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1 검안및콘택트렌즈학회지 2018 년제 17 권제 4 호 Ann Optom Contact Lens 2018;17(4):83-88 ISSN (Print) ISSN (Online) Review Article 미숙아망막병증진단과치료의최신지견 Update on Diagnosis and Treatment of Retinopathy of Prematurity 허환 Hwan Heo, MD, PhD 전남대학교의과대학안과학교실 Department of Ophthalmology, Chonnam National University Medical School, Gwangju, Korea Retinopathy of prematurity is still the leading cause of blindness in children. It is on the rise due to the development of postnatal care technology in developing and developed countries. However, due to the lack of experts, appropriate diagnosis and treatment are often not available. Therefore, it is necessary to develop technologies such as telemedicine and diagnostic automation technology for retinopathy of prematurity. Experts should know that the difference of timing and nature of recurrence between intravitreal anti-vascular endothelial growth factor (anti-vegf) injection and laser treatment. And, after verifying safety dose and systemic complication, guidelines for safe use of intravitreal anti-vegf injection should be developed. Ann Optom Contact Lens 2018;17(4):83-88 Key Words: Bevacizumab; Ranibizumab; Retinopathy of prematurity; Telemedicine 서 론 미숙아망막병증 (retinopathy of prematurity, ROP) 은미숙아에서비정상적인망막신생혈관이발생하여망막견인과박리로실명까지발생할수있는질환이다. 미숙아망막병증의병태생리는월경후주령 (postmenstrual age, PMA) 22 주에서 30주사이에정상혈관의성장이멈추고, 미성숙한망막혈관의폐쇄가일어나서망막주변부무혈관상태가되는 1기, 그후 PMA 31주에서 44주사이에무혈관망막주변부의저산소에의한혈관증식이발생하는 2기로진행하면서발생한다. 1 미숙아망막병증의발생에적혈구생성인자 (erythropoietin) 와인슐린유사성장인자 -1 (insulin-like growth Received: Revised: Accepted: Address reprint requests to Hwan Heo, MD, PhD Department of Ophthalmology, Chonnam National University Medical School, #42 Jebong-ro, Dong-gu, Gwangju 61469, Korea Tel: , Fax: opheye@hanmail.net factor-1) 도관여하지만주로혈관내피성장인자 (vascular endothelial growth factor, VEGF) 가 1기에는감소하고 2기에는과도하게생성되면서비정상적인망막혈관증식이발생한다. 2 미숙아망막병증은선별검사, 진단및치료에있어서최근수년간많은발전이있었다. 본종설에서는미숙아망막병증진단과치료의최신지견을소개하고자한다. 본론 1. 미숙아망막병증의선별검사미국에서한해약 4백만명의신생아가태어나며그중약 40만명이미숙아로출생한다. 그중약 8만여명의미숙아가미숙아망막병증선별검사를받게되는데, 선별검사를받은미숙아의약 20% 에서미숙아망막병증이발생하며 8.3% 에서치료까지시행받게된다. 3,4 실제선별검사를하는미숙아중 90% 이상이치료가필요하지않으므로, 미숙아에게스트레스를주는이러한선별검사를줄이기위한방법들이개발되었다. 대표적으로 weight, insulin-like growth Copyright 2018, The Korean Optometry Society The Korean Contact Lens Study Society Annals of Optometry and Contact Lens is an Open Access Journal. All articles are 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. 83

2 - 검안및콘택트렌즈학회지 2018 년제 17 권제 4 호 - factor-i, Neonatal, ROP (WINROP), The Children's Hospital of Philadelphia, ROP (CHOP-ROP), The Colorado, ROP (CO-ROP) 등으로주로출생후체중증가정도가부족할수록미숙아망막병증발생위험도가높아진다는알고리즘을이용하였고, CHOP-ROP는출생체중과출생시제태연령도인자에포함하였다. 최근보고에의하면 CHOP-ROP 는 98.5% 민감도를보이고선별검사하는미숙아의수를 28.4% 줄일수있었고, CO-ROP는민감도 96.9% 를보이며선별검사수를 26.1% 줄일수있다고보고하였다. 5 다양한국가와인종에대해적용하여검증하고있었던 WINROP의경우 % 사이의민감도를보였고, 저자가우리나라에서도적용하여조사한결과 90% 민감도를보였다. 6,7 스웨덴과같은선진국에서는 100% 가까운민감도를보였지만개발도상국에서는민감도가낮았는데, 최근보고에의하면혈중산소농도를 88-92% 로조절했던미숙아에서는 87.5% 의민감도를보였지만, 91-95% 로조절했을때는 48% 민감도를보여, 높은혈중산소농도로유지하면출생후체중증가정도를미숙아망막병증발생을예측하는데사용하기는무리가있다고하였다. 8 또한, 뇌수종이나패혈증, 수술등의기왕력이있을경우비정상적인체중증가로인해적용하는데주의가필요하여, 아직새로개발된알고리즘을적용하기는어려운상황이다. 2. 미숙아망막병증의진단미숙아망막병증의진단은현재까지전문가가도상검안경과렌즈를이용하여검사하는것이가장정확한방법으로알려져있다. 최근에선진국에서는제태연령이매우낮은미숙아의생존율이증가하고, 중국과인도에서도신생아중환자실의시설과기술이좋아지면서생존하는미숙아가늘어나면서전세계적으로미숙아망막병증이증가하고있다. 반면진단과치료를위한전문의사인력이부족하여진단의기계화와원격진단의기술에대한연구가활발히이루어지고있다. 원격진단은인도에서 Karnataka Internet Assisted Diagnosis of ROP (KIDROP), Vittala, ROP Eradication Save Our Sight (ROPE-SOS) project 등이개발되었고, 칠레에서는국가차원에서미숙아망막병증원격진단시스템을도입했다 (Fig. 1). 9,10 미국에서는 1,200여명의미숙아대상으로원격진단이충분히유용하다고보고한바있다. 11 미숙아망막병증의심한정도와 plus 징후등이전문가들사이에서도차이가난다는보고가있다. 미숙아 1,553안의망막사진을미숙아망막병증을 10년이상진단하고치료하였던두명의전문가에게 stage와 plus 징후여부를판단하게하였더니, stage는 40%, plus 징후는 18% 의불일치를보 였다. 12 이러한판단의불일치를보완하고자컴퓨터이미지프로세싱을통해 stage와 plus 징후를객관적으로판단하려는연구가이루어졌고, 최근에는이미지분석딥러닝기술이발전하여이를미숙아망막병증진단에적용하는연구도이루어졌다 미숙아망막병증의치료미숙아망막병증의치료는 1992년다이오드레이저가안과적으로사용되면서무혈관부위의레이저광응고술이냉동응고술대체하여효과는좋고부작용은적은치료법으로현재까지사용되고있다. 나이관련황반변성에서항-VEGF 의유리체강내주사가효과적인치료법으로대두되면서, 2007년 aggressive posterior-rop (AP-ROP) 에서항-VEGF 주사효과를보고하였고, 그이후미숙아망막병증에서항 -VEGF 치료가지속적으로증가하고있다. 2011년미숙아망막병증에서항-VEGF인 bevacizumab 유리체강내주사효과에대한대단위전향적무작위연구가발표되면서항-VEGF 치료에대한근거가마련되었다. 16 연구결과 zone 2 미숙아망막병증에서는레이저치료와효과차이를보이지않으나, zone 1 미숙아망막병증에서는재발률이 6% 로레이저 26% 에비하여의미있게감소하였다. 하지만평균재발시기는레이저에서는 6.4주, bevacizumab 치료에서는 19.2주로레이저보다더오랜기간추적관찰이필요하다고보고하였다. 그후분자량이적고체외배출이빨라서전신부작용이적을것으로예상되는 ranibizumab 도사용되면서대단위임상시험이이루어졌으며, 새로운융합단백질로개발된 aflibercept와 conbercept도사용하여효과적이었다는보고들이있다 레이저치료와비교하여항-VEGF 의유리체강내주사의장점은시술이간단하고, 주변부망막이보존된다는점과근시의발생이레이저에비하여적다는점이다. 하지만 VEGF 의억제로정상망막혈관의발달을방해하지는않는지, 재발시기와양상이다른지, 유리체강내로주사하는용량이적절한지, 전신적으로안전한방법인지에대한논의가필요할것이다. 1) 정상망막혈관의성장 VEGF가과도하게생성되면미숙아망막병증이발생하지만, 정상혈관발달에도필요한인자이다. 최근연구에의하면 bevacizumab을주사한미숙아망막병증환아 55% 에서망막혈관이망막주변부까지완전히자라지않는다고하였고, ranibizumab에서도보고되었다. 20 저자가우리나라에서도 AP-ROP로 bevacizumab 치료후 4개월까지도정상혈관이주변부망막까지완전히자라지않았다고보고한 84

3 - 허 환 : 미숙아망막병증의 최신 지견 - Figure 1. Computer screenshot of the interface of a telemedicine software. A standard set of six photos is captured (external photo, posterior pole centered around the optic nerve, temporal, nasal, inferior, and superior). The software is capable of generating a montage of the acquired images. 10 OD = oculus dexter; ROP = retinopathy of prematurity; PM A = postmenstrual age. 바 있다(Fig. 2).21 최근에 이러한 현상을 chronic vascular 6.4주이지만 bevacizumab 주사 후의 재발 시기는 평균 19.2주 arrest와 scalloped regression이라는 용어를 사용하였고, 항 로 약 3배 이상 길었다. 그 후에 항-VEGF 치료 후 1개월 16 -VEGF 치료를 시행한 미숙아의 경우 재태연령 60주에 전 에서 18개월까지 후에도 재발하는 사례들이 보고되었고, 신마취 후 형광안저촬영을 하여 무혈관 망막 부위가 남아 재발의 형태도 레이저 치료 후에 발생하는 재발의 경우는 있으면 레이저 치료를 하는 것이 추후 미숙아망막병증의 혈관 부위와 무혈관 부위 경계에서 발생하는 반면, 항 재발이나 합병증 발생을 막을 수 있을 것이라고 보고한 연 -VEGF 치료 후에는 경계가 아닌 좀 더 후방부에서 신생혈 22 구도 있다. 관과 혈관 누출이 발생하면서 재발이 나타나므로, 항-VEGF 의 치료 후 경과관찰 시 이러한 재발 특징을 알고 혈관 부 2) 재발 시기와 형태 위와 무혈관 부위 경계뿐만 아니라 후방부도 자세히 관찰 Bevacizumab Eliminates the Angiogenic Threat of ROP 해야 한다고 보고하였다. 23 (BEAT-ROP) 보고에서 레이저 치료 후 재발 시기는 평균 85

- 검안및콘택트렌즈학회지 2018 년제 17 권제 4 호 - A D B E C F Figure 2. Bilateral fundus photographs and montage fluorescein angiography (FA) of aggressive posterior retinopathy of prematurity.

4 - 검안및콘택트렌즈학회지 2018 년제 17 권제 4 호 - A D B E C F Figure 2. Bilateral fundus photographs and montage fluorescein angiography (FA) of aggressive posterior retinopathy of prematurity. (A) Fundus photograph before treatment shows severe vessel tortuosity, loop-shaped large vessels, a few hemorrhages with plus disease and immature development of the retinal vessels that stopped in zone 1. (B) FA before treatment shows a significant delay of choroidal filling, loop-shaped large arteriovenous shunts, capillary non-perfusion inside loop and leakages from diffuse flat neovascularization and arteriovenous shunt vessels. (C) One month after treatment, FA shows relatively normal choroidal filling, and stabilization and growth of retinal vessels without significant leakages. (D) Two months after treatment, montage FA shows that retinal vessels grew and reached at zone 2. (E) Four months after treatment, montage FA shows terminal point leakages at the bilateral temporal vascular and avascular junction. (F) Five months after treatment, montage FA shows decreased terminal point leakages and a peripheral retinal avascular area. 21 3) 용량미숙아망막병증에서항-VEGF 의치료는초기연구들과 BEAT- ROP 연구에서성인용량의절반을사용하였다. Bevacizumab의경우성인용량 1.25 mg의절반인 mg을사용하였고 ranibizumab의경우도 0.5 mg의절반인 0.25 mg을사용하였다. 16,24 하지만미숙아는유리체용량이성인의 1/3, 몸무게는 1/15로단순히절반으로줄여사용하기에는미숙아에게과도한용량일수있다. 그래서최근에는용량을줄여사용한후효과를본연구들이보고되고있다. Bevacizumab 0.25 mg, mg, mg, mg을각각주사한후재발률을알아보았더니총 61명중 11명 (18%) 에서재발하여치료가필요하였지만, 용량과상관성은보이지않았고, ranibizumab에서도 0.2 mg과 0.12 mg으로치료후비교한결과재발률이 85.7% 와 88.9% 로차이를보이지않았다. 25,26 4) 안전성미숙아망막병증에서항-VEGF의치료는효과가매우좋음에도불구하고전신안정성에대한우려가항상있다. 유리체강내로주사한항-VEGF는눈밖으로나와전신의 VEGF를억제한다는것은이미알려져있어서, 미숙아의경우뇌, 폐, 신장등혈관이풍부한기관이아직미성숙한상태로혈관형성이필요한상황에서전신 VEGF를억제할경우심각한전신부작용이우려되었던것이었다. 2013년 ranibizumab 0.2 mg을유리체내에주사한미숙아에서 3주째혈장 VEGF가 0으로감소한후 4주째회복된다고발표한보고가있었다. 27 최근에는 ranibizumab 0.12 mg과 0.20 mg 을주입한총 10명미숙아를대상으로조사한결과혈장 VEGF는두농도모두에서감소하지않았다고보고되었으며, 다른연구에서는 5명의미숙아를대상으로 0.5 mg ranibizumab을주사하고치료전약 46 pg/ml였던혈장 VEGF 가치료하루후약 11 pg/ml까지감소하지만 1주후에는 86

5 - 허환 : 미숙아망막병증의최신지견 - 회복된다고보고하였다. 28,29 미숙아망막병증에서최초로항 -VEGF 치료를시작한 2007년부터약 10여년이지난현재까지항-VEGF 치료후전신부작용을보고한연구는단하나로, 레이저치료한군에비하여 bevacizumab 치료한군에서 18개월째중증신경발달장애 (severe neurodevelopmental disabilities) 가약 3배정도더발생한다고하였다. 30 하지만 bevacizumab으로치료한군이 zone 1 ROP의비율이더높고, 중증신경발달장애에시력저하, 황반끌림등눈관련장애도포함되어해석에주의가필요할것으로생각된다. 이보고를제외하고대단위연구에서심각한전신부작용은보고되지않았다. 16,28,31 결 론 본종설을통해현재미숙아망막병증의진단과치료에관한최근동향을알아보았다. 현재개발도상국과선진국에서미숙아관리기술이발전함에따라미숙아망막병증이다시증가하는추세이다. 하지만전문의료인력의부족으로적절한진단과치료가이루어지지못하는경우가많아, 원격진료와진단의자동화기술등의기술개발이필요하고, 새로운치료법인항-VEGF 유리체강내주사를안전하게미숙아에게사용할수있는가이드라인이필요함을강조하고자한다. REFERENCES 1) Smith LEH. Through the eyes of a child: understanding retinopathy through ROP the Friedenwald lecture. Invest Ophthalmol Vis Sci 2008;49: ) Pierce EA, Avery RL, Foley ED, et al. Vascular endothelial growth factor/vascular permeability factor expression in a mouse model of retinal neovascularization. Proc Natl Acad Sci U S A 1995;92: ) Ludwig CA, Chen TA, Hernandez-Boussard T, et al. The epidemiology of retinopathy of prematurity in the United States. Ophthalmic Surg Lasers Imaging Retina 2017;48: ) Martin JA, Hamilton BE, Osterman MJK, et al. Births: final data for Natl Vital Stat Rep 2018;67: ) Binenbaum G, Ying GS, Tomlinson LA; Postnatal Growth and Retinopathy of Prematurity (G-ROP) Study Group. Validation of the Children s Hospital of Philadelphia Retinopathy of Prematurity (CHOP ROP) Model. JAMA Ophthalmol 2017;135: ) Sanghi G, Narang A, Narula S, Dogra MR. WINROP algorithm for prediction of sight threatening retinopathy of prematurity: initial experience in Indian preterm infants. Indian J Ophthalmol 2018; 66: ) Choi JH, Löfqvist C, Hellström A, Heo H. Efficacy of the screening algorithm WINROP in a Korean population of preterm infants. JAMA Ophthalmol 2013;131: ) Lundgren P, Hård AL, Wilde Å, et al. Implementing higher oxygen saturation targets reduced the impact of poor weight gain as a predictor for retinopathy of prematurity. Acta Paediatr 2018;107: ) Moshfeghi DM. Systemic solutions in retinopathy of prematurity. Am J Ophthalmol 2018;193: ) Thanos A, Yonekawa Y, Todorich B, et al. Screening and treatments using telemedicine in retinopathy of prematurity. Eye Brain 2016;8: ) Quinn GE, Ying GS, Daniel E, et al. Validity of a telemedicine system for the evaluation of acute-phase retinopathy of prematurity. JAMA Ophthalmol 2014;132: ) Campbell JP, Ryan MC, Lore E, et al. Diagnostic discrepancies in retinopathy of prematurity classification. Ophthalmology 2016; 123: ) Rajashekar D, Srinivasa G, Vinekar A. Comprehensive retinal image analysis for aggressive posterior retinopathy of prematurity. PLoS One 2016;11:e ) Hu J, Chen Y, Zhong J, et al. Automated analysis for retinopathy of prematurity by deep neural networks. IEEE Trans Med Imaging 2018; doi: /TMI [Epub ahead of print]. 15) Brown JM, Campbell JP, Beers A, et al. Automated diagnosis of plus disease in retinopathy of prematurity using deep convolutional neural networks. JAMA Ophthalmol 2018;136: ) Mintz-Hittner HA, Kennedy KA, Chuang AZ; BEAT-ROP Cooperative Group. Efficacy of intravitreal bevacizumab for stage 3+ retinopathy of prematurity. N Engl J Med 2011;364: ) Novartis Pharmaceuticals. Randomized study for Efficacy and Safety of Ranibizumab 0.5mg in Treat-extend and Monthly Regimens in Patients With namd. Clinical Trials.gov. gov/ct2/show/nct Accessed April 17, ) Sukgen EA, Söker G, Koçluk Y, Gülek B. Effect of intravitreal aflibercept on central retinal arterial blood flow in type 1 retinopathy of prematurity. Eur J Ophthalmol 2017; doi: /ejo [Epub ahead of print]. 19) Bai Y, Nie H, Wei S, et al. Efficacy of intravitreal conbercept injection in the treatment of retinopathy of prematurity. Br J Ophthalmol 2018; pii: bjophthalmol doi: / bjophthalmol [Epub ahead of print]. 20) Tahija SG, Hersetyati R, Lam GC, et al. Fluorescein angiographic observations of peripheral retinal vessel growth in infants after intravitreal injection of bevacizumab as sole therapy for zone I and posterior zone II retinopathy of prematurity. Br J Ophthalmol 2014;98: ) Park SW, Jung HH, Heo H. Fluorescein angiography of aggressive posterior retinopathy of prematurity treated with intravitreal anti-vegf in large preterm babies. Acta Ophthalmol 2014;92: ) Toy BC, Schachar IH, Tan GS, Moshfeghi DM. Chronic vascular arrest as a predictor of bevacizumab treatment failure in retinopathy of prematurity. Ophthalmology 2016;123: ) Hu J, Blair MP, Shapiro MJ, et al. Reactivation of retinopathy of prematurity after bevacizumab injection. Arch Ophthalmol 2012; 130: ) Castellanos MA, Schwartz S, García-Aguirre G, Quiroz-Mercado H. Short-term outcome after intravitreal ranibizumab injections for the treatment of retinopathy of prematurity. Br J Ophthalmol 2013; 97: ) Wallace DK, Dean TW, Hartnett ME, et al. A dosing study of bevacizumab for retinopathy of prematurity: Late recurrences and additional treatments. Ophthalmology 2018; doi: /j.ophtha [Epub ahead of print]. 87

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A 617 Special Issue Diabetic Retinopathy Won Ki Lee, M.D. Department of Ophthalmology The Catholic University of Korea College of Medicine Kangnam St. Mary s Hospital E mail : wklee@catholic.ac.kr Abstract R