Melody Ryan; John T. Slevin

Disclosures

Am J Health Syst Pharm. 2006;63(17):1599-1612. 

In This Article

Pathophysiology

Secondary RLS

Of individuals with conditions associated with iron-deficiency states, including pregnancy, renal failure, and anemia, 25-30% may develop RLS.[31] Individuals with renal failure or who are pregnant may have RLS symptoms without significant anemia but with deficient iron stores (defined by a serum ferritin concentration of <50 µg/L). Oral and i.v. iron therapy may improve or resolve RLS symptoms in patients with clear iron-deficiency anemia and also in RLS of pregnancy and renal disease where iron stores may be reduced without obvious anemia.[31] Conversely, 75% of individuals with RLS symptoms may have decreased iron stores,[32] and iron deficiency has been considered a significant contributing cause for more than 50 years.[33] Similar to RLS, serum iron has a marked circadian variation, with as much as a 30-50% drop in serum iron concentration at night.[34] A 68% decrease in cerebrospinal fluid (CSF) ferritin and a greater than threefold increase in CSF transferrin, indicative of low brain iron, have been reported in patients with idiopathic RLS in whom serum ferritin and transferrin equaled controls.[35] Finally, using special magnetic resonance imaging techniques to quantify brain iron, Allen et al.[36] demonstrated lower iron concentrations in the substantia nigra and putamen in proportion to severity of symptoms in RLS patients compared to controls.

Primary RLS

The mechanisms underlying primary RLS remain unknown. Because they frequently coexist and respond to the same medications, it is reasonable to presume that RLS and periodic limb movement disorder (PLMD) likely have a shared, but not identical, pathophysiology. Many causes of RLS have been proposed but not completely elucidated.[37] Using electrophysiological methods, Bara-Jimenez et al.[38] demonstrated that periodic limb movements and spinal flexor reflexes share common spinal mechanisms. Furthermore, compared with controls, patients with RLS had increased spinal cord excitability, as indicated by lower threshold and greater spatial spread of the evoked spinal flexor reflex, which was more prominent during sleep. These data suggest that the final common pathway for RLS and PLMD is enhanced spinal cord excitability. Thus, it is noteworthy that RLS has been reported in association with chronic myelopathy, peripheral neuropathy, and lumbosacral radiculopathy.[39]

Because dopaminergic mechanisms are involved in spinal flexor reflex control and dopamine agonists provide symptomatic relief of RLS and PLMD (discussed later), it has been hypothesized that this neurotransmitter is central in their pathophysiology. However, imaging studies scrutinizing either the dopamine type 2 (D2)-receptor or dopamine transporter have yielded mixed results, with three demonstrating reduced synaptic activity[40,41,42] and two showing no difference from controls.[43,44] Regardless, the therapeutic effect of dopamine agonists and the increase in RLS symptoms and periodic leg movements in response to dopamine antagonists provide strong support for this hypothesis.[37] Furthermore, proteins involved in dopamine transmission exhibit circadian rhythms, possibly providing an explanation for the circadian character of RLS.[45] The similarities in treatment response suggest a potential shared pathophysiology between RLS and Parkinson's disease. However, current evidence does not convincingly show more than a casual association.[46]

Given the similar circadian rhythms of serum iron levels, the proteins involved in dopamine transmission, and RLS symptoms, it is difficult not to hypothesize a connection. In fact, iron is a cofactor for tyrosine hydroxylase, which is the rate-limiting enzyme for dopamine synthesis.[47] Thus, a decrease in iron may decrease dopamine synthesis and therefore dopamine availability. However, studies in iron-deficient animals have also demonstrated a decrease in D1- and D2-receptors in the caudate-putamen,[48] a decrease in dopamine transporter function[49] and density,[49,50] and an elevation in extra-cellular dopamine.[49] Clearly, if there is an iron-dopamine connection in RLS, it is complex and it will need to be elucidated.

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