하지불안증후군의진단및치료 정기영 Hanyang Med Rev 2013;33: pissn X eissn 고려대학교의과대학신경과학교실 Diagnosi

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1 하지불안증후군의진단및치료 정기영 pissn X eissn 고려대학교의과대학신경과학교실 Diagnosis and Treatment of Restless Legs Syndrome Ki-Young Jung Department of Neurology, Korea University College of Medicine, Seoul, Korea Restless legs syndrome (RLS) is a sensorimotor neurologic disorder, in which the primary symptom is a compelling urge to move the legs accompanied by unpleasant and disturbing sensations in the legs. RLS is relatively common, affecting 2.5 to 15% of the general population, with prevalence rates increasing alongside age. Sleep disturbance is the most common symptom owing to RLS leg symptoms. In addition, daytime dysfunction, cognitive decline, and mood disturbance are also common in patients with RLS. Iron and dopamine are implicated in the pathophysiology of RLS, however, the underlying pathophysiology of RLS is still not fully understood. The diagnosis can be made based on the symptom characteristics, differential diagnosis is important because many conditions could mimic RLS symptoms. Dopaminergic agents are recommended for the first line treatment of RLS. Alpha2delta anticonvulsants such as gabapentin and pregabalin are also effective for controlling RLS symptoms. Key Words: Restless Legs Syndrome; Diagnosis; Therapeutics; Dyssomnias Correspondence to: Ki-Young Jung 우 , 서울시성북구인촌로 73 고려대학교안암병원신경과 Department of Neurology, Korea University Anam Hospitar, 73 Inchon-ro, Seongbukgu, Seoul , Korea Tel: Fax: jungky@korea.ac.kr Received 19 August 2013 Revised 14 October 2013 Accepted 21 October 2013 This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 서론하지불안증후군 (restless legs syndrome, RLS) 은다리를움직이고싶은견딜수없는충동이나타남과함께다리에매우불편하고불쾌한감각증상이동반되는감각운동신경질환이다. 이런감각운동증상은안정시에주로발생하고, 야간에악화되며, 수면장애및주간의업무장애, 우울증등을흔히동반하고만성적인경과를보인다 [1]. 본론 1. 증상다음 4가지가하지불안증후군의필수증상이다 [2]. 1) 다리를움직이고싶은충동 (urge to move) 이있으며, 억제하려고해도억제하기가힘들고, 결국은움직여야마음이편안해진다고 호소한다. 많은환자에서다리가의식적으로억제되지않는짧게수축하는현상이나타나고이불수의적운동이 20-40초정도의간격으로일정하게반복되는데, 이를주기적다리움직임 (periodic leg movements, PLM) 이라고한다. PLM은주로야간수면중에잘나타나며이를 periodic limb movements in sleep (PLMS) 라고하고, 깨어있을때도나타날수있다 (periodic limb movements in wake, PLMW). 다리의움직이고싶은충동과함께다리에말로표현하기어려운불편한감각증상이동반되는경우가흔하다. 약 85% 정도의환자에서불편한감각증상을호소하며, 대체로다리의안쪽깊은곳에서느껴진다고호소하는경우가많다. 환자들은 벌레가기어간다, 스멀거린다, 간지러운느낌, 터질것같은느낌, 쥐어짜는느낌 등다양하게묘사를하며, 아프다고표현하는경우도약 50% 정도에서호소한다는보고도있다. 감각증상은주로양하지에대칭적으로있는경우가전형적이며, 하지중에서도종아리부위가가장많이침범되며, 정강이, 허벅지부위가다음으로흔히 Hanyang University College of Medicine

2 정기영 하지불안증후군의진단및치료 침범된다. 다리이외에도몸통이나상지에감각증상이나타나는경우가있는데, 병의경과가오래되었거나, 중증인경우에보일수있다. 2) 다리를움직이고싶은충동은가만히있는안정상태에서주로느끼며, 오래움직이지않을수록불편감이점차증가한다. 3) 다리의감각운동증상은다리를움직여주면일시적으로호전을보이는데, 다리를능동적으로움직이지않고주무르거나비비거나당기거나하여도일시적완화가된다. 이러한완화는일시적이어서환자는지속적으로다리를움직이거나주물러야하는데, 이로인하여수면장애가흔히동반된다. 환자에따라서는자신이고안한특이한자세나방법을이용하여증상을완화시키려고노력을하며, 때로는매우이상한자세를취하기도한다. 4) 하지의감각및운동증상은주간에는나타나지않고, 주로저녁에시작되는일주기변동성을보이는것이특징이며, 초기에는주로잠자려고누울때발생한다. 주간에는, 특히초기에는거의증상이나타나지않으나, 증상이악화되는경우에는증상의발현시간이점차빨라지면서중증인경우에는초저녁이나심지어는오후나오전에도증상을느끼게된다. 도파민작용제를투여하는경우에초기에는증상이잘조절되나, 장기간사용시에증상의발현시간이빨라지고, 증상분포가넓어지는증강현상 (augmentation) 이나타날수있다 ( 치료참조 ). 수면장애는하지불안증후군환자의상당수에서호소하는증상이며, 내원하는환자의상당수가하지불안증후군과함께수면장애가동반되어이로인하여내원하는경우가많다. 수면장애는잠들기가어려운경우가가장흔하며, 잠이들어도자주깨고다시잠들기어려운불면증을호소하는경우가많다. 따라서, 환자는전체수면시간이부족하고아침에일어나도개운하지않고, 낮에피로감을많이호소하나, 주간졸림증은드물다. 주간업무능력의저하도비교적흔하게호소하는데, 장시간안정상태로있는경우에는주간에도감각운동증상이나타날수있으며, 수면장애로인한주간피로감, 그리고흔히동반되는우울증등이원인이될수있다 [3,4]. 하지불안증후군환자는일반인에비해서불안및우울증이 2-3 배가량높으며, 신체화경향을포함하여다양한정신신체증상을호소한다 [5]. 결과적으로, 하지불안증후군환자는일반인에비해삶의질이현저히저하되어있으며, 당뇨, 퇴행성관절염등만성질환에비해서도삶의질이대등하거나낮은것으로보고되었다. 2. 수면중주기적사지움직임증 (periodic limb movements in sleep, PLMS) PLMS는짧게지속되는다리의움직임이불수의적으로주기적으로반복되는것을말한다. 주로수면중에발생하지만, 깨어있을때에도나타날수있으며, 하지뿐만아니라상지에도나타날수있다. 수면다원검사 (polysomnography) 에서앞정강근 (tibialis anterior) 에부착한근전도의활성이 0.5초에서 10초이내로수축하고, 이런움직임이 5-90초사이의간격으로나타나며, 적어도 4회이상연속적으로나타날때로정의한다 [6]. PLMS는하지불안증후군의 90% 에서관찰되며, 하지불안증후군의진단을지지하는소견에해당된다. 또한, 하지불안증후군의중등도와어느정도의상관관계를보인다. PLMS는각성 (EEG arousal) 및수면분절을초래할수있으며, 뇌파변화가보이지않는다하더라도심박수및혈압상승과연관된다. 아직 PLMS의발생기전은정확히밝혀지지않았으나, 최근의연구에의하면뇌파에서델타파및세타파가다리움직임에선행하여증가하며, 이어서다리움직임과함께교감신경활성에따른심박상승이동반된다 [7]. PLMS는수면장애를전혀호소하지않는정상인의 4-11% 에서관찰되고, 연령이증가함에따라서그빈도가증가한다. 또한, PLMS 는하지불안증후군에서높은동반율을보이지만렘수면행동장애 (REM sleep behavior disorder), 폐쇄성수면무호흡증및기면증등다른수면질환에서도자주관찰된다 [8]. 3. 진단하지불안증후군은진단에도움이되는생물표지자 (biomarker) 가아직까지없는실정으로, 환자가주관적으로호소하는증상에의존하여진단한다. 1995년 International Restless Legs Syndrome Study Group (IRLSSG) 에서진단기준을마련하였고, 2003년에수정되었으며, 2012년에다시수정안이발표되었으나큰변화는없다 [2]. 위증상편에서기술한 1-4) 의특징이모두존재하고, 증상을설명할만한다른질환이없어야하지불안증후군으로진단할수있다 (Table 1). 특히, 4가지특징이모두존재한다고하더라도많게는 16% 에서하지불안증후군이아니라고하는연구가있으므로, 하지불안증후군을흉내내는다른질환 (RLS mimics) 의배제가매우중요하다 [9]. 따라서, 진단은경험이많은전문가의자세한문진과신경진찰에의해서이루어져야한다. 진단도구로는 Hopkins telephone diagnostic interview (HTDI) 가가장많이이용되며, 민감도 97%, 특이도 92% 로신뢰도가잘정립되어있다 [10,11]. 중등도를평가하기위해서는 International Restless Legs Syndrome Study Group Rating Scale (IRLS) 이널리이용된다. 하지불안증후군의원인을확인하기위해서는철분상태, 빈혈, 당뇨, 만성신질환에대한검사가필요하며, 말초신경질환이의심되는경우에는신경전도검사를시행한다. 수면다원검사는하지불안증후군을진단하는데필수적인것은아니나, PLMS의유무및정량화, suggested immobilization test (SIT) 를시행할수있으며, 동반된다른수면장애가의심될경우에는도움이될수있다. 4. 감별진단다리의통증, 자세불편감 (positional discomfort), 경련 (cramp), 217

3 Ki-Young Jung Diagnosis and Treatment of Restless Legs Syndrome Table 1. Revised International Restless Legs Syndrome Study Group (IRLSSG) diagnostic criteria (2012) Essential diagnostic criteria (all must be met) 1. Urge to move the legs usually but not always accompanied by or felt to be caused by uncomfortable or unpleasant sensation in the legs 2. The urge to move the legs and any accompanying unpleasant sensations begin or worsen during period of rest or inactivity 3. The urge to move the legs and any accompanying unpleasant sensations are partially or totally removed by movement 4. The urge to move the legs and any accompanying unpleasant sensations during rest or inactivity only occur or are worse in the evening or night 5. Above features are not solely account for as symptoms primary to another medical or a behavioral condition (e.g. myalgia, venous stasis, leg edema, arthritis, leg cramps, positional discomfort, habitual foot tapping etc.) Specifiers for clinical course of RLS A. Chronic persistent RLS: > 2/wk B. Intermittent RLS: < 2/wk but at least 5 life time events Specifiers for clinical significance of RLS The symptoms of RLS cause distress or impairment in social, occupational, educational or other important areas of functionality by the impact on sleep, energy/vitality, daily activities, behavior, cognition or mood. RLS, restless legs syndrome. 관절염, 척추질환, 하지정맥류등이다리에불편감을초래할수있으면서움직임에일시적인호전을보일수있으므로감별을해야한다 [12]. 5. 역학성인에서의하지불안증후군의유병률은전세계적으로약 5-15% 정도로보고되나, 인종이나국가별로다소차이가있다 [13]. IRLSSG 필수진단기준 4항목을바탕으로조사한연구에서는 % 정도로보고되나주당 2회이상또는중등도이상의증상이있는경우에는 % 로나타났다. 북미와유럽의하지불안증후군유병률은아시아보다높으며, 여성이남성에비해유병률이더높으며, 나이가들수록높다. 국내연구를살펴보면, IRLSSG 필수진단기준을이용한연구와 HTDI를이용한연구에서는유병률이 % 로보고되었으며, 이중유병률이 0.9% 로낮게보고된연구를제외하면유병률이 % 로외국의연구와유사한수준이다 [14,15]. RLS는증상발현의나이에따라조기발병형 (early onset) 과후기발병형 (late onset) 으로나눌수있다. 조기발병형은 45세이전에증상이시작되는군으로보이는경우가많으며후기발병형에비해진행이느리다. 후기발병형은말초신경염과관련이많아두가지표현형은병태생리적으로다르다고보고있다. RLS는연관된질환의유무에따라원발성 RLS와이차성 RLS로나눌수있는데원발성 RLS는이차성 RLS에비해가족력을보이는경우가많다. 이차성 RLS는임신, 빈혈, 만성신부전, 철결핍성빈혈및말초신경염등의질환에서흔히동반된다. 하지불안증후군은섬유근통 (fibromyalgia), 과민성대장증후군 (irritable bowel syndrome), 편두통등중추감작 (central sensitization) 과연관이있는질환에서정상인에비해동반이환이매우높게나타난다 [16]. 6. 병태생리철분과도파민이하지불안증후군의병태생리에중요하다고알 려져있으나아직정확한기전은명확하지않다 [17]. 1) 철분과하지불안증후군하지불안증후군환자에서철분결핍이일반인보다높고, 철분이부족한임신상태, 만성콩팥질환및혈액공여자에서하지불안증후군의유병률이높고, 철분을정맥주사하였을때하지불안증후군증상이호전된다. MRI 연구에서흑질의철분농도가대조군에비해서유의하게감소되었다. 하지불안증후군환자는혈청의페리틴 (ferritin) 이감소되어있고, 트랜스페린 (transferrin) 이증가되어있으며, 뇌척수액에서도마찬가지소견을보인다. 조기발병형에서혈청의페리틴은증상의중등도와유의한상관관계를보였다. 철분의이동에관여하는다양한단백질의이상소견을보이고, 철분이도파민시스템의조절에관여하고, 철분부족이도파민의일주기변동을증가시킴으로써하지불안증후군의발현에관여할것으로생각되고있다. 그러나혈청의철분상태와뇌척수액철분농도가정확히비례하지않으며, 개체간의차이가심한점은말초보다는혈액뇌장벽 (blood-brain barrier) 혹은뇌세포내의복잡한유전조절에의해서조절됨을시사한다 [18]. 2) 도파민기전도파민및도파민작용제가하지불안증후군에임상적으로매우효과적이며, 도파민길항제를투여하였을때증상이악화된다는점은도파민이하지불안증후군의발생기전에관여된다는것을시사한다. 이전에는중추신경계의도파민기능저하가설이제안되었으나, 뇌척수액연구에서는오히려도파민의생성이증가되는소견을보이고있으며, 방사성동위원소연구에서는엇갈리는결과가보고되어, 도파민의기능저하인지혹은기능항진에의한것인지는논란이많다. 최근에는도파민의일주기변동이항진되어야간에도파민의농도가정상적으로낮아지는정도가심해져서일시적인도파민기능저하로증상이발생한다는가설이지지를받고있다

4 정기영 하지불안증후군의진단및치료 7. 치료하지불안증후군의치료는환자가호소하는증상의강도와이러한증상이환자의수면및낮활동에미치는영향등을고려하여치료를시작하여야한다. 치료는크게비약물치료와약물치료로나누며, 두가지를병행하는것이바람직하다. 1) 비약물치료증상이경미하거나, 드물게발생하는경우에는비약물적치료만으로도조절이가능하다. 증상이심한경우라도약물적치료와함께병행하는것이좋다. 수면습관을규칙적으로지키고, 지나친음주, 카페인음료섭취및과식은증상을악화시키므로삼가는것이좋다. 자기전가벼운운동이나스트레칭, 맨손체조, 다리마사지등이도움이된다. 항도파민제제, 항히스타민제및항우울제는증상을악화시킬수있으므로피하도록한다. 2) 약물치료도파민작용제, 벤조디아제핀제, 일부항경련제가주로사용되며, 철분투여도중요한치료중의하나이다. 증상의중등도및주로호소하는증상에따라적절히선택해서처방하며 [19], 단일요법이원칙이나, 도파민제제를기본으로다른제제를병용하여처방할수있다 [20,21]. (1) 도파민작용제도파민 D2/D3 수용체작용제는하지불안증후군의감각증상, 움직이고싶은충동및 PLMS 개선에효과가우수하여일차치료제로사용한다. 현재 non-ergot 제제인 pramipexole (Mirapex ), ropinirole (Requip ), 그리고패취제제인 rotigotine (Neupro ) 이식약청승인된약품이다 (Table 2). 세가지약제모두효과가우수하며대개투여첫날부터증상개선이나타난다. 증상이주로저녁에잘때나타나므로, 투약은잠들기 1-2시간전에하루 1회투여로시작한다. 투약시간은환자의증상발생시각에따라조정을하여야한다. 가령증상이심해지고발생시각이빨라져서오후 8시경부터시작된다면오후 7시경에투약을지시하는것이증상조절에보다더효과적이다. 도파민작용제를수개월이상장기간복용하는경우에, 환자의증상이악화되는증강현상 (augmentation) 이나타날수있다 [22]. 증강현상은증상의발생시각이빨라지거나, 안정후에증상이발생하는시간이짧거나, 증상이더악화되면서다리이외의신체부위에증상이나타나는것이특징이다. 39개월간추적한연구에의하면, 환자의 48% 에서증강현상이발생하였다 [23]. 증강현상은도파민작용제의용량이많거나하지불안증후군가족력이있는경우에더잘발생한다. 증강현상이나타나는경우에, 용량을오히려줄이거나, 항경련제나아편양제제를병용하거나치환하여사용한다. 하지불안증후군은장기간치료를요하므로, 가장효과적인최소용량으로유지하고, 증상이상당히개선된경우에는간헐적인투약요법으로전환하는것이증강현상을예방할수있는하나의방법이다. (2) 벤조디아제핀제불면증이심하게동반된하지불안증후군인경우에벤조디아제핀제제가도움이될수있으며, Clonazepam이대표적으로사용된다 mg을취침전에투여하며, 하지의감각증상과뇌파의각성을효과적으로감소시켜준다. 그러나, 도파민제제와는달리 PLMS 에는큰효과가없다 [24]. (3) 항경련제다양한항경련제가하지불안증후군의감각증상, 수면장애및 PLMS를개선시켜준다. 예전에는 carbamazepine을처방하였으나, 현재는 gabapentin 및 pregabalin 이효과가우수한것으로알려졌다. 특히, 통증성의감각증상을주로호소하는환자에게효과가좋지만, 전반적인증상개선효과가우수하다. (4) 아편양제제심한하지불안증후군이나증강현상이나타난경우에적응이된다. 대표적인약물로는 oxycodone, propoxyphene, methadone 및 tramadol이있다. (5) 철분제제철분제제가하지불안증후군에효과가있다는보고는있으나, 아직까지많이사용되고있지는않다. 철분은경구투여와정맥주사투여가가능하며, 페리틴수치가 50 ug/l 미만인경우에는투여하는것이도움이된다. Table 2. Dopaminergic agents for restless legs syndrome Half life Time to peak Receptor Therapeutic dose Comments Pramipexole 6-10 hr 2-3 hr D3> D mg Renal elimination Ropinirole 4-6 hr 1 hr D3> D2> D mg Hepatic elimination Rotigotine 6 hr* 16 hr D3> D2> D1 1-2 mg Transdermal, renal (71%), Gastrointestinal (23%), no drug interaction *Median terminal elimination half-life amounts to 6 hr

5 Ki-Young Jung Diagnosis and Treatment of Restless Legs Syndrome 결론 하지불안증후군은성인의 5-10% 정도로유병률이매우높고, 나 이가들수록유병률이증가하며, 수면장애뿐만아니라, 주간기능 저하, 인지기능저하및우울증이잘동반되는만성신경질환이다. 하지불안증후군은특징적인증상으로의심하고, 유사한질환을 배제함으로써진단이가능하며, 도파민작용제및항경련제에효과 적으로반응하므로진단을하면환자들에게큰도움을줄수있다. ACKNOWLEDGEMENT This study was supported by a grant from the National Research Foundation of Korea (No ). REFERENCES 1. Trenkwalder C, Paulus W. Restless legs syndrome: pathophysiology, clinical presentation and management. Nat Rev Neurol 2010;6: Allen RP, Picchietti D, Hening WA, Trenkwalder C, Walters AS, Montplaisi J. 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: Choi JW, Lee JK, Ko D, Lee GT, Jung KY, Kim KH. Fronto-temporal interactions in the theta-band during auditory deviant processing. 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untitled pissn 1976-8753 eissn 2383-9910 Brain & NeuroRehabilitation Vol. 9, No. 1, March, 2016 http://dx.doi.org/10.12786/bn.2016.9.1.25 Review Article 하지불안증후군의진단과치료 경북대학교의과대학경북대학교병원재활의학교실 민유선 Diagnosis and Treatment