Download pdf - The restless legs syndrome

Review

Introduction and clinical featuresThe restless legs syndrome is defined by some people asa syndrome, by some as a sleep disorder, some refuse toaccept it as a problem at all, and few know that it hasclearly defined clinical diagnostic criteria. Theprevalence of the syndrome has been underestimated inthe past and epidemiological population-based studiesshow that between 3% and 10% of the population havecardinal symptoms.1–3 In several studies a femalepreponderance has been described.2–5 Most patients withmild symptoms do not need any pharmacologicaltreatment. Patients who need continuous treatment aremostly older than 50 years, consistent with the mean ageof populations in trials for treatment of the syndrome.

In 1995, clinical diagnostic criteria for the restless legssyndrome were established by the International RestlessLegs Syndrome Study Group (IRLSSG).6 During aNational Institutes of Health conference in May, 2002,experts, including members of the IRLSSG andauthorities on epidemiology and scale design, editedthese criteria for improved clarity. The criteria were thenfurther reviewed by the IRLSSG and published in 2003.7

The panel lists the clinical characteristics of thesyndrome. All four essential criteria must be met for apositive diagnosis.

The restless legs syndrome has been described as anidiopathic disorder with no apparent cause or as asymptomatic syndrome often associated with irondeficiency, pregnancy, or end-stage renal disease.However, the syndrome could also be described as acomplex disorder with underlying genetic orenvironmental components, or both. Onset in childhoodimplies a strong genetic component for the syndrome,8

although the age of onset in general is known to varywidely, from childhood to over 80 years of age.9,10 Clinicalexperience shows severe restless legs syndrome to bemostly a chronic progressive disorder that, once started,needs lifelong treatment. Variations in the clinicalcourse, with periods of remission, are especiallycommon in young adults.7

The key characteristic of the syndrome is an urge tomove the legs, often accompanied by a wide range of

sensory symptoms. These symptoms are usuallyassociated with very unpleasant sensations felt mostlydeep inside the limbs, occurring unilaterally orbilaterally, affecting the ankle, knee, or the entire lowerlimb. With progressive disease, an involvement of thearms has been described in up to 48% of patients.11 Insome patients, pain dominates the picture and can leadto the syndrome being misdiagnosed as a chronic painproblem. The sensory symptoms occur duringwakefulness, mostly when the patient is sitting or lyingdown, and at night. Movement brings about at leasttemporary and partial relief of the discomfort, especially

Lancet Neurol 2005; 4: 465–75

Paracelsus Elena Klinik, Centreof Parkinsonism andMovement Disorders, Kassel,Germany (C Trenkwalder MD);Department of ClinicalNeurophysiology, University ofGöttingen, Göttingen,Germany (W Paulus MD); andNew Jersey NeuroscienceInstitute, JFK Medical Center,Seton Hall University School ofGraduate Medical Education,Edison, NJ, USA(A S Walters MD)

Correspondence to:Prof Claudia Trenkwalder,Paracelsus Elena Klinik, Centre ofParkinsonism and MovementDisorders, 34128 Kassel,Klinikstr. 16, [email protected]

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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.

The restless legs syndromeClaudia Trenkwalder, Walter Paulus, Arthur S Walters

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 featuresNatural clinical course of the disorderCan 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 clinicalcourse is sometimes seen. Remissions of a month or more are sometimes reported.

Sleep disturbanceThe leg discomfort and the need to move result in insomnia.

Medical investigation/neurological examinationA neurological examination is usual in idiopathic and familial forms of the syndrome.Peripheral neuropathy or radiculopathy are sometimes carried out in the non-familialform 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 andresearch purposes, a severity rating scale has beendeveloped and validated by the IRLSSG.12

Children and the restless legs syndromeAlthough most patients seen in clinical practice aremiddle-aged or older, the restless legs syndrome canoccur in children. From studies of families with thesyndrome we know that symptoms in severely affectedpatients can begin in childhood13,14 and can bemisdiagnosed as growing pains.15 Restless legssyndrome in children should be differentiated fromattention-deficit hyperactivity disorder (ADHD).16 Theneed to move because of leg discomfort distinguishesrestless legs syndrome from ADHD. However, thesituation is more complex since patients with restlesslegs may also manifest symptoms of ADHD morefrequently than controls.17,18

Periodic limb movements In addition to the voluntary movements that patientsmake to alleviate their leg discomfort, involuntarymovements also occur either during sleep or whenawake. These movements recur periodically and arecalled periodic limb movements. Diagnosis of periodiclimb movements during sleep is based on the definitionof the American Sleep Disorders Association.19 Thesemovements are measured by surface electromyographyfrom the tibialis muscle and show muscle activation in asequence of at least four muscle contractions lasting0·5–5 s and recurring at intervals of 5–90 s. The musclecontractions must be at least 25% of the amplitude ofthe voluntary leg movements the patient is asked to dofor purposes of calibration before the start of a sleepstudy. Periodic limb movements during sleep are

similar to the triple flexion reflex of the hip, knee, andankles and to the Babinski sign.20 These movements canoccur with or without arousals or during wakefulness(figure 1).

About 80% of patients with the restless legs syndromehave periodic limb movements during sleep.21 However,there is much night-to-night variation in the number ofmovements in individual patients,22 and if a secondnight’s recording is undertaken, 87% of patients willhave periodic limb movements during sleep on at leastone of two nights of recording. These movements arealso not specific for the diagnosis of restless legssyndrome because they can occur in other disorders oras an isolated occurrence.

Individuals with the syndrome might also complain ofinvoluntary twitching movements of the legs duringwakefulness when they are sitting or lying. Thesemovements may be periodic and take the form ofperiodic limb movements during wakefulness oraperiodic movements. The phrase dyskinesias whileawake has been used to describe involuntary movementsduring wakefulness in restless legs syndrome, whichincludes both periodic and aperiodic types.23,24 Unlikeperiodic limb movements during sleep, dyskinesiasduring wakefulness can sometimes be faster or ofmyoclonic speed. In only about 15% of patients with thesyndrome are these movements during wakefulness partof the chief complaint,6 possibly because patients withmild dyskinesias while awake move to relieve their painand successfully suppress future severe dyskinesias.However, if patients are asked to lie perfectly still, theoccurrence of periodic limb movements duringwakefulness seems to be a reliable characteristicoccurrence in patients with the restless legs syndromeand can be quantified by an immobilisation test.24 In thistest, patients are asked to lie still and not move whileelectromyography of the tibialis anterior muscle isrecorded during wakefulness. Depending on the severityof the syndrome, patients start to complain aboutsensory symptoms and an urge to move the limbs after15–30 min. Periodic limb movements duringwakefulness occur during this time and are recordedover 1 h. The suggested immobilisation test can be used to quantify the restless legs syndrome and tomonitor treatment.

Actigraphy is another method used to measureperiodic limb movements in wakefulness during thesuggested immobilisation test, general motor activityduring wakefulness, or periodic limb movements duringthe sleep period.25,26

Symptomatic restless legs syndromeIron deficiency is assumed to be the most frequent causeof symptomatic restless legs syndrome next to theuraemic form. The manifestation or worsening ofrestless legs syndrome may be associated with low bloodconcentrations of ferritin, often during blood

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Nasal air flow

Abdominal belt

Figure 1: Polysomnogram (30 s) of a typical patient with the restless legs syndrome with a sequence ofperiodic limb movements during wakefulnessPeriodic limb movements in the left leg are recorded with surface electromyography (EMG) of the left tibialisanterior muscle (bottom). Electroencephalographic (top), chin electromyographic (middle), and respiratoryrecordings (nasal airflow and abdominal belt) are shown.

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donations.27,28 In most patients, iron deficiency is notdetected because there is no anaemia, and low ferritin isthe only pathological parameter. Another frequentassociation is that of renal failure.29–31 The sleep quality ofpatients with uraemic restless legs syndrome is poor31

and morbidity is high. Additionally, the syndrome oftenoccurs with rheumatoid arthritis, fibromyalgia, or inpregnancy.32–34 Some women have the disorder for thefirst time or have symptoms that worsen temporarilyduring pregnancy;34 individuals who experiencesymptoms during pregnancy often have a family historyof the disorder.10 The restless legs syndrome can be seenin association with peripheral neuropathy orradiculopathy.35–37

Differential diagnosisAlthough the restless legs syndrome might be triggeredby peripheral neuropathy or radiculopathy, a distinctionshould be made between the disorders. In pureperipheral neuropathy and radiculopathy, patients donot have the compelling need to move to relieve legdiscomfort and the symptoms are not consistently worseat rest or at night. The restless legs syndrome shouldalso be distinguished from neuroleptic-inducedakathisia, which is motor restlessness induced byantipsychotic agents that block dopamine receptors.38 Inthis disorder patients feel compelled to move because ofan inner sense of restlessness rather than a need tospecifically move the legs. The restless legs syndromeshould be differentiated from positional discomfort: ifthe only movement needed is a small brief positionchange to relieve pressure—eg, on an arthritic hip—thisdiscomfort is not the restless legs syndrome.

Diagnostic work-upIf the neurological examination suggests an associatedperipheral neuropathy or radiculopathy, electromyo-graphy and nerve conduction studies should beundertaken to document these disorders. Since therestless legs syndrome is frequently associated with irondeficiency, all patients should have a test for serumferritin concentration, which is thought to be the mostsensitive measure of iron deficiency.

GeneticsEkbom33 described the familial component of thesyndrome in 1945, and since then many studies havebeen published on the familial forms of the disorder.Clinically, these forms cannot be differentiated fromsporadic or symptomatic forms.10 Taking together theclinical manifestations and the course of the disease, theidiopathic and symptomatic forms do not differ. Ingenetic studies, environmental factors have played anessential part in the manifestation of symptoms. Only inearly-onset in individuals with a positive family history isthere strong evidence that a major genetic susceptibilitycould explain the syndrome.8

Molecular genetic studies have identified at least threemajor susceptibility loci in large families from Canada,Italy, USA, and Germany, although at present the lodscores are far from conclusive with respect to the size ofthe families investigated. The syndrome might not becaused by a single genetic defect as, for example, inHuntington’s disease, but could be a disorder with acomplex inheritance, as for many neurological disorderssuch as Alzheimer’s disease, dementia, or migraine.

The first locus conferring susceptibility to the restlesslegs syndrome was mapped in 2001. This locus was onchromosome 12q and connected with a series ofadjacent microsatellite markers with an autosomalrecessive mode of inheritance.39 However, thesefindings were not confirmed a year later in threeEuropean families.40 In the chromosome-12-linkedCanadian families, neurotensin and other modulatorsof dopaminergic neurotransmission located in thetarget region are probably not the responsible genes.41

The Canadian locus on chromosome 12 has beenconfirmed in five more families, but the researchersconcluded that genetic heterogeneity should beconsidered.42 A further locus was found in thechromosome 14q13–21 region in a 30-member, three-generation Italian family, and later confirmed inanother Canadian family.43,44 Large CAG trinucleotideexpansions at the spinocerebellar ataxia type 3 locus arenot associated with idiopathic restless legs syndrome.45

However, the prevalence of symptoms in patients withspinocerebellar ataxia 1–346 is higher than in the generalpopulation.47 A model-based linkage analysis, with theassumption of an autosomal-dominant mode ofinheritance, indicated a 9p24–22 linkage for the restlesslegs syndrome in two large families from the USA.48

PathophysiologyAnimal and imaging studiesThe study of the restless legs syndrome in animalmodels is in its infancy. One model has shownage-dependent, spontaneous, periodic hind-limbmovements in sleeping rats.49 An intriguing approach isthe targeting of the dopaminergic A11 cell group as apossible pathophysiological correlate of the syndrome.50

A11 cells are the only cells that provide dopaminergicaxons to the spinal cord. There are probably no intrinsicdopaminergic cells in the spinal cord. Dysfunction oratrophy of these cells could explain the excellenttreatment response to dopaminergic drugs and thecircadian rhythm of the syndrome since these cells arein close proximity to the hypothalamic circadianpacemaker (figure 2). Selective lesion of A11 neurons isalmost impossible without damaging other structuresin their vicinity. Therefore, and for othermethodological reasons, these findings are not fullyconvincing. Nevertheless A11 cells should remain thefocus of future pathophysiological research because oftheir strategic location.


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The essentially normal presynaptic dopaminergicbinding studies using 18F-dopa PET51–53 or �-CIT-SPECT54–56 in patients with the restless legs syndromelend support to the hypothesis that A11 dopaminergicneurons and spinal pathways could be more involved inthe pathophysiological mechanisms of the syndromethan the nigrostriatal system.57 An fMRI imaging studyshowed bilateral activations of the cerebellum andbrainstem and contralateral activation of the thalamusin various constellations during different combinedperiodic limb movement and sensory leg discomfortdisorders.58

Neurophysiological studiesIn patients, the soleus H-reflex recovery curves(H-response/M-response after paired tibial nervestimulation over interstimulus interval time) showedincreased late facilitation and depressed late inhibition,both indicating diminished inhibition due to post-synaptic central activity and probably due to alteredfunction of the descending spinal tracts, peripheral

influence or changes in the interneural circuitry at thespinal level itself, or combinations of these threepossibilities.59 In another neurophysiological study,patients had substantially increased spinal cordexcitability, indicated by reduced threshold andheightened spatial spread of the flexor reflex, whichwas more prominent during sleep. Multiple lateresponses with a very long duration and a latency rangeof 250–800 ms were recorded during sleep in allpatients and in some controls at raised thresholds.60

Impairment of temperature perception was found in72% of symptomatic patients and in 55% of patientswith idiopathic restless legs syndrome.61 Theresearchers also reported that in symptomatic patients,impaired peripheral C-fibre function, as specificallytested, is probably caused by small fibre neuropathy,whereas in idiopathic restless legs syndrome, normalC-fibre function indicates a functional impairment ofcentral somatosensory processing.61 In another study,eight of 22 patients had a neuropathy (three pure largefibre, two mixed, and three isolated small fibrepolyneuropathies).35 Patients with the restless legssyndrome also have substantial static hyperalgesia, butno dynamic mechanical hyperalgesia or allodynia,which is probably mediated by central sensitisation toan A-delta-fibre high-threshold mechanoreceptorinput, such as in neuropathic pain.62 This statichyperalgesia to pin-prick was reversed only by long-term, individually tailored, dopaminergic treatment.

Peripheral somatosensory input is not a necessaryprecondition for the syndrome: a patient withsymptoms of the restless legs syndrome in the absentportions of his lower extremities, after bilateral above-knee amputations, responded well to dopamine agonisttreatment.63 Central pain perception could also have arole in the pathophysiological mechanisms of restlesslegs syndrome. Opioid receptor binding was measuredby (11 C) diprenorphine, a non-selective opioidreceptor ligand, in 12 patients with the restless legssyndrome and in controls. Binding in patientscorrelated with the severity of the syndrome: the moresevere the disease, the greater the release ofendogenous opioids within the medial pain system.64

IronWhereas the pharmacological treatment data stronglylend support to a dopaminergic abnormality in therestless legs syndrome, iron depletion should beregarded as the most relevant additional factor for theclinical manifestations of the syndrome and can beassessed in patients by measuring ferritinconcentrations.65–67 Several studies showed a relationbetween low ferritin concentrations and symptoms ofthe syndrome,68,69 especially when ferritin wasmeasured in the CSF.70,71 In a neuropathological study,neuromelanin cells from brains of four patients andfour controls were studied for iron metabolism.


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

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Ferritin and divalent-metal transporter-1 weredecreased in neuromelanin cells of disease brains, andtransferrin increase was altogether consistent with irondeficiency. Transferrin receptor expression, however,was reduced rather than increased and was notconsistent with an iron deficiency model of the restlesslegs syndrome. The researchers postulated that a defectin iron regulatory protein 1 in neuromelanin cellscould promote destabilisation of the transferrinreceptor mRNA, leading to cellular iron deficiency.72

These same authors have shown similar changes inbrain iron content in patients compared with controlsby use of MRI with specialised parameters.73

Circadian influencesSome evidence exists to suggest that levodopasensitivity is heightened at night.74 At present thequestion is still unresolved as to whether periodic limbmovements during sleep are simply a painless formefruste of the restless legs syndrome or represent adifferent disorder. There is a clear circadian rhythm ofthe subjective complaints of the syndrome, and similartime of night variations can be seen for periodic limbmovements during sleep and during wakefulnessindependent from the condition of sleep or ofrecumbency.56,75–77 The changes in melatonin secretion,as a marker of the circadian rhythm, were the onlychanges that preceded the increase in sensory andmotor symptoms in patients with the syndrome,implicating melatonin in the worsening of symptomsin the evening and during the night by exertion of aninhibitory effect on central dopamine secretion.78

TreatmentAugmentationAugmentation is caused by dopaminergic treatment in patients with the restless legs syndrome.Augmentation has been defined as an early onset ofsymptoms of the syndrome during the day, an increasein severity of symptoms, and the involvement of otherbody parts.79 Whether all these criteria are necessary todefine augmentation is not clear since the early onsetof symptoms seems to be the most frequent andreliable criterion. In augmentation, despite nightlydoses of short-term dopaminergic agents, symptomsthat were once confined to the night-time can appear inthe early afternoon of the next day when the drug islong out of the system. For once-nightly treatmentswith carbidopa or levodopa, augmentation can becomea severe problem. This increase in symptoms occurredin the afternoon and in the early part of the eveningbefore taking the next nightly dose in 31% to 82% ofpatients in this series.79 Augmentation was highest forpatients with severe symptoms of the syndrome, butwas unrelated to sex, age, or baseline severity of thesyndrome. Symptoms during augmentation can alsoaffect other body parts and can be more severe than the

symptoms of the syndrome per se.79 Augmentation hasbeen described as a consequence of treatment withdopaminergic agonists, such as pramipexole.80

In smaller open label studies, augmentation has beenreported during treatment with pergolide,81,82 althoughcases were usually mild and did not need a change ofmedication. Controlled studies of pergolide83 andropinirole84,85 are either short-term investigations oraugmentation has not been prospectively investigatedaccording to its current definition.

Severe augmentation usually resolves with cessationof medication; mild forms may be manageable byadding a dose of medication earlier in the day, assuggested by Winkelman and co-workers in 2004.80

Augmentation usually resolves with cessation of themedication and can be kept to a minimum by keepingthe dose low. Guidelines for management ofaugmentation have not been published yet. There areno published studies on rebound or augmentation withnon-dopaminergic agents.

One hypothesis to explain augmentation suggeststhat dopaminergic treatment shifts the circadiantiming of the appearance of symptoms of thesyndrome to an earlier time of day. This can happeneither within the striatal, hypothalamic, or spinaldopaminergic system, with the highest doses oflevodopa usually associated with augmentation.74

Augmentation is the most serious problem ofdopaminergic treatment in patients with the restlesslegs syndrome and all physicians treating thesepatients should be aware of this occurrence. Fromclinical experience and open follow-up treatment trials,dose escalation could be an additional treatmentproblem in the restless legs syndrome, although thereare few data from controlled studies.

ReboundRebound should be distinguished from augmentation.Rebound is the appearance of symptoms at a time thatis compatible with the half-life of the drug, when theeffects of the drug are wearing off, and is equivalent towithdrawal. Rebound was first noticed in the morningwith increases of leg movements in about a quarter ofpatients treated with levodopa.86 Rebound occurs aftermorning awakening and consists of more severesymptoms of the syndrome in the morning than occurswithout treatment.

LevodopaLevodopa was effective in treating nocturnal symptomsof the restless legs syndrome and improving subjectiveand objective quality of sleep in patients with idiopathicand uraemic disease in controlled trials.87–90 Levodopaplus benserazide has been approved for treatment ofthe syndrome in Germany, Switzerland, and Austriafor several years. Levodopa is a short-acting drug and isan appropriate treatment for mild and intermittent


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disease, although all treatment trials to date have beendone in patients with moderate to severe and morepersistent disease. A combination of slow-releaselevodopa and standard levodopa is superior to standardlevodopa alone.91,92 The rapid onset and offset of actionof levodopa has been recorded.93 All of these treatmentstudies were undertaken by use of a randomisedcontrolled design. Long-term studies of levodopa areavailable only in an open design.92,94 40% of patientstreated in an open follow-up study developedaugmentation that needed termination of levodopawithin a year of treatment.94 Nausea and dizziness areother minor side-effects of levodopa treatment.

Dopamine agonists The ergot-dopamine agonists bromocriptine,pergolide, and cabergoline, and the non-ergotdopamine agonists pramipexole, ropinirole, androtigotine have all been shown to be effective indouble-blind studies. The first double-blindrandomised crossover study of a dopamine agonistused 7·5 mg bromocriptine at bedtime with five out ofsix patients having partial subjective improvement inrestlessness and paraesthesias.95 In a double-blindcontrolled study, pergolide was efficacious at a dose of0·05–0·65 mg per day.96 In another study with thisdrug, the mean dose was titrated to 0·51 mg.97 In alarge multicentre (PEARLS) study with 100 patients,pergolide decreased severity of the restless legssyndrome, measured with the international restlesslegs syndrome severity rating scale (IRLS score 12·2pergolide vs 1·8 placebo), and was associated with animproved patient global impression response.83

Polysomnographic improvements occurred in theperiodic limb movements during sleep index andarousal index after 6 weeks (p�0·001). After12 months of double-blind treatment with pergolide,improvements in these index scores were maintainedat a mean dose of 0·52–0·72 mg per day; the side-effects were nausea and headache.83

A recent controlled trial with the long-acting ergot-agonist cabergoline in 85 patients with severe restlesslegs syndrome showed a stable, clinically relevantimprovement for all efficacy measures (IRLS, clinicalglobal impression) over a year with a mean dose of2·2 mg cabergoline per day. During this long-termtreatment, six of 66 patients treated with the drug wereaffected by mild augmentation.98 Valvular fibrosis ofthe heart has been described in association withpergolide treatment in doses higher than 4 mg.99

Whether this side-effect applies only for pergolide orfor all ergot-agonists and whether it is dose dependentis not yet clear. Dose increases of such substancesshould be managed cautiously.

Ropinirole has been approved as a treatment for therestless legs syndrome in the US, France, andSwitzerland. Ropinirole was investigated in several

controlled studies. One such study was a European,12-week, prospective, double-blind, randomisedcomparison of 284 patients, with a mean dose of1·90 mg of ropinirole. In the treatment group therewas a significant 11-point improvement on the severityscale (IRLS, 0–40 points), compared with an 8-pointimprovement in the placebo group.84 In another study,eight of 22 patients had complete resolution ofsymptoms with ropinirole,100 in line with a furthercontrolled 12-week study.85 Ten patients on chronichaemodialysis reported a 33·5% improvement in the6-item IRLS score during levodopa slow-releasetreatment (190 mg per day) and a 73·5% improvementduring ropinirole (1·45 mg per day) treatment in anopen study.101 In a controlled polysomnographictreatment trial, 59 patients were treated with ropinirole.The number of periodic limb movements during sleepper hour decreased more with ropinirole than withplacebo (48·5 to 11·8). The arousal index decreasedfrom 7·0 to 2·5 with ropinirole, but increased from 4·2to 6·0 with placebo. The number of periodic limbmovements while awake decreased from 56·5 to 23·6per hour with ropinirole but increased from 46·6 to56·1 per hour with placebo. Sleep efficiency measuredby polysomnography was not improved, whereas sleepadequacy on a subjective scale (MOS scale) wassignificantly improved with ropinirole treatment.102

In ten patients with the restless legs syndrome,pramipexole reduced both the periodic limb movementduring sleep index to normal values and the indexduring wakefulness significantly in a 1-monthcontrolled treatment study with a single dose of0·25–0·75 mg.103 Long-term observations in aretrospective case series of 60 patients over 2 yearsprovided stable treatment results with a dose increasefrom 0·38 mg to 0·63 mg pramipexole and a rate ofmild augmentation in 33% of patients who weretreatable with increased doses early in the day.104

The rotigotine patch has been tested at three differentdosages (1·13 mg, 2·25 mg, and 4·5 mg) in a 1-weekcontrolled trial. The IRLS score differed significantlybetween the highest dose and placebo.105 Daytimesymptoms improved with all doses, measured with thesix-item IRLS, a non-validated scale. Other dopamineagonists have been investigated in open trials or caseseries.106 Treating the restless legs syndrome withdopamine agonists in general raises unresolvedquestions as to the role of the dose escalation related tothe development of augmentation or rebound. Furthertrials should look more specifically into these issues.107

OpiatesOpiates were described as treatment options by Willisas early as 1684.108 In a double-blind, randomised,crossover trial, oxycodone at an average dose of15·9 mg reduced leg sensations and motorrestlessness, and improved daytime symptoms of the


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syndrome. A significant reduction in the periodic limbmovement during sleep index and arousal index wasrecorded polysomnographically in a controlled study.109

A second double-blind study of opiates for periodiclimb movements during sleep reported a low dose ofdextropropoxyphene, a less potent opioid thanoxycodone, to be effective (though less effective thanlevodopa) in the treatment of these movements.90 Long-term data are only available as a case series110 and showa minimum risk of dependency, but some worsening ofsleep apnoea may occur with chronic opioids.110

Gabapentin and other anticonvulsantsGabapentin has proven effective for the treatment ofthe restless legs syndrome in a controlled study with amean dose of 1855 mg per day.111 In a further controlledcomparative study, gabapentin, at a mean dose of800 mg, and ropinirole, at a mean dose of 0·78 mg,provided a similarly well-tolerated and effectivetreatment of periodic limb movements during sleepand sensorimotor symptoms in patients with idiopathicrestless legs syndrome.112 In haemodialysis patients, areduced dose of 200–300 mg after each dialysis isneeded.113

The first controlled study ever undertaken in patientswith the restless legs syndrome was done withcarbamazepine, with a success rate of 50% in sixpatients.114 The efficacy of carbamazepine was laterconfirmed in 174 patients in a double-blind study.115

When 200 mg slow release levodopa was comparedwith 600 mg slow release valproic acid, there was nomajor difference in efficacy.116 The periodic limbmovement sleep index and arousal index significantlydecreased with levodopa. However, arousals notassociated with periodic limb movements during sleepwere significantly increased with levodopa but notvalproic acid, indicating that slow-release valproic acidcan be a treatment alternative for these movementsduring sleep in patients with the restless legssyndrome.116

BenzodiazepinesClonazepam was effective in improving sleep in severalstudies in patients with the restless legs syndrome andperiodic limb movements during sleep.117–120 Twostudies concluded that the induced sleep changes wereconsistent with those produced by sedativebenzodiazepines in general without reducing thenumber of periodic limb movements during sleep.118,121

In a cross-over study of clonazepam (1 mg) comparedwith temazepam (30 mg), total leg movements of sixpatients with the restless legs syndrome and periodiclimb movements during sleep were not changed inboth treatment groups; however, 0·125 mg triazolamincreased total sleep time, sleep efficiency, and daytimefunction, while decreasing the number of sleep stagechanges, but not changing total leg movements.122

IronIn a randomised, double-blind, placebo-controlled trialin 28 patients with the restless legs syndrome, ironsulfate did not significantly improve the disorder, butpatients were not selected according to ferritinconcentrations, which seems to be the importantparameter to diagnose and treat iron deficiency.123 Inanother study, high-dose iron dextran infusion wasassociated with a significant, but transient, reduction insymptoms of the restless legs syndrome in patients withend-stage renal disease.124 In an open study in which tenpatients with the restless legs syndrome received asingle 1000 mg intravenous iron infusion, seven patientsshowed a substantial improvement in symptoms2 weeks later. The measured serum ferritin valuessuggest that greater-than-expected iron loss occurs afterintravenous iron loading.69

Other treatmentsClonidine is an effective treatment for some patients withthe restless legs syndrome who do not have largenumbers of sleep-disrupting periodic limb movementsbut do have delayed sleep onset due to leg sensations andsubsequent motor restlessness.125 In a blinded study,126

baclofen reduced the force and amplitude of periodiclimb movements without changing their duration.

Overall treatment recommendationsBefore starting a pharmacological treatment, sleephygiene measures should be instituted and allpossibilities for treating symptomatic restless legssyndrome should be considered. Iron should besupplemented if ferritin is low. From a practical point ofview, and according to the guidelines of the AmericanAcademy of Sleep Medicine,127,128 we would emphasisedopaminergic agents as the first line of treatment for thesyndrome, followed by opioids, anticonvulsants, andbenzodiazepines. Of the anticonvulsants, gabapentin ispreferable because of its superior efficacy, and amongthe benzodiazepines, clonazepam is preferable becauseof its long half-life.

Treatments should be applied close to when thesymptoms usually occur. If symptoms begin earlierrather than later in the evening, splitting doses may benecessary, for example at 6 pm, 9 pm, and midnight, orduring the early hours of the morning. But single night-time doses should be tried first. Intermittent treatmentduring the day might be helpful for events such asattending the theatre, aeroplane flights, or otheractivities involving long periods of sitting.

Dopaminergic treatment Treatment should be started with the lowest dosepossible. With mild or intermittent restless legssyndrome, levodopa may be adequate. With moderate orsevere disease or daytime symptoms, or both, a dopamineagonist should be used as the first line of treatment.


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Titration should be carried out slowly and attentionpaid to possible side-effects of dopaminergic agents,such as nausea, arterial hypotension, dizziness, and,sometimes, daytime sleepiness. The possibledevelopment of augmentation should be consideredduring any treatment with dopaminergic drugs,especially with levodopa. Patients should be asked forany evidence of early onset of symptoms during theday once medication has been started. If augmentationbecomes a persistent problem, the dopaminergic agentshould be lowered or discontinued, at which time thesymptoms should disappear during the daytime andremit back to the night-time hours.

OpioidsOpioids are regarded as a second-choice treatment. Inpatients who cannot tolerate dopaminergic agents,opioids are given as first-choice medication. Wheneverpossible, opioids should be used in sustained-releaseforms to avoid addiction and to benefit from acontinuous efficacy in more severe cases of the restlesslegs syndrome. Sedation and precipitation orexacerbation of sleep apnoea have been observed in afew patients treated with opioids. No augmentation hasbeen reported so far. Addiction and tolerance seem tobe low in long-term treatment follow-up studies.

Combination treatmentAlthough only case reports are available, many patientswith more severe forms of the syndrome have beenefficiently treated with a combination of dopaminergicagents and an opioid.

Among the anticonvulsants, gabapentin is preferredbecause of its efficacy and also because it is possiblybetter tolerated than carbamazepine, although nocontrolled comparative studies have been done.Studies have shown that gabapentin needs to betitrated up to 1800 mg or 2000 mg for optimumefficacy. Adverse events are sedation and dizziness atthese doses. At low doses (300–600 mg), few or noadverse events occur. Benzodiazepines are helpfuladditional drugs. Although there are no controlledstudies on non-benzodiazepine hypnosedative drugsthat bind to the benzodiazepine receptor—eg,zolpidem—these drugs may be substituted for thebenzodiazepines.

ConclusionsBy comparison with pathophysiological notions,treatment options for the restless legs syndrome areadvanced and have been investigated in large trials.Future research should concentrate on the remainingproblems of augmentation and its pathomechanism tooptimise treatment strategies of the restless legssyndrome. Genetic insights could reveal furtherspecific treatment regimens other than the presentempirical therapeutic strategies.

Authors’ contributionsAll authors contributed equally to this review.

Conflicts of interestAll authors have received honoraria and research support from Pfizer,GlaxoSmithKline, and Novartis. CT has received additional honorariafrom Hoffman La Roche. CT and AW have received honoraria fromUCB-Pharma and Boehringer. AW has also received honoraria fromKyowa, Xenoport.

Role of the funding sourceNo funding source had a role in the preparation of this article or thedecision to submit it for publication.

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