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1 원저 울산대학교의과대학신경과학교실, 서울아산병원파킨슨병센터 이유진정선주김성렬이태연이재홍이명종 Delusion and Hallucination in Parkinson s Disease: A Pilot Study of Clinical Features and Pathogenesis Eugene Lee, M.D., Sun Ju Chung, M.D., Sung Reul Kim, R.N., Tae Yeon Lee, M.D., Jae-Hong Lee, M.D., Myoung Chong Lee, M.D. Center for Parkinsonism and Other Movement Disorders, Department of Neurology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea Background: Although the clinical and epidemiological characteristics of delusions and visual hallucinations in Parkinson s disease (PD) have been described, the underlying etiology and pathogenesis of those neuropsychiatric manifestations in PD remains a matter of debate. The purpose of this study was to investigate whether or not delusion is in the same spectrum of dopamine related neuropsychiatric manifestations as visual hallucination is in patients with PD. Methods: We studied the clinical features of 13 PD patients with delusions and 32 with hallucinations. Patients with a history of psychotic symptoms before the onset of PD were excluded. Results: Age at onset of PD was younger in patients with delusions (56.3±8.7 years) than in those with hallucinations (63.9±9.2 years) (p=0.019). The level of education was higher in patients with delusions than those with hallucinations (p=0.006). Daily levodopa equivalent dosages were higher in patients with delusions (982±653.7 mg/day) than those with hallucinations (559±311.2 mg/day) (p=0.002). Dopamine agonists were more frequently used in patients with delusions than in those with hallucinations (p=0.020). Conclusions: Compared with PD patients with hallucinations, those with delusions were associated with longer disease durations, higher levodopa-equivalent daily doses, and use of dopamine agonists. To evaluate the role of dopaminergic dysfunction for the development of delusions and hallucinations in PD patients, further welldesigned prospective studies are needed. J Korean Neurol Assoc 25(3): , 2007 Key Words: Parkinson s psychosis, Hallucination, Delusion, Parkinson s disease, Dopaminergic system 서론 파킨슨병 (Parkinson s disease) 은떨림, 근경직, 서동증, 보행동결을특징으로하는신경계의퇴행성질환이다. 파킨슨 Received February 16, 2007 Accepted April 23, 2007 *Sun Ju Chung. M.D., PhD. Department of Neurology, Asan Medical Center University of Ulsan College of Medicine, Pungnap-dong, Sonpa-gu, Seoul, , Korea Tel: Fax: sjchung@amc.seoul.kr 병은나이에따라서유병률이점차증가하여국내유병률은 65세이상인구에서 1-1.6% 로, 의학의발전으로인해평균수명이증가하고빠르게노령사회로진행되고있는우리나라에서는중요한질환이다. 1 파킨슨병의경과중에발생할수있는합병증으로는운동합병증 (motor complication) 과비운동합병증 (non-motor complication) 이있다. 비운동합병증에는자율신경기능이상, 통증과감각이상, 우울증상, 인지기능이상및치매등이있고, 이중에서특히정신병증상 (psychotic symptom) 은 Lewyrelated pathology나 Alzheimer disease-type pathology를 312 대한신경과학회지제 25 권제 3 호, 2007

2 동반하는다른종류의신경퇴행성질환에서도나타날수있는데파킨슨병에서의환각 (hallucination) 과망상 (delusion) 은 30-50% 로매우흔한것으로되어있다. 2,3 파킨슨병의정신병증상중가장흔한것은환시이며많은환자는환시가실제로존재하지않는다는사실을알고별다른감정의동요없이지나가지만, 일부환자는환시에대한병식 (insight) 이없거나망상이동반되어환자들의주된행동장애 (behavioral disability) 를초래한다. 심할경우에는가족들의심리적, 경제적부담으로이어져환자및가족모두의삶의질을떨어뜨릴수있으므로파킨슨병의정신병증상을다루는것은매우중요하다. 4-7 파킨슨병의환각은잘밝혀져있지않지만질병의경과중에약물부작용 ( 레보도파, 도파민효현제, 항콜린제제등 ), 감염혹은대사성질환등내과적질환의병발등과관계되어잘나타날수있으며이런요소들이복합적으로작용할수도있다. 8,9 Moskovitz 등은 1978 년에 Kindling phenomenone 과 continuum theory 로파킨슨병의정신병증상이질병의경과중에생기며, 가장가볍게는생생한꿈 (vivid dream) 에서환각그리고망상으로발전하고심할경우혼돈상태 (confusional state) 가초래된다고했으며장기간의도파민치료와연관된다고하였다. 5,9,10 그러나환각과망상이정신병증상의경하고심한정도의차이일뿐한병태생리영역의두가지다른증상의발현인지, 아니면이둘사이에서서로다른계통의병태생리적기전이존재할가능성이있는지에대한연구는이루어지지않은상태이다. 11 따라서본연구에서는파킨슨병에서의환각과망상이도파민계통의병태생리의증상아형 (subtype) 들인지여부를알기위해서환각을가진환자와망상을가진환자들의임상적특징을비교분석해보기로하였다. 대상과방법 1. 대상 1997 년 4월부터 2005 년 6월까지신경과에입원하거나외래를방문한파킨슨병으로진단된환자들중에서 Parkinsonism Registry 에최소 1개월이상 12 정신병증상이있다고등록된환자들을대상으로하였다. 파킨슨병의진단은 UK Parkinson s Disease Society Brain Bank 임상진단기준에근거하였고정신병증상은환자와보호자들의보고에따라서 3명의신경과의사들에의해평가되었다. 13 이들중에서 1) 비특이성혹은속발성파킨슨증후군 (atypical or secondary parkinsonism) 이의심되는경우 2) 파킨슨병증상시작전에정신병이있었던경우 3) 파킨슨병의운동증상발현후 1년이내정신병증상이생긴경우 4) 정신병증상당시에의식변화와심한내과적질환이동반되어섬망 (delirium) 가능성이있는경우는연구대상에서제외하였다. 3,5,14 2. 방법환자들의병력기록지와 registry 를중심으로환자들의나이, 성별, 파킨슨병증상이시작된나이와정신병증상이나타난시기등의임상적특징을후향적으로조사하였다 (Table 1). 또한환자들의교육정도와정신병증상이나타날당시의 MMSE (Mini- Mental State Examination), on 시기의 Hoehn and Yahr stage 를살펴보았다. 정신병증상이나타날무렵 ( 증상이나타날시기의최대 3개월전까지의용량 ) 의사용약물중레보도파 (levodopa) 와도파민효현제및항콜린성약물, amantadine 과 selegiline 등의약물용량을평가하였다. 레보도파효현제의 equivalent 용량은다음과같은상대용량계산법으로 standard levodopa dose 1 + slow release levodopa bromocriptine 10 + ropinirole 20 + pergolide pramipexole 100으로, entacapone을사용한경우 {standard levodopa dose + (slow release levodopa 0.75)} 를이용하였다. 15 또한환각과망상때문에항정신병약물을투여했는지유무를조사하였고치매증상과운동동요 (motor fluctuation) 를동반한빈도를같이살펴보았다. 저자들은수면장애 (REM sleep behavior disorder, vivid dreaming, daytime sleepiness and sleep quality) 와우울증상의동반여부를차트분석 (chart review) 에서조사하였으나기록되지않은경우가많아서분석단계에서는제외하였다. 환각은 1) 외부자극이없는상태에서실제로존재하지않는것이보인다고하거나들린다고하거나만져진다고하는경우로정의하였으며환시 (visual hallucination), 환청 (auditory hallucination), 환촉 (tactile hallucination), 환미 (gustatory hallucination), 환후 (olfactory hallucination) 등이있는지를평가하였다. 7,16 망상은환각이있으면서실제존재하지않는사실에대한헛된믿음 (false belief) 이나환각이존재한다고믿는것으로정의하였고피해망상 (persecutory delusion), 의처증이나의부증처럼배우자 (spouse) 의부정에대한의심으로나타나는질투형망상 (delusion of infidelity), 색정망상 (erotic delusion), 과대망상 (grandiose delusion), 신체망상 (somatic delusion) 등의유무를조사하였다. 11 환각과망상모두그형태에있어서는복수응답이가능하게했다. J Korean Neurol Assoc Volume 25 No. 3,

3 이유진정선주김성렬이태연이재홍이명종 Table 1. Clinical characteristics of the patients (n=45) Mean±SD or % Age (years) 73.9±8.0 Age at onset of Parkinson s disease (years) 61.7±9.6 Disease duration (years) a 6.8±4.6 Males (%) 46.7 Hoehn and Yahr stage in on state 2.5±0.9 Education level b 2.1±1.3 MMSE score (n=18) 21.5±5.3 Treatment with levodopa (%) 97.8 Treatment with dopaminergic agonists (%) 55.6 Treatment with anticholinergics (%) 11.1 Treatment with amantadine (%) 64.4 Treatment with selegiline (%) 24.4 Treatment with entacapone (%) 2.2 Levodopa daily dose (mg) 614.2±427.3 Levodopa-equivalent daily dose (mg) 656.2±444.7 Frequency of antipsychotics use (%) 74.4 Motor fluctuation (%) 64.4 a At time of hallucination or delusion from initial motor symptom onset. b Education level; 0=lack of schooling, 1=primary, 2=middle, 3=high, 4=college, 5=graduate school. 3. 통계분석 저자들은조사한환자들을환각만있는군과, 망상또는환각과망상을동시에보인환자군의두개의그룹으로나누어 SPSS 12.0 프로그램을이용하여분석하였다. 두집단간의나이와레보도파용량과같은변수의성질을갖는경우비모수검정 (Mann-Whitney U test) 을사용하였고, 성별, 레보도파효현제사용유무, 운동동요동반유무등과같은비연속적범주형변수의성질을갖는요인들에대해서는 Fisher s exact test 를시행하였다. p값이 0.05 미만인경우를통계적으로의미있게보았다. 1. 임상양상 결과 총 45명의정신병증상이있는환자들중환각이있는환자는 32명으로 71.1%, 환각과망상이같이있는환자는 8명으로 17.8%, 망상이있는환자는 5명으로 11.1% 였으며이들을환각만있는군 (32명) 과망상이있는 (13명) 두개의그룹으로나누어분석하였다. 환자들의평균나이는 73.9±7.97 세였으며파킨슨병의증상이나타난평균나이는 61.7±9.6 세였다 (Table 1). 파킨슨병의운동증상이나타난후부터처음으로정신병증상이나타나기까지는평균 6.8±4.6 년이걸렸다. 남녀의비는비슷하였고정신병증상이나타났을때의 Hoehn and Yahr stage 는 on 시기에평균 2.5±0.9였다. 도파민효현제 (pergolide) 만을사용한 1명의환자를제외하고는모두레보도파치료를받았으며 (97.8 %), 도파민효현제와 amantadine 을사용했던환자도과반수가넘었다. 정신병증상으로인하여환자들의 74.4% 가 quetiapine( 평균용량 : 66.0±61.6 mg) 이나 clozapine( 평균용량 : 42.0±49.5 mg) 의항정신병약물을병용하였고이에더하여 olanzapine, risperidone 등두가지이상의항정신병약물을쓴경우도 26.8% 나되었다. 2. 환각이있는환자군과망상이있는환자군의비교양군의임상적비교분석은 Table 2와같다. 환각이있는환자의평균나이는 76.2±6.8 세로망상이있는환자의 68.4± 8.1 세보다좀더많았다 (Table 2). 레보도파효현제를사용한빈도와항정신병약물을투여한빈도는망상이있는환자가더많았다. 파킨슨병의경과중에생기는 wearing off 현상은망상이있던환자에서더높았으나이상운동증 (dykinesia) 의빈도는두군에서의미있는차이가없었다. 환각이있는환자들보다망상이있는환자들에서파킨슨병이좀더젊은나이에생긴것으로나타났고, 파킨슨병의운동증상이생긴시기에서부터환각이처음생길때까지는평균 5.8± 4.4 년, 망상이생길때까지는평균 9.4±4.2 년으로나타났다 (Table 3). 망상이있는환자들은환각이있는환자들에비해서긴유병기간을가지고있었다. 전체적인레보도파의사용량은두군에서통계적인차이는없었으나레보도파 equivalent 용 Table 2. Comparison of patients with hallucination and delusion: non-parametric variables Hallucination (n=32) Delusion (n=13) p-value Sex (male/female) 13/19 9/ Frequency of Dopaminergic agonists use (%) Frequency of antipsychotics use (%) Motor fluctuation (%) Wearing off (%) Dyskinesia (%) 대한신경과학회지제 25 권제 3 호, 2007

4 량은망상이있는환자군이환각이있는환자군보다통계적으로의미있게높았고, 도파민효현제의사용량도망상이있는환자들에서좀더많았다. 두군간의교육정도는망상이있는환자에서더높았으며, 조사된환자수는적었으나 MMSE 수치도망상이있는군이더높았다. 사용한항정신병약물의개수와용량도망상군이더많았으며, 두환자군사이의 on 상태에서의 Hoehn and Yahr stage 는차이가없었다. 3. 환각및망상의형태환각의유형으로는환시 (n=41) 가가장흔하였고, 환촉 (n=3) 이나환후 (n=1) 는상대적으로적게관찰되었다. 환미는관찰되지않았으며환청 (n=5) 이두번째로흔한환각증세였는데, 망상이있는환자군에서좀더많이관찰되었으나통계적으로는유의하지않았다. 대부분의환자들은주로사람이나유령 (n=21), 곤충들 (n=14), 동물 (n=9) 이보인다고했으나풍선, 벽, 거미줄, 솜털등의사물 (n=7) 이보인다는환자들도있었다. 망상의유형으로는자신이괴롭힘을당하고있거나염탐당하고있다는생각과누군가자신의약에독을넣었다고믿는등의피해망상 (n=13) 이가장흔하였고배우자의부정을의심하는질투형망상 (n=5) 이다음으로많았으며신체망상 (n=2) 과과대망상 (n=1) 이뒤를이었다. 고찰 파킨슨병의정신병증상중망상의빈도는 % 로, 30-50% 를보이는환각에비하여적으며, 망상만존재하는경우는 2-8% 내외로더욱드문것으로알려져있다. 7,9,11,16,17 기존의연구에서는파킨슨병에서생기는정신병증상으로서환각과망상을조사하고증상의빈도, 구체적인형태, 위험인자등에대해서주로언급했으나이두가지증상을따로구분한연구는거의없다. 본연구는파킨슨병의정신병증상연구에서특히, 환각과망상을보이는파킨슨병환자두그룹간의특성을차별화해서보려는새로운시도이다. 파킨슨병의정신병증상은환자를돌보는가족들의부담을증가시키며환자가간호요양시설에머물게되는위험인자가될수있다. 4-6,17 또한정신병증상을호전시키기위해서레보도파및도파민효현제를감량하고항정신병약물을사용하게됨으로써환자의운동증상이악화될가능성이많아파킨슨병의환각과망상은임상적으로매우다루기까다로운문제다. 18 기존의연구들에서는환각이발생하게되는위험요소로서유병기간혹은병의진행자체 (disease progression), 인지기능의장애, 나쁜운동기능상태, 수면장애, 우울증과같은정동장애, 레보도파및도파민효현제사용, 정신병의병력등의가능성을제시하고있으나각각의요소에대해서는보고마다일치하지않는경우가있어논란의여지가있다. 5,17,19-23 이들중환자들의불면증과 REM 수면이상이파킨슨병의초기증상이될수있으며환각과연관이있다는연구들이최근까지있었다. 11,24 이와관련해서기존의 continuum theory 에의하면파킨슨병의정신증상이수면이상, 경한환시 (benign hallucination) 및환각, 망상에서심한치매로시간이지나고질병이심해지면서순차적으로진행하는것을보여준다고했다. 5,10,19,23,24 하지만본연구에서는망상을지닌환자들이유병기간은더길었다고하더라도환각만있는환자군에비해서나이 Table 3. Comparison of patients with hallucination and delusion: parametric variables Hallucination (n=32) (Mean±SD) Delusion (n=13) (Mean±SD) p-value Mean age (years) 76.2± ± Age at onset of Parkinson s disease (years) 63.9± ± Disease duration a (years) 5.8± ± Levodopa daily dose (mg) 522.7± ± Dopaminergic agonists daily dose (mg) 34.9± ± Levodopa-equivalent daily dose (mg) 559.9± ± Quetiapine use (n=10/8) 31.3± ± Clozapine use (n=11/7) 14.1± ± Education level b 1.7± ± MMSE (n=10/8) 18.7± ± Number of antipsychotics 0.7± ± Hoehn & Yahr stage in on state 2.7± ± a At time of hallucination or delusion. b Education level; 0=lack of schooling, 1=primary, 2=middle, 3=high, 4=college, 5=graduate school. J Korean Neurol Assoc Volume 25 No. 3,

5 이유진정선주김성렬이태연이재홍이명종 가오히려젊었던점이 continuum theory 와는잘맞지않는면을보여준다. 또한환각에서망상그리고심한치매와혼돈상태로순차적으로진행한다고생각하기에는망상이있는환자들의교육수준이환각을지닌환자들의교육수준보다높게관찰되고 MMSE 가더높은점, 좀더젊은연령이었던것은, 치매에대한자세한검사가이루어지지않았다고하더라도기존의이론인 continuum theory 와는일치하지않는결과를보여준다. 여기에는여러가지혼란변수가있겠지만나이가젊고교육수준이높을수록좀더체계화된망상을나타낸다고할수도있겠고경한형태의망상장애나망상형인격장애등이파킨슨병과별도로존재할가능성도있다. 그외처음에보고자하였던우울및치매증상과수면장애에관한것은기록되지않은경우가많아서분석할수없었으나파킨슨병의정신병증상이나타나는데중요한영향을미칠수있다고알려져있어본연구의혼란변수로작용할수있을것으로생각된다. 20,25 레보도파나도파민효현제를사용하지않은파킨슨병환자에서도심하지않은양성환각 (benign hallucination 또는 minor hallucination) 이파킨슨병자체의경과중에나타날수있다고알려져있다. 이것은파킨슨병의환각증상이레보도파를사용하기이전부터보고되고있었던점을생각하면이해할수있다. 9 그러나본연구에서는한명을제외한나머지 44명의환자들이환각이나망상이나타날당시최소 3개월전부터모두레보도파를사용한과거력을가지고있었다. 이전연구에의하면파킨슨병의정신병증상발현에는레보도파와레보도파효현제가모두관계한다는의견과레보도파효현제만의미있는관계를보였다는상반되는의견이있는데후자의근거는레보도파가주로운동합병증에관여한다면레보도파효현제는 mesolimbic/mesocortical system 의시냅스후도파민수용체에보다선택적으로작용하기때문에좀더환각을잘일으킬것이라는이유였다. 22 본연구에서는사용한레보도파용량이망상이있는환자에서많은경향을보였으나통계적으로유의하지는않았고레보도파효현제의용량은망상이있는환자에서의미있게많았다. 이는망상이환각보다도파민계통이상의좀더심한형태일수있으며, 환각과망상이도파민계통의이상중에서도서로다른도파민수용체반응에의한정신병적증상일수있음을시사한다. 20,26 기존의문헌에서는아세틸콜린이나세로토닌과같은비도파민성신경전달물질 (neurotransmitter) 의불균형이중요한역할을담당할가능성이많다고언급하였다. 17,25 이점에대해서저자들은파킨슨병의정신병증상의발생에이러한아세틸콜린이나세로토닌의불균형에더불어, 정신병증상중망상의발생에도파민계통 (dopaminergic system) 의이상도일부기여할가능성을보여준다고 생각한다. 파킨슨병에서와마찬가지로루이체치매의경과중에서도환시가나타날수있다. 루이체치매는임상적으로파킨슨병과구별이어려울수있고두질병의경계가현재분명하지않은상태이다. 3 본연구에서는 research criteria 를기준으로파킨슨병의운동증상이생긴이후 1년이내정신병증상이생긴환자들을제외하였지만 ( 1-year rule ) 실제로는파킨슨병의환각과루이체치매의환각이유사한종류의병태생리기전을공유할가능성을배제할수없다. 14,27,28 이는실제로루이체치매와파킨슨병치매에대한전향적연구가이루어짐으로써해결될수있을것이다. 파킨슨병의환각에대한연구가어려운것은전향적인연구설계가아닐때발생하는문제점으로환자나보호자가스스로보고하지않게될때실제보다더적은빈도로관찰된다는점이다. 4,9 본연구역시후향적으로분석한연구이기때문에환각과망상의빈도에있어서전향적연구에비해부정확할수있으며, 조사되지않거나빠져있는데이터가연구의혼란변수로작용할수있다. 또한정신병증상이있는환자군과정신병증상이없었던환자군 (control group) 간비교가되지않은것과다기관 (multicenter) 연구가아니면서조사된환자수가적어선택변수가있을수있는점이본연구의한계점이될수있다. 그리고망상만을가지는절대적인환자수가적어서 (N=5) 망상만있는환자, 망상과환각을동시에가진환자, 환각만가지는환자의세군간의비교를하지못한것도부족한점이될수있다. 마지막으로, 기존의연구들에서처럼정신병증상발현시레보도파및도파민효현제를감량하거나중단한후정신병증상이완전히사라졌는지를명확히조사할수가없었기때문에환각과망상의발생에어느정도가파킨슨병자체에의한것이고어느정도가도파민성약물에의한것인지를명확하게분석할수가없었다. 결론적으로파킨슨병환자의정신병증상은개별적이고자세한병력청취와약물사용에대한전향적연구에의해정확하게이루어질수있으며본연구는이에필요한예비적임상연구 (pilot clinical study) 로서의역할을한다고할수있다. 저자들은앞으로큰규모의여러기관의환자들을대상으로정신병증상이있는환자와없는환자들을비교하고이들을장기간추적조사하는임상연구가필요하며, 더불어파킨슨병환자들의정신병증상을자세하고정확하게평가할수있는적당한도구 (inventory or rating scale) 가필요하리라고본다. 316 대한신경과학회지제 25 권제 3 호, 2007

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한국성인에서초기황반변성질환과 연관된위험요인연구

한국성인에서초기황반변성질환과 연관된위험요인연구 한국성인에서초기황반변성질환과 연관된위험요인연구 - - i - - i - - ii - - iii - - iv - χ - v - - vi - - 1 - - 2 - - 3 - - 4 - 그림 1. 연구대상자선정도표 - 5 - - 6 - - 7 - - 8 - 그림 2. 연구의틀 χ - 9 - - 10 - - 11 -