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 of Restless Legs Syndrome Yu-Sun Min, M.D. Department of Physical Medicine and Rehabilitation, Kyungpook National University Hospital, Kyungpook National University School of Medicine Restless legs syndrome (RLS) is a neurological disorder characterized by an irresistible urge to move one's body to stop uncomfortable or odd sensations. It most commonly affects the legs. Moving the affected body part, such as walking or stretching provide relief the urge to move the legs and any accompanying unpleasant sensation partially or totally. RLS is relatively common, affecting 5 to 15 % of the general population, with prevalence rates increasing alongside age. Restless legs syndrome can lead to sleep-onset or sleep-maintenance insomnia, and occasionally excessive daytime sleepiness, all leading to significant morbidity. Dopaminergic systems are known to be strongly related with RLS that are closely linked to CNS iron homeostasis. Besides defective dopaminergic system that is closely related with iron metabolism, genetic factors play a role in early-onset individual with a positive family history. The diagnosis can be made based on the symptom characteristics, differential diagnosis is important because many conditions could mimic RLS symptoms. Dopamine agonists (DAs) have been considered the first-line therapy, but with the growing appreciation of problems associated with long-term treatment, particularly augmentation and impulse control disorder, alpha-2-delta drugs, such as gabapentin, are now considered the first line of treatment in patients with troublesome RLS. In more severe cases, a combination therapy may be required. (Brain & NeuroRehabilitation 2016; 9: 25-30) Key Words: Restless Legs Syndrome, Dopamine agonist, Augmentation, Sleep disturbance 서론 하지불안증후군 (restless legs syndrome, 이하 RLS) 은다리를움직이고자하는충동과함께다리에매우불편하고불쾌한감각증상이동반되는감각운동신경질환이다. 성인에서의 RLS는전세계적으로약 5 15% 정도로보고되고있지만, 인종이나국가별로차이가있다. 1 국내에서도유병률이 6.5 8.3% 로외국의연구와유사한수준으로보고되었다. 2 대체적으로나이가들어감에따라서더많이발생하는경향이있지만, 발병연령은다양하다. 중증도가심한 RLS 에서는 33 40% 에서 20대에처음증상이발생하지만대 Correspondence to: Yu-Sun Min, Department of Physical Medicine and Rehabilitation, Kyungpook National University Hospital, Kyungpook National University School of Medicine, 807, Hoguk-ro, Buk-gu, Daegu 41404, Korea Tel: 053-200-2167, Fax: 053-200-2028 E-mail: ssuni119@naver.com 개진단은그이후에이루어진다. 여자에서남자보다 2:1 의비율로더많이발생한다. 이는임신과관련이있을것으로생각되며, 출산하지않은여자는남자와발생률이같다. 3 발병시연령을기준으로조기발병형 (early onset) 과, 후기발병형 (late onset) 형으로나눈다. 조기발병형은 45세이전에증상이시작되며, 후기발병형에비해서진행이느리다. 후기발병형은말초신경염과관련성이높게나타난다. 따라서이둘의병태생리는다를것으로생각된다. 원인질환의유무에따라서원발성 RLS와이차성 RLS로나눈다. 원발성 RLS는 25 75% 에서가족력을가지고있으며, 가족력이있는 RLS는 45세이전에조기발병되는경우가흔하며, 천천히진행하는양상을보인다. 세대가내려감에따라서증상의발현시점이빨라지는유전적표현촉진현상 (genetic anticipation) 도관찰된다. 원발성 RLS와달리이차성 RLS는동반질환의유병률이높다. 이차성 RLS에서는철결핍성빈혈, 임신, 말기신부전, 말초신경염등의질환이흔히동반된다. 4 엽산 (folate), 마그네슘 (mag- 25
Brain & NeuroRehabilitation 2016; 9: 25-30 nesium) 결핍증, 아밀로이도시스 (amyloidosis), 당뇨 (diabetes mellitus), 요천추신경근병증 (lumbosacral radiculopathy), 류마티스관절염, 쇼그렌신드롬, 요독증, 비타민 B-12 결핍증과관련해서도나타날수있다. 1,5 이중임신은 RLS 를유발하는요소중하나이다. 임신한여성의약 25 40% 에서 RLS 증상을나타내며, 출산후몇주이내로증상이사라진다. 출산시 RLS 증상을나타냈던여성은추후 RLS가발생할위험이 4배높아진다. 6 말기신부전환자의 25-40% 에서 RLS가발생한다. 처음에는투석중다리가불편한증상으로나타나며, 신장이식후에증상이호전되는경향을보인다. 항도파민제제, 항히스타민제, 항우울증제, 술, 카페인, 베타차단제같은약물은증상을더악화시킬수있다. 8 본론 1) 증상 RLS의필수증상은다음 4가지이다. 9 1) 다리를움직이고싶은충동이있으며, 불편하고불쾌한감각증상이다리에서나타난다. 보통팔과몸통보다는다리의불쾌한감각을호소하며, 바늘로찌르는느낌, 스물스물기어가는느낌, 벌레가기어가는느낌, 간지러운느낌, 터질것같은느낌, 쥐어짜는느낌 등으로다양하게표현된다. 감각증상은양하지에대칭적으로분포하고, 하지중에서는종아리부위가가장많이침범되며, 그이외에서정강이허벅지부위에증상이나타날수있다. 또한증상이오래지속된환자에게서는다리뿐만아니라, 몸통이나상지에감각증상이나타나기도한다. 2) 다리를움직이고싶은충동은가만히있거나쉬는상태에서주로느끼며, 오래움직이지않으면불편감이증가한다. 이때쉰다는것은육체적으로가만히있는다는의미뿐만아니라정신적으로긴장이풀린상태를의미한다. 신체적으로휴식시간이충분이길다면증상이유발되어야한다. 3) 다리의감각운동증상은다리를움직여주면나아진다. 주무르거나비비거나당겨도완화된다. 운동에대한반응이있다는것으로논쟁등정신적인활동이있어도증상이호전되는특징이있다. 이러한완화는일시적이기때문에지속적으로다리를주무르거나움직여야하므로, 수면장애가흔히동반된다. 4) 증상은주간보다저녁이나밤에시작되는일주기변동성을보인다. 증상이악화되는경우에는증상의발현시간이오후혹은초저녁으로빨라진다. 이러한일주기양상 을보이는것은도파민과철분의일주기변화와야간멜라토닌증가와관련이있다. 도파민작용제를장기간투여할경우에는증상의발현시간이빨라지고, 증상분포가넓어지는증강현상 (augmentation) 이나타날수있다. 상당수의환자가수면장애를호소하며, 이를주소로내원하기도한다. 잠을쉽게들지못하거나, 수면중잠에서깨는경우다리증상으로다시잠들기가어렵다. 이런이유로 RLS는불면증과주간졸음을유발하며나아가삶의질을낮추고불안및우울증등의정동장애를유발한다. 3,10 편두통 (migrane) 및긴장성두통 (tension-type headache) 의두통을호소하기도한다. 학습및기억력의장애도보고되고있으며이는야간수면의질저하에따른 2차적인증상일것으로생각된다. 11 수면중주기적사지움직임증 (periodic limb movements in sleep, PLMS) 는주기적으로반복되는다리의불수의적인움직임이특징이다. 13 PLMS는수면다원검사 (polysomnography) 에서앞정강근 (tibialis anterior) 의근전도활성이 0.5 5초동안지속되고, 이런움직임이 5 90초사이간격으로나타나며, 적어도 4회이상연속적으로나타날때로정의한다. RLS 환자의 85% 90% 환자에서수면중주기성다리의움직임이있고이는 RLS 진단을지지하는소견이되며, RLS 의중증도와상관관계를보인다. 하지만, 수면장애를전혀호소하지않는정상인의 4 11% 에서 PLMS가관찰되며, 렘수면행동장애 (REM sleep behavior disorder), 폐쇄성수면무호흡증및기면증등다른질환에서도자주관찰된다. 14 2) 병태생리철분과도파민시스템의이상및유전적요인이병태생리와관련이있다. 15,16 RLS 환자는철분결핍이일반인보다많고, 말기신장질환, 임신, 철결핍성빈혈에서 RLS 유병률이높은데, 이는모두철분부족과연관되어있다. 철분이부족한 RLS 환자에서철분을정맥주사하면증상이호전됨을보인다. 흑질 (substantia nigra) 의철분농도가대조군에비해서유의하게감소되어있음이뇌 MRI 검사상확인되었다. 혈청및뇌척수액에서는 RLS 환자에서페리틴 (ferritin) 의감소및트랜스페린 (transferrin) 의증가가관찰되었다. 조기발병형 RLS에서는혈청페리틴농도와증상의중등도와유의한상관관계를가진다. 이는철분부족이 RLS와밀접한관련이있음을시사하는소견이다. RLS 환자에서도파민및도파민작용제가증상완화에매우효과적이며, 도파민길항제를투여하면악화소견을보이는것은도파민시스템의이상이 RLS를유발할수있 26
민유선 : 하지불안증후군의진단과치료 음을보여준다. RLS 환자의뇌척수액에서도파민생성이증가되는소견을보이는반면뇌 SPECT를이용한연구에서는도파민 D2 리셉터의저하가발견되어, 도파민의기능저하에의한것인지기능항진에의한것인지는아직정확히밝혀지지않았다. 최근에는도파민의일주기변동이항진되어야간도파민농도가낮아지는정도가심해지므로일시적인도파민기능저하로증상이발생한다는가설이설득력을얻고있다. 철분과도파민의상관성에대해서는여러연구들이있다. 철분부족은도파민기능이상과밀접한관련이있다. 흑색질 (substantia nigra) 에있는도파민세포의철분이용이떨어지면세포기능이저하되어선조체 (striatum) 에대한도파민활동이줄어든다. 또한철분이부족하면도파민의일주기변동을증가시키므로 RLS의증상을나타낸다고추정한다. 그러나혈청의철분상태가뇌척수액과정확히일치하지않으며, 개체간의차이도심해서 RLS 의발현이혈액뇌장벽 (blood-brain barrier) 혹은뇌세포내의복잡한유전조절과관련이있을것으로생각된다. 17 Ekbom이 RLS의유전적영향에대해언급한이후에많은연구가있었다. 일차성 RLS의가족력과이른발병연령은및유전적감수성 (genetic susceptibility) 을시사한다. 18 현재까지유전자는 12q, 14q, 9p, 20p, 4q, 17p 등의다양한염색체부위 (chromosomal loci) 에위치하고있으며, 상염색체우성혹는열성양식으로유전된다. 16,18 3) 진단 RLS의진단은임상적인증상을바탕으로 4가지기준을모두만족하면진단되지만감별진단및이차성 RLS를판단하고, 향후치료의지침을결정하기위해좀더정확한검사도구 ( 설문지 ) 등이사용된다. International Restless Legs Syndrome Study Group (IRLSSG) 에서 1995년진단기준을마련하였고, 2003년, 2012년에수정안이발표되었지만이전과큰변화는없으며, DSM-5 진단기준과동일하다 (Table 1). 증상편에서기술한 4가지증상이존재하면서, 근육통, 정맥류, 하지부종, 관절염, 경련 (cramps), 자세불편함 (positional discomfort), 습관적발두드림 (habitual foot tapping) 에의한것이아니어야한다. International Classification of Sleep Disorders 2 nd Edition (ICSD-2) 는위의진단기준과비슷하지만증상의빈도및기간은기술되지않은차이점이있다. 4가지특징이모두존재한다고하더라도 16% 에서 RLS이아니라는보고도있으므로, 다른질환을배제하는것이매우중요하다. 19 진단도구로는 Hopkins telephone diagnostic interview (HTDI) 가이용되며, 신뢰도가높다. 20 중증도평가는 International Restless Leg Syndrome Study Group Rating Scale (IRLS) 가사용된다. RLS가의심되는모든환자는철분에대한검사가중요한데, iron level, ferritin, transferrin, total iron binding capacity (TIBC) 가추천된다. 21,22 이차성 RLS가의심되거나치료에반응이없거나신경학적검사상이상소견이발견되면 CBC, BUN, creatine, fasting blood glucose, magnesium, thyroid-stimulating hormone (TSH), vitamin B-12, folate 등의추가검사를한다. 그리고, 말초신경염이나, 신경근병증등이의심되는환자는근전도검사를시행을고려한다. 23 수면다원검사 (Polysomnography) 는제한적으로시행되는데, 1) RLS의진단이확실하지않을때, 2) RLS 환자에서수면장애가심하게동반될때, 3) 수면무호흡증이동반되거나의심될때, 4) PLMS 이동반될때선택적으로실시할수있다. 4) 치료증상의중증도, 수면및낮활동에미치는영향을고려 Table 1. International Restless Legs Syndrome Study Group (IRLSSG) Consensus Diagnostic Criteria for Restless Legs Syndrome (RLS) Essential diagnostic criteria (all must be met): 1. An urge to move the legs usually but not always accompanied by, or felt to be caused by, uncomfortable and unpleasant sensations in the legs. 2. The urge to move the legs and any accompanying unpleasant sensations begin or worsen during periods of rest or inactivity such as lying down or sitting. 3. The urge to move the legs and any accompanying unpleasant sensations are partially or totally relieved by movement, such as walking or stretching, at least as long as the activity continues. 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 than during the day. 5. The occurrence of the above features is not solely accounted 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). Specifiers for clinical course of RLS: A. Chronic-persistent RLS: symptoms when not treated would occur on average at least twice weekly for the past year. B. Intermittent RLS: symptoms when not treated would occur on average <2/week for the past year, with at least five lifetime events. Specifier for clinical significance of RLS: The symptoms of RLS cause significant distress or impairment in social, occupational, educational or other important areas of functioning by their impact on sleep, energy/vitality, daily activities, behavior, cognition or mood. 27
Brain & NeuroRehabilitation 2016; 9: 25-30 해서치료를시작한다. 치료는크게비약물치료및약물치료로나뉘는데두가지를병행하는것이좋다. 11 (1) 비약물치료증상이경미하거나, 드물게발생하는환자들은비약물치료를우선적으로고려한다. 수면습관을개선하고, 잠들기전에커피나카페인이들어있는음료나술을피한다. 증상의원인이되거나악화시키는요인이되는항도파민제제, 항히스타민제및항우울제는가능하다면중지하는것이좋다. 온열치료, 월풀, 마사지, 전기자극치료등의물리치료는일시적으로효과를보인다. 적당한운동, 맨손체조, 마사지, 정신적인활동 ( 예, 퍼즐게임, 비디오게임 ) 은증상을완화시키는데도움이된다. 24 2014년미국 FDA는무작위대조임상연구에서수면의질에서대조군에비해월등한효과를나타낸것을근거로, 환자의다리에진동자극을주는 Relaxis 패드장비를승인하였다. 25 (2) 약물치료원발성 RLS에대한약물치료는대부분증상완화를위한대증적치료이다. 호소하는증상에따라적절히선택해서사용하며, 도파민제제를기본으로해서다른제제를병용하여처방한다. 환자가 1주에적어도 3일이상야간에증상이있으면약물치료를고려할수있다. 약물로쓰이는종류는다음과같다. 가 ) 도파민작용제 : 도파민작용제는 RLS의감각증상, 움직이고싶은충동, PLMS 개선에효과가우수하여일차치료제로사용한다. RLS에서 levodopa 효과가 1982년처음보고된이후널리사용되어오다가증강 (augmentation) 및반동 (rebound) 현상이알려진이후에는거의사용되지않고있다. Ergot-related 도파민작용제는섬유증과심장판막이상등의심각한부작용을일으키는경우가있어최근에는거의권장되지않으며, 부작용이상대적으로적은 non-ergot 제재를사용한다. 경구제제인 Pramipexole (Mirapex R ), Ropinirole (Requip R ), 과패치형태 (patch formulation) rotigotine (Neupro R ) 가 FDA 승인된제품이다. 26-29 세약제모두효과가우수하며, 투여첫날부터증상이개선된다. 투약은잠들기전 1 2 시간전에하루 1회투여로시작한다. 도파민작용제를장기간복용하게되면증강현상 (augmentation) 이나타날수있다. 증강현상이란증상의발생시각이빨라지거나, 안정상태이후에증상이발생하는시간이짧거나, 증상이더악화되면서다리이외의신체부위에도증상이나타나게된다. 도파민작용제의용량을줄이거나, 항경련제나아편양제재를병용하거나치환하여서사용한다. 증강현상은도파민용량이많을때더자주나타나므로, 이를예방하기위해서는최소한의용량 을유지하고, 증상이개선되었을때는간헐적인투약방법으로전환하는것을고려한다. 30 나 ) 벤조디아제핀제 : 증상이경미하거나, 동반된불면증을호소하는환자에게서도움이되며, 주로 clonazepam을사용한다. 0.5 1 mg을취침전에투여한다. 하지의감각증상과뇌파의각성을감소시키지만, PLMS 개선에는효과가없다. 31 다 ) 항경련제 : 통증을호소하거나, 말초신경염이있는환자에게서단독혹은병용해서사용한다. Gabapentine Enacarbil (Horizant R ), gabapentine (Neurontin R ), pregabalin (lyrica R ) 을사용한다. 32 전반적인증상개선효과가우수하다. 라 ) 아편양제제 : 증상이경미한환자에게 low potency opioid (e.g codein), 증상이심한환자는 higher potency opioid (oxycodone hydrochloride, methadone hydrochloride) 를용할수있다. 중독의위험이있으므로주의해서사용한다. 증강현상이나타나거나, 심한통증을호소하는환자들에게서사용을고려한다. 마 ) 철분제제 : 혈청페리틴이 50 ng/ml 이하인환자는철분제치료를고려한다. 22 철분제복용방법은 ferrous sulfate 325 mg과비타민 C 250 mg의용량을하루에 3번공복식사 60분전에섭취하면위장관흡수를촉진할수있다. 결론 하지불안증후군은심각하고만성적인신경계질환으로수면장애및주간피로등으로삶의질에많은영향을미친다. 유병률이 5 15% 에이를정도로흔한질환이지만질병으로인식하지않아병원을찾지않거나, 의사들도익숙치않아진단하지못하는경우가많다. 도파민작용제및항경련제의치료효과가우수하므로수면장애와동시에다리가불편한증상을호소하는환자에게적극적인진단과치료를하면환자들에게큰도움을줄수있다. References 1) Restless legs syndrome: detection and management in primary care. National Heart, Lung, and Blood Institute Working Group on Restless Legs Syndrome. Am Fam Physician. 2000;62:108-114 2) Cho YW, Shin WC, Yun CH, Hong SB, Kim JH, Allen RP, Earley CJ. Epidemiology of restless legs syndrome in Korean adults. Sleep. 2008;31:219-223 3) Berger K, Luedemann J, Trenkwalder C, John U, Kessler C. Sex and 28
민유선 : 하지불안증후군의진단과치료 the risk of restless legs syndrome in the general population. Arch Intern Med. 2004;164:196-202 4) Hattan E, Chalk C, Postuma RB. Is there a higher risk of restless legs syndrome in peripheral neuropathy? Neurology. 2009;72:955-960 5) Evidente VG, Adler CH. How to help patients with restless legs syndrome. Discerning the indescribable and relaxing the restless. Postgrad Med. 1999;105:59-61, 65-56, 73-54 6) Cesnik E, Casetta I, Turri M, Govoni V, Granieri E, Strambi LF, Manconi M. Transient RLS during pregnancy is a risk factor for the chronic idiopathic form. Neurology. 2010;75:2117-2120 7) Takaki J, Nishi T, Nangaku M, Shimoyama H, Inada T, Matsuyama N, Kumano H, Kuboki T. Clinical and psychological aspects of restless legs syndrome in uremic patients on hemodialysis. Am J Kidney Dis. 2003;41:833-839 8) Lane RM. SSRI-induced extrapyramidal side-effects and akathisia: implications for treatment. J Psychopharmacol. 1998;12:192-214 9) 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;4:101-119 10) Abetz L, Allen R, Follet A, Washburn T, Earley C, Kirsch J, Knight H. Evaluating the quality of life of patients with restless legs syndrome. Clin Ther. 2004;26:925-935 11) Ekbom K, Ulfberg J. Restless legs syndrome. J Intern Med. 2009;266:419-431 12) Kim JB, Koo YS, Eun MY, Park KW, Jung KY. Psychosomatic symptom profiles in patients with restless legs syndrome. Sleep Breath. 2013;17:1055-1061 13) American Academy of Sleep Medicine. The International Classification of Sleep Disorders. 2nd ed. Westchester, Illinois; 2005 14) Eun M-Y, Seok HY, Kim JB, Jung K-Y. Comparison of Sleep Quality and Polysomnographic Findings in Patients with RLS according to the Presence of Periodic Limb Movements during Sleep. J Korean Sleep Res Soc. 2012;8:4-8 15) Allen RP, Earley CJ. Restless legs syndrome: a review of clinical and pathophysiologic features. J Clin Neurophysiol. 2001;18: 128-147 16) Winkelman JW. Considering the causes of RLS. Eur J Neurol. 2006;13 Suppl 3:8-14 17) Connor JR, Ponnuru P, Wang XS, Patton SM, Allen RP, Earley CJ. Profile of altered brain iron acquisition in restless legs syndrome. Brain. 2011;134:959-968 18) Trenkwalder C, Hogl B, Winkelmann J. Recent advances in the diagnosis, genetics and treatment of restless legs syndrome. J Neurol. 2009;256:539-553 19) Hening WA, Allen RP, Washburn M, Lesage SR, Earley CJ. The four diagnostic criteria for Restless Legs Syndrome are unable to exclude confounding conditions ("mimics"). Sleep Med. 2009;10:976-981 20) Hening WA, Allen RP, Thanner S, Washburn T, Heckler D, Walters AS, Earley CJ. The Johns Hopkins telephone diagnostic interview for the restless legs syndrome: preliminary investigation for validation in a multi-center patient and control population. Sleep Med. 2003;4:137-141 21) Gamaldo CE, Earley CJ. Restless legs syndrome: a clinical update. Chest. 2006;130:1596-1604 22) Hening WA. Restless Legs Syndrome. Curr Treat Options Neurol. 1999;1:309-319 23) Ferreri F, Rossini PM. Neurophysiological investigations in restless legs syndrome and other disorders of movement during sleep. Sleep Med. 2004;5:397-399 24) Giannaki CD, Hadjigeorgiou GM, Karatzaferi C, Maridaki MD, Koutedakis Y, Founta P, Tsianas N, Stefanidis I, Sakkas GK. A single-blind randomized controlled trial to evaluate the effect of 6 months of progressive aerobic exercise training in patients with uraemic restless legs syndrome. Nephrology Dialysis Transplantation. 2013;28:2834-2840 25) Mitchell UH. Medical devices for restless legs syndrome - clinical utility of the Relaxis pad. Ther Clin Risk Manag. 2015;11:1789-1794 26) 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 27) Ondo W. Ropinirole for restless legs syndrome. Movement Disorders. 1999;14:138-140 28) Giorgi L, Asgharian A, Hunter B. Ropinirole in Patients With Restless Legs Syndrome and Baseline IRLS Total Scores >= 24: Efficacy and Tolerability in a 26-Week, Double-Blind, Parallel-Group, Placebo- Controlled Study Followed by a 40-Week Open-Label Extension. Clinical Therapeutics. 2013;35:1321-1336 29) Baldwin CM, Keating GM. Rotigotine transdermal patch - In restless legs syndrome. Cns Drugs. 2008;22:797-806 30) Garcia-Borreguero D, Allen RP, Kohnen R, Hogl B, Trenkwalder C, Oertel W, Hening WA, Paulus W, Rye D, Walters A, Winkelmann J, 29
Brain & NeuroRehabilitation 2016; 9: 25-30 Earley CJ. Diagnostic standards for dopaminergic augmentation of restless legs syndrome: report from a World Association of Sleep Medicine-International Restless Legs Syndrome Study Group consensus conference at the Max Planck Institute. Sleep Med. 2007;8:520-530 31) Manconi M, Ferri R, Zucconi M, Bassetti CL, Fulda S, Arico D, Ferini-Strambi L. Dissociation of periodic leg movements from arousals in restless legs syndrome. Ann Neurol. 2012;71:834-844 32) Bogan RK, Bornemann MAC, Kushida CA, Tran PV, Barrett RW, Grp XS. Long-term Maintenance Treatment of Restless Legs Syndrome With Gabapentin Enacarbil: A Randomized Controlled Study. Mayo Clinic Proceedings. 2010;85:512-521 30