대한안과학회지 2017 년제 58 권제 3 호 J Korean Ophthalmol Soc 2017;58(3):289-295 ISSN 0378-6471 (Print) ISSN 2092-9374 (Online) https://doi.org/10.3341/jkos.2017.58.3.289 Original Article 국한성맥락막혈관종에서발생한장액망막박리에대한치료결과 Treatment Outcome of Serous Macular Detachment in Circumscribed Choroidal Hemangioma 권정민 1 이승민 1 권한조 2 박성후 2,3 이지은 2,3 변익수 1,3 Jeong Min Kwon, MD 1, Seung Min Lee, MD 1, Han Jo Kwon, MD 2, Sung Who Park, MD 2,3, Ji Eun Lee, MD, PhD 2,3, Ik Soo Byon, MD 1,3 양산부산대학교병원안과학교실의생명융합연구소 1, 부산대학교병원안과학교실의생명연구소 2, 부산대학교의학전문대학원안과학교실 3 Research Institute for Convergence of Biomedical Science and Technology, Department of Ophthalmology, Pusan National University Yangsan Hospital 1, Yangsan, Korea Medical Research Institute, Department of Ophthalmology, Pusan National University Hospital 2, Busan, Korea Department of Ophthalmology, Pusan National University School of Medicine 3, Yangsan, Korea Purpose: To determine the clinical outcome of anti-vascular endothelial growth factor (anti-vegf) and photodynamic therapy (PDT) for circumscribed choroidal hemangioma (CCH) with serous retinal detachment. Methods: The medical records of patients having CCH with serous retinal detachment in macula were retrospectively reviewed. CCH and serous retinal detachment were evaluated via fundus photography, optical coherence tomography, indocyanine green angiography, and ultrasonography. Results: A total of 9 eyes were enrolled in this study. The average follow-up period was 19.2 months. The mean visual acuity was 0.51 ± 0.52 (logmar) and the mean maximum diameter and thickness of the tumor were 6,154.4 ± 2,019.9 μm and 2,224.4 ± 862.1 μm, respectively. Of the 6 eyes receiving anti-vegf (mean number of injections: 3.16) as the first treatment for serous retinal detachment, 5 had sustained or recurred intraretinal/subretinal fluid (IRF/SRF) and needed additional PDT and transpupillary thermotherapy. In the 3 eyes that received PDT (mean number of treatments: 1.3) as an initial treatment, IRF/SRF was completely resolved. Finally, 8 eyes achieved complete resolution of SRF and IRF; however visual recovery was limited. Conclusions: PDT, even with a small number of treatments, can alleviate IRF/SRF in CCH, while anti-vegf did not. J Korean Ophthalmol Soc 2017;58(3):289-295 Keywords: Circumscribed choroidal hemangioma, Serous retinal detachment, Photodynamic therapy Received: 2016. 9. 1. Revised: 2017. 1. 25. Accepted: 2017. 3. 1. Address reprint requests to Ik Soo Byon, MD Department of Ophthalmology, Pusan National University Yangsan Hospital, #20 Geumo-ro, Mulgeum-eup, Yangsan 50612, Korea Tel: 82-55-360-2592, Fax: 82-55-360-2161 E-mail: isbyon@pusan.ac.kr * This work was supported by clinical research grant from Pusan National University Yangsan Hospital. * This study was presented as an e-poster at the 115th Annual Meeting of the Korean Ophthalmological Society 2016. 맥락막혈관종 (choroidal hemangioma) 은드문양성혈관종양으로선천적으로발생하여안구가성장함에따라같이성장한다. 1 맥락막침범정도에따라국한성과미만성으로나뉘며국한성맥락막혈관종은일반적으로후극부의시신경유두이측에서주로관찰된다. 1,2 전형적인국한성맥락막혈관종은오렌지색을띠며, 종양이크거나황반아래에발생하지않는다면성인이될때까지증상이잘나타나지않아대개 20대에서 40대사이에진단된다. 2 종양이황반을침범하거나장액망막박리가발생하면시력저하를일으키게되며, 동반되는낭포황반부종, c2017 The Korean Ophthalmological Society This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/3.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited. 289
- 대한안과학회지 2017 년제 58 권제 3 호 - 망막색소상피변화등에의해서도시력저하가발생할수있다. 1,3-7 장액망막박리가발생한맥락막혈관종에서는레이저광응고술, 냉동요법, 국소방사선치료, 경동공온열요법, 광역학요법등이치료에사용되어왔으며, 8 최근에는항혈관내피성장인자도소개되었다. 9 하지만국한성맥락막혈관종에대한국내외의보고가많지않아장액망막박리의치료예후에대하여잘알려지지않은실정이다. 이에저자들은국한성맥락막혈관종에서발생한장액망막박리의치료결과에대해알아보고자한다. 대상과방법 2010년부터 2016년까지부산대학교병원과양산부산대학교병원에서국한성맥락막혈관종으로진단받은 16명환자의의무기록과영상을후향적으로분석하였다. 본연구는양산부산대학교병원의학연구윤리심의위원회 (institutional review board, IRB) 의승인하에진행되었으며 ( 승인번호 : 05-2016-108), 헬싱키선언 (Declaration of Helsinki) 을준수하였다. 국한성맥락막혈관종의진단은안저검사에서오랜지-적색의종괴가관찰되며, 안초음파 A 스캔에서종양표면에는높은반향이나타나고내부에는중등도-고반향의내반사파 (50-100%) 가관찰되는경우로하였다. 의무기록을이용하여대상환자의나이, 성별, 최대교정시력을조사하였다. 종양의위치, 크기, 두께와장액망막박리에서망막내액, 망막하액의존재는안초음파 (AVISO, Quantel Medical, Clermont-Ferrand, France), 빛간섭단층촬영 (Cirrus OCT, Carl Zeiss Meditec, Dublin, CA, USA), 형광안저혈관조영및인도사이아닌그린혈관조영 (FF450 plus IR, Carl Zeiss Meditec, Dublin, CA, USA), (Spectralis HRA, Heidelberg Engineering GmbH, Heidelberg, Germany) 을시행하여조사하였다. 종양의크기와두께는안초음파영상에서측정된최대지름으로하였다. 치료방법장액망막박리가동반된환자는술자의판단에따라항혈관내피성장인자유리체내주사, 광역학치료, 경동공온열치료를이용하여치료하였다. 항혈관내피성장인자유리체내주사는 0.5% proparacaine 점안액 (Alcaine, Alcon Laboratories, Fort Worth, TX, USA) 으로점안마취를한다음, 5% povidone-iodine을사용하여눈알결막과눈주변피부를소독하였다. 각막윤부에서 3.5 mm 떨어진곳에 30 gauge 주사바늘을이용하여베바시주맙 (Avastin, Roche, Basel, Switzerland) 1.25 mg/0.05 ml를주입하였다. 광역학요법은환자의체표면적당 6 mg의 Verteporfin (Visudyne, Novartis Ophthalmics AG, Basel, Switzerland) 을 10분동안정맥내주사한뒤주사시점에서 15분후에 689 nm 파장의레이저를표준치료방법 (power = 50 J/cm 2, intensity 600 mw/cm 2, duration = 83 sec) 을이용하여조사하였다. 10 레이저조사범위는인도사이아닌그린혈관조영에서측정된종양의크기보다 500 μm 더큰직경으로시행하였다. 경동공온열요법은동공이완전히산대된상태에서점안마취를한뒤세극등현미경을이용하여 810 nm 파장의적외선다이오드레이저 (OcuLight, Iris Medical Instruments, Mountain View, CA, USA) 를지속적으로조사하였다. 레이저조사반경은종양의최대직경에따라시행하였다. 레이저조사는종양의모든범위를포함하여이루어졌으며, 레이저세기는 400-600 mw의범위에서치료하였다. 치료전후의시력과망막내 / 하액의변화를조사하였다. 통계를위해스넬렌시력표를이용하여측정한시력을 logmar 시력으로변환하였다. 치료전후의시력변화를위해 Wilcoxon signed rank test를사용하였으며, p<0.05인경우를통계적으로유의하다고하였다. Table 1. Patients characteristics Sex Age Follow up Treatment BCVA (logmar) SRF IRF Tumor size (μm) (years) (months) (2nd treatment) Initial Final Initial Final Initial Final Width Thickness 1 F 54 26 Anti-VEGF, (PDT) 0.4 0.3 + - - - 7,810 1,450 2 M 44 43 Anti-VEGF, (TTT) 0.2 0.4 + - - - 5,400 2,760 3 F 49 33 Anti-VEGF, (PDT) 0.1 0 + - - - 4,310 1,320 4 M 34 18 Anti-VEGF, (PDT) 0.4 0.1 + - - - 2,840 1,210 5 M 53 11 Anti-VEGF, (PDT) 1.4 1.4 + + + + 5,020 1,760 6 F 68 9 Anti-VEGF 1.4 1.7 + - - - 8,620 2,980 7 M 60 14 PDT 0.1 0.2 + - - - 5,360 2,060 8 F 56 12 PDT 0.4 0.1 + - + - 8,120 3,650 9 M 44 7 PDT 0.2 0.2 + - - - 7,910 2,830 BCVA = best corrected visual acuity; SRF = subretinal fluid; IRF = intraretinal fluid; F = female; M = male; Anti-VEGF = anti-vascular endothelial growth factor; PDT = photodynamic therapy; TTT = transpupillary thermotherapy. 290
- 권정민외 : 국한성맥락막혈관종 - 결과 총 16명이국한성맥락막혈관종으로진단되어경과관찰하였다. 12안에서황반부에맥락막혈관종이위치하였으며, 모두단안에종양이있었다. 10안에서황반부장액망막박리가발생하여치료를시행받았다. 2안은망막하액과함께 망막내액이동반되어있었다. 1안은치료후경과관찰이되지않아최종적으로 9안이본연구에포함되었다. 장액망막박리가발생한환자는남자가 5명 (55.6%), 여자가 4명 (44.4%) 이었고, 평균연령은 51.3 ± 10.0세 (34-68세) 였다. 치료전평균시력은 0.51 ± 0.52 (0.10-1.40), 종양의지름은평균 6,154.4 ± 2,019.9 μm ( 범위, 2,840-8,620), 두께는 A B C Figure 1. Representative case 4 having an exudative retinal detachment in circumscribed choroidal hemangioma (CCH). (A) At the presentation, fundus photograph showed that an orange colored CCH at the supero-nasal macula in the left eye. Indocyanine green angiography and ultrasonography showed CCH at the same location. Optical coherence tomography showed subretinal fluid (SRF) at the macula. The central macular thickness was 542 μm and visual acuity was 0.4 (logmar). The maximum diameter and thickness of the tumor was 2,840 μm and 1,210 μm, respectively. (B) Six months after intravitreal bevacizumab injection, SRF did not change. Visual acuity was 0.4. (C) Two months after photodynamic therapy, SRF disappeared, macualr thickness decreased to 204 μm and visual acuity increased to 0.1. Exduative retinal detachment did not recur during 9 months follow-up period. 291
- 대한안과학회지 2017 년제 58 권제 3 호 - 평균 2,224.4 ± 862.1 μm ( 범위, 1,210-3,650) 였다. 치료후경과관찰기간은 19.2 ± 12.3개월 (9-43개월) 이었다 (Table 1). 장액망막박리에대한첫치료로 9안중 6안은항혈관내피성장인자유리체내주사를평균 3.16회 (2-6회) 시행받았다. 유리체내주사는 4주간격으로경과관찰하면서망막하액이증가하면다음주사를시행하였다. 1안은항혈관내피성장인자유리체내주사를 2회시행한후완전한망막하액의소실을얻을수있었다. 1안은항혈관내피성장인자유리체내주사후망막하액의소실이있었으나 2개월뒤재발하였다. 추가적인항혈관내피성장인자유리체내주사를하였으나반응이없어 3회의경동공온열치료를시행하고망막 내 / 하액이완전히소실되었다. 4안은주사후 4주째경과관찰에서망막내 / 하액의변화가없거나오히려증가하여추가적인광역학치료를시행하였으며, 그중 3안에서완전한망막내 / 하액의소실을얻었으나 1안에서는남았다 (Fig. 1). 첫치료로 9안중 3안은광역학치료를시행받았다. 평균 1.33 회 (1-2회) 의치료를통해모두완전한망막내 / 하액의소실을얻었으며, 경과관찰기간동안재발이없었다 (Fig. 2). 최종적으로장액망막박리로치료받은전체 9안중 8안은망막내 / 하액이소실되었으며 1안은남았다. 치료방법에따른결과는첫치료로항혈관내피성장인자로치료받은 6안중 1안 (16.7%) 에서, 광역학치료를받은 3안 (100.0%) 은모 A B Figure 2. Representative case 9 having an exudative retinal detachment in circumscribed choroidal hemangioma (CCH). (A) At the presentation, fundus photograph showed that an orange colored CCH at the infero-nasal macula in the right eye. Indocyanine green angiography and ultrasonography showed CCH at the same location. Optical coherence tomography showed intraretinal and subretinal fluid (intraretinal fluid [IRF]/subretinal fluid [SRF]) at the macula. The central macular thickness was 400 μm and visual acuity was 0.2 (logmar). The maximum diameter and thickness of the tumor was 7,910 μm and 2,830 μm, respectively. (B) Two months after photodynamic therapy, IRF/SRF disappeared, central macular thickness decreased to 220 μm but visual acuity did not changed. Exudative retinal detachment did not recur during 10 months follow-up period. 292
- 권정민외 : 국한성맥락막혈관종 - 두망막내 / 하액의완전한소실을이룰수있었다. 항혈관내피성장인자주사에재발하거나반응이없던환자 5안에서시행한추가치료에서는, 광역학치료를받은 4안중 3안 (75.0%) 에서, 경동공온열치료를받은 1안에서망막내 / 하액의완전한소실을이룰수있었다. 최대교정시력 (logmar) 은치료전평균 0.51에서치료후 0.49로유의한시력변화는없었다 (p=0.732). 2안 (22.2%) 에서 2줄이상의시력상승이있었으며, 2안 (22.2%) 에서 2 줄이하의시력저하가있었다. 고찰 국한성맥락막혈관종 (circumscribed choroidal hemangioma) 이황반부를침범하거나장액망막박리가발생하여시력저하를일으키는경우에는레이저광응고술, 국소방사선치료, 양성자선을이용한방사선치료, 정위적방사선치료, 경동공온열요법, 광역학요법, 항혈관내피성장인자유리체내주사등을이용하여치료하게된다. 8,11-16 하지만맥락막혈관종에서발생한장액망막박리의치료방법에대해무작위전향적연구가시행된적이없어, 각각의치료방법의장 단점을술자가판단하여환자의상태에맞추어시행하고있는실정이다. 본연구에서는국한성맥락막혈관종양에서환자에서발생한장액망막박리에대하여항혈관내피성장인자유리체내주사, 광역학치료, 경동공온열치료를이용하여치료하였다. 광역학치료가다른치료에비해망막내 / 하액의감소에있어서우수한결과를보였다. 항혈관내피성장인자는혈관투과성을감소시키고신생혈관을퇴축시키는효과가있어당뇨망막병증과망막분지정맥폐쇄와같은망막혈관질환이나삼출성나이관련황변변성에서의맥락막신생혈관같은혈관증식성질환의치료에이용되고있다. 17 눈속종양세포도혈관내피성장인자를분비하여내피세포의치밀결합구조에영향을끼쳐혈관투과성을증가시키고황반부종이나장액망막박리를일으키게되는데, 18,19 항혈관내피성장인자는이러한기전을억제할수있어혈관증식성눈속종양 (vasoproliferative intraocular tumor) 의치료에효과가있다고보고되었다. 20 Kwon et al 21 은항혈관내피성장인자유리체내주사를시행한 9안중에서 3안에서만망막내 / 하액의소실을얻을수있었으며 Mandal et al 9 은망막하액은소실되었으나망막내액은모두남았다고하였다. 본연구에서도항혈관내피성장인자주사치료만으로는완전한망막내 / 하액의소실을얻는데부족하였는데, 항혈관내피성장인자의눈속반감기가짧아효과적인치료농도를유지하지못한것이원인일수있다. 또한눈속 에주입된약제의농도와주사간격은삼출성나이관련황반변성과당뇨황반부종등의치료에사용되는용량을이용하였는데, 맥락막혈관종에서발생한장액망막박리의치료에는부족했을수도있다. 광역학치료는 689 nm 파장의레이저에의해활성화된광감작물질이활성산소및자유유리기를발생하여광화학반응을일으키게되고망막조직을피해서선택적으로병변의혈관내피세포손상을일으키게되고혈관폐쇄를유도하게된다. 22 따라서황반부중심을침범한병변의경우에도치료의적응이된다. Barbazetto and Schmidt-Erfurth 23 과, Schmidt-Erfurth et al 24 이맥락막혈관종혈관들은혈관벽두께에비해많은양의혈액이존재하여광역학치료가종양의퇴축에효과적이라고보고한이후로, 여러연구들에서맥락막혈관종에서발생한장액망막박리의치료와시력개선에있어서우수한결과들이보고되었다. 11,25-28 본연구에서도광역학치료를받은 3안은모두망막내 / 하액이소실되었으며, 이전다른치료에반응이없어추가적인광역학치료를시행받은 4안중 3안에서도완전한망막내 / 하액의소실을이룰수있었다. 하지만시력은치료전후차이가없었는데, 광역학치료가맥락막모세혈관의폐쇄에의한황반부허혈과위축으로인해시력개선에제한점이될수있으며, 23,25 광역학치료전시력저하가심한환자에서는시력예후가불량하다고보고된바있다. 29 한편, 항혈관내피성장인자와광역학치료를함께시행하여광역학치료의횟수를줄이고종양의퇴축을달성할수있다고보고된적이있어, 30 심한장액망막박리가있는환자에서는병합치료도고려해볼수있겠다. 경동공온열치료는 810 nm 파장의다이오드레이저를오랜시간노출하여종양내온도를상승시킴으로써비가역적인단백질변성, 세포막파괴, 혈관통로경화를야기하여국한성맥락막혈관종의망막내 / 하액을효과적으로감소시킬수있다. 12,31 하지만경동공온열치료는크기가큰종양 ( 직경 10 mm 이상이거나두께 4 mm 이상 ) 과중심와아래에위치하거나시신경유두와인접해있는종양에는시행할수없는단점이있다. 12,31 게다가반복적인경동공온열치료는낭포성황반부종, 망막앞섬유증, 국소적인홍채위축, 망막혈관폐쇄의위험을증가시킬수도있다. 12 본연구에서는항혈관내피성장인자치료후재발한 1안에서종양이중심와밖에위치하여, 추가적인경동공온열치료를시행하여장액망막박리가호전되었다. 본연구는후향적연구로서치료대상이적으며, 치료후안초음파를시행하지못하여종양의크기변화를측정하지못한제한점이있으나국한성맥락막혈관종에서발생한장액망막박리에대하여항혈관내피성장인자주사와광역학 293
- 대한안과학회지 2017 년제 58 권제 3 호 - 치료를시행하여장기결과를알아볼수있었다. 결론적으로국한성맥락막혈관종에서장액망막박리의치료에있어서항혈관내피성장인자단독주사는반복적인치료에도불구하고장기간경과에서망막내 / 하액이남거나재발하는경향이있었으나, 광역학치료는비교적적은치료횟수로망막내 / 하액의소실을얻을수있었다. 향후더많은환자들을대상으로국한성맥락막혈관종에서발생한장액망막박리의치료에대한연구가필요할것으로생각된다. REFERENCES 1) Augsburger JJ, Shields JA, Moffat KP. Circumscribed choroidal hemangiomas: long-term visual prognosis. Retina 1981;1:56-61. 2) Chisholm IH, Blach RK. Choroidal hemangioma, a diagnostic and therapeutic problem. Trans Ophthalmol Soc U K 1973;93:161-9. 3) Ferry AP. Lesions mistaken for malignant melanoma of the posterior uvea. A clinicopathologic analysis of 100 cases with ophthalmoscopically visible lesions. Arch Ophthalmol 1964;72:463-9. 4) Gass JDM. Differential Diagnosis of Intraocular Tumors: a Stereoscopic Presentation, 1st ed. St. Louis: Mosby, 1974; 113-38. 5) Kamal A, Watts AR, Rennie IG. Indocyanine green enhanced transpupillary thermotherapy of circumscribed choroidal haemangioma. 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- 권정민외 : 국한성맥락막혈관종 - = 국문초록 = 국한성맥락막혈관종에서발생한장액망막박리에대한치료결과 목적 : 장액망막박리가발생한국한성맥락막혈관종에서항혈관내피성장인자주사와광역학치료결과를알아보고자하였다. 대상과방법 : 국한성맥락막혈관종환자중에서황반부장액망막박리가발생하여치료가필요했던환자들의치료방법과결과를의무기록을통해후향적으로조사하였다. 종양의진단과치료경과는안저사진, 인도사이아닌그린혈관조영술, 빛간섭단층촬영, 안초음파검사를시행하여분석하였다. 결과 : 총 9 명 9 안을치료후평균 19.2 개월동안경과관찰하였다. 평균시력은 0.51 ± 0.52 (logmar), 종양의최대지름은평균 6,154.4 ± 2,019.9 μm, 두께는평균 2,224.4 ± 862.1 μm 였다. 첫치료로항혈관내피성장인자유리체내주사를받은 6 안중 5 안은평균 3.16 회의치료에반응이없거나재발하여, 추가적인광역학치료와경동공온열치료가필요하였다. 광역학치료를받은 3 안은평균 1.3 회의치료후망막내 / 하액이소실되고재발은없었다. 최종적으로 8 안에서완전한망막내 / 하액의소실을얻을수있었으나, 평균시력은치료전과차이가없었다. 결론 : 국한성맥락막혈관종에서발생한장액망막박리에대하여항혈관내피성장인자유리체내주사의효과는제한적이었으며, 광역학치료가적은치료횟수로망막하액의소실을얻을수있었다. < 대한안과학회지 2017;58(3):289-295> 295