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1 대한안과학회지 2013 년제 54 권제 8 호 J Korean Ophthalmol Soc 2013;54(8): pissn: eissn: = 증례보고 = 결절경화증환자에서발생한성상세포과오종과연관된시신경섬유결손 이가현 이나은 이창규 홍사민 성공제 김찬윤 연세대학교의과대학안과학교실, 시기능개발연구소 목적 : 시신경유두및망막의과오종과연관되어시신경섬유층의결손이발생한결절경화증환자를경험하여이를보고하고자한다. 증례요약 : 결절경화증으로진단받고항경련제 Vigabatrin 을복용중인 6 세남아가약제에의한시야변화확인을위해소아신경과에서의뢰되었다. 환아는안저검사상우안의시신경유두위쪽테두리에연접한 1/2 시신경유두크기의성상세포과오종이확인되었으며다른특이소견은관찰되지않았다. 초진당시좌안에는특이소견이없었다. 초진 1 년 6 개월후우안의시신경유두주위성상세포과오종의크기가다소증가하였고좌안에는 1.5 유두직경거리의황반하측에새로운망막과오종이발생하였다. 초진 3 년후우안에크기가증가했던시신경유두성상세포과오종이과오종부위에상이측과중심하부방향으로시신경섬유결손이발생하였다. 결론 : 결절경화증환자에서성상세포과오종은일반적으로변하지않는다고알려졌으나본증례와같이크기가증가하면서시신경섬유결손을야기할수도있으므로이를염두에두고면밀히추적관찰하여야할것이다. < 대한안과학회지 2013;54(8): > 결절경화증은신경섬유종증, 스터지웨버증후군등과함께눈, 중추신경, 피부와내장을주로침범하는대표적인눈신경피부증후군중의하나로, 인구 5,000-10,000명당한명꼴로발생하며, 1,2 상염색체성우성으로유전된다. 3,4 결절경화증은여러기관에과오종을형성하는질환으로, 1908년 Vogt는간질, 지능저하및피지선종을세가지주증상으로제시하였으나, 5 현재는뇌의결절, 안면부의피지선종, 조갑섬유종, 망막의과오종, 심장의횡문근종등의다양한임상양상을포함하는포괄적진단기준을사용하고있다. 6 망막의과오종은결절경화증환자의 34-87% 에서나타나는데, 7,8 대부분선천성으로발생하여진행하거나변화하지않으며시력에영향을미치지않으므로대부분의경우치료를필요로하지않으나, 9 드물게과오종으로인한망막하삼출이나유리체출혈등이보고된바있어주의를요한다 Received: Revised: Accepted: Address reprint requests to Chan Yun Kim, MD, PhD The Institute of Vision Research, Department of Ophthalmology, Severance Hospital, #50 Yonsei-ro, Seodaemun-gu, Seoul , Korea Tel: , Fax: kcyeye@yuhs.ac * This study was presented as a poster at the 108th Annual Meeting of the Korean Ophthalmology Society * This study was supported by a grant of the Korea Health technology R&D Project, Ministry of Health & Welfare, Republic of Korea (A101727). 국내에도이러한결절경화증환자에서의망막과오종예가여러차례보고되었다 그러나이러한보고에따르면망막과오종은저시력이나사시와연관된경우가있었으나, 15,19,21 진행하거나망막신경섬유층과의관계는언급되지않았다 이에저자들은 3년이상추적관찰한결절경화증환아에서망막과오종의크기가증가하고그부위에망막신경섬유층의결손이발생하는것을관찰하였기에이를보고하는바이다. 증례보고 결절경화증으로진단받은 6세남아가안저검사및약물부작용여부를판단하기위해소아신경과에서의뢰되었다. 출생력상임신 32주에제왕절개로분만되었으며, 신생아황달및가사의기왕력이있었다. 뇌자기공명영상결과대뇌반구내수개의피질및피질하결절이관찰되었으며, 양측측뇌실부근의조영증강되는상의하세포종소견보여결절경화증에합당하였다 (Fig. 1). 환자는생후 6개월부터결절경화증을진단받고난치성간질발작증상을조절하기위해 Vigabatrin (Sabril Lundbeck Inc, Deerfield, IL) 500 mg을 b.i.d로복용중이었으며, 타병원안과에서주기적으로경과관찰한과거력은있었지만구체적인의무기록은없었다. 본원안과초진시교정시력은우안 0.3, 좌안 0.3이었고, 1282

2 - 이가현외 : 성상세포과오종과연관된시신경섬유결손진행 - 고 찰 Figure 1. Axial T2-weighted images of MR show that subependymal nodule (black arrow head) projecting into lumen of left lateral ventricle and multiple subtle bilateral cortical and subcortical tubers (white arrow heads). TonoPen XL (Medtronic Solan, Jacksonville, FL, USA) 로측정한안압은우안 12, 좌안 12 mmhg 였다. 전안부검사상특이소견은발견되지않았으며, 양안동공반응정상으로상대성구심성동공운동이상은관찰되지않았다. 조절마비제점안하시행한타각적굴절검사상우안 +sph4.25 cyl3.00 Axis180, 좌안 +sph4.50 -cyl3.00 Axis180 이었고, 최대교정시력은우안 0.7, 좌안 0.6이었다. 안저검사상우안시신경상이측에연접한 1/2 유두직경거리크기의석회화를동반한뽕나무열매모양의융기된과오종이관찰되었으며, 좌안망막에는특이이상소견이관찰되지않았다 (Fig. 2A). 초진 6개월후와 1년후시행한안저검사상특이변화는관찰되지않았다. 초진 1년 6개월후시행한안저검사결과우안의시신경과오종의크기가다소증가하였으며, 이전검사상특이소견이없었던좌안에도황반하측에성상세포과오종이새롭게발견되었다 (Fig. 2B). 초진으로부터 3년경과후시행한안저검사상, 우안의크기가증가한시신경과오종부위에시신경섬유층결손이발견되었고황반아래쪽으로도시신경섬유결손이관찰되었다. 하지만초진 1년 6개월후새로이발생했던좌안의성상세포과오종부위에는시신경섬유결손등의이상소견은없었다 (Fig. 2C). 결절경화증환자에서나타나는안과적병변중가장흔한것은망막의과오종으로환자의 50% 이상에서발생하지만, 대부분진행하지않으며시력에영향을미치지않아치료가필요하지않다고알려졌다 본증례의환자의경우, 망막의성상세포과오종이추적관찰기간동안크기가증가하였고, 이에따라녹내장에서와유사하게시신경섬유주행방향을따라나타나는망막신경섬유층결손이발생하였다. 또한대개망막의과오종이선천적으로발생하는것과달리, 정상소견을보이던좌측망막에도추적관찰기간동안편평하고투명한결절이새로이발생하였다. 아직까지결절경화증환자에서시신경유두부과오종의크기증가에따른망막신경섬유층결손발생은보고된바없었다. 환아의경우결절경화증에동반된간질로 Vigabatrin (Sabril ) 을복용중으로, 초진당시 vigabatrin을 500 mg b.i.d로복용중이었으며, 본원에서경과관찰하던기간동안총 3,500 g 이상의 vigabatrin을복용하였다. Vigabatrin 은선택적불가역적 GABA aminotransferase 억제제로서, 뇌에서작용하는억제성신경전달물질인 GABA의농도를높이는작용을하는약제로, 22,23 주로난치성부분간질환자에효과적으로작용한다. 그러나이약제를사용한경우, 10-50% 의환자에서비가역적인시야손상을특징으로하는망막병증이발생한다 Vigabatrin과연관되어발생하는시신경손상은비측의신경섬유층두께의감소를주로동반하는데, 이측의신경섬유층두께는정상인것이특징이다. 27 또한 2012년 Clayton et al 28 이발표한연구에따르면 Vigabatrin을총 1,000 g 이상복용한환자들에서그렇지않은군에비하여시신경주변부의시신경섬유층두께감소의정도는 Vigabatrin의총용량에비례하였는데, 특히상비측의시신경섬유두께가가장감소되어있으며, 상대적으로이측, 상이측및하이측은덜침범하는모습을보였다. 본증례의경우환아가복용한 Vigabatrin의총용량이 1,000 g을초과하므로신경섬유층두께의감소를유발하였을수있으나, 본증례의망막신경섬유층결손은 Vigabatrin 복용시일반적으로나타나는것과달리비측의신경섬유층결손이뚜렷하지않은데반하여, 시신경과오종이있는상이측부위에한정되어뚜렷하게나타나며, 시신경과오종의크기가증가함에따라망막신경섬유층의결손또한진행되는모습을보이기때문에환아의망막신경섬유층결손은항경련약물보다는시신경과오종의영향을받은것으로생각한다. 본증례의망막신경섬유층결손은안저사진만으로판단하였는데불행하게도시행한시야검사는신뢰도 1283

- 대한안과학회지 2013 년제 54 권제 8 호 - A B C Figure 2.

hamartoma in a patient with tuberous sclerosis.

diameter-sized mulberry-like protruding tumor above the right optic

(B) One year and 6 months after the first visit, fundus photograph

Newly onset retinal astrocytic hamartoma (black arrow) is found on

(C) Three years later, fundus photograph shows development of retinal

3 - 대한안과학회지 2013 년제 54 권제 8 호 - A B C Figure 2. Development of nerve fiber layer defect associated with astrocytic hamartoma in a patient with tuberous sclerosis. (A) Fundus photograph of the initial visit shows a 1/2 disc diameter-sized mulberry-like protruding tumor above the right optic disc and normal fellow eye. (B) One year and 6 months after the first visit, fundus photograph shows enlarged right optic disc hamartoma. Newly onset retinal astrocytic hamartoma (black arrow) is found on the fundus of the left eye. (C) Three years later, fundus photograph shows development of retinal nerve fiber layer defects (white arrows). 가낮아판별하기가힘들었고광간섭단층촬영은환아가거부하여시행할수없었다. 하지만사진상시신경섬유결손이명확하여정성적인 (quantitative) 판단을하기에는충분하다고생각한다. 결절경화증환자의과오종이어떻게시신경섬유결손을야기하는지는기존의보고가없었기에기전을정확히알수는없다. 과오종과의감별해야하는질환중에하나인시신경드루젠의경우 53-75% 의환자에서시야결손을보이는 1284

4 - 이가현외 : 성상세포과오종과연관된시신경섬유결손진행 - 데, 29,30 그기전으로제시되는것은드루젠으로인한직접적인압박효과로드루젠이시신경의혈관을압박하여시신경의혈액공급에이상을일으키기때문에발생하는것으로알려졌다. 29,31 지금까지결절경화증환자에서시신경부위의과오종에의한시신경섬유층두께의감소는보고된바가없으나, 본증례에서발견된시신경섬유층의두께감소도시신경드루젠과마찬가지로시신경및시신경혈관의압박으로인한시신경섬유층의손상에의해발생하지않았을까추정된다. 물론이환자의시신경주위과오종은융기된형태로드루젠과는명확히구별되어드루젠에의한시신경섬유결손은아닌것으로생각한다. 또한 Carol et al 32 은 2006 년망막의성상세포과오종은망막내층혹은망막의전층을침범하여정상망막조직구조의혼란 (disorganization) 을발생시키는것을보고하였는데, 본증례에서발생한신경섬유층의결손도이와마찬가지로과오종에의하여발생한정상망막구조의혼란과연관되어발생했을가능성이있다. 결론적으로이증례에서경험하였듯이일반적으로진행하지않는것으로알려진결절경화증환자의망막과오종이진행하는경우가있으며, 특히시신경주위에발생한성상세포과오종은드물게녹내장에서나타나는시신경섬유층결손과유사하게시신경섬유주행방향을따라시신경섬유층결손을유발하고진행시킬수있으므로, 이러한환자는주의깊은관찰이필요할것으로생각한다. REFERENCES 1) Curatolo P, Bombardieri R, Jozwiak S. Tuberous sclerosis. Lancet 2008;372: ) Osborne JP, Fryer A, Webb D. Epidemiology of tuberous sclerosis. Ann N Y Acad Sci 1991;615: ) van Slegtenhorst M, de Hoogt R, Hermans C, et al. Identification of the tuberous sclerosis gene TSC1 on chromosome 9q34. Science 1997;277: ) European Chromosome 16 Tuberous Sclerosis Consortium. Identification and characterization of the tuberous sclerosis gene on chromosome 16. Cell 1993;75: ) Vogt H. Zur diagnostik der tuberosen sclerose. Z Erforsch Benhandl Fugendl Schwachsinns 1908;2: ) Roach ES, Gomez MR, Northrup H. Tuberous sclerosis complex consensus conference: revised clinical diagnostic criteria. J Child Neurol 1998;13: ) Rowley SA, O'Callaghan FJ, Osborne JP. Ophthalmic manifestations of tuberous sclerosis: a population based study. Br J Ophthalmol 2001;85: ) Kiribuchi K, Uchida Y, Fukuyama Y, Maruyama H. High incidence of fundus hamartomas and clinical significance of a fundus score in tuberous sclerosis. Brain Dev 1986;8: ) Töteberg-Harms M, Sturm V, Sel S, et al. Retinal astrocytomas: long-term follow-up. Klin Monbl Augenheilkd 2011;228: ) Gass JDM. Stereoscopic atlas of macular disease: Diagnosis and treatment, 1st ed. St. Louis: Mosby, 1997; ) Lagos JC, Gomez MR. Tuberous sclerosis: Reappraisal of a clinical entity. Mayo Clin Proc 1967;42: ) Nyboer JH, Robertson DM, Gomez MR. Retinal lesions in tuberous sclerosis. Arch Ophthal 1976;94: ) Yoon DK. A case of tuberous sclerosis. J Korean Ophthalmol Soc 1974;15: ) Kim JH, Shin HH. Two cases of tuberous sclerosis. J Korean Ophthalmol Soc 1982;23: ) Kwon OW, Kim YW. A case of tuberous sclerosis. J Korean Ophthalmol Soc 1983;24: ) Yoo KH, Oum BS. Two cases of tuberous sclerosis. J Korean Ophthalmol Soc 1987;28: ) Kim SM, Hahn YH, Kim SD. Two cases of tuberous sclerosis. J Korean Ophthalmol Soc 1988;29: ) Ku YJ, Kim EA, Han YB. A case of tuberous sclerosis. J Korean Ophthalmol Soc 1995;36: ) Ji JY, Lee JH, Choi WS. A case of bilateral tuberous sclerosis. J Korean Ophthalmol Soc 1996;37: ) Lee JH, Han KS, Han YB. One case of tuberous sclerosis. J Korean Ophthalmol Soc 1999;40: ) La TY, Kim CW, Lee YS, Kim MH. A case of retinal astrocytic hamartoma causing blindness in tuberous sclerosis. J Korean Ophthalmol Soc 1999;40: ) Dichter MA, Brodie MJ. New antiepileptic drugs. N Engl J Med 1996;334: ) Ben-Menachem E. Vigabatrin. Epilepsia 1995;36 Suppl 2:S ) Maguire MJ, Hemming K, Wild JM, et al. Prevalence of visual field loss following exposure to vigabatrin therapy: a systematic review. Epilepsia 2010;51: ) Roubertie A, Bellet H, Echenne B. Vigabatrin-associated retinal cone system dysfunction. Neurology 1998;51: ) Miller NR, Johnson MA, Paul SR, et al. Visual dysfunction in patients receiving vigabatrin: clinical and electrophysiologic findings. Neurology 1999;53: ) Lawthom C, Smith PE, Wild JM. Nasal retinal nerve fiber layer attenuation: a biomarker for vigabatrin toxicity. Ophthalmology 2009;116: ) Clayton LM, Devile M, Punte T, et al. Patterns of peripapillary retinal nerve fiber layer thinning in vigabatrin-exposed individuals. Ophthalmology 2012;119: ) Roh S, Noecker RJ, Schuman JS, et al. Effect of optic nerve head drusen on nerve fiber layer thickness. Ophthalmology 1998;105: ) Savino PJ, Glaser JS, Rosenberg MA. A clinical analysis of pseudopapilledema. II. Visual field defects. Arch Ophthalmol 1979; 97: ) Sarkies NJ, Sanders MD. Optic disc drusen and episodic visual loss. Br J Ophthalmol 1987;71: ) Shields CL, Benevides R, Materin MA, Shields JA. Optical coherence tomography of retinal astrocytic hamartoma in 15 cases. Ophthalmology 2006;113:

5 - 대한안과학회지 2013 년제 54 권제 8 호 - =ABSTRACT= Retinal Nerve Fiber Layer Defect Associated with Astrocytic Hamartoma in a Patient with Tuberous Sclerosis Ka Hyun Lee, MD, Naeun Lee, MD, Chang Kyu Lee, MD, Sa Min Hong, MD, Gong Je Seong, MD, PhD, Chan Yun Kim, MD, PhD The Institute of Vision Research, Department of Ophthalmology, Yonsei University College of Medicine, Seoul, Korea Purpose: To report the progression of an astrocytic hamartoma of the right optic nerve head as well as the retina, and the progression of retinal nerve fiber defect associated with astrocytic hamartoma in a patient with tuberous sclerosis. Case summary: A 6-year-old boy with tuberous sclerosis and an astrocytic hamartoma of the right optic nerve head, which was found at the time of ophthalmologie examinations, was referred from the pediatric neurologist for evaluation of the vigabatrin-associated visual field changes. Fundus examination revealed 1/2 disc diameter (DD)-sized astrocytic hamartoma located at the margin of the superior part of the optic nerve. The retina of the left eye was normal. Eighteen months after the first visit, enlarged optic disc hamartoma of the right eye and newly onset retinal astrocytic hamartoma located approximately 1.5 DD inferior to the fovea of the left eye were found. Three years later, an increase in the size of the astrocytic hamartoma of the right optic nerve and development of retinal nerve fiber defects were observed. Conclusions: Astrocytic hamartoma in patients with tuberous sclerosis is usually stable without progression. However, in our patient, astrocytic hamartoma showed progression, and development of retinal nerve fiber defects occurred. Regular follow-up is necessary for astrocytic hamartoma in patients with tuberous sclerosis. J Korean Ophthalmol Soc 2013;54(8): Key Words: Astrocytic hamartoma, Retinal nerve fiber layer defect, Tuberous sclerosis Address reprint requests to Chan Yun Kim, MD, PhD The Institute of Vision Research, Department of Ophthalmology, Severance Hospital #50 Yonsei-ro, Seodaemun-gu, Seoul , Korea Tel: , Fax: , kcyeye@yuhs.ac 1286

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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