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1 대한안과학회지제 49 권제 3 호 2008 J Korean Ophthalmol Soc 49(3): , 2008 DOI : /jkos = 증례보고 = 급성림프구성백혈병환자에서동종골수이식후발생한골수이식망막병증 조영준 왕선진 김정열 충남대학교의과대학안과학교실 목적 : 급성림프구성백혈병으로동종골수이식을시행받고 18 개월이경과한후골수이식망막병증이발생한예가있어보고하고자한다. 증례요약 : 20 세의남자환자가급성림프구성백혈병으로골수이식을받고 18 개월후좌안의시력저하를주소로내원하였다. 교정시력은우안 1.0, 좌안 0.6 이었다. 안저검사에서양안에다수의면화반및점상출혈이있었고, 좌안에황반부종이관찰되었다. 형광안저혈관조영에서좌안상비측에모세혈관비관류가관찰되었다. 4 개월후좌안교정시력이 0.3 으로감소되었고안저검사상신생혈관이관찰되었으며, 형광안저혈관조영에서증가된모세혈관비관류, 신생혈관, 그리고황반부허혈을확인할수있었다. 신생혈관및모세혈관비관류가있는부위에 2 차례에걸쳐레이저광응고술을시행하였다. 1 년후좌안교정시력 0.6 으로다소회복되었으나형광안저혈관조영에서황반부허혈의부위에는변함이없었고, 새로운부위에신생혈관및모세혈관비관류가관찰되어 2 회의추가레이저광응고술을시행하였다. < 한안지 49(3): , 2008> 백혈병은백혈병세포가직접안조직에침착되어문제를일으키기도하지만, 빈혈, 혈액점도증가, 혈소판감소증과같은혈액학적인이상도눈에영향을미친다. 또한백혈병의치료로사용되는항암화학요법, 방사선요법, 골수이식도눈에악영향을끼칠수있다. 1 골수이식의전신적부작용으로는혈액무형성증으로인한출혈과감염, 면역억제로인한부작용등이있다. 2 골수이식후발생할수있는안과적문제로전안부합병증으로는이식편대숙주반응에의한건성각결막염, 백내장, 각막감염등이있으며, 3-7 후안부합병증으로는흔하지는않지만, 유리체출혈또는망막출혈, 미세혈관장애망막병증, 시신경유두부종, 감염등이있다. 1,8-11 본증례에서는항암화학요법과방사선요법후동종 < 접수일 : 2007 년 5 월 15 일, 심사통과일 : 2007 년 9 월 21 일 > 통신저자 : 김정열대전시중구대사동 640 충남대학교병원안과 Tel: , Fax: kimjy@cnu.ac.kr * 본논문의요지는 2007 년대한안과학회제 97 회춘계학술대회에서포스터로발표되었음. 골수이식을시행받은환자에서 18 개월후황반부종과모세혈관비관류를동반하는골수이식망막병증이발생한환자가있어이를보고하고자한다. 증례보고 18 개월전에급성림프구성백혈병으로동종골수이식을받은 20 세남자환자가좌안시력저하를주소로본원안과에내원하였다. 이환자는 4 년전급성림프구성백혈병으로진단받고 Vincristine, Adriamycin, Cytarabine, Etoposide 로 6 개월간의전신항암화학요법후완전관해되었다. 항암요법 15 개월후중추신경계재발이발생하여 Methotrexate, Cytarabine 을뇌척수액내에 2 회주사하고, 두경부방사선요법을 200 cgy 로 12 회조사받았다. Vincristine, Daunorubicin, Cytarabine 으로전신항암요법을재시행하여 2 차관해를유도한후동종골수이식을받았다. 골수이식을시행받고 2 개월후이식편대숙주반응이피부에발생하여지속적으로 Cyclosporine 을복용하였다. 내원시교정시력은우안 1.0, 좌안 0.6 이었다. 양안모두대광반사는정상반응을보였고, 구심동공운동장애는없었다. 골드만압평안압계로측정한안압은우안 514

대한안과학회지제 49 권제 3 호 2008 년 Figure 1. Fundus photographs and fluorescein angiographs at the initial visit. (A) Fundus photographs show multiple cottonwool spots and dot-like hemorrhages.

2 대한안과학회지제 49 권제 3 호 2008 년 Figure 1. Fundus photographs and fluorescein angiographs at the initial visit. (A) Fundus photographs show multiple cottonwool spots and dot-like hemorrhages. (B) Fluorescein angiographs show capillary nonperfusion in both eyes and macular ischemia in the left eye. 12 mmhg, 좌안 11 mmhg 로정상범위였다. 전안부에는특이소견없었으며안저검사에서양안에다수의면화반및점상출혈이있었고, 좌안에황반부종이관찰되었다. 형광안저혈관조영에서좌안상비측에모세혈관비관류가관찰되었다 (Fig. 1). 4 개월후좌안교정시력이 0.3 으로감소되었고안저검사에서신생혈관이관찰되었으며, 형광안저혈관조영상증가된모세혈관비관류, 신생혈관, 그리고황반부허혈을확인할수있었다. 신생혈관및모세혈관비관류가있는부위에 2 차례에걸쳐레이저광응고술을시행하였다 (Fig. 2). 1 년후좌안교정시력은 0.8 로회복되었으나형광안저혈관조영에서황반부허혈의부위에는변함이없었고, 새로운부위에신생혈관및모세혈관비관류가관찰되어 2 회의추가레이저광응고술을시행하였다 (Fig. 3). 고 찰 골수이식망막병증은골수이식후발생하는합병증의 하나로서면화반, 망막출혈, 미세혈관류, 지질삼출물, 망막신생혈관, 유리체출혈, 견인망막박리, 시신경위축, 홍채신생혈관, 신생혈관녹내장등의소견을보이는폐쇄성망막미세혈관병증이다. 1,9-12 이러한망막증은방사선조사, 고용량의항암제사용, 이식편대숙주반응및이식편대숙주반응의예방및치료를위해사용하는면역억제제등이복합적으로작용하여발생하는것으로알려져있다. 9 일부에서는골수이식망막병증이단순한방사선망막병증의일종이라고얘기하기도하지만, 방사선조사를받지않은눈에서도골수이식망막병증이발생하기때문에유일한원인으로볼수는없다. Cunningham et al 12 은방사선요법을시행하지않은백혈병환자에서 Cytarabine 과 Daunorubicin 으로관해후, 동종골수이식을시행받고 Busulfan 과 Etoposide 투여 1 년후양안에면화반과망막내출혈이발생한증례를보고하였고, Johnson et al 13 은방사선요법은받지않고 Cyclophosphamide, 515

조영준외 : 골수이식후골수이식망막병증 Figure 2. Fundus photographs and fluorescein angiographs at 4 months after the initial visit. (A) Fundus photographs show new vessels.

3 조영준외 : 골수이식후골수이식망막병증 Figure 2. Fundus photographs and fluorescein angiographs at 4 months after the initial visit. (A) Fundus photographs show new vessels. (B) Fluorescein angiographs show increased capillary nonperfusion and leakage from new vessels in both eyes. Cisplatin 을고용량투여받은자가조혈모세포이식을받은환자 140 명중 34 명에서면화반, 망막출혈, 시신경유두부종이발생한것을보고한바있다. 이는방사선조사가없어도항암화학요법과골수이식이망막혈관에독성을나타낼수있음을보여주는것이라하겠다. 방사선조사량과망막증의발생에관한많은연구가보고되어왔는데보통 3,000 cgy 이하의방사선요법으로는방사선망막병증의발생은드문것으로알려져있고, 14 6,000 cgy 의방사선요법후에는 50% 가, 7,000~8,000 cgy 후에는 85-95% 의환자가방사선망막병증으로진행한다는보고가있다. 15 본증례는방사선조사량이 2,400 cgy 로비교적적은양의방사선이조사되었으므로방사선요법단독에의한것이라기보다는다른요소들과병합되어망막증이발생하였다고볼수있다. 이식편대숙주반응은골수이식후흔하게발생하는부작용으로만성안구이식편대숙주반응은 60~90% 까지발생하는것으로보고되어있다. 3,4 안과적으로건성각결막염, 공막염, 토안, 망막미세혈관질환등을일으킬수있으며, 5-7 안증상의치료를위해인공누액, 스테로이드및 Cyclosporine 점안액등을보조적으로사 용하며, 전신적으로장기간 Cyclosporine 을투여한다. Cyclosporine 은골수이식후이식편대숙주반응의억제를위해가장널리쓰이는약물로서신경독성, 이를테면경련, 구음장애, 뇌피질맹, 뇌압상승, 시신경유두부종을일으키는것으로알려져있다. 8 Coskuncan et al 2 은동종골수이식을받은환자 372 명을대상으로한연구에서 8 명 (2%) 이 Cyclosporine 으로인한것으로추정되는양안시신경유두부종이발생한것을보고하였다. 또한전신방사선요법과 Cyclosporine 의병합시허혈성망막병증이일어난예가수차례보고되었다. 9-11,16,17 이밖에골수이식후생기는합병증으로는면역력의저하로인한안구감염, 2 거대세포바이러스 18 나대상포진바이러스에의한망막염, 19 candida 나 aspergillus 에의한망막염과안내염도보고되고있다. 20 또한골수이식후고용량의스테로이드, 스트레스, 고혈압, Cyclosporine 과연관되어드물게중심성장액맥락망막병증이발생하였다는보고도있다 본증례에서골수이식망막병증은중추신경계재발의치료로시행한두경부방사선요법, 백혈병관해를위해사용한 Vincristine, Cytarabine 등의항암요법, 516

대한안과학회지제 49 권제 3 호 2008 년 Figure 3. Fundus photographs and fluoresein angiographs at 1 year after the initial visit. (A) Fundus photographs show new vessels in the other areas.

4 대한안과학회지제 49 권제 3 호 2008 년 Figure 3. Fundus photographs and fluoresein angiographs at 1 year after the initial visit. (A) Fundus photographs show new vessels in the other areas. (B) Fluoresein angiographs show leakage from new vessels. 이식편대숙주반응및이식편대숙주반응의치료를위해사용한 Cyclosporin 이복합적으로작용하여허혈성망막병증을일으킨것으로생각된다. 결론적으로골수이식후드물지만진행성의망막허혈을보이는골수이식망막병증이발생할수있음을알수있었고, 골수이식후주기적인안과적검사가필요할것으로생각된다. 참고문헌 1) Jack MK, Hicks JD. Ocular complications in high-dose chemoradiotherapy and marrow transplantation. Ann Ophthalmol 1981;13: ) Coskuncan NM, Jabs DA, Dunn JP, et al. The eye in bone marrow transplantation.Ⅵ. Retinal complications. Arch Ophthalmol 1994;112: ) Fisher VL. Long-term follow-up in hematopoietic stem cell transplant patient. Pediatr Transplant 1999;3: ) Franklin RM, Kenyon KR, Tutschka PJ, et al. Ocular manifestations of graft-vs-host disease. Ophthalmology 1983;90: ) Kim RY, Anderlini P, Naderi AA, et al. Scleritis as the initial clinical manifestation of graft versus host disease after allogenic bone marrow transplantation. Am J Ophthalmol 2002;133: ) Arocker-Mettinger E, Skorpik F, Grabner G, et al. Manifestations of graft-versus-host disease following allogenic bone marrow transplantation. Eur J Ophthalmol 1991;1: ) Anderson NG, Regillo C. Ocular manifestations of grafthost-versus disease. Curr Opin Ophthalmol 2004;15: ) Avery R, Jabs DA, Wingard JR, et al. Optic disc edema after bone marrow transplantation. Possible role of cyclosporine toxicity. Ophthalmology 1991;98: ) Bernauer W, Gratwohl A, Keller A, Daicker B. Microvasculopathy in the ocular fundus after bone marrow transplantation. Ann Intern Med 1991;115: ) Gloor B, Gratwohl A, Hahn H, et al. Multiple cotton wool spots following bone marrow transplantation for treatment of acute lymphatic leukaemia. Br J Ophthalmol 1985;69: ) Lopez PF, Sternberg P Jr, Dabbs CK, et al. Bone marrow transplant retinopathy. Am J Ophthalmol 1991;112: ) Cunningham ET Jr, Irvine AR, Rugo HS. Bone marrow transplantation retinopathy in the absence of radiation therapy. Am J Ophthalmol 1996;122: ) Johnson DW, Cagnoni PJ, Schossau TM, et al. Optic disc and retinal microvasculopathy after high-dose chemotherapy and 517

5 조영준외 : 골수이식후골수이식망막병증 autologous hematopoietic progenitor cell support. Bone Marrow Transplant 1999;24: ) Perrers-Taylor M, Brinkley D, Reynolds T. Choroido-retinal damage as a complication of radiotherapy. Acta Radiol Ther Phys Biol 1965;3: ) Nakissa N, Rubin P, Strohl R. Keys H. Ocular and orbital complications following radiation therapy of paranasal sinus malignancies and review of literature. Cancer 1983;51: ) Vogler WR, Winton EF, Helffner LT, et al. Ophthalmological and other toxicities related to cytosine arabinoside and total body irradiation as preparative regimen for bone marrow transplantation. Bone Marrow Transplant 1990;6: ) Tiscelli A. Late ocular complications after bone marrow transplantation. Nouv Rev Fr Hematol 1994;36:S ) Wingard JR, Piantadosi S, Burns WH, et al. Cytomegalovirus infections in bone marrow transplant recipients given intensive cytoreductive therapy. Rev Infect Dis 1990;12: ) Walton RC, Reed KL. Herpes zoster ophthalmicus following bone marrow transplantation in children. Bone Marrow Transplant 1999;23: ) Rao NA, Hidayat A. A comparative clinicopathologic study of endogenous mycotic endophthalmitis: variations in clinical and histopathologic changes in candidiasis compared to aspergillosis. Trans Am Ophthalmol Soc 2000;98:183?93. 21) Karashima K, Fujioka S, Harino S. Two cases of central serous chorioretinopathy treated with photocoagulation after bone marrow transplantation. Retina 2002;22: ) Fawzi AA, Cunningham ET Jr. Central serous chorioretinopathy after bone marrow transplantation. Am J Ophthalmol 2001;131: ) Cheng LL, Kwok AK, Wat NM, et al. Graft-vs-host-diseaseassociated conjunctival chemosis and central serous chorioretinopathy after bone marrow transplant. Am J Ophthalmol 2002;134: =ABSTRACT= Bone Marrow Transplantation Retinopathy in a Patient with Acute Lymophocytic Leukemia Following Bone Marrow Transplantation Young Joon Jo, M.D., Seon Jin Wang, M.D., Jung Yeul Kim, M.D. Department of Ophthalmology, Chungnam National University College of Medicine, Daejeon, Korea Purpose: To report a case in of a patient who developed bone marrow transplantation retinopathy at 18 months after receiving allograft bone marrow transplantation for acute lymphocytic leukemia. Case summery: A 20-year-old male patient complained of a decrease in visual activity in his left eye 18 months after receiving a bone marrow transplantation for acute lymphocytic leukemia. The corrected visual activity was 1.0 for the right eye and 0.6 for the left. On fundus examination, both eyes showed cotton wool patches and dot hemorrhage, and the left eye showed macula edema. On fluorescein angiography, capillary nonperfusion was observed in the superior nasal area of the left eye. Four months after initial examination, the corrected visual activity of the left eye decreased to 0.3 and neovascularization was observed on fundus examination. On fluorescein angiography, capillary nonperfusion, neovascularization, and macular ischemia were observed. Laser photocoagulation was performed twice on the area with neovascularization and capillary nonperfusion. One year later, the corrected visual activity of the left eye recovered to 0.8. However, the area of macular ischemia on fluorescein angiography showed no change, and neovascularization and capillary nonperfusion were observed in new areas, which were treated with two additional laser photocoagulations. J Korean Ophthalmol Soc 49(3): , 2008 Key Words: Acute lymphocytic leukemia, Bone marrow transplantation retinopathy Address reprint requests to Jung Yeul Kim, M.D. Department of Ophthalmology, Chungnam National University Hospital #640 Daesa-dong, Jung-gu, Daejeon , Korea Tel: , Fax: , kimjy@cnu.ac.kr 518

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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