Elsevier

Sleep Medicine

Volume 5, Issue 4, July 2004, Pages 385-391
Sleep Medicine

Udine Special Section
Dopamine and iron in the pathophysiology of restless legs syndrome (RLS)

https://doi.org/10.1016/j.sleep.2004.01.012Get rights and content

Abstract

Background and purpose: The evaluation of the pathophysiology of restless legs syndrome (RLS) stems largely from recognition of the information provided by both pharmacological treatment of the disorder and the secondary forms of the disorder. This article examines the pathophysiological implications of each of these clinical aspects of RLS.

Patients and methods: The article reviews the existing literature in relation to possible pathology suggested by the clinical data. It will then explore other data supporting each of the possible pathologies and examine the relationships between these pathologies.

Results: The pharmacological treatment data strongly support a dopaminergic abnormality for RLS. Other pharmacological data and some imaging data also support this, although the data are not entirely consistent. The secondary forms of RLS strongly support an iron deficiency abnormality for RLS, further documented by several other studies. Some animal studies have shown a relation between iron deficiency and dopaminergic abnormalities that have some similarity to those seen in the RLS patient.

Conclusions: It is concluded that there may be an iron–dopamine connection central to the pathophysiology of RLS for at least some if not most patients with this disorder.

Section snippets

Introduction—development of the RLS program at Johns Hopkins University

The involvement of the Johns Hopkins group in the study of the restless less legs syndrome (RLS) started with a review of our clinical sleep medicine cases that I conducted in 1988–1989. When I reviewed the cases I found a large number that had been diagnosed with periodic limb movement disorder (PLMD) who had in general not benefited from our treatment, which was entirely restricted to the use of benzodiazepines and some behavioral sleep treatments. Some complained of having an expensive test

Evidence for dopaminergic pathology in RLS

The strongest evidence for a dopaminergic pathology in RLS comes from the pharmacological response to medications. To date, all evaluated agents that enhance dopamine activity have been found to reduce RLS symptoms in open-label uncontrolled trials. Double-blinded, placebo-controlled studies have demonstrated the treatment benefit for levodopa [12], [16], [17] and for the currently used major dopamine agonists, i.e. pergolide [18], [19], pramipexole [20] and ropinirole [21]. These medications

Evidence for iron pathology in RLS

The potential central role of iron insufficiency to RLS is indicated primarily by the secondary causes of RLS, but also from some limited pharmacological study. Three causes of secondary RLS have been well established. RLS develops with the development of each of these disorders, is more common for patients with these disorders than expected for the population, and disappears when the disorders are treated. End stage renal disease (ESRD) with dialysis is perhaps the best studied of the

Evaluation of iron status in RLS

If we assume that the primary pathology of RLS involves iron insufficiency, then we want to measure the iron status and relate it to the RLS status. Our group at Johns Hopkins and Hershey School of Medicine has explored four different methods for evaluating the iron status of RLS patients; i.e. serum measures of ferritin, CSF measures of ferritin and transferrin, magnetic resonance imaging (MRI) measures of regional brain iron concentrations and autopsy evaluations of brain iron status. All of

Possible connections between iron and dopamine pathology in RLS

Iron is known to be a co-factor at the rate-limiting step in the production of dopamine, and decreased iron may reduce the tyrosine hydroxylase activity. This, however, was not clearly shown in the autopsy study [58], and the role of iron in this step may not be very sensitive to iron loss. Iron deprived rats with brain iron deficiency have been found to have decreased D1 and D2 receptors [59], decreased DAT [60], and increased extra-cellular dopamine in the striatum [61] and a more consistent

Conclusions

The data reviewed above provides support for the view that iron and dopamine may be linked in producing RLS symptoms. Further evaluation of the iron–dopamine connection in general, and particularly in relation to RLS, is needed.

Acknowledgements

This work was supported in part by US NIH grant R01-NS38704.

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