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1 대한안과학회지 2016 년제 57 권제 10 호 J Korean Ophthalmol Soc 2016;57(10): ISSN (Print) ISSN (Online) Original Article 안와감압술이갑상선안병증환자의삶의질에미치는영향 Change in Quality of Life after Orbital Decompression Surgery in Patients with Dysthyroid Ophthalmopathy 허정 이정규 Jung Huh, MD, Jeong Kyu Lee, MD, PhD 중앙대학교의과대학안과학교실 Department of Ophthalmology, Chung-Ang University College of Medicine, Seoul, Korea Purpose: To evaluate the effect of orbital decompression surgery on quality of life in thyroid-associated ophthalmopathy (TAO) patients. Methods: From August 2014 to December 2015, 80 patients diagnosed with TAO at our clinic were retrospectively analyzed. The patients were divided into 2 groups: 30 patients who underwent orbital decompression surgery and 50 patients who did not receive surgery. The Korean version of the Grave s ophthalmopathy specific quality of life (GO-QoL) questionnaire was completed by all patients. We compared questionnaire scores between groups and analyzed demographic and clinical factors affecting change in GO-QoL. Results: The patients who underwent orbital decompression had lower mean GO-QoL score for appearance in comparison with patients without orbital decompression (p < 0.001). The mean GO-QoL score for appearance was increased from 28.8 ± 17.1 to 51.5 ± 18.8 after orbital decompression (p = 0.024). The mean GO-QoL score for visual function was not different between the patients who did not receive surgery and the orbital decompression group. The mean GO-QoL score for visual function was not changed after orbital decompression. There was a significant relation between postoperative proptosis degree and change in GO-QoL score for appearance after orbital decompression. Conclusions: GO-QoL score for appearance was significantly improved after orbital decompression surgery, and psychological interventions should be considered to enhance the quality of life outcomes. J Korean Ophthalmol Soc 2016;57(10): Keywords: Dysthyroid ophthalmopathy, Orbital decompression, Quality of life 갑상선안병증은갑상선외적증상중가장흔하게발생하고 45% 의그레이브스병을앓고있는환자에서나타나게된다. 1 정확한병태생리는밝혀진바없지만, 갑상선안병증은안와내세포에발현되는 thyroid stimulating hormone Received: Revised: Accepted: Address reprint requests to Jeong Kyu Lee, MD, PhD Department of Ophthalmology, Chung-Ang University Hospital, #102 Heukseok-ro, Dongjak-gu, Seoul 06973, Korea Tel: , Fax: Lk1246@hanmail.net (TSH) 수용체와여기에작용하는 TSH 수용체자극항체가중요한역할을하는자가면역질환의일종으로여겨지고있다. 2 안구돌출로인한각막의손상이나외안근기능의변화로인한복시증상, 나아가서는압박시신경병증은시각기능의저하를가져올수있으며, 진행되는안구돌출및눈꺼풀뒤당김등의외모변화는환자의삶의질에심각한영향을미칠수있다. 국내에서진행된연구에서도, 갑상선안병증이삶의질을감소시킨다는결과가발표된바있다. 3-5 갑상선안병증의급성기에는보존적치료나염증을조절하기위한부신피질호르몬제치료를시행하며, 안정기에 c2016 The Korean Ophthalmological Society 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. 1514
2 - 허정 이정규 : 안와감압술후삶의질의변화 - 접어들어 6개월이상안구돌출, 외안근기능등의변화가없는경우안와감압술을고려할수있다. 6,7 안와감압술은심한안구돌출이있는환자에서기능적, 미용적목적등을위하여시행하거나약물치료에반응하지않는압박시신경병증이있는경우시행된다. 7,8 외국에서진행된안와감압술을받은환자를대상으로한연구에서안와감압술이외모에연관된삶의질을향상시키는것을확인한바있으며, 안와감압술이신체뿐만아니라정신적인활동에도긍정적인영향을끼친다고평가된바있다. 9,10 이와같이외국에서는안와감압술과삶의질에대한연구가진행되고있는반면, 아직까지국내에서는안와감압술을받은환자를대상으로한수술전후삶의질변화와관련된보고는없다. 이에저자들은갑상선안병증환자들에서주관적인삶의질평가를통하여안와감압술을통해환자들이느끼는삶의질차이를확인하고나아가수술을받은환자와받지않은환자를비교하여안와감압술을받는환자에대한이해의폭을넓히고자하였다. 사, 색각검사, 눈꺼풀검사, 헤스스크린검사, 프리즘교대가림검사, 안구운동성검사, 세극등현미경을통한전안부및안저검사, Hertel 안구돌출도검사등을시행하였으며임상활동도점수를이용하여환자의임상양상을확인하였다. 임상활동도점수는눈주위의동통, 안구운동시동통, 눈꺼풀부종, 눈꺼풀홍반, 결막의충혈, 결막부종, 눈물언덕부종의 7가지항목을각항목당 1점씩, 총 0점부터 7점까지점수로하여평가하였다. 11 연구에쓰인설문지는그레이브스안병증환자에맞춘삶의질평가문항 (Grave s ophthalmopathy specific quality of life survey, GO-QoL survey) 10,12 을한국어로번역하여사용하였다 (Appendix 1). GO-QoL 설문지는크게시각기능과관련된삶의질 (1-8번), 외모와관련된삶의질 (9-16 번 ) 의두가지항목으로이루어져있으며, 각각의문항에 대상과방법 2014년 8월부터 2015년 12월까지본원에내원하여갑상선안병증으로진단받은 80명을대상으로의무기록을분석하였다. 위연구는중앙대학교병원생명윤리위원회 (institutional review board, IRB) 의승인을받았다. 안구주위동통이나압박감, 안구돌출, 눈꺼풀부종등의갑상선안병증에서일반적으로확인되는증상이나소견이확인되는환자를갑상선안병증으로진단하였다. 백내장, 녹내장, 갑상선안병증과관계없는각막의이상, 황반변성, 망막전막과같이삶의질에영향을끼칠수있는질병을가지고있는환자를의무기록을통해대상에서제외시켰다. 모든환자에서갑상선병증의유병기간, 갑상선병증의치료및안정여부, 갑상선안병증에대한치료, 흡연여부등의과거력과가족력을확인하였다. 최대교정시력, 안압검 Figure 1. Grave s ophthalmopathy specific quality of life (GO- QoL) scores for visual function and appearance. There was no significance difference in GO-QoL score for visual function between each groups. The patients who underwent orbital decompression had lower mean GO-QoL score for appearance in comparison with patients without orbital decompression ( * p < 0.001). The mean GO-QoL score for appearance was increased after orbital decompression ( p = 0.024). Table 1. Characteristic of study population No-surgery group Decompression group p-value Number Sex (male/female) 18/32 12/ * Age (years) 34.7 ± 12.4 (16-63) 33.8 ± 11.0 (18-60) Family history of thyroid disease (n, %) 17 (34) 13 (43.3) * Smoker (n, %) 9 (18) 4 (13.3) Duration of eye symptoms (months) 34.5 ± 40.5 (6-144) 41.9 ± 56.5 (10-180) Clinical activity score 2.2 ± ± Exophthalmos 18.8 ± ± Compression neuropathy (n, %) 5 (10) 2 (6.7) Values are presented as mean ± standard deviation. Chi-square test; Fisher s exact test; Unpaired t-test. 1515
3 - 대한안과학회지 2016 년제 57 권제 10 호 - Table 2. Factors associated with changes in quality of life (QoL) parameter after orbital decompression Age Duration CAS Pre-op Exo Exo change Post-op Exo Visual score Pearson coefficient p-value Appearance score Pearson coefficient p-value Total QoL score Pearson coefficient p-value CAS = clinical activity score; Pre-op = preoperative; Post-op = postoperative; Exo = exophthalmometer. 대하여환자들이 심각한제한이있다 (1점), 약간제한이있다 (2점), 전혀제한이없다 (3점) 에체크하였다. 1-8번 ( 시각기능점수 ) 까지와 9-16번 ( 외모관련점수 ) 까지각각점수를합산하여그점수를다음과같은공식으로 100점으로환산하였다 : 총점 = [ 합산점수 완료한문항수 ]/[2 완료한문항수 ] 100. 총점이 100점에가까울수록평가항목에대한만족도가높고, 0점에가까울수록만족도가낮은것으로판단하였다. 모든환자들은외래에내원하여처음갑상선안병증을진단받을때설문지를작성하였으며, 안와감압술을받은경우수술후 6개월이상지난시점에설문지를다시작성하였다. 수술을받지않은환자와수술을받은환자의 2개군으로분류하여통계분석을시행하였다 (SPSS 20.0; SPSS Inc., IBM, Armonk, NY, USA). 수술전후삶의질의비교를위해대응표본 T 검정을시행하였고, 수술을받지않은환자와수술을받은환자의삶의질점수비교를위해독립표본 T 검정을시행하였다. 나이, 질병의유병기간, 임상활동도점수, 수술전후의안구돌출도의절대값, 수술을통해감소된안구돌출도의변화량과삶의질점수의변화의관계를확인하기위하여피어슨상관분석을시행하였다. 모든통계분석시유의확률 0.05 미만인경우를통계적으로유의하다고정의하였다. 결과 수술을받지않은환자는 50명, 수술을받은환자는 30명으로환자의평균연령은 34.7 ± 12.4세, 33.8 ± 11.0이었고안구돌출도는각각 18.8 ± 2.2 mm, 19.8 ± 2.5 mm였다 (Table 1). 두군의성비, 평균연령, 초진당시까지질병의유병기간, 임상활동도점수, 안구돌출도는통계적으로유의한차이를보이지않았다 (p>0.05). 안와감압술은세벽감압술 (3-wall decompression) 17건, 내하벽감압술 (inferomedial wall decompression) 13건을시행하였으며, 1건을제외하고모두지방제거술을시행하였다. 안와감압술후안구돌출도는평균 16.3 ± 1.5 mm였으며수술전에비해 3.5 mm의감소를보였다. 수술을받지않은환자는시각기능과관련된삶의질점수가 79.0 ± 21.5점이었으며외모와관련된삶의질점수는 47.2 ± 21.1점이었다. 안와감압술을받은환자는수술전에는삶의질점수가각각 69.5 ± 23.0점, 28.8 ± 17.1점이었으며, 수술후에는각각 70.9 ± 23.7점, 51.5 ± 18.8점이었다 (Fig. 1). 시각기능과관련된삶의질점수는수술을받지않은환자, 수술을받은환자간의차이가없었으며 (p=0.146), 수술을받은환자에서도수술전후의변화가없었다 (p=0.781). 그에반해, 외모와관련된삶의질점수는수술을받지않은환자에서수술을받은환자보다유의하게높았으며, 수술을받은환자에서는수술전후에유의한삶의질의향상을확인할수있었다 (p<0.001). 여자의경우외모와관련된삶의질점수가 35.6 ± 34.97점증가했으며, 남자는 7.9 ± 31.7점증가하여유의한차이를보였다 (p=0.036). 수술을받은환자에서삶의질점수에영향을미칠수있는인자인나이, 질병의유병기간, 임상활동도점수, 수술전후안구돌출도에대한상관관계분석에서는수술후의안구돌출도만이외모와관련된삶의질점수와유의한음의상관관계를보였다 (p=0.02, Pearson coefficient = ) (Table 2). 세부평가항목의답변결과에서는, 모든군에서심각한시각능력의저하를호소하지는않았지만외모적인면에대부분의환자들이큰변화를느꼈다고하였다 (Table 3). 수술을받지않은환자들은그들이원하는무언가를할때 (76%), 책읽기 (48%), 취미활동 (42%) 에제한이생겼다고답하였으며, 외모에관한문항에는외모의변화 (100%), 사진을덜찍게된다 (90%), 자존감의감소 (88%) 순으로변화되었다고답하였다. 수술을받은환자들의경우에도그들이원하는무언가를할때 (80%), 책읽기 (63.3%), 취미활동 (56.7%) 에제한이있었다고하였으며, 외모와관련된문항에서는외모의변화, 자존감의감소 (100%) 에모든환자가문제를느끼고있었으며사진찍기나외부의시선과관련된다른문제들에도제한을느낀다고답하였다. 수술후환자들은시각기능에대한점수는크게변하지않았으나, 길거리에서사람들이쳐다본다, 사회적으로소외된다, 친구를만드는데영향이있다 등의외부시선과관련된항목에서특히더높은점수의증가를보였다. 1516
4 - 허정 이정규 : 안와감압술후삶의질의변화 - Table 3. Frequencies of responses from Grave s ophthalmopathy specific quality of life (GO-QoL) questionnaire Yes, severely limited (%) Yes, a little limited (%) No, not at all limited (%) Follow up Decompression Decompression Decompression Follow up Follow up Before After Before After Before After Visual Riding a bicycle Driving Moving around the house Walking outdoors Reading Watching TV Hobbies or pastimes Hindered from doing something Appearance Changed appearance Stared in the streets People react unpleasantly Influence on self confidence Socially isolated Influence on making friends Appear less on photos Mask changes of appearance 고찰 갑상선안병증은자가면역을통하여안와내세포들에염증을일으켜부종과림프구의침윤을유발하고안와내용물의용적을증가시켜안구돌출을일으키며더나아가각막의손상이나압박시신경병증을나타낼수있는질환이다. 1,13 특히안구돌출과눈꺼풀후퇴, 눈꺼풀내림지연, 토안이동반되는경우외모의변화를보이게되며그과정에서환자들은삶의질이하락하고사회생활에제한을받는것이확인된바있다. 4,5 이번연구에서도환자들은외모의변화, 자존감의감소등을호소하며특히외모와관련된삶의질점수가낮아져있는것을확인할수있었다. 안와감압술은갑상선안병증의대표적인수술적치료법으로이전에는심한안구돌출이있는환자에서노출각막염을치료하거나약물치료에반응하지않는압박시신경병증이있는경우시행하였지만최근심하지않은갑상선안병증에서도미용적목적의안와감압술을시행하는경우가증가하고있다. 7 이번연구에서는수술전후의삶의질점수를비교하여안와감압술이외모의변화를돌리고시력회복에도움을줌으로써환자의삶의질에미치는영향을확인하고자하였는데, 시각기능관련삶의질점수는유의하게변화하지않았다. 이는환자들중압박시신경병증으로수술을한환자가 2명 (6.7%) 이었기때문에안와감압술로기대되는시력회복효과가통계적으로유의성을나타내지못했을것으로생각할수있다. 또한환자중시력에영향을미칠정도의각막손상이있는경우가없어술후의 안구돌출도의감소가시력향상에크게도움을주지못했을것이고, 시각기능과관련된삶의질점수를낮출수있는갑상선안병증의외안근침범으로인한복시나안구운동장애증상의경우안와감압술로치료되지않기때문에삶의질에변화가없었을것이라고짐작된다. 14,15 그에반해외모관련삶의질점수는 22.7점증가했는데, 점수의증가정도는수술후의안구돌출도가작을수록더크게확인되었다 (p=0.02). 나이, 유병기간, 수술전안구돌출도, 수술전후안구돌출도의변화값은유의한차이를보이지않았으며, 환자들은수술전후안구돌출의감소정도보다는정상상태와비슷한안구돌출이없는상태에서더만족한다는것을알수있었다. 안와감압술은안구돌출을감소시켜환자의삶의질까지향상시키는것으로보이며, 수술을시행할때합병증이생기지않을범위에서최대한감압을하는것이환자의삶의질에좋은영향을미친다는것을고려해야하겠다. 수술을시행하지않은환자와수술을시행한환자를비교한결과에서는, 수술을시행하지않은환자의시각기능점수가 8.1점높았으나이는통계적으로유의하지는않았으며, 외모관련점수는 19.2점높아유의한차이를보였다. 두군의성비, 평균연령, 안구돌출도, 임상활동도점수가통계적유의성없이비슷한것을고려하고, 이전에발표된국내의갑상선안병증환자의외모관련점수가 61.9점이었으며해외의발표에서도 60.1점으로차이가큰것을보았을때수술을받은환자들이비슷한임상양상에도불구하고삶의질을낮게느끼는환자들이수술을받는경우가많 1517
5 - 대한안과학회지 2016 년제 57 권제 10 호 - 다고볼수있겠다. 3,16 보존적치료나방사선치료, 안검성형술과같은다른치료에비해안와감압술의경우입원이꼭필요하며전신마취의필요성이있다. 17 또한수술후에도부종및통증으로인하여회복기간이필요하기때문에환자에게시간적, 경제적부담이가해지게된다. 이런부담에도불구하고환자가수술을결정하는경우외모의변화를환자가어떻게받아들이는지와그로인한삶의질변화가영향을미칠것으로보인다. 수술을받은환자들의안구돌출도가거의정상수준으로돌아왔음에도수술을받지않은갑상선환자들과비슷한외모관련삶의질점수를가지고있는것을고려할때, 수술과같은치료뿐만아니라환자의성향을파악하고심리적접근이나조언도함께주어지는것이필요하겠다. 안와감압술을받은환자를대상으로한수술전후삶의질의변화를확인한본연구에서안와감압술이안구돌출도감소에따른외모개선등을통하여삶의질개선에도움을준다는결과를얻었다. 갑상선안병증의병의경과가길며환자들마다다양하게발현되기때문에진료시에안구돌출도나임상적인지표들과더불어환자가느끼는질병의정도나그에따른삶의질의변화를고려하여치료방침을결정하는것이필요하다고생각한다. 본연구의한계로는압박시신경병증으로수술을한환자의수가상대적으로적어이환자들에대한수술후삶의질변화에대해통계적으로분석하지못했다는점이있다. 그리고수술을하지않은환자의경우시간경과에따른변화를확인하지못하여자연경과상의호전등으로인한삶의질변화를반영하지못하였다. 또한환자의외모에관한삶의질점수에영향을끼칠수있는눈꺼풀뒤당김, 눈꺼풀처짐등의외모변화를분석에반영하지못했다. 이는갑상선안병증에서흔히나타나는눈꺼풀의변화를정확한수치나변인으로지정하기어려웠기때문인데, 환자들의삶의질과눈꺼풀의변화가큰상관관계가없다는연구결과가나온바있으나 10,18 이에대한추가적인연구가필요하겠다. REFERENCES 1) Burch HB, Wartofsky L. Graves' ophthalmopathy: current concepts regarding pathogenesis and management. Endocr Rev 1993;14: ) Bahn RS. Understanding the immunology of Graves' ophthalmopathy. Is it an autoimmune disease? Endocrinol Metab Clin North Am 2000;29:287-96, vi. 3) Choi YJ, Lim HT, Lee SJ, et al. Assessing Graves' ophthalmopathy-specific quality of life in Korean patients. Eye (Lond) 2012;26: ) Son BJ, Lee SY, Yoon JS. Evaluation of thyroid eye disease: quality-of-life questionnaire (TED-QOL) in Korean patients. Can J Ophthalmol 2014;49: ) Lee H, Roh HS, Yoon JS, Lee SY. Assessment of quality of life and depression in Korean patients with Graves' ophthalmopathy. Korean J Ophthalmol 2010;24: ) Bartalena L, Marocci C, Bogazzi F, et al. Glucocorticoid therapy of Graves' ophthalmopathy. Exp Clin Endocrinol 1991;97: ) Lyons CJ, Rootman J. Orbital decompression for disfiguring exophthalmos in thyroid orbitopathy. Ophthalmology 1994;101: ) Fatourechi V, Garrity JA, Bartley GB, et al. Graves ophthalmopathy. Results of transantral orbital decompression performed primarily for cosmetic indications. Ophthalmology 1994;101: ) Wickwar S, McBain H, Ezra DG, et al. The psychosocial and clinical outcomes of orbital decompression surgery for thyroid eye disease and predictors of change in quality of life. Ophthalmology 2015;122: e1. 10) Terwee CB, Dekker FW, Mourits MP, et al. Interpretation and validity of changes in scores on the Graves' ophthalmopathy quality of life questionnaire (GO-QOL) after different treatments. Clin Endocrinol (Oxf) 2001;54: ) Mourits MP, Prummel MF, Wiersinga WM, Koornneef L. Clinical activity score as a guide in the management of patients with Graves' ophthalmopathy. Clin Endocrinol (Oxf) 1997;47: ) Terwee CB, Gerding MN, Dekker FW, et al. Test-retest reliability of the GO-QOL: a disease-specific quality of life questionnaire for patients with Graves' ophthalmopathy. J Clin Epidemiol 1999;52: ) Achtsidis V, Tentolouris N, Theodoropoulou S, et al. Dry eye in Graves ophthalmopathy: correlation with corneal hypoesthesia. Eur J Ophthalmol 2013;23: ) Abràmoff MD, Kalmann R, de Graaf ME, et al. Rectus extraocular muscle paths and decompression surgery for Graves orbitopathy: mechanism of motility disturbances. Invest Ophthalmol Vis Sci 2002;43: ) Garrity JA, Fatourechi V, Bergstralh EJ, et al. Results of transantral orbital decompression in 428 patients with severe Graves' ophthalmopathy. Am J Ophthalmol 1993;116: ) Terwee CB, Gerding MN, Dekker FW, et al. Development of a disease specific quality of life questionnaire for patients with Graves' ophthalmopathy: the GO-QOL. Br J Ophthalmol 1998;82: ) Soeters MR, van Zeijl CJ, Boelen A, et al. Optimal management of Graves orbitopathy: a multidisciplinary approach. Neth J Med 2011;69: ) Carr T, Moss T, Harris D. The DAS24: a short form of the Derriford Appearance Scale DAS59 to measure individual responses to living with problems of appearance. Br J Health Psychol 2005;10(Pt 2):
6 - 허정 이정규 : 안와감압술후삶의질의변화 - Appendix 1. Grave s ophthalmopathy specific quality of life (GO-QoL) questionnaire in Korean used on this study. 갑상선안병증환자의 삶의질 설문지 등록번호 지난 1 주일간의생활속에서갑상선안병증으로인해다음과같은활동들이얼마나제한을받았는지생각해보고, 알맞은칸에표시 (V) 해주세요 심각한제한이있다약간제한이있다전혀제한이없다 타는법을배우지않았다. 1. 자전거타기 2. 운전 3. 실내에서돌아다니기 4. 실외에서돌아다니기 5. 책, 신문읽기 6. TV 를보기 7. 취미활동, 여가생활 8. 하고자하는일을할때갑상선안병증때문에방해를받습니까? 다음은갑상선안병증과관련된전반적인질문입니다. 알맞은칸에표시해주세요 9. 갑상선안병증으로당신의외모가바뀌었다고생각하나요? 10. 갑상선안병증때문에길에서다른사람이당신을쳐다본다고생각하나요? 11. 갑상선안병증때문에사람들이당신을불쾌하게대한다고생각하나요? 12. 갑상선안병증이당신의자존감에영향을미치나요? 13. 갑상선안병증때문에사회적으로격리되었다고생각하나요? 14. 갑상선안병증이친구를사귀는데영향을미친다고생각하나요? 15. 갑상선안병증으로당신은사진을찍는게꺼려지시나요? 16. 갑상선안병증으로인해생긴외모의변화를화장이나안경, 모자등을이용하여가리고자하시나요? 심각한제한이있다약간제한이있다전혀제한이없다 1519
7 - 대한안과학회지 2016 년제 57 권제 10 호 - = 국문초록 = 안와감압술이갑상선안병증환자의삶의질에미치는영향 목적 : 갑상선안병증환자에서안와감압술수술후의환자의삶의질변화를조사하였다. 대상과방법 : 2014 년 8 월부터 2015 년 12 월까지본원에내원하여갑상선안병증으로진단받고수술을받은 30 명과경과관찰만을한 50 명을대상으로의무기록을분석하였다. 환자들은수술전후에 Grave s ophthalmopathy specific quality of life (GO-QoL) 설문지를작성하였다. 설문조사결과를비교하고이에영향을줄수있는나이, 유병기간, 안구돌출도등의인자들을조사하였다. 결과 : 안와감압술을받은환자들 (28.8 ± 17.1 점 ) 은경과관찰만하는환자들 (42.7 ± 21.1 점 ) 에비해수술전더낮은외모관련삶의질점수를보였다 (p<0.001). 안와감압술후에, 외모관련삶의질점수는 28.8 ± 17.1 점에서 51.5 ± 18.8 로증가했다 (p=0.024). 시각관련삶의질점수는안와감압술을받은환자와받지않은환자에서차이가없었다. 안와감압술시행전과후를비교한결과에서도시각관련삶의질점수는유의한차이는보이지않았다. 술후의환자의시각관련삶의질점수의향상정도는술후환자의안구돌출도와유의한상관관계를보였다. 결론 : 안와감압술은외모와관련된삶의질점수를증가시켰다. 심리적접근또한환자의삶의질을높이는데필요하겠다. < 대한안과학회지 2016;57(10): > 1520
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