Updates on the Diagnosis and Treatment of Restless Legs Syndrome

Seung-Gul Kang

doi:10.4306/jknpa.2020.59.1.13

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Kang: Updates on the Diagnosis and Treatment of Restless Legs Syndrome

Special Article

J Korean Neuropsychiatr Assoc 2020;59(1):13-19.

Published online: 17 January 2020

DOI: https://doi.org/10.4306/jknpa.2020.59.1.13

Updates on the Diagnosis and Treatment of Restless Legs Syndrome

Seung-Gul Kang, 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

Revised 7 January 202020 January 2020 Accepted 22 January 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.

Keywords: Restless legs syndrome, Diagnosis, Polysomnography, Treatment, Anticonvulsants, Dopamine agonist, Iron

REFERENCES

1). Willis T. De Animae Brutorum. London: Wells and Scott;1672.

2). Ekbom KA. Restless legs. Stockholm: Ivar Haeggströms;1945.

3). Michaud M, Chabli A, Lavigne G, Montplaisir J. Arm restlessness in patients with restless legs syndrome. Mov Disord. 2000; 15:289–293.

4). Allen RP, Picchietti DL, Garcia-Borreguero D, Ondo WG, Walters AS, Winkelman JW, et al. 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. 2014; 15:860–873.

5). 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. editors.Principles and practice of sleep medicine. 6th ed.Philadelphia, PA: Elsevier;2017. p. 923–934. e926.

6). Phillips B, Hening W, Britz P, Mannino D. Prevalence and correlates of restless legs syndrome: results from the 2005 National Sleep Foundation Poll. Chest. 2006; 129:76–80.

7). Cho YW, Shin WC, Yun CH, Hong SB, Kim JH, Allen RP, et al. Epidemiology of restless legs syndrome in Korean adults. Sleep. 2008; 31:219–223.

8). Allen RP, Walters AS, Montplaisir J, Hening W, Myers A, Bell TJ, et al. Restless legs syndrome prevalence and impact: REST general population study. Arch Intern Med. 2005; 165:1286–1292.

9). 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. 2001; 16:1159–1163.

10). Winkelman JW, Shahar E, Sharief I, Gottlieb DJ. Association of restless legs syndrome and cardiovascular disease in the Sleep Heart Health Study. Neurology. 2008; 70:35–42.

11). Hwang IC, Na KS, Lee YJ, Kang SG. Higher prevalence of hypertension among individuals with restless legs syndrome: a metaanalysis. Psychiatry Investig. 2018; 15:701–709.

12). Kurlan R, Rabin M. Augmentation in restless legs syndrome: poor response to sudden withdrawal of dopaminergic therapy. J Parkinsonism Restless Legs Syndr. 2013; 3:49–52.

13). Allen RP, Chen C, Garcia-Borreguero D, Polo O, DuBrava S, Miceli J, et al. Comparison of pregabalin with pramipexole for restless legs syndrome. N Engl J Med. 2014; 370:621–631.

14). Winkelman JW, Armstrong MJ, Allen RP, Chaudhuri KR, Ondo W, Trenkwalder C, et al. 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. 2016; 87:2585–2593.

15). Garcia-Borreguero D, Silber MH, Winkelman JW, Högl B, Bainbridge J, Buchfuhrer M, et al. 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. 2016; 21:1–11.

16). American Academy of Sleep Medicine. International classification of sleep disorders. 3rd ed.Darien, IL: American Academy of Sleep Medicine;2014.

17). American Psychiatry Association. Diagnostic and statistical manual of mental disorders, 5th edition: DSM-5. Arlington, VA: American Psychaitry Association;2013.

18). 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. 2013; 88:261–264.

19). 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. 2004; 43:663–670.

20). Winkelmann J, Stautner A, Samtleben W, Trenkwalder C. Longterm course of restless legs syndrome in dialysis patients after kidney transplantation. Mov Disord. 2002; 17:1072–1076.

21). Cho YW, Na GY, Lim JG, Kim SH, Kim HS, Earley CJ, et al. Prevalence and clinical characteristics of restless legs syndrome in diabetic peripheral neuropathy: comparison with chronic osteoarthritis. Sleep Med. 2013; 14:1387–1392.

22). Lee HB, Hening WA, Allen RP, Kalaydjian AE, Earley CJ, Eaton WW, et al. Restless legs syndrome is associated with DSM-IV major depressive disorder and panic disorder in the community. J Neuropsychiatry Clin Neurosci. 2008; 20:101–105.

23). Rios Romenets S, Dauvilliers Y, Cochen De Cock V, Carlander B, Bayard S, Galatas C, et al. Restless legs syndrome outside the blood-brain barrier–exacerbation by domperidone in Parkinson's disease. Parkinsonism Relat Disord. 2013; 19:92–94.

24). Kang SG, Lee HJ, Jung SW, Cho SN, Han C, Kim YK, et al. Characteristics and clinical correlates of restless legs syndrome in schizophrenia. Prog Neuropsychopharmacol Biol Psychiatry. 2007; 31:1078–1083.

25). Aggarwal S, Dodd S, Berk M. Restless leg syndrome associated with atypical antipsychotics: current status, pathophysiology, and clinical implications. Curr Drug Saf. 2015; 10:98–105.

26). Trotti LM, Bliwise DL, Greer SA, Sigurdsson AP, Gudmundsdóttir GB, Wessel T, et al. Correlates of PLMs variability over multiple nights and impact upon RLS diagnosis. Sleep Med. 2009; 10:668–671.

27). Haba-Rubio J, Sforza E. Test-to-test variability in motor activity during the suggested immobilization test in restless legs patients. Sleep Med. 2006; 7:561–566.

28). 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.

29). Fahn S, Marsden CD, Van Woert MH. Myoclonus: advances in neurology. New York, NY: Raven Press;1986.

30). 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. 2006; 29:1183–1187.

31). 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. 2000; 7:331–336.

32). Nicolas A, Lespérance P, Montplaisir J. Is excessive daytime sleepiness with periodic leg movements during sleep a specific diagnostic category? Eur Neurol. 1998; 40:22–26.

33). Michaud M, Paquet J, Lavigne G, Desautels A, Montplaisir J. Sleep laboratory diagnosis of restless legs syndrome. Eur Neurol. 2002; 48:108–113.

34). 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; 135:74–80.

35). Mitchell UH, Myrer JW, Johnson AW, Hilton SC. Restless legs syndrome and near-infrared light: an alternative treatment option. Phys-iother Theory Pract. 2011; 27:345–351.

36). Koo YS, Kim SM, Lee C, Lee BU, Moon YJ, Cho YW, et al. 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. 2015; 16:280–287.

37). 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. 2010; 85:512–521.

38). Adler CH. Treatment of restless legs syndrome with gabapentin. Clin Neuropharmacol. 1997; 20:148–151.

39). Mellick GA, Mellick LB. Management of restless legs syndrome with gabapentin (Neurontin). Sleep. 1996; 19:224–226.

40). 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. 2002; 59:1573–1579.

41). Montplaisir J, Nicolas A, Denesle R, Gomez-Mancilla B. Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology. 1999; 52:938–943.

42). Winkelman JW, Johnston L. Augmentation and tolerance with longterm pramipexole treatment of restless legs syndrome (RLS). Sleep Med. 2004; 5:9–14.

43). 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. 2006; 21:1627–1635.

44). Allen RP, Ondo WG, Ball E, Calloway MO, Manjunath R, Higbie RL, et al. Restless legs syndrome (RLS) augmentation associated with dopamine agonist and levodopa usage in a community sample. Sleep Med. 2011; 12:431–439.

45). Allen RP, Earley CJ. Augmentation of the restless legs syndrome with carbidopa/levodopa. Sleep. 1996; 19:205–213.

46). 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. 2011; 12:906–913.

47). Manconi M, Ferri R, Zucconi M, Bassetti CL, Fulda S, Aricò D, et al. Dissociation of periodic leg movements from arousals in restless legs syndrome. Ann Neurol. 2012; 71:834–844.

Table 1.

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

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