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