung AY, Kotagal S. Treatment of childhood-onset restless legs syndrome and periodic limb movement disorder using intravenous iron sucrose. Sleep Med 2013; 14 (11) 1100-1104
  • 5 Halac G, Sezer GM, Saglam NO. , et al. The relationship between Willis-Ekbom disease and serum ferritin levels among children in Northwestern Turkey. Neurosciences (Riyadh) 2015; 20 (04) 336-340
  • 6 Allen RP, Auerbach S, Bahrain H, Auerbach M, Earley CJ. The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia. Am J Hematol 2013; 88 (04) 261-264
  • 7 Allen RP. Controversies and challenges in defining the etiology and pathophysiology of restless legs syndrome. Am J Med 2007; 120 (01) (Suppl. 01) S13-S21
  • 8 Allen R. Dopamine and iron in the pathophysiology of restless legs syndrome (RLS). Sleep Med 2004; 5 (04) 385-391
  • 9 Dye TJ, Jain SV, Simakajornboon N. Outcomes of long-term iron supplementation in pediatric restless legs syndrome/periodic limb movement disorder (RLS/PLMD). Sleep Med 2017; 32: 213-219
  • 10 Picchietti D, Allen RP, Walters AS, Davidson JE, Myers A, Ferini-Strambi L. Restless legs syndrome: prevalence and impact in children and adolescents--the Peds REST study. Pediatrics 2007; 120 (02) 253-266
  • 11 Zhang J, Lam SP, Li SX, Li AM, Kong AP, Wing YK. Restless legs symptoms in adolescents: epidemiology, heritability, and pubertal effects. J Psychosom Res 2014; 76 (02) 158-164
  • 12 Kotagal S, Silber MH. Childhood-onset restless legs syndrome. Ann Neurol 2004; 56 (06) 803-807
  • 13 Garcia-Borreguero D, Egatz R, Winkelmann J, Berger K. Epidemiology of restless legs syndrome: the current status. Sleep Med Rev 2006; 10 (03) 153-167
  • 14 Allen RP, Walters AS, Montplaisir J. , et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med 2005; 165 (11) 1286-1292
  • 15 Bjorvatn B, Leissner L, Ulfberg J. , et al. Prevalence, severity and risk factors of restless legs syndrome in the general adult population in two Scandinavian countries. Sleep Med 2005; 6 (04) 307-312
  • 16 Innes KE, Selfe TK, Agarwal P. Prevalence of restless legs syndrome in North American and Western European populations: a systematic review. Sleep Med 2011; 12 (07) 623-634
  • 17 Connor JR, Ponnuru P, Wang XS, Patton SM, Allen RP, Earley CJ. Profile of altered brain iron acquisition in restless legs syndrome. Brain 2011; 134 (Pt 4): 959-968
  • 18 Silva GE, Goodwin JL, Vana KD, Vasquez MM, Wilcox PG, Quan SF. Restless legs syndrome, sleep, and quality of life among adolescents and young adults. J Clin Sleep Med 2014; 10 (07) 779-786
  • 19 Seidel S, Böck A, Schlegel W. , et al. Increased RLS prevalence in children and adolescents with migraine: a case-control study. Cephalalgia 2012; 32 (09) 693-699
  • 20 Konofal E, Lecendreux M, Deron J. , et al. Effects of iron supplementation on attention deficit hyperactivity disorder in children. Pediatr Neurol 2008; 38 (01) 20-26
  • 21 Rana AQ, Mosabbir AA, Qureshi AR, Abbas M, Rana MA. Restless leg syndrome: a risk factor of higher prevalence of anxiety and depression in Parkinson's disease patients. Neurol Res 2016; 38 (04) 309-312
  • 22 Becker PM, Sharon D. Mood disorders in restless legs syndrome (Willis-Ekbom disease). J Clin Psychiatry 2014; 75 (07) e679-e694
  • 23 Whittom S, Dauvilliers Y, Pennestri MH. , et al. Age-at-onset in restless legs syndrome: a clinical and polysomnographic study. Sleep Med 2007; 9 (01) 54-59
  • 24 Winkelman JW. Periodic limb movements in sleep--endophenotype for restless legs syndrome?. N Engl J Med 2007; 357 (07) 703-705
  • 25 Picchietti DL, Rajendran RR, Wilson MP, Picchietti MA. Pediatric restless legs syndrome and periodic limb movement disorder: parent-child pairs. Sleep Med 2009; 10 (08) 925-931
  • 26 Stefansson H, Rye DB, Hicks A. , et al. A genetic risk factor for periodic limb movements in sleep. N Engl J Med 2007; 357 (07) 639-647
  • 27 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 (08) 1000-1006
  • 28 McLean E, Cogswell M, Egli I, Wojdyla D, de Benoist B. Worldwide prevalence of anaemia, WHO vitamin and mineral nutrition information system, 1993–2005. Public Health Nutr 2009; 12 (04) 444-454
  • 29 Cogswell ME, Looker AC, Pfeiffer CM. , et al. Assessment of iron deficiency in US preschool children and nonpregnant females of childbearing age: National Health and Nutrition Examination Survey 2003-2006. Am J Clin Nutr 2009; 89 (05) 1334-1342
  • 30 Gupta PM, Perrine CG, Mei Z, Scanlon KS. Iron, anemia, and iron deficiency anemia among young children in the United States. Nutrients 2016; 8 (06) 330
  • 31 Silva B, Faustino P. An overview of molecular basis of iron metabolism regulation and the associated pathologies. Biochim Biophys Acta 2015; 1852 (07) 1347-1359
  • 32 Kim A, Nemeth E. New insights into iron regulation and erythropoiesis. Curr Opin Hematol 2015; 22 (03) 199-205
  • 33 Looker AC, Dallman PR, Carroll MD, Gunter EW, Johnson CL. Prevalence of iron deficiency in the United States. JAMA 1997; 277 (12) 973-976
  • 34 Centers for Disease Control and Prevention. Recommendations to prevent and control iron deficiency in the United States. MMWR Recomm Rep 1998; 47 (RR-3): 1-29
  • 35 World Health Organization. Iron Deficiency Anaemia: Assessment, Prevention and Control. A Guide for Programme Managers. Geneva, Switzerland: World Health Organization; 2001
  • 36 Life Sciences Research Office. Assessment of the Iron Nutrition Status of the U.S. Population Based on Data Collected in the Second National Health and Nutrition Survey. Bethesda, MD: Federation of American Societies for Experimental Biology; 1984
  • 37 Cook JD, Finch CA. Assessing iron status of a population. Am J Clin Nutr 1979; 32 (10) 2115-2119
  • 38 Cook JD, Flowers CH, Skikne BS. The quantitative assessment of body iron. Blood 2003; 101 (09) 3359-3364
  • 39 Skikne BS, Flowers CH, Cook JD. Serum transferrin receptor: a quantitative measure of tissue iron deficiency. Blood 1990; 75 (09) 1870-1876
  • 40 Lozoff B. Early iron deficiency has brain and behavior effects consistent with dopaminergic dysfunction. J Nutr 2011; 141 (04) 740S-746S
  • 41 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; 15 (11) 1288-1301
  • 42 Pappas SS, Behrouz B, Janis KL, Goudreau JL, Lookingland KJ. Lack of D2 receptor mediated regulation of dopamine synthesis in A11 diencephalospinal neurons in male and female mice. Brain Res 2008; 1214: 1-10
  • 43 Patrick LR. Restless legs syndrome: pathophysiology and the role of iron and folate. Altern Med Rev 2007; 12 (02) 101-112
  • 44 Clemens S, Rye D, Hochman S. Restless legs syndrome: revisiting the dopamine hypothesis from the spinal cord perspective. Neurology 2006; 67 (01) 125-130
  • 45 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 2000; 54 (08) 1609-1616
  • 46 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 (08) 1698-1700
  • 47 Picchietti MA, Picchietti DL. Advances in pediatric restless legs syndrome: Iron, genetics, diagnosis and treatment. Sleep Med 2010; 11 (07) 643-651
  • 48 Simakajornboon N, Gozal D, Vlasic V, Mack C, Sharon D, McGinley BM. Periodic limb movements in sleep and iron status in children. Sleep 2003; 26 (06) 735-738
  • 49 Sun ER, Chen CA, Ho G, Earley CJ, Allen RP. Iron and the restless legs syndrome. Sleep 1998; 21 (04) 371-377
  • 50 O'Keeffe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in the elderly. Age Ageing 1994; 23 (03) 200-203
  • 51 Minár M, Košutzká Z, Habánová H, Rusňák I, Planck K, Valkovič P. Restless legs syndrome in pregnancy is connected with iron deficiency. Sleep Med 2015; 16 (05) 589-592
  • 52 Trenkwalder C, Allen R, Högl B, Paulus W, Winkelmann J. Restless legs syndrome associated with major diseases: A systematic review and new concept. Neurology 2016; 86 (14) 1336-1343
  • 53 Tilma J, Tilma K, Norregaard O, Ostergaard JR. Early childhood-onset restless legs syndrome: symptoms and effect of oral iron treatment. Acta Paediatr 2013; 102 (05) e221-e226
  • 54 Mohri I, Kato-Nishimura K, Kagitani-Shimono K. , et al. Evaluation of oral iron treatment in pediatric restless legs syndrome (RLS). Sleep Med 2012; 13 (04) 429-432
  • 55 Tarsy D. Treatment of restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in adults. Uptodate. 2016. . Available at: https://www.uptodate.com/contents/treatment-of-restless-legs-syndrome-willis-ekbom-disease-and-periodic-limb-movement-disorder-in-adults . Accessed January 30, 2017
  • 56 Dosman C, Witmans M, Zwaigenbaum L. Iron's role in paediatric restless legs syndrome - a review. Paediatr Child Health 2012; 17 (04) 193-197
  • 57 Picchietti DL, Chervin RD, Hoppin AG. Restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in children. Uptodate 2016
  • 58 Kryger MH, Otake K, Foerster J. Low body stores of iron and restless legs syndrome: a correctable cause of insomnia in adolescents and teenagers. Sleep Med 2002; 3 (02) 127-132
  • 59 Picchietti DL, Stevens HE. Early manifestations of restless legs syndrome in childhood and adolescence. Sleep Med 2008; 9 (07) 770-781
  • 60 Dosman CF, Drmic IE, Brian JA. , et al. Ferritin as an indicator of suspected iron deficiency in children with autism spectrum disorder: prevalence of low serum ferritin concentration. Dev Med Child Neurol 2006; 48 (12) 1008-1009
  • 61 Oner P, Dirik EB, Taner Y, Caykoylu A, Anlar O. Association between low serum ferritin and restless legs syndrome in patients with attention deficit hyperactivity disorder. Tohoku J Exp Med 2007; 213 (03) 269-276
  • 62 Furudate N, Komada Y, Kobayashi M, Nakajima S, Inoue Y. Daytime dysfunction in children with restless legs syndrome. J Neurol Sci 2014; 336 (1-2): 232-236
  • 63 Peirano P, Algarin C, Chamorro R, Manconi M, Lozoff B, Ferri R. Iron deficiency anemia in infancy exerts long-term effects on the tibialis anterior motor activity during sleep in childhood. Sleep Med 2012; 13 (08) 1006-1012
  • 64 Wang J, O'Reilly B, Venkataraman R, Mysliwiec V, Mysliwiec A. Efficacy of oral iron in patients with restless legs syndrome and a low-normal ferritin: A randomized, double-blind, placebo-controlled study. Sleep Med 2009; 10 (09) 973-975
  • 65 Ondo WG. Clinical features and diagnosis of restless legs syndrome/Willis-Ekbom disease and periodic limb movement disorder in adults. Uptodate 2016