대한안과학회지 2009 년제 50 권제 8 호 J Korean Ophthalmol Soc 2009;50(8):1232-1236 DOI : 10.3341/jkos.2009.50.8.1232 = 증례보고 = 접수번호 : 50-08-12-18 황반부종에대한베바시주맙유리체강내주사의효과 문선경 1 이수영 2 이정희 1 이화여자대학교의학전문대학원안과학교실 1, 국립의료원안과 2 목적 : 황반부종의원인질환에따른베바시주맙유리체강내주사의효과를비교하고자하였다. 대상과방법 : 망막분지정맥폐쇄와망막중심정맥폐쇄, 당뇨망막병증에의해이차적으로황반부종이발생한환자들에게베바시주맙유리체강내주사를시행한후 6 개월동안추적관찰하며최대교정시력의변화및황반두께의변화를알아보았다. 결과 : 원인질환이망막분지정맥폐쇄군은베바시주맙유리체강내주사전의평균최대교정시력 logmar 0.62±0.30 에서주사후 1 개월, 3 개월, 6 개월째 0.43±0.37, 0.34±0.40, 0.38±0.37, 평균황반두께도 451.2±118.9 μm 에서주사후 1 개월, 3 개월, 6 개월째 280.3± 124.6 μm, 345.8±157.1 μm, 312.9±174.4 μm 로각각유의하게감소하였다. 망막중심정맥폐쇄군과당뇨망막병증군에서도최대교정시력의호전과황반두께의감소를보였으나통계적으로유의하지는않았다. 결론 : 베바시주맙유리체강내주사는황반부종을야기시키는질환에서시력호전과황반두께의감소를기대해볼수있으며, 망막분지정맥폐쇄에의한경우는통계학적으로도유의한호전을가져올수있는유용한치료로생각된다. < 대한안과학회지 2009:50(8):1232-1236> 황반부종은내측혈액망막장벽의파괴로체액과혈장성분이누출되어망막의외망상층이나내과립층에고여황반부의망막두께가증가되는것으로, 이는당뇨망막병증이나망막정맥폐쇄등에서시력저하를야기시키는주원인으로알려져있다. 1 당뇨황반부종의발병기전은망막저산소증이관여하는것으로보고있으며 2 저산소증은혈관투과성을유도하는혈관내피성장인자 (vascular endothelial growth factor, VEGF) 의발현을증가시킨다. 3,4 망막정맥폐쇄또한다양한정도의망막허혈과관련되어이로인해 VEGF 발현이증가된다. 5 이렇듯증가된 VEGF는망막혈관으로부터누출을증가시켜여러종류의망막질환에서황반부종을일으키는주요매개체임이최근연구를통해밝혀졌다. 6 베바시주맙 (Avastin R, Genentech, Inc., San Francisco, CA) 은 VEGF의모든아형들과결합하는유전자재조합인간단일클론항체 (recombinant humanized monoclonal anti- VEGF antibody) 7 로써현재망막질환, 특히나이관련황반변성의치료제로주목받고있으며, 최근베바시주맙유리체강내주사는망막중심정맥폐쇄에의해야기된황반부종을감소시킬뿐만아니라, 증식당뇨망막병증에서혈관투과성과 접수일 : 2008 년 12 월 29 일 심사통과일 : 2009 년 5 월 12 일 책임저자 : 이정희서울시양천구목 6 동 911-1 이화여자대학교목동병원안과 Tel: 02-2650-5154, Fax: 02-2654-4334 E-mail: leejhoph@ewha.ac.kr * 본논문의요지는 2007 년대한안과학회제 98 회추계학술대회에서구연으로발표되었음. 섬유혈관증식을줄인다는보고가있었다. 8-11 본연구에서는베바시주맙유리체강내주사의황반부종치료효과를알아보고, 황반부종을일으키는원인질환에따라치료효과에차이가있는지분석해보고자하였다. 대상과방법 2007년 1월 1일부터 2007년 12월 31일까지본원안과에내원하여망막분지정맥폐쇄와망막중심정맥폐쇄, 당뇨망막병증에의한이차적인황반부종으로진단받은환자들중치료에동의를하고 6개월간추적관찰이가능했던 28명, 총 31안을대상으로하였다. 황반부종은세극등현미경을이용한안저검사상황반중심으로부터 1 유두지름내망막이두꺼워져있고빛간섭단층촬영 (STRATUS OCT 3000, Carl Zeiss, Meditec Inc., San Leandro, CA) 상 macular thickness map의 1 mm 범위의중심망막두께가 300 µm 이상인경우로정의하였다. 단, 시력저하를유발할수있는다른안과적질환을가진경우나최근 6개월내에안과적수술을받은환자는대상에서제외시켰다. 베바시주맙유리체강내주사전에최대교정시력, 안압검사, 세극등현미경검사, 안저검사, 빛간섭단층촬영, 형광안저혈관조영술을시행하였다. 시술을위해환자의눈을 0.5% Proparacaine hydrochloride (Alcaine R, Alcon) 로점안마취한후 5% Povidone-iodine 용액으로안검을소독하고개검기를착용시켰다. 수정체안에서는윤부에서 3.5 mm, 인공수정체안또는무수정체안에서는 3.0 mm 떨어진하이 1232
- 문선경외 : 황반부종에서베바시주맙주사의효과 - 측섬모체평면부를통해 30게이지주사바늘을사용하여베바시주맙 (2.5 mg/0.1 cc) 을유리체강내로주사하였고, 일주일동안 1일 4회씩항생제 (Ofloxacin, Tarivid R ) 를점안하였다. 시술후 1일째최대교정시력, 안압검사및세극등현미경검사, 안저검사, 빛간섭단층촬영을시행하였고, 그후 4주간격으로 6개월동안추적관찰하였다. 추적관찰하는동안황반부종이지속되거나빛간섭단층촬영상황반두께가증가한경우에는베바시주맙유리체강내주사를반복하였다. 최대교정시력은 logmar (logarithm of the minimal angle of resolution) 시력으로전환하였으며, 황반두께는빛간섭단층촬영을시행하여측정하였고, 베바시주맙유리체강내주사의효과를알아보기위해황반부종의원인질환에따라분류하여비교하였다. 통계학적분석은 SPSS (version 12.0, SPSS Inc., Chicago, IL) 를이용하여 Wilcoxon signed-rank test, Mann-Whitney U test, Kruskal-Wallis test를시행하였고 p-value가 0.05 미만인경우를통계학적의의가있는것으로정의하였다. 결과 대상환자는 28명, 31안이었으며, 황반부종의원인질환으로는망막분지정맥폐쇄군 9안, 망막중심정맥폐쇄군 5안, 당뇨망막병증군이 17안이었으며, 각군별로평균연령, 이전에격자레이저나유리체강내스테로이드주입술을받은횟수, 시술전평균최대교정시력, 시술전평균황반두께는통계학적으로유의한차이가없었다 (Table 1). 평균베바시주맙유리체강내주사횟수는망막분지정맥폐쇄군 2.89± 1.11회, 망막중심정맥폐쇄군 2.2±1.1회, 당뇨망막병증군 2.41±0.9회로각군간의통계학적인차이는없었다. 베바시주맙유리체강내주사전의평균최대교정시력은 logmar 0.59±0.30, 평균황반두께는 424.9±108.8 μm이었다. 시술후 4주, 8주, 3개월, 6개월째평균최대교정시력은각각 logmar 0.47±0.34, 0.46±0.35, 0.43±0.36, 0.40±0.32로시술전보다통계학적으로유의한시력호전을보였다 (p<0.05). 평균황반두께도시술후 4주, 8주, 3개월, 6개월째각각 332.4±132.4 μm, 316.5±119.3 μm, 387.6±141.5 μm, 349.0±144.3 μm로통계학적으로유의하게감소하였다 (p< 0.05). 황반부종의원인질환별로망막분지정맥폐쇄군의경우는, 시술전평균최대교정시력은 logmar 0.62±0.30, 평균황반두께는 451.2±118.9 μm이었고, 시술후 4주, 8주, 3개월, 6개월째평균최대교정시력은 logmar 0.43±0.37, 0.48±0.34, 0.34±0.40, 0.38±0.37, 평균황반두께는 280.3±124.6 μm, 294.6±136.8 μm, 345.8±157.1 μm, 312.9±174.4 μm로시술전보다통계학적으로유의한시력호전및황반두께의감소를보였다 (p<0.05, Fig. 1, 2). 망막중심정맥폐쇄군에서는, 시술전평균최대교정시력은 logmar 0.62±0.36, 평균황반두께는 451.4±107.7 μm 이었고, 시술후 4주, 8주, 3개월, 6개월째평균최대교정시력은 logmar 0.41±0.42, 0.41±0.46, 0.50±0.44, 0.42± 0.44, 평균황반두께는 276.0±66.9 μm, 291.0±113.4 μm, 315.8±123.8 μm, 319.8±125.5 μm로시술전보다시력호전및황반두께의감소를보였으나통계학적으로유의하지는않았다 (Fig. 1, 2). 당뇨망막병증군에서는, 시술전평균최대교정시력은 logmar 0.56±0.30, 평균황반두께는 403.1±105.3 μm 이었다. 시술후 4주, 8주, 3개월, 6개월째평균최대교정시력은 logmar 0.51±0.32, 0.48±0.34, 0.46±0.34, 0.41± 0.26, 평균황반두께는 379.3±139.3 μm, 343.9±113.9 μm, 426.0±135.7 μm, 385.2±129.8 μm로시술전보다는시력호전및황반두께의감소를보였으나역시통계학적으로 Table 1. Preoperative characteristics of 31 patients who underwent intravitreal bevacizumab injections for macular edema BRVO * CRVO DMR Total p No, eyes (%) 9 (29.1) 5 (16.1) 17 (54.8) 31 (100.0) Age (years) Mean±SD 60.4±6.8 53.6±13.5 54.5±12.9 56.1±11.6 0.349 Systemic disease DM, eyes (%) HTN, eyes (%) 0 3 (33.3) 0 2 (40.0) 17 (100) 4 (23.5) Previous treatment No, eyes (%) 2 (22.2) 2 (40.0) 11 (64.7) Preoperative BCVA П 0.62±0.30 0.62±0.36 0.56±0.30 0.59±0.30 0.737 Preoperative CMT # 451.2±118.9 451.4±107.7 403.1±105.3 424.9±108.8 0.592 * BRVO=branch retinal vein occlusion; CRVO=central retinal vein occlusion; DMR=diabetic retinopathy; Grid laser or IVTA (intravitreal triamcinolone acetonide injection); П BCVA=best-corrected visual acuity, logmar; # CMT=central macular thickness, μm. 1233
- 대한안과학회지 2009 년제 50 권제 8 호 - Figure 1. Changes in best-corrected visual acuity after intravitreal bevacizumab injection. In the branch retinal vein occlusion group, a statistically significant improvement in best-corrected visual acuity was observed at each time point, compared with the baseline BCVA ( * p<0.05). 유의하지는않았다 (Fig. 1, 2). 시술후 6개월간추적관찰하는동안안압상승, 백내장, 망막박리, 유리체출혈, 안내염등의합병증과전신적합병증은발생하지않았다. 고 찰 황반부종은여러질환에서시력저하를유발시키는주원인으로알려져있으며, 병리생리학적기전은확실하게밝혀지지않았으나내측혈액망막장벽을악화시키는내적인자가작용하는것으로알려져있다. 즉망막허혈에의하여프로스타글란딘의분비가증가되고혈관투과를증가시키는 VEGF 가분비되며, 혈액망막장벽의파괴로인한혈관투과증가로인해발생되는것으로생각된다. 1 또한망막중심정맥폐쇄의동물모델을통해 VEGF는저산소증에의해유발되며안내신생혈관생성과황반부종의주요매개체임이밝혀졌다. 12 그러므로이론상으로 VEGF의발현억제는손상된혈액망막장벽을안정시키고황반부종을감소시켜시력개선을가져올것으로기대해볼수있다. 황반부종에대한기존의치료법인유리체강내스테로이드주입술은프로스타글란딘이나인터루킨등과같은염증매개물질을억제하여이러한물질들이황반부종을일으키는과정을차단함으로써효과를나타내거나, 혈관투과성을증가시키는 VEGF를억제함으로써효과를나타내는것으로알려져있다. 13,14 그러나유리체강내스테로이드주입술에대하여 Jonas et al 15 는 25 mg 의트리암시놀론사용 1~2 개월 Figure 2. Changes in central macular thickness after intravitreal bevacizumab injection. In the branch retinal vein occlusion group, a statistically significant decrease in central macular thickness was observed at each time point, compared with the baseline CMT ( * p<0.05). 후약 50% 에서안압상승이있었다고보고하였고, Martidis et al 16 는 6개월동안 16안중 1안에서수정체혼탁이있었음을보고하였다. Ciardella et al 17 는 1차주입시는평균 6개월, 2차주입시는 3.7개월이지나면서유리체강내스테로이드재주입술이필요하였고주입횟수가증가할수록그효과의지속시간이떨어지고시력개선및황반두께감소정도도저하된다는제한점을지적하였다. 따라서황반부종에대한새로운치료법으로황반부종을야기시키는매개체중하나인 VEGF의작용을선택적으로억제하기위하여 anti-vegf 항체인베바시주맙을사용한연구가활발히이루어지고있다. Iturralde et al 11 는망막중심정맥폐쇄에의한황반부종의치료로유리체강내스테로이드주입술에실패한환자들을대상으로베바시주맙유리체강내주사를시행한결과거의모든경우에서해부학적개선및시력호전이있었다고보고하였다. Rabena et al 18 는망막분지정맥폐쇄에의해황반부종이발생한환자들에게베바시주맙유리체강내주사를시행한결과, 모든환자에서시력호전이되었고 92% 에서황반두께가감소하였다고발표하였다. Haritoglou et al 19 는지속적인미만형당뇨황반부종환자에게베바시주맙유리체강내주사후모든환자에서시력호전및황반두께감소가있었다고하였다. 본연구에서도망막분지정맥폐쇄, 망막중심정맥폐쇄, 당뇨망막병증에의해이차적으로황반부종이발생한 28명 31안모두에서베바시주맙유리체강내주사후시력호전및황반두께가감소되면서해부학적구조의개선을보였다. 황반부종을유발시킨원인질환에따른비교에서는, 망막분지정맥폐쇄군이망막중심정맥폐쇄군과당뇨망막병증군보다통 1234
- 문선경외 : 황반부종에서베바시주맙주사의효과 - 계학적으로유의한시력호전및황반두께의감소를보였다. 이는당뇨망막병증과망막중심정맥폐쇄에의한황반부종은전반적인망막의혈관장애로인한문제인데반해, 망막분지정맥폐쇄의경우는황반부허혈의정도가일반적으로다른질환에비해적고폐쇄된정맥부위의망막이외에는망막기능이상대적으로좋기때문에치료효과가다른군에비해좋게나타났을수있다. 그러나본연구는황반부종의원인질환별로베바시주맙유리체강내주사의효과를비교하기에는대상환자수가적었으며, 망막의허혈상태에따라분류하여치료효과를비교하지못하였다는제한점이있다. 결론적으로베바시주맙유리체강내주사는황반부종을야기시키는여러가지질환에서특별한부작용없이단기적인시력호전및해부학적개선을가져올수있는비교적간단하며안전한치료방법이다. 그러나보다많은환자를대상으로이치료방법의효과및안정성평가를위한장기적인연구가필요할것으로생각된다. 참고문헌 1) Ryan SJ. Nonproliferative diabetic retinopathy. In: Chew EY, Ferris FL III, eds. Retina, 4th ed. New York: Mosby, Elsevier Inc., 2006; v. 2. chap. 67. 2) Nguyen QD, Shah SM, van Anden E, et al. Supplementaloxygen improves diabetic macular edema: a pilot study. Invest Ophthalmol Vis Sci 200445:617-24. 3) Ozaki H, Hayashi H, Vinores SA, et al. Intravitreal sustained release of VEGF causes retinal neovascularization in rabbits and breakdown of the blood-retinal barrier in rabbits and primates. Exp Eye Res 1997;64:505-17. 4) Derevjanik NL, Vinores SA, Xiao WH, et al. Quantitative assessment of the integrity of the blood-retinal barrier in mice. Invest Ophthalmol Vis Sci 2002;43:2462-7. 5) Boyd SR, Zachary I, Chakravarthy U, et al. Correlation of increased vascular endothelial growth factor with neovascularization and permeability in ischemic central retinal vein occlusion. Arch Ophthalmol 2002;120:1644-50. 6) Funatsu H, Yamashita H, Noma H, et al. Aqueous humor levels of cytokines are related to vitreous levels and progression of diabetic retinopathy in diabetic patients. Graefes Arch Clin Exp Ophthalmol 2005;243:3-8. 7) Ferrara N, Hillan KJ, Gerber HP, Novotny W. Discovery and development of bevacizumab, an anti-vegf antibody for treating cancer. Nat Rev Drug Discov 2004;3:391-400. 8) Spaide RF, Fisher YL. Intravitreal bevacizumab (Avastin) treatment of proliferative diabetic retinopathy complicated by vitreous hemorrhage. Retina 2006;26:275-8. 9) Michels S, Rosenfeld PJ, Puliafito CA, et al. Systemic bevacizumab (Avastin) therapy for neovascular age-related macular degeneration. Twelve-week results of an uncontrolled open-label clinical study. Ophthalmology 2005;112:1035-47. 10) Avery RL, Pieramici DJ, Rabena MD, et al. Intravitreal bevacizumab (Avastin) for neovascular age-related macular degeneration. Ophthalmology 2006;113:363-72. 11) Iturralde D, Spaide RF, Meyerle CB, et al. Intravitreal bevacizumab (Avastin) treatment of macular edema in central retinal vein occlusion: a short-term study. Retina 2006;26:279-84. 12) Vinores SA, Youssri AI, Luna JD, et al. Upregulation of vascular endothelial growth factor in ischemic and non-ischemic human and experimental retinal disease. Histol Histopathol 1997;12:99-109. 13) Fischer S, Renz D, Schaper W, et al. In vitro effects of dexamethasone on hypoxia-induced hyperpermeability and expression of vascular endothelial growth factor. Eur J Pharmacol 2001;411: 231-43. 14) Nauck M, Karakiulakis G, Perruchoud AP, et al. Corticosteroids inhibit the expression of vascular endothelial growth factor gene in human vascular smooth muscle cells. Eur J Pharmacol 1998; 341:309-15. 15) Jonas JB, Kreissig I, Degenring R. Intraocular pressure after intravitreal injection of triamcinolone acetonide. Br J Ophthalmol 2003;87:24-7. 16) Martidis A, Duker JS, Greenberg PB, et al. Intravitreal triamcinolone for refractory diabetic macular edema. Ophthalmology 2002;109:920-7. 17) Ciardella AP, Klancnik J, Chiff W, et al. Intravitreal triamcinolone for the treatment of refractive diabetic macular edema with hard exudate: an optical coherence tomography study. Br J Ophthalmol 2004;88:1131-6. 18) Rabena MD, Pieramici DJ, Castellarin AA, et al. Intravitreal bevacizumab (Avastin) in the treatment of macular edema secondary to branch retinal vein occlusion. Retina 2007;27:419-25. 19) Haritoglou C, Kook D, Neubauer A, et al. Intravitreal bevacizumab (Avastin) therapy for persistent diffuse diabetic macular edema. Retina 2006;26:999-1005. 1235
- 대한안과학회지 2009 년제 50 권제 8 호 - =ABSTRACT= The Efficacy of Intravitreal Bevacizumab in the Treatment of Macular Edema Sun-Kyung Moon, MD 1, Soo Young Lee, MD, PhD 2, Jeong-Hee Lee, MD, PhD 1 Department of Ophthalmology, School of Medicine, Ewha Womans University 1, Seoul, Korea Department of Ophthalmology, National Medical Center 2, Seoul, Korea Purpose: To investigate the efficacy in best corrected visual acuity (BCVA) and central macularthickness after intravitreal bevacizumab injection in patients with macular edema. Methods: Patients with macular edema due to branch retinal vein occlusion, central retinal vein occlusion, and diabetic retinopathy received intravitreal injection of bevacizumab (2.5 mg/0.1cc). Complete ophthalmic examinations including best corrected visual acuity and optical coherence tomography (OCT) were performed at baseline and follow-up visits for 6 months. Results: In macular edema secondary to branch retinal vein occlusion, the mean BCVA improved from logmar 0.62±0.30 at baseline to logmar 0.43±0.37 at 1 month, 0.34±0.40 at 3 months and 0.38±0.37 at 6 months (p<0.05). The mean central macular thickness decreased from 451.2±118.9 μm at baseline to 280.3±124.6 μm at 1 month, 345.8±157.1 μm at 3 months and 312.9±174.4 μm at 6 months (p<0.05). In macular edema secondary to central retinal vein occlusion and diabetic retinopathy, visual improvement and macular thickness reduction were not statistically significant. Conclusions: Intravitreal bevacizumab injection appears to be more effective for macular edema due to branch retinal vein occlusion than macular edema secondary to central retinal vein occlusion and diabetic retinopathy. J Korean Ophthalmol Soc 2009;50(8):1232-1236 Key Words: Bavacizumab, Diabetic retinopathy, Macular edema, Retinal vein occlusion Address reprint requests to Jeong-Hee Lee, MD, PhD Department of Ophthalmology, Ewha Womans University College of Medicine, Mokdong Hospital #911-1 Mok-dong, Yangcheon-gu, Seoul 158-710, Korea Tel: 82-2-2650-5154, Fax: 82-2-2654-4334, E-mail: leejhoph@ewha.ac.kr 1236