jkna Journal of Korean Neuropsychiatric Association J Korean Neuropsychiatr Assoc 1015-4817 2289-0963 Korean Neuropsychiatric Association 10.4306/jknpa.2020.59.1.13 jkna-59-13 Special Article Updates on the Diagnosis and Treatment of Restless Legs Syndrome KangSeung-Gul MD, PhD Department of Psychiatry, Gil Medical Center, Gachon University College of Medicine, Incheon, Korea Address for correspondence Seung-Gul Kang, MD, PhD Department of Psychiatry, Gil Medical Center, Gachon University College of Medicine, 21 Namdong-daero 774beon-gil, Incheon 21565, Korea Tel +82-32-458-2818 Fax +82-32-468-9962 E-mail kangsg@gachon.ac.kr 12020 1712020 591 1319 7012020 20012020 22012020 Copyright © 2020 Korean Neuropsychiatric Association 2020 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. Abstract

Restless legs syndrome (RLS) is a neurological sleep disorder characterized by an urge to move the legs or arms and is associated with discomfort and paresthesia in the legs. RLS is diagnosed based on the clinical symptoms, and polysomnography is performed to quantify the periodic limb movements during sleep or in patients who undergo the suggested immobilization test. Determining the cause of RLS is important for accurately diagnosing and evaluating this condition. The treatment of RLS varies according to the etiology, severity, and frequency of the patients’ symptoms. Accurate identification and treatment of the cause of RLS are important in patients with secondary RLS. Iron supplementation could be useful in patients with uremia, iron deficiency, and for RLS during pregnancy. Dopamine agonists have been used as the first-line treatment for primary RLS. On the other hand, augmentation is a known adverse effect associated with the longterm use of dopamine agonists. Therefore, recent treatment guidelines recommend the administration of anticonvulsants, such as pregabalin and gabapentin, to treat RLS. Iron, opioids, or benzodiazepines may be useful in patients refractory to anticonvulsants or dopamine agonists. RLS is a chronic condition. Therefore, it is essential to establish a longterm treatment plan, considering both the efficacy and adverse effects of therapeutic agents used in patients.

 Restless legs syndrome Diagnosis Polysomnography Treatment Anticonvulsants Dopamine agonist Iron REFERENCES Willis T De Animae Brutorum London Wells and Scott 1672 Ekbom KA Restless legs Stockholm Ivar Haeggströms 1945 Michaud M Chabli A Lavigne G Montplaisir J Arm restlessness in patients with restless legs syndrome Mov Disord 200015 289293 Allen RP Picchietti DL Garcia-Borreguero D Ondo WG Walters AS Winkelman JW Restless legs syndrome/Willis-Ekbom disease diagnostic criteria: updated International Restless Legs Syndrome Study Group (IRLSSG) consensus criteria–history, rationale, description, and significance Sleep Med 201415 860873 Allen RP Montplaisir J Walters AS Ferini-Strambi L Högl B Restless legs syndrome and periodic limb movements during sleep Kryger M Roth T Dement WC editors. Principles and practice of sleep medicine 6th ed. Philadelphia, PA Elsevier 2017 923934 e926. Phillips B Hening W Britz P Mannino D Prevalence and correlates of restless legs syndrome: results from the 2005 National Sleep Foundation Poll Chest 2006129 7680 Cho YW Shin WC Yun CH Hong SB Kim JH Allen RP Epidemiology of restless legs syndrome in Korean adults Sleep 200831 219223 Allen RP Walters AS Montplaisir J Hening W Myers A Bell TJ Restless legs syndrome prevalence and impact: REST general population study Arch Intern Med 2005165 12861292 Ulfberg J Nyström B Carter N Edling C Prevalence of restless legs syndrome among men aged 18 to 64 years: an association with somatic disease and neuropsychiatric symptoms Mov Disord 200116 11591163 Winkelman JW Shahar E Sharief I Gottlieb DJ Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study Neurology 200870 3542 Hwang IC Na KS Lee YJ Kang SG Higher prevalence of hypertension among individuals with restless legs syndrome: a metaanalysis Psychiatry Investig 201815 701709 Kurlan R Rabin M Augmentation in restless legs syndrome: poor response to sudden withdrawal of dopaminergic therapy J Parkinsonism Restless Legs Syndr 20133 4952 Allen RP Chen C Garcia-Borreguero D Polo O DuBrava S Miceli J Comparison of pregabalin with pramipexole for restless legs syndrome N Engl J Med 2014370 621631 Winkelman JW Armstrong MJ Allen RP Chaudhuri KR Ondo W Trenkwalder C Practice guideline summary: treatment of restless legs syndrome in adults: report of the guideline development, dissemination, and implementation subcommittee of the American Academy of Neurology Neurology 201687 25852593 Garcia-Borreguero D Silber MH Winkelman JW Högl B Bainbridge J Buchfuhrer M Guidelines for the first-line treatment of restless legs syndrome/Willis-Ekbom disease, prevention and treatment of dopaminergic augmentation: a combined task force of the IRLSSG, EURLSSG, and the RLS-foundation Sleep Med 201621 111 American Academy of Sleep Medicine International classification of sleep disorders 3rd ed. Darien, IL American Academy of Sleep Medicine 2014 American Psychiatry Association Diagnostic and statistical manual of mental disorders, 5th edition: DSM-5 Arlington, VA American Psychaitry Association 2013 Allen RP Auerbach S Bahrain H Auerbach M Earley CJ The prevalence and impact of restless legs syndrome on patients with iron deficiency anemia Am J Hematol 201388 261264 Sloand JA Shelly MA Feigin A Bernstein P Monk RD A double-blind, placebo-controlled trial of intravenous iron dextran therapy in patients with ESRD and restless legs syndrome Am J Kidney Dis 200443 663670 Winkelmann J Stautner A Samtleben W Trenkwalder C Longterm course of restless legs syndrome in dialysis patients after kidney transplantation Mov Disord 200217 10721076 Cho YW Na GY Lim JG Kim SH Kim HS Earley CJ Prevalence and clinical characteristics of restless legs syndrome in diabetic peripheral neuropathy: comparison with chronic osteoarthritis Sleep Med 201314 13871392 Lee HB Hening WA Allen RP Kalaydjian AE Earley CJ Eaton WW Restless legs syndrome is associated with DSM-IV major depressive disorder and panic disorder in the community J Neuropsychiatry Clin Neurosci 200820 101105 Rios Romenets S Dauvilliers Y Cochen De Cock V Carlander B Bayard S Galatas C Restless legs syndrome outside the blood-brain barrier–exacerbation by domperidone in Parkinson's disease Parkinsonism Relat Disord 201319 9294 Kang SG Lee HJ Jung SW Cho SN Han C Kim YK Characteristics and clinical correlates of restless legs syndrome in schizophrenia Prog Neuropsychopharmacol Biol Psychiatry 200731 10781083 Aggarwal S Dodd S Berk M Restless leg syndrome associated with atypical antipsychotics: current status, pathophysiology, and clinical implications Curr Drug Saf 201510 98105 Trotti LM Bliwise DL Greer SA Sigurdsson AP Gudmundsdóttir GB Wessel T Correlates of PLMs variability over multiple nights and impact upon RLS diagnosis Sleep Med 200910 668671 Haba-Rubio J Sforza E Test-to-test variability in motor activity during the suggested immobilization test in restless legs patients Sleep Med 20067 561566 Iber C The AASM manual for the scoring of sleep and associated events: rules, terminology, and technical specification 1st ed. Westchester, IL American Academy of Sleep Medicine 2007 Fahn S Marsden CD Van Woert MH Myoclonus: advances in neurology New York, NY Raven Press 1986 Pennestri MH Whittom S Adam B Petit D Carrier J Montplaisir J PLMS and PLMW in healthy subjects as a function of age: prevalence and interval distribution Sleep 200629 11831187 Karadeniz D Ondze B Besset A Billiard M Are periodic leg movements during sleep (PLMS) responsible for sleep disruption in insomnia patients? Eur J Neurol 20007 331336 Nicolas A Lespérance P Montplaisir J Is excessive daytime sleepiness with periodic leg movements during sleep a specific diagnostic category? Eur Neurol 199840 2226 Michaud M Paquet J Lavigne G Desautels A Montplaisir J Sleep laboratory diagnosis of restless legs syndrome Eur Neurol 200248 108113 Lettieri CJ Eliasson AH Pneumatic compression devices are an effective therapy for restless legs syndrome: a prospective, randomized, double-blinded, sham-controlled trial Chest 2009135 7480 Mitchell UH Myrer JW Johnson AW Hilton SC Restless legs syndrome and near-infrared light: an alternative treatment option Phys-iother Theory Pract 201127 345351 Koo YS Kim SM Lee C Lee BU Moon YJ Cho YW Transcranial direct current stimulation on primary sensorimotor area has no effect in patients with drug-naïve restless legs syndrome: a proof-of-concept clinical trial Sleep Med 201516 280287 Bogan RK Bornemann MA Kushida CA Trân PV Barrett RW Longterm maintenance treatment of restless legs syndrome with gabapentin enacarbil: a randomized controlled study Mayo Clin Proc 201085 512521 Adler CH Treatment of restless legs syndrome with gabapentin Clin Neuropharmacol 199720 148151 Mellick GA Mellick LB Management of restless legs syndrome with gabapentin (Neurontin) Sleep 199619 224226 Garcia-Borreguero D Larrosa O de la Llave Y Verger K Masramon X Hernandez G Treatment of restless legs syndrome with gabapentin: a double-blind, cross-over study Neurology 200259 15731579 Montplaisir J Nicolas A Denesle R Gomez-Mancilla B Restless legs syndrome improved by pramipexole: a double-blind randomized trial Neurology 199952 938943 Winkelman JW Johnston L Augmentation and tolerance with longterm pramipexole treatment of restless legs syndrome (RLS) Sleep Med 20045 914 Montplaisir J Karrasch J Haan J Volc D Ropinirole is effective in the longterm management of restless legs syndrome: a randomized controlled trial Mov Disord 200621 16271635 Allen RP Ondo WG Ball E Calloway MO Manjunath R Higbie RL Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample Sleep Med 201112 431439 Allen RP Earley CJ Augmentation of the restless legs syndrome with carbidopa/levodopa Sleep 199619 205213 Allen RP Adler CH Du W Butcher A Bregman DB Earley CJ Clinical efficacy and safety of IV ferric carboxymaltose (FCM) treatment of RLS: a multi-centred, placebo-controlled preliminary clinical trial Sleep Med 201112 906913 Manconi M Ferri R Zucconi M Bassetti CL Fulda S Aricò D Dissociation of periodic leg movements from arousals in restless legs syndrome Ann Neurol 201271 834844 Tables

Pharmacotherapy for restless legs syndrome

Intervention Medication Dosage
1st Alpha-2-delta ligands
 Pregabalin 50-450 mg per day
 Gabapentin 100-1800 mg per day
2nd or 1st Dopamine agonists Pramipexole 0.125-0.5 mg per day
 Ropinirole 0.5-4 mg per day
 Rotigotine 1-3 mg per 24 hours
3rd Levodopa (could be used as needed) 100/25-200/50 mg per day
 Levodopa-carbidopa  
 Levodopa-benserazide  
Next Iron (could be considered concomitantly with 1st to 3rd line medications or earlier when ferritin levels are ＜75 μg/L)
   Ferrous sulfate (oral) 325 mg per day
   Ferric carboxymaltose (intravenous) Opiates 500-1500 mg per injection
   Oxycodone-naloxone 10/5-40/20 mg per day
   Oxycodone Benzodiazepines 5-40 mg per day
   Clonazepam 0.25-2 mg per day
   Lorazepam 0.5-2 mg per day

Medications unavailable in South Korea are not listed in this table. The therapeutic strategy presented is not absolute and may vary depending on the cause and symptom characteristics of restless legs syndrome