46 Copyright 2001 by the Korean Neurological Association Choong-Kun Ha, M.D.

46 Copyright 2001 by the Korean Neurological Association Choong-Kun Ha, M.D.

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Table 1. Diagnostic criteria for restless legs syndrome by The International RLS Study Group Essential Features Nonessential but Common Features 1. Desire to move the limbs usually associated with 1. Sleep disturbance and consequences paresthesias or dysesthesias 2. PLMS 2. Motor restlessness 3. Involuntary limp movements while awake and at rest 3. Symptoms are worse or exclusively present at rest with (similar to PLMS and disappearing when patient gets at least partial and temporary relief by activity up to walk) 4. Symptoms must be worse in the evening or during the night 4. Neurological examination: no abnormalities in the primary from, but in the secondary form, but in the secondary form signsof a peripheral neuropathy or radiculopathy may be present 5. Clinical course: may beginat any age but most severely affected patients are middle to older age; is usually progressive but a static course or remission may occur 6. Family history: sometimes present and suggestive of an autosomal dominant mode of inheritance PLMS, periodic leg movements during sleep. J Kor Neurol Ass / Volume 19 / Sup 1, 2001 49

Figure 1. Polysomnogram showing a periodic limp movement that is not accompanied by arousal. Leg jerk in dicated by electromyogram(emg) burst in left and right leg(combined) tibialis anterior EMG(bottom channel). Ongoing Stage 3 sleep is not disrupted(no arousal). EOG=electrooculogram; C 3 =left hifht central electroencepahlogram(eeg); C 4 =right high central EEG; O 2 =right occipital EEG; A 2 -right ear; A 1 =left ear. Figure 2. Polysomnogram showing a periodic limp movement that that is accompanied by arousal. Leg jerk in tibialis anterior elecromyogram(emg)(bottom channel) is followed by electroencephalogram(eeg) arousal, with increased chin muscle activity(emg) and eye movement. EOG=electrooculogram; C 3 =left high central EEG; C 4 = r i g h t high central EEG; O 2 =right occipital EEG; A 2 =right ear; A 1 =left ear 50 J Kor Neurol Ass / Volume 19 / Sup 1, 2001

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Table 2. Flow chart for management of restless legs syndrome Agents Dosages(mg) Side Effects Countermeasures Step 1 DA Agonists Nausea and orthostatic Slowly increase dosage or use Pramipexole 0.125-1.0 hypotension domperidone if available Pergolide 0.1-0.5 (10-30 mg) Insomnia Use small dose of benzodiazepaines in association with DA agonists Daytime fatigue and Reduce dosage or discontinue somnolence Da agonists and use levodopa (if severe and persistent) Hallucinations Tolerance Discontinue DA agonists Drug holiday for 2 weeks, then return to lower dosage Step 2 DA Precursors Same as for dopaminergic See countermeasures for DA Levodopa with benserazide Regular or slow Agonists agonists above or carbidopa release: 100-25, Morning rebound or Use small extra dose of 200-50 augmentation of RLS in levodopa during datime or Step 3 Step 4 Step 5 early evening reduce dosage or combine levodopa with DA agonists or bezodiazepines or discontinue levodopa(if severe and persistent) Benzodiazepines Clonazepam 0.5-2.0 Daytime somnolence Reduce dosage or use 1-2 h before bedtime Temazepam 15-30 Tolerance Drug holiday for 2 weeks, then return to lower dosage Nitrazepam 5-10 Opiates Oxycodone 5 Constipation Symptomatic treatment Propoxyphene 200 Dependency Drug holiday or withdrawal Codeine 15-60 Antiepileptic Drugs Cartbamazepine 200-400 Nephrotoxicity Monitor blood level regularly and adjust dosage Gabapentin 100-400 Daytime fatigue and Reduce dosage somnolenmce At bedtime. At bedtime; repeated once during the night if needed. Slow release preparation not usually repeated. DA, dopamine; RLS, restless legs syndrome. 54 J Kor Neurol Ass / Volume 19 / Sup 1, 2001

15. Mahowald MW, Schenck CH. REM sleep behavior 11. Lugaresi E, Cirignotta F, Coccagna G, Montagna P. Nocturnal myoclonus and restless legs syndrome. A d v Neurol 1986;43:295-307. 12. Trenkwalder C, Walters AS, Hening W. Periodic limb movements and restless legs syndrome. Neurol Clin 1996; 14:629-649. 13. American Sleep Disorders Association. International classification of sleep disorders, revised:diagnostic and coding manual. Rochester: American Sleep Disorders A s s o c i a t i o n. 1997;65-68. 14. Coleman RM, Pollack C, Weitzmann ED. Periodic movements in sleep (nocturnal myoclonus) :relation to sleep-wake disorders. Ann Neurol 1980;8:416-421. 15. Nicolas A, Michaud M, Lavigne G, Montplaisir J. The influence of sex, age, and sleep/wake state on characteristics of periodic leg movements in restless legs syndrome patients. Clin Neurophysiol 1 9 9 9 ; 1 1 0 : 1 1 6 8-1174. 16. Reite M, Ruddy J, Nagel K. Concise guide to evaluation and management of sleep disorders. 2nd ed. Washington: American Psychiatric Press. 1997:80-89. 17. Ekbom KA. Restless legs. Acta Med Scand 1 9 4 5 ; 1 5 8 (Suppl):4-123. 18. Walters AS. Toward a better definition of the restless legs syndrome. The International Restless Legs Syndrome Study Group. Mov Disord 1995;10:634-642. 19. Montplaisir J, Boucher S, Poirier G, Lavigne G, Lapierre O, Lesperance P. Clinical, polysomnographic, and genetic characteristics of restless legs syndrome: A study of 133 patients diagnosed with new standard criteria. Mov Disord 1997;12:61-65. 10. Montplaisir J, Nicolas A, Godbout R, Walters A. Restless legs syndrome and periodic limb movement disorder. In: Kryger MH, Roth T, Dement WC. Principles and practice of sleep medicine. 3rd ed. Philadelphia: W.B. Saunders Company. 2000;742-752. 11. Culpepper J, Shaffer J, Badia P. Within night variability in nocturnal myoclonus. Sleep Rearch 1989;18:217-221. 12. Sforza E, Nicolas A, Lavigne G, Gosselin A, Petit D, Montplaisir J. EEG and cardiac activation during periodic leg movement in sleep. Neuology 1999;52:786-791. 13. Montplaisir J, Godbout R. Nocturnal sleep of narcoleptic patients. Sleep 1986;9:159-161. 14. Fry JM, DiPhillipo MA, Pressman MR. Periodic leg movements in sleep following treatment of obstructive sleep apnea with nasal continuous positive airway pressure. Chest 1989;96:89-91. disorder. In: Thorpy MJ. Handbook of sleep disorders. New York:Marcel Dekker. 1990:567-593. 16. American Sleep Disorders Association. International classification of sleep disorders, revised: diagnostic and coding manual. Rochester: American Sleep Disorders Association. 1997;69-71. 17. Walters AS. Restless legs syndrome, periodic limb movements in sleep, and other sleep-related movement disorders. In: Jankovic J, Tolosa E. Parkinson s disease and movement disorders. 3rd ed. Baltimore: Lippincott Williams & Wilkins. 1998;601-621. 18. Walters AS, Hening WA, Chokroverty S. Review and videotape recognition of idiopathic restless legs syndrome. Mov Disord 1991;6:105-110. 19. Bliwise DL, Carskadon MA, Dement WC. Nightly variation of periodic movements in sleep in middle aged and elderly individuals. Arch Gerontol Geriatr 1 9 8 8 ; 7 : 2 7 3-2 7 9. 20. Coleman RM, Bliwise DL, Sajben N, Dement WC. Epidemiology of periodic movements during sleep. In: Guilleminault C, Lugaresi E. Sleep/wake disorders. Natural history, epidemiology and long term evolution. New York: Raven Press. 1988;217-229. 21. Lavigne GJ, Montplaisir J. Restless legs syndrome and sleep bruxism: Prevalence and association among Canadians. Sleep 1994;17:739-743. 22. Ondo W, Jankovic J. Restless legs syndrome: clinicoetiologic correlates. Neurology 1996;47:1435-1441. 23. Walters AS, Hickey K, Maltzman J, Verrico T, Joseph D, Hening W, et al. A questionnaire study of 138 patients with restless legs syndrome: The night-walkerssurvey. Neurology 1996;46:92-95. 24. Walters AS, Picchietti DL, Ehrenberg BL, Wagner ML. Restless legs syndrome in childhood and adolescence. Pediatr Neurol 1994;11:241-245. 25. Trenkwalder C, Seidel VC, Gasser T, Oertel WH. Clinical symptoms and possible anticipation in a large kindred of familial restless legs syndrome. Mov Disord 1996;11:389-394. 26. Lazzarini A, Walters AS, Hickey K, Coccagna G, Lugaresi E, Ehrenberg BL, et al. Studies of penetrance and anticipation in five autosomal-dominant restless legs syndrome pedigrees. Mov Disord 1999;14:111-116. 27. Iannaccone S, Zucconi M, Marchettini P, Ferini-Strambi L, Nemni R, Quattrini A, et al. Evidence of peripheral neuropathy in primary restless legs syndrome. Mov Disord 1995;10:2-9. 28. Rutkove SB, Matheson JK, Logigian EL. Restless legs syndrome in patients with polyneuropathy. Muscle Nerve 1996;19:670-672. 29. Watanabe S, Ono A, Naito H. Periodic leg movements during epidural or spinal anesthesia in an elderly man without sleep-related (nocturnal) myoclonus. Sleep 1 9 9 0 ; J Kor Neurol Ass / Volume 19 / Sup 1, 2001 55

13:262-266. 30. Jackson J. Periodic movements of sleep in T10 paraplegic with failure to respond to parlodel. Sleep Res 1990;19:326. 31. Yogota T, Hirose K, Tanabe H, Tsukagoshi H. Sleeprelated periodic leg movements (nocturnal myoclonus) due to spinal cord lesions. J Neurol Sci 1991;104:13-18. 32. de Mello MT, Lauro FAA, Silva AC, Tufik S. Incidence of periodic leg movements and restless legs syndrome during sleep following physical activity in spinal cord injury subjects. Spinal Cord 1996;34:294-296. 33. Smith RC. Relationship of periodic movements in sleep (nocturnal myoclonus) and the Babinski sign. Sleep 9 8 5 ; 8:239-243. 34. Fujiki A, Shimizu A, Yamada Y, Yamamoto J, Kaneko Z. The Babinski reflex during sleep and wakefulness. Electroencephalogr Clin Neurophysiol 1971;31:610-613. 35. Wechsler LR, Stakes J, Shanhani BT, Blusis NA. Periodic leg movements of sleep (nocturnal myoclonus): an electrophysiological study. Ann Neurol 1986;19:168-173. 36. Bucher SS, Seelos KC, Oertel WH, Reiser M, Trenkwalder C. Cerebral generators involved in the pathogenesis of the restless legs syndrome. Ann Neurol 1 9 7 7 ; 4 1 : 6 3 9-6 4 5. 37. Lugaresi E, Coccagna G, Mantovani M, Rebrun R. Some periodic phenomena arising during drowsiness and sleep in man. E l e c t r o e n c e p h a l o g r Clin Neurophysiol 1 9 7 2 ; 3 2 : 701-705. 38. Evans BM. Periodic activity in cerebral arousal mechanisms-the relationship to sleep and brain damage. Electroencephalogr Clin Neurophysiol 1992;83:130-137. 39. Terzano MG, Parino L. Clinical application of cyclic alternating pattern. Physiol Behav 1993;54:807-813. 40. Trenkwalder C, Bucher SF, Oertel WA. Electrophysiological pattern of involuntary limb movements in the restless legs syndrome. Muscle Nerve 1996;19:155-162. 41. Lang AE, Johnson K. Akathisia in idiopathic Parkinson s disease. Neurology 1987;30:477-481. 42. Staedt J, Stoppe G, Kogler A, Riemann H, Hajak G, Munz DL. Single photon emission tomography (SPECT) imaging of dopamine D2 receptors in the course of dopamine replacement therapy in patients with nocturnal myoclonus syndrome. J Neurol Transm Gen Sect 1 9 9 5 ; 99:187-193. 43. Turjanski N, Lees AJ, Brooks DJ. Striatal dopaminergic function in restless legs syndrome: 1 8 F-dopa and 1 1 C - raclopride PET studies. Neurology 1999;52:932-937. 44. Hening WA, Walters A, Kavey N, Gidro-Frank S, Cote L, Fahn S. Dyskinesia while awake and periodic movements in sleep in restless legs syndrome treatment with opioids. Neurology 1986;36:1363-1366. 45. Earley CJ, Allen RP, Beard JL, Connor JR. Insight into the pathophysiology of restless legs syndrome. J Neurosci Res 2000;62:623-628. 46. Sowers JR, Vlachakis N. Circadian variation in dopamine level in man. J Endocrinol Invest 1984;7:341-345. 47. Shade R, Vick R, Ott T, Sohr R, Pfister C, Bellach J, et al. Circadian rhythm of dopamine and cholecystokinin in nucleus accumbens and striatum of rat-influence on dopaminergic stimulation. Chronobiol Int 1995;12:87-99. 48. Earley CJ, Connor JR, Beard JL, Malecki EA, Epstein DR, Allen RP. Abnormalities in CSF concentration of ferritin and transferrin in restless legs syndrome. Neurology 2000; 54:1698-1700. 49. Allen RP, Barker PB, Wehr F, Song HK, Earley CJ. Magnetic resonance image measurement of regional brain iron content in patients with restless legs syndrome. Neurology 2001 (in press). 50. Scale WE, Vander AJ, Brown MB, Kluger MJ. Human circadian rhythms in temperature, trace metals, and blood variables. J Appl Physiol 1988;65:1840-1846. 51. Sun ER, Chen CA, Ho G, Earley CJ. Iron and the restless legs syndrome. Sleep 1998;21:371-377. 52. Bradbury MWB. Transport of iron in the blood-braincerebrospinal fluid system. J Neurochem 1 9 9 7 ; 6 9 : 4 4 3-454. 53. Malecki EA, Devenyi AG, Beard JL, Connor JR. Existing and emerging mechanisms for transport of iron and manganese to the brain. J Neurosci Res 1999;56:113-122. 54. Montplaisir J, Boucher S, Nicolas A, Lesperance P, Gosselin A, Pompre P, et al. Immobilization tests and periodic leg movements in sleep for the diagnosis of the restless legs syndrome. Mov Disord 1998;13:342-349. 55. Hening W, Allen R, Earley C, Kushida C, Picchietti D, Silber M. The treatment of restless legs syndrome and periodic limb movement disorder. Sleep 1999;22:970-990. 56. Banno K, Delaive K, Walld R, Kryger MH. Restless legs syndrome in 218 patients: associated disorders. Sleep Med 2000;1:221-229. 57. Lavigne GL, Lobbezoo F, Rompre PH, Nielsen TA, Montplaisir J. Cigarette smoking as a risk factor or an exacerbating factor for restless legs syndrome and sleep bruxism. Sleep 1997;20:290-293. 58. O Keeffe ST, Gavin K, Lavan JN. Iron status and restless legs syndrome in elderly. Age Ageing 1994; 23:200-203. 59. Yasuda T, Nishimura A, Katsuki Y, Tsuji Y. Restless legs syndrome treated successfully by kidney transplantation: A case report. Clin Transplant 1986;138:138. 60. Trenkwalder C, Stiasny K, Pollmaecher T, Wetter T, Schwarz J, Kohnen R, et al. L-dopa therapy of uremic and idiopathic restless legs syndrome: A double-blind crossover trial. Sleep 1995;18:681-688. 61. Hening WA, Walter AS, Chokroverty S. Treatment of the restless legs syndrome: Current practice of sleep experts. Neurology 1995;45(suppl 4):445 62. Becker PM, Jamieson AO, Brown WD. Dopaminergic agents in restless legs syndrome and periodic limb movements of sleep: Response and complications of extended treatment in 49 cases. Sleep 1993; 16:713-716. 56 J Kor Neurol Ass / Volume 19 / Sup 1, 2001

63. Stiasny K, Wetter TC, Trenkwalder C, Oertel WH. Restless legs syndrome and its treatment by dopamine agonists. Parkin Relat Disord 2001;7:21-25. 64. Collado-Seidel V, Kazenwadel J, Wetter TC, Kohnen R, Winkelmann J, Selzer R, et al. A controlled study of additional sr-l-dopa in L-dopa-responsive restless legs syndrome with late-night symptoms. N e u r o l o g y 1999;52:285-290. 65. Montplaisir J, Nicolas A, Denesle R, Gomez-Mancilla B. Restless legs syndrome improved by pramipexole: a double-blind randomized trial. Neurology 1 9 9 9 ; 5 2 : 9 3 8-943. 66. Stiasny K, Roebbecke J, Schueler P, Oertel WH. Treatment of restless legs syndrome(rls) with cabergoline. J Neurol 1998;245:408. J Kor Neurol Ass / Volume 19 / Sup 1, 2001 57