Elsevier

Sleep Medicine

Volume 15, Issue 11, November 2014, Pages 1288-1301
Sleep Medicine

Review Article
Altered Brain iron homeostasis and dopaminergic function in Restless Legs Syndrome (Willis–Ekbom Disease)

https://doi.org/10.1016/j.sleep.2014.05.009Get rights and content

Highlights

  • The role of altered iron homeostasis in restless legs syndrome (RLS) is reviewed.

  • Iron-deficient rodent as a model for understanding RLS pathology is explored.

  • A role for the activation of the hypoxia pathway in RLS pathology is discussed.

  • The data on dopaminergic system involvement in RLS are reviewed.

  • Possible alterations in synaptic dopaminergic dynamic in RLS are discussed.

  • A theoretical model for dopamine-agonist-induced augmentation is presented.

Abstract

Restless legs syndrome (RLS), also known as Willis–Ekbom Disease (WED), is a sensorimotor disorder for which the exact pathophysiology remains unclear. Brain iron insufficiency and altered dopaminergic function appear to play important roles in the etiology of the disorder. This concept is based partly on extensive research studies using cerebrospinal fluid (CSF), autopsy material, and brain imaging indicating reduced regional brain iron and on the clinical efficacy of dopamine receptor agonists for alleviating RLS symptoms. Finding causal relations, linking low brain iron to altered dopaminergic function in RLS, has required however the use of animal models. These models have provided insights into how alterations in brain iron homeostasis and dopaminergic system may be involved in RLS. The results of animal models of RLS and biochemical, postmortem, and imaging studies in patients with the disease suggest that disruptions in brain iron trafficking lead to disturbances in striatal dopamine neurotransmission for at least some patients with RLS. This review examines the data supporting an iron deficiency–dopamine metabolic theory of RLS by relating the results from animal model investigations of the influence of brain iron deficiency on dopaminergic systems to data from clinical studies in patients with RLS.

Introduction

Restless legs syndrome (RLS), also known as Willis–Ekbom disease (WED), is a common sensorimotor disorder that has a prominent circadian pattern [1]. Evidence has accumulated for the role of brain iron insufficiency and dopamine (DA) neurotransmission abnormalities in the etiology of RLS. The suspected role of a DA abnormality in RLS is due in large part to the remarkable treatment response seen with levodopa and dopaminergic (DAergic) agonists in alleviating RLS symptoms versus the symptom exacerbation observed with DA antagonists [2], [3], [4], [5], [6]. However, the mechanisms by which abnormalities in DAergic neurotransmission or in DA metabolism result in the development of RLS have remained elusive.

An association between iron deficiency and RLS was originally identified by Nordlander in the 1950s [7]. Further studies have shown a higher prevalence of RLS symptoms in conditions that compromise iron availability [8]. A recent study in a population of patients with iron-deficiency anemia reported finding a 31.5% prevalence of RLS [9], which is six times higher than the general USA population prevalence for RLS [10]. Most patients with RLS, however, do not have an obvious iron deficiency. This point was evident to Nordlander, who proposed that: “It is possible, however, that there can exist an iron deficiency in the tissue in spite of normal serum iron.” [11] True to that hypothesis, despite the lack of an apparent systemic iron deficiency in most RLS patients, an iron-insufficient state appears to exist in the brains of RLS patients [2]. This brain-specific deficit in iron may be a consequence of the tight regulation of iron transportation by the blood–brain barrier [12]. Iron is normally transported into the brain from the plasma by the choroid plexus within the cerebral ventricles and by binding to the transferrin receptor expressed on endothelial cells in the brain microvasculature [13], [14], [15]. However, recent postmortem studies by Connor et al. [16] suggested that the expression and activity of iron-management proteins, including transferrin and its receptor, in the choroid plexus and brain microvasculature in the brains of patients with RLS differ from that observed in healthy control subjects without RLS.

Iron is an important modulator of DA neurotransmission [14]. However, the process by which disruption of brain iron homeostasis leads to alterations in DAergic neurotransmission and the development of RLS remains unknown. Iron deficiency can be reproduced experimentally in animal models, thus providing an opportunity to explore how changes in iron metabolism affect DAergic signaling pathways, putatively resulting in the development of RLS in humans. Nonetheless, there are other potential pathways by which an individual with otherwise normal-range iron levels and DA metabolism may develop RLS. Therefore, the iron–DA theory of RLS is a singular hypothesis for which additional causative factors or intervening systems, including adenosinergic [17], opioid [18], or glutamatergic [19] systems, may be involved pathologically in RLS. The purpose of this review is to examine and evaluate the evidence for one major conceptual framework for a biological basis of RLS: the iron deficiency–DA metabolic theory of RLS. It relates the findings from animal models investigating the influence of brain iron deficiency on DAergic systems to data from clinical studies in patients with RLS.

Section snippets

Animal models of brain iron deficiency and DA abnormalities in RLS

The iron-deficient (ID) rodent (mouse and rat) is a compelling animal model for RLS. It has permitted the evaluation of the pathway between iron deficiency and the DAergic system and has helped identify possible biological endpoints, including the role of iron-transport proteins and changes in DA receptor expression, which may underlie the disease pathology [20], [21], [22], [23], [24], [25], [26], [27], [28], [29].

Clinical studies of iron deficiency and DA function in RLS

Clinical studies analyzing the cerebrospinal fluid (CSF) and postmortem brain tissue from patients with RLS have reported findings consistent with the diet-induced, ID rodent model. Imaging studies have further extended these postmortem observations to provide additional clinical evidence for the effects of iron deficiency on DAergic function in patients with RLS. Although the sections that follow focus on the effects of iron and DA dysfunction, it is important to note that many patients with

A putative model for the role of iron in RLS pathology

Understanding the complex nature of iron regulation and its role in the pathology of RLS is a challenge, but there is a need to at least develop a testable conceptual framework from the existing data. Therefore, the model proposed here is one viewpoint for the role of iron homeostasis in RLS pathology. It is, however, not a construct based solely on theoretical views of the CNS, but rather on experimental results. It is derived directly from the existing data from both RLS studies and animal

A putative model for the role of DA in RLS pathology

The DA agonists have been shown to be highly effective in treating RLS symptoms. Administration of the specific D2R antagonist, metoclopramide, induces RLS-like symptoms, that is, akathisia [131], and use of similar drugs in RLS will aggravate symptoms [132]. This indicates that decreased signaling through the D2R is important in the development of akathisia, the key feature of RLS symptomology. Thus, the clinical data support the concept that decreased DAergic “signal” is at least an

Conclusions

The etiology of RLS is complex and the concepts advanced in this article present a partial description of one major potential pathophysiological pathway in the development of RLS, the iron deficiency–DA interaction. Because iron deficiency can precipitate RLS-related symptoms, the rodent animal model of iron deficiency allows for the exploration of the effects of iron deficiency and circadian or diurnal regulation on brain iron metabolism and DAergic neurotransmission in a controlled

Conflict of interest

The ICMJE Uniform Disclosure Form for Potential Conflicts of Interest associated with this article can be viewed by clicking on the following link: http://dx.doi.org/10.1016/j.sleep.2014.05.009.

. ICMJE Form for Disclosure of Potential Conflicts of Interest form.

Acknowledgments

The authors wish to acknowledge the work done be Nathan Silver on MEIS1 effects in human lymphoblast presented in Fig. 4. The authors also acknowledge Richard Fay, PhD, CMPP, of Evidence Scientific Solutions, Philadelphia, PA, for medical writing support and editorial assistance, which was funded by UCB Pharma, Smyrna, GA. UCB Pharma was offered the opportunity to comment on this article: changes resulting from the comments were made on the basis of scientific and editorial merit.

References (152)

  • MeffordI.N.

    Application of high performance liquid chromatography with electrochemical detection to neurochemical analysis: measurement of catecholamines, serotonin and metabolites in rat brain

    J Neurosci Methods

    (1981)
  • RefshaugeC. et al.

    New high performance liquid chromatographic analysis of brain catecholamines

    Life Sci

    (1974)
  • CheferV.I. et al.

    Quantitative no-net-flux microdialysis permits detection of increases and decreases in dopamine uptake in mouse nucleus accumbens

    J Neurosci Methods

    (2006)
  • UngerE.L. et al.

    Dopamine D2 receptor expression is altered by changes in cellular iron levels in PC12 cells and rat brain tissue

    J Nutr

    (2008)
  • EarleyC.J. et al.

    The dopaminergic neurons of the A11 system in RLS autopsy brains appear normal

    Sleep Med

    (2009)
  • Collado-SeidelV. et al.

    Clinical and biochemical findings in uremic patients with and without restless legs syndrome

    Am J Kidney Dis

    (1998)
  • AraujoS.M. et al.

    Restless legs syndrome in end-stage renal disease: clinical characteristics and associated comorbidities

    Sleep Med

    (2010)
  • ClardyS.L. et al.

    Is ferroportin-hepcidin signaling altered in restless legs syndrome?

    J Neurol Sci

    (2006)
  • GanzT. et al.

    Hepcidin and iron homeostasis

    Biochim Biophys Acta

    (2012)
  • EarleyC.J. et al.

    Circadian changes in CSF dopaminergic measures in restless legs syndrome

    Sleep Med

    (2006)
  • AllenR.P. et al.

    Abnormally increased CSF 3-Ortho-methyldopa (3-OMD) in untreated restless legs syndrome (RLS) patients indicates more severe disease and possibly abnormally increased dopamine synthesis

    Sleep Med

    (2009)
  • EarleyC.J. et al.

    MRI-determined regional brain iron concentrations in early- and late-onset restless legs syndrome

    Sleep Med

    (2006)
  • ZhengW. et al.

    Measuring iron in the brain using quantitative susceptibility mapping and X-ray fluorescence imaging

    Neuroimage

    (2013)
  • KvernmoT. et al.

    A review of the receptor-binding and pharmacokinetic properties of dopamine agonists

    Clin Ther

    (2006)
  • LohseM.J. et al.

    Kinetics and mechanism of G protein-coupled receptor activation

    Curr Opin Cell Biol

    (2014)
  • MetayeT. et al.

    Pathophysiological roles of G-protein-coupled receptor kinases

    Cell Signal

    (2005)
  • SemenzaG.L.

    Hypoxia-inducible factor 1: regulator of mitochondrial metabolism and mediator of ischemic preconditioning

    Biochim Biophys Acta

    (2011)
  • SemenzaG.L.

    Involvement of oxygen-sensing pathways in physiologic and pathologic erythropoiesis

    Blood

    (2009)
  • BenediktsdottirB. 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)
  • Lo CocoD. et al.

    Increased frequency of restless legs syndrome in chronic obstructive pulmonary disease patients

    Sleep Med

    (2009)
  • OhayonM.M. et al.

    Prevalence of restless legs syndrome and periodic limb movement disorder in the general population

    J Psychosom Res

    (2002)
  • PhillipsB. et al.

    Prevalence and correlates of restless legs syndrome: results from the 2005 National Sleep Foundation Poll

    Chest

    (2006)
  • HeningW.A. et al.

    Circadian rhythm of motor restlessness and sensory symptoms in the idiopathic restless legs syndrome

    Sleep

    (1999)
  • Garcia-BorregueroD. et al.

    Algorithms for the diagnosis and treatment of restless legs syndrome in primary care

    BMC Neurol

    (2011)
  • TrenkwalderC. et al.

    Treatment of restless legs syndrome: an evidence-based review and implications for clinical practice

    Mov Disord

    (2008)
  • TrenkwalderC. et al.

    Restless legs syndrome: pathophysiology, clinical presentation and management

    Nat Rev Neurol

    (2010)
  • WinkelmanJ.W. et al.

    Restless legs syndrome: nonpharmacologic and pharmacologic treatments

    Geriatrics

    (2007)
  • NordlanderN.B.

    Therapy in restless legs

    Acta Med Scand

    (1953)
  • AllenR.P. et al.

    The role of iron in restless legs syndrome

    Mov Disord

    (2007)
  • AllenR.P. et al.

    The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia

    Am J Hematol

    (2013)
  • AllenR.P. et al.

    Restless legs syndrome prevalence and impact: REST general population study

    Arch Intern Med

    (2005)
  • NordlanderN.B.

    Restless legs

    Br J Phys Med

    (1954)
  • BeardJ.L.

    Iron biology in immune function, muscle metabolism and neuronal functioning

    J Nutr

    (2001)
  • BeardJ.L. et al.

    Iron in the brain

    Nutr Rev

    (1993)
  • FishmanJ.B. et al.

    Receptor-mediated transcytosis of transferrin across the blood-brain barrier

    J Neurosci Res

    (1987)
  • ConnorJ.R. et al.

    Profile of altered brain iron acquisition in restless legs syndrome

    Brain

    (2011)
  • AllenR.P. et al.

    Thalamic glutamate/glutamine in restless legs syndrome: increased and related to disturbed sleep

    Neurology

    (2013)
  • BiancoL.E. et al.

    Iron deficiency alters the day-night variation in monoamine levels in mice

    Chronobiol Int

    (2009)
  • BiancoL.E. et al.

    Iron deficiency alters dopamine uptake and response to L-DOPA injection in Sprague-Dawley rats

    J Neurochem

    (2008)
  • ConnorJ.R. et al.

    Altered dopaminergic profile in the putamen and substantia nigra in restless leg syndrome

    Brain

    (2009)
  • Cited by (0)

    View full text