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1 종설 J Kor Sleep Soc / Volume 6 / June, 2009 렘수면행동장애의치료 문혜진 남현우 서울대학교보라매병원신경과 Treatment of REM Sleep Behavior Disorder Hye-Jin Moon, M.D., Hyunwoo Nam, M.D. Department of Neurology, Boramae Hospital, Seoul National University, Seoul, Korea REM sleep behavior disorder (RBD) is clinically characterized by the intermittent loss of normal skeletal muscle atonia during rapid eye movement (REM) sleep with the appearance of elaborate motor activity associated with dream mentation. Clonazepam, a sedating benzodiazepine, is currently regarded as the treatment of choice for RBD. In patients with contraindications to clonazepam, in those unresponsive to clonazepam, or in whom tolerance or serious side effects are observed, a therapeutic trial with melatonin up to 12 mg is recommended. The effect of acetylcholinesterase inhibitors and dopaminergics on RBD symptoms needs future validation. There is no clear evidence of beneficial effect of bilateral subthalamic nucleus stimulation despite the improvement of the sleep architecture. Key Words : REM sleep behavior disorder, Clonazepam, Melatonin, Pramipexole, Levodopa 서 론 렘수면행동장애 (REM sleep behavior disorder, RBD) 는렘수면동안정상적으로발생하는골격근의무긴장증 (atonia) 이소실되어, 꿈의내용과관련된움직임이나타나는것을특징으로하는질환으로, 국제수면장애분류 2차개정판 (International Classification of Sleep Disorders 2nd edition, 2005) 에따르면야뇨증, 몽유병, 야경, 악몽등과함께사건수면 (parasomnia) 에해당된다. 1 렘수면행동장애는특별한원인을찾을수없는특발성과기면증, 2 α-synucleinopathies 3 등다른질환과연관되어나타나거나, 약물의사용혹은중단에의해유발되는증후성으로나눌수있다. 퇴행성신경질환의경우, 렘수면행동장애가다른증상에선행하여발생할수있다고알려져있으며, 실제로특발성렘수면행동장애환자를추적관찰하였 * Address of correspondence Hyunwoo Nam, M.D., Ph.D. Associate Professor, Department of Neurology, Boramae Hospital, Shindaebang 2-dong 395, Dongjak-ku, Seoul, Korea, Tel: Fax: hwnam@brm.co.kr 을때, 65% 에서파킨슨병이나치매가발생하였다는보고가있어, 4 진단초기에특발성렘수면행동장애로분류되어도이후에세심한추적관찰을요한다. 렘수면행동장애환자는누군가와대결을벌이거나, 공격을받고, 쫓기는등의불쾌하고폭력적인내용의꿈을꾸면서, 꿈의내용을행동화하여침대에서떨어져다치거나, 함께잠을자는파트너를공격하여다치게할수있다. 이러한수면관련외상은멍, 찰과상에서부터척추골절, 경막하출혈까지보고되었으며, 환자의 79%~96% 까지경험한다고알려져있어, 5,6 이를예방하기위한치료가필요하다. 본종설에서는렘수면행동장애의치료에대해이전의연구결과를토대로하여간략히기술하고자한다. 본론 1. Clonazepam Clonazepam 은현재까지시도된방법중, 가장효과적인 24 수면

2 렘수면행동장애의치료 Table 1. Clonazepam treatment data Schenck CH. et al. 8 Population studied (n) Dosage (mg) PSG Results Idiopathic RBD and RBD associated with other disorders (57) 0.25~3.0 Yes (n=8) Full control (77.2%), partial control (12.3%) Olson EJ. et al. 6 Idiopathic RBD and RBD associate with neurological disorders (38) 0.25~1.5 NA Full control (55%), partial control (32%) Lapierre O. et al. 7 Idiopathic RBD (5) 0.5~2 Yes in REM phasic EMG activity RBD, REM sleep behavior disorder; PSG, polysomnography 렘수면행동장애의치료방법이다. 비교적낮은용량인 0.5~ 2.0 mg qd hs에서거의 87~90% 가까이효과를보인다. 5-7 Clonazepam 의효과를가장처음보고한 Schenck CH 등에따르면, 총 57명의환자중, 효과를보인환자는 51명으로 89.5% 에달하였으며, 7 이후 Mayo Clinic series 에서도 6 87% 의효과를보고하였다 (Tabel 1). Clonazepam 치료의부작용으로는아침시간대의진정, 발기부전, 탈모, 두통등이보고되어있으며, 그빈도가낮아치료를유지하기쉽다. 또한 clonazepam 은수면과관련된행동장애를조절할뿐아니라생생하고기분나쁜꿈도줄여주는것으로알려져있다. 8 그러나 clonazepam 을중단하면렘수면행동장애가즉시재발하고, 렘수면행동장애가저절로사라지는현상은거의알려져있지않아평생치료가필요하다. 또한 clonazepam 사용시, 수면무호흡증, 해리장애, 외상후스트레스장애등이악화될수있고, 낙상의위험이증가한다. 렘수면행동장애와감별이필요한몇몇질환에서 clonazepam 에대해부분적인효과가있을수있어, 수면다원검사를시행하지않고 clonazepam 에대한반응을보아진단을확인 Table 2. Polysomnographic data on acute (first night) effects of clonazepam in 8 patients with typical chronic RBD 8 Sleep measures (mean ± SD) The night before clonazepam treatment The night of clonazepam treatment 1 Total sleep time, mins (±39.1) (±76.4) 2 Sleep efficacy, % 75.0(±6.7) 79.4 (±11.7) 3 Sleep latency, mins 40.7 (±41.6) 28.7 (±21.8) 4 REM latency, mins 79.0 (±19.0) 60.5 (±25.8) 5 Stage 1% 10.9 (±10.4) 11.2 (±9.1) 6 Stage 2% 49.7 (±12.5) 52.2 (±10.3) 7 Stage 3/4% 19.8 (±9.0) 19.3 (±9.2) 8 REM % 19.5 (±4.8) 17.3 (±6.1) RBD, REM sleep behavior disorder 하려는시도는오히려진단을그르칠가능성이있다. Clonazepam 은렘수면행동장애환자의비렘수면시나타나는주기사지운동장애에효과가있다는점에착안하여경험적으로사용되기시작한약으로, 렘수면행동장애에대한뚜렷한효과가입증되었으나아직그기전에대해서는알려진바가없다. 다만, clonazepam 투여군에서수면다원검사상여러가지수치에변화가없어 (Tabel 2), 렘수면억제가효과의기전은아닌것으로보인다. Schenck CH 등은 clonazepam 이뇌간에서 phasic locomotor activity 를직접조절하거나, 대뇌피질에작용하여비정상적인꿈을조절함으로써효과를나타낸다는가설을제시하였다. 또한 activation-synthesis model 에근거하여 clonazepam 이뇌간의 dream action pattern generator 와 locomotor pattern generator 를억제함으로써효과를나타낸다는가설도제시하였으나, 8 현재까지증명된바는없다. 2. Melatonin Melatonin 은주로일주기수면장애에사용되어왔으나, 여러가지이유로 clonazepam 치료를지속하기어려운경우의대안으로시도되었다 년 Kunz 와 Bes 가 64세렘수면행동장애남자환자에게 melatonin 을사용하여효과를보고한 9 이후, 몇몇소규모연구에서그효과가보고되었다. Takeuchi 등에 10 의하면총 15명의환자중 13명의환자에게서렘수면행동장애개선효과가나타났다. 몇몇환자에게서는용량에비례하는효과를보였고, 수면다원검사의여러수치중에서는치료전후의 %tonic REM activity 에서의미있는감소를보였다. 환자들의평균최고기초 melatonin 농도가 33.5 pg/ml 로낮았으며, 15명중 10명은 30 pg/ml 로더욱낮은농도를보였다. 이렇게기초 melatonin 농도가낮은환자들에서melatonin 치료의효과가좋았다. Boeve Vol.6, No.1 / June,

3 문혜진 남현우 Table 3. Melatonin treatment data Population studied (n) Dosage (mg) PSG Results Takeuchi N. et al. 10 Idiopathic RBD (15) 3~9 Yes in RBD symptoms (87%), in REM tonic EMG activity Boeve BF. et al. 11 RBD associate with neurological disorders (14) 3~12 (± clonazepam) No RBD, REM sleep behavior disorder; PSG, polysomnography Full control (6/14), markedly improved but not control (4/14) 등에 11 의하면 clonazepam 과 melatonin 의병용시 addictive effect가있음이보고되었다 (Tabel 3). 이러한 melatonin 의효과기전은 melatonin 이렘수면행동장애와관련되어일주기리듬이비동기화된것을일부회복시키기때문이라는주장이있다. 9 Clonazepam과의 addictive effect 에대해서, clonazepam 은주로렘수면의 phasic EMG activity를줄이고 melatonin은 tonic EMG activity 를줄이기때문으로설명한다. 10,11 Melatonin 의부작용으로는망상, 환각, 두통, 아침시간대의진정등이보고되어있다 Pramipexole과 Levodopa 신경영상연구를통해, 렘수면행동장애환자에게서 striatal presynaptic dopaminergic transporter 와의결합이감소하고, 12 nigrostiratal dopaminergic innervation이감소한다는 13 사실이알려졌다. 또한, 렘수면행동장애환자에게서파킨슨병이발생하는경향이있다는점, 4 도파민이상과관련된운동현상인주기사지운동장애가잘발생한다는점은 14 nigrostriatal dopaminergic system의이상에의해렘수면행동장애가발생한다는가설을뒷받침한다. 이러한가설을토대로도파민계약물과 Levodopa 를렘수면행동장애의치료에사용한연구들이있었다. Fantini 등은 8 명의환자를대상으로 pramipexole 치료 (0.5~1 mg/d) 를하였는데, 5명의환자에게서지속적인효과가있다고보고하였다. 15 또한수면다원검사에서 simple motor behavior 가유의하게감소하였고, 렘수면의총시간이감소하는경향이있다고하였다. 이는 pramipexole 이 clonazepam 이나 melatonin 과는달리, 렘수면억제효과가있음을시사한다. 그러나최근에 Kumru 와 Iranzo 등의보고에따르면, 파킨슨병환자에서 pramipexole 이파킨슨증상은호전시켰으나, 렘수면행동장애에는효과가없었다. 16 도파민계약물 의효과를명확히규명하기위한추가연구가필요하겠다. Levodopa 에대해서는, Adrian Tan 등이 3명의환자에대해 levodopa 를사용하여 vivid dream의빈도가줄어들고, 수면시사지의운동과복합운동이감소하였다고보고하였다. 17 Levodopa 가렘수면의시간을줄여렘수면행동장애를조절한다는기전이가설로제시되었으나, 당시연구에는수면다원검사가포함되지않아가설을뒷받침할만한근거가부족하며, 이후현재까지타연구를통해일관된효과가증명된바없다. 4. Carbamazepine 여러정신병에서격하고공격적인행동을조절하는데사용되어온 carbamazepine 이렘수면행동장애조절에도효과를보였다는보고가있다. Bamford 에의하면한명의환자에서 carbamazepine 100 mg tid를투여하여약 75% 의증상호전을보였다고한다. 18 또한이론적으로, 삼환계항우울제는수면해리를유발하여렘수면행동장애를악화시키는것으로되어있으나, carbamazepine 과화학적으로비슷한 imipramine 이 3명의렘수면행동장애환자에게서좋은결과를보였다는보고도있다. 19 저자들은일부환자에게서기존의렘수면행동장애의발생기전과는달리, 변연계에들어오는자극이증가하여렘수면행동장애가발생할수있으며, 이런환자의경우에만 carbamazepine 이나 imipramine 이효과를보인다고설명한다. 5. Donepezil과 rivastigmine 아세틸콜린이렘수면의조절에영향을미칠수있다는연구결과들이보고되면서 21 acetylcholine esterase 억제제를렘수면행동장애의치료에사용해본시도가있었으 26 수면

4 렘수면행동장애의치료 나, 현재로서는그효과가뚜렷하지않다. Ringman 등은 donepezil(10-15 mg qd) 을사용하여렘수면행동장애를효과적으로조절한 3명의환자에대해보고하였다. 20 그러나이후의연구에서는일관된효과가나타나지않았다. 11,21 Rivastigmine에대해서는 dementia with Lewy bodies 환자를대상으로한 case series 에서야간행동장애와수면장애에호전이있었다는보고가있으나렘수면행동장애에대한직접적인효과는보고된바없다 Bilateral subthalamic stimulation 말기파킨슨병환자들이 bilateral subthalamic stimulation 치료를받기시작한이후, 렘수면행동장애증상을포함한수면문제들이어떻게변하였는지를보고한 2개의보고가있었다. Iranzo 등은파킨슨병환자 11명의수면의질과수면다원검사상의수면구조가수술후호전을보였으나, 렘수면행동장애증상은수술전후의차이가없음을보고하였다. 24 Arnulf 등은 bilateral subthalamic stimulation 치료이후, 야간운동불능증과이른아침의근육긴장이상증이호전되었고총수면시간이연장되었으며수면이후각성 (WASO) 이줄어들었으나, 주기사지운동장애나렘수면행동장애증상은지속되었다고보고하였다. 25 결론렘수면행동장애의일차선택약제는 clonazepam(0.5~2 mg qd hs) 이나, clonazepam 을복용하기어려운환자, 예를들어인지장애환자, 수면무호흡증환자, 낙상위험이높은환자, clonazepam 에효과를보이지않는환자, 부작용으로사용이어려운환자등에게는 melatonin(~12 mg까지 ) 을시도해볼수있다. Clonazepam 과 melatonin 에모두반응을보이지않을경우, pramipexole 이나 acetylcholine esterase inhibitor 가대안이될수있으나아직까지는일관된성적을보이지않고있어향후좀더연구가필요하다. 약물치료와더불어수면장소의환경을안전하게조절하는것도외상을방지하는중요한방법이된다. 또한렘수면행동장애를유발또는악화시킬수있는삼환계항우울 제, 26 MAO 억제제, 27 SSRI 28 등은주의하여처방하고, 초콜릿등의과잉섭취를피하도록교육하는것이좋다. 29 REFERENCES 1. Atlas Task Force of the American Sleep Disorders Association (ASDA). The International Classification of Sleep Disorders - Diagnostic and Coding Manual. Minnesota: Rochester; Nightingale S, Orgill JC, Ebrahim IO, de Lacy SF, Agrawal S, Williams AJ. The association between narcolepsy and REM behavior disorder (RBD). Sleep Med 2005;6: Boeve BF, Silber MH, Fermann TJ, Lucas JA, Parisi JE. Association of REM sleep behavior disorder and neurodegenerative disease may reflect an underlying synucleinopathy. Mov Disord 2001;16: Schenck CH, Bundlie SR, Mahowald MW. REM behavior disorder (RBD): delayed emergence of parkinsonism and/or dementia in 65% of older men initially diagnosed with idiopathic RBD, and an analysis of the minimum and maximum tonic and/or phasic electromyographic abnormalities found during REM sleep. Sleep 2003;26 (Suppl):0794.M. 5. Schenck CH, Hurwitz TD, Mahowald MW. REM sleep behaviour disorder: an update on a series of 96 patients and a review of the world literature. J Sleep Res 1993;2: Olson EJ, Boeve BF, Silber MH. Rapid eye movement sleep behavior disorder: demographic, clinical and laboratory findings in 93 cases. Brain 2000;123: Lapierre O, Montplaisir J. Polysomnographic features of REM sleep behavior disorder: development of a scoring method. Neurology 1992; 42: Schenck CH, Mahowald MW. Polysomnographic, neurologic, psychiatric, and clinical outcome report on 70 consecutive cases with REM sleep behavior disorder (RBD) : sustained clonazepam efficacy in 89.5% of 57 treated patients. Cleve Clin J Med 1990;57(Suppl):S9-S Kunz D, Bes F. Melatonin effects in a patient with severe REM sleep behavior disorder: case report and theoretical considerations. Neuropsychobiology 1997;36: Takeuchi N, Uchimura N, Hashizume Y, et al. Melatonin therapy for REM sleep behavior disorder. Psychiatry Clin Neurosciences 2001;55: Boeve BF. Melatonin for treatment of REM sleep behavior disorder in neurologic disorders: results in 14 patients. Sleep Med 2003 Jul;4(4): Eisensehr I, Linke R, Noachtar S, Schwarz J, Gildehaus FJ, Tatsch K. Reduced striatal dopamine transporters in idiopathic rapid eye movement sleep behaviour disorder. Comparison with Parkinson s disease and controls. Brain 2000;123: Albin RL, Koeppe RD, Chervin RD, et al. Decreased striatal dopaminergic innervation in REM sleep behavior disorder. Neurol- Vol.6, No.1 / June,

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Video Analysis of Dream-Enacting Behaviors in RBD Patients 양하다단순히누군가와대화하듯이중얼거리는잠꼬대에 서웃거나욕설을하거나누군가와싸우듯이소리지르고외 치는증상싸우거나쫓기는꿈과함께발로차는듯한행동 주먹으로때리는듯한행동과같은과격한

Video Analysis of Dream-Enacting Behaviors in RBD Patients 양하다단순히누군가와대화하듯이중얼거리는잠꼬대에 서웃거나욕설을하거나누군가와싸우듯이소리지르고외 치는증상싸우거나쫓기는꿈과함께발로차는듯한행동 주먹으로때리는듯한행동과같은과격한 ORIGINAL ARTICLE J Sleep Med 2015;12(2):47-52 pissn 2384-2423 / eissn 2384-2431 http://dx.doi.org/10.13078/jsm.15009 Video Polysomnographic Analysis of Dream-Enacting Behaviors in the Patients with REM