The restless legs syndrome

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    Introduction and clinical featuresThe restless legs syndrome is dened 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 dened 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.13 In several studies a femalepreponderance has been described.25 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 irondeciency, 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: 46575

    Paracelsus Elena Klinik, Centreof Parkinsonism andMovement Disorders, Kassel,Germany (C Trenkwalder MD);Department of ClinicalNeurophysiology, University ofGttingen, Gttingen,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, Germanyctrenkwalder@gmx.de

    http://neurology.thelancet.com Vol 4 August 2005 465

    The restless legs syndrome is a common disorder that encompasses an idiopathic form of genetic or unknown originand symptomatic forms associated with many causes. Symptomatic forms occur during pregnancy and arecoincident with uraemia, iron depletion, polyneuropathy, spinal disorders, and rheumatoid arthritis. For thehereditary forms, at least three gene loci, located on chromosomes 12, 14, and 9, have been traced so far. Prevalencein 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 rst choice in idiopathic restless legssyndrome, but augmentation and rebound should be monitored in long-term treatment. Various other drugs, suchas 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-decit 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 denitionof 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 lasting055 s and recurring at intervals of 590 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 exion reex of the hip, knee, andankles and to the Babinski sign.20 These movements canoccur with or without arousals or during wakefulness(gure 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 secondnights recording is undertaken, 87% of patients willhave periodic limb movements during sleep on at leastone of two nights of recording. These movements arealso not specic 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 quantied 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 after1530 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 deciency 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

    466 http://neurology.thelancet.com Vol 4 August 2005

    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 airow and abdominal belt) are shown.

  • Review

    donations.27,28 In most patients, iron deciency is notdetected because there is no anaemia, and low ferritin isthe only pathological parameter. Another frequentassociation is that of renal failure.2931 The sleep quality ofpatients with uraemic restless legs syndrome is poor31

    and morbidity is high. Additionally, the syndrome oftenoccurs with rheumatoid arthritis, bromyalgia, or inpregnancy.3234 Some women have the disorder for therst 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.3537

    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 tospecically move the legs. The restless legs syndromeshould be differentiated from positional discomfort: ifthe only movement needed is a small brief positionchange to relieve pressureeg, on an arthritic hipthisdiscomfort 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 irondeciency, all patients should have a test for serumferritin concentration, which is thought to be the mostsensitive measure of iron deciency.

    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 identied 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, inHuntingtons disease, but could be a disorder with acomplex inheritance, as for many neurological disorderssuch as Alzheimers disease, dementia, or migraine.

    The rst 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, thesendings were not conrmed 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 beenconrmed in ve more families, but the researchersconcluded that genetic heterogeneity should beconsidered.42 A further locus was found in thechromosome 14q1321 region in a 30-member, three-generation Italian family, and later conrmed 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 withsp...

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