The restless legs syndrome

Progress in Neurobiology 77 (2005) 139–165 www.elsevier.com/locate/pneurobio

The restless legs syndrome G. Barrie`re a,d, J.R. Cazalets a, B. Bioulac a,b, F. Tison a,c, I. Ghorayeb a,b,* b

a Laboratoire de Neurophysiologie, UMR-CNRS 5543, Universite´ Bordeaux 2, Bordeaux, France Service d’Explorations Fonctionnelles du Syste`me Nerveux, Hoˆpital Pellegrin, Place Ame´lie Raba-Le´on, 33076 Bordeaux cedex, France c Service de Neurologie, Hoˆpital du Haut Le´veˆque, Avenue de Magellan, 33604 Pessac cedex, France d De´partement de Physiologie, Centre de Recherche en Sciences Neurologiques, Faculte´ de Me´decine, Universite´ de Montre´al, CP 6128, Succursale Centre-Ville, Montre´al, Que., Canada H3C 3JT

Received 8 August 2005; received in revised form 19 October 2005; accepted 21 October 2005

Abstract The restless legs syndrome (RLS) is one of the commonest neurological sensorimotor disorders at least in the Western countries and is often associated with periodic limb movements (PLM) during sleep leading to severe insomnia. However, it remains largely underdiagnosed and its underlying pathogenesis is presently unknown. Women are more affected than men and early-onset disease is associated with familial cases. A genetic origin has been suggested but the mode of inheritance is unknown. Secondary causes of RLS may share a common underlying pathophysiology implicating iron deficiency or misuse. The excellent response to dopaminegic drugs points to a central role of dopamine in the pathophysiology of RLS. Iron may also represent a primary factor in the development of RLS, as suggested by recent pathological and brain imaging studies. However, the way dopamine and iron, and probably other compounds, interact to generate the circadian pattern in the occurrence of RLS and PLM symptoms remains unknown. The same is also the case for the level of interaction of the two compounds within the central nervous system (CNS). Recent electrophysiological and animals studies suggest that complex spinal mechanisms are involved in the generation of RLS and PLM symptomatology. Dopamine modulation of spinal reflexes through dopamine D3 receptors was recently highlighted in animal models. The present review suggests that RLS is a complex disorder that may result from a complex dysfunction of interacting neuronal networks at one or several levels of the CNS and involving numerous neurotransmitter systems. # 2005 Elsevier Ltd. All rights reserved. Keywords: Restless legs syndrome; Periodic limb movements; Dopamine; Iron; Opioids; Noradrenaline; Spinal cord

Contents 1. 2. 3. 4. 5. 6. 7.

Introduction . . . . . . . . . . . . . . . . . . . . . Clinical presentation. . . . . . . . . . . . . . . . Epidemiology . . . . . . . . . . . . . . . . . . . . Genetics . . . . . . . . . . . . . . . . . . . . . . . . Periodic limb movements . . . . . . . . . . . . Circadian rhythm of RLS and PLM . . . . . Secondary RLS . . . . . . . . . . . . . . . . . . . 7.1. Iron deficiency . . . . . . . . . . . . . . . 7.2. Uremia and end-stage renal disease

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Abbreviations: CNS, central nervous system; CPG, central pattern generator; CSF, cerebrospinal fluid; CSP, cortical silent period; D3KO, D3 knock-out; DAT, dopamine transporter; EMG, electromyography; GH, growth hormone; ICF, intracortical facilitation; ICI, intracortical inhibition; IRLSSG, international restless legs syndrome study group; IRPs, iron regulatory proteins; MEP, motor evoked potentials; MRI, magnetic resonance imaging; PAM, periodic arm movements; PET, positron emission tomography; PLM, periodic limb movements; PD, Parkinson’s disease; PRL, prolactin; PSG, polysomnography; RLS, restless legs syndrome; SN, substantia nigra; BH4, tetrahydrobiopterin; TfR, transferrin receptor; TH, tyrosine hydroxylase; SSRIs, selective serotonin re-uptake inhibitors; SPECT, singlephoton emission computed tomography; TMS, transcranial magnetic stimulation; VTA, ventral tegmental area * Corresponding author. Tel.: +33 556 79 55 13; fax: +33 556 79 61 09. E-mail address: [email protected] (I. Ghorayeb). 0301-0082/$ – see front matter # 2005 Elsevier Ltd. All rights reserved. doi:10.1016/j.pneurobio.2005.10.007

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8. 9. 10. 11. 12.

13.

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7.3. Pregnancy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.4. Neuropathy . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7.5. Parkinson’s disease . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Dopamine and RLS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Opioids and RLS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Iron and RLS . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Brain structures . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sensorimotor processes at the spinal cord level . . . . . . . . . . . . . . . . . . . . . . 12.1. Spinal origin of RLS? . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.2. Is there a spinal pattern generator involved in PLM? . . . . . . . . . . . . . 12.3. State- and task-dependent modulation of spinal sensorimotor networks . 12.3.1. Sleep-wake modulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . 12.3.2. Task-dependent modulation . . . . . . . . . . . . . . . . . . . . . . . . . 12.4. Neuromodulatory control of spinal sensorimotor networks. . . . . . . . . . 12.4.1. L-DOPA and catecholamines . . . . . . . . . . . . . . . . . . . . . . . . 12.4.2. The action of dopamine on the spinal cord networks . . . . . . . 12.4.3. The action of noradrenaline on the spinal cord networks. . . . . 12.4.4. Inhibitory mechanisms in the spinal cord . . . . . . . . . . . . . . . 12.4.5. The opiate system in the spinal cord. . . . . . . . . . . . . . . . . . . Animal models of RLS and PLM . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.1. Spontaneous behavioral approaches . . . . . . . . . . . . . . . . . . . . . . . . . 13.2. Lesioning approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.3. Pharmacologic approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.4. Metabolic approaches . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 13.5. Genetic approaches. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Conclusion . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

1. Introduction The restless legs syndrome (RLS) remains one of the most intriguing and commonest chronic sensorimotor disorders, yet it is still a poorly recognized condition in primary care settings as physicians are frequently unaware of the condition and misdiagnosis is common (Allen et al., 2005; Hening, 2004; Tison et al., 2005; Van De Vijver et al., 2004; Walters et al., 1996). Even though RLS was first identified and characterized in the forties (Ekbom, 1945), it is only recently that the International Restless Legs Syndrome Study Group (IRLSSG) outlined its clinical features (Allen et al., 2003). The underlying neurophysiological and biochemical mechanisms are currently being investigated and recent animal and molecular studies have also begun to elucidate the still uncertain nature of the basic pathophysiology of RLS. In the present review, we have attempted to summarize the most relevant and recent clinical, epidemiological and genetic aspects of RLS. Much of the manuscript also concerns the secondary forms of RLS as we believe that some may share a similar pathophysiology. The latter has been discussed in separate sections devoted to major biochemical and neurotransmitter systems, brain structures and particularly to spinal mechanisms thought to be involved in the pathophysiology of RLS. Finally, the article concludes with a summary of certain major animal models with pathophysiological significance which have emerged over recent years and which are likely to influence future research in this field.

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Despite extensive literature on the topic, RLS appears increasingly to be a complex disorder whose underlying pathophysiology is still unraveled. However, this should not impede clinical and fundamental research efforts for better recognition of the disease. 2. Clinical presentation RLS is a common and treatable chronic sensorimotor disorder clinically characterized by a compelling urge to move the limbs, accompanied by uncomfortable and unpleasant sensations in the extremities. Typically, the legs are mostly affected but arm involvement has also been reported (Ekbom, 1960; Michaud et al., 2000; Montplaisir et al., 1997; Ondo and Jankovic, 1996). The diagnosis of RLS is clinical and is based on the patient’s description. Subjective symptoms, which are the hallmark of the condition, were first extensively described by Ekbom in the 1940s (Ekbom, 1945), but consensual diagnostic criteria were recently outlined allowing a more uniform diagnosis worldwide (Walters, 1995), and were then updated by the IRLSSG (Allen et al., 2003). Accordingly, four mandatory clinical features are required to establish the diagnosis of RLS, namely (i) an urge to move the legs, usually accompanied or caused by uncomfortable and unpleasant sensations in the legs; (ii) an urge to move or unpleasant sensations that begin or worsen during periods of rest or inactivity such as lying or sitting; (iii) an urge to move or unpleasant sensations that are partially or totally relieved by movement, such as walking or stretching, at least as long as the

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activity continues; (iv) an urge to move or unpleasant sensations that are worse in the evening or night than during the day or only occur in the evening or night. Thus, symptoms of RLS show a characteristic circadian evolution with a nocturnal worsening leading to severe insomnia, consequent daytime sleepiness and reduced quality of life (Allen et al., 2005; Ekbom, 1945). However, when symptoms are very severe, their circadian fluctuation may not be noticeable but must have been present earlier in the disease course. A family history of RLS, a positive response to dopaminergic treatment, and an association with stereotyped periodic limb movements (PLM) both in sleep and wakefulness are additional clinical features that may provide support for the diagnosis in some atypical clinical presentations. Although RLS can occur at any age, its onset is usually in the second decade of life and initially it often follows a mild fluctuating course with periods of remission that may be misleading (Ekbom, 1960; Walters et al., 1996). However, in all individuals with RLS, the frequency and severity of symptoms tend to increase over time together with the progression of the disease (Walters et al., 1996), and a more rapid progressive phenotype has also been described in late-onset forms of RLS (Allen and Earley, 2000). The expressivity of symptoms may also vary from one patient to another and even within a single family (Lazzarini et al., 1999; Trenkwalder et al., 1996b; Walters et al., 1990). Therefore, although RLS prevalence is rather high, only 11.9% of patients with the condition will be led to consult (Ohayon and Roth, 2002), and severe forms that lead to the seeking of treatment are present in only about 3.4% of patients (Hening, 2004). For patients with moderate to severe symptoms, drug therapy is required. First choice treatment relies on low doses of dopamine agonists or levodopa, but gabapentin, opioids and clonazepam are alternative treatment possibilities either alone or in combination with dopaminegic therapy (Hening et al., 1999a; Thorpy, 2005). 3. Epidemiology Prevalence rates of RLS, at least in Western countries, clearly identify this disorder as one of the most common neurological movement disorders. However, prevalence estimates in general populations do not overlap across studies even when the IRLSSG criteria are strictly applied. The subjective nature of the complaints, the fluctuating and intermittent course of initial symptoms, different targeted patient populations, and the various methodological tools used such as mailed questionnaires, telephone interviews, or direct face-to-face interviews may partly account for these discrepancies. Furthermore, few studies have involved large population-based samples of subjects screened using the IRLSSG criteria. If only IRLSSG criteria-based studies in Western countries are considered, the RLS prevalence rate ranges from 7.2 to 11.5% in the general population (Allen et al., 2005; Bjorvatn et al., 2005). In these and other studies, a marked female preponderance was demonstrated (Berger et al., 2002, 2004; Lavigne and Montplaisir, 1994; Nichols et al., 2003; Ohayon and Roth, 2002; Rijsman et al., 2004; Rothdach et al., 2000; Tison et al., 2005; Ulfberg et al., 2001a,b; Van De Vijver et al.,

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2004) with prevalence estimates ranging from 9 to 14.2% among women and from 5.4 to 9.4% among men (Allen et al., 2005; Bjorvatn et al., 2005; Hogl et al., 2005). Whether parity or postmenopausal intake of estrogen are to be considered as major factors in explaining this sex difference awaits further confirmation (Berger et al., 2004; Rothdach et al., 2000). Epidemiology also suggests ethnic variation. Asian IRLSSG criteria-based studies indicate a prevalence rate of 0.6% in a selected healthy general population 55 years of age and older, and of 0.1% in a primary healthcare centre population aged 21 years and older in Singapore (Tan et al., 2001). A similar low prevalence of 0.8 and 1.06% was also reported in India (Krishnan et al., 2003) and in Japan (Mizuno et al., 2005b), respectively. The low prevalence of RLS in these studies precluded analysis of predisposing risk factors or associations. Another study performed in Turkey found a prevalence rate of 3.19% (Sevim et al., 2003). In Israel, it was evaluated at 2.9% (Machtey, 2001). Prevalence estimates may also vary in Western countries. RLS prevalence is significantly higher in Norway than in Denmark (14.3 and 8.8%, respectively) (Bjorvatn et al., 2005). These regional variations may be due to the complex influence of variable genetic susceptibility and/or still undetermined environmental factors. However, the 12.1% prevalence rate of RLS recently reported in a large Korean cohort makes it difficult to support such a claim, even though the study did not include the IRLSSG criteria (Kim et al., 2005). Prevalence of RLS also increases with age (Allen et al., 2005; Hening, 2004; Kim et al., 2005; Lavigne and Montplaisir, 1994; Ohayon and Roth, 2002; Phillips et al., 2000; Rijsman et al., 2004; Tison et al., 2005; Ulfberg et al., 2001a,b), women being affected more than men in all age categories (Allen et al., 2005; Kim et al., 2005; Rothdach et al., 2000; Tison et al., 2005; Van De Vijver et al., 2004) except for subjects 80 and older in whom RLS symptoms were found to be slightly more common in men than women (Nichols et al., 2003). A decrease in prevalence with older age has also been reported (Allen et al., 2005; Nichols et al., 2003; Tison et al., 2005), particularly in men (Hogl et al., 2005; Rothdach et al., 2000). Increasing comorbidity in the very old, however, may interfere with the accurate identification of RLS and lead to misestimating the true prevalence. No definite age of onset can be determined from available studies. Onset before 18 years of age has been reported (Ekbom, 1960; Ohayon and Roth, 2002; Walters et al., 1996) and 38–45% of adults with RLS have onset of symptoms before the age of 20 years (Montplaisir et al., 1997; Walters et al., 1996). Juvenile onset is not rare (Ekbom, 1960; Montplaisir et al., 1997; Walters et al., 1994, 1996) but prevalence studies on RLS in childhood are scarce. One difficulty is that children with RLS report different phenotypes that do not meet IRLSSG criteria but rather resemble ‘‘growing pains’’ or attention deficit-hyperactivity disorder (Chervin et al., 2002; Ekbom, 1960, 1975; Picchietti et al., 1999; Rajaram et al., 2004; Walters et al., 1994, 1996). Using the newly established diagnostic criteria for RLS in children (Allen et al., 2003), one recent study established the prevalence rate in children to be 5.9% (Kotagal and Silber, 2004).

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4. Genetics A positive family history of RLS is supportive of the diagnosis of RLS (Allen et al., 2003). Clinical surveys have shown that in idiopathic forms of the disease, 40.9–92% of patients report having a family history of RLS, suggesting the contribution of genetic factors to the development of this condition (Bjorvatn et al., 2005; Lavigne and Montplaisir, 1994; Montplaisir et al., 1997; Ondo and Jankovic, 1996; Tison et al., 2005; Walters et al., 1996; Winkelmann et al., 2000, 2002a). In childhood, familial history was reported in 71% of the cases (Kotagal and Silber, 2004). Although clinical features do not differ between familial and sporadic cases of RLS (Ondo and Jankovic, 1996; Winkelmann et al., 2000), familial RLS significantly correlates with an earlier age at onset, a slowly progressive development of symptoms (Ondo et al., 2000b; Walters et al., 1996; Winkelmann et al., 2000, 2002a), and a limited relation to serum iron status in contrast to late-onset RLS patients (Allen and Earley, 2000). Investigations of single families with RLS as well as monozygotic twins studies are consistent with an autosomal dominant mode of inheritance with high and age-dependent penetrance, variable expressivity and possible anticipation in some families (Bonati et al., 2003; Chen et al., 2004; Lazzarini et al., 1999; Montplaisir et al., 1985; Ondo et al., 2000b; Trenkwalder et al., 1996b; Walters et al., 1990; Winkelmann et al., 2000, 2002a). This observation is reinforced by reports of RLS in certain familial forms of diseases such as Charcot-Marie-Tooth type 2 (Gemignani et al., 1999) and autosomal dominant cerebellar ataxia (Schols et al., 1998). A predilection for mother-to-child transmission has also been suggested in earlier case reports and more recent studies (Ekbom, 1975; Kotagal and Silber, 2004; Walters et al., 1994). However, the first study to identify a susceptibility locus for RLS in a single large French-Canadian family suggested a recessive pattern of transmission mimicking a ‘pseudodominant pattern of inheritance’ because of the high defective gene-carrier frequency (Desautels et al., 2001b). Using a genome-wide linkage approach, the first susceptibility genetic locus for RLS (RLS1) was identified on chromosome 12q (Desautels et al., 2001b), and this linkage was further confirmed in additional French-Canadian families (Desautels et al., 2005). This result, however, was not confirmed either in two large South Tyrolean families (Kock et al., 2002) or in two other Northern Italian families (Bonati et al., 2003; Ferini-Strambi et al., 2004). Subsequently, two other putative susceptibility loci for RLS were identified on chromosomes 14q in a North Italian family (Bonati et al., 2003), and chromosome 9p in North American families (Chen et al., 2004). The 14q locus was not formally replicated in the French-Canadian family (Levchenko et al., 2004) and linkage for RLS on chromosome 9p is still debated (Ray and Weeks, 2005). Therefore, and as for other neurological diseases, uncertainties persist regarding the results of association studies and RLS (Cardon and Bell, 2001). Potential problems with linkage studies in RLS, a complex trait disease, may in part arise from its subjective nature and the lack of objective criteria to define the disorder.

In view of the dopaminergic hypothesis to account for RLS, molecular genetic studies have also investigated RLS candidate genes among those encoding receptors, enzymes and neurotransmitters involved in dopaminergic transmission and metabolism, including D1 to D5 dopamine-receptors, dopamine transporter (DAT), tyrosine hydroxylase (TH), dopamine b-hydroxylase, GTP-cyclohydrolase, monoamine oxidase A and B, and neurotensin. No evidence for linkage could be found for any of these chromosomal regions in the French-Canadian family investigated (Desautels et al., 2001a) except for the monoamine oxidase A in severely affected women (Desautels et al., 2002). Without dwelling unduly on the strengths and weaknesses of these genetic association studies, current thinking points to a polygenic basis for RLS with possible complex interactions between multiple genes and putative environmental factors yet to be determined (Chen et al., 2004). 5. Periodic limb movements Another feature of RLS seen in most patients is the presence of unilateral or bilateral recurring movements of the lower limbs referred to as PLM (Coleman et al., 1980). This condition is characterized by periodic episodes of involuntary repetitive and highly stereotyped extension of the big toe and dosiflexion of the ankle with occasional flexion of the knee and hip. The movements usually involve the legs, but in severely affected RLS patients, the arms may also be involved (Chabli et al., 2000). During sleep, PLM are defined as the occurrence of four or more consecutive limb movements at intervals of 5–90 s and duration of 0.5–5 s, predominantly during light sleep stages 1 and 2. Diagnosis of PLM disorder requires the establishment of a mean of 5 PLM per hour of sleep. These involuntary limb movements can also occur while awake, periodically or not, almost exclusively at rest and particularly in severely affected patients with RLS (Chabli et al., 2000; Hening et al., 1999b; Pollmacher and Schulz, 1993; Walters, 1995). As for RLS, PLM exhibit a circadian pattern, women are more likely to be affected than men and prevalence increases with age (AncoliIsrael et al., 1991; Nicolas et al., 1999; Ohayon and Roth, 2002; Roehrs et al., 1983). First described as nocturnal myoclonus (Symonds, 1953), the association of PLM with RLS was confirmed as early as the sixties (Lugaresi et al., 1965). However, although the presence of PLM is not mandatory for the diagnosis of RLS, an elevated PLM index during sleep is supportive of the diagnosis, and it is now considered that patients without PLM are unlikely to have RLS (Allen et al., 2003). Nearly 82–100% of patients with RLS have a PLMS index greater than 5 on polysomnography (PSG) (Montplaisir et al., 1997; Winkelmann et al., 2000). In a telephone interview-based study, however, prevalence was much lower as only 18.5% of RLS subjects also had PLM (Ohayon and Roth, 2002). PLM also occur in a number of sleep disorders such as narcolepsy (Montplaisir and Godbout, 1986), sleep apnea syndrome (Fry et al., 1989) and REM-sleep behavior disorder (Lapierre and Montplaisir, 1992). They can also occur as an isolated condition in otherwise healthy

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subjects, especially in the elderly (Ancoli-Israel et al., 1991; Roehrs et al., 1983), and it is currently controversial whether PLM during sleep cause a sleep disorder by themselves (Mendelson, 1996; Nicolas et al., 1998). 6. Circadian rhythm of RLS and PLM Even if sleep deprivation increases the degree of subjective discomfort through a homeostatic process, the striking diurnal fluctuation of RLS symptoms suggests that independent circadian mechanisms play an essential role in the pathophysiology of the disorder. Worsening of both sensory and motor symptoms in RLS has been shown to follow a circadian pattern that parallels core body temperature rhythm, independently from the general level of activity, sleep deprivation, drowsiness or fatigue. Peak intensity of symptoms occurs when core body temperature rhythm decreases, whereas symptom severity decreases when core temperature increases (Hening et al., 1999b; Michaud et al., 2004; Trenkwalder et al., 1999a). In RLS, however, the basic circadian rhythm does not seem to be altered, as shown by the normal 24-h profiles of stable markers of the endogenous pacemaker – the suprachiasmatic nucleus – i.e., core body temperature, cortisol, and melatonin excretion (Michaud et al., 2004; Tribl et al., 2003; Wetter et al., 2002; Winkelmann et al., 2001). Since the dopaminergic system seems to play a central role in the pathophysiology of RLS, it is likely that alteration in the circadian variation of the dopaminergic system or related compounds might account for RLS symptom fluctuations. Interestingly, some patients with Parkinson’s disease (PD) display daily variations in the severity of symptoms, and others experience a sleep benefit defined as a restoration of mobility on awakening from sleep prior to drug intake (Hogl and Gershanik, 2000), indicating potential communication between the dopamine system and the circadian clock. Despite the fact that dopaminergic neurons do not show state-dependent changes in their firing rate in contrast to other monoaminergic cell groups (Miller et al., 1983; Steinfels et al., 1983), circadian variations have been described for key elements of the dopaminergic system. Circadian variations have been shown in plasma dopamine and its metabolites in humans (Sowers and Vlachakis, 1984), in non-human primate cerebrospinal fluid (CSF) (Perlow et al., 1977) and in the rat striatum (Castaneda et al., 2004; Schade et al., 1995), with a pattern characterized by a peak in the morning and a nadir at night (Kawano et al., 1990; Wilkes et al., 1981). This is particularly true for hypothalamic dopamine (Carlsson et al., 1980). A clear circadian gene expression pattern was also demonstrated in brain regions involved in motor regulation, e.g. TH mRNA levels in the substantia nigra (SN) pars compacta and in the ventral tegmental area (VTA), and dopamine D2 receptor mRNA levels in the caudate putamen (Weber et al., 2004). Circadian expression of TH was also recently demonstrated at the level of the spinal cord (Clemens et al., 2005). While no direct assumption can be made about striatal dopamine concentration from TH mRNA levels in the SN, the finding of a TH upregulation during the light period

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is in accordance with findings of a striatal dopamine concentration peak during the day (Castaneda et al., 2004; Schade et al., 1995), thus providing some clues to explain the mechanism underlying the phenomenon of sleep benefit in patients with PD. Finally, circadian modulation of dopamine receptor responsiveness was demonstrated in decapitated Drosophila melanogaster at the level of the nerve cord (Andretic and Hirsh, 2000). Therefore, dopamine levels, receptor status and dopamine-synthesizing enzyme expression may play a role in circadian regulation and expression of RLS by influencing sensorimotor processing at the spinal level in a circadian fashion, as already suggested for pain perception (Glynn and Lloyd, 1976). However, circadian dysfunction of the dopamine system has not yet been demonstrated in RLS, as most investigations for both plasma and CSF biochemical abnormalities have not included an assessment of circadian function. So far, blood and CSF dopamine and serotonin metabolite concentrations have not been found to differ between patients and controls (Earley et al., 2001; StiasnyKolster et al., 2004b). Only one study reported elevated CSF dopamine and homovanillic acid levels in one patient (Montplaisir et al., 1985). Possible dopaminergic system dysfunction in RLS was also investigated by examining the secretion pattern of neuroendocrine hormones whose release is modulated by dopamine, such as prolactin (PRL) and growth hormone (GH). In normal people, levodopa suppresses PRL release and stimulates GH secretion (Boyd et al., 1970; Malarkey et al., 1971), whereas in PD the results are quite contradictory as both GH and PRL responses to levodopa have been reported to be reduced, within the normal range or even increased (Kimber et al., 1999). In RLS, PRL and GH secretion profiles in patients were unaltered (Winkelmann et al., 2001) and were found to be similar when compared to controls (Garcia-Borreguero et al., 2004; Wetter et al., 2002). However, when challenged with levodopa at night, patients with RLS showed a significant decrease in plasma PRL levels and a significant increase in plasma GH levels, suggesting increased sensitivity of dopamine postsynaptic receptors at night, at least at the level of the tubero-infundibular-dopaminergic system (Garcia-Borreguero et al., 2004). Taken together, the findings suggest an increase in the amplitude of the circadian variation of dopaminergic function in RLS compared to healthy controls. Other major actors of the dopaminergic system have been studied with regard to the circadian fluctuation of RLS symptoms, including iron and tetrahydrobiopterin (BH4). Both compounds are TH cofactors and display circadian fluctuations (Fitzpatrick, 1989; Furukawa et al., 1999; Lee and Mandell, 1985; Scales et al., 1988). Interestingly, BH4 is found to be decreased in the autosomal dominant form of levodoparesponsive dystonia, another neurological disorder that shares some clinical features with RLS, i.e., a distinct circadian pattern of severity and a high sensitivity to low doses of levodopa (Fink et al., 1988). At least in rats, CSF levels of BH4 have been found to have a diurnal pattern that parallels diurnal CSF dopamine changes (Lee and Mandell, 1985). In RLS patients, CSF levels of BH4 were not found to be significantly different from those of controls (Earley et al., 2001; Stiasny-Kolster et al., 2004b).

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Serum iron shows a marked circadian variation that parallels the circadian variation of CSF dopamine with a low point in the evening and early night (Scales et al., 1988), a time that coincides with maximal severity of symptoms. CSF iron levels are low in RLS patients (Earley et al., 2000; Mizuno et al., 2005a) but it is not known whether iron-brain concentrations follow this circadian iron-serum level variation and to what extent this might impact TH synthesis and consequent dopamine synthesis. Of interest is the interaction between melatonin circadian rhythm secretion and dopamine. Circadian variations in the melatonin secretion might influence dopamine release. Physiologic concentrations of melatonin have been shown to exert an inhibitory effect on stimulated dopamine secretion in specific areas of the mammalian central nervous system (CNS) but not in the striatum (Zisapel et al., 1982). As the peak of melatonin secretion precedes the increase in sensory and motor symptoms of RLS patients, it was suggested that melatonin might be involved in the worsening of RLS symptoms in the evening and at night (Michaud et al., 2004). A therapeutic effect of melatonin in patients with PLM but without RLS was also reported (Kunz and Bes, 2001) whereas treatment with levodopa was associated with an earlier dim light melatonin onset in patients experiencing levodopa-related aggravation of RLS symptoms (Garcia-Borreguero et al., 2004). This phaseshifting effect of dopamine on melatonin secretion was already reported in PD patients (Bordet et al., 2003), so it could be considered of little or no specific significance in RLS. Therefore, no reliable biologic marker for primary RLS has been identified so far to explain the circadian aggravation of symptoms, despite the extensive literature in the field. However, no single study has yet investigated the relationship between secretion patterns of serum melatonin, CSF iron compounds, CSF dopamine, core body temperature and RLS symptom circadian evolution in naı¨ve RLS patients. This would be of interest since the 24-h pattern of changes in plasma iron concentrations was also shown to approximate an inverse relationship with rectal temperature (Scales et al., 1988). This does not concord with the increased severity of RLS symptoms with the nadir of core body temperature (Hening et al., 1999b; Michaud et al., 2004; Trenkwalder et al., 1999a). 7. Secondary RLS Whilst most cases may be idiopathic, RLS may also occur in acquired forms associated with a variety of neurological disorders, including parkinsonian syndromes, and several other medical conditions, some of which involve a possible iron deficiency. Iron deficiency, end-stage renal disease and pregnancy are thus well established secondary causes of RLS. Although diabetes and neuropathy are commonly given as causes for secondary RLS, supporting data are limited and survey studies using full diagnostic criteria do not support this claim (Hogl et al., 2005; Rutkove et al., 1996; Winkelmann et al., 2000). Numerous other associations exist, but owing to the high prevalence rate of RLS in the general population, the specificity of such an association is questionable. It is therefore

beyond the scope of this paper to discuss all the different pathologic conditions associated with RLS as corroborative evidence is lacking. Although not yet formally studied, the secondary forms of RLS share the same clinical features as idiopathic RLS, suggesting a similar underlying pathophysiological basis (Winkelmann et al., 2000). 7.1. Iron deficiency Investigating the complex relationship between iron and RLS has generated the most important body of literature related to the condition. The presence of low serum iron levels in 25% of patients with severe RLS was first reported by Ekbom (Ekbom, 1960). On the other hand, another study reported complaints of ‘leg restlessness’ in 43% of the patients with iron deficiency (Matthews, 1976). Several ensuing papers have since pointed to a strong association between the occurrence of RLS and reduced iron stores, with or without anemia (Aul et al., 1998; O’Keeffe et al., 1994; Silber and Richardson, 2003; Sun et al., 1998). Subjective RLS severity also correlated significantly with serum ferritin levels even for ferritin values in the normal range along with normal iron and transferrin concentrations (Allen and Earley, 2000; O’Keeffe et al., 1994; Sun et al., 1998). An older age at onset, as is the case in nonfamilial RLS, appears to be strongly associated with low serum ferritin levels whereas a younger age at onset, as is the case in familial RLS, generally are not (Allen and Earley, 2000). However, a serum ferritin level below the normal range (<50 mg/l) was found in up to 83% of the children reporting RLS symptoms (Kotagal and Silber, 2004). Recent studies have also documented an increased prevalence of RLS in subjects who donate blood frequently (Silber and Richardson, 2003; Ulfberg and Nystrom, 2004). In a recent large population-based survey using the IRLSSG criteria, levels of hemoglobin, free serum iron, plasma transferrin, ferritin concentrations, mean levels of Vitamin B12 and folic acid were similar in subjects with or without RLS (Hogl et al., 2005). However, the same study provided the first epidemiologic evidence to support the iron deficiency hypothesis in the pathogenesis of RLS by showing an elevated concentration of soluble transferrin receptor in patients with RLS, particularly in men (Hogl et al., 2005). Soluble transferrin receptor is considered as a more potent marker of iron deficiency than ferritin and its concentration increase is considered to be the initial response to declining body iron supply (Cook, 1999). In another study with a smaller and older sample, the same parameters of iron metabolism, including soluble transferrin receptor, were similar between subjects with RLS or without (Berger et al., 2002). Normal levels of iron, ferritin and transferrin were also found in patients’ serum with low CSF-iron and ferritin concentrations and increased CSF-transferrin (Earley et al., 2000; Mizuno et al., 2005a), suggesting brain iron insufficiency. The latter was confirmed by direct magnetic resonance imaging (MRI) assessment of brain regional iron relative concentration in five RLS patients that demonstrated a significant decrease in iron stores in the SN and in the putamen, which correlated with the

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severity of symptoms in comparison to healthy controls (Allen et al., 2001). An additional iron decrease in the red nucleus and the pallidum, but not in the putamen, was also demonstrated in two RLS patients with hemochromatosis (Haba-Rubio et al., 2005). Altogether, these findings suggest a possible role of a local brain iron deficiency in the pathophysiology of RLS, even in patients with systemic iron overload. Pathological autopsy findings in a few individuals with RLS showed no evidence of pathologic inclusions or neuronal loss in the SN but a decreased iron staining in neuropils consistent with MRI data (Connor et al., 2003). A decrease in staining for ferritin and an increase in transferrin immunostaining in the neuromelanin cells in RLS patients was also found but with a paradoxical transferrin receptor (TfR) staining decrease in these iron-deficient cells (Connor et al., 2003). Although it is admitted that an increase in TfR expression in the presence of limited iron cellular availability is a standard response related to post-transcriptional stabilization of the TfR mRNA by iron regulatory proteins (IRPs) (Eisenstein, 2000), evidence suggests that neuronal TfR mRNA expression may be regulated by a mechanism other than the post-transcriptional regulation mechanism, which has been attributed to cells of non-neural tissue (Moos et al., 1999). Nevertheless, in RLS, a primary defect in IRPs leading to TfR decreased expression on neuromelanin cells seems more likely (Connor et al., 2004). Subsequent impaired neuronal iron uptake may alter the function of these neuromelanin-containing, dopamine-producing cells and ultimately manifest as RLS symptoms. Further support for a putative iron-pathophysiologic basis in RLS was provided by reports showing remission of RLS symptoms with iron supplementation (Nordlander, 1953; O’Keeffe et al., 1994). However, the beneficial effect of oral iron supplementation on RLS remains controversial as a more recent and robust controlled study failed to confirm previous findings (Davis et al., 2000). Limited oral iron absorption may account for this as intravenous iron substitution appears to be more effective on RLS symptoms (Earley et al., 2004, 2005; Nordlander, 1953). Further studies are warranted in order to better clarify the role of iron supplementation and route in the treatment of RLS. 7.2. Uremia and end-stage renal disease Sleep-wake complaints are very common in long-term dialysis therapy patients and are reported by up to 83.3% of patients (Sabbatini et al., 2002; Walker et al., 1995; Winkelman et al., 1996). Of these, RLS and PLM are the most common disorders (Holley et al., 1992; Walker et al., 1995; Wetter et al., 1998). IRLSSG-based studies reported uremic RLS prevalence rates of 6.6% to 62% (Bhowmik et al., 2003; Collado-Seidel et al., 1998; Hui et al., 2000; Siddiqui et al., 2005). Inaccurate diagnoses, small cohorts of patients and ethnic differences as in idiopathic RLS may account for this wide variation in prevalence rates (Kutner and Bliwise, 2002). Moreover, the reliability of the self-administered IRLSSG questionnaire for screening RLS in uremic patients is questionable since these patients also suffer from a high incidence of other leg

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complaints related to peripheral neuropathy, pain and pruritus (Cirignotta et al., 2002; Sabbatini et al., 2002). Interestingly, in a large IRLSSG criteria-based survey, renal insufficiency was not more frequent in patients with RLS than in those without (Hogl et al., 2005). The pathogenesis of uremic RLS is not clear. Obviously and even if suggested previously (Walker et al., 1995), no association with any marker of renal function has been found (ColladoSeidel et al., 1998; Gigli et al., 2004; Sabbatini et al., 2002; Siddiqui et al., 2005; Takaki et al., 2003), although the degree of RLS symptoms alleviation appears to be correlated with improved kidney function after transplantation (Winkelmann et al., 2002b). One study linked uremic RLS to hyperphosphotemia (Takaki et al., 2003) and another showed lower parathormone levels in uremic patients with RLS than in those without RLS but with normal calcium and phosphate concentrations (Collado-Seidel et al., 1998). Uremic patients with RLS had lower hemoglobin than those without RLS (Roger et al., 1991; Takaki et al., 2003) and correction of anemia with intravenous iron and erythropoietin also improved the RLS symptoms in patients on dialysis (Benz et al., 1999; Roger et al., 1991). So far, however, it is unclear whether iron abnormalities may underlie RLS in dialysis patients since other studies failed to document any association between iron, anemia and RLS (Collado-Seidel et al., 1998; Gigli et al., 2004; Hui et al., 2000; Siddiqui et al., 2005). The routine and extensive use of erythropoietin and highdose intravenous iron in modern dialysis management may make it difficult to establish such a link (Kavanagh et al., 2004; Sabbatini et al., 2002). Uremic and idiopathic RLS might also share the same physiopathological process. An increase in spinal cord excitability was found in uremic RLS patients as in those with idiopathic RLS (Aksu and Bara-Jimenez, 2002; Bara-Jimenez et al., 2000) and female gender was found to be an independent risk factor for RLS (Siddiqui et al., 2005). 7.3. Pregnancy RLS symptoms are reported in 11–26.6% of pregnant women in Western countries (Ekbom, 1960; Manconi et al., 2004), despite supplementation with folate and iron. An almost similar prevalence rate, 19.9%, was found in a recent large Japanese survey (Suzuki et al., 2003). Symptoms may appear during pregnancy but pre-existing RLS is also significantly exacerbated by pregnancy, mostly during the third trimester (Ekbom, 1960; Goodman et al., 1988; Lee et al., 2001; Manconi et al., 2004; Suzuki et al., 2003). In the cohort of Manconi et al., 16.7% never experienced RLS symptoms in their life, whereas 9.9% already experienced RLS symptoms before pregnancy (Manconi et al., 2004). In most cases, symptoms are mild and transitory as they usually resolve after delivery. Despite the very frequent association of the two conditions and in contrast to other medical disorders associated with RLS, relatively few studies have been conducted on the association between pregnancy and RLS. Indeed, only one IRLSSG-based study has been performed in pregnant women to date (Manconi et al., 2004).

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Pregnancy-related risk factors for the development or the worsening of pre-existing RLS have not yet been identified. The high incidence of RLS in pregnancy may be related to the common occurrence of iron and/or folate deficiency, particularly during the second half of pregnancy (Botez and Lambert, 1977; Ekbom, 1960; Lee et al., 2001; Manconi et al., 2004). Indeed, a low hemoglobin level has been shown to be significantly associated with the risk of developing RLS during pregnancy (Manconi et al., 2004), a result not found by a previous study (Goodman et al., 1988). Low serum ferritin at preconception, but not during pregnancy, was also found in pregnant women with RLS (Lee et al., 2001). However, they also exhibited significantly lower serum folate levels when compared to asymptomatic pregnant women, although the levels remained within the normal range (Botez and Lambert, 1977; Lee et al., 2001). A significant association between RLS and parity was found (Suzuki et al., 2003) but not in a more robust IRLSSG-based study (Manconi et al., 2004). Whether hormonal changes, particularly in relation to the increase in PRL, progesterone and estrogens during late pregnancy, trigger RLS symptoms has never been considered. The rapid improvement in RLS symptoms after delivery stresses the need to evaluate further the relevance of hormonal factors in this condition. 7.4. Neuropathy Investigating the association of RLS and neuropathy is not an easy matter depending on whether RLS is sought among patients with neuropathy or vice-versa. The association between the two conditions therefore remains unclear. Studies evaluating the presence of RLS in patients presenting with neuropathy have not shown higher than expected prevalences of RLS. One retrospective study evaluating diabetic patients for neuropathic features found that 8.8% complained of RLS compared to 7% of controls (O’Hare et al., 1994). A prospective study evaluating 154 consecutive patients with electrophysiological evidence of polyneuropathy reported that 5.2% met the clinical criteria for RLS (Rutkove et al., 1996), a prevalence lower than that usually reported in the general population. Unlike normal subjects, diabetics were four times more likely to have RLS (Phillips et al., 2000). Studies investigating neuropathy in RLS patients have yielded different results. Nerve biopsies showed subtle neuropathy with otherwise normal standard electrophysiological testing in eight RLS patients (Iannaccone et al., 1995). Small fiber neuropathy was also found on skin biopsies in eight out of 22 patients with RLS and this subgroup tends to have a later age at disease onset and generally have no family history of RLS (Polydefkis et al., 2000). However, quantitative nociceptor axon reflex test did not reveal any evidence of peripheral small fiber damage in RLS patients with temperature perception impairment (Schattschneider et al., 2004). Furthermore, 36% of RLS patients had neurophysiologic but not clinical evidence of neuropathy (Ondo and Jankovic, 1996), but only 11% showed signs of mild to moderate axonal polyneuropathy on electromyography (EMG) (Winkelmann

et al., 2000). Nonetheless, in the largest survey ever performed with EMG and nerve conduction studies, electrophysiological signs of polyneuropathy were less prevalent in patients with RLS than in those without (Hogl et al., 2005). Interestingly, RLS-positive subjects reported less diabetes than those without RLS (Hogl et al., 2005). 7.5. Parkinson’s disease Owing to the putative dopaminergic basis of RLS, a common pathophysiology with PD has been suggested. Alleviation of RLS and PLM has been reported in PD after pallidotomy (Rye and DeLong, 1999), but the emergence of RLS during subthalamic stimulation in PD has also been described (Kedia et al., 2004). Very few IRLSSG criteria-based studies have actually addressed the issue of RLS prevalence in PD, but even when strictly applied, these criteria have yielded contradictory results (Krishnan et al., 2003; Ondo et al., 2002; Tan et al., 2002). As for idiopathic RLS, racial differences in the prevalence of RLS are also to be found in PD. In Singapore, RLS prevalence in a PD cohort (0%) was not significantly different from that in population-based (0.6%) and hospitalbased samples (0.1%) studied by the same authors (Tan et al., 2002; Tan et al., 2001). These results corroborated the findings of earlier studies in which no definite RLS symptoms were found in PD patients (Bodenmann et al., 2001; Lang and Johnson, 1987). By contrast, one Indian study demonstrated a significantly greater frequency of RLS in a PD cohort compared to controls with prevalence rates of 7.9% versus 0.8% (Krishnan et al., 2003). However, this frequency was much lower than the 20.8% rate found in 303 consecutive PD patients (Ondo et al., 2002). In that study, the risk factor for RLS in PD was lower serum ferritin levels. Interestingly, PD symptoms preceded RLS symptoms in 68% of cases, suggesting that RLS is not a risk factor for developing PD. Although the study found a high prevalence of RLS symptoms, it did not address the issue of whether or not they occur more commonly in PD patients than in the general population owing to the lack of a control group. In another population-based study with a larger sample, no parkinsonian symptoms were found among RLS-positive individuals (Rothdach et al., 2000). Overall, the occurrence of RLS in PD remains controversial but they certainly do not share the same pathophysiology. Both disorders are common in the elderly and methodological problems due to confounding factors complicate prevalence studies of RLS in treated PD. Dopaminergic treatment may either mask or augment RLS symptomatology and RLS symptoms may be confused with other common symptoms in PD such as wearing-off episodes, akathisia, internal tremor and nocturnal motor fluctuations (Poewe and Hogl, 2004; Tan et al., 2002). In patients with PD, the olfactory function is abnormal whereas it is normal in patients with RLS, reflecting the integrity of the A16 dopaminergic group (Adler et al., 1998). Moreover, in PD, an increase in total iron concentration in the SN was demonstrated by both pathologic and MRI techniques (Dexter et al., 1987; Gorell et al., 1995; Sofic et al., 1988), whereas the contrary was demonstrated in RLS (Allen et al.,

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2001; Haba-Rubio et al., 2005). Finally, RLS patients did not develop a higher percentage of PD than an age-matched population and to date, no neurodegenerative changes have been documented in RLS (Connor et al., 2003; Connor et al., 2004; Pittock et al., 2004). 8. Dopamine and RLS The strongest evidence for a primary dopaminergic role in RLS and PLM is to be found in the excellent pharmacological response to low-dose dopaminergic medications (Hening et al., 1999a) and the worsening of symptoms with dopamine release blocker (Kraus et al., 1999; Montplaisir et al., 1991). Investigation for a potential nigrostriatal dopaminergic dysfunction in patients with idiopathic RLS by means of functional neuroimaging techniques has produced conflicting results and overall no obvious dopaminergic deficit in RLS. Decreased regional cerebral blood flow to the caudate nucleus was reported in two patients with painful familial RLS (San Pedro et al., 1998). Fluorodopa-positron emission tomography (PET) striatal uptake was normal in four patients with RLS (Trenkwalder et al., 1999b), but was mildly reduced in the putamen and the caudate nucleus in two other PET studies with a larger sample size, suggesting mild nigrostriatal dopaminergic dysfunction (Ruottinen et al., 2000; Turjanski et al., 1999). Significant additional reduced D2 receptor binding in the caudate and the putamen was found in RLS patients compared with control subjects (Turjanski et al., 1999). Using singlephoton emission computed tomography (SPECT) with the DAT ligand IPT and the D2 receptor ligand IBZM, one study did not find any differences in presynaptic DAT and striatal D2 receptor binding between RLS patients and controls (Eisensehr et al., 2001). Similar results were also obtained in another study using IBZM SPECT (Tribl et al., 2002). Yet other SPECT studies showed decreased striatal D2 receptor binding in patients with PLM (Michaud et al., 2002; Staedt et al., 1993, 1995a) that increased under dopamine replacement therapy (Staedt et al., 1995b) but again no differences in striatal DAT between RLS patients and controls (Linke et al., 2004; Michaud et al., 2002; Mrowka et al., 2005), suggesting normal pre-synaptic nigrostriatal terminal function in RLS. Furthermore, no common characteristics were found between RLS patients, controls and patients with early PD as detected by DAT-SPECT (Linke et al., 2004). These findings are supported by limited pathological findings in RLS patients where no dopaminergic cell loss was found (Connor et al., 2003). This is also in accordance with the normal motor function of RLS patients. However, as these studies were limited to the nigrostriatal system, the possibility that other extra-nigral dopaminergic and/or non-dopaminergic systems could be involved cannot be precluded. 9. Opioids and RLS Successful treatment of RLS and PLM with opioid drugs has led to speculation that the endogenous opiate system may be involved in the pathogenesis of RLS and PLM (Hening et al.,

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1986; Walters et al., 1986). However, prospective, doubleblind, placebo-controlled trials with a significant large sample of RLS patients are scarce (Walters et al., 1993). Many of the studies are small and have yielded contradictory results, while other studies have demonstrated only marginal benefit of opioid agents on PLM (Kaplan et al., 1993). The exact mechanism of action by which opioids improves RLS is not known. Some evidence suggests that the efficacy of opioids is not related to their analgesic properties as clinical response to methadone, a m-specific opioid agonist, is delayed by up to a week (Ondo, 2005). Under blinded conditions, naloxone, a specific opiate antagonist, blocked the therapeutic benefit of opioids in two patients with RLS (Hening et al., 1986; Walters et al., 1986) but did not block the therapeutic effects of levodopa and dopamine agonists in a single patient (Akpinar, 1987). In contrast, pimozide, a dopamine receptor antagonist, blocked the therapeutic effects of opioids in one patient (Montplaisir et al., 1991). However, in another more extensive study with drug-naı¨ve patients, RLS sensory and PLM could not be induced by infusion of naloxone and metoclopramide, another dopamine receptor antagonist, under blinded conditions (Winkelmann et al., 2001). Although certainly more complex, the available data suggest that the effect of opioids is mediated by dopaminergic mechanisms and not the contrary. Therefore, deficiencies of the endogenous opioid system thought to underlie RLS symptoms are unlikely. This was further confirmed by recent PET-scan investigation of the endogenous opioid system revealing no difference in opioid receptor binding between RLS patients and controls (von Spiczak et al., 2005). 10. Iron and RLS Based on the evidence of deficient iron storage in RLS patients and marked improvement in some patients with iron supplementation, it is likely that brain iron status plays a role in the pathogenesis of RLS (Allen, 2004). However, although compelling data suggest possible connections between iron and dopamine pathology in RLS, it is still unknown how iron impacts the dopaminergic system to produce RLS symptoms. In the brain, iron is unevenly distributed with the highest concentrations of iron to be found in regions associated with motor functions (Koeppen, 1995). Large amounts of iron bound to neuromelanin in the dopaminergic neurons of the SN and high iron concentrations are found in the red nucleus, deep cerebellar nucleus and the striatum. This might explain why movement disorders are commonly associated with iron imbalance in the brain. It is generally accepted that iron accumulates in the brain as a function of age, with a linear increase in iron concentration in the SN, and there is compelling evidence that such iron accumulation can cause a wide range of neurodegenerative disorders such as PD (Gotz et al., 2004). On the other hand, low iron concentrations within these areas may alter regional dopamine synthesis and result in RLS symptoms through complex mechanisms whose circadian pattern is not well understood (Allen et al., 2001; Connor et al., 2003, 2004; Haba-Rubio et al., 2005).

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Iron is an essential cofactor for many proteins involved in the normal function of neurons including TH, an enzyme required for dopamine synthesis (Fitzpatrick, 1989). At autopsy, RLS patients’ brains showed normal TH staining along with local iron insufficiency in the SN (Connor et al., 2003). Therefore, one hypothesis is that this iron insufficiency could limit TH activity and consequently dopamine synthesis, leading to RLS symptoms. Thy-1 is another molecule that is regulated by iron (Ye and Connor, 2000). Thy-1 is a cell adhesion molecule that plays a regulatory role in the vesicular release of neurotransmitters (Jeng et al., 1998) and in the formation of axonal connections between the SN and the striatum (Shults and Kimber, 1993). One recent study provided strong evidence to support a relationship between iron and Thy-1 expression regulation. Iron chelation was shown to produce a significantly decreased expression of Thy-1 in PC12 cells in a dose- and timedependent manner (Wang et al., 2004). The same study also showed a significant decrease in Thy-1 in brain homogenates of iron-deficient rats and, most interestingly, that the Thy-1 concentration was less than half that of controls in the SN of brains obtained from four individuals with primary RLS, suggesting that the neurons of the SN are iron-insufficient in these patients (Wang et al., 2004). This study raises the hypothesis that a decrease in brain Thy-1 at the level of the SN may be another possible mechanism by which iron deficiency compromises dopaminergic transmission in RLS, a notion consistent with available data pointing to a central role of iron and dopamine in RLS. However, in that study, correlations between iron metabolism parameters of RLS patients and Thy1 levels in the SN were not investigated, so it is not known whether iron deficiency accounted for these findings. Overall, no single pathophysiological explanation for RLS and/or PLM can be derived from currently available data dealing with iron metabolism, dopaminergic and opioidergic systems at the level of the supraspinal structures. Several other neurotransmitter systems might also be involved in the pathogenesis of the disorder. Evidence exists that the GABAergic system is also iron-responsive (Hill, 1985), and iron is known to be involved in the synthesis and catabolism of other monoamines. Iron deficiency decreases the density of serotonin transporters in mice (Burhans et al., 2005), serotonin levels in rat brain (Green and Youdim, 1977), and alters noradrenergic function (Beard et al., 1994; Chen et al., 1995; Youdim et al., 1989). Interestingly, selective serotonin reuptake inhibitors (SSRIs) and noradrenergic drugs have been found to affect RLS symptomatology, the former inducing aggravation (Schillevoort et al., 2002) in contrast to the latter (Wagner et al., 1996; Zoe et al., 1994). 11. Brain structures A direct participation of the cerebral cortex in the genesis of RLS seems to be excluded since electroencephalographic backaveraging elicited no cortical pre-potentials in association with PLM in RLS patients (Provini et al., 2001; Trenkwalder et al., 1993), although a preparatory cortical activation was shown to

precede leg movements on functional electroencephalography (Rau et al., 2004). Motor descending pathway excitability is also normal, as studied by transcranial magnetic stimulation (TMS) techniques confirming that the motor corticospinal circuits are not involved in RLS and PLM (Quatrale et al., 2003; Smith et al., 1992; Tergau et al., 1999). TMS has proven to be a reliable tool to investigate the functional integrity of the corticospinal tract. When delivered to the motor cortex, it induces excitatory motor evoked potentials (MEP) in contralateral limb muscles but also inhibitory effects in volontary contrated muscles. However, TMS studies have so far yielded contradictory results, partly owing to several methodological discrepancies between studies. One study demonstrated reduced intracortical inhibition (ICI) for both feet and hand muscles and decreased intracortical facilitation (ICF) only in the lower limbs in 18 patients with RLS in comparison to agematched controls (Tergau et al., 1999). Similarly, reduced ICI was also reported in other studies (Scalise et al., 2004) but with increased ICF (Quatrale et al., 2003). One of the inhibitory effects that can be elicited by TMS is the cortical silent period (CSP) that directly follows the MEP on EMG. Consistent with reduced supraspinal inhibition in RLS, a shorter CSP in patients with RLS than in controls has been reported by TMS studies (Entezari-Taher et al., 1999; Stiasny-Kolster et al., 2003). In other studies, however, the duration of the CSP in RLS patients was not different from that of controls (Quatrale et al., 2003; Tergau et al., 1999). Finally, TMS was reported to be normal in patients with idiopathic RLS (Provini et al., 2001). Although contradictory, TMS findings pointed to a hyperactivity of the motor cortex due to a decrease in the inhibitory tone of subcortical inputs to motor cortices, probably at the level of the basal ganglia (Hanajima and Ugawa, 2000), as was found in PD (Nakashima et al., 1995; Priori et al., 1994). Therefore, dopaminergic modulation of intracortical excitability might play a key role in these dynamics (Ziemann et al., 1997), which is in line with an impairment of the dopaminergic-mediated mechanisms in RLS. Accordingly, reduced supraspinal inhibition in patients with PD improved after levodopa intake (Nakashima et al., 1995; Priori et al., 1994). Using high functional MRI, one study demonstrated bilateral activation of the cerebellum and a contralateral activation of the thalamus during the sensory manifestations of RLS, whereas additional activation of the red nucleus and the pons was elicited when the sensory events were accompanied by PLM (Bucher et al., 1997). These results suggest that subcortical generators are involved in the pathogenesis of RLS. These findings could also account for the increased excitability of brainstem neurons, as suggested by other electrophysiological studies showing abnormalities in blink reflexes in patients with PLM (Wechsler et al., 1986) but without RLS (Briellmann et al., 1996), although the results of both studies did not overlap. However, other studies with a larger sample of RLS patients showed no abnormalities in brainstem reflexes in patients with RLS when compared to healthy controls (Bucher et al., 1997; Mosko and Nudleman, 1986). Difficulties in interpreting results of electrophysiological studies of brainstem function arise from the lack of a quantitative approach that could assess the topodiagnostic value of several

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brainstem reflexes (Cruccu et al., 2005). Therefore, RLS appears as a complex movement disorder affecting several levels of the neuraxis, even though the precise pathoanatomic location of this dysfunction has not yet been determined.

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However, to date, it is not known whether abnormal sensorimotor integration, enhanced spinal cord excitability or putative disinhibited spinal generators in RLS/PLM are primary phenomena or result from the loss of dopaminergic and/or other neurotransmitter supraspinal inhibitory influences.

12. Sensorimotor processes at the spinal cord level 12.2. Is there a spinal pattern generator involved in PLM? 12.1. Spinal origin of RLS? In the RLS, clinical and electrophysiological studies have provided evidence for impairment of sensorimotor processing at the level of the spinal cord, suggesting enhanced spinal excitability and/or diminished central inhibition. One recent clinical study demonstrated static mechanical hyperalgesia in patients with RLS and suggested the latter to be a primary pain modulation disorder involving central sensitization probably within the spinal cord (Stiasny-Kolster et al., 2004a). This is in keeping with the results of previous elecrophysiological studies. Indeed, surface EMG recording from various leg and forelimb muscles in idiopathic RLS patients failed to evidence a constant recruitment pattern of muscular activation even in the same patient, and co-contraction of agonist and antagonist muscles was also observed in some individuals (Provini et al., 2001; Trenkwalder et al., 1996a). PLM activity was shown to start more often in muscles of the lower limbs but additional involvement of the muscles of the upper limbs was also seen in a majority of patients, whereas axial muscles were rarely involved (Provini et al., 2001). The authors suggest that these findings indicate an abnormal hyperexcitability of different and unsynchronized primary lumbosacral and, to a lesser extent, cervical generators (Provini et al., 2001; Trenkwalder et al., 1996a). This is in agreement with observations from studies reporting RLS and sleep-related PLM in patients with complete spinal cord lesions (de Mello et al., 1996; Hartmann et al., 1999; Lee et al., 1996; Yokota et al., 1991). Interestingly, in these patients, symptoms were successfully alleviated by dopaminergic medication (De Mello et al., 2004; de Mello et al., 1999). Similarly, transient RLS symptoms as well as PLM were also described in 8.7% of patients after spinal anesthesia with higher percentages in women than in men (Hogl et al., 2002; Watanabe et al., 1990). Changes in the excitability of spinal inter-neuronal circuitry were also demonstrated by H-reflex study techniques, indicating diminished inhibition at the spinal level in patients with PLM (Rijsman et al., 2005). Investigation of spinal reflexes yielded similar results. By contrast to controls, RLS patients showed marked spinal hyperexcitability as indicated by a lower threshold and greater spatial spread of the flexor reflex, which was more prominent during sleep (Bara-Jimenez et al., 2000). A similar abnormal flexor reflex was found in spinal cordinjured subjects (Roby-Brami and Bussel, 1987). Because diurnal fluctuation of symptoms is a hallmark of RLS, the demonstration of state-dependent changes in spinal cord excitability in patients with RLS and PLM further indicates that spinal mechanisms play an essential role in the pathogenesis of the disorder and may account for the nocturnal aggravation of RLS symptoms and PLM occurrence.

Investigations in experimental animals have unambiguously shown that the spinal cord has the intrinsic ability of generating locomotor activity through central pattern generator (CPG). A spinal cord from a spinalized curarized animal, i.e., devoid of proprioceptive feedback and descending inputs, may generate a relatively complex motor pattern comparable to that recorded in the intact animal (Forssberg and Grillner, 1973; Jankowska et al., 1967a,b; Viala and Buser, 1969; Viala et al., 1974). Little information is available in non-human primates as to date only one convincing study has been performed in the decerebrate, spinalized and curarized marmoset (Fedirchuk et al., 1998). In humans, it is difficult to approach CPG directly. The pseudo-rhythmic characteristics of the motor pattern in PLM together with the urge to move that is relieved by movements indicate that spinal networks could be one source of dysfunctioning in this disorder. The occurrence of RLS and PLM in paraplegic patients also raises the possibility that socalled CPGs could be involved in this disorder (de Mello et al., 1996; Hartmann et al., 1999; Lee et al., 1996; Yokota et al., 1991). One unresolved issue is the possible existence of a spinal locomotor network in humans that could be the analog of that in other animal species (Duysens and Van de Crommert, 1998). In humans, no direct demonstration has been provided. The most convincing arguments come from experimental observations in patients suffering from spinal cord injury. In patients with a complete spinal cord section, electrical stimulation involving the flexor reflex afferents induces a late flexor reflex comparable to that observed in an acute spinal cat injected with L-DOPA (Roby-Brami and Bussel, 1987). Moreover, as in the cat treated with L-DOPA, the late flexor discharge is accompanied by an inhibition of the late contralateral flexors and a reduction of the early flexor reflex. These observations clearly show some similarities between the function of spinal circuitry in humans and in animals. One patient with a transection at the cervical level was able to produce rhythmic movements of the trunk and legs that were triggered and modulated by stimulation of flexor reflex afferents (Bussel et al., 1988, 1996). In another patient with a partial lesion, persistent and coordinated movements were also observed showing similarities with locomotor activity (Calancie et al., 1994). These observations suggest that an interruption of supraspinal inhibitory influences could make the spinal cord capable of rhythmic coordinated activity in humans. Locomotor capabilities of patients with a complete spinal cord section were also tested by epidural stimulation of the spinal cord at various levels from T10 to S1. In response to tonic electrical stimulation, EMG activities and stereotyped movements comparable to those observed during locomotion were recorded. This stimulation was only effective when delivered at

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the segmental lumbar level L2 (Dimitrijevic et al., 1998). Whether or not a spinal locomotor network exists in humans, it has not been possible to readily activate it sublesionally in paraplegics unlike in spinal animals (Barbeau et al., 1999). The occurrence of arm restlessness and periodic arm movements (PAM) suggests that both the lumbar and the cervical segments are involved in the sensorimotor abnormalities observed in RLS patients with PLM. Recent evidence of the existence of a spinal pattern generator for rhythmic arm movements in humans (Zehr et al., 2004) could have some implication in the understanding of PAM. Furthermore, functional coupling between upper and lower limbs has been suggested in humans (Zehr et al., 2001) and stimulation of the cutaneous afferents has been shown to trigger both arm and leg networks during static contraction or walking (Zehr et al., 2004). Similar findings have been found in the neonatal rat where the propriospinal pathways in the thoracic cord were shown to play a critical role in the coupling of both cervical and lumbar spinal pattern generators for locomotion (Juvin et al., 2005). In view of these data and since PAM can occur alone or in conjunction with PLM (Chabli et al., 2000; Provini et al., 2001; Trenkwalder et al., 1996a), it can be hypothesized that impairment of the spinal sensorimotor integration at any level may somehow amplify sensory inputs, ultimately leading to an outburst of both spinal generators. 12.3. State- and task-dependent modulation of spinal sensorimotor networks 12.3.1. Sleep-wake modulation Clinical evidence suggests state-dependent changes in spinal cord excitability in patients with RLS and PLM (Bara-Jimenez et al., 2000). During sleep, the regulation of sensory information is in fact profoundly modified and studies on the descending control of sensorimotor function have focused on REM sleep (Velluti, 1997). Therefore, little is known about the descending control of spinal networks during non-REM sleep. During REM sleep, muscle tone inhibition is partly induced by the activity of neurons in the pontine inhibitory area (Lai et al., 1993, 2001) and motoneuron tonic hyperpolarization during active sleep (Morales and Chase, 1978) is mediated by glycine (Chase et al., 1989). Chemical or electrical stimulation of the inhibitory mesopontine region produces tone suppression of respiratory and hindlimb muscles and a concomitant decrease in noradrenaline and serotonin levels, whilst the dopaminergic tone remains unchanged (Lai et al., 2001). Similarly, it has been suggested that the suppression of ascending sensory information observed during active (REM) sleep in cats is due to a descending suppressor drive (Soja et al., 1993), and that state-specific inhibition of ascending sensory transmission is mediated by GABA and glycine (Taepavarapruk et al., 2004). In addition, evidence was found for an active sleep-related suppression of sensory neuron activity, with a possible involvement of presynaptic inhibition via primary afferent depolarization (Cairns et al., 1996) which is known to rely on GABAergic mechanisms in the spinal cord (Rudomin

and Schmidt, 1999). The medullary reticulospinal tract mediates motor inhibition in cat through its actions on gamma and alpha motoneurons as well as on inhibitory interneurons interposed in reflex pathways (Takakusaki et al., 2001). Thus, during active (REM) sleep, an enhancement of the spinal GABAergic system and a dysfacilitatory action linked to the reduced release of noradrenaline and serotonin in the spinal cord (Lai et al., 2001), resulting in muscle atonia and inhibition of sensory information, may account for the absence of PLM during REM sleep. Removal of this inhibitory descending control during sleep may explain the occurrence of PLM in some patients suffering from spinal cord injury (Dickel et al., 1994). 12.3.2. Task-dependent modulation Spinal sensorimotor modulation is not only linked to the sleep-wake cycle since modulation of presynaptic inhibition is also known to be task-dependent (Faist et al., 1996; Llewellyn et al., 1990; Perreault et al., 1999; Stein and Capaday, 1988). It also accompanies the selection of appropriate interneural networks interposed in reflex pathways (McCrea, 2001). In the absence of locomotor activity, cutaneous nerve stimulation increases primary afferent depolarization of Ib fibers (Rudomin et al., 1983) whilst during fictive locomotion the opposite action is observed (Duenas and Rudomin, 1988). Within an episode of locomotion, the level of primary afferent depolarization and dorsal root reflex is also phase-dependent (Beloozerova and Rossignol, 1999, 2004; Dubuc et al., 1988; Gossard, 1996; Gossard et al., 1989). Interestingly, it has been shown in animals and humans that the presynaptic control of sensory afferent information inflow outlasts the period of locomotor activity for a few minutes (Gosgnach et al., 2000; Perreault et al., 1999; Voigt et al., 1998). This may in part contribute to the transitory movement-induced relief of sensory discomfort and the urge to move in primary RLS patients and in those suffering from spinal cord injury (De Mello et al., 2002, 2004). During locomotion, all spinal reflex pathways are modified (McCrea, 2001). These modifications include changes of reflex gain and selection of appropriate reflex pathways allowing an effective integration of sensory information in relation to locomotor activity. Furthermore, the sensory information provided by the movement itself contributes to the shape of the locomotor activity. Together with the sleep-wake changes in spinal sensorimotor excitability, impairment in sensory information integration may explain the circadian pattern and the nature of RLS symptoms. 12.4. Neuromodulatory control of spinal sensorimotor networks The fact that various therapeutic agents are effective in RLS and PLM suggests a multiple neuromodulatory basis in this condition (Hening et al., 1999a; Sandyk et al., 1988; Thorpy, 2005). One strong hypothesis is that the observed abnormal hyperexcitability of the spinal cord that leads to sensory and motor discomfort in RLS patients may result from a change in ‘‘neuromodulatory homeostasis’’. The effects of various

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neuromodulators including amino acids, biogenic amines and peptides have been extensively described in various animal models and preparations, but no single specific role has yet been ascribed to the majority of these neurotransmitters/neuromodulators. Their actions can be exerted on several components of the spinal circuitry, postsynaptically to control target cell excitability but also presynaptically on nerve terminals to adjust the rate of transmitter release, or both. So at the same time and depending on its site of action and on the receptor subtypes it activates, a single neurotransmitter can mediate its excitatory influence on neurons or nerve endings and/or its inhibitory influence on others. Furthermore, additional complexity in modulatory processes is found when the action of different neurotransmitters is considered at the same time: firstly because they can have an opposing, additional or masking action on neurons; secondly because a neurotransmitter can act on the release of others neuromediators, with the result that part of its effects may be mediated by another neuromodulator. 12.4.1. L-DOPA and catecholamines L-DOPA has been one of the most prominent substances to activate directly the spinal locomotor network. Administration of L-DOPA in a spinal cat depresses the short latency flexor reflex whilst late flexor reflex discharge and crossed extensor discharge are prolonged (Jankowska et al., 1967a,b). In the same preparation, L-DOPA can release locomotor movements. In the spinal cat, L-DOPA has been shown to depress flexors and nociceptive reflexes as well as non-nociceptive excitatory pathways (Schomburg and Steffens, 1998). Since dopaminergic therapy constitutes one of the best forms of medication used in RLS and PLM (Akpinar, 1987) and given the extensive data on the role of the dopaminergic system, it would be tempting to ascribe a central role to the spinal dopaminergic pathway in the regulation of this sensorimotor disorder. However, careful analysis of the available data indicates that such a view does not completely reflect the complexity of the disorder. L-DOPA is converted into dopamine via the action of DOPA-decarboxylase and dopamine is in turn converted into noradrenaline via the action of dopamine-b-hydroxylase. In fact, there is evidence that most of the reported effects of L-DOPA in spinal cats are due to activation of noradrenergic receptors (Barbeau and Rossignol, 1991; Chau et al., 1998a,b; Forssberg and Grillner, 1973; Kiehn et al., 1992). By contrast, in the rat, it has been reported that D1 and D2 dopaminergic receptor antagonists (McCrea et al., 1997), as well as a1 and a2 receptor antagonists (Taylor et al., 1994), block L-DOPA induced air-stepping. In the adult decerebrate rat, administration of L-DOPA elicits fictive locomotor patterns in hindlimb nerves (Iles and Nicolopoulos-Stournaras, 1996). These results suggest that, at least in the rat, the initiation of locomotor activity by LDOPA does not apparently rely exclusively on noradrenergic pathways. Other findings also support the idea that dopamine may trigger spinal locomotor networks, since it has been reported that it directly activates the lumbar networks (Barriere et al., 2004; Kiehn and Kjaerulff, 1996). Therefore, a central question is whether or not part of the action of the monoaminergic systems relies on dopaminergic and/or

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noradrenergic pathways. Definitive conclusions should not be drawn before elucidating this issue. 12.4.2. The action of dopamine on the spinal cord networks The beneficial therapeutic effects of dopaminergic medication – most of which acts through D2-D3-like receptors – in relieving sensory and motor symptoms in RLS patients point to the key role of dopaminergic signaling in this disorder (Earley et al., 1998; Montplaisir et al., 1991, 1999; Ondo, 1999), even in spinal cord-injured subjects (de Mello et al., 1999). However, as mentioned above, clear evidence of a nigrostriatal dysfunction is far from clear and the involvement of other extra-nigral dopaminergic systems should not be disregarded. This was further suggested by the selective destruction of diencephalo-spinal dopaminergic neurons in rats in which increased motor activity, similar to human motor restlessness, was consequently elicited (Ondo et al., 2000a). Thus, the descending dopaminergic system may be either implicated directly or indirectly in the pathophysiology of RLS/PLM since it is considered as the largest source of spinal dopamine, the descending fibers originating in the VTA being involved to a lesser extent (Albanese et al., 1986; Hokfelt et al., 1979; Qu et al., 2005; Skagerberg and Lindvall, 1985). The neurons of origin are mainly located in the caudal diencephalic A11 group and project predominantly at all levels in the dorsal horns and in the intermediolateral cell columns of the spinal cord. Dopaminergic fibers are detected in the ventral and dorsal horn, the intermediolateral area and around the central canal (Holstege et al., 1996; Ridet et al., 1992; Shirouzu et al., 1990; Skagerberg et al., 1982) as well as dopamine D1 and D2 receptors (Levant and McCarson, 2001; van Dijken et al., 1996). Moreover, high densities of D3 receptors in rat spinal cord were found to be expressed in the dorsal horn of the cervical and lumbar regions and in the pars centralis (Levant and McCarson, 2001). Although the exact physiological role and behavioral relevance of the spinal dopaminergic system has not yet been fully determined, its role in sensory, nociceptive processing, motor functions and sensorimotor integration has been hypothesized. Both stimulation of the A11 dopaminergic cell group and exogenous application of dopamine can elicit antinociception (Fleetwood-Walker et al., 1988). Several studies have shown that dopamine turnover in the dorsal horn increases in response to a noxious stimulus, which could reflect an increased activity of the descending dopaminergic system (Gao et al., 2001b; Men and Matsui, 1994; Weil-Fugazza and Godefroy, 1993). Stimulation of the A11 nucleus reduces the behavioral response to noxious stimuli via the activation of D2 receptors (Carr, 1984), resulting in the inhibition of projection neurons in the dorsal horn (Fleetwood-Walker et al., 1988) and also probably in presynaptic inhibition at primary afferent terminal level (Formenti et al., 1998; Garraway and Hochman, 2001). D2 but not D1 receptor antagonists selectively antagonize the antinociceptive action of D2 agonist (Barasi et al., 1987; Gao et al., 2001a; Jensen and Yaksh, 1984; Liu et al., 1992). However, activation of the D1 receptor family exerts the opposite effect upon nociceptive stimuli (Gao et al.,

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2001a), in part by a facilitatory action on the release of transmitters from the primary afferent terminals (Bourgoin et al., 1993). Dopamine also exerts a depressive action on sensorimotor pathways (Carp and Anderson, 1982). Activation of D2-like receptors depresses both the monosynaptic transmission between the Ia afferent fibers and motoneurons and polysynaptic reflex pathways (Clemens and Hochman, 2004; Kitazawa et al., 1985; Maitra et al., 1992). Using an in vitro preparation of mouse lumbar cord, it was also demonstrated that the depressant effects of dopamine and D3 receptor agonists on the monosynaptic stretch reflex and longer latency polysynaptic reflexes were, respectively, absent and reversed in hyperactive D3 knock-out (D3KO) mice (Clemens and Hochman, 2004). These data point to the important role of the spinal dopaminergic system, and particularly of the dopamine D3 receptor subtype, in the control of reflex excitability. Therefore, the dysfunction of the dopamine diencephalospinal pathways would provide the most unifying explanation for the spinal hyperexcitability that may underlie RLS (Bara-Jimenez et al., 2000). It might also account for the circadian pattern of the condition since the A11 nucleus receives diffuse projections from the suprachiasmatic nucleus, which largely controls circadian rhythms (Abrahamson and Moore, 2001; Reuss, 1996). However, whether a dysregulation or a dysfunction of the D3 receptor in the spinal cord of RLS patients occurs remains unknown. In the ventral horn, less attention has been paid to the dopaminergic system than to the noradrenergic and serotoninergic systems. Dopamine is known to exert an excitatory and inhibitory action on motoneurons mediated through the activation of D1 and D2 receptors, respectively (Barasi and Roberts, 1977; Kitazawa et al., 1985; Smith et al., 1995; van Dijken et al., 1996). In neonatal rat spinal cord preparations, dopamine triggers a slow locomotor-like activity recorded from the ventral roots (Atsuta et al., 1991; Barriere et al., 2004; Smith et al., 1988) or from hindlimb muscles (Kiehn and Kjaerulff, 1996). This rhythmogenic effect of dopamine at the lumbar level is linked to activation of the D1-like receptors, the precise contribution of the D2-like receptors remaining unknown (Barriere et al., 2004). Interestingly, the slow time course (30– 60 s) of motor activities induced by dopamine and the D1-like receptor agonist, SKF-81297, is comparable with the periodicity of the recurrent clusters of motor activities occurring in PLM and underlines the need to determine whether such a receptor could contribute to their production. However, these excitatory actions of dopamine on the CPG in experimental animals are in sharp contrast with the blocking effect of dopaminergic therapy on PLM. Whether this is related to species differences deserves further investigation into the spinal action of dopamine in non-human primates. 12.4.3. The action of noradrenaline on the spinal cord networks In the rat, noradrenergic projections to the spinal cord originate from nuclei localized in the A5 and A6 regions (locus coeruleus nuclei) (Proudfit and Clark, 1991), mostly innervat-

ing the ventral part of the cord, whilst the A7 (subcoeruleus) nucleus mainly provides noradrenaline to the dorsal horn (Kwiat and Basbaum, 1992; Tavares et al., 1996; Tucker et al., 1987). The spinal noradrenergic fibers and terminals are highly concentrated in every part of the spinal cord, i.e., in the dorsal horn, around the central canal, in the intermediolateral cell column and among the various groups of motoneurons (Rajaofetra et al., 1992). Within the cord, the three noradrenergic receptor subtypes, a1, a2 and b receptors, are present and participate in the various noradrenaline spinal effects (Millan, 2002). At the dorsal horn level, noradrenaline has been shown to produce both antinociceptive and pro-nociceptive effects depending on the noradrenergic receptor activated. Activation of spinal a2-noradrenergic receptors results in the reduced excitability of projection neurons and excitatory interneurons and the reduced release of transmitters at the primary afferent fiber terminals (Millan, 2002). In humans, studies have shown that the spinal administration of a2-noradrenergic receptor agonist clonidine relieves pain, suggesting a direct spinal antinociceptive action of noradrenaline through this receptor subtype (Eisenach et al., 1996, 2000). Clonidine has also been shown to be effective in relieving RLS symptoms (Wagner et al., 1996; Zoe et al., 1994). The action of noradrenaline has been extensively documented in the cat, since it was thought to be the neurotransmitter involved in L-DOPA-induced locomotor initiation (Barbeau and Rossignol, 1991; Forssberg and Grillner, 1973; Grillner, 1986; Kiehn et al., 1992). Evidence exists of a respective contribution to a1 and a2 receptors to the locomotor pattern in spinal cats (Chau et al., 1998b). Although activation of both classes of receptors can initiate locomotion, a1 receptors appear to be more involved in increasing the motoneuronal burst amplitude, whereas the a2 receptors are more involved in the timing of the motor pattern. In the rat, the action of noradrenaline seems more complex since neither noradrenaline nor its a1 agonists initiate locomotor-like activity; they elicit only slow motor rhythms or enhance an existing locomotor activity, whilst a2 agonists inhibit any ongoing sequence of locomotor activity (Sqalli-Houssaini and Cazalets, 2000). Again, this raises the question of species-related differences and questions the relevance of conclusions drawn from experimental animals in the context of human pathology. 12.4.4. Inhibitory mechanisms in the spinal cord Inhibitory mechanisms in the spinal cord may be relevant to RLS pathophysiology as the administration of baclofen (Guilleminault and Flagg, 1984), clonazepam (Thorpy, 2005) and gabapentin, a drug structurally related to GABA, appears to be an effective treatment for both primary and secondary RLS (Adler, 1997; Happe et al., 2003; Micozkadioglu et al., 2004). Baclofen, a GABA(B) antagonist, is also widely used to treat spinal spasticity (Vacher and Bettler, 2003). Neuronal inhibition in the spinal cord may be obtained in different ways as a neuromodulator can act (i) through postsynaptic receptors to hyperpolarize a target cell; (ii) through presynaptic receptors to inhibit or reduce afferent information; and (iii) indirectly through the activation of spinal

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inhibitory GABAergic interneurons. Indeed, anatomical data point to the central role of GABA in the inhibitory control of spinal sensorimotor networks (Holstege and Calkoen, 1990; Magoul et al., 1987) through (i) axo-somatic synapses mediating the classical postsynaptic inhibition and (ii) axoaxonic synapses which are candidates for mediating presynaptic inhibition. GABA also decreases the excitability of motoneurons (Curtis et al., 1959) and plays a key role in mediating one of the most studied physiological processes, i.e., the presynaptic inhibition of sensory afferents. This provides central mechanisms capable of modulating the synaptic effectiveness of sensory fibers ending in the spinal cord and is one strategy by which the CNS selects at the spinal cord level, the relevant information from among the mass of information arriving from the periphery at any time (Rudomin and Schmidt, 1999). In humans, presynaptic control of afferent sensory inflow has been reported not only during active (Burke et al., 1992; Hultborn et al., 1987b; Iles and Pisini, 1992a; Llewellyn et al., 1990; Perreault et al., 1999; Stein, 1995; Stein and Capaday, 1988; Yang and Whelan, 1993) and passive movements (Faist et al., 1996; Hultborn et al., 1987a; Misiaszek et al., 1995; Nielsen and Kagamihara, 1993) but also during postural changes (Hayashi et al., 1997; Iles and Pisini, 1992b; Koceja et al., 1993). Presynaptic control involves axo-axonic synapses made by GABAergic interneurons on the afferent fiber terminals including group I, group II as well as large cutaneous afferent terminals (Lamotte d’Incamps et al., 1998; Maxwell et al., 1990; Maxwell and Riddell, 1999). To date, there have been few reports on GABAergic control of locomotor networks in mammals. In chronic spinal cats, it has been shown that bicuculline, a GABA(A)-receptor antagonist, greatly improves the locomotion of adult spinalized cats compared to cats spinalized at birth (Robinson and Goldberger, 1986). Using an isolated spinal cord newborn rat preparation, it has been shown that GABA can fine tune the motor pattern acting directly on the pre-motoneuronal locomotor network, thus adjusting the level of motoneuronal activity (Cazalets et al., 1994). GABA also acts presynaptically to control the outflow of the pre-motoneuronal network, thus reducing the synaptic drive received by the motoneurons (Bertrand and Cazalets, 1999). Altogether, these data suggest possible complex interactions in the regulation of spinal cord excitability even through the single GABAergic system. The fact that gabapentin is effective in the management of RLS suggests possible interactions with the GABAergic system, since it has been shown that gabapentin may activate GABA(B)-receptors (Ng et al., 2001), although this is still debated (Lanneau et al., 2001). In addition to the identification of the cellular mechanisms of the action of gabapentin, its targets also need to be identified since it also has antinociceptive effects on neuropathic pain (Kayser and Christensen, 2000).

originates from the spinal cord in which they are synthesized by local neurons or primary afferent fibers, and some of them are also present in descending pathways originating from supraspinal centers (Hokfelt et al., 2000; Millan, 2002; Tsuchiya et al., 1999). Opiates mediate their effects through the activation of the m, d and k receptors subtypes which are present at the level of sensory afferent terminals in the dorsal horn (Fields et al., 1980; Gouarderes et al., 1991; Lamotte et al., 1976). Endogenous opioids can presynaptically reduce the inflow of sensory information in addition to inhibiting the projection neurons and excitatory interneurons in the dorsal spinal cord (Millan, 2002). Some of their effects appear to be indirectly mediated through an increase in dopamine within the spinal cord (Weil-Fugazza and Godefroy, 1991), a finding in accordance with data obtained in RLS patients (Akpinar, 1987; Montplaisir et al., 1991). The antinoceptive action of opioids has also been shown to be potentiated by D2-receptor agonists (Ben-Sreti et al., 1983; Rooney and Sewell, 1989). Furthermore, the important role played by the dopaminergic system in opiate-mediating effects has been highlighted by the fact that the D2-receptor antagonist pimozide antagonizes the beneficial effect of opiate therapy in RLS (Montplaisir et al., 1991). Opioids play an important role in the control of sensory inputs to spinal motor circuits, since the use of opioid receptor antagonists enhances nociceptive as well as non-nociceptive spinal reflexes and enhances motoneuronal activity (Clarke et al., 1998, 1992; Duggan et al., 1984; Goldfarb and Hu, 1976; Schomburg and Steffens, 1995; Tao et al., 2005). Moreover, endorphins are involved in the habituation process in the reflex response which occurs following repetitive stimulation of the sural nerve in the cat, a mechanism reversed by naloxone (Fernandez-Guardiola et al., 1989). Intrathecal injection of endomorphine 1 and endomorphine 2 acting through m receptors dose-dependently depresses the nociceptive flexor reflex in decerebrate, spinalized and unanesthetized rats (Grass et al., 2002). In addition to the widely studied effects of opiates on general activity and locomotion (Bodnar and Klein, 2004), naloxone, which is assumed to block opiate receptors, has been shown to greatly facilitate the generation of locomotor activity induced by the a2-agonist clonidine in the acute and chronic spinal cat (Pearson et al., 1992). This could be explained by an action on the locomotor network itself or on sensory afferent pathways. In the spinal cat, it has been shown that enkephalins depress or abolish L-DOPA-induced rhythmic activity, an effect prevented by prior injection of naloxone (Schomburg and Steffens, 1995). Finally, exercise has been shown to increase opioid release in humans (Fraioli et al., 1980; Harber and Sutton, 1984), a mechanism which may contribute to the relief of RLS symptoms in paraplegic patients following exercise (De Mello et al., 2002).

12.4.5. The opiate system in the spinal cord Since opioids are also effective in RLS and PLM, the spinal mechanisms of opiates and the action of related compounds could be investigated. The content of spinal cord opioids

The use of animal models is a pillar of the basic neuroscience research conduced into the understanding, prevention and treatment of neurological diseases, particularly in the field of movement disorders. The adequacy of any model is determined

13. Animal models of RLS and PLM

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by its relevant pathological and behavioral features. This is particularly difficult in RLS as the clinical diagnosis relies exclusively on subjective symptoms, and any pathological features, if present, are so far undetermined. To the best of our knowledge, no attempts have been made to date to model RLS/ PLM in a non-human primate. Although attempts have been made in small animals, attention to behavioral disorders, if assessed, has so far focused on increased locomotor activity, possibly originating from an urge to move and thus reflecting a sort of motor restlessness. Worsening of motor restlessness in the evening or at night has never been quantified in these animal models, nor have clear histopathological and biological correlations been established with behavioral modifications. Modeling PLM in animals would appear as an alternative, for this clinical feature is more easily clinically observed and objectively quantifiable. The relevance of PLM animal models to RLS pathophysiology somehow remains questionable. In any case, the reliability and the validity of available RLS/PLM animal models have not been examined. 13.1. Spontaneous behavioral approaches Based on the observation that the occurrence and the number of PLM during sleep increase with age (Ancoli-Israel et al., 1991), one study investigated the occurrence of spontaneous PLM in aged rodents. Hindlimbs were implanted subcutaneously with magnets that allowed the detection of movements by a magneto-inductive device (Baier et al., 2002). Nocturnal hindlimb movements were then assessed and compared between two groups of young and old rats. Two animals out of 10 in the old group exhibited a PLM-like index >5/h of sleep. In this old group, dopaminergic antagonist injection neither aggravated nor attenuated these PLM during sleep. Response to dopamine agonist was not investigated nor was the 24-h general level of activity. The results of these studies have not been replicated elsewhere, but similar to these findings in rats, jerky, unilateral or bilateral leg movements during sleep were previously observed in narcoleptic canines but were not extensively investigated (Okura et al., 2001). The extent to which these movements resemble PLM or are related to RLS has to be investigated further. 13.2. Lesioning approaches Periodic limb movements have also been reported in animals with various lesions within the CNS. Lesions in the area of the A8 dopaminergic retrorubral nucleus and the ventral mesopontine junction induce spontaneous or sensory myoclonus and locomotion in decerebrated cats (Lai and Siegel, 1997). These results indicate that dysfunction of the retrorubral nucleus and the ventral mesopontine junction could release motor activity in sleep and therefore contribute to the occurrence of PLM in RLS. In that study, however, the most common location for myoclonus was in the neck muscles and the shoulder musculature, in contrast to what is seen in humans where the axial muscles are rarely involved (Provini et al., 2001).

Bilateral lesioning of the VTA, which contains the A10 dopaminergic neurons of the mesocortical and mesolimbic dopaminergic systems, induced a complex behavior characterized by persistent hyperactivity and hyperlocomotion in rats that was reversed by dopamine substitution (Le Moal et al., 1975). This model is relevant since reduced dopaminergic transmission in the mesocortical and mesolimbic circuits is associated with increased motor activity, a finding consistent with the motor restlessness of RLS and its hypodopaminergic hypothesis. In patients with RLS, however, no evidence exists of neuronal dysfunction within the frontal and prefrontal cortex areas. Reduced dopaminergic transmission at the level of the spinal cord has also been investigated in rodents by direct injection of 6-hydroxydopamine into the A11 area (Ondo et al., 2000a). Bilateral lesioning of the dopaminergic diencephalic spinal neurons resulted in hyperactive behavior with a significant increase in the number of standing episodes and total standing time in the lesioned animals compared to controls. Interestingly, these behavioral changes believed to be the correlate of clinical RLS were reversed by the dopamine-agonist pramipexole. Although that study was limited by its small sample size and lacked adequate behavioral analysis, it was the first to test the validity of the involvement of the dopaminergic A11 area in the pathogenesis of RLS. The occurrence of PLM in patients with spinal cord injury (de Mello et al., 1996; Lee et al., 1996) has prompted some investigators to look for limb movements during sleep in animals with spinal cord injury. Rats with differing degrees of spinal cord injury at the level of the ninth thoracic vertebra exhibited spontaneous limb movements during light periods of sleep with a pattern similar to PLM in human (Esteves et al., 2004). In that model, the efficacy of dopaminergic drugs was not tested, but it may prove useful to closely scrutinize the spinal mechanisms of PLM and their circadian pattern. 13.3. Pharmacologic approaches Reports of akathisia induced by SSRIs (Lipinski et al., 1989) led investigators to test the effects of these drugs on motor activity in rodents. Transient restless movements were thus elicited by injection of high doses of fluoxetine in a background of an unchanged general baseline level of activity (Teicher et al., 1995). These findings were interpreted as being akin to restlessness and therefore a model of akathisia. As SSRIs have also been found to exacerbate RLS (Schillevoort et al., 2002), one may question whether this model is not also suitable for RLS. Only better characterization of SSRIs-elicited behavioral disorder in this model will definitely answer the question. 13.4. Metabolic approaches Experimental manipulation of iron in animals highlighted the pivotal role of iron in the neurotoxicity and pathogenesis of neurodegenerative disorders, and recent MRI and pathological data suggest that the amount of iron in the patient’s brain tissue could be a major contributing factor to the manifestation of RLS symptoms (Allen et al., 2001; Connor et al., 2003).

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Quantitative genetic analysis also suggested a link between ventral midbrain iron concentrations and central dopamine function (Jones et al., 2003). Genetically engineered animal models with iron overload in specific brain regions are associated with dysfunction of the dopaminergic system (Grabill et al., 2003; LaVaute et al., 2001). The same applies for animal models with deficient iron levels in the brain. In rats with nutritional iron deficiency, an alteration in DAT was thought to account for increased extracellular dopamine levels in the caudate-putamen (Beard et al., 1994; Nelson et al., 1997), and significant reduced DAT density was thereafter demonstrated (Erikson et al., 2000). Iron deficiency also decreases D1 and D2 receptor density in the caudate-putamen of rat brains (Ashkenazi et al., 1982; Erikson et al., 2001) without alteration of either D1 or D2 mRNA expression (Erikson et al., 2001). Despite these numerous data, firm connections between neurochemical events and behavioral changes are still lacking. Contrary to what is expected with regard to RLS, iron-deficient animals exhibit decreased motor activity and have markedly diminished behavioral responses to centrally acting drugs (Ashkenazi et al., 1982; Glover and Jacobs, 1972; Hunt et al., 1994; Youdim et al., 1981). In those studies, the general circadian activity pattern was also not formally investigated (Hunt et al., 1994; Youdim et al., 1981). Interestingly, reduced levels of activity in iron-deficient animals could be paralleled with the reduced spontaneous activity observed in humans with iron-deficiency anemia (Angulo-Kinzler et al., 2002). One possible explanation is that iron deficiency does not affect all brain regions equally. Whereas the caudate-putamen shows a 30% loss of iron concentration in iron-deficient rats, other regions such as the SN are unaffected (Erikson et al., 1997). Iron deficiency may also impact the expression of other molecules such as Thy-1. In this respect, only one animal study showed reduced Thy-1 expression in brain homogenates of iron-deprived rats (Wang et al., 2004) but the behavioral aspect of this model was not studied. 13.5. Genetic approaches Knock-out technology in mice has given clear insights into the function of specific proteins of the CNS. In line with this, Thy-1 null mice provide a potential model to determine the role of Thy-1 in RLS. Analysis of Thy-1 null mice has shown the presence of excessive GABAergic inhibition of neurotransmission in the dentate gyrus of the hippocampal formation selectively and a resulting long-term potentiation defect, but without any apparent neurological or behavioral effects (Mayeux-Portas et al., 2000; Nosten-Bertrand et al., 1996). Using D3KO mice is another promising approach to model RLS in animals. In these mice, dopamine was shown to deeply impact spinal reflexes through the D3 receptors. At low doses, the modulatory effect of dopamine on spinal reflexes was converted from depressant in wild type mice to facilitatory in D3KO animals because of loss of D3 receptor function (Clemens and Hochman, 2004). Because RLS symptoms (i) peak at night when dopamine levels are lowest (Carlsson et al., 1980); (ii) are better relieved by dopamine agonists acting

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preferentially on D3 receptors (Thorpy, 2005); and (iii) likely involve increased spinal cord reflex excitability (Bara-Jimenez et al., 2000), the dopamine D3KO mouse has so far been the best generated animal model to explain how impaired D3 activity could contribute to this sensorimotor disorder. To further validate the D3KO mouse as a potential animal model of RLS, the same authors also demonstrated reversal of the circadian expression of TH in the spinal cord of these animals (Clemens et al., 2005). Combined with the circadian hypothalamic fluctuations in dopamine release (Carlsson et al., 1980), this finding may account for the increase in spinal cord excitability in D3KO mice and suggests a similar mechanism underlying the increased spinal cord reflex excitability (Bara-Jimenez et al., 2000). This may also account for the hyperactivity and the increased locomotor activity spontaneously observed in D3KO mice (Accili et al., 1996; Xu et al., 1997), a phenotype that resembles features of RLS, although other studies failed to demonstrate any difference in the level of spontaneous locomotor activity between D3KO mice and controls (Boulay et al., 1999). 14. Conclusion In a dysesthesic context, the involuntary advent of elementary motor programs predominantly in the legs should be subject to relatively simple central mechanisms. On the contrary, the pathophysiology of the RLS is really complex and its primum movens remains unknown. However, the following evidence can be put forward. (1) The spontaneous emergence of this abnormal motor activity may depend on an increase in the neuronal excitability of different spinal areas involving the motor sector or even spinal pattern generators of locomotion and/or the sensory sector, where gain changing could make certain afferent messages abnormally efficient. (2) The sources of these excitability changes may be due to a dysfunction of the modulatory descending pathways such as the spinal dopaminergic pathways, which serve as conductor for the latter, and particularly the pathway whose perikarya are located in the hypothalamus, i.e., the A11 dopaminergic cell group. Hypoactivity of this system could be responsible for the loss of inhibitory control exerted upon both the sensory and motor spinal sectors. Such a disinhibition would result in overactivity of the spinal pattern generators. The excellent therapeutic efficacy of levodopa and dopaminergic agonists would plead in favor of such a hypothesis. Moreover, the data obtained from functional neural imaging in RLS patients, although controversial, partly support this hypothesis by showing a striatal decrease in D2 dopaminergic receptors, which mainly exert an inhibitory function. This disinhibition would appear to instigate a more general hyperexcitability of the spinal target sensorimotor neurons. (3) The decrease in dopaminergic activity is most probably linked to the iron insufficiency reported mainly in secondary but also in primary forms of RLS. Iron is a

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cofactor of the rate-limiting step in dopamine synthesis and any iron decrease or misuse might reduce the TH activity. Moreover, iron intervenes in dopaminergic receptor constitution and iron supplementation also induces a substantial remission of RLS. (4) Further evidence in favor of ‘‘hypodopaminergy’’ in RLS can be seen in the efficacy of opiate therapy. The interactions between the dopaminergic and endogenous opioid systems have been widely studied and it could be assumed any dysfunction within this interplay would generate both sensory symptoms at the level of the dorsal horn, and repetitive motor activity via spinal pattern generators. (5) Two other clues lend pathophysiological weight to what might be termed the ‘‘hypodopaminergic hypothesis’’. First, there is the frequent but still controversial association of RLS with PD which translates a global disturbance of the central dopaminergic systems. However, these pathways would be differentially impaired and would concern the A11 cell group for the RLS and the SN pars compacta (A9) and the VTA (A10) for PD. The other clue concerns the intrinsic circadian rhythm of RLS and PLM. The latter is coupled to that of melatonin and uncoupled from that of dopamine production. Moreover, melatonin and dopamine are two interacting compounds. As a rule, RLS and PLM occur within periods of low dopamine production. (6) To this coherent set of arguments encompassing hypodopaminergic activity, iron insufficiency and dysfunction of the endogenous opioid system may be added further evidence implicating other neurotransmitter systems such as the noradrenergic descending pathway, the GABAergic system (descending pathways and/or spinal interneurons) and, to a lesser extent, the serotoninergic pathways. Simply put, their dysfunction might also contribute to the genesis of spinal cord hyperexcitability in RLS. Lastly, it must be kept in mind that these complex pathophysiological mechanisms might express more the consequences than the prime mechanism of RLS. Recent advances achieved thanks to pathological and functional brain MRI studies have emphasized the pivotal role of brain iron in primary RLS and its role in secondary RLS is more than plausible. This compound may therefore be considered as the most unifying ‘‘missing’’ link for interconnecting the pathophysiological hypotheses of this sensorimotor disorder proposed so far, both in its secondary and primary forms. Since the intimate mechanisms of this link have yet to be examined, this challenge will pave the way for many more years of fascinating research in the field. References Abrahamson, E.E., Moore, R.Y., 2001. Suprachiasmatic nucleus in the mouse: retinal innervation, intrinsic organization and efferent projections. Brain Res. 916, 172–191. Accili, D., Fishburn, C.S., Drago, J., Steiner, H., Lachowicz, J.E., Park, B.H., Gauda, E.B., Lee, E.J., Cool, M.H., Sibley, D.R., Gerfen, C.R., Westphal, H., Fuchs, S., 1996. A targeted mutation of the D3 dopamine receptor gene

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