RLS: Imbalance between thyroid and dopamine Pereira Jr. JC et al. explained by the common biofeedback mechanism that occurs when a hormone is being artificially diminished. Tolerance for a drug that is both an inducer and substrate of CYP450 could also explain some of the characteristics of the augmentation phenomenon. For example, tolerance to carbamazepine,49 which is also an effective treatment for RLS, is common. This drug, an inducer and substrate of CYP450, slowly causes tolerance because the induction of CYP also increases the speed with which carbamazepine itself is metabolized, rendering it less effective at inducing metabolism of TH. Notwithstanding, we do agree that there is not, as yet, a cognizance of the real causes of the augmentation phenomenon. Thus, it is difficult to explain why RLS symptoms start earlier in the day after the RLS augmentation phenomenon has been initiated. RLS is more common in older patients who are known to have a slower metabolism of TH compared to younger subjects. Hypothyroidism in older patients usually requires lower doses of thyroid hormone replacement.50 In light of the hypothesis of this work, there is a reasonable possibility that the slower metabolism of TH in the older subjects makes them more susceptible to RLS. In addition, subclinical hyperthyroidism is also more common (2%) in elderly subjects.50 “Growing pains” are common in childhood RLS,51 and some adult patients also complain of pain concomitant with other classical symptoms of RLS in the legs.3,5 A very important study by Ondo and colleagues (2000) demonstrated that the dopaminergic system in rats sends long projections from the midbrain into the spinal cord, which influences the gating of peripheral nociceptive input.52 With the profuse data demonstrating the tight interactions between TH and DA, it seems plausible that TH mediates these nociceptive inputs and that pain ensues when these inputs are not counterbalanced by DA. Growing pains occur mainly in the evening or night when TH levels are higher; they usually do not occur during the day when TH levels are lower. Rye and Freeman reported that DA synthesis, release, and signaling peak early during the active period and reach their nadir in the sleep phase.53 DA allows the gating of REFERENCES CLINICS 2010;65(5):547-54 inputs via alteration of membrane properties and specific ion conductances.54 Rye and Freeman explain that the physiological effects of the DA system are best characterized as “neuromodulatory,” rather than eliciting excitatory or inhibitory postsynaptic potentials.53 From the considerations about RLS clinical and physiopathology issues described above, it is possible to infer that the DA system also has a hormonal modulatory effect on TH. The hypothesis we presented refers only to primary RLS cases and those that are secondary to iron deficiency and pregnancy, which constitute the great majority of RLS patients. For these clinical situations, we have found strong evidence to support the hypothesis. We did not attempt to theorize about the pathophysiology of other secondary cases of RLS because we believe that doing so would be only speculation, in light of the few existent data on secondary RLS cases at this moment. We have also chosen not to address “Periodic Limb Movement in Sleep” for the same reason. This theoretical study attempts to establish a unified theory for RLS pathophysiology through a review of the current knowledge on this topic. A hypothesis is rendered and void if it is not supported by experimentation to validate it. Studies focusing on the TH axis and DA system in patients suffering from RLS might teach us more about this very serious human disease. A more detailed understanding of the importance of the cytochrome P450 enzyme system in RLS is warranted, as are studies of the genetics of the cytochrome P450 system. Moreover, iron deprivation might not be a concern restricted to RLS. Another issue raised by this paper is whether deviations of the normality of TH axis and DA system interaction might actually influence the quality of sleep in sleep disturbances other than RLS. Thus, RLS could be considered a paradigmatic disease for other sleep disturbances. We are much indebted to Dr Arthur S. Walters, Professor of Neurology Vanderbilt School of Medicine, Nashville, Tenesee, USA, for help criticism of the manuscript and kindly attention. We also thank to Dr Thales M. Pereira for drawing the figures of this manuscript. 1. American Academy of Sleep Medicine. International classification of sleep disorders, sec. edition. Diagnostic and coding manual. Wetchester, Illinois: American Academy of Sleep Medicine, 2005. 2. Allen R, Picchietti D, Hening W, Tremkwalder C, Walters AS, Montplaisir J. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4:101-19. 3. Lee Chiong TL, Sateia M, Carskadon M, Eds. Sleep Medicine. Philadelphia, PA: Hanley&Belfus (Elsevier), 2002. 4. 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. Sleep. 2006;29:29A70. 5. Earley C. Clinical practice. Restlesslegs syndrome. N Engl J Med. 2003;348:2103-9. 552 Copyright © 2010 CLINICS