The restless legs syndrome

The restless legs syndrome

Review The restless legs syndrome Claudia Trenkwalder, Walter Paulus, Arthur S Walters The restless legs syndrome is a common disorder that encompas...

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Review

The restless legs syndrome Claudia Trenkwalder, Walter Paulus, Arthur S Walters

The restless legs syndrome is a common disorder that encompasses an idiopathic form of genetic or unknown origin and symptomatic forms associated with many causes. Symptomatic forms occur during pregnancy and are coincident with uraemia, iron depletion, polyneuropathy, spinal disorders, and rheumatoid arthritis. For the hereditary forms, at least three gene loci, located on chromosomes 12, 14, and 9, have been traced so far. Prevalence in the general population is between 3% and 9%, increases with age, and is higher in women than in men. Treatment is needed only in the moderate to severe forms of the disorder and mostly in elderly people. Pathophysiology and treatment may be closely linked to the dopaminergic system and iron metabolism. Dopaminergic treatment with levodopa and dopamine agonists is the first choice in idiopathic restless legs syndrome, but augmentation and rebound should be monitored in long-term treatment. Various other drugs, such as opioids, gabapentin, and benzodiazepines, provide alternative treatment possibilities.

Introduction and clinical features The restless legs syndrome is defined by some people as a syndrome, by some as a sleep disorder, some refuse to accept it as a problem at all, and few know that it has clearly defined clinical diagnostic criteria. The prevalence of the syndrome has been underestimated in the past and epidemiological population-based studies show that between 3% and 10% of the population have cardinal symptoms.1–3 In several studies a female preponderance has been described.2–5 Most patients with mild symptoms do not need any pharmacological treatment. Patients who need continuous treatment are mostly older than 50 years, consistent with the mean age of populations in trials for treatment of the syndrome. In 1995, clinical diagnostic criteria for the restless legs syndrome were established by the International Restless Legs Syndrome Study Group (IRLSSG).6 During a National Institutes of Health conference in May, 2002, experts, including members of the IRLSSG and authorities on epidemiology and scale design, edited these criteria for improved clarity. The criteria were then further reviewed by the IRLSSG and published in 2003.7 The panel lists the clinical characteristics of the syndrome. All four essential criteria must be met for a positive diagnosis. The restless legs syndrome has been described as an idiopathic disorder with no apparent cause or as a symptomatic syndrome often associated with iron deficiency, pregnancy, or end-stage renal disease. However, the syndrome could also be described as a complex disorder with underlying genetic or environmental components, or both. Onset in childhood implies a strong genetic component for the syndrome,8 although the age of onset in general is known to vary widely, from childhood to over 80 years of age.9,10 Clinical experience shows severe restless legs syndrome to be mostly a chronic progressive disorder that, once started, needs lifelong treatment. Variations in the clinical course, with periods of remission, are especially common in young adults.7 The key characteristic of the syndrome is an urge to move the legs, often accompanied by a wide range of http://neurology.thelancet.com Vol 4 August 2005

sensory symptoms. These symptoms are usually associated with very unpleasant sensations felt mostly deep inside the limbs, occurring unilaterally or bilaterally, affecting the ankle, knee, or the entire lower limb. With progressive disease, an involvement of the arms has been described in up to 48% of patients.11 In some patients, pain dominates the picture and can lead to the syndrome being misdiagnosed as a chronic pain problem. The sensory symptoms occur during wakefulness, mostly when the patient is sitting or lying down, and at night. Movement brings about at least temporary and partial relief of the discomfort, especially

Lancet Neurol 2005; 4: 465–75 Paracelsus Elena Klinik, Centre of Parkinsonism and Movement Disorders, Kassel, Germany (C Trenkwalder MD); Department of Clinical Neurophysiology, University of Göttingen, Göttingen, Germany (W Paulus MD); and New Jersey Neuroscience Institute, JFK Medical Center, Seton Hall University School of Graduate Medical Education, Edison, NJ, USA (A S Walters MD) Correspondence to: Prof Claudia Trenkwalder, Paracelsus Elena Klinik, Centre of Parkinsonism and Movement Disorders, 34128 Kassel, Klinikstr. 16, Germany [email protected]

Panel: Essential criteria, supportive criteria, and associated features Essential criteria ● An urge to move the legs, usually accompanied by uncomfortable or unpleasant sensations in the legs ● Unpleasant sensations or the urge to move begin or worsen during periods of rest or inactivity such as lying or sitting ● Unpleasant sensations or the urge to move are partly or totally relieved by movement such as walking, bending, stretching, etc, at least for as long as the activity continues ● Unpleasant sensations or the urge to move are worse in the evening or at night than during the day, or only occur in the evening or night Supportive criteria Positive response to dopaminergic treatment ● Periodic limb movements (during wakefulness or sleep) ● Positive family history of the restless legs syndrome suggestive of an autosomal dominant mode of inheritance. ●

Associated features Natural clinical course of the disorder Can begin at any age, but most patients seen in clinical practice are middle-aged or older. Most patients seen in the clinic have a progressive clinical course, but a static clinical course is sometimes seen. Remissions of a month or more are sometimes reported. Sleep disturbance The leg discomfort and the need to move result in insomnia. Medical investigation/neurological examination A neurological examination is usual in idiopathic and familial forms of the syndrome. Peripheral neuropathy or radiculopathy are sometimes carried out in the non-familial form of the syndrome. A low serum ferritin (50 g/L) may be found in the syndrome.

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walking, stretching, or bending the legs. For clinical and research purposes, a severity rating scale has been developed and validated by the IRLSSG.12

Children and the restless legs syndrome Although most patients seen in clinical practice are middle-aged or older, the restless legs syndrome can occur in children. From studies of families with the syndrome we know that symptoms in severely affected patients can begin in childhood13,14 and can be misdiagnosed as growing pains.15 Restless legs syndrome in children should be differentiated from attention-deficit hyperactivity disorder (ADHD).16 The need to move because of leg discomfort distinguishes restless legs syndrome from ADHD. However, the situation is more complex since patients with restless legs may also manifest symptoms of ADHD more frequently than controls.17,18

Periodic limb movements In addition to the voluntary movements that patients make to alleviate their leg discomfort, involuntary movements also occur either during sleep or when awake. These movements recur periodically and are called periodic limb movements. Diagnosis of periodic limb movements during sleep is based on the definition of the American Sleep Disorders Association.19 These movements are measured by surface electromyography from the tibialis muscle and show muscle activation in a sequence of at least four muscle contractions lasting 0·5–5 s and recurring at intervals of 5–90 s. The muscle contractions must be at least 25% of the amplitude of the voluntary leg movements the patient is asked to do for purposes of calibration before the start of a sleep study. Periodic limb movements during sleep are

Nasal air flow

Abdominal belt

similar to the triple flexion reflex of the hip, knee, and ankles and to the Babinski sign.20 These movements can occur with or without arousals or during wakefulness (figure 1). About 80% of patients with the restless legs syndrome have periodic limb movements during sleep.21 However, there is much night-to-night variation in the number of movements in individual patients,22 and if a second night’s recording is undertaken, 87% of patients will have periodic limb movements during sleep on at least one of two nights of recording. These movements are also not specific for the diagnosis of restless legs syndrome because they can occur in other disorders or as an isolated occurrence. Individuals with the syndrome might also complain of involuntary twitching movements of the legs during wakefulness when they are sitting or lying. These movements may be periodic and take the form of periodic limb movements during wakefulness or aperiodic movements. The phrase dyskinesias while awake has been used to describe involuntary movements during wakefulness in restless legs syndrome, which includes both periodic and aperiodic types.23,24 Unlike periodic limb movements during sleep, dyskinesias during wakefulness can sometimes be faster or of myoclonic speed. In only about 15% of patients with the syndrome are these movements during wakefulness part of the chief complaint,6 possibly because patients with mild dyskinesias while awake move to relieve their pain and successfully suppress future severe dyskinesias. However, if patients are asked to lie perfectly still, the occurrence of periodic limb movements during wakefulness seems to be a reliable characteristic occurrence in patients with the restless legs syndrome and can be quantified by an immobilisation test.24 In this test, patients are asked to lie still and not move while electromyography of the tibialis anterior muscle is recorded during wakefulness. Depending on the severity of the syndrome, patients start to complain about sensory symptoms and an urge to move the limbs after 15–30 min. Periodic limb movements during wakefulness occur during this time and are recorded over 1 h. The suggested immobilisation test can be used to quantify the restless legs syndrome and to monitor treatment. Actigraphy is another method used to measure periodic limb movements in wakefulness during the suggested immobilisation test, general motor activity during wakefulness, or periodic limb movements during the sleep period.25,26

Symptomatic restless legs syndrome Figure 1: Polysomnogram (30 s) of a typical patient with the restless legs syndrome with a sequence of periodic limb movements during wakefulness Periodic limb movements in the left leg are recorded with surface electromyography (EMG) of the left tibialis anterior muscle (bottom). Electroencephalographic (top), chin electromyographic (middle), and respiratory recordings (nasal airflow and abdominal belt) are shown.

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Iron deficiency is assumed to be the most frequent cause of symptomatic restless legs syndrome next to the uraemic form. The manifestation or worsening of restless legs syndrome may be associated with low blood concentrations of ferritin, often during blood http://neurology.thelancet.com Vol 4 August 2005

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donations.27,28 In most patients, iron deficiency is not detected because there is no anaemia, and low ferritin is the only pathological parameter. Another frequent association is that of renal failure.29–31 The sleep quality of patients with uraemic restless legs syndrome is poor31 and morbidity is high. Additionally, the syndrome often occurs with rheumatoid arthritis, fibromyalgia, or in pregnancy.32–34 Some women have the disorder for the first time or have symptoms that worsen temporarily during pregnancy;34 individuals who experience symptoms during pregnancy often have a family history of the disorder.10 The restless legs syndrome can be seen in association with peripheral neuropathy or radiculopathy.35–37

Differential diagnosis Although the restless legs syndrome might be triggered by peripheral neuropathy or radiculopathy, a distinction should be made between the disorders. In pure peripheral neuropathy and radiculopathy, patients do not have the compelling need to move to relieve leg discomfort and the symptoms are not consistently worse at rest or at night. The restless legs syndrome should also be distinguished from neuroleptic-induced akathisia, which is motor restlessness induced by antipsychotic agents that block dopamine receptors.38 In this disorder patients feel compelled to move because of an inner sense of restlessness rather than a need to specifically move the legs. The restless legs syndrome should be differentiated from positional discomfort: if the only movement needed is a small brief position change to relieve pressure—eg, on an arthritic hip—this discomfort is not the restless legs syndrome.

Molecular genetic studies have identified at least three major susceptibility loci in large families from Canada, Italy, USA, and Germany, although at present the lod scores are far from conclusive with respect to the size of the families investigated. The syndrome might not be caused by a single genetic defect as, for example, in Huntington’s disease, but could be a disorder with a complex inheritance, as for many neurological disorders such as Alzheimer’s disease, dementia, or migraine. The first locus conferring susceptibility to the restless legs syndrome was mapped in 2001. This locus was on chromosome 12q and connected with a series of adjacent microsatellite markers with an autosomal recessive mode of inheritance.39 However, these findings were not confirmed a year later in three European families.40 In the chromosome-12-linked Canadian families, neurotensin and other modulators of dopaminergic neurotransmission located in the target region are probably not the responsible genes.41 The Canadian locus on chromosome 12 has been confirmed in five more families, but the researchers concluded that genetic heterogeneity should be considered.42 A further locus was found in the chromosome 14q13–21 region in a 30-member, threegeneration Italian family, and later confirmed in another Canadian family.43,44 Large CAG trinucleotide expansions at the spinocerebellar ataxia type 3 locus are not associated with idiopathic restless legs syndrome.45 However, the prevalence of symptoms in patients with spinocerebellar ataxia 1–346 is higher than in the general population.47 A model-based linkage analysis, with the assumption of an autosomal-dominant mode of inheritance, indicated a 9p24–22 linkage for the restless legs syndrome in two large families from the USA.48

Diagnostic work-up If the neurological examination suggests an associated peripheral neuropathy or radiculopathy, electromyography and nerve conduction studies should be undertaken to document these disorders. Since the restless legs syndrome is frequently associated with iron deficiency, all patients should have a test for serum ferritin concentration, which is thought to be the most sensitive measure of iron deficiency.

Genetics Ekbom33 described the familial component of the syndrome in 1945, and since then many studies have been published on the familial forms of the disorder. Clinically, these forms cannot be differentiated from sporadic or symptomatic forms.10 Taking together the clinical manifestations and the course of the disease, the idiopathic and symptomatic forms do not differ. In genetic studies, environmental factors have played an essential part in the manifestation of symptoms. Only in early-onset in individuals with a positive family history is there strong evidence that a major genetic susceptibility could explain the syndrome.8 http://neurology.thelancet.com Vol 4 August 2005

Pathophysiology Animal and imaging studies The study of the restless legs syndrome in animal models is in its infancy. One model has shown age-dependent, spontaneous, periodic hind-limb movements in sleeping rats.49 An intriguing approach is the targeting of the dopaminergic A11 cell group as a possible pathophysiological correlate of the syndrome.50 A11 cells are the only cells that provide dopaminergic axons to the spinal cord. There are probably no intrinsic dopaminergic cells in the spinal cord. Dysfunction or atrophy of these cells could explain the excellent treatment response to dopaminergic drugs and the circadian rhythm of the syndrome since these cells are in close proximity to the hypothalamic circadian pacemaker (figure 2). Selective lesion of A11 neurons is almost impossible without damaging other structures in their vicinity. Therefore, and for other methodological reasons, these findings are not fully convincing. Nevertheless A11 cells should remain the focus of future pathophysiological research because of their strategic location. 467

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Figure 2: A11 cells are clustered in the midbrain close to the hypothalamus and project into the cortex, the limbic system, and the spinal cord The A11 cell bodies project into the dorsal horns and intermediolateral tracts of the spinal cord. In the ventral horn a dopaminergic terminal plexus in lamina IX at all spinal levels is shown.

The essentially normal presynaptic dopaminergic binding studies using 18F-dopa PET51–53 or -CITSPECT54–56 in patients with the restless legs syndrome lend support to the hypothesis that A11 dopaminergic neurons and spinal pathways could be more involved in the pathophysiological mechanisms of the syndrome than the nigrostriatal system.57 An fMRI imaging study showed bilateral activations of the cerebellum and brainstem and contralateral activation of the thalamus in various constellations during different combined periodic limb movement and sensory leg discomfort disorders.58

Neurophysiological studies In patients, the soleus H-reflex recovery curves (H-response/M-response after paired tibial nerve stimulation over interstimulus interval time) showed increased late facilitation and depressed late inhibition, both indicating diminished inhibition due to postsynaptic central activity and probably due to altered function of the descending spinal tracts, peripheral 468

influence or changes in the interneural circuitry at the spinal level itself, or combinations of these three possibilities.59 In another neurophysiological study, patients had substantially increased spinal cord excitability, indicated by reduced threshold and heightened spatial spread of the flexor reflex, which was more prominent during sleep. Multiple late responses with a very long duration and a latency range of 250–800 ms were recorded during sleep in all patients and in some controls at raised thresholds.60 Impairment of temperature perception was found in 72% of symptomatic patients and in 55% of patients with idiopathic restless legs syndrome.61 The researchers also reported that in symptomatic patients, impaired peripheral C-fibre function, as specifically tested, is probably caused by small fibre neuropathy, whereas in idiopathic restless legs syndrome, normal C-fibre function indicates a functional impairment of central somatosensory processing.61 In another study, eight of 22 patients had a neuropathy (three pure large fibre, two mixed, and three isolated small fibre polyneuropathies).35 Patients with the restless legs syndrome also have substantial static hyperalgesia, but no dynamic mechanical hyperalgesia or allodynia, which is probably mediated by central sensitisation to an A-delta-fibre high-threshold mechanoreceptor input, such as in neuropathic pain.62 This static hyperalgesia to pin-prick was reversed only by longterm, individually tailored, dopaminergic treatment. Peripheral somatosensory input is not a necessary precondition for the syndrome: a patient with symptoms of the restless legs syndrome in the absent portions of his lower extremities, after bilateral aboveknee amputations, responded well to dopamine agonist treatment.63 Central pain perception could also have a role in the pathophysiological mechanisms of restless legs syndrome. Opioid receptor binding was measured by (11 C) diprenorphine, a non-selective opioid receptor ligand, in 12 patients with the restless legs syndrome and in controls. Binding in patients correlated with the severity of the syndrome: the more severe the disease, the greater the release of endogenous opioids within the medial pain system.64

Iron Whereas the pharmacological treatment data strongly lend support to a dopaminergic abnormality in the restless legs syndrome, iron depletion should be regarded as the most relevant additional factor for the clinical manifestations of the syndrome and can be assessed in patients by measuring ferritin concentrations.65–67 Several studies showed a relation between low ferritin concentrations and symptoms of the syndrome,68,69 especially when ferritin was measured in the CSF.70,71 In a neuropathological study, neuromelanin cells from brains of four patients and four controls were studied for iron metabolism. http://neurology.thelancet.com Vol 4 August 2005

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Ferritin and divalent-metal transporter-1 were decreased in neuromelanin cells of disease brains, and transferrin increase was altogether consistent with iron deficiency. Transferrin receptor expression, however, was reduced rather than increased and was not consistent with an iron deficiency model of the restless legs syndrome. The researchers postulated that a defect in iron regulatory protein 1 in neuromelanin cells could promote destabilisation of the transferrin receptor mRNA, leading to cellular iron deficiency.72 These same authors have shown similar changes in brain iron content in patients compared with controls by use of MRI with specialised parameters.73

Circadian influences Some evidence exists to suggest that levodopa sensitivity is heightened at night.74 At present the question is still unresolved as to whether periodic limb movements during sleep are simply a painless forme fruste of the restless legs syndrome or represent a different disorder. There is a clear circadian rhythm of the subjective complaints of the syndrome, and similar time of night variations can be seen for periodic limb movements during sleep and during wakefulness independent from the condition of sleep or of recumbency.56,75–77 The changes in melatonin secretion, as a marker of the circadian rhythm, were the only changes that preceded the increase in sensory and motor symptoms in patients with the syndrome, implicating melatonin in the worsening of symptoms in the evening and during the night by exertion of an inhibitory effect on central dopamine secretion.78

Treatment Augmentation Augmentation is caused by dopaminergic treatment in patients with the restless legs syndrome. Augmentation has been defined as an early onset of symptoms of the syndrome during the day, an increase in severity of symptoms, and the involvement of other body parts.79 Whether all these criteria are necessary to define augmentation is not clear since the early onset of symptoms seems to be the most frequent and reliable criterion. In augmentation, despite nightly doses of short-term dopaminergic agents, symptoms that were once confined to the night-time can appear in the early afternoon of the next day when the drug is long out of the system. For once-nightly treatments with carbidopa or levodopa, augmentation can become a severe problem. This increase in symptoms occurred in the afternoon and in the early part of the evening before taking the next nightly dose in 31% to 82% of patients in this series.79 Augmentation was highest for patients with severe symptoms of the syndrome, but was unrelated to sex, age, or baseline severity of the syndrome. Symptoms during augmentation can also affect other body parts and can be more severe than the http://neurology.thelancet.com Vol 4 August 2005

symptoms of the syndrome per se.79 Augmentation has been described as a consequence of treatment with dopaminergic agonists, such as pramipexole.80 In smaller open label studies, augmentation has been reported during treatment with pergolide,81,82 although cases were usually mild and did not need a change of medication. Controlled studies of pergolide83 and ropinirole84,85 are either short-term investigations or augmentation has not been prospectively investigated according to its current definition. Severe augmentation usually resolves with cessation of medication; mild forms may be manageable by adding a dose of medication earlier in the day, as suggested by Winkelman and co-workers in 2004.80 Augmentation usually resolves with cessation of the medication and can be kept to a minimum by keeping the dose low. Guidelines for management of augmentation have not been published yet. There are no published studies on rebound or augmentation with non-dopaminergic agents. One hypothesis to explain augmentation suggests that dopaminergic treatment shifts the circadian timing of the appearance of symptoms of the syndrome to an earlier time of day. This can happen either within the striatal, hypothalamic, or spinal dopaminergic system, with the highest doses of levodopa usually associated with augmentation.74 Augmentation is the most serious problem of dopaminergic treatment in patients with the restless legs syndrome and all physicians treating these patients should be aware of this occurrence. From clinical experience and open follow-up treatment trials, dose escalation could be an additional treatment problem in the restless legs syndrome, although there are few data from controlled studies.

Rebound Rebound should be distinguished from augmentation. Rebound is the appearance of symptoms at a time that is compatible with the half-life of the drug, when the effects of the drug are wearing off, and is equivalent to withdrawal. Rebound was first noticed in the morning with increases of leg movements in about a quarter of patients treated with levodopa.86 Rebound occurs after morning awakening and consists of more severe symptoms of the syndrome in the morning than occurs without treatment.

Levodopa Levodopa was effective in treating nocturnal symptoms of the restless legs syndrome and improving subjective and objective quality of sleep in patients with idiopathic and uraemic disease in controlled trials.87–90 Levodopa plus benserazide has been approved for treatment of the syndrome in Germany, Switzerland, and Austria for several years. Levodopa is a short-acting drug and is an appropriate treatment for mild and intermittent 469

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disease, although all treatment trials to date have been done in patients with moderate to severe and more persistent disease. A combination of slow-release levodopa and standard levodopa is superior to standard levodopa alone.91,92 The rapid onset and offset of action of levodopa has been recorded.93 All of these treatment studies were undertaken by use of a randomised controlled design. Long-term studies of levodopa are available only in an open design.92,94 40% of patients treated in an open follow-up study developed augmentation that needed termination of levodopa within a year of treatment.94 Nausea and dizziness are other minor side-effects of levodopa treatment.

Dopamine agonists The ergot-dopamine agonists bromocriptine, pergolide, and cabergoline, and the non-ergot dopamine agonists pramipexole, ropinirole, and rotigotine have all been shown to be effective in double-blind studies. The first double-blind randomised crossover study of a dopamine agonist used 7·5 mg bromocriptine at bedtime with five out of six patients having partial subjective improvement in restlessness and paraesthesias.95 In a double-blind controlled study, pergolide was efficacious at a dose of 0·05–0·65 mg per day.96 In another study with this drug, the mean dose was titrated to 0·51 mg.97 In a large multicentre (PEARLS) study with 100 patients, pergolide decreased severity of the restless legs syndrome, measured with the international restless legs syndrome severity rating scale (IRLS score 12·2 pergolide vs 1·8 placebo), and was associated with an improved patient global impression response.83 Polysomnographic improvements occurred in the periodic limb movements during sleep index and arousal index after 6 weeks (p0·001). After 12 months of double-blind treatment with pergolide, improvements in these index scores were maintained at a mean dose of 0·52–0·72 mg per day; the sideeffects were nausea and headache.83 A recent controlled trial with the long-acting ergotagonist cabergoline in 85 patients with severe restless legs syndrome showed a stable, clinically relevant improvement for all efficacy measures (IRLS, clinical global impression) over a year with a mean dose of 2·2 mg cabergoline per day. During this long-term treatment, six of 66 patients treated with the drug were affected by mild augmentation.98 Valvular fibrosis of the heart has been described in association with pergolide treatment in doses higher than 4 mg.99 Whether this side-effect applies only for pergolide or for all ergot-agonists and whether it is dose dependent is not yet clear. Dose increases of such substances should be managed cautiously. Ropinirole has been approved as a treatment for the restless legs syndrome in the US, France, and Switzerland. Ropinirole was investigated in several 470

controlled studies. One such study was a European, 12-week, prospective, double-blind, randomised comparison of 284 patients, with a mean dose of 1·90 mg of ropinirole. In the treatment group there was a significant 11-point improvement on the severity scale (IRLS, 0–40 points), compared with an 8-point improvement in the placebo group.84 In another study, eight of 22 patients had complete resolution of symptoms with ropinirole,100 in line with a further controlled 12-week study.85 Ten patients on chronic haemodialysis reported a 33·5% improvement in the 6-item IRLS score during levodopa slow-release treatment (190 mg per day) and a 73·5% improvement during ropinirole (1·45 mg per day) treatment in an open study.101 In a controlled polysomnographic treatment trial, 59 patients were treated with ropinirole. The number of periodic limb movements during sleep per hour decreased more with ropinirole than with placebo (48·5 to 11·8). The arousal index decreased from 7·0 to 2·5 with ropinirole, but increased from 4·2 to 6·0 with placebo. The number of periodic limb movements while awake decreased from 56·5 to 23·6 per hour with ropinirole but increased from 46·6 to 56·1 per hour with placebo. Sleep efficiency measured by polysomnography was not improved, whereas sleep adequacy on a subjective scale (MOS scale) was significantly improved with ropinirole treatment.102 In ten patients with the restless legs syndrome, pramipexole reduced both the periodic limb movement during sleep index to normal values and the index during wakefulness significantly in a 1-month controlled treatment study with a single dose of 0·25–0·75 mg.103 Long-term observations in a retrospective case series of 60 patients over 2 years provided stable treatment results with a dose increase from 0·38 mg to 0·63 mg pramipexole and a rate of mild augmentation in 33% of patients who were treatable with increased doses early in the day.104 The rotigotine patch has been tested at three different dosages (1·13 mg, 2·25 mg, and 4·5 mg) in a 1-week controlled trial. The IRLS score differed significantly between the highest dose and placebo.105 Daytime symptoms improved with all doses, measured with the six-item IRLS, a non-validated scale. Other dopamine agonists have been investigated in open trials or case series.106 Treating the restless legs syndrome with dopamine agonists in general raises unresolved questions as to the role of the dose escalation related to the development of augmentation or rebound. Further trials should look more specifically into these issues.107

Opiates Opiates were described as treatment options by Willis as early as 1684.108 In a double-blind, randomised, crossover trial, oxycodone at an average dose of 15·9 mg reduced leg sensations and motor restlessness, and improved daytime symptoms of the http://neurology.thelancet.com Vol 4 August 2005

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syndrome. A significant reduction in the periodic limb movement during sleep index and arousal index was recorded polysomnographically in a controlled study.109 A second double-blind study of opiates for periodic limb movements during sleep reported a low dose of dextropropoxyphene, a less potent opioid than oxycodone, to be effective (though less effective than levodopa) in the treatment of these movements.90 Longterm data are only available as a case series110 and show a minimum risk of dependency, but some worsening of sleep apnoea may occur with chronic opioids.110

Gabapentin and other anticonvulsants Gabapentin has proven effective for the treatment of the restless legs syndrome in a controlled study with a mean dose of 1855 mg per day.111 In a further controlled comparative study, gabapentin, at a mean dose of 800 mg, and ropinirole, at a mean dose of 0·78 mg, provided a similarly well-tolerated and effective treatment of periodic limb movements during sleep and sensorimotor symptoms in patients with idiopathic restless legs syndrome.112 In haemodialysis patients, a reduced dose of 200–300 mg after each dialysis is needed.113 The first controlled study ever undertaken in patients with the restless legs syndrome was done with carbamazepine, with a success rate of 50% in six patients.114 The efficacy of carbamazepine was later confirmed in 174 patients in a double-blind study.115 When 200 mg slow release levodopa was compared with 600 mg slow release valproic acid, there was no major difference in efficacy.116 The periodic limb movement sleep index and arousal index significantly decreased with levodopa. However, arousals not associated with periodic limb movements during sleep were significantly increased with levodopa but not valproic acid, indicating that slow-release valproic acid can be a treatment alternative for these movements during sleep in patients with the restless legs syndrome.116

Benzodiazepines Clonazepam was effective in improving sleep in several studies in patients with the restless legs syndrome and periodic limb movements during sleep.117–120 Two studies concluded that the induced sleep changes were consistent with those produced by sedative benzodiazepines in general without reducing the number of periodic limb movements during sleep.118,121 In a cross-over study of clonazepam (1 mg) compared with temazepam (30 mg), total leg movements of six patients with the restless legs syndrome and periodic limb movements during sleep were not changed in both treatment groups; however, 0·125 mg triazolam increased total sleep time, sleep efficiency, and daytime function, while decreasing the number of sleep stage changes, but not changing total leg movements.122 http://neurology.thelancet.com Vol 4 August 2005

Iron In a randomised, double-blind, placebo-controlled trial in 28 patients with the restless legs syndrome, iron sulfate did not significantly improve the disorder, but patients were not selected according to ferritin concentrations, which seems to be the important parameter to diagnose and treat iron deficiency.123 In another study, high-dose iron dextran infusion was associated with a significant, but transient, reduction in symptoms of the restless legs syndrome in patients with end-stage renal disease.124 In an open study in which ten patients with the restless legs syndrome received a single 1000 mg intravenous iron infusion, seven patients showed a substantial improvement in symptoms 2 weeks later. The measured serum ferritin values suggest that greater-than-expected iron loss occurs after intravenous iron loading.69

Other treatments Clonidine is an effective treatment for some patients with the restless legs syndrome who do not have large numbers of sleep-disrupting periodic limb movements but do have delayed sleep onset due to leg sensations and subsequent motor restlessness.125 In a blinded study,126 baclofen reduced the force and amplitude of periodic limb movements without changing their duration.

Overall treatment recommendations Before starting a pharmacological treatment, sleep hygiene measures should be instituted and all possibilities for treating symptomatic restless legs syndrome should be considered. Iron should be supplemented if ferritin is low. From a practical point of view, and according to the guidelines of the American Academy of Sleep Medicine,127,128 we would emphasise dopaminergic agents as the first line of treatment for the syndrome, followed by opioids, anticonvulsants, and benzodiazepines. Of the anticonvulsants, gabapentin is preferable because of its superior efficacy, and among the benzodiazepines, clonazepam is preferable because of its long half-life. Treatments should be applied close to when the symptoms usually occur. If symptoms begin earlier rather than later in the evening, splitting doses may be necessary, for example at 6 pm, 9 pm, and midnight, or during the early hours of the morning. But single nighttime doses should be tried first. Intermittent treatment during the day might be helpful for events such as attending the theatre, aeroplane flights, or other activities involving long periods of sitting.

Dopaminergic treatment Treatment should be started with the lowest dose possible. With mild or intermittent restless legs syndrome, levodopa may be adequate. With moderate or severe disease or daytime symptoms, or both, a dopamine agonist should be used as the first line of treatment. 471

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Titration should be carried out slowly and attention paid to possible side-effects of dopaminergic agents, such as nausea, arterial hypotension, dizziness, and, sometimes, daytime sleepiness. The possible development of augmentation should be considered during any treatment with dopaminergic drugs, especially with levodopa. Patients should be asked for any evidence of early onset of symptoms during the day once medication has been started. If augmentation becomes a persistent problem, the dopaminergic agent should be lowered or discontinued, at which time the symptoms should disappear during the daytime and remit back to the night-time hours.

Opioids Opioids are regarded as a second-choice treatment. In patients who cannot tolerate dopaminergic agents, opioids are given as first-choice medication. Whenever possible, opioids should be used in sustained-release forms to avoid addiction and to benefit from a continuous efficacy in more severe cases of the restless legs syndrome. Sedation and precipitation or exacerbation of sleep apnoea have been observed in a few patients treated with opioids. No augmentation has been reported so far. Addiction and tolerance seem to be low in long-term treatment follow-up studies.

Combination treatment Although only case reports are available, many patients with more severe forms of the syndrome have been efficiently treated with a combination of dopaminergic agents and an opioid. Among the anticonvulsants, gabapentin is preferred because of its efficacy and also because it is possibly better tolerated than carbamazepine, although no controlled comparative studies have been done. Studies have shown that gabapentin needs to be titrated up to 1800 mg or 2000 mg for optimum efficacy. Adverse events are sedation and dizziness at these doses. At low doses (300–600 mg), few or no adverse events occur. Benzodiazepines are helpful additional drugs. Although there are no controlled studies on non-benzodiazepine hypnosedative drugs that bind to the benzodiazepine receptor—eg, zolpidem—these drugs may be substituted for the benzodiazepines.

Conclusions By comparison with pathophysiological notions, treatment options for the restless legs syndrome are advanced and have been investigated in large trials. Future research should concentrate on the remaining problems of augmentation and its pathomechanism to optimise treatment strategies of the restless legs syndrome. Genetic insights could reveal further specific treatment regimens other than the present empirical therapeutic strategies. 472

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