Restless legs syndrome

Handbook of Clinical Neurology, Vol. 100 (3rd series) Hyperkinetic Movement Disorders W.J. Weiner and E. Tolosa, Editors # 2011 Elsevier B.V. All rights reserved

Chapter 47

Restless legs syndrome LYNN MARIE TROTTI* AND DAVID B. RYE Department of Neurology, Emory University School of Medicine, Atlanta, GA, USA

DESCRIPTION AND EPIDEMIOLOGY Restless legs syndrome (RLS) is a common syndrome defined by consensus criteria including: (1) an urge to move the legs (which may be associated with unpleasant leg sensations); (2) worsening at rest; (3) temporary relief with movement; and (4) a proclivity to occur in the evening or night. The presence of all four diagnostic criteria is considered sufficient for diagnosis in adults, although several confirmatory features can aid in the diagnosis in ambiguous cases. These features include periodic limb movements of sleep (PLMS), a favorable response to dopaminergic therapy, and a family history. PLMS are regularly occurring, stereotyped movements of the legs, most commonly great toe flexion and ankle dorsiflexion. PLMS are observed in 85% of RLS patients (Trotti et al., 2009), but may also occur independently of RLS or in association with other neurological conditions. Response to dopaminergic therapy can be documented either by retrospective query or by a prospective, single-dose levodopa administration followed by 2 hours of self-reported symptom monitoring, and improves diagnostic accuracy and may help exclude conditions that mimic RLS (StiasnyKolster et al., 2006; Benes et al., 2008). A history of exacerbation of symptoms with administration of dopamine antagonists can also serve as a useful clue to the diagnosis. Careful attention to diagnostic and supportive criteria can thus distinguish RLS from its mimics. For instance, in myelopathy and radiculopathy, there may be discomfort in the legs provoked by sitting or lying down, but there is no urge to move nor response to dopaminergics (Benes et al., 2007). Neuropathy can cause uncomfortable leg sensations, but typically without an associated urge to move, nocturnal predominance, or

improvement with movement (Benes et al., 2007). Additionally, while neuropathy commonly is symmetric and predominantly affects the feet, RLS often exhibits asymmetry and typically spares the feet. The urge to move of RLS is similar to that seen in neurolepticinduced akathisia, but akathisia does not preferentially affect the legs, does not have a circadian pattern of symptom expression, and is not associated with uncomfortable sensory symptoms accompanying the urge to move (Chaudhuri et al., 2008). Nocturnal leg cramps have a circadian pattern and preferentially affect the legs, but are not associated with an urge to move and do not improve with movement (Chaudhuri et al., 2008). The prevalence of RLS in populations of western European descent ranges from 3 to 15% (Lavigne and Montplaisir, 1994; Phillips et al., 2000; Ulfberg et al., 2001, 2007; Hening et al., 2004; Allen et al., 2005; Happe et al., 2008). “Clinically significant” RLS, that is, symptoms that are deemed frequent or severe enough to require treatment, is less common, occurring in about 1.6–2.8% of these populations (Allen et al., 2005; O’Keeffe et al., 2007; Happe et al., 2008). Prevalence of RLS in other ethnic groups is low: 0.1% in Singapore (Tan et al., 2001), 1.8% in rural Japan (Nomura et al., 2008), 2.0% in Ecuador (Castillo et al., 2006), 3.2% in Turkey (Sevim et al., 2003), and 3.9% in Korea (Cho et al., 2008). RLS is more common in older individuals (Winkelman et al., 2006b), but is also present in children. Definite RLS occurs in nearly 2% of school-aged children in the USA and UK (Picchietti et al., 2007), although children may have sleep disturbance for many years (mean 11.8 years) before meeting criteria for definite RLS (Picchietti and Stevens, 2008). RLS is more common in women than men: women may have an earlier age of

*Correspondence to: Lynn Marie Trotti, Assistant Professor of Neurology, 1841 Clifton Road NE, Atlanta, GA 30329, USA. Tel: 404-712-0586, Fax: 404-712-8145, E-mail: [email protected]

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onset of symptoms (Nichols et al., 2003), and women appear to have more night-to-night variability in PLM counts (Trotti et al., 2009). Prior pregnancy is a risk factor for RLS, with nulliparous women having an RLS prevalence similar to that of men (up to the age of 64), but multiparous women having RLS risk that increases with each subsequent pregnancy. Women who have had a single pregnancy have an odds ratio for RLS of 1.98; this increases to 3.04 for two pregnancies and 3.57 for three (Berger et al., 2004). RLS is seen with increased frequency in several neurological conditions, including Parkinson’s disease (GomezEsteban et al., 2007), Charcot–Marie–Tooth type 2 (Gemignani et al., 1999), spinocerebellar ataxia types 1, 2, and 3 (Abele et al., 2001), migraine (d’Onofrio et al., 2008), and multiple sclerosis (Manconi et al., 2007). RLS is also seen in association with several medical conditions, including iron deficiency (Earley et al., 2000), endstage renal disease (Winkelman et al., 1996), pregnancy (Manconi et al., 2004), rheumatologic disorders (Hening and Caivano, 2008), diabetes (Merlino et al., 2007), pulmonary hypertension (Minai et al., 2008), and chronic obstructive pulmonary disease (Lo Coco et al., 2008). The increased prevalence of RLS in so many diverse conditions suggests that RLS is not “secondary” to these conditions, as often characterized, but rather that a variety of conditions enhance RLS expressivity and that the prevalence of RLS in a particular population is determined by genetic diathesis (i.e., genetic makeup fixed at birth) interacting with environmental, medical, and additional genetic factors that have yet to be defined (Fig. 47.1).

HEALTH-RELATED SIGNIFICANCE OF RESTLESS LEGS SYNDROME Health-related quality of life is lower in RLS patients than in the general population, and is even lower than that observed in type 2 diabetics (Kushida et al., 2007). Yet, despite this negative impact on RLS sufferers, RLS remains underrecognized by both patients and physicians. Surveys of people with clinically significant RLS have shown that between 32% and 81% have consulted a physician about their symptoms, but only 6–17% report having received a diagnosis of RLS (Allen et al., 2005; O’Keeffe et al., 2007). Epidemiological data are accruing that the negative impact of RLS upon health extends beyond the impact on quality of life. RLS produces sleep disruption and is associated with increased rates of depression and panic disorders (Lee et al., 2008). Treatments are symptomatic, not curative, and because RLS is a chronic, progressive disorder, the diagnosis portends lifelong pharmacotherapy. Recent converging lines of evidence highlight strong associations between RLS and

Fig. 47.1. Expressivity of genes responsible for restless legs syndrome (RLS) symptoms is influenced by genetic and environmental/medical factors. Curve A represents a population of European descent. The area under the curve to the right of the arrow marked “Symptom threshold” defines the proportion of the population with RLS symptoms. The area under the curve to the right of the arrow marked “Clinically significant” represents the smaller proportion of the population in whom RLS is severe enough to necessitate treatment. The remaining curves demonstrate populations in which expressivity is different from this baseline population. Curve B represents a population of Asian descent, with a lower genetic diathesis to RLS. Curve C represents the population homozygous for BTBD9, with a correspondingly higher genetic diathesis to RLS. Curve D represents a population of patients with end-stage renal disease on dialysis, in whom medical factors increase the expression of RLS. (Reproduced from Trotti LM, Bhadriraju S, Rye DB (2008) An update on the pathophysiology and genetics of restless legs syndrome. Curr Neurol Neurosci Rep 8: 281–287, with kind permission from Current Medicine Group LLC.)

cardiovascular disease. The odds ratio for cardiovascular disease in subjects with RLS is 2.07 after controlling for known confounds, and the association is even stronger in those experiencing more frequent or severe RLS symptoms (Winkelman et al., 2008). PLMS exceeding 30/hour in RLS patients increase the odds ratio for prevalent hypertension to 2.26 after controlling for known contributors to hypertension (such as age and body mass index) (Billars et al., 2000). RLS is also associated with type 2 diabetes. While some of the increased risk of RLS in diabetics appears to be mediated through the presence of peripheral neuropathy, the association between RLS and diabetes remains significant even in patients without neuropathy (Merlino et al., 2007). These cardiovascular risks are of the same order of magnitude as those attributable to obstructive sleep apnea. Even mortality appears to be affected by RLS in some populations, as patients with end-stage renal disease experiencing RLS (Winkelman et al., 1996) or PLMS (Benz et al., 2000) have shorter median survival times than those without.

RESTLESS LEGS SYNDROME

GENETICS OF RESTLESS LEGS SYNDROME The heritability (i.e., the proportion of phenotypic variation attributable to genes) of RLS ranges from 54 to 83% (Ondo et al., 2000; Chen et al., 2004; Desai et al., 2004). Linkage studies have identified several regions of interest in RLS. Five are formally classified as loci RLS1-5, with several more recently identified loci not yet having designations assigned (Winkelmann et al., 2007a; Kemlink et al., 2008; Lohmann-Hedrich et al., 2008). Several of these have been shown in families from more than one population (e.g., RLS1 in French-Canadian, Icelandic, and German families) while others have only been shown in families from one region and may not be a common variant, even in other families from the same region (as is the case with RLS5) (Winkelmann et al., 2007a). Recent investigation at the RLS1 region of chromosome 12 has identified a specific association to the neuronal nitric oxide synthase (NOS1) gene (Winkelmann et al., 2008). While interesting for their potential relevance to RLS pathophysiology, linkage studies are hampered by several methodological factors. Ascertainment of disease status can be challenging, as subjective symptoms that are mild and infrequent at symptom onset can delay or prevent presentation, leading to falsenegative diagnoses. False-positive diagnoses are also problematic given the large number of recognized RLS “mimics,” e.g., akathisia, paresthesias, and nocturnal leg cramps. Moreover, given the assumptions that must be made about inheritance pattern, penetrance, allele frequency, and phenocopy rates for the purpose of linkage analyses, the significance of linkage findings is far from clear. In contrast, genomewide association (GWA) studies, in which subjects with a disease of interest are compared to a large population of controls (in whom disease frequency reflects background prevalence) at a vast number of single-nucleotide polymorphisms (SNPs), are less likely to be confounded by the limitations discussed above as they avoid these a priori assumptions about inheritance pattern, penetrance, allele frequency, and phenocopy rates. Three GWAs have recently been completed in RLS subjects, yielding four significant associations. The BTBD9 gene on chromosome 6 is associated in Icelandic, US, German, and Canadian patient cohorts with an increased risk of RLS (Stefansson et al., 2007; Winkelmann et al., 2007b). This gene variant confers an odds ratio of 1.5–1.8 (odds ratios of 1.3 are considered large effects for GWAs of common diseases), increasing the risk of RLS with PLMS by 70–80% for those carrying one copy compared to those without the variant

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(Stefansson et al., 2007). Because the frequency of this variant in the Caucasian population is high (68%), the population impact is substantial (e.g., accounting for  50% of the population attributable risk for RLS/ PLMS). This association is notable in that it is larger for PLMS in asymptomatic family members of RLS probands and those experiencing “atypical” RLS sensory symptoms as compared to individuals with genuine RLS. It also exhibits a dose–response relationship to PLMS, such that number of PLMS increases with each additional copy of the at-risk variant (Stefansson et al., 2007). Taken together, these findings suggest that the association of BTBD9 to RLS is driven by the underlying biological phenomenon of PLMS. The Meis1 gene on 2p14, the region containing the MAP2K5 and LBXCOR1 genes on chromosome 15q23 (Winkelmann et al., 2007b) and the PTPRD gene on 9p23-24 (Schormair et al., 2008), are also associated with RLS. Together, BTBD9, Meis1, and MAP2K5/LBXCOR1 account for 70% of the population-attributable risk for RLS. The credibility of the first two GWA findings is substantial as the associations are robust, findings for BTBD9 and Meis1 have been replicated in five different populations of European descent, and the magnitude is consistent across study populations (Stefansson et al., 2007; Winkelmann et al., 2007b; Vilarino-Guell et al., 2008). Confirmation of the results of the most recent GWA is pending. The at-risk SNPs in all four instances are common, present within noncoding, intronic or intergenic regions, and largely implicate genes that are widely expressed in the central nervous system and other organs. Very little is known about the normal function of these genes, let alone how they contribute specifically to the pathophysiology of RLS/PLMS, although all appear to have functions in the development of structures involved in the expression of RLS (i.e., sensory tracts, limbs). BTBD9 is named for its BTB domain, short for “broad complex, tramtrack, and bric a brac,” genes that in Drosophila are involved in embryonic development and limb formation (Winkelmann et al., 2007b). Meis1 is a gene containing a homeobox domain critical in embryonic limb formation and the establishment of spinal motor neuron connectivity (Winkelmann et al., 2007b). The MAP2K5 gene, one of the mitogen-activated protein kinases, is involved in muscle cell differentiation and neuroprotection of dopamine neurons, while the LBXCOR1 gene is another homeobox gene that is involved in development of the pain and temperature pathway in the spinal cord (Winkelmann et al., 2007b). PTPRD, or protein tyrosine phosphatase receptor type delta, appears to be involved with embryonic motor neuron

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axon guidance and termination (Schormair et al., 2008). Despite an incomplete understanding of the functions of these genes, these GWA results provide a critical step toward biological dissection of the pathophysiology of the RLS and PLMS. These results also offer explanations for some of the epidemiological features of RLS. The iron deficiency commonly seen in RLS appears to be attributable to, or a factor influencing expressivity of, the at-risk variant of the BTBD9 gene. Each copy of the at-risk variant predicts a 13% lower average serum ferritin (Stefansson et al., 2007). These findings also shed light on ethnic differences in RLS prevalence. Although these differences could reflect cultural differences in symptom experience or reporting, the most parsimonious explanation for ethnic differences in RLS prevalence is that the population frequencies of the at-risk alleles differ in a manner that mirrors the frequencies of RLS. Indeed, data from the International HapMap Project (http://www. hapmap.org) indicate that groups of European descent have higher allele frequencies of the at-risk variants at BTBD9, Meis1, and MAP2K5/LBXCOR1, although not PTPRD, than do those from Asia and Africa. Finally, the phenomenon of anticipation commonly observed in RLS families most likely reflects the high carrier frequency of the at-risk variants in asymptomatic or presymptomatic individuals, as opposed to expanded triplet repeats known to be absent in RLS (Desautels et al., 2003; Konieczny et al., 2006).

THE SIGNIFICANCE OF PERIODIC LIMB MOVEMENTS OF SLEEP Although the clinical significance of PLMS encountered on routine polysomnography has been debated, PLMS are increasingly recognized as part of the clinical spectrum of RLS. PLMS commonly occur as an asymptomatic condition in individuals who later develop classic RLS symptoms (personal observations), as well as in RLS family members (Birinyi et al., 2006). The results of the GWA further confirm that PLMS in the absence of complaints of restlessness are part of the biologic and phenotypic spectrum of RLS and identify PLMS as an endophenotype for RLS (Winkelman, 2007). The diagnostic criteria for RLS are a human construct, necessarily informed by physician experience, clinical expediency, and regulatory agencies, but an imperfect reflection of the underlying biology of the disorder. PLMS, on the other hand, are a genetically mediated, objective, biological phenomenon and remain an important tool in our understanding of RLS.

PATHOPHYSIOLOGY OF RLS/PLMS Pending a more complete understanding of the pathways involved with RLS based on genetic risk variants, theories about the pathophysiology of RLS have been derived in large part from clinical experience with the disorder. For example, a hypodopaminergic state has long been postulated as the cause of RLS, based on clinical response to treatment with dopaminergics. Indeed, the clinical response to dopaminergics is pronounced enough that a positive response is codified within the diagnostic criteria as supportive (Allen et al., 2003) and improves specificity of RLS diagnosis when added to the four cardinal criteria (Benes et al., 2008). Further, dopamine antagonists (e.g., metoclopramide, prochlorperazine, antipsychotics) can unveil or exacerbate RLS symptoms (Earley et al., 2000). The circadian pattern of RLS symptoms emulates that of dopa-responsive dystonia (Segawa syndrome), in which a GTP-cyclohydrolase deficiency limits production of tetrahydrobiopterin and decreases dopamine synthesis (Earley et al., 2000). Yet clear evidence for a hypodopaminergic state in RLS has not emerged. Multiple imaging studies failed to demonstrate unequivocal dopamine loss or hypofunctioning in RLS. Binding of single-photon emission computed tomography (SPECT) ligands to presynaptic dopamine transporters is similar in treated RLS patients, drugnaı¨ve RLS patients, and controls (Michaud et al., 2002; Tribl et al., 2002). SPECT studies of postsynaptic D2 dopamine receptor binding have been conflicting, with some showing decreased striatal binding and others showing no difference (Michaud et al., 2002; Tribl et al., 2002). Presynaptic evaluation using PET has shown either normal or reduced uptake of fluorodopa in the putamen and caudate (Trenkwalder et al., 1999; Turjanski et al., 1999; Ruottinen et al., 2000). Postsynaptic evaluation with PET has been even more inconclusive, with both decreased and increased D2 binding shown (Turjanski et al., 1999; Cervenka et al., 2006). Ultrasound studies have shown that RLS patients have hypoechogenicity of the substantia nigra (Schmidauer et al., 2005; Godau et al., 2008a), which could implicate dopaminergic dysfunction but could alternatively be an indication of iron deficiency (Schmidauer et al., 2005). Some of these inconsistent results could be due to methodology. To the extent that dopamine fluctuates with a circadian rhythm, testing paradigms at single time points may obscure true dopamine abnormalities, and cerebrospinal fluid dopamine appears to exhibit a circadian rhythm, with peak levels at 10 a.m. (Poceta et al., 2009). Additionally, there is a natural bias to focus on the brain’s largest and most conspicuous

RESTLESS LEGS SYNDROME dopamine circuit, i.e., the nigrostriatal system, traditionally taught to be the principal arbiter of hypoand hyperkinetic movement disorders; RLS pathology may reside in different circuitry. However, there is also mounting evidence suggesting that the dopamine dysfunction in RLS is more complicated than mere dopamine deficiency, involving alterations in the synaptic availability of dopamine through interactions with iron. A hypodopaminergic theory of RLS pathology would suggest that brain tyrosine hydroxylase would be decreased (as tyrosine hydroxylase is the ratelimiting enzyme in dopamine synthesis). While it was initially reported that tyrosine hydroxylase was not decreased in RLS brains compared to controls (Connor et al., 2003), more recent work by this group has shown that patients with RLS have increased tyrosine hydroxylase in the putamen (Allen et al., 2008; Wang et al., 2009). Furthermore, patients with RLS appear to have increased 3-ortho-methyldopa (3OMD) levels in spinal fluid compared to controls, with significant differences being seen in two studies (Earley et al., 2006; Allen et al., 2008) and a nonsignificant trend in the third (Stiasny-Kolster et al., 2004a). Levodopa can be metabolized by dopa-decarboxylase into dopamine or by catechol-o-methyltransferase (COMT) into 3OMD. Increased 3OMD levels can be explained in several ways: by increased amounts of levodopa (resulting in increased substrate for COMT), by decreased activity of dopadecarboxylase, or by increased activity of COMT. As RLS patients with elevated 3-OMD also have elevated homovanillic acid (the breakdown product of dopamine), the most consistent explanation for increased 3OMT is increased levodopa (Allen et al., 2008). The increased tyrosine hydroxylase on autopsy of RLS brains also has implications for our understanding of iron and RLS. Iron has been implicated in RLS pathology for several reasons. As with dopamine, serum iron has a circadian pattern, with an apex at noon and a nadir between 8 p.m. and midnight (Earley et al., 2000). Brain iron concentration also appears to vary with diurnal phase, with reduced whole-brain iron during the light phase but not the dark phase in irondeficient mice, although a similar effect was not seen for individual brain regions, including the substantia nigra and ventral tegmental area (Unger et al., 2009). Within the cerebrospinal fluid, RLS patients have lower ferritin and higher transferrin (a pattern consistent with insufficient iron) than controls, even in the setting of normal serum levels of ferritin and transferrin (Earley et al., 2000). Magnetic resonance imaging measuring brain iron concentration in RLS patients showed lower concentrations than controls in the substantia nigra, head of the caudate, and thalamus (Godau et al., 2008b). Postmortem evaluation of brains of

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RLS patients has shown decreased staining for iron, ferritin, and transferrin receptors, with increased staining of transferrin, consistent with decreased iron acquisition in the substantia nigra (Connor et al., 2003). Clinically, a number of RLS patients manifest peripheral iron deficiency, and several of the clinical conditions known to increase risk for RLS, such as pregnancy and renal failure, are also associated with iron deficiency (Allen, 2004). Additionally, the severity of iron deficiency (as measured by serum ferritin levels) is correlated with RLS symptom severity (O’Keeffe et al., 1994). The finding of increased tyrosine hydroxylase in RLS brains initially seems at odds with these data, as iron is a necessary cofactor for tyrosine hydroxylase. However, this autopsy finding has been confirmed in a cell culture model as well as an animal model (Allen et al., 2008), and is consistent with the findings of Nelson et al. (1997) that iron-deficient rats have increased extracellular dopamine in the caudate and putamen. Based on their cerebrospinal fluid study results and in the context of the autopsy findings, Allen et al. (2008) propose that, at least for a subset of RLS patients, the pathology may be central nervous system iron deficiency leading to increased tyrosine hydroxylase and increased dopamine synthesis. Their patients without elevated 3-OMD did not have elevated homovanillic acid levels, suggesting that increased dopamine may not explain RLS symptoms in all patients (Allen et al., 2008).

LOCALIZATION OF RLS PATHOLOGY WITHIN THE NERVOUS SYSTEM The anatomic substrate for RLS is an active area of investigation. Functional magnetic resonance imaging in RLS patients during sensory symptoms has shown activation of the cerebellum bilaterally and the thalamus contralateral to symptoms. When patients are experiencing PLMS in addition to sensory symptoms, there is additional activation of the red nuclei and the brainstem near the reticular activating system (Bucher et al., 1997). SPECT imaging of regional cerebral blood flow in a father and daughter with RLS has shown blood flow to be decreased in the caudate and increased in the thalamus and anterior cingulate in patients experiencing painful RLS during immobility (San Pedro et al., 1998). Diffusion tensor imaging has shown abnormalities of multiple areas of frontal and parietal white matter in RLS patients (Unrath et al., 2008). Transcranial magnetic stimulation studies have shown abnormal motor cortex excitability in RLS, which is reversible by dopamine agonist administration (Scalise et al., 2004; Nardone et al., 2006). Focal subcortical strokes can result in RLS (Lee et al., 2009).

666 L.M. TROTTI AND D.B. RYE Taken together, these studies suggest dysfunction of did not have a significant increase in their iron stores, subcortical and cortical networks in the production of yet the subset of patients who did have improvement RLS symptomatology. in RLS symptoms also had a significant increase in In addition to investigations implicating cortical and iron. A more recent randomized, controlled trial of subcortical networks, several investigative teams have oral iron in RLS patients with low-normal ferritin did recently posited that the principal pathology in RLS show a significant reduction in RLS severity (Wang might alternatively reside in the small, relatively underet al., 2009). studied diencephalospinal pathway originating from Intravenous (IV) iron dextran has been shown to be the dorsal-posterior hypothalamic A11 dopaminergic beneficial in patients with end-stage renal disease cell group and projecting diffusely to the spinal cord (Sloand et al., 2004), but only open-label case series (Clemens et al., 2006). Lesions to the A11 cell group support its use in patients without renal disease in mice result in increased locomotion (Qu et al., (Nordlander, 1953; Earley et al., 2004). A randomized, 2007). Extending the similarities with human RLS, in placebo-controlled trial of IV iron sucrose was stopped these A11 lesioned animals, coexisting iron deficiency early due to lack of convincing benefit (Earley et al., further increases this motor hyperactivity and treat2008), but whether this reflects a failure of IV iron ment with the dopamine agonist ropinirole reduces it or just of IV iron sucrose is not yet apparent. Although (Qu et al., 2007). Evidence of spinal cord pathology low ferritin ( 50 mg/L) does not appear to interfere in RLS patients comes from the observation that RLS with response to dopaminergic therapy for RLS patients have hyperexcitability of spinal sensorimotor (Morgan et al., 2008), very low ferritin ( 20 mg/L) circuits that is sleep-specific and manifests as a flexor does increase the risk of treatment complications, spereflex with a lower threshold and greater spread to cifically augmentation (Trenkwalder et al., 2008b). If adjacent muscles than that seen in controls (Barairon repletion is desired, a number of formulations of Jimenez et al., 2000; Aksu and Bara-Jimenez, 2002). iron are available. In oral form, there are several differRLS and PLMS otherwise indistinguishable from “idioent salts and formulations, including ferrous sulfate, pathic” RLS and PLMS, including in their responsiveferrous gluconate, and ferrous fumarate. Many of the ness to dopaminergics, can emerge after spinal cord oral preparations cause gastrointestinal side-effects insults (Trotti and Rye, 2007). Several patients with such as constipation, diarrhea, nausea, and abdominal medically refractory RLS have experienced dramatic pain. These side-effects can be minimized by reducing symptomatic relief with intrathecal administration of the amount of elemental iron absorbed, by taking the morphine (Jakobsson and Ruuth, 2002; Lindvall et al., iron with food, lowering the dose of iron, or using a 2008; Ross et al., 2008). preparation with a relatively low amount of elemental iron such as ferrous gluconate (Umbreit, 2005). Several IV formulations are also available. Of these, TREATMENT iron dextran has the highest rate of serious anaphylaxis The treatment of RLS demands a thorough clinical (0.6–0.7%) and other adverse events, present in up to evaluation to rule out coexisting conditions that are 50% of patients (Silverstein and Rodgers, 2004). Iron likely to enhance expressivity of RLS. The most comsucrose and ferric gluconate have lower rates of mon of these is iron deficiency. Because a substantial serious anaphylaxis (0.002% and 0.04%, respectively) number (about two-thirds in our clinic population) of and adverse events (36% and 35%) (Silverstein and iron-deficient patients do not exhibit coexisting anemia Rodgers, 2004), although their use outside chronic (i.e., pre-anemic iron deficiency), a serum iron panel renal failure constitutes off-label use and the single (iron, total iron-binding capacity, percent transferrin negative study of iron sucrose in RLS raises questions saturation, and ferritin) is the preferred screen for iron about its efficacy relative to iron dextran. deficiency in RLS patients. The RLS Foundation treatMedications known or suspected to worsen RLS ment algorithm recommends iron repletion when ferrishould be discontinued when possible. These include tin is below 20 ng/mL and consideration of iron antihistamines, dopamine antagonists, antidepressants, repletion on a case-by-case basis when the ferritin is neuroleptics, and lithium (Hornyak et al., 2006; above 20 but lower than 45–50 ng/mL (Silber et al., Hening, 2007; Rottach et al., 2008; Urbano and Ware, 2004). Although this is an expert guideline, data to sup2008). Of the selective serotonin reuptake inhibitor port iron supplementation are still mixed. A rando(SSRI) and selective serotonin and norepinephrine mized, controlled trial of oral iron sulfate in RLS reuptake inhibitor (SNRI) antidepressants, mirtazapine patients not stratified by iron status did not show a appears to have the highest rate of new or worsened benefit on sleep or RLS symptoms (Davis et al., RLS (occurring in 28% of treated patients, versus 9% 2000). However, as a group, the subjects taking iron of patients treated with any SSRI or SNRI) (Rottach

RESTLESS LEGS SYNDROME et al., 2008). Similarly, the use of tobacco, alcohol, and caffeine has been implicated in worsening RLS (Hening, 2007) and should be avoided. When pharmacologic treatment for RLS is needed, the first line of treatment is dopaminergic agents. The only two medications presently approved by the US Food and Drug Administration (FDA) for treatment of RLS are the dopamine agonists ropinirole and pramipexole. Dopamine agonists alleviate RLS symptoms in 70–90% of patients in randomized trials (Happe and Trenkwalder, 2004). Pramipexole is a nonergot-derived dopamine D3 and D2 agonist that has been proven to be effective for both RLS and PLMS (Montplaisir et al., 1999, 2000; Partinen et al., 2006; Winkelman et al., 2006a; Ferini-Strambi et al., 2008). The mean effective daily dose ranged from 0.25 to 1 mg (Trenkwalder et al., 2008a). Pramipexole is renally excreted. Ropinirole is also a nonergotderived dopamine agonist that works primarily on D3 and D2 receptor subtypes and is effective for RLS and PLMS (Adler et al., 2004; Allen et al., 2004; Trenkwalder et al., 2004; Walters et al., 2004; Bliwise et al., 2005; Bogan et al., 2006). The mean effective daily dose of ropinirole is about 2 mg (Trenkwalder et al., 2008a). Ropinirole is metabolized through the CYP1A2 isoenzyme of the cytochrome P450 system, and has important drug interactions with inhibitors and inducers (including nicotine) of this system. Because of this, warfarin levels can be increased by concomitant use of ropinirole, making pramipexole a potentially safer choice in patients on warfarin. Cabergoline is an ergot-derived dopamine agonist that is effective for RLS treatment (Benes et al., 2004; Oertel et al., 2006; Trenkwalder et al., 2007), but because all ergot-derived dopamine agonists increase risk for valvular heart disease (Zanettini et al., 2007), cabergoline is not considered first-line therapy for RLS. Transdermal delivery of dopamine agonists has also been preliminarily investigated for treatment of RLS. Continuous administration via transdermal application potentially could lead to fewer side-effects by maintaining more stable plasma levels (Benes, 2006) and benefit patients with daytime symptoms (StiasnyKolster et al., 2004b). Pilot and open-label data support the use of rotigitine (Stiasny-Kolster et al., 2004b; Oertel et al., 2008) and lisuride (Benes, 2006) for RLS. Rotigotine is available in parts of Europe, although it was recently removed from the market in the USA due to abnormal crystallization of medication within the patch substrate. Lisuride is an ergot-derived dopamine agonist, but long-term safety (especially regarding the potential for development of fibrotic disease) is not known (Trenkwalder et al., 2008a). The adverse effects associated with dopamine agonists

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include nausea, somnolence, headache, dizziness, nasal rhinitis, and peripheral edema. Dopamine can also be supplied directly in the form of levodopa for the treatment of RLS. Although levodopa is effective for RLS, it appears to be more strongly associated with the development of augmentation than the dopamine agonists, which can limit its usefulness (Paulus and Trenkwalder, 2006). However, for patients with sporadic symptoms who need a “rescue” medication but not a daily prophylactic medication, levodopa (100–200 mg) is a good choice because of its quick onset of action. Side-effects of levodopa are similar to those of the dopamine agonists and include hypotension, hallucinations, sleepiness, and gastrointestinal distress. Several other classes of medications have been used for the treatment of RLS (Table 47.1). The Movement Disorders Society (MDS) recently appointed a task force to review the evidence for RLS treatments. Based on this systematic review, the MDS task force classified gabapentin as effective for RLS (in addition to dopaminergic agents) (Trenkwalder et al., 2008a). The mean effective daily dose of gabapentin was 1855 mg/day, divided into two daily doses (GarciaBorreguero et al., 2002). Patients with painful RLS benefited more than patients without pain.

Table 47.1 Treatments for restless legs syndrome First-line Dopamine agonists Pramipexole Ropinirole Second-line* Gabapentin Levodopa Third-line* Cabergoline Carbamazepine Clonidine Oxycodone Transdermal rotigotine Valproic acid Investigational* Amantadine Clonazepam Methadone Topiramate Tramadol Transdermal lisuride Zolpidem *Use of these medications constitutes “off-label” use in the USA.

668 L.M. TROTTI AND D.B. RYE Open-label investigation of pregabalin, a related sufficient evidence to support their use except as compound, has shown preliminary support for its experimental therapy (Trenkwalder et al., 2008a). Exerbenefit in RLS (Sommer et al., 2007). A gabapentin cise (aerobic and lower-body conditioning) may reduce prodrug (currently known as XP13512/GSK 1838262) RLS symptoms (Aukerman et al., 2006), but is still is under development for use in RLS, with data from considered investigational (Trenkwalder et al., 2008a). two randomized controlled trials suggesting that a single daily dose can significantly improve RLS severity TREATMENT COMPLICATIONS scale scores (Kushida et al., 2009a, b). Augmentation is a troubling clinical phenomenon, The MDS task force identified several other medifairly unique to RLS, in which the symptoms of RLS cations as “likely efficacious” in RLS, based on the intensify after a period of effective pharmacological level of evidence supporting their use. These included intervention. Symptoms may become more severe than oxycodone, carbamazepine, valproic acid, and cloniin the pretreatment condition. The increase in severity dine (Trenkwalder et al., 2008a). Given concerns about manifests as either the occurrence of symptoms earlier long-term use of opioid treatment, Walters et al. (2001) in the day, or at least two of the following: spread of performed a retrospective review of 36 patients who symptoms to previously unaffected body parts such had attempted opioid monotherapy for RLS. Of these, as the arms, sooner onset of symptoms upon becoming 20 patients remained on monotherapy for an average inactive, increase in symptom intensity, shorter duraof almost 6 years. Of the one-third of patients who tion of treatment effect, or the appearance of periodic did not remain on monotherapy, eight had discontinued limb movements while awake (Garcia-Borreguero due to side-effects, seven had incomplete response, et al., 2007a). It has been suggested that the most and only one patient developed signs of addiction specific symptom of augmentation is the development and tolerance. Of note, when seven of the 20 patients of RLS symptoms earlier in the day and that the most who remained on monotherapy were studied with polysensitive symptom of augmentation is increased seversomnography, two had developed new sleep apnea and ity of RLS symptoms (Paulus and Trenkwalder, 2006). a third had exacerbation of previously diagnosed apnea Augmentation can range from a minor problem to a (Walters et al., 2001). These results suggest that opioids severe clinical complication. Augmentation occurs may have long-term effectiveness for some patients predominantly with dopaminergic medications, but with RLS, but that side-effects and sleep-disordered has also been reported to occur with tramadol (Earley breathing may interfere with treatment for others. Cloand Allen, 2006). Estimates of augmentation rates nidine was shown to be effective for RLS, but not are limited by the short duration of most RLS clinical PLMS, in a single small but controlled trial (Wagner trials (weeks to months) in comparison to the length et al., 1996). Other medications considered investigaof time augmentation takes to develop (months to tional by the MDS task force include methadone, trayears) and by a lack of systematic methods to evaluate madol, clonazepam, zolpidem, amantadine, and augmentation (Trenkwalder et al., 2008a) prior to the topiramate (Trenkwalder et al., 2008a). recent publication of an augmentation rating scale Several nonpharmacologic or nonprescription inter(Garcia-Borreguero et al., 2007b). However, data sugventions are also under investigation for use in RLS. gest that levodopa has a rate of augmentation as high A small trial comparing pneumatic compression as 60–73% (Garcia-Borreguero et al., 2007b, c), while devices to sham devices, both used for at least 1 hour rates for pramipexole are lower (8–56%); convincing a day prior to typical symptom onset, showed signifirates for ropinirole are not yet available (Garcia-Borrecant benefits in RLS severity (Lettieri and Eliasson, guero et al., 2007c). Mild cases of augmentation may 2008). In patients with coexisting superficial venous be treated by moving the medication dosage earlier in insufficiency and RLS, treatment with endovascular the day (Garcia-Borreguero et al., 2007c). For more laser ablation significantly reduced RLS symptoms severe cases, the patient should be changed to a differcompared to a no-treatment placebo group (Hayes ent medication, typically gabapentin or an opiate et al., 2008). Several groups have investigated the use (Garcia-Borreguero et al., 2007c). Changing from one of acupuncture for RLS, but presently there is insuffidopamine agonist to another in cases of augmentation cient evidence to support or refute its use (Cui et al., is controversial (Garcia-Borreguero et al., 2007c) but 2008). Botulinum toxin injection has been attempted can be beneficial (Silber et al., 2004). as treatment for RLS, with promising early results There have been recent reports of compulsive behafrom a case series (Rotenberg et al., 2006) that have viors associated with the treatment of RLS with dopaminot been corroborated by a single, small but blinded nergic agents (Quickfall and Suchowersky, 2007; and controlled clinical trial (Nahab et al., 2008). MagTippmann-Peikert et al., 2007). One questionnaire-based nesium and folate supplementation do not have

RESTLESS LEGS SYNDROME study found that 6% of RLS patients noted increased urges to gamble and increased time spent gambling after starting dopaminergic medications and 4% noted increased sexual desire (Driver-Dunckley et al., 2007). In patients with either RLS or Parkinson’s disease taking dopamine agonists, younger age and higher doses of dopamine agonists were risk factors for the development of increased gambling, spending, or sexual activity (Ondo and Lai, 2008). Patients should be alerted to this potentially serious complication, although prospective longitudinal studies with validated measures of impulse control are needed to clarify any cause-and-effect relationship.

TREATMENT IN SPECIAL CLINICAL SITUATIONS Patients with end-stage renal disease have a high prevalence of RLS, ranging from 6.6 to 62% of dialysis patients, with similar prevalence in patients receiving peritoneal dialysis and hemodialysis (Kavanagh et al., 2004). Dialysis itself does not relieve the symptoms of RLS, but renal transplantation frequently does (Winkelmann et al., 2002; Molnar et al., 2005). As with idiopathic RLS, dopaminergic medications are considered first-line therapy for patients with end-stage renal disease (Kavanagh et al., 2004). Pramipexole and levodopa have been shown to be effective in this population (Kavanagh et al., 2004; Miranda et al., 2004). Nondopaminergic therapies used in primary RLS have also been studied and shown to be beneficial in uremic patients, including clonazepam, gabapentin, and clonidine (Kavanagh et al., 2004). RLS in pregnancy presents a particular challenge, as RLS is common in pregnancy, with a prevalence of 26% (Manconi et al., 2004), yet medications typically used in the treatment of RLS are not considered safe in pregnancy. RLS medications that are US FDA class C (for which animal data demonstrate harm but no human data exist, or for which neither animal nor human data exist) include ropinirole, pramipexole, levodopa, clonidine, and gabapentin. Medications that are pregnancy class D (having evidence of fetal risk in human studies) include carbamazepine and some benzodiazepines. Additionally, infants born to mothers taking benzodiazepines or opioids near the end of pregnancy are at risk for withdrawal symptoms (Chesson et al., 1999). Thus, nonpharmacologic therapies should be used when possible. Iron deficiency should be corrected when present in pregnancy and some authors propose the use of magnesium for the treatment of RLS, based on cases of RLS improving when pregnant women are given intravenous magnesium for tocolysis (Bartell and Zallek, 2006).

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