대한안과학회지 2016 년제 57 권제 12 호 J Korean Ophthalmol Soc 2016;57(12):1976-1980 ISSN 0378-6471 (Print) ISSN 2092-9374 (Online) http://dx.doi.org/10.3341/jkos.2016.57.12.1976 Case Report 항바이러스제정맥주사후급성신손상이발생한급성망막괴사환자의치료 Treatment of Acute Retinal Necrosis with Acute Kidney Injury after Intravenous Antiviral Injection 황선진 김두루 강민호 성민철 조희윤 신용운 Sun Jin Hwang, MD, Du Roo Kim, MD, Min Ho Kang, MD, PhD, Min Cheol Seong, MD, PhD, Hee Yoon Cho, MD, PhD, Yong Un Shin, MD, PhD 한양대학교의과대학한양대학교구리병원안과학교실 Department of Ophthalmology, Hanyang University Guri Hospital, Hanyang University College of Medicine, Guri, Korea Purpose: In the present study, a case of acute retinal necrosis with acute renal injury due to high-dose intravenous antiviral injection which was treated by intravitreal ganciclovir injection is reported. Case summary: A 46-year-old female visited our clinic complaining of red eye and decreased vision in the right eye. At the first visit, her corrected visual acuity was finger count in the right eye, and 20/20 in the left eye. Fundus examination of the right eye revealed multiple peripheral arterial occlusion, papilledema, and whitish necrotic infiltration at the periphery. Clinically diagnosed as acute retinal necrosis, the patient was started on intravenous acyclovir. Two days after injection, her serum creatinine level increased, therefore, intravenous acyclovir was discontinued and she was started on intravitreal ganciclovir. Five days after the intravenous injection was discontinued, the serum creatinine level returned to normal range. Four months after the first visit, visual acuity was 20/100 and no recurrence was observed. Conclusions: Intravitreal ganciclovir injection can be an effective alternative in patients with acute retinal necrosis and poor kidney function. J Korean Ophthalmol Soc 2016;57(12):1976-1980 Keywords: Acute renal injury, Acute retinal necrosis, Acyclovir, Antiviral, Ganciclovir 급성망막괴사증후군 (acute retinal necrosis syndrome) 은면역능력이정상인사람에서헤르페스바이러스군에의해발생하는질환으로괴사성망막염, 폐쇄성망막혈관염, 유리체염이급속히진행하는것이특징이다. 1 급성망막괴사증후군의진단은임상소견과질병의진행양상에의하며, 병의 Received: 2016. 8. 11. Revised: 2016. 10. 20. Accepted: 2016. 11. 23. Address reprint requests to Yong Un Shin, MD, PhD Department of Ophthalmology, Hanyang University Guri Hospital, #153 Gyeongchun-ro, Guri 11923, Korea Tel: 82-31-560-2522, Fax: 82-31-564-9479 E-mail: Syu2000@hanmail.net 원인또는환자의면역상태는진단기준에포함되어있지않다. 2 임상적으로는갑작스런시력저하를보이고, 50-75% 의환자에서망막박리가발생하여시력예후가불량하다. 3 급성망막괴사증후군의주된원인은수두대상포진바이러스 (varicella zoster virus, VZV), 단순헤르페스바이러스 (Herpes simplex virus, HSV), 거대세포바이러스 (cytomegalovirus, CMV) 와같은헤르페스바이러스군으로확진을위해망막조직검사, 바이러스배양검사, polymerase chain reaction 등을시행할수있다. 4,5 급성망막괴사증후군은대개 acyclovir 정맥주사로치료하지만, acyclovir 정맥주사에반응이없을경우 foscarnet 정맥주사로변경하거나유리체강내 ganciclovir를 c2016 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. 1976
- 황선진외 : 급성망막괴사의치료 - 병용하여치료를할수있다. 6 망막박리가있는경우레이저광응고술, 유리체절제술, 공막돌륭술, 가스주입술, 실리콘기름주입술등의수술적치료를시도할수있는것으로알려져있다. 7,8 Acyclovir는헤르페스바이러스감염등에사용하는항바이러스제로약제사용으로인해급성신부전이발생할수있다. 저자들은급성망막괴사증후군의심환자에서항바이러스제정맥투여후급성신부전이발생한환자를 acyclovir 를중단하고유리체강내 ganciclovir 단독주입술로변경하여호전된증례를관찰하였고, 이를문헌고찰과함께보고하고자한다. 증례보고 54세여자환자로내원 10일전발생한우안시력저하를주소로내원하였다. 안과적으로특별한과거력은없고, 내과적으로 10년된당뇨와심근경색으로타원진료를받고있었다. 개인병원에서포도막염의심하에스테로이드점안약을사용하고있었으나호전이없어의뢰된환자였다. 초진시최대교정시력우안이 0.02, 좌안이 1.0이었고, 안압은우안이 13 mmhg, 좌안이 15 mmhg였다. 세극등현미경검사에서우안각막뒷면침착물및홍채뒤유착이관찰되었고, 다발성주변부망막동맥폐쇄, 시신경부종, 주변부망막의백색괴사성침윤등이관찰되었으며양안망막 4분역모두에서미세혈관류및출혈이관찰되었다 (Fig. 1). 좌안의염증소견은없었다. 우안급성망막괴사및양안심한비증식당뇨망막병증으로진단하여, 입원후혈액검사및혈청학적검사를실시하였고, acyclovir 10 mg/kg 용량으로하루 3회정맥투여를시작하였다. 혈액학적검사및전해질 검사, 기본신기능검사는정상이었고, 혈청학적검사에서 HSV, VZV, CMV에대한 IgG 항체는모두양성이었으나 IgM 항체는음성이었고, Venereal Disease Research Laboratory test, Fluorescent treponemal antibody absorption test 검사와 toxoplasma, Human Immunodeficiency Virus 항체는음성이었다. 주사치료 2일째, 망막주변부괴사진행소견은관찰되지않았으나, 추적관찰한혈액검사상크레아티닌수치가치료전 1.0 mg/dl에비해 3.0 mg/dl로상승되었고, 사구체여과율은치료전 64.024 ml/min 에서 15.690 ml/min 으로감소되었다. 신장내과협진후 acyclovir에의한급성신손상진단하에 acyclovir 정맥주사를중단하였고, 신장내과로전과하여수액치료등내과적처치를시작하였다. Acyclovir 정맥주사중단 5일후혈청크레아티닌수치는 1.5 mg/dl로감소하였고 9일째에는 1.2 mg/dl로회복되었다. Acyclovir 정맥주사중지직후부터유리체강내 ganciclovir (2 mg/0.05 ml) 주입술을 1주일에 2회씩총 3주간시행하였고경구스테로이드는하루 30 mg으로시작하여 1주에 5 mg씩감량하여약 1달간사용하였다 (Fig. 2). 유리체강내 ganciclovir 주입술을시작한후안저에보이던침윤은빠르게호전되었으며약 1달째레이저치료를시행하였다. 3주간의유리체강내 ganciclovir 주사후저용량경구 acyclovir를복용하였으며, 3개월뒤모든병변은소실되었으며망막박리는발생하지않았다. 최종시력은 0.2였다 (Fig. 3). 고찰 급성망막괴사증후군의원인으로헤르페스바이러스군이알려진후로 acyclovir 정맥주사가급성망막괴사증후군 Figure 1. Fundus photograph and fluorescein angiography at initial visit. Confluent, whitish, and necrotic infiltrations are seen around peripheral retina. Obstructive arteritis, vitreous haziness and disc edema are also observed. 1977
- 대한안과학회지 2016 년제 57 권제 12 호 - A B Figure 2. Fundus photographs after administration. (A) Hospital day #2. After intravenous acyclovir, the progression of the diseases was stopped, however, acyclovir-induced acute renal injury was occurred. (B) Hospital day #7. Instead of IV acyclovir, intravitreal gancyclovir was performed 2 times per week. The area of infiltrations began to decrease. A B C D Figure 3. Chronologic order of ultra-wide fundus images during the patient s clinical course. (A) One month after initial visit. Peripheral confluent whitish lesions were moved to more peripheral area. At that time, 360 barrier laser was done. 6 week (B) and 8 weeks (C) later, peripheral infiltrations were significantly improved. 3 months later (D), no infiltration was observed. 1978
- 황선진외 : 급성망막괴사의치료 - 의공인된치료방법이다. 1,500 mg/m 2 /day의용량을하루세번으로나누어 5-10일정도투여하며, 치료시작후 48 시간이내새로운망막괴사병변이나타나지않으면, 4-5 일후대개병변이호전된다. 9 이후경구약제로변경하여 (acyclovir 800 mg, 하루 5번복용 ) 6주에서 8주동안복용한다. Acyclovir 정맥주사외에항혈소판제제, 전신적스테로이드를같이사용할수있으며망막박리예방을위해예방적레이저광응고술을시행한다. Acyclovir는혈장에서빠르게제거되고소변에서낮은용해도를가지는특징이있어소변에서불용상태로존재하는양이많아져세뇨관에결정형성을유도한다. 10 따라서 acyclovir를고농도로빠르게정맥투여하였을경우세뇨관결정생성으로인한폐쇄성신장병증과요세관사이질콩팥염 (tubulo-interstitial nephritis) 에의한급성신부전이발생할수있다. 11 앞선국내보고에따르면고용량의 acyclovir 정맥투여로급성신부전이발생할수있으므로, 천천히주입하면서수액치료를병행하여이를예방해야한다고강조하였다. 12 하지만, 기저신장질환이있거나체용적이적은경우예방적요법을적용하더라도급성신부전에빠지게될위험이높다. 10 따라서고용량 acyclovir 정맥주사의사용에있어이러한점에주의를기울여야한다. 고용량 acyclovir 정주의부작용과경구 acyclovir 의낮은생체이용률로, 최근에는 valacyclovir, famciclovir, valganciclovir 등여러경구약제들이소개되고있다. 경구 valacyclovir와 famciclovir는 acyclovir 정주와거의동일한생체이용률을보이며, famciclovir의경우신장기능에영향을끼지지않는다. 13 또한경구 valacyclovir 또는경구 famciclovir 단독으로급성망막괴사의치료에효과를보였다는보고도있었다. 14 Ganciclovir는 HSV, VZV, CMV에 acyclovir보다강한항바이러스효과를보이나, 그전신적독성이심하여급성망막괴사증후군에일차약제로사용되지는않고, 면역기능이저하된환자나 acyclovir 치료에반응이없는경우사용하기도한다. 9 유리체내에서도 ganciclovir는 HSV, VZV, CMV에항바이러스작용을하는것으로알려져있다. Liu et al 15 은급성망막괴사증후군에서고용량 acyclovir 정맥투여후급성신부전이발생한환자에서유리체내 ganciclovir 와 foscarnet을함께사용하여치료한증례를보고하였다. 국내에서도고용량 acyclovir 정맥주사에반응이없는급성망막괴사증후군에서유리체강내 ganciclovir 주입술을병행하여효과를보았다. 16 급성망막괴사의고전적인치료는우선적으로전신항바이러스제치료를시작하는것이나최근에는유리체강내항바이러스제주사를조기에투여하거나처음부터병합하는치료가시도되고있다. 최근 Yeh et al 17 은급성망막괴사 가치료에있어유리체강내항바이러스제주사와함께전 신항바이러스제투여복합치료가전신항바이러스제투여 단독치료보다시력예후및망막박리발생을줄이는데도 움이된다고보고하였다. 또한 Wong et al 13 은심한혈관염, 후극부를침범한장액박리혹은시신경병증이동반된경우 에는전신항바이러스제치료와더불어유리체강내항바 이러스제치료를즉시병합하는것이치료에도움이된다 고추천하였다. 본증례에서는고용량 acyclovir 정맥주사후급성신부 전이발생한환자에서유리체내 ganciclovir 주사치료를단 독으로시행하여치료하였다. 신장기능이떨어져있거나 오래된당뇨를앓고있는경우고용량 acyclovir 정맥주사 후초기에신장기능확인검사가중요하며정맥주사전에 유리체강내 ganciclovir 주입술을먼저고려하는것이전신 적인부작용의위험을줄이면서보다효과적인방법이될 수있을것으로생각된다. 저자들은당뇨환자에서발생한 급성망막괴사증후군 1 예를 acyclovir 정맥주사로치료했으 나, 급성신부전이발생하여유리체내 ganciclovir 주입술로 바꾸어호전된증례를경험하여이를보고하는바이다. REFERENCES 1) Lau CH, Missotten T, Salzmann J, Lightman SL. Acute retinal necrosis features, management, and outcomes. Ophthalmology 2007;114:756-62. 2) Holland GN. Standard diagnostic criteria for the acute retinal syndrome. Executive Committee of the American Uveitis Society. Am J Ophthalmol 1994;117:663-7. 3) Clarkson JG, Blumenkranz MS, Culbertson WW, et al. Retinal detachment following the acute retinal necrosis syndrome. Ophthalmology 1984;91:1665-8. 4) Freeman WR, Thomas EL, Rao NA, et al. Demonstration of herpes group virus in acute retinal necrosis syndrome. Am J Ophthalmol 1986;102:701-9. 5) de Boer JH, Verhagen C, Bruinenberg M, et al. Serologic and polymerase chain reaction analysis of intraocular fluids in the diagnosis of infectious uveitis. Am J Ophthalmol 1996;121:650-8. 6) Chau Tran TH, Cassoux N, Bodaghi B, Lehoang P. Successful treatment with combination of systemic antiviral drugs and intravitreal ganciclovir injections in the management of severe necrotizing herpetic retinitis. Ocul Immunol Inflamm 2003;11:141-4. 7) Mastsuo T. Vitrectomy and silicone oil tamponade as an initial surgery for retinal detachment after acute retinal necrosis syndrome. Ocul Immunol Inflamm 2005;13:91-4. 8) McDonald HR, Lewis H, Kreiger AE, et al. Surgical management of retinal detachment associated with the acute retinal necrosis syndrome. Br J Ophthalmol 1991;75:455-8. 9) Duker JS, Blumenkranz MS. Diagnosis and management of the acute retinal necrosis (ARN) syndrome. Surv Ophthalmol 1991; 35:327-43. 10) Markowitz GS, Perazella MA. Drug-induced renal failure: a focus 1979
- 대한안과학회지 2016 년제 57 권제 12 호 - on tubulointerstitial disease. Clin Chim Acta 2005;351:31-47. 11) Bean B, Aeppli D. Adverse effects of high-dose intravenous acyclovir in ambulatory patients with acute herpes zoster. J Infect Dis 1985;151:362-5. 12) Cho JH, Jang JH, Lee DH, et al. Acyclovir-induced acute renal failure in a patient with suspected acute retinal necrosis syndrome. J Korean Ophthalmol Soc 2010;51:1528-31. 13) Wong RW, Jumper JM, McDonald HR, et al. Emerging concepts in the management of acute retinal necrosis. Br J Ophthalmol 2013;97:545-52. 14) Emerson GG, Smith JR, Wilson DJ, et al. Primary treatment of acute retinal necrosis with oral antiviral therapy. Ophthalmology 2006;113:2259-61. 15) Liu DT, Lee VY, Lam PT, Lam DS. Acyclovir-induced nephrotoxicity in a patient with acute retinal necrosis. Hong Kong Med J 2007;13:155-6. 16) Yang JW, Kim WJ, Park YH. Two cases of acute retinal necrosis treated with systemic antiviral drugs and intravitreal antiviral injections. J Korean Ophthalmol Soc 2009;50:794-9. 17) Yeh S, Suhler EB, Smith JR, et al. Combination systemic and intravitreal antiviral therapy in the management of acute retinal necrosis syndrome. Ophthalmic Surg Lasers Imaging Retina 2014;45: 399-407. = 국문초록 = 항바이러스제정맥주사후급성신손상이발생한급성망막괴사환자의치료 목적 : 급성망막괴사의치료를위해항바이러스제정맥투여후급성신손상이발생한환자에서정맥투여중단후유리체강내 ganciclovir 단독주입술로호전된환자 1 예를보고하고자한다. 증례요약 : 46 세여자가 10 일전시작된우안충혈, 시력저하로내원하였다. 초진당시교정시력우안안전수지, 좌안 1.0 이었으며, 안저검사상우안은다발성주변부망막동맥폐쇄, 시신경부종, 주변부망막의백색괴사성침윤등이관찰되었다. 우안급성망막괴사진단하에 acyclovir 정맥투여를시작하였다. 주사치료 2 일째혈액검사에서혈청크레아티닌수치가상승되었고사구체여과율은감소하여 acyclovir 에의한급성신손상으로보고정맥주사를중지하였다. 정맥주사중지직후부터유리체강내 ganciclovir 주입술을시행하였으며, 중지 5 일후혈청크레아티닌은정상범위로회복되었고, 발병 4 달째나안시력우안 0.2 로유지되었으며, 진행및재발소견은관찰되지않았다. 결론 : 유리체강내 ganciclovir 단독주사치료가신장기능이좋지않은환자의급성망막괴사치료에있어효과적인대체치료법이될수있을것으로생각된다. < 대한안과학회지 2016;57(12):1976-1980> 1980