Restless leg syndrome or Willis-Ekbom disease (RLS/WED) is a common movement disorder characterized by an uncomfortable urge to move the (typically lower) extremities, frequently in conjunction with additional dysesthesias. Symptoms are heightened with prolonged immobility, temporarily relieved with movement, and predominantly or exclusively present during the hours prior to typical sleep onset. Intermittent RLS is invoked when symptoms occur less than twice per week, and chronic persistent RLS is invoked when symptoms occur with greater frequency. Thomas Willis, an English Physician to Charles II, described this condition as early as 1672.1 Much later, in 1950, Ekbom published a case series comprised of 70 subjects.2
Although not life-threatening, individuals suffering from RLS/WED describe significant impairments in quality of life (QOL). RLS/WED affects both physical (summary scores 1.08 SD below norms) and mental/emotional health-related QOL (summary scores were 0.40 SD below norm).3 The burden on patients who suffer from this disease is reflected by economic data. During a 3-month period, the estimated cost of RLS/WED was calculated to be $2,613 dollars.4
Apart from its impact on QOL, RLS/WED bears direct relevance to mental health providers, by virtue of psychiatric comorbidities.5 In a study of 246 patients receiving hemodialysis, the presence of RLS/WED was associated with excessive sleepiness, increased anxiety, and sexual dysfunction.6 A separate study found that RLS/WED patients were more likely to have attention-deficit hyperactivity/ disorder when compared with healthy controls and patients who had insomnia (26% RLS/WED vs 5% for healthy controls and 6% for the insomnia control group).7 Using Diagnostic and Statistical Manual of Mental Disorders, fourth edition (DSM-IV) diagnostic criteria, Lee et al.8 studied a population-based sample, and reported an association of RLS/WED with major depressive disorder (odds ratio 4.7) and panic disorder (odds ratio 9.7).
The cumulative incidence of RLS/WED has been reported as 7% and 9.1% within two large population-based studies.9 Prevalence estimates vary based on the severity and frequency of the symptoms assessed.10 An overall prevalence of 10% is reported if severity and frequency are not taken into account, with increased prevalence with advanced age and female gender.11,12
A genetic component has been suggested for primary RLS/WED.11 Genome-wide association studies have identified RLS-associated variants within regions of MEIS1 (homeodomain transcription factor that encodes homeobox protein meis 1; chromosome 2p), BTBD9 (zinc finger transcription factor; gene involved in synaptic plasticity on chromosome 6p), genes encoding mitogen-activated protein kinase MAP2K5, and the transcription factor LBXCOR1 (chromosome15q).12
Multiple areas of the central and peripheral nervous system have been implicated in the pathophysiology of RLS. A detailed discussion is beyond the scope of this article but has been reviewed in the literature.13 Dopaminergic dysfunction has been more generally proposed as a causative factor, as reflected in the commonly provided dopaminergic therapies.14 Recently, a rat model suggested that endogenous opioids play a protective role when iron deficiency and dopamine dysfunction are present.15
Secondary RLS/WED occurs in association with numerous other conditions, including pregnancy, uremia, iron deficiency (impaired iron acquisition by the neuro-melanin cells16), polyneuropathy, spinal cord diseases, and rheumatoid arthritis.14 Weinstock et al.17 did an extensive review of the literature and identified 54 conditions associated with the induction or exacerbation of RLS/WED. Among those conditions with the most prominent associations, 95% were also associated with inflammatory or immune changes, leading the authors to propose that immune dysfunction may play a role in RLS/WED.
RLS/WED is diagnosed based on clinical history. The International RLS Study Group proposed four essential criteria that were ultimately adopted by the National Institutes of Health.18 These include an urge to move the legs (with or without accompanying dysesthesias), enhanced discomfort with immobility, temporary relief of symptoms with movement, and worsening or exclusive representation of symptoms during evening hours (depending on the individual’s habitual sleep/wake schedule) (Table 1).
Mnemonic to Diagnose Restless Leg Syndrome
A fifth criterion emphasizes the exclusion of other conditions such as myalgias, peripheral edema, arthritis, leg cramps, positional discomfort, and habitual foot tapping.19 Ondo20 provides additional “RLS mimics.” Hening et al.21 illuminated the frequent diagnostic inaccuracy associated with RLS/WED. Using a telephone interview, they noted that, of 1,255 subjects thought to have the condition, it was found to be definitive among 32%, possible among 3.3%, and erroneously diagnosed among 62.8%. Periodic limb movements of sleep (PLMS) are polysomnographically observed phenomena, and occur commonly in patients with RLS/WED. Although PLMS are not typically associated with subjective complaints, a discrete association with objectively assessed daytime sleepiness results in a diagnosis of periodic limb movement disorder.
DSM and RLS/WED
In DSM-IV-TR,22 RLS/WED was relegated to a dyssomnia NOS (not otherwise specified) designation. In DSM-V,23 sleep disorders are defined more specifically, and the elimination of primary and secondary criteria highlights the fact that two disorders may be present at the same time but are not necessarily causally related (Table 2).
Changes in Restless Leg Syndrome/Willis-Ekbom Disease from DSM-IV-TR to DSM-V
Treatment of RLS/WED
The American Academy of Sleep Medicine (AASM) published detailed reviews of RLS/WED treatments in 1999,24 2004,25 and 2012.26,27 The Medical Advisory Board of the Willis-Ekbom Disease Foundation also issued treatment guidelines.28
As compared to pharmacological management options, evidence is limited with respect to behavioral sleep medicine (BSM) interventions for RLS/WED, and the most recent AASM guidelines (2009) concluded that there was insufficient evidence to provide conclusive recommendations.26 Various remedies have nonetheless been described. Mentally stimulating activities such as crossword puzzles and video games could potentially be helpful.28 Elimination of caffeine, nicotine, and alcoholic beverages may also afford some relief.29 Hornyak et al.30 reported benefit when RLS/WED patients utilized mindfulness-based strategies and cognitive behavioral therapy techniques in group therapy sessions. One study found that use of pneumatic compression devices during symptomatic periods alleviated complaints.31
Exercise therapy can also be helpful in treating symptoms of RLS/WED.32 Pigeon and Yurcheshen29 provide an excellent review of various utilized BSM strategies and their limitations. Behavioral modification techniques such as cognitive behavioral therapy for insomnia (CBT-I) can help treat insomnia or related symptoms. Sleep hygiene can be addressed as a part of CBT-I. Behavioral modification techniques can be used for healthy lifestyle modifications. The authors of this review also suggest using chronic disease management principles to help patients deal with RLS/WED.
There are conflicting data as to whether antipsychotic medications33 and selective serotonin reuptake inhibitors (SSRIs) are associated with induction or exacerbation of RLS/WED symptoms.34 Lee et al.8 did not find any association between antidepressant use and symptoms of RLS. A retrospective chart review of 200 patients also did not find an association.35 A separate study described an overall SSRI-RLS association in males (respiratory rate [RR] = 1.77; 95% confidence interval [CI] 1.26, 2.48) but not in females (RR = 0.79), with the exception of fluoxetine, where the association was present among both genders. Among males, citalopram and paroxetine were most strongly associated.36
If a trial of a lower dosage of the putative exacerbating agent is not practical or ineffective, and if discontinuation is feasible, one may consider a trial of bupropion (a dopamine agonist), as it has not been associated with induction/exacerbation of RLS/WED symptoms.
Address Comorbid Conditions
Patients need to be assessed for iron deficiency. Serum ferritin levels ≤50 mcg/L are statistically associated with increased severity of RLS symptoms, and are commonly seen among those with a refractory response to proven effective medications. Iron supplementation should be provided to such patients, with rechecking of ferritin levels at appropriate intervals to assess progress and to avoid the rare complication of hemochromatosis.28
A wide variety of medications have been used to treat RLS/WED, with varying levels of supporting evidence (Table 3). Categories are based on the organizational structure used in AASM’s treatment guidelines.26
Medications for Restless Leg Syndrome/Willis-Ekbom Disease
Pramipexole is a nonergot-derived dopamine agonist. The usual starting dose is 0.125 mg 2–3 hours before bedtime. This can be increased weekly, to a typical maximum dosage of 0.5 mg daily. In patients with compromised renal function (creatinine clearance 20–60 mL/min), the dose should be titrated more cautiously. Orthostatic hypotension can occur in up to 53% of patients.37 Other common side effects include nausea, constipation, and dizziness.37 Clinicians must also be aware of the rare induction of compulsive behaviors, including gambling or sexual indiscretion.38
Like pramipexole, ropinirole is also a nonergot-derived dopamine agonist. The starting dose is 0.25 mg 1-3 hours before bedtime. The typical titration schedule is 0.25 mg for the first 2 days, then 0.5 for 5 days, 1 mg for 1 week, and subsequently increasing by 0.5 mg/week to a maximum of 4 mg by week 7. Nausea (11%–60%), vomiting (7%–12%), constipation (4%–5%), abdominal pain (5%–7%), dizziness (6%–40%) are common side effects.37 Concerns regarding the possible induction of compulsive behaviors (as described in association with pramipexole) also apply to this medication.
Transdermal rotigotine represents another nonergot-derived dopamine agonist. It is started at 1 mg every 24 hours and can be increased by 1 mg every 24 hours, to a maximum dosage of 3 mg daily. Silber et al.28 recommend using it for chronic persistent RLS/WED. Nausea (28%–48%), headache (8%–14%), orthostatic hypotension (18%), and arthralgia (11%) are some of the more common side effects.36
In 2011, gabapentin enacarbil extended release was approved by the US Food and Drug Administration (FDA) for treatment of moderate to severe RLS. It is started at 600 mg once daily for 3 days and then increased to 600 mg twice daily. Sedation (20%), dizziness (13%–17%), and headache (10%–12%) are common side effects.37
A variety of off-label medications have demonstrated efficacy in the treatment of RLS/WED.39 Carbidopa/levodopa is quite effective in the intermittent setting, but daily use reliably results in augmentation and rebound. Low-potency opioids or opioid receptor agonists (ie, tramadol) may also be effective for intermittent RLS/WED. Tramadol has been associated with seizure induction, and is the only nondopaminergic drug occasionally associated with augmentation. High-potency opioids may be indicated for select cases of refractory RLS/WED. Benzodiazepines or benzodiazepine-receptor agonists demonstrate particular utility among those with other drivers of poor sleep consolidation. The well-documented risks associated with these medications are not unique to the RLS/WED population. In the setting of chronic persistent RLS/WED, three alpha-2-delta calcium channel ligands (gabapentin, pregabalin, and gabapentin enacarbil) have demonstrated efficacy, although only the latter is FDA-approved for this condition.
Impulse Control Disorders and Dopaminergic Medications
Medications such as dopaminergic agonists used to treat RLS/WED are associated with compulsive behaviors such as pathological gambling.40 Other impulse control disorders (ICDs) such as pathological eating, compulsive shopping, hypersexuality, and punding have been reported in RLS/WED patients receiving dopaminergic medications.40 Not unlike patients with Parkinson’s disease, dopamine dysregulation syndrome41 has been reported in RLS/WED patients treated with dopaminergic medications. Possibly these medications are affecting receptors in brain areas that are involved in reward and motivations.42 One study found that patients who had RLS preferred risky choices in decision-making43; therefore, it’s important to screen for ICDs before and during RLS/WED treatment.
RLS/WED is a common disease with high morbidity. Although there is no cure for it, effective pharmacological and nonpharmacological interventions are available. It is frequently comorbid with other psychiatric and medical conditions and affects quality of life. DSM-V now includes this as a specific diagnostic category reflecting its relevance and importance to psychiatry. Treating psychiatrists need to be aware of possible impact of psychotropic medications on RLS symptoms, various impulse control disorders, and poor QOL issues associated with RLS/WED. A multidisciplinary and comprehensive RLS/WED treatment approach that includes both pharmacological and nonpharmacological treatment approaches is more likely to be of benefit. The issue of antidepressant and neuroleptic medications’ impact RLS symptoms is an area for future research.
- Willis T. The London Practice of Physick: Or the Whole Practical Part of Physick Contained in the Works of Dr. Willis. London: Thomas Basset and William Crooke; 1685.
- Ekbom KA. Restless legs: a report of 70 new cases. Acta Med Scand Suppl. 1950;246:64–68.
- Kushida C, Martin M, Nikam P, et al. Burden of restless legs syndrome on health-related quality of life. Qual Life Res. 2007;16(4):617–624. doi:10.1007/s11136-006-9142-8 [CrossRef]
- Salas RE, Kwan AB. The real burden of restless legs syndrome: clinical and economic outcomes. Am J Manag Care. 2012;18(9 Suppl):S207–212.
- Trautmann E, Barke A, Frisch JU, et al. Restless legs syndrome: psychiatric comorbidities are more important than neuroticism. Behav Sleep Med. 2014;1–12. doi:10.1080/15402002.2014.919917 [CrossRef]
- Dikici S, Bahadir A, Baltaci D, et al. Association of anxiety, sleepiness, and sexual dysfunction with restless legs syndrome in hemodialysis patients. Hemodial Int. doi:10.1111/hdi.12175 [CrossRef] [Epub ahead of print]. May 28 2014.
- Wagner ML, Walters AS, Fisher BC. Symptoms of attention-deficit/hyperactivity disorder in adults with restless legs syndrome. Sleep. 2004;27(8):1499–1504.
- Lee HB, Hening WA, Allen RP, et al. Restless legs syndrome is associated with DSM-IV major depressive disorder and panic disorder in the community. J Neuropsychiatr Clin Neurosci. 2008;20(1):101–105. doi:10.1176/jnp.2008.20.1.101 [CrossRef]
- Szentkiralyi A, Fendrich K, Hoffmann W, Happe S, Berger K. Incidence of restless legs syndrome in two population-based cohort studies in Germany. Sleep Med. 2011;12(9):815–820. doi:10.1016/j.sleep.2011.06.016 [CrossRef]
- Ohayon MM, O’Hara R, Vitiello MV. Epidemiology of restless legs syndrome: a synthesis of the literature. Sleep Med Rev. 2012;16(4):283–295. doi:10.1016/j.smrv.2011.05.002 [CrossRef]
- Trenkwalder C, Hogl B, Winkelmann J. Recent advances in the diagnosis, genetics and treatment of restless legs syndrome. J Neurol. 2009;256(4):539–553. doi:10.1007/s00415-009-0134-9 [CrossRef]
- Winkelmann J, Schormair B, Lichtner P, et al. Genome-wide association study of restless legs syndrome identifies common variants in three genomic regions. Nat Genet. 2007;39(8):1000–1006. doi:10.1038/ng2099 [CrossRef]
- Paulus W, Dowling P, Rijsman R, Stiasny-Kolster K, Trenkwalder C. Update of the pathophysiology of the restless-legs-syndrome. Mov Disord. 2007;22:(Suppl 18):S431–439. doi:10.1002/mds.21824 [CrossRef]
- Trenkwalder C, Paulus W, Walters AS. The restless legs syndrome. Lancet Neurol. 2005;4(8):465–475. doi:10.1016/S1474-4422(05)70139-3 [CrossRef]
- Sun YM, Hoang T, Neubauer JA, Walters AS. Opioids protect against substantia nigra cell degeneration under conditions of iron deprivation: a mechanism of possible relevance to the restless legs syndrome (RLS) and Parkinson’s disease. J Neurol Sci. 2011;304(1–2):93–101. doi:10.1016/j.jns.2011.02.003 [CrossRef]
- Connor JR, Boyer PJ, Menzies SL, et al. Neuropathological examination suggests impaired brain iron acquisition in restless legs syndrome. Neurology. 2003;61(3):304–309. doi:10.1212/01.WNL.0000078887.16593.12 [CrossRef]
- Weinstock LB, Walters AS, Paueksakon P. Restless legs syndrome--theoretical roles of inflammatory and immune mechanisms. Sleep Med Rev. 2012;16(4):341–354. doi:10.1016/j.smrv.2011.09.003 [CrossRef]
- Allen RP, Picchietti D, Hening WA, et al. Restless legs syndrome: diagnostic criteria, special considerations, and epidemiology. A report from the restless legs syndrome diagnosis and epidemiology workshop at the National Institutes of Health. Sleep Med. 2003;4(2):101–119. doi:10.1016/S1389-9457(03)00010-8 [CrossRef]
- International Restless Legs Syndrome Study G. 2012 Revised IRLSSG Diagnostic Criteria for RLS. 2012; http://irlssg.org/diagnostic-criteria/. Accessed December 19, 2014.
- Ondo WG. Common comorbidities and differential diagnosis of restless legs syndrome. J Clin Psychiatry. 2014;75(3):e06. doi:10.4088/JCP.12074nr2c [CrossRef]
- Hening WA, Allen RP, Washburn M, Lesage SR, Earley CJ. The four diagnostic criteria for restless legs syndrome are unable to exclude confounding conditions (“mimics”). Sleep Med. 2009;10(9):976–981. doi:10.1016/j.sleep.2008.09.015 [CrossRef]
- American Psychiatric Association. Diagnostic and Statistical Manual of Mental Disorders. 4th Edition (revised). Washington, DC: American Psychiatric Association; 2000.
- American Psychiatric Association. Desk Reference to the Diagnostic Criteria From DSM-5. Arlington, VA: American Psychaitric Association; 2013.
- Hening W, Allen R, Earley C, Kushida C, Picchietti D, Silber M. The treatment of restless legs syndrome and periodic limb movement disorder. An American Academy of Sleep Medicine Review. Sleep. 1999;22(7):970–999.
- Hening WA, Allen RP, Earley CJ, Picchietti DL, Silber MHRestless Legs Syndrome Task Force of the Standards of Practice Committee of the American Academy of Sleep Medicine. An update on the dopaminergic treatment of restless legs syndrome and periodic limb movement disorder. Sleep. 2004;27(3):560–583.
- Aurora RN, Kristo DA, Bista SR, et al. Update to the AASM Clinical Practice Guideline: the treatment of restless legs syndrome and periodic limb movement disorder in adults-an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses. Sleep. 2012;35(8):1037.
- Aurora RN, Kristo DA, Bista SR, et al. Update to the AASM Clinical Practice Guideline: The treatment of restless legs syndrome and periodic limb movement disorder in adults-an update for 2012: practice parameters with an evidence-based systematic review and meta-analyses. Sleep. 2012;35(8):1037.
- Silber MH, Becker PM, Earley C, Garcia-Borreguero D, Ondo WGMedical Advisory Board of the Willis-Ekbom Disease F. Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome. Mayo Clin Proc. 2013;88(9):977–986. doi:10.1016/j.mayocp.2013.06.016 [CrossRef]
- Pigeon WR, Yurcheshen M. Behavioral sleep medicine interventions for restless legs syndrome and periodic limb movement disorder. Sleep Med Clin. 2009;4(4):487–494. doi:10.1016/j.jsmc.2009.07.008 [CrossRef]
- Hornyak M, Grossmann C, Kohnen R, et al. Cognitive behavioural group therapy to improve patients’ strategies for coping with restless legs syndrome: a proof-of-concept trial. J Neurol Neurosurg Psychiatry. 2008;79(7):823–825. doi:10.1136/jnnp.2007.138867 [CrossRef]
- Lettieri CJ, Eliasson AH. Pneumatic compression devices are an effective therapy for restless legs syndrome: a prospective, randomized, double-blinded, sham-controlled trial. Chest. 2009;135(1):74–80. doi:10.1378/chest.08-1665 [CrossRef]
- Aukerman MM, Aukerman D, Bayard M, Tudiver F, Thorp L, Bailey B. Exercise and restless legs syndrome: a randomized controlled trial. J Am Board Fam Med. 2006;19(5):487–493. doi:10.3122/jabfm.19.5.487 [CrossRef]
- Aggarwal S, Dodd S, Berk M. Restless leg syndrome associated with atypical antipsychotics: current status, pathophysiology, and clinical implications. Curr Drug Saf. [Epub ahead of print]. May 27, 2014.
- Picchietti D, Winkelman JW. Restless legs syndrome, periodic limb movements in sleep, and depression. Sleep. 2005;28(7):891–898.
- Brown LK, Dedrick DL, Doggett JW, Guido PS. Antidepressant medication use and restless legs syndrome in patients presenting with insomnia. Sleep Med. 2005;6(5):443–450. doi:10.1016/j.sleep.2005.03.005 [CrossRef]
- Baughman KR, Bourguet CC, Ober SK. Gender differences in the association between antidepressant use and restless legs syndrome. Mov Disord. 2009;24(7):1054–1059. doi:10.1002/mds.22517 [CrossRef]
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- Silber MH, Becker PM, Earley C, Garcia-Borreguero D, Ondo WGMedical Advisory Board of the Willis-Ekbom Disease Foundation. Willis-Ekbom Disease Foundation revised consensus statement on the management of restless legs syndrome. Mayo Clin Proc. 2013 2013;88:977–986. doi:10.1016/j.mayocp.2013.06.016 [CrossRef]
- Cornelius JR, Tippmann-Peikert M, Slocumb NL, Frerichs CF, Silber MH. Impulse control disorders with the use of dopaminergic agents in restless legs syndrome: a case-control study. Sleep. 2010;33(1):81–87.
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Mnemonic to Diagnose Restless Leg Syndrome
Urge to move
Gets better with activity
Evening and night worsening
Changes in Restless Leg Syndrome/Willis-Ekbom Disease from DSM-IV-TR to DSM-V
||Dyssomnia NOS (307.47) reserved for residual diagnoses that are not included as independent sleep disorders
||RLS (333.94) is now a separate and specific diagnostic category
||Urge to move legs or arms, dysesthesias, relieved by movement, worse at rest at night or evening leading to sleep delay and interruptions, and daytime sleepiness/fatigue
||Symptoms listed in Criteria A in DSM-5are similar to DSM-IV-TR.
|Duration and frequency of symptoms
||Symptoms causing distress need to be present for at least 3 months and must occur at least three times per week
||RLS diagnostic Criteria D and E in DSM-5require excluding other “RLS mimics” such as akathisia, leg cramps, arthritis, drug abuse, and medication use
Medications for Restless Leg Syndrome/Willis-Ekbom Disease
|Ergot-derived dopaminergic agents
||Pergolide, although effective, is no longer available in the US. It was withdrawn due to the risk of cardiac valvulopathy. For similar concerns, cabergoline is not used commonly.
|Nonergot-derived dopaminergic medications
||Pramipexole, ropinirole, levodopa, rotigotine
||Pramipexole, ropinirole, and rotigotine are FDA-approved for RLS treatment.
|Opioids/opioid receptor agonists
||Codeine, tramadol, methadone
||Potential for abuse. Opioids may worsen symptoms of sleep apnea.1 Not FDA-approved for RLS.
||Gabapentin, enacarbil, gabapentin, pregabalin
||Gabapentin enacarbil is FDA-approved for RLS treatment
||Ferrous sulfate/vitamin C (oral)
Iron sucrose (IV)
Iron dextran (IV)
||Iron supplementation may show benefits in patients who have low iron levels or have refractory RLS1
|Benzodiazepines/benzodiazepine receptor agonists
||Temazepam, eszopiclone, zolpidem, zaleplon
||Not FDA-approved for RLS