Dopamine and Iron in the Pathophysiology of Restless Legs Syndrome (RLS)

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Sleep Medicine 5 (2004) 385–391 www.elsevier.com/locate/sleep Udine Special Section Dopamine and iron in the pathophysiology of restless legs syndrome (RLS)

Richard Allen*

Neurology and Sleep Medicine, Johns Hopkins Bayview Medical Center, Asthma and Allergy Bldg 1B46b, 5501 Hopkins Bayview Circle, Baltimore, MD 21224, USA

Received 1 January 2003; accepted 15 October 2003

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. q 2004 Elsevier B.V. All rights reserved.

Keywords: Restless legs syndrome; Dopamine; Iron; Pathophysiology; Ferritin; CSF

1. Introduction—development of the RLS program the RLS could be a major cause of PLMS. We were all at Johns Hopkins University aware that this connection had been made many years earlier by Lugaresi et al. [1], but had simply considered the The involvement of the Johns Hopkins group in the study PLMD diagnosis to be not only more common but also of the restless less legs syndrome (RLS) started with a clinically more significant. At that time, however, there was review of our clinical sleep medicine cases that I conducted no well-established diagnostic criterion for RLS and no in 1988–1989. When I reviewed the cases I found a large awareness of its prevalence or clinical significance. The number that had been diagnosed with periodic limb sleep education provided by the professional organization movement disorder (PLMD) who had in general not now recognized as the American Academy of Sleep benefited from our treatment, which was entirely restricted Medicine provided little information or education about to the use of benzodiazepines and some behavioral sleep RLS. The limited education provided about RLS (e.g. two treatments. Some complained of having an expensive test slides in a 1-h talk) recommended treatment based on and no help. More than half had discontinued their current literature with opiates [2], clonazepam [3] or medications. In the face of these discouraging results I did carbamazepine [4–7], specifically recommending avoid- a review of the literature regarding periodic limb move- ance of dopaminergic agents because they were expected to ments in sleep (PLMS) and PLMD and realized we had exacerbate the condition, based on reports of effects on failed in our sleep medicine program to appreciate that myoclonus [8]. Professional and scientific interest focused on the periodic limb movements of sleep (PLMS). RLS was * Tel.: þ1-410-550-2609; fax: þ1-410-550-3364. a casual afterthought and the impression given was that it E-mail address: [email protected]. was difficult to treat and not a common problem.

The recent literature at the time of our review also of the predictions and research gains from a putative revealed that Akpinar [9,10], who was unaware of the dopamine–iron connection in RLS. recommendation to avoid the use of levodopa to treat RLS, had described a serendipitous finding to the contrary. He reported that levodopa provided dramatic and almost 2. Evidence for dopaminergic pathology in RLS complete relief of RLS symptoms for his patients, maintained with continued use of the medication. The The strongest evidence for a dopaminergic pathology in efficacy of this treatment had been further documented by RLS comes from the pharmacological response to medi- the excellent studies of Montplaisir and colleagues [11,12]. cations. To date, all evaluated agents that enhance dopamine At the same time, however, Walters, Hening and Kavey activity have been found to reduce RLS symptoms in open- were reporting effective treatment of RLS with opioids label uncontrolled trials. Double-blinded, placebo-con- including propoxyphene [13]. My first goal, then, was to trolled studies have demonstrated the treatment benefit for determine which of these treatments we should use and levodopa [12,16,17] and for the currently used major whether they were suitable for all patients with PLMD or dopamine agonists, i.e. pergolide [18,19], pramipexole only those with RLS. We conducted a double-blinded [20] and ropinirole [21]. These medications are effective crossover pilot study to determine the relative efficacy of at remarkably low doses relative to that given for carbidopa/levodopa and propoxyphene for treatment of Parkinson’s disease, sometimes at the minimum tablet size patients with PLMS, provided they had RLS or significant available to the patient, e.g. carbidopa/levodopa at 25/100 or daytime complaints indicating that PLMS disturbed their pergolide at 12.5 mg. Moreover, they are effective immedi- normal functioning. We excluded patients with other sleep ately after the first therapeutic dose for virtually all patients disorders. Almost all selected patients had RLS, and to our with RLS. The immediate, universal and almost complete surprise all showed dramatic reduction in PLMS on a very reduction of RLS symptoms by low doses of levodopa low dose of either 50/100 or 100/200 carbidopa/levodopa provides strong support for a possible dopaminergic and only marginally significant reductions on either 100 or abnormality in this disorder. 200 mg of propoxyphene [14,15]. We concluded that Dopamine antagonists generally exacerbate RLS symp- dopaminergic medications should be considered as the toms, suggesting a primary role for the dopamine system. treatment of first choice for RLS, and possibly for PLMD In the first report of this effect, Pimozide, a dopamine contingent on the patient showing significant daytime antagonist was shown to reverse treatment benefits of the dysfunction associated with the PLMS. Moreover, we opioid Codeine in one patient [22]. In a later study, agreed with Montplaisir that the excellent pharmacological Metoclopramide given IV produced increased RLS symp- response at a very low dose suggested specific dopaminergic toms on a suggested immobilization test in five out of six pathology for RLS. This appeared to be a potentially subjects evaluated [23] and produced an increase in significant area for further study. At that time we decided to prolactin release [23] that was at least three times greater focus attention on RLS and its pathology, and this effort was than that expected from age-matched normals [24]. greatly enhanced when Dr Christopher J. Earley joined the Dopaminergic abnormalities in the tuberoinfundibular clinical and research team and committed to advancing system have been further supported by the exaggerated its work. response of prolactin to levodopa [25]. Further examination of all the data on RLS provided two It deserves note that all other types of medications used different bases for assessing potential pathophysiology: to treat RLS require doses equivalent to those used to treat pharmacological response and secondary forms of RLS. The other conditions. The doses for the opioids are usually in the first strongly supports the dopaminergic abnormality, and same range as that used for the analgesic treatments; e.g. the this has been the emphasis of most studies to date. The average effective dose of oxycodone in one double-blind second, however, fails to provide any support for RLS as a controlled study was 15.7 mg (about three 5 mg tablets) primarily dopaminergic disorder, but rather posits the [26]. Similarly, the average effective dose of the antic- clearly established secondary causes of RLS as iron onvulsant gabapentin in a double-blind controlled study was deficiency anemia, end stage renal disease, and pregnancy, 1,855 mg [27], about the same as that used for seizure all involving iron insufficiency. (Note that although diabetes control. The effects of these medications on RLS symptoms and neuropathy are commonly given as causes for may therefore be indirect, such as a non-specific effect on secondary RLS, the data supporting this claim do not nociception. Moreover, naloxone does not exacerbate RLS currently exist.) There are also many other reported causes symptoms, and when it was given IV did not produce of secondary RLS, but none aside from these three have increased symptoms during a SIT test [23]. Thus, the been clearly documented, with the possible exception of pharmacological evidence supports a dopaminergic gastric surgery. The following provides a review of the abnormality more than it does for any other neurotransmitter evidence, separately for each of the suggested pathophy- system. siologies for RLS, and then briefly examines some possible Imaging studies have produced mixed results. The one connections between these two pathologies noting some PET study with an adequate sample size found decreased R. Allen / Sleep Medicine 5 (2004) 385–391 387 striatal D2R binding [28]. Two of four SPECT studies also for the population, and disappears when the disorders are found decreased striatal D2R binding [29,30], but one of treated. End stage renal disease (ESRD) with dialysis is these studies [30] was compromised by having significantly perhaps the best studied of the secondary causes of RLS. younger controls than patients; thus the well established RLS develops with the disorder and occurs in 20–60% of decrease in D2R binding with age could explain these patients on dialysis [35–37], or about 2–6 times more results. The other study had no similar problem and was frequently than expected. The RLS symptoms with ESRD particularly well controlled. Two other similarly well- have been related to increased mortality [35]. Kidney controlled SPECT studies, however, failed to find any transplants resolving the renal disease also lead to a difference in striatal D2R binding [31,32]. Two SPECT disappearance of all RLS symptoms within 1–21 days studies failed to find differences in striatal dopamine after transplant for all patients who have been reported transporter (DAT) [29,32]. But it should be noted that all [38,39]. RLS also develops in about 20–30% of pregnant of these studies were conducted in the daytime when RLS women [40,41]. Women with RLS before pregnancy symptoms are minimal. It may be that evaluation of the reported increased severity of RLS symptoms during dopaminergic system when the patient has few symptoms pregnancy [41]. The RLS symptoms are clinically reported will produce variable results depending on the degree of to usually resolve after pregnancy, and did so in 85% of the symptom expression, thus explaining the conflicting results cases in one study [40]. Ekbom [42] identified RLS as reported above. Evaluation during the symptomatic period commonly occurring with iron deficiency anemia and this is needed, but has not yet been done. There is one report of a has gained wide clinical acceptance, although there have PET study showing significant circadian changes in D1 been few studies documenting this relationship. O’keeffe receptor binding [33], and it seems reasonable to assume the found that oral iron supplement treatment of iron deficiency same may occur for D2 receptors. Moreover, DAT plays a among older patients with RLS reduced or reversed the RLS significant role in the substantia nigra in regulating the symptoms [43]. Data indicate that two other conditions nigrostriatal dopaminergic system, and this has not yet been increasing the risk of RLS are gastric surgery and frequent studied. There have also been two good studies using blood donations. The increased prevalence of RLS after F-dopa PET that both found significantly less uptake by gastrectomy was described by Ekbom [44] and supported by about 11% in the putamen for RLS patients compared to subsequent study [45]. More recent studies have documen- normal controls [28,34]. One of these studies reported ted the increased prevalence of RLS for frequent blood approximately the same difference ðP , 0:05Þ for the donors [46]. Both neuropathy and diabetes have been caudate [34], while the other found no significant difference reported to be associated with the development of RLS, but for the caudate [28]. These studies are somewhat difficult to survey studies using full diagnostic criteria have failed to interpret. They suggest decreased pre-synaptic uptake, but it find any significant increase in the prevalence of RLS for deserves note that in Parkinson’s disease even patients with either neuropathy [47] or diabetes [48]. significant cell loss have normal F-dopa striatal uptake. This small decrease may reflect changes in the status of the All of the established causes of secondary RLS involve growth or integrity of the terminals of the dopaminergic compromise of iron sufficiency. Treatment with IV iron and cells. Since fluorodopa is also taken up by serotonergic cells erythropoietin reduced the RLS symptoms of PLMS in one there may be some uncertainty regarding the specificity of study of patients on dialysis [49]. Iron deficiency commonly this finding for the dopaminergic cells. Finally, there is a occurs in pregnancy, and the pregnant women at risk of RLS problem with competitive binding for receptor uptake. An showed compromise in iron status before pregnancy [40], increase in extracellular dopamine would produce a although it was noted that folate may also be involved. decrease in dopamine receptor binding. The currently Correcting iron status in patients with iron deficiency has available data do not permit controlling for this possibility. been found to reduce RLS symptoms [43]. Both gastric Overall, the imaging data, while not entirely consistent, surgery and frequent blood donations have a support some mild reductions in the nigrostriatal dopamin- well-recognized increased risk of reduced iron sufficiency. ergic system, but further study is needed to confirm this and Virtually all the conditions clearly associated with common better describe the characteristics of this abnormality. occurrence of secondary RLS involve problems with iron metabolism, and the obverse is also true; all conditions involving iron insufficiency increase the risk of 3. Evidence for iron pathology in RLS developing RLS. The relationship between iron and RLS was recognized The potential central role of iron insufficiency to RLS is much earlier by Nordlander, who postulated that a tissue indicated primarily by the secondary causes of RLS, but also deficiency in iron might be responsible for the occurrence of from some limited pharmacological study. Three causes of RLS. He also used IV iron to treat RLS patients, including secondary RLS have been well established. RLS develops several without clear anemia, and reported complete with the development of each of these disorders, is more remission of symptoms lasting several months for 21 of common for patients with these disorders than expected the 22 patients. [50,51]. Thus, pharmacological data as well 388 R. Allen / Sleep Medicine 5 (2004) 385–391 as data from secondary RLS strongly support a relation between iron deficiency and RLS.

4. 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 these have supported the view that there is a brain iron deficiency in RLS patients. Fig. 1. Serum ferritin levels and RLS severity for a consecutive available The serum ferritin had previously been found by RLS patients. (reprinted with permission from Sun, et al. 1998). O’Keeffe to correlate with RLS symptoms for older patients. O’Keeffe correctly recognized that serum ferritin provides the best measure of peripheral iron stores. Serum measures. Thus, all RLS patients in this study showed measures of iron and transferrin relate more to immediate abnormally reduced CNS iron status. A particularly striking activity of iron transport and only very poorly to the status finding from that study was the positive correlation between of the body stores of iron. Even the serum measure of the serum and CSF ferritin. Higher levels of ferritin in the serum soluable transferrin receptor [52], when in the normal range, were associated with higher levels in the CSF for both relates to the rate of erythropoiesus more than to iron stores, normal controls and RLS patients, but the slope of this although when abnormal provides a more reliable measure relationship was much lower for the RLS patients. Thus, for of the iron deficiency. Ferritin, in contrast, relates to iron RLS patients, higher levels of 200 mcg/l or greater for stores over a wider range with the exception of the elevated serum ferritin tended to occur with CSF ferritin in the low values seen in response to disease states. We decided to range of the usual normal levels. replicate the O’Keeffe finding and extend it to a full age The MRI has long been known to be altered by the range of RLS patients. For our study we also developed and amount of iron in ferritin, and recent studies have developed validated a fairly simply clinical rating scale for RLS a valid MRI measure of regional brain iron concentration. severity, the Johns Hopkins Restless Legs Scale (JHRLSS). For this measure the transverse relaxation rates or the This scale assessed RLS severity by the patients’ report of inverses of the relaxation times are used, and it has been 0 ; the usual time of symptom onset, with 0 indicating no found that R2 representing the relaxation resulting from symptoms, 1 symptoms only at or after bedtime, 2 field inhomogeneities that can be reversed by an 1808 pulse, symptoms in the evening (after 6 p.m.) but not earlier, and provides the most specific measure of regional brain iron. R2 3 symptoms earlier in the day. This scale correlated is measured as the irreversible transverse relaxation rate and p 0 : p significantly with the objective polysomnographic measures R2 represents the sum of R2 and R2 The images with R2 will of sleep disruption from RLS of PLMS/h of sleep and sleep have the most sensitive measure of iron content and are used 0 efficiency [53] and has been shown to be responsive enough for identification of significant regions, but the values of R2 to detect treatment benefits in small-size, double-blinded are the most specific for iron since they will not be medication trials [54]. In a consecutive series of available contaminated by other factors affecting R2 relaxation rates RLS patients we found approximately the same degree of such as brain water content [56]. In our study of five RLS correlation between our subjective scale for RLS severity patients and five age-matched controls the RLS patients : ; : 0 and serum ferritin (r ¼ 0 48 P ¼ 0 02; see Fig. 1) [55] as showed significant decreases in R2 in the substantia nigra, was reported by O’Keeffe for his older RLS patients. which correlated significantly with the JHRLSS measure of In a subsequent study, morning CSF iron measures severity [57]. The much lower iron content in the substantia were obtained from 16 consenting RLS patients and eight nigra can be clearly seen for the RLS patient compared to age-matched normal controls. Studies with iron-deprived the control (shown in Fig. 2). Thus, the brain iron problems rats indicate that low CSF ferritin and high transferrin can for RLS involve particularly significant iron reduction in the be expected to occur with reduced brain iron. The RLS substantia nigra, which appears not only to be related to patients compared to controls showed differences for both occurrence of RLS but also to its severity. iron status measures in the CSF ðP , 0:02Þ; despite having Finally, a recent initial report of an autopsy analyses of normal serum levels for all iron measures, and all 16 the substantia nigra for an RLS patient compared to controls patients were abnormal in at least one of these CSF showed reduced iron content in the cells, an apparent R. Allen / Sleep Medicine 5 (2004) 385–391 389

p p Fig. 2. R2 images in (A) a 70-year-old RLS patient and (B) a 71-year-old control subject. Much lower R2 relaxation rates are apparent in the RLS case in the substantia nigra and also the red nucleus. (Reprinted with permission from Allen et al., 2001.) reduction in H-ferritin along with an abnormal cellular period from the last part of the rest period through the first distribution of L-ferritin [58]. part of the active period (from light to dark periods). The The combined impact of all these studies can leave little normal animal showed a significant increase in extra- doubt that at least some, and probably most RLS patients cellular dopamine, but the iron-deprived rat showed an have an abnormality of iron metabolism that appears central increase that was four times greater [61]. This is particularly to the pathology of the disorder. The question remains about hard to explain given that motor activity is, if anything the connection between these two pathologies for RLS: iron generally decreased for these iron-deprived animals during and dopamine. the active period. The issue of circadian variation in dopamine function in relation to iron deficiency deserves to be more carefully explored, especially given the 5. Possible connections between iron and dopamine pronounced circadian pattern of RLS symptoms. pathology in RLS

Iron is known to be a co-factor at the rate-limiting step in 6. Conclusions the production of dopamine, and decreased iron may reduce the tyrosine hydroxylase activity. This, however, was not The data reviewed above provides support for the view clearly shown in the autopsy study [58], and the role of iron that iron and dopamine may be linked in producing RLS in this step may not be very sensitive to iron loss. Iron symptoms. Further evaluation of the iron–dopamine deprived rats with brain iron deficiency have been found to connection in general, and particularly in relation to RLS, have decreased D1 and D2 receptors [59], decreased DAT is needed. [60], and increased extra-cellular dopamine in the striatum [61] and a more consistent decrease in H- than L-ferritin in brain regions [62]. As noted above, two imaging studies of Acknowledgements RLS patients suggest a possible decrease in the D2R binding [28,29], which could reflect a decrease in the D2 receptors, This work was supported in part by US NIH grant an increase in extra-cellular dopamine, or both. The autopsy R01-NS38704. studies have also shown a greater decrease in H- than L-ferritin [58]. These results are in general consistent for both the RLS patients and the effects of iron deprivation on References dopaminergic function in the rat brain. The findings for the DAT are, however, not the same for the rat iron-deficiency [1] Lugaresi G, Coccagna G, Berti Ceroni G, Ambrosetto C. Restless legs and human RLS, but the DAT studies for RLS patients syndrome and nocturnal myoclonus. In: Gastaut H, Lugaresi E, Berti involved only daytime evaluations and did not use the more Ceroni G, editors. The abnormalities of sleep in man. Bologna: Aulo sensitive PET measures. These need to be extended before it Gaggi Editore; 1968. p. 285–94. is clear that this is a real difference. The similarities of the [2] Hening WA, Walters A, Kavey N, et al. Dyskinesias while awake and periodic movements in sleep in restless legs syndrome: treatment with dopaminergic abnormalities resulting from brain iron opioids. Neurology 1986;36:1363–6. deprivation in the rat and those observed to occur in RLS [3] Montagna P, de Bianchi LS, Zucconi M, et al. Clonazepam and patients indicate a possible strong iron-dopamine connec- vibration in restless legs syndrome. Acta Neurol Scand 1984;69(6): tion in RLS pathology that should be further explored. 428–30. It is particularly interesting to note that most of these [4] Telstad W, Sorensen O, Larsen S, Lillevold PE, Stensrud P, Nyberg- Hansen R. Treatment of the restless legs syndrome with carbamaze- animal studies have neglected to examine the circadian pine: a double blind study. Br Med J 1984;288(6415):444–6. effects. One study evaluated changes in the extra-cellular [5] Lundvall O, Abom PE, Holm R. Carbamazepine in restless legs. A dopamine of normal and iron-deprived rats over the time controlled pilot study. Eur J Clin Pharmacol 1983;25(3):323–4. 390 R. Allen / Sleep Medicine 5 (2004) 385–391

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