대한안과학회지 2014 년제 55 권제 7 호 J Korean Ophthalmol Soc 2014;55(7):1039-1048 pissn: 0378-6471 eissn: 2092-9374 http://dx.doi.org/10.3341/jkos.2014.55.7.1039 Original Article 신생혈관녹내장에서베바시주맙의전방과유리체내동시주입과유리체내단독주입의치료효과 Comparision between Simultaneous Intracameral and Intravitreal Injection and Intravitreal Injection of Bevacizumab in Neovascular Glaucoma 허현도 1 한용섭 1,2 정인영 1,2 서성욱 1,2 박종문 1,2 유지명 1,2 김성재 1,2 Hyoun Do Huh, MD 1, Yong Seop Han, MD, PhD 1,2, In Young Chung, MD, PhD 1,2, Seong Wook Seo, MD, PhD 1,2, Jong Moon Park, MD, PhD 1,2, Ji Myong Yoo, MD, PhD 1,2, Seong Jae Kim, MD, PhD 1,2 경상대학교의학전문대학원안과학교실 1, 경상대학교건강과학연구원 2 Department of Ophthalmology, Gyeongsang National University School of Medicine 1, Jinju, Korea Gyeongsang Institute of Health Science, Gyeongsang National University 2, Jinju, Korea Purpose: To compare the clinical efficacy of simultaneous intracameral and intravitreal injection and intravitreal single injection of bevacizumab in patients with neovascular glaucoma (NVG). Methods: The medical records of 43 eyes of 43 patients, who had treated with simultaneous intracameral and intravitreal injection (Group I) or intravitreal single injection (Group II) of bevacizumab 1.25 mg from January 2010 to December 2012, were retrospectively reviewed. The best corrected visual acuity (BCVA), intraocular pressure (IOP), regression time of new vessel in the iris (NVI) and anterior chamber angle (NVA), progression of peripheral anterior synechiae (PAS), and corneal parameters were measured preoperatively and one day, three days, 1 week, 1 month, and 3 months postoperatively. Results: There was significant changes of IOP between the two groups at 1, 3 days postoperatively (p = 0.001, p < 0.001). The regression time of NVI and NVA in Group I was significantly faster than Group II (p = 0.026, p = 0.033). In the phakic eyes, regression time of NVI and NVA was significantly longer than aphakic and pseudophakic eyes in group II (p = 0.006, p = 0.005). Also, in the phakic NVG patients, the formation of PAS in Group I was significantly less than in Group II for the postoperative three months (p = 0.020). Conclusions: Simultaneous intravitreal and intracameral injection of bevacizumab seem to be more effective for the early lowering of IOP and regression of NVI and NVA, and inhibiting further PAS formation in NVG patients, especially in the phakic eyes. Therefore, simultaneous intracameral and intravitreal injection of bevacizumab may be considered as an adjunct to management of NVG in the phakic eyes. J Korean Ophthalmol Soc 2014;55(7):1039-1048 Key Words: Bevacizumab, Intraocular pressure, Lens, Neovascular glaucoma, Peripheral anterior synechiae Received: 2014. 1. 25. Revised: 2014. 2. 24. Accepted: 2014. 6. 24. Address reprint requests to Seong Jae Kim, MD, PhD Department of Ophthalmology, Gyeongsang National University Hospital, #79 Gangnam-ro, Jinju 660-702, Korea Tel: 82-55-750-8468, Fax: 82-55-758-4158 E-mail: Maya12kim@naver.com * This study was presented as an e-poster at the 110th Annual Meeting of the Korean Ophthalmological Society 2013. 신생혈관녹내장은당뇨망막병증, 망막혈관폐쇄, 내경동맥협착, 방사선망막병증, 만성포도막염등망막의허혈을일으키는다양한안질환에서유발되며, 허혈부위에서생성된혈관내피세포성장인자에의해전방에섬유혈관증식이일어남으로써발생한다. 1-4 전방각의섬유혈관증식은섬유주폐쇄를일으키며폐쇄된섬유주를따라주변홍채앞유착이발생하고영구적인전방각폐쇄로이어져안압이상 c2014 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. 1039
- 대한안과학회지 2014 년제 55 권제 7 호 - 승하고안구통증, 시력저하가일어난다. 2 Tripathi et al 5 은신생혈관녹내장환자에서전방과유리체내에혈관내피세포성장인자의농도가높다고보고하였으며, 이는항혈관내피세포성장인자가신생혈관녹내장의초기치료에도움이된다는근거가되고있다. 이에따라 SooHoo et al 6 은신생혈관녹내장의최신치료방법으로초기안압을낮춘후망막이관찰되면, 먼저범망막광응고술을시행하여허혈망막을파괴함으로써혈관내피세포성장인자의생산을감소시키고, 항혈관내피세포성장인자를유리체내에주입하여유리체와전방에존재하는혈관내피세포성장인자를줄이는것을제시하였다. 만약, 초기에망막이관찰되지않으면항혈관내피세포성장인자를유리체내에먼저주입하여혈관내피세포성장인자를줄임으로써신생혈관의퇴화를유도하여안압조절을한후, 망막이관찰되면범망막광응고술을시행하도록권고하고있다. 베바시주맙 (Avastin ; Genetech, Inc., San Francisco, USA) 은혈관내피세포성장인자를억제함으로써맥락막신생혈관, 당뇨망막병증, 망막혈관폐쇄등의유리체내에주입하여치료제로사용되고있다. 7-11 신생혈관녹내장의치료로는베바시주맙을전방이나유리체내에주입하여단기간의안압하강과빠른신생혈관의소멸효과를보인다는보고가있으며, 12-15 이에따라베바시주맙을유리체내또는전방에주입하는것이신생혈관녹내장의초기치료로병행되고있다. 16-18 하지만아직까지국내외에베바시주맙의전방과유리체내에동시주입하는방법과유리체내단독주입하는방법의치료효과를비교한연구는없었다. 따라서본연구에서는, 신생혈관녹내장의치료에서베바시주맙을전방과유리체내에동시주입한군과유리체내에단독주입한군간의시력과안압의변화, 신생혈관소멸속도, 주변홍채앞유착의진행정도와각막에대한영향등을분석하고자하였다. 대상과방법 대상환자 2010년 1월부터 2012년 12월까지신생혈관녹내장으로본원에내원한 53명 ( 남자 35명, 여자 18명 ) 환자의의무기록을후향적으로분석하였다. 이들중시술후 3개월까지경과관찰이되지않았던환자 4명, 시술전 3개월이내에안과수술을시행받은환자 2명 ( 백내장수술 1명, 유리체절제술 1명 ), 타병원에서베바시주맙유리체내주입술을시행받은환자 1명, 그리고각막부종, 전방및유리체출혈로망막이관찰되지않았던환자 2명등총 9명이대상에서제외되어 44명의신생혈관녹내장이대상이되었다. 안압조절및범망막광응고술의시행내원한환자들은시력과안압을측정하고, 전안부평가를위한세극등검사및전방각경검사와유리체망막의평가를위한안저검사를시행하였다. 안압조절을위해안압약은 0.15% brimonidine tartrate (Alphagan-P, Allergan, Waco, USA), 0.5% brinzolamide-timolol (Elazop, Alcon, Ft Worth, USA) 과 0.004% travoprost (Travatan, Ft Worth, USA) 를사용하고, 경구용 acetazolamide (Diamox 250 mg, SK chemicals, Korea) 와정맥주사용고삼투압제 (15% Mannitol, CJ pharma., Korea) 를투여하였다. 이후베바시주맙주입전에형광안저촬영을시행하여허혈이있는망막부위에범망막광응고술을시행하였다. 레이저광응고반의크기는 500 μm로, 레이저노출시간은 0.1초로지정하였다. 광응고반의강도는 L Esperance scale 3단계 19 에해당하는회백색의광응고반이나타나도록레이저출력을조절하였고, 광응고반의간격은 1광응고반크기를유지하였으며, 광응고반의개수는최소 1,800-2,000개가되도록시행하였다. 베바시주맙안내주입술의시행베바시주맙안내주입은범망막광응고술시행직후무균상태의수술실에서시행하였다. 점안마취제 (Alcaine, Alcon, Fort Worth, USA) 를점안후에 10% Povidone-iodine 용액으로안와주위피부와안구를소독하였다. 유수정체안에서는각막윤부에서 3.5 mm, 인공수정체안과무수정체안의경우에는각막윤부에서 3.0 mm 떨어진하이측부위의평면부에 30 gauge 주사기를이용하여베바시주맙 1.25 mg (0.05 cc) 을유리체내에주입하였다. 전방과유리체내에베바시주맙동시주입은베바시주맙 1.25 mg (0.05 cc) 을상기방법으로유리체내에주입후상비측각막윤부에서 30 gauge 주사기를이용하여베바시주맙 1.25 mg (0.05 cc) 을전방에주입하였다. 두군모두에서전방천자는시행하지않았으며, 소독면봉을이용하여주입부를눌러누출이없는것을확인후, 1% ofloxacin 연고 (Effexin, Ildong, Korea) 를점안하였다. 주입 1시간후에안압을측정하고 0.5% moxifloxacin (Vigamox, Alcon, Fort Worth, USA) 과 1% prednisolone acetate (1% Pred Forte, Allergan, TX, USA) 를하루 6회점안토록하였다. 이후안압조절은술전에사용하던안약을계속해서사용토록하였으며, 이들환자중최대약물요법으로안압이 7일이상 22 mmhg 이상지속되는경우방수유출장치삽입술 (Ahmed valve implantation) 을시행하였다. 시술전후의변화관찰최대교정시력을측정하여 Saito et al 20 이기술한범위로 1040
- 허현도외 : 신생혈관녹내장에서베바시주맙주입효과 - 나누었으며, 이는 1단계 : 안전수지혹은그이하, 2단계 : 0.01에서 0.1, 3단계 : 0.2에서 0.5, 그리고 4단계 : 0.6에서 1.0으로정의하고각단계를각각 1, 2, 3, 4점의점수로계산하여분석하였다. 안압은골드만압평안압계로측정한술전, 술후 1일, 3일, 7일, 1달그리고 3달째의값을비교하였다. 홍채및전방각의신생혈관소멸을확인하기위해서완전소멸이이루어질때까지, 매일하루 2회씩동일한시간에 1명의검사자에의해세극등검사및전방각경검사를시행하였다. 주변홍채앞유착의정도는 1명의검사자에의해전방각경검사를시행하여측정하고, Brouzas et al 21 이기술한바에따라유착각도에따라 none=0, 0 <mild 90, 90 <moderate 180, 180 <severe 270, 270 <very severe 360 로나누고, 각각 0, 1, 2, 3, 4의점수로계산하여분석하였다. 각막내피세포수 (cells/mm 2 ), 세포변이계수 (Coefficient of variation), 육각세포비율 (%) 은비접촉성경면현미경 (Noncon Robo-CA, Konan, Japan) 을사용하여측정하였고, 중심각막두께 (μm) 는 Pentacam (Oculus, Wetzlar, Germany) 을이용하여측정하였다. 전신질환의유무, 수정체의종류, 안압조절을위해사용한약물의개수, 시술후 안내염증상태및수정체손상, 유리체출혈, 망막박리, 안내염발생유무는의무기록을토대로분석하였다. 통계적분석통계학적분석은 SPSS (version 15.0, Chicago, IL) 프로그램을이용하여두군간의연령, 시술전, 후의안압변화, 최대교정시력, 각막내피세포수, 세포변이계수, 육각세포비율, 중심각막두께의변화와수정체종류에따른주변홍채앞유착의진행정도, 시술후방수유출장치삽입술시행비율, 시술후홍채신생혈관과전방각신생혈관의소멸시기, 수정체종류에따른홍채신생혈관과전방각신생혈관의소멸시기의차이는 Paired t-test로비교하였으며, 각군의성별, 시술전기저질환, 진단명, 수정체종류및주변홍채앞유착의정도는 Fisher s exact test로비교하였다. 시술전과시술후 3개월째시력의변화, 수정체종류에따른각군의홍채신생혈관과전방각신생혈관의소멸시기, 주변홍채앞유착의변화는 ANOVA test로비교하였다. 모든경우에서 p 값이 0.05 미만인경우를통계적인의의가있는것으로간주하였다. Table 1. Demographics of enrolled patients Group I Group II Total p-value (n = 23) (n = 21) (n = 44) Age (years) 58.7 ± 9.9 60.5 ± 8.8 0.556 * 59.9 ± 9.2 Sex (n) Male 14 16 30 Female 9 5 0.731 14 Underlying diseases (n) DM 14 14 28 HTN 3 2 5 DM and HTN 6 5 0.668 11 Preoperative diagnosis (n) PDR 16 17 33 CRVO 7 4 0.672 11 Lens status (n) Phakia 12 12 24 Pseudophakia 9 8 17 Aphakia 2 1 0.805 3 PAS (n) None 11 8 20 Mild 4 1 5 Moderate 3 1 4 Severe 2 5 7 Very severe 3 5 0.374 8 Ahmed valve implant surgery (n) 5 7 0.425 * 12 Values are presented as mean ± SD; Group I: simultaneous intravitreal and intracameral bevacizumab injection group; Group II: intravitreal bevacizumab injection group; PAS range: none = 0, 0 < mild 90, 90 < moderate 180, 180 < severe 270, 270 < very severe 360. DM = diabetic mellitus; HTN = hypertension; PDR = proliferative diabetic retinopathy; CRVO = central retinal vein occlusion; PAS = peripheral anterior synechiae. * Paired t-test; Fisher s exact test. 1041
- 대한안과학회지 2014 년제 55 권제 7 호 - 결과 전체 44명 44안중단독주입군과동시주입군은각각 23 안, 21안이었다. 전체환자의평균연령은 59.9 ± 9.2세 (40-75세) 였고, 남자가 30명, 여자가 14명이었다. 기저질환을살펴보면, 당뇨 28명, 고혈압 5명, 당뇨와고혈압이함께있는환자가 11명이었고시술전진단명은당뇨망막병증과중심망막정맥폐쇄가각각 33안, 11안이었다. 수정체종류는유수정체안 24안, 인공수정체안 17안, 무수정체안 3안이었다. 시술전주변홍채앞유착은 none이 20안, mild가 5안, moderate가 4안, severe가 7안, very severe가 8안이었다. 안압조절이되지않아방수유출장치삽입술을동시주입군에서 5명, 단독주입군에서는 7명이시행받았다. 이상의수술전후임상인자들은단독주입군과동시주입군사이에통계적으로유의한차이가없었다 (Table 1). 시력의변화시술후 3개월째동시주입군은시력호전 4안, 시력변화없음 18안, 시력저하 1안이고단독주입군은시력호전 5 안, 시력변화없음 15안, 시력저하 1안으로각군내에서시술전과술후 3개월째의시력은통계적으로유의한변 화가관찰되지않았다 (p=0.658, p=0.624). 그리고두군간의시술전과시술후 3개월째의시력변화도통계적으로유의하지않았다 (p=0.882, Table 2). 안압의변화두군간의안압하강정도를비교하기위해안압이조절되지않아방수유출장치삽입술을시행받은동시주입군 5명, 단독주입군 7명을제외하고비교하였다. 동시주입군의시술전평균안압은 36.0 ± 4.1 mmhg (24-48 mmhg), 단독주입군의평균안압은 34.9 ± 4.2 mmhg (20-42 mmhg) 로, 두군간의시술전안압에는차이가없었다 (p=0.637, Table 3). 그러나시술후 1일째의안압하강정도는동시주입군이 9.5 ± 3.4 mmhg, 단독주입군은 5.5 ± 3.8 mmhg로, 3일째의안압하강정도는동시주입군이 15.9 ± 3.9 mmhg, 단독주입군은 7.5 ± 3.6 mmhg 로동시주입군이단독주입군에비해통계적으로유의하게큰안압하강을보였다 (p=0.003, p=0.009, Fig. 1). 하지만술후 1주일, 1달, 3달째의안압변화정도는두군간의차이가없었다 (p=0.315, p=0.957, p=0.841, Fig. 1). 두군에서시술전후에안압하강을위해사용한점안약개수도유의한차이가없었다 (p=0.164, p=0.189, Table 3). Table 2. Change of visual acuity between pre-injection and post-injection 3 months later in both groups Group I (n = 23) Group II (n = 21) p-value Total (n = 44) Better (n) 4 5 9 Same (n) 18 15 33 Worse (n) 1 1 2 p-value * 0.658 0.624 0.638 VA (mean ± SD, n) 0.22 ± 0.36 0.24 ± 0.32 0.882 0.23 ± 0.34 Group I: simultaneous intravitreal and intracameral bevacizumab injection group; Group II: intravitreal bevacizumab injection group. SD = standard deviation; VA = visual acuity difference between pre-injection and post-injection after 3 months (visual acuity range: 1 = counting fingers or worse, 2 = 0.01-0.1, 3 = 0.2-0.5, 4 = 0.6-1.0). * ANOVA test; Paired t-test. IOP difference between pre-injection and post-injection (mm Hg) 0-5 -10-15 -20-25 -30 1 day p = 0.003* 3 days 1 week 1 month 3 months p = 0.009* p = 0.315 p = 0.957 p = 0.841 Group 1 Group 2 Time Figure 1. IOP difference between post-injection and pre-injection in both groups. Group I: simultaneous intravitreal and intracameral bevacizumab injection group; Group II: intravitreal bevacizumab injection group. IOP = intraocular pressure. * Paired t-test, p-value < 0.05. 1042
- 허현도외 : 신생혈관녹내장에서베바시주맙주입효과 - Table 3. Change of IOP and number of IOP lowering medications in pre-injection and 3 months after injection in both groups Group I Group II Total ( * n = 18) ( * p-value n = 14) (n = 32) IOP (mm Hg) Pre-op 36.0 ± 4.1 34.9 ± 4.2 0.637 35.4 ± 7.6 Post-op 1 day 26.5 ± 4.8 29.3 ± 3.1 0.385 27.9 ± 7.6 Post-op 3 days 20.1 ± 3.4 27.4 ± 3.3 0.042 23.7 ± 7.8 Post-op 1 week 18.8 ± 3.7 23.0 ± 3.2 0.208 20.9 ± 7.7 Post-op 1 month 15.9 ± 3.6 16.0 ± 3.8 0.935 16.0 ± 3.6 Post-op 3 months 14.4 ± 2.5 16.0 ± 2.4 0.230 15.2 ± 2.6 IOP lowering medications (n) Pre-op 3.00 ± 0.0 2.91 ± 0.3 0.164 2.96 ± 0.2 Post-op 3 months 2.47 ± 0.4 2.36 ± 1.1 0.189 2.42 ± 0.6 Values are presented as mean ± SD; Group I: simultaneous intravitreal and intracameral bevacizumab injection group; Group II: intravitreal bevacizumab injection group. IOP = intraocular pressure; Pre-op = pre-injection; Post-op = post-injection. * Number of patient exception Ahmed valve implant surgery received; Paired t-test, p-value < 0.05. Table 4. Comparison of regression time of NVI and NVA in both groups Group I (n = 23) Group II (n = 21) p-value Total (n = 44) Regression time of NVI (days) 3.1 ± 1.2 3.9 ± 1.6 0.026 * 3.5 ± 1.5 Regression time of NVA (days) 3.2 ± 1.4 4.0 ± 1.5 0.033 * 3.6 ± 1.5 Values are presented as mean ± SD; Group I: simultaneous intravitreal and intracameral bevacizumab injection group; Group II: intravitreal bevacizumab injection group. NVI = neovascular iridis; NVA = neovascular angle. * Paired t-test, p-value < 0.05. Table 5. Comparison of regression time of NVI and NVA according to lens status in both groups Phakia (Group I: n = 12, Group II: n = 12) Pseudophakia (Group I: n = 9, Group II: n = 8) Aphakia (Group I: n = 2, Group II: n = 1) p-value Regression time of NVI (day) Group I 3.2 ± 1.4 3.1 ±1.0 2.0 ± 0.5 0.291 Group II 4.2 ± 1.9 3.3 ± 1.3 2.0 ± 0.0 0.006 p-value * 0.01 0.565 1.000 Regression time of NVA (day) Group I 3.2 ± 1.3 3.1 ± 1.4 2.0 ± 0.5 0.242 Group II 4.2 ± 1.9 3.4 ± 1.5 2.0 ± 0.0 0.005 p-value * 0.009 0.549 1.000 Values are presented as mean ± SD; Group I: simultaneous intravitreal and intracameral bevacizumab injection group; Group II: intravitreal bevacizumab injection group. NVI = neovascular iridis; NVA = neovascular angle. * Paired t-test; p-value < 0.05; ANOVA test. 신생혈관의변화홍채신생혈관과전방각신생혈관의소멸시기를관찰한결과, 홍채신생혈관과전방각신생혈관은모든환자에서소멸되었다. 홍채신생혈관은동시주입군에서 3.1 ± 1.2일, 단독주입군에서는 3.9 ± 1.6일이걸렸으며, 전방각신생혈관은동시주입군에서 3.2 ± 1.4일, 단독주입군에서는 4.0 ± 1.5일이소요되어, 홍채와전방각신생혈관모두동시주입군에서통계학적으로유의하게빨리소멸되었다 (p=0.026, p=0.033, Table 4). 수정체종류에따른홍채신생혈관소멸시기를살펴보면, 유수정체안에서동시주입군은 3.2 ± 1.4일, 단독주입군은 4.2 ± 1.9일로두군간에유의한차이를보였다 (p=0.01, Table 5). 그러나인공수정체안과무수정체안에서는두군 간에통계학적으로유의한차이가없었다 (p=0.565, p=1.000). 전방각신생혈관소멸시기도유수정체안에서는동시주입군이 3.2 ± 1.3일, 단독주입군은 4.2 ± 1.9일로두군간의통계학적으로유의한차이가보였지만 (p=0.009), 인공수정체안과무수정체안에서는차이가없었다 (p=0.549, p=1.00, Table 5). 동시주입군에서수정체종류에따른홍채와전방각신생혈관소멸시기는유의한차이를보이지않았으나 (p=0.291, p=0.242), 단독주입군에서는유수정체안인경우인공수정체안과무수정체안에비해홍채및전방각신생혈관의소멸속도가통계적으로유의하게길었다 (p=0.006, p=0.005, Table 5). 1043
- 대한안과학회지 2014 년제 55 권제 7 호 - Table 6. Change of corneal parameters in pre-injection and 3 months after injection in both groups Group I ( * n = 18) Group II ( * n = 14) p-value Total (n = 32) ECC Pre 2380.60 ± 278.95 2444.8 ± 360.50 0.342 2389.20 ± 322.42 Post 2264.65 ± 257.45 2377.05 ± 360.95 0.442 2319.85 ± 310.20 p-value 0.228 0.364 0.569 ECC 77.95 67.75 0.064 CV Pre 17.50 ± 5.87 18.55 ± 3.76 0.537 18.03 ± 4.90 Post 15.60 ± 5.42 16.75 ± 5.76 0.418 16.18 ± 5.70 p-value 0.210 0.256 0.309 CV 1.9 1.8 0.602 Hexa Pre 51.89 ± 4.19 53.39 ± 2.65 0.290 52.64 ± 3.54 Post 51.20 ± 4.18 52.64 ± 3.60 0.349 51.91 ± 3.92 p-value 0.685 0.630 0.627 Hexa 0.69 0.75 0.598 Pachy Pre 620.64 ± 38.53 625.18 ± 26.48 0.671 622.80 ± 32.85 Post 566.55 ± 36.75 573.81 ± 26.65 0.615 569.03 ± 31.80 p-value 0.014 0.036 0.015 Pachy 54.09 51.37 0.762 Values are presented as mean ± SD; Group I: simultaneous intravitreal and intracameral bevacizumab injection group; Group II: intravitreal bevacizumab injection group. Pre = pre-injection; Post = 3 months after injection; ECC = endothelial cell count (cells/mm2); CV = coefficient of variation; Hexa = hexagonality (%); Pachy = pachymetry (um); = difference between pre-injection and 3 months after injection. * Number of patient exception Ahmed valve implant surgery received; Paired t-test. Table 7. PAS change according to lens status in both groups Phakia (Group I: n = 12 Group II: n = 12) Pseudophakia (Group I: n = 9 Group II: n = 8) Aphakia (Group I: n = 2 Group II: n = 1) p-value Total (n = 44) Preop PAS Group I 1.12 ± 0.45 1.00 ± 0.56 3.00 ± 0.00 0.112 2.12 ± 0.74 Group II 1.22 ± 0.76 2.42 ± 0.66 4.00 ± 0.00 0.142 3.64 ± 0.82 Postop PAS Group I 1.83 ± 0.52 1.69 ± 0.58 3.00 ± 0.00 0.346 3.52 ± 0.61 Group II 2.03 ± 0.82 3.14 ± 0.64 4.00 ± 0.00 0.052 5.17 ± 0.73 PAS Group I 0.71 ± 0.12 0.69 ± 0.09 0 0.650 0.70 ± 0.18 Group II 0.81 ± 0.18 0.72 ± 0.12 0 0.262 0.76 ± 0.15 p-value * 0.020 0.317 0.068 Values are presented as mean ± SD; Group I: simultaneous intravitreal and intracameral bevacizumab injection group; Group II: intravitreal bevacizumab injection group. PAS = peripheral anterior synechiae (PAS range: 0 = 0, 0 < 1 90, 90 < 2 180, 180 < 3 270, 270 < 4 360 ); Pre-op = pre-injection; Post-op = post-injection at 3 months; PAS = PAS difference between pre-injection and 3 months after injection. * Paired t-test; p-value < 0.05; ANOVA test. 각막의변화두군에서베바시주맙주입이각막에미치는영향을알아보기위해이들시술이외에각막의변화에영향을줄수있는방수유출장치삽입술을받은동시주입군 5명, 단독주입군 7명을제외하고분석하였다. 두군에서방수유출장치삽입술을받은 12명을제외한 32명전체환자의각막내피세포수는 2389.2 ± 322.42 cells/mm 2, 세포변이계수는 18.03 ± 4.90, 육각세포비율은 52.64 ± 3.54%, 그리고중심각막두께는 622.80 ± 32.85 μm였다. 두군간의시술전의각막내피세포수와세포변이계수, 육각세포비율, 그리고중심각막두께는통계학적유의한차이는없었다 (Table 6). 시술후 3개월째전체환자의각막내피세포수와세포변이계 수, 그리고육각세포비율은시술전과차이가없었으나, 중심각막두께는 569.03 ± 31.80 μm로시술전에비해시술후 3개월째통계적으로유의하게감소하였다 (p=0.015). 주변홍채앞유착의변화시술전주변홍채앞유착의정도는동시주입군과단독주입군간의통계학적차이가없었다 (p=0.374). 시술후 3 개월째의주변홍채앞유착의변화량은동시주입군이 0.70 ± 0.18, 단독주입군은 0.76 ± 0.15로두군간의유의한차이는없었다 (p=0.068). 시술전과시술후 3개월째에동시주입군과단독주입군내에서수정체종류에따른주변홍채앞유착의변화를분석한결과도유의한변화는없었다 1044
- 허현도외 : 신생혈관녹내장에서베바시주맙주입효과 - (p=0.650, p=0.262). 하지만유수정체안인경우동시주입군과단독주입군간의시술전과시술후 3개월째의주변홍채앞유착의변화를살펴본결과는동시주입군에서단독주입군에비해통계적으로유의하게주변홍채앞유착이덜진행되었다 (p=0.020). 인공수정체안과무수정체안에서는두군간의차이는유의하지않았다 (p=0.317, p=1.000, Table 7). 시술과관련된합병증시술후수정체손상, 전방및유리체의출혈, 망막박리, 그리고안내염등의시술과관련된합병증은관찰되지않았다. 고찰 신생혈관녹내장은시력의소실뿐아니라안구통증을유발하여환자의삶의질을낮출수있는질환으로당뇨망막병증, 망막혈관폐쇄, 내경동맥협착등의다양한안질환에서망막에허혈이생겨그곳에서만들어진혈관내피세포성장인자가전방각등에신생혈관을생성시켜발생한다. 1-4 따라서신생혈관녹내장에서는최대한빨리혈관내피세포성장인자를줄이는것이치료의핵심이며, Diabetic Retinopathy Study에서는범망막광응고술로혈관내피세포성장인자의발생을효과적으로줄이는것을증명하였다. 22 그러나범망막광응고술후유리체내혈관내피세포성장인자농도감소까지수주가걸린다는보고가있으며, 23 또한각막부종, 전방출혈, 유리체출혈등망막에이르는매체혼탁으로시행하지못할때가있어문제가된다. 15 이때는초기안압하강과빠른신생혈관소멸을위해항혈관내피세포성장인자를유리체내또는전방내에주입을시행하는것이최선의치료방법이다. 16-18,24-26 하지만, 베바시주맙과같은항혈관내피세포성장인자들을사용할때에도신생혈관녹내장의발생원인이나수정체종류, 유리체절제술시행여부등과같은인자들에의해치료효과가다르게나타날수있으며, 안압상승으로인한각막부종이심한상태에서이러한시술들을시행함에따른각막내피세포의소실등의부작용의발생등을고려하여시행해야한다. 이러한배경에서본연구는신생혈관녹내장에서베바시주맙의전방과유리체내동시주입과유리체내단독주입에따른안압조절과신생혈관의소멸속도차이, 주변홍채앞유착의진행, 수정체종류에따른신생혈관의소멸과주변홍채앞유착의진행정도의차이및시술에따른각막내피세포의독성여부를알아보고자한것이었다. 그결과신생혈관녹내장에서베바시주맙을전방과유리체내동시에주입하는것이유리체내단독주입하는것보다각막독성없이초기안압조절및신 생혈관소멸에더효과적이며, 특히유수정체안에서발생한신생혈관녹내장의경우에는신생혈관의소멸속도와주변홍채앞유착의진행억제에있어동시주입이더효과적이라는것을확인할수있었다. 신생혈관녹내장에서전방과유리체내에혈관내피세포성장인자의농도가높다는것은잘알려졌다. 이러한혈관내피세포성장인자의활성을억제하기위해서주입하는항혈관내피세포성장인자는주입방법에따라전방내농도와반감기등이차이가난다. Bakri et al 27 은토끼를이용한실험에서유리체내베바시주맙을주입한후에유리체내반감기가 4.88일이며, 전방내농도가최대로상승할때까지약 3 일이걸린다고보고하였다. Matsuyama et al 28 은베바시주맙을유리체내에주사하고나서 7일후에전방내에서혈관내피세포성장인자의농도가통계적으로유의하게감소한다고보고하였다. 이런보고에따르면전방과유리체내에동시에베바시주맙을주입하는것과유리체내에만단독으로주입하는것은혈관내피세포성장인자의활성을유지하는정도에차이가있을것이라추론할수있다. 실제로두군을나누어진행한연구는아직없지만, 따로보고된연구에따르면, 신생혈관녹내장에서전방과유리체내에베바시주맙 1.25 mg (0.05 cc) 을함께주입한 Yuzbasioglu et al 25 과베바시주맙을유리체내에단독주입한 Ilieve et al 16 의연구에서홍채신생혈관소멸되는시간을비교해보면, 각각 36시간, 48시간으로동시주입한연구에서빠르게소멸되는것을확인할수있었다. 본연구에서도동시주입군이초기안압하강효과도크고, 홍채신생혈관소멸속도가빠른것으로나타나이전발표와일치함을확인하였고, 이러한결과는신생혈관녹내장에서베바시주맙을유리체내에만주입하는것보다전방과유리체내에동시주입하는것이더빠른효과를볼수있다는것을뒷받침한다. 신생혈관녹내장에서항혈관내피세포성장인자의전방내농도에영향을미칠수있는또하나의인자는수정체의종류이다. 무수정체안은유리체에서전방으로혈관내피세포성장인자가확산되는데방벽이되는수정체가제거된상태이며, 인공수정체안의경우에도수정체제거시정상적인수정체와수정체소대의해부학적구조를변형시켜혈관내피세포성장인자가쉽게전방에도달하게된다고한다. 29,30 이것은항혈관내피세포성장인자와같은다른약물이이동하는경우에도마찬가지로적용될수있다. 즉, 유리체내주입술을시행하는경우유수정체안에서인공수정체안이나무수정체안보다전방내약물농도가더느리게상승한다는것이다. 본연구의결과에서유리체내에단독주입한군에서유수정체안의경우신생혈관소멸의속도가인공수정체안과무수정체안에비해느렸던것도, 인공수정 1045
- 대한안과학회지 2014 년제 55 권제 7 호 - 체안과무수정체안에서유수정체안에비해유리체내베바시주맙이전방으로수월하게이동할수있다는것을의미한다고볼수있으며, 이에따라, 신생혈관녹내장에서베바지주맙의주입을할때수정체종류도고려해야만한다. 증식성당뇨망막병증의치료에서베바시주맙을유리체내에주입하는경우신생혈관이퇴축되면서견인막이발생하여망막박리가발생하는것을종종볼수있다. 31 이러한이유를혈관내피세포성장인자가감소하면서 CTGF (Connective tissue growth factor) 등의섬유화와관련된인자들의농도가상대적으로증가하면서발생하는것으로설명한다. 32 결국신생혈관녹내장에서도전방각등에발생한신생혈관들이많을수록, 혈관이퇴축되더라도섬유화, 즉주변홍채앞유착이발생하여안압조절에실패할가능성이높게된다. 본연구에서도방수유출장치삽입술을시행받은군 (12안) 과받지않은군의시술전의안압은 33.5 ± 3.8 mmhg, 35.4 ± 7.6 mmhg로유의한차이는없었지만, 시술전의주변홍채앞유착은시행받은군이 3.25 ± 0.12, 받지않은군이 1.50 ± 1.02이었다. 결과를종합해보면, 결국신생혈관녹내장의치료의성패는얼마나빨리전방각의신생혈관을소멸시키는가에달려있다고볼수있다. 특히신생혈관녹내장초기에는신생혈관이생성되기전에상승된혈관내피세포성장인자에의해혈관의확장이나울혈로안압이상승하는경우가있는데 33 이러한경우에는신생혈관이생성되어발생하는합병증을예방하기위해서빨리혈관내피세포성장인자의농도를낮추는치료가필요하다. 본연구에서유수정체안인경우동시주입군과단독주입군간의시술전과시술후 3개월째에동시주입군에서단독주입군에비해주변홍채앞유착이통계적으로유의하게덜진행되었다는결과를볼때, 빠른신생혈관의소멸이주변홍채앞유착의진행을억제하는요소로생각한다. 신생혈관녹내장이발생하면시력에대한예후는나쁜것으로알려졌다. 이는신생혈관녹내장에서유리체강내베바시주맙의효과를증명하기위해범망막광응고술만시행한군과범망막광응고술과함께유리체강내베바시주맙주입을시행한군을비교한 Ehlers et al 34 의연구에서두군에서시력호전이통계적으로유의하지않았고최종시력이 20/100 이하가 70% 이상으로보고하여신생혈관녹내장의시력예후가불량함을보고하였다. 이번연구에서도각군내에서시술전과시술후 3개월째시행한교정시력의호전은통계적으로유의하지않았으며두군간의시술전과시술후 3개월째교정시력의변화도통계적으로유의한차이가없었다 (p=0.658, p=0.624, p=0.882). 전방내베바시주맙을주입한후각막내피세포의독성을연구한 Rusovici et al 35 과유리체내베바시주맙을주입후 각막내피세포의독성을연구한 Chalam et al 36 과 Suh et al 37 의보고에따르면, 시술전후의각막내피세포수, 세포변이계수와육각세포비율이통계적으로유의한차이가없었다. 본연구에서도전체환자군에서시술전과시술후 3개월째각막내피세포수와세포변이계수와육각세포비율은통계적으로유의한차이는없었다. 중심각막두께는전체군에서와동시주입군과단독주입군모두에서시술전과시술후 3개월째통계적으로유의한차이를보였다 (p=0.015, p=0.014, p=0.036). 이것은안압하강으로각막부종의감소로인한것으로생각한다. 따라서베바시주맙이각막내피세포에미치는영향을모두평가하기는힘들지만동시주입과단독주입의차이에따른각막내피세포에미치는영향은적을것으로생각한다. 본연구의제한점으로는후향적연구라는점, 시술전홍채및전방각신생혈관의심한정도를분류하지않은점, 그리고전방과유리체내혈관내피세포성장인자의농도를측정하지못한점, 홍채및전방각신생혈관의소멸을형광촬영을이용하여감별한것이아닌관찰자의맨눈으로판독한점, 관찰기간이 3개월로짧았다는점, 초기망막이관찰되지않아범망막광응고술을시행하지못한환자를제외한점, 각군의크기가각각 23명, 21명으로적었고유수정체안에비해무수정체나인공수정체증례가적은점, 그리고유리체내와전방내각각베바시주맙 1.25 mg (0.05 cc) 주입과유리체내에베바시주맙 1.25 mg (0.05 cc) 을주입하여총량에서차이가있어전방과유리체내단독주입의비교를시행하지못한것이다. 하지만이런제한점에도불구하고전방과유리체내동시주입과유리체내단독주입의효과를비교한첫연구이며, 수정체종류에따라베바시주맙의전방과유리체내동시주입과유리체내단독주입시홍채신생혈관과전방각신생혈관의소멸시기가다름을보여주는첫연구이다. 결론적으로, 신생혈관녹내장에서베바시주맙을전방과유리체내동시에주입하는것이유리체내에만단독주입하는것보다각막독성없이시술후초기 3일이내안압조절및신생혈관소멸에더효과적이며, 특히유수정체안에서발생한신생혈관녹내장의경우에는신생혈관의소멸속도와주변홍채앞유착의진행억제에있어동시주입이더효과적이라는것을확인하였다. 그리고베바시주맙의안내주입시수정체종류도고려해야한다. REFERENCES 1) Sivak-Callcott JA, O Day DM, Gass JD, Tsai JC. Evidence-based recommendations for the diagnosis and treatment of neovascular glaucoma. Ophthalmology 2001;108:1767-76. 1046
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- 대한안과학회지 2014 년제 55 권제 7 호 - = 국문초록 = 신생혈관녹내장에서베바시주맙의전방과유리체내동시주입과유리체내단독주입의치료효과 목적 : 신생혈관녹내장에서베바시주맙의전방과유리체내동시주입군과유리체내단독주입군의치료효과를비교하였다. 대상과방법 : 신생혈관녹내장으로베바시주맙 (Avastin R ; Genetech, Inc., San Francisco, USA) 1.25 mg 을전방과유리체내에동시에주입한 23 안과유리체내에만단독주입한 21 안을대상으로시력, 안압, 홍채및전방각신생혈관소멸속도, 주변홍채앞유착진행정도를비교하였다. 결과 : 시술후 1, 3 일째안압변화량은동시주입군이 9.5, 15.9 mmhg, 단독주입군은 5.6, 7.5 mmhg 로동시주입군에서유의하게더하강되었고 (p=0.001, p<0.001), 홍채및전방각신생혈관소멸은동시주입군에서각각 3.1, 3.2 일로단독주입군 3.9, 4.0 일보다빨리소멸되었다 (p=0.026, p=0.033). 수정체종류에따른홍채및전방각신생혈관소멸은단독주입군에서유수정체안인경우 4.2, 4.2 일로인공수정체안 3.3, 3.4 일, 무수정체안 2.0, 2.0 일에비해유의하게늦었다 (p=0.006, p=0.005). 시술후 3 개월째주변홍채앞유착의진행은유수정체안에서동시주입군이단독주입군보다유의하게적었다 (p=0.020). 결론 : 신생혈관녹내장치료에서베바시주맙을전방과유리체내동시주입하는것이유리체내단독주입하는것보다시술후 3 일이내의초기안압조절및신생혈관소멸에더효과적이고, 특히, 유수정체안인경우신생혈관의소멸속도와주변홍채앞유착의진행억제에있어동시주입이더효과적이다. < 대한안과학회지 2014;55(7):1039-1048> 1048