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Kornea merupakan jaringan penghubung yang bersifat avaskular dan transparant.

Kornea berfungsi sebagai sawar mekanik dan media refraksi anterior pada permukaan mata. Arteri silliaris, yang merupakan percabangan arteri oftalmikus yang terbagi dan berakhir di plexus perikorneal pada daerah sekitar limbus, memberikan pasokan kepada kornea. 34 Kornea mendapatkan kewenangan khusus oleh sistem imun, sehingga lebih mendapatkan proteksi khusus oeh struktur mata yang terorganisasi dan juga memberikan kontribusi kepada tingginya angka kesuksesan transplantasi kornea.123 Angiogenesis adalah proses pertumbuhan pembuluh darah baru yang terjadi pada keadaan patologis yang berat. pembuluh darah yang baru yang berasal dari pembuluhpembulah kapiler dan venula plexus perikorneal, akan menghalangi sinar masuk ke dalam mata, mengganggu penglihatan mata dan memperburuk prognosis dari transplantasi kornea akan mengarah kepada proses inflamasi, bekas luka pada kornea dan edema. 23 Pada keadaan tertentu, jaringan kornea yang pada keadaan normal bersifat avaskular dapat timbul pembuluh darah baru dan dikenal sebagai neovaskularisasi kornea. Keadaan tersebut disebabkan oleh ketidakseimbangan antara faktor angiogenik dan antiangiogenik pada kornea sehingga menyebabkan pada gangguan faktor pro-angiogenik dan defisiensi faktor antiangiogenik.3 Salah satu faktor penting yang menjadi mediator proses angiogenesis adalah VEGF (Vascular Endothelial Growth Factor). Pada saat terjadi angiogensis, VEGF akan meningkat dan menyebabkan peradangan pada kornea.46 Selain pada kornea, peningkatan VEGF dan timbulnya neovaskularisasi juga terdapat pada penyakit seperti retinopati diabetikum, degenerasi makula terkait usia dan penyakit pembuluh darah intraokluar lainnya. Penyakitpenyakit tersebut juga memberikan gambaran-gambaran klinis selain neovaskularisasi kornea seperti atrofi, edema, perdarahan dan fibrosis. (Ophthalmology 2013;120:106114 2013 by the American Academy of Ophthalmology.) Neovaskularisasi kornea dapat menjadi penyakit sekunder seperti pada pasien dengan iskemia, infeksi, trauma dan terpapar bahan kimia. Neovaskularisasi kornea merupakan penyebab utama pada kebutaan yang mempengaruhi sampai 4,14%. Kasusnya dapat terjadi pada 1,4 juta orang per tahun.9 Terdapatnya laporan yang mengindikasikan bahwa penyakit infeksi, pemakaian lensa kontak dan respon vaskular pada transplantasi kornea merupakan penyebab utama terjadinya neovaskularisasi kornea.82 Dewasa ini pengobatan neovaskularisasi kornea termasuk kortikosteroid topikal dan obat anti inflamasi non steroid, terapi fotodinamik, fotokoagulasi laser, diatrhermi jarum halus dan transplantasi membran amnion, limbal dan konjungtiva. 23,82,115 Namun sayangnya, semua pengobatan tersebut memiliki keterbatasan dalam efektifitas klinik dan menyebabkan

efek samping yang serius seperti peningkatan tekanan intra okuler dan katarak posterior subskapular yang berkaitan dengan penggunaan steroid. Pengobatan yang memiliki sasaran pada segmen anterior mata harus memiliki kemampuan yang unik, yaitu dapat menembus lapisan luar epitel yang utuh. Lebih penting lagi, tidak ada satupun pengobatan pada neovaskularisasi kornea di atas yang mengarah pada molekul yang menjadi mediator angiogenesis, yaitu VEGF.2 Peningkatan regulasi VEGF yang diinduksi oleh cedera pada kornea dan neovaskularisasi akan di hambat oleh antibodi anti-VEGF. Agen anti-VEGF merupakan pilihan terapi yang efektif dalam penanganan neovaskularisasi kornea. 65 AntiVEGF juga efektif dalam mengatasi, penyakit lain seperti neovaskularisasi pada degenarasi makula terkait usia, retinopati diabetikum dan neovaskularisasi glaukoma. 126 Beberapa studi telah melakukan [ercobaan klinis untuk menilai efektifitas dan keamanan anti-VEGF seperti bevacizumab, ranibizumab dan pegaptanib pada pengobatan gangguan retina. 53,110,118,128

34: DelMonte DW, Kim T. Anatomy and physiology of the cornea. J Cataract Refract Surg. 2011;37:58898 123: Streilein JW. Ocular immune privilege: therapeutic opportunities from an experiment of nature. Nat Rev Immunol. 2003;3:87989 23: Chang JH, Gabison EE, Kato T, et al. Corneal neovascularization. Curr Opin Ophthalmol. 2001;12:242--9 3: Ambati BK, Nozaki M, Singh N, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature. 2006;443:9937 46:Ferrara N, Gerber HP, LeCouter J. The biology of VEGF and its receptors. Nat Med. 2003;9:66976 9. Bachmann BO, Bock F, Wiegand SJ, et al. Promotion of graft survival by vascular endothelial growth factor a neutralization after high-risk corneal transplantation. Arch Ophthalmol. 2008;126:71--7 82. Lee P, Wang CC, Adamis AP. Ocular neovascularization: an epidemiologic review. Surv Ophthalmol. 1998;43:24569 115. Shakiba Y, Mansouri K, Arshadi D, et al. Corneal neovascularization: molecular events and therapeutic options. Recent Pat Inflamm Allergy Drug Discov. 2009;3:22131 2. Amano S, Rohan R, Kuroki M, et al. Requirement for vascular endothelial growth factor in wound- and inflammation-related corneal neovascularization. Invest Ophthalmol Vis Sci. 1998;39:1822 65. Hosseini H, Nejabat M. A potential therapeutic strategy for inhibition of corneal neovascularization with new anti- VEGF agents. Med Hypotheses. 2007;68:799801 126. Tolentino M. Systemic and ocular safety of intravitreal anti- VEGF therapies for ocular neovascular disease. Surv Ophthalmol. 2011;56:95--113 53. Gragoudas ES, Adamis AP, Cunningham ET Jr, et al. Pegaptanib for neovascular agerelated macular degeneration. N Engl J Med. 2004;351:280516

110. Rosenfeld PJ, Rich RM, Lalwani GA. Ranibizumab: phase III clinical trial results. Ophthalmol Clin North Am. 2006; 19:36172 118. Singerman LJ, Masonson H, Patel M, et al. Pegaptanib sodium for neovascular agerelated macular degeneration: third-year safety results of the VEGF Inhibition Study in Ocular Neovascularisation (VISION) trial. Br J Ophthalmol. 2008;92:160611 128. Tufail A, Patel PJ, Egan C, et al. Bevacizumab for neovascular age related macular degeneration (ABC Trial): multicentre randomised double masked study. BMJ. 2010; 340:c2459

Kornea merupakan jaringan yang avaskular, bersifat transparan, berukuran 11-12 mm horizontal dan 10-11 mm vertikal, serta memiliki indeks refraksi 1,37. Kornea memberikan kontribusi 74 % atau setara dengan 43,25 dioptri (D) dari total 58,60 kekuatan dioptri mata manusia. Kornea juga merupakan sumber astigmatisme pada sistem optik. Dalam nutrisinya, kornea bergantung pada difusi glukosa dari aqueus humor dan oksigen yang berdifusi melalui lapisan air mata. Sebagai tambahan, kornea perifer disuplai oksigen dari sirkulasi limbus. Kornea adalah salah satu organ tubuh yang memiliki densitas ujung-ujung saraf terbanyak dan sensitifitasnya adalah 100 kali jika dibandingkan dengan konjungtiva. Kornea dipersarafi oleh banyak saraf sensoris terutama berasal dari saraf siliar longus, saraf nasosiliar, saraf ke V, saraf siliar longus yang berjalan suprakoroid, masuk ke dalam stroma kornea, menembus membran Bowman melepas selubung Schwannya. Seluruh lapis epitel dipersarafi sampai pada kedua lapis terdepan. Sensasi dingin oleh Bulbus Krause ditemukan pada daerah limbus
3

Kornea dalam bahasa latin cornum artinya seperti tanduk, merupakan selaput bening mata, bagian dari mata yang bersifat tembus cahaya, merupakan lapis dari jaringan yang menutup bola mata sebelah depan dan terdiri atas : 1. Epitel Terdiri dari sel epitel squamos yang bertingkat, terdiri atas 5 lapis sel epitel tidak bertanduk yang saling tumpang tindih; sel poligonal dan sel gepeng. Tebal lapisan epitel kira-kira 5 % (0,05 mm) dari total seluruh lapisan kornea. Epitel dan film air mata merupakan lapisan permukaan dari media penglihatan. Pada sel basal sering terlihat mitosis sel, dan sel muda ini terdorong ke depan menjadi lapis sel sayap dan semakin maju ke depan menjadi sel gepeng, sel basal berikatan erat dengan sel basal di sampingnya dan sel poligonal di depannya melalui desmosom dan makula okluden; ikatan ini menghambat pengaliran air, elektrolit dan glukosa melalui barrier. Sel basal menghasilkan membran basal yang melekat erat kepadanya. Bila terjadi gangguan akan mengakibatkan erosi rekuren. Sedangkan epitel berasal dari ektoderem permukaan. Epitel memiliki daya regenerasi 2. Membran bowman
3,4

Membran yang jernih dan aselular, Terletak di bawah membran basal dari epitel. Merupakan lapisan kolagen yang tersusun tidak teratur seperti stroma dan berasal dari epitel bagian depan stroma. Lapisan ini tidak mempunyai daya generasi 3. Stroma Lapisan ini mencakup sekitar 90% dari ketebalan kornea. Merupakan lapisan tengah pada kornea. Bagian ini terdiri atas lamel fibrilfibril kolagen dengan lebar sekitar 1 m yang saling menjalin yang hampir mencakup seluruh diameter kornea, pada permukaan terlihat anyaman yang teratur sedang di bagian perifer serat kolagen ini bercabang; terbentuknya kembali serat kolagen memakan waktu lama, dan kadang sampai 15 bulan. Keratosit merupakan sel stroma kornea yang merupakan fibroblas terletak di antara serat kolagen stroma. Diduga keratosit membentuk bahan dasar dan serat kolagen dalam perkembangan embrio atau sesudah trauma 4. Membran Descemet Merupakan membran aselular dan merupakan batas belakang stroma kornea yang dihasilkan oleh endotel. Bersifat sangat elastis dan jernih yang tampak amorf pada pemeriksaan mikroskop elektron, membran ini berkembang terus seumur hidup dan mempunyai tebal + 40 mm. Lebih kompak dan elastis daripada membran Bowman. Juga lebih resisten terhadap trauma dan proses patologik lainnya dibandingkan dengan bagian-bagian kornea yang lain 5. Endotel Berasal dari mesotelium, terdiri atas satu lapis sel berbentuk heksagonal, tebal antara 20-40 mm melekat erat pada membran descemet melalui taut. Endotel dari kornea ini dibasahi oleh aqueous humor. Lapisan endotel berbeda dengan lapisan epitel karena tidak mempunyai daya regenerasi, sebaliknya endotel mengkompensasi sel-sel yang mati dengan mengurangi kepadatan seluruh endotel dan memberikan dampak pada regulasi cairan, jika endotel tidak lagi dapat menjaga keseimbangan cairan yang tepat akibat gangguan sistem pompa endotel, stroma bengkak karena kelebihan cairan (edema kornea) dan kemudian hilangnya transparansi (kekeruhan) akan terjadi. Permeabilitas dari kornea ditentukan oleh epitel dan endotel yang merupakan membrane semipermeabel, kedua lapisan ini mempertahankan kejernihan daripada kornea, jika terdapat kerusakan pada lapisan ini maka akan terjadi edema kornea dan kekeruhan pada kornea

http://www.oftalmoskop.net/?p=493 FISIOLOGI Fungsi utama kornea adalah sebagai membrane protektif dan sebuah jendela yang dilalui cahaya untuk mencapai retina. Transparansi kornea dimungkinkan oleh sifatnya yang avaskuler, memiliki struktur yang uniform yang sifat deturgescence nya. Transparansi stroma dibentuk oleh pengaturan fisis special dari komponen komponen fibril. Walaupun indeks refraksi dari masing masing fibril kolagen berbeda dari substansi infibrilar, diameter yang kecil (300 A) dari fibril dan jarak yang kecil diantara mereka (300 A) mengakibatkan pemisahan dan regularitas yang menyebabkan sedikit pembiasan cahaya dibandingkan dengan inhomogenitas optikalnya. Sifat deturgescence di jaga dengan pompa bikarbonat aktif dari endotel dan fungsi barbier dari epitel dan endotel. Kornea di jaga agar tetap berada pada keadaan basah dengan kadar air sebanyak 78%.5,6 Peran kornea dalam proses refraksi cahaya bagi penglihatan seseorang sangatlah penting. Pembiasan sinar terkuat dilakukan oleh kornea, dimana 43,25 dioptri dari total 58,6 kekuatan dioptri mata normal manusia, atau sekitar 74% dari seluruh kekuatan dioptri mata normal. Hal ini mengakibatkan gangguan pada kornea dapat memberikan pengaruh yang cukup signifikan dalam fungsi fisus seseorang. 7 Kornea merupakan struktur vital dari mata dan oleh karenanya kornea sangat lah sensitif. Saraf saraf kornea masuk dari stroma kornea melalui membrana bowman dan berakhir secara bebas diantara sel sel

epithelial serta tidak memiliki selebung myelin lagi sekitar 2 3 mm dari limbus ke sentral kornea, sehingga menyebabkan sensitifitas yang tinggi pada kornea.6 Kornea menerima suplai sensoris dari bagian oftalmik nervus trigeminus. Sensasi taktil yang terkecil pun dapat menyebabkan refleks penutupan mata. Setiap kerusakan pada kornea (erosi, penetrasi benda asing atau keratokonjungtivitis ultraviolet) mengekspose ujung saraf sensorik dan menyebabkan nyeri yang intens disertai dengan refleks lakrimasi dan penutupan bola mata involunter. Trias yang terdiri atas penutupan mata involunter (blepharospasme), refleks lakrimasi (epiphora) dan nyeri selalu mengarahkan kepada kemungkinan adanya cedera kornea.8 Seperti halnya lensa, sklera dan badan vitreous, kornea merupakan struktur jaringan yang bradittrofik, metabolismenya lambat dimana ini berarti penyembuhannya juga lambat. Metabolisme kornea (asam amino dan glukosa) diperoleh dari 3 sumber, yaitu : 8 Difusi dari kapiler kapiler disekitarnya Difusi dari humor aquous Difusi dari film air mata Tiga lapisan film air mata prekornea memastikan bahwa kornea tetap lembut dan membantu nutrisi kornea. Tanpa film air mata, permukaan epitel akan kasar dan pasien akan melihat gambaran yang kabur. Enzim lisosom yang terdapat pada film air mata juga melindungi mata dari infeksi.3

1. G.Lang. Flexybook Ophtalmology. 2nd edition. New York. Thieme. 2006. p.115, 125, 130. 2. Oliver.J. Ophthalmology At a Glance. Blackwell Science. London. 2005. p.33

3. Ilyas S. Anatomi dan Fisiologi Mata. Dalam : Ilyas S. Ilmu Penyakit Mata. Edisi ketiga. Jakarta : Balai Penerbit FKUI ; 2008. h. 1-13 4. K.Weng Sehu et all. Opthalmologic Pathology. Blackwell Publishing. UK. 2005. p.62 5. Pavan-Langston D. Cornea and External Desease. In: Pavan-Langston D. Manual of Ocular Diagnosis and Theraphy. 5th edition. Philadelphia; Lippincott Williams & Wilkins; 2002. p. 67-129 6. Biswell R. Cornea. In: Vaughan D, Asbury T, Riordon-Eva P. General Ophthalmology. 15th edition. Connecticut ; Appleton & Lange; 1999. p. 119-41 7. Skuta GL,Cantor LB,Weiss JS. Clinical Approach to Immune-Related Disorders of the External Eye. In : Skuta GL, Cantor LB, Weiss JS. Basic and Cliniccal Science Cources : External Disease dan Cornea 2008-2009. Singapore : American Academy of Ophthalmology ; 2007. p.205-41 8. Lang GK. Cornea. In : Lang GK. Ophthalmology A Pocket Textbook Atlas. 2nd edition. Stuttgart ; thieme ; 2007. p. 115-60 9. Doggart JH. Superficial Punctate Keratitis [online]. 1933 [cited 2012 July]; [1 screen]. Available from URL:http://bjo.bmj.com/cgi/pdf_extract 10.Ilyas S. Mata Merah dengan Penglihatan Turun Mendadak. Dalam : Ilyas S. Ilmu Penyakit Mata. Edisi ketiga. Jakarta : Balai Penerbit FKUI ; 2008. H 147-78 11.Skuta GL,Cantor LB,Weiss JS. Structure dan Function of the External Eye dan Cornea. In : Skuta GL, Cantor LB, Weiss JS. Basic and Cliniccal Science Cources : External Disease dan Cornea 2008-2009. Singapore : American Academy of Ophthalmology ; 2007. p.5-14

Sifat avaskular pada kornea dipertahakan oleh beberapa faktor seperti thrombospondins 1 dan 2, endostatin, angiostatin, pigment ephitelium-derived factor, matrix metalloproteinases (MMPs). Thrombospondins termasuk dalam golongan protein dan ditemukan di dalam extracellular matrix (ECM) yang menetralkan pertumbuhan pembuluh darah oleh beberapa mekanisme. Thrombospondin 1 dan thrombospondin 2 bertindak melalui sebuah jalur yang akan menginduksi apoptosis pada sel endotel pembuluh darah dan juga diperkirakan mencapai keterbatasan dari ketersediaan faktor pertumbuhan lainnya melalu interaksi dengan ECM. Angiostatin adalah fragmen proteolitik 38-kDa dai plasminogen yang ditemukan di dalam epitel kornea. Endostatin adalah fragmen proteolitik 20-kDa dari kolagen XVIII yang ditemikan di dalam kornea, retina dan lensa. Pigment ephitelium-derived factor memiliki kedua antiangiogenik dan neurotropik. Matrix metalloproteinase adalah group endopeptidase zinc-dependent yang ikut serta dalam remodelling ECM dan angiogensis. MMPs memiliki

kemampuan menjadi angiogenik atau antiangiogenik dalam kondisi yang berbeda. MMPs terlibat dalam pembelahan proteolitik proenzim dan sebagai hasilnya memproduksi fragmen antiangiogenik. Pada kornea manusia, 8 dari 24 MMPs yang diketahui diekspresikan. Termasuk di dalamnya kolagenase I dan II, gelatinase A dan B, stromelysin, matrilysin dan MMP tipe membran. 1 1. Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet 2009;88:495515. Pada keadaan tertentu, jaringan kornea yang pada keadaan normal bersifat avaskular dapat timbul pembuluh darah baru dan dikenal sebagai neovaskularisasi kornea. Berbagai macam infeksi, inflamasi dan gangguan karena trauma akan mengarah kepada noevaskularisasi kornea. 127 Pola neovaskular dapat dibagi menjadi tiga grup klinik: neovaskularisasi dalam diatasnya membran descemet, neovaskularisasi stroma dan vaskular pannus.42 Khas pada keratitis akan menyebabkan neovaskularisasi dan biasanya disebabkan oleh infeksi yang berasal dari family herpes virus (herpes simplex dan herpes zooster). Terdapat keraguan tentang mekanisme neovaskularisasi diawali oleh infeksi oleh family herpes virus dan peningkatan VEGF142, namun bukti mengatakan bahwa IL-6 dan matrix metalloproteinase-9 memainkan peran. 17,83 Bakteri (Chlamydia sp), parasit (Onchocerca volvulus) dan jamur (Candida sp, Fusarium sp, and Aspergillus sp) dapat menyebabkan keratitis. 23 Penyebab lain dari neovaskularisasi kornea ada pemakaian lensa kontak yang berlebihan, luka bakar oleh zat kimia dan defisiensi stem cell limbus. 19 Neovaskularisasi kornea dapat juga disebabkan oleh proses degenerasi seperti pada pterygium dan degenerasi Terrien marginal. 87 Neovaskularisasi kornea merupakan penyebab utama pada kebutaan yang mempengaruhi sampai 4,14%. Kasusnya dapat terjadi pada 1,4 juta orang per tahun. (Bachmann BO, Bock F, Wiegand SJ, dkk, 2008) Tabel 1. Keadaan Klinis yang Berhubungan dengan Neovaskularisasi Kornea JS14
Infectious Herpes simplex keratitis Herpes zoster keratitis Syphilis Pseudomonas Chlamydia trachomatis Candidiasis Fusarium Aspergillosis Onchocerciasis Graft rejection Acne rosacea Stevens-Johnson syndrome Graft-versus-host disease Pemphigoid Atopic conjunctivitis Alkali burns Contact lens Ulceration Terrien marginal degeneration Pterygium Aniridia

Inflammatory

Trauma

Degenerative

Keadaan tersebut disebabkan oleh ketidakseimbangan antara faktor angiogenik dan antiangiogenik pada kornea sehingga menyebabkan pada gangguan faktor pro-angiogenik dan defisiensi faktor antiangiogenik (Ambati BK, Nozaki M, Singh N, dkk, 2001).
Angiogenesis diperantari

oleh beberapa faktor seperti basic fibroblast growth factor,

Platelet-Derived Growth Factor (PDGF), dan Vascular Endothelial Growth Factor (VEGF) di dalam kornea. PDGF mendukung proses maturasi pembuluh darah. Basic fibroblast growth factor termasuk family Fibroblast Growth Factor (FGF) yang berinteraksi dengan reseptor FGF (FGFRs; e.g., FGFR-1, FGFR-2, FGFR-3, FGFR-4) dan proteoglikan heparin sulfat berlokasi di dalam ECM.
2

Interaksi proteoglikan FGF heparin sulfat adalah bagian

integral dari pengaturan angiogenesis. FGF menginduksi sebuah sinyal melalui jalur protein kinase mitogen teraktivasi dan protein kinase C (PKC), yang secara efektif menginduksi degradasi ECM dan angiogenesis melalui VEGF. 1 1. Qazi Y, Maddula S, Ambati BK. Mediators of ocular angiogenesis. J Genet 2009;88:495515. 2. Ambati BK, Nozaki M, Singh N, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature 2006;443:9937. Vascular Endothelial Growth Factor (VEGF) umumnya dianggap sebagai faktor angiogenik yang paling menonjol dan molekul angiogenik lain yang bertindak secara tidak langsung melalui sinyal VEGF. Family VEGF termasuk VEGF-A, VEGF-B, VEGF-C, VEGF-D dan VEGF-E, terlibat di dalam pertumbuhan pembuluh darah dan limfatik. VEGF-A dianggap sebagai faktor utama yang terlibat di dalam hemangiogenesis dan terbagi-bagi di dalam isoform-isoform. VEGF-C dan VEGF-D memainkan peran penting dalam proses limfangiogenesis. Reseptor VEGF bertanggung jawab mengembalikan keseimbangan peranan dari VEGF. Epitel kornea mengekspresikan soluble VEGF receptor-1, yang bertindak sebagai reseptor umpan fisiologis untuk VEGF-A, yang mengeksekusi dan menginaktivasikan potensi angiogenik tersebut. 2 Chemokine penting dalam memperantarai perkembangan dari angiogenesis kornea. Ketiadaan dari chemokine (C-C motif) receptor (CCR2) dan CCR5 pada mencit menghambat perkembangan dai cedera yang diinduksi oleh neovaskularisasi kornea. 5,6 2. Ambati BK, Nozaki M, Singh N, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature 2006;443:9937. 5. Ambati BK, Joussen AM, Kuziel WA, et al. Inhibition of corneal neovascularization by genetic ablation of CCR2. Cornea 2003;22:4657.

6. Ambati BK, Anand A, Joussen AM, et al. Sustained inhibition of corneal neovascularization by genetic ablation of CCR5. Invest Ophthalmol Vis Sci 2003;44:590 3. Tabel 2. Faktor Angiogenik dan Antiangiogenik dalam Neovaskularisasi Kornea
Angiogenic molecules VEGF CTGF sVEGFR-1, 2, 3 IL-1, -8 FGF MCP-1 PlGF IGF Angiogenin PDGF Leptin PEDF IL-18 Endostatin Angiostatin Arestin Canstatin PRL TGF- , TGF- Integrins ( V 3) TXA-2, COX-2 MMPs NO HGF/SF PAF TNF-

Antiangiogenic molecules

Tumstatin TIMPs TNF- TSP-1, TSP-2 MMPs IL-4, IL-12, IL-13 IFN-

COX-2 = cyclooxygenase-2; CTGF = connective tissue growth factor; FGF = fibroblast growth factor; HGF/SF = Hepatocyte growth factor/ scatter factor; IFN = interferon; IGF = insulin-like growth factor; IL = interleukin; MCP = monocyte chemotactic protein; MMP = matrix metalloproteinase; NO = nitrous oxide; PAF _=platelet activating factor; PDGF = platelet derived growth factor; PEDF = pigment epithelium derived growth factor; PIGF = Phosphatidylinositol-glycan biosynthesis class F protein; PRL = prolactin; TGF = transforming growth factor; TIMP = tumor inhibitor of metalloproteinase; TNF = tumor necrosis factor; TSP = total serum protein; TXA = thromboxane A2; VEGF = vascular endothelial growth factor.

Salah satu faktor penting yang menjadi mediator proses angiogenesis adalah VEGF (Vascular Endothelial Growth Factor). Pada saat terjadi angiogensis, VEGF akan meningkat dan menyebabkan peradangan pada kornea. (Ferrara N, Gerber HP, LeCouter J, 2003) Selain pada kornea, peningkatan VEGF dan timbulnya neovaskularisasi juga terdapat pada penyakit seperti retinopati diabetikum, degenerasi makula terkait usia dan penyakit
vaskular intraokluar lainnya. Penyakit-penyakit tersebut juga memberikan gambaran-

gambaran klinis lain seperti atrofi, edema, perdarahan dan fibrosis. (American Academy of
Ophthalmology,2013)

JS 14 Fotografi menunjukan neovaskularisasi kornea berat yang merupakan komplikasi dari herpes simplex keratitis. Salah satu kabar utama yang berkaitan dengan topik neovaskularisasi kornea adalah reaksi rejeksi allograft setelah transplantasi kornea. Transplantasi di atas lapisan kornea yang mengandung pembuluh darah merupakan resiko tinggi untuk dilakukan transplantasi karena terjadi penolakan sistem imun.JS13 Sang penerima yang telah mengalami neovaskularisasi akan memberikan resiko penolakan menjadi dua kali lipat. 8 Terlebih lagi, neovaskularisasi kornea dapat juga diinduksi pasca operasi. 9 Tidak dapat dipahami sepenuhnya alasan yang tepat bahwa kornea yang secara normal bersifat avaskular adalah daerah yang mempunyai kewenangan khusus oleh sistem imun tubuh, dan toleransi ini terganggu selama proses neovaskularisasi. Pada respon imun yang khas, pembuluh-pembuluh limfatik bertindak sebagai serabut afferen dengan membiarkan antigen-presenting dan sel-sel imun untuk masuk ke daerah limfonodus, dan pembuluh-pembuluh darah bertindak sebagai serabut efferen dengan membiarkan sel-sel effektor mengakses jaringan yang dituju. Oleh karena itu, berkurangnya neovaskularisasi seharusnya akan memperkecil respon peradangan sistem imun setelah transplantasi kornea dan meningkatkan angka keberhasilan. 28

127. Tshionyi M, Shay E, Lunde E, et al. Hemangiogenesis and lymphangiogenesis in corneal pathology. Cornea. 2012; 31(1):7480

42. Ellenberg D, Azar DT, Hallak JA, et al. Novel aspects of corneal angiogenic and lymphangiogenic privilege. Prog Retin Eye Res. 2010;29:20848 17. Biswas PS, Banerjee K, Kinchington PR, et al. Involvement of IL-6 in the paracrine production of VEGF in ocular HSV- 1 infection. Exp Eye Res. 2006;82:4654 83. Lee S, Zheng M, Kim B, Rouse BT. Role of matrix metalloproteinase-9 in angiogenesis caused by ocular infection with herpes simplex virus. J Clin Invest. 2002; 110:1105--11 23: Chang JH, Gabison EE, Kato T, et al. Corneal neovascularization. Curr Opin Ophthalmol. 2001;12:242--9 19. Bock F, Konig Y, Kruse F, et al. Bevacizumab (Avastin) eye drops inhibit corneal neovascularization. Graefes Arch Clin Exp Ophthalmol. 2008;246:281--4 87. Lopez JS, Price FW Jr, Whitcup SM, et al. Immunohistochemistry of Terriens and Moorens corneal degeneration. Arch Ophthalmol. 1991;109:98892 90. Maguire MG, Stark WJ, Gottsch JD, et al. Risk factors for corneal graft failure and rejection in the collaborative corneal transplantation studies. Collaborative Corneal Transplantation Studies Research Group. Ophthalmology. 1994;101:1536--47 131. Volker-Dieben HJ, DAmaro J, Kok-van Alphen CC. Hierarchy of prognostic factors for corneal allograft survival. Aust NZ J Ophthalmol. 1987;15:11--8 8. Bachmann B, Taylor RS, Cursiefen C. Corneal neovascularization as a risk factor for graft failure and rejection after keratoplasty: an evidence-based meta-analysis. Ophthalmology. 2010;117:13005 9. Bachmann BO, Bock F, Wiegand SJ, et al. Promotion of graft survival by vascular endothelial growth factor a neutralization after high-risk corneal transplantation. Arch Ophthalmol. 2008;126:71--7 28. Cursiefen C, Chen L, Dana MR, et al. Corneal lymphangiogenesis: evidence, mechanisms, and implications for corneal transplant immunology. Cornea. 2003;22:273--81

Vascular endothelial growth factor (VEGF) is a chemical signal produced by cells that stimulates the growth of new blood vessels. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, and new vessels (collateral circulation) to bypass blocked vessels. When VEGF is overexpressed, it can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express VEGF are able to grow and metastasize. Overexpression of VEGF can cause vascular disease in the

retina of the eye and other parts of the body. Drugs such as bevacizumab can inhibit VEGF and control or slow those diseases. VEGF is a sub-family of growth factors, specifically the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis (the ''de novo'' formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). Vascular endothelial growth factor (VEGF) is a chemical signal produced by cells that stimulates the growth of new blood vessels. It is part of the system that restores the oxygen supply to tissues when blood circulation is inadequate. VEGF's normal function is to create new blood vessels during embryonic development, new blood vessels after injury, and new vessels (collateral circulation) to bypass blocked vessels. When VEGF is overexpressed, it can contribute to disease. Solid cancers cannot grow beyond a limited size without an adequate blood supply; cancers that can express VEGF are able to grow and metastasize. Overexpression of VEGF can cause vascular disease in the retina of the eye and other parts of the body. Drugs such as bevacizumab can inhibit VEGF and control or slow those diseases. VEGF is a sub-family of growth factors, specifically the platelet-derived growth factor family of cystine-knot growth factors. They are important signaling proteins involved in both vasculogenesis (the ''de novo'' formation of the embryonic circulatory system) and angiogenesis (the growth of blood vessels from pre-existing vasculature). Kim R. Introduction, mechanism of action and rationale for anti-vascular endothelial growth factor drugs in age-related macular degeneration. Indian J Ophthalmol 2007;55:413-5 Impact Factor for 2010 is 0.827 Click here to download free Android Application for this and other journals Click here to view optimized website for mobile devices Journal is indexed with MEDLINE/Index Medicus and Science Citation Index Expanded

SYMPOSIUM Year : 2007 | Volume : 55 | Issue : 6 | Page : 413-415 Introduction, mechanism of action and rationale for anti-vascular endothelial growth factor drugs in age-related macular degeneration Ramasamy Chief-Retina Vitreous Services, Aravind eye Hospital, Madurai, India Date of Submission Date of Acceptance Correspondence Ramasamy 01-Apr-2007 16-Jul-2007 Address: Kim Kim

ChiefIndia

Retina

Vitreous

Services,

Aravind

Eye

Hospital,

Madurai

DOI: 10.4103/0301-4738.36473 PMID: 17951895

Abstract Recent developments may provide an opportunity to improve outcome in individuals who develop neovascular age-related macular degeneration (ARMD). Several therapies have been introduced that show promise for halting the progression of this disorder. However, data from controlled clinical trials to test the relative efficacy of different management strategies across the subtypes of disease remain limited. New treatment modalities that target the neovascularization process, including leakage from choroidal neovascularization (CNV), are currently being developed. Vascular endothelial growth factor (VEGF) has been implicated as a key mediator in the pathogenesis of ARMD-related CNV. Anti-VEGF strategies show promise as potential therapeutic agents for the treatment of CNV and are currently undergoing active clinical investigation. Such strategies include anti-VEGF antibodies, anti-VEGF aptamer, gene therapy and protein kinase C inhibition. This article reviews the mechanism of action and rationale for anti-VEGF drugs in ARMD.

Keywords: Age-related macular degeneration, anti-vascular endothelial growth factor

How to cite this article: Kim R. Introduction, mechanism of action and rationale for anti-vascular endothelial growth factor drugs in age-related macular degeneration. Indian J Ophthalmol 2007;55:413-5 How to cite this URL: Kim R. Introduction, mechanism of action and rationale for anti-vascular endothelial growth factor drugs in age-related macular degeneration. Indian J Ophthalmol [serial online] 2007 [cited 2011 Nov 29];55:413-5. Available from: http://www.ijo.in/text.asp?2007/55/6/413/36473 Choroidal neovascularization (CNV) in patients with age-related macular degeneration (ARMD) is the leading cause of irreversible vision loss in the elderly. Neovascularization derived from choroidal blood vessels usually breaks through Bruch's membrane and grows under the retinal pigmented epithelium (RPE). Currently available therapeutic modalities are not highly efficacious in the treatment of CNV from ARMD. To date, the two treatments shown by large clinical trials to have some efficacy are thermal laser treatment (photocoagulation) and photodynamic therapy (PDT). Laser photocoagulation is only useful in a small percentage of patients that have well-defined areas of classic CNV. [1],[2],[3] In addition, central vision is preserved only if these lesions are in either an extrafoveal or juxtafoveal location. Moreover, recurrences after laser photocoagulation are common and

occur in approximately 50% of patients. [3] Photodynamic therapy with verteporfin (Visudyne , Novartis AG, Basel, Switzerland) has been shown to reduce vision loss for subfoveal CNV secondary to ARMD, particularly if angiography demonstrates the lesion to be predominantly classic CNV. [4] However, many patients have lesions that are not amenable to treatment and vision improvement is unusual. New treatment modalities that target the neovascularization process including leakage from CNV are currently being developed. Vascular endothelial growth factor has been demonstrated in human specimens of CNV and animal models have confirmed that this protein is capable of inducing CNV. [5] Therefore, targeted inhibition of VEGF seems to be a reasonable approach for the treatment of CNV. VEGF appears to be an important growth factor for angiogenesis and has been shown to be necessary in normal vascular development. VEGF is highly selective for vascular endothelial cells and induces angiogenesis by serving as a potent endothelial cell mitogen. It has been shown to be secreted by hypoxic RPE cells and induces endothelial cell proliferation and retinal vascular permeability. VEGF has also been shown to be necessary and sufficient for the development of retinal and iris neovascularization in experimental models. [6] It has been identified as a major mediator of retinal ischemia-associated neovascularization. VEGF is up-regulated by hypoxia and its levels are increased in the vitreous and retina of patients and laboratory animals with active neovascularization from ischemic retinopathies such as proliferative diabetic retinopathy, central retinal vein occlusion and retinopathy of prematurity. Polarized secretion of VEGF by RPE cells is thought to direct VEGF toward the choroidal vasculature, where it may regulate choroidal integrity by binding to its receptors on the adjacent choriocapillaris. The importance of VEGF for the development of ARMD-related CNV has led to the development of strategies to block its effects. Such strategies include anti-VEGF antibodies, anti-VEGF aptamer, gene therapy and protein kinase C inhibition. The hope is that blocking the actions of VEGF will prove to be an effective strategy for the treatment of CNV. [6] Angiogenesis is the development of new capillaries from preexisting vascular network. It may occur in a variety of ocular disorders, such as retinopathy of prematurity, retinal artery or vein occlusion, diabetic retinopathy and ARMD. The discovery of such factors as VEGF and their mechanisms of action has led to the development of drugs specifically targeting the molecules or their signal transduction pathways. [7] Rationale

VEGF appears to be one of the major regulators in CNV among the angiogenic factors studied so far; VEGF plays a central role in the development of CNV. The VEGF family includes placenta growth factor, VEGF-A, VEGF-B, VEGF-C, VEGF-D and VEGF-E. Briefly, VEGF-A plays a pivotal role in the development of pathologic angiogenesis in ischemic and inflammatory diseases. VEGF is a 35- to 45-kd homodimeric protein originally isolated as a vasopermeability factor and later cloned and identified as an angiogenesis factor. Up to six different VEGF isoforms are derived through alternative splicing of messenger RNA (mRNA). VEGF165 appears to be the isoform most responsible for pathologic ocular neovascularization. Hypoxia is a major regulator of VEGF expression which distinguishes VEGF from other growth factors that have been postulated to have a role in ocular neovascular diseases, including insulin-like growth factor-1, fibroblast growth factors (FGF), epidermal growth factor and placenta growth factor. Many cells in the eye produce VEGF and within the retina, these include RPE, pericytes, endothelial cells, glial cells, muller cells and ganglion cells. In the human eye, elevated vitreous and aqueous VEGF levels strongly correlate with retinal ischemia-associated neovascularization in conditions like diabetic retinopathy, retinal vein occlusion and retinopathy of prematurity. [7]

The importance of VEGF as a therapeutic target derives from its roles in two of the most basic processes within a typical lesion of advanced ARMD: neovascularization and vascular leakage. The neovascular form is responsible for 80 to 90% of cases of severe vision loss due to ARMD. Given the increasing prevalence of neovascular ARMD and the burden of associated vision loss, it is important to define treatment benefits that are meaningful to the patient. Neovascular ARMD often has a poor prognosis, resulting in a rapid and progressive loss of visual acuity and contrast sensitivity. Such losses have a profound effect on patients' quality of life and their ability to perform everyday tasks. Photodynamic therapy, currently the most thoroughly investigated definitive therapy, is useful mainly for the classic types of neovascular ARMD. However, most angiographic lesions of patients who undergo fluorescein angiography for neovascular ARMD are subfoveal and occult; only 20% of subfoveal lesions are predominantly classic. Other treatment options such as submacular surgery and steroid-based therapies appear less favorable on current evidence. The strong supportive evidence from animal studies defined VEGF as an optimal therapeutic target. It is hoped that by using a more selective and less destructive approach, vision loss induced by the treatment itself might be reduced. VEGF over expression induces endothelial cell proliferation and increases vascular permeability, properties that can be detected clinically as the presence of subretinal fluid or enlarging CNV. Anti-VEGF therapy might reduce subretinal fluid, a theoretic possibility with VEGF inhibition, [8] resulting in short-term vision improvement. Mechanism of Action

The role of VEGF as a critical factor in the control of the growth of abnormal blood vessels from the choroid directly attacks a central problem in this disease. The profound vascular permeability induced by VEGF is potentially of even greater importance in the treatment of established neovascular ARMD lesions, in which leakage of fluid from new vessels causes visual loss through retinal edema and exudation, subretinal fluid and hemorrhage. [7] Anti-VEGF aptamers are stable small RNA-like molecules that bind exclusively and with high affinity to the 165-kDa isoform of human VEGF [Figure - 1]. Pegaptanib sodium, an oligonucleotide known as an aptamer, binds and inhibits only the extracellular isoforms of VEGF that are at least 165 amino acids in length. [9] Multiple biologically active forms of VEGF-A are generated by both alternative mRNA splicing and posttranslational modification (proteolytic cleavage), [10] and two of these forms (VEGF165 and VEGF121) have been detected in choroidal neovascular lesions. Pegaptanib (Macugen, Pfizer) can only bind and inhibit the larger VEGF165 isoform. In contrast to pegaptanib, bevacizumab (Avastin; Genentech, South San Francisco) a fulllength, humanized monoclonal antibody against VEGF and ranibizumab (Lucentis; Genentech, South San Francisco, California), a recombinant, humanized, monoclonal antibody antigen-binding fragment (Fab), bind and neutralize all the biologically active forms of VEGF. [11],[12],[13] The similar VEGF binding properties of bevacizumab and ranibizumab can be explained by their common molecular lineage. Both drugs are proteins that were genetically modified from the same murine monoclonal antibody against VEGF. The two proteins differ in their size and affinity for VEGF. Whereas bevacizumab is a humanized, murine full-length antibody with two binding sites for VEGF, ranibizumab is a humanized, murine antigen-binding fragment (Fab) with only a single affinity-matured binding site for

VEGF. [13] Bevacizumab is currently approved as an intravenous treatment for metastatic colorectal cancer. There is anecdotal evidence that off-label use intravitreal bevacizumab improves short-term visual outcomes in patients with neovascular ARMD. [14] VEGF-Trap(R1R2) is a fusion protein that combines ligand-binding elements taken from the extracellular domains of VEGFR-1 and VEGFR-2 fused to the Fc portion of IgG. This potent high-affinity VEGF blocker effectively suppresses tumor growth and vascularization in vivo , resulting in almost completely avascular tumors. Subcutaneous injections or a single intravitreous injection of VEGF-Trap(R1R2) strongly suppressed CNV in mice with laserinduced rupture of Bruch's membrane, and subretinal neovascularization in transgenic mice expressing VEGF in photoreceptor cells. [15] RNAi is a double-stranded piece of interference RNA that is taken up by chorioretinal cells, activating a protein that breaks down the antisense mRNA. Destruction of VEGF mRNA prevents the production of VEGF protein. The whole process is catalytic, so the RNAi may be a very potent and efficient blockade of VEGF. RNAi may have a long biologic half-life, indicating a much longer interval between intravitreal injections. Anti-VEGF RNAi for the treatment of CNV is currently being tested in clinical trials. [15]

Keywords:

anti-VEGF; bevacizumab; diabetic retinopathy; macular oedema; ranibizumab Abstract. The aim of this review is to summarize the latest developments in the treatment of diabetic retinopathy (DR) with anti-vascular endothelial growth factor (VEGF) drugs. We reviewed recent studies that evaluated the role of the anti-VEGF agents bevacizumab, ranibizumab and pegaptanib in the treatment of DR. There was only one large randomized controlled trial that evaluated the role of ranibizumab in diabetic macular oedema (DME). Other prospective and retrospective studies provided important insight into the role of anti-VEGF drugs in DR, but most of them were not conducted in large scales. The growing evidence indicates that anti-VEGF drugs are beneficial in DR, especially in DME. Further studies are needed to fully evaluate the role of these agents, especially in proliferative DR and in DR candidates for vitrectomy surgery. Introduction

Diabetic retinopathy (DR) is the leading cause of blindness among working-age adults in the United States and one of the leading causes of blindness and visual impairment worldwide (Fong et al. 2004). Until recently, the armamentarium for treating DR included laser treatment, steroid injections and surgery. In the 1980s and 1990s, the results of the Early Treatment Diabetic Retinopathy Study (ETDRS) demonstrated that focal/grid photocoagulation for clinically significant macular oedema (CSME) reduces the risk for moderate visual loss by 50% after 3 years of follow-up (Early Treatment Diabetic Retinopathy Study Research group 1985, 1991). The results of the Diabetic Retinopathy Study (DRS) demonstrated a 50% or greater reduction in the rate of severe visual loss in eyes treated with panretinal photocoagulation (PRP) for high-risk characteristic (HRC) proliferative diabetic retinopathy (PDR) after 5 years of follow-up (The Diabetic Retinopathy Study Research Group 1981). These studies continue to be the mainstays of the treatment of DR until today. In more severe cases, such as nonclearing vitreous haemorrhage (VH) or tractional retinal detachment (TRD), pars plana vitrectomy (PPV) may result in improvement in visual acuity (VA) (Diabetic Retinopathy Vitrectomy Study Research group 1990) as may intravitreal steroid injections for persistent diabetic macular oedema (DME). The revolutionary results of the treatment of neovascular age-related macular degeneration (AMD) with ranibizumab that were published in 2006 (Brown et al. 2006; Rosenfeld et al. 2006) encouraged researchers to investigate the role of anti-vascular endothelial growth factor (VEGF) drugs in DR as well. Three major anti-VEGF drugs were suggested for the treatment of DR. In December, 2004, pegaptanib (Macugen) became the first anti-VEGF drug approved by the US Food and Drug Administration (FDA) for intravitreal injection in the treatment of neovascular AMD. This drug, which is an aptamer, is targeted against only one isoform of VEGF (VEGF-165), and some earlier studies suggested that it may also be beneficial for DME (Cunningham et al. 2005; Querques et al. 2009). Its current use, however, is rather limited because of the availability of other anti-VEGF agents that are targeted against all active forms of VEGF-A. Ranibizumab (Lucentis), a recombinant humanized monoclonal antibody fragment, was specifically designed for ophthalmic use. This drug was approved by the FDA for the treatment of neovascular AMD, but it is relatively costly. Bevacizumab (Avastin), a full-length anti-VEGF antibody, was originally formulated for intravenous administration in the treatment of colon cancer. The low-cost off-label use of intravitreal injections of bevacizumab encouraged many physicians to use this drug mainly for AMD as well as for other retinal pathologies (Waisbourd et al. 2007). The aim of this review is to provide updated data on the treatment of DR with anti-VEGF agents. Anti-VEGF Agents for DME The recently published results of the DR Clinical Research network (DRCR net) for evaluating the role of ranibizumab and triamcinolone (Kenalog) in DME (Protocol I) provided one of the important cornerstones in the treatment DR. This randomized, large-scale

multicenter clinical trial, supported by the American National Eye Institute/National Institute of Health (NEI/NIH), evaluated the efficacy and safety of 0.5 mg intravitreal ranibizumab plus prompt (within 1 week) or deferred laser (24 week), or 4 mg intravitreal triamcinolone plus prompt (within 1 week) laser and compared the results with sham plus prompt laser treatment (Table 1). A total of 854 eyes (691 participants) were enrolled in the study, and 87% of them completed the 2-year follow-up. The underlying rationale of the treatment algorithm was to continue treatment as needed until stabilization, or no further improvement was noted. The difference in mean change in VA from the sham plus prompt laser treatment at 2 years was +5 letters for the ranibizumab plus prompt laser group (p = 0.01), +7.2 letters for the ranibizumab plus deferred laser group (p < 0.001) and 1.6 for the triamcinolone plus prompt laser group (p = 0.43). The difference in mean retinal thickening change from sham plus laser group at 2 years was 31 m for the ranibizumab plus prompt laser group (p = 0.01), 36 m for the ranibizumab plus deferred laser group (p = 0.004) and 3 m for the triamcinolone plus prompt laser group (p = 0.81). The results of this study suggested that ranibizumab should be considered for patients with DME and the characteristics similar to those of the subjects in that clinical trial (The Diabetic Retinopathy Clinical Research Network 2010; Elman et al. 2010). This important study (DRCR net protocol I) differed from the previously conducted DRCR net protocol B study, a randomized trial that compared intravitreal triamcinolone and laser photocoagulation for DME. The Protocol B study showed superiority of the focal/grid photocoagulation when compared with intravitreal triamcinolone for most patients with DME who had characteristics similar to the cohort in this trial (The

Diabetic Retinopathy Clinical Research Network 2008). Inclusion criteriaAt least one eye meeting all of the following criteria: ETDRS BCVA approxi (854 eyes20/32 to 20/320 Definite retinal thickening owing to DME involving the centre randomized) macula on clinical examination Central subfield 250 m 1.

ETDRS = early treatment diabetic retinopathy study, VA = visual acuity, BCVA = best co

visual acuity, OCT = optical coherence tomography, DME = diabetic macular oedema.

Difference in mean VARanibizumab + Prompt Laser Ranibizumab + Deferred Laser Triamcinolone + Promp change from +7.2 letters [p < 0.001] 1.6 letters [p = 0.43] Sham + Prompt Laser +5.0 letters [p = 0.01]

Difference in meanRanibizumab + Prompt Laser Ranibizumab + Deferred Laser Triamcinolone + Promp OCT thickening change from31 m [p = 0.01] 36 m [p = 0.004] 3 m [p = 0.81] Sham + Prompt Laser Rationale of the To continue treatment, as needed, until stabilization or lack of further improvement is treatment algorithm

Table 1. Summary of the 2- year results of the Diabetic Retinopathy Clinical Research N Randomized Trial for evaluating ranibizumab plus prompt (within 1 week) or deferred laser (24 we triamcinolone plus prompt laser for DME.

Nguyen et al. randomized 126 patients with DME to receive ranibizumab (baseline, months 1, 3 and 5), laser (baseline and month 3 if needed) or a combination (baseline, month 3). In this phase 2 study, the mean gain in VA at month 6 was significantly greater in the ranibizumab group (+7.24 letters, p = 0.01,) compared with the laser group (0.43 letters), while the gain in the combination group (+3.80 letters) was not significantly different from that of other groups. Excess foveal thickness was reduced by 50%, 33% and 45%, respectively, suggesting that ranibizumab alone, according to their protocol, is a better option than laser in this short-term trial (READ-2 study) (Nguyen et al. 2009). The RESOLVE trial, a 12-month randomized control trial, involved 151 DME patients treated over 12 months with 6 mg/ml ranibizumab (n = 51), 10 mg/ml ranibizumab (n = 51) or sham injection (n = 49). Three initial monthly injections were followed by retreatment based on success, futility or safety criteria. The mean average best corrected visual acuity (BCVA) change from baseline was +7.8 letters for ranibizumab (pooled groups) versus 0.1 letters for the sham group (p < 0.0001). (Hansen & Resolve Study Group 2010) Other studies, conducted for shorter periods of time, also supported the use of ranibizumab for DME (Chun et al. 2006). Additional phase 3 studies are currently ongoing; the initial results of the RESTORE trial (ClinicalTrials.gov: NCT00687804) that is evaluating the efficacy and safety of ranibizumab in patients with visual impairment owing to DME were recently released. That study found that 37% of patients treated with ranibizumab alone and 43% of those treated with ranibizumab plus laser therapy gained a substantial vision improvement of 10 letters or more compared with 16% of patients treated with laser alone after 1 year (http://clinicaltrials.pharmaceutical-businessreview.com/news/novartis_releases_ranibizumab_restore_phase_iii_study_results_100524/) . The RISE trial (NCT00-473330) and the RIDE trial (NCT-00473382) evaluated the use of ranibizumab in subjects with CSME with centre involvement. The estimated date for primary completion of their data is expected in 2012. The use of bevacizumab has also been investigated in DME. Michaelides et al. 2010 prospectively evaluated 80 eyes of 80 patients with centre involving CSME for 1 year (BOLT study). In that masked study, patients were randomized to either bevacizumab (6 weekly; minimum of three injections and maximum of nine injections in the first 12 months) or macular laser therapy (4 monthly; minimum of one treatment and maximum of four treatments in the first 12 months). At 12 months, the bevacizumab group had gained a median of 8 ETDRS letters, whereas the laser group lost a median of 0.5 ETDRS letters (p = 0.0002). The mean central macular thickness (CMT) decreased from 507 m at baseline to 378 m (p < 0.001) in the bevacizumab group, whereas it decreased from 481 to 413 m in the laser group (p = 0.02) (Michaelides et al. 2010). Kook et al. (2008) found that a long-term decrease in CMT and a gain in VA can be observed following repeated intravitreal injections of bevacizumab even in cases with

chronic diffuse ischaemic DME. Other studies found no difference between intravitreal bevacizumab at doses of 1.25 or 2.5 mg (Arevalo et al. 2009a,bLam et al. 2009). The combination therapy of bevacizumab with triamcinolone was also evaluated by several groups. Soheilian et al. randomized 150 eyes of 129 patients with CSME to three arms: bevacizumab 1.25 mg alone, a combination of bevacizumab with triamcinolone 2 mg and a laser group. Retreatment was performed at 12-week intervals whenever indicated. At 24 weeks, the bevacizumab group yielded better visual outcomes when compared to the laser treatment, but no adjunctive effect of triamcinolone was demonstrated (Soheilian et al. 2009). Shimura et al. (2008), however, found better results in reducing DME and in the improvement in VA with triamcinolone when compared with bevacizumab. Paccola et al. (2008) also suggested that one single injection of triamcinolone may offer certain advantages over bevacizumab in the short-term management of refractory DME, and others suggested only short-term effect to the conjunction of triamcinolone to bevacizumab (Ahmadieh et al. 2008; Faghihi et al. 2008). Intravitreal administration of triamcinolone may, however, result in intraocular pressure (IOP) elevation as well as formation or progression of cataract. The recent results of the DRCR net study cited earlier suggested that treatment of intravitreal triamcinolone combined with laser did not result in superior VA outcomes compared with laser alone. In an analysis limited to pseudophakic eyes, the triamcinolone groups outcome for VA appeared to be similar to that of the ranibizumab groups, but it was associated with an increased risk of IOP elevation. Pegaptanib was also evaluated in patients with DME in a phase 3 multicentre randomized controlled trial (NCT00605280). Two hundred and sixty patients with DME received pegaptanib or sham procedure every 6 weeks in year 1. In year 2, subjects could receive injections according to prespecified criteria. Up to three focal or grid laser treatments per year were permitted beginning at week 18. Positive results were recently published, showing 10 letter gains in 37% of patients who received pegaptanib compared with 20% of patients receiving sham treatment at 54 weeks (p = 0.0047). At the end of year 2, mean VA improved in 6.1 letters in the pegaptanib group compared with 1.3 letters in the sham group (p < 0.01). (http://www.eyetech.com/content/pr/Eyetech_News_Release %20_WOC_FINAL_06_05%2010.pdf). Safety issues Sight-threatening adverse events of intravitreal injections of anti-VEGF drugs are very rare and include endophthalmitis and retinal detachment (Waisbourd et al. 2007). In the DRCR net study, the endophthalmitis cases related to the drug injection in the ranibizumab groups were 0.08% of all injections given. There was also a single case of traction retinal detachment in a patient with PDR and prior PRP treatment at baseline (<1%). In their case report, Chen et al. (2009) suggested that intravitreal bevacizumab may also result in acute

reduction in VA in chronic DME by disrupting an already fragile vascular perfusion status, leading to macular ischaemia, as demonstrated by enlargement of the foveal avascular zone and persistent late leakage on fluorescein angiogram. Altogether, there is cumulating evidence that anti-VEGF drugs may be beneficial in the treatment of DME, especially after the publication of the 2-year results of the DRCR net study. Anti-VEGF Agents for PDR Anti-VEGF agents have also been studied for the treatment of PDR. Unlike DME, the data available for these agents in PDR are relatively limited, and no large prospective randomized studies have been published thus far. Avery et al. retrospectively evaluated 44 PDR eyes that had been treated with intravitreal bevacizumab. All of their studied eyes had complete or partial reduction in fluorescein angiography (FA) leakage of the neovascularization within 1 week after the injection. Complete resolution of neovascularization of the disc (NVD) was noted in 73% of the treated eyes (Avery et al. 2006). Mirshahi et al. (2008) prospectively evaluated 80 eyes of 40 HRC PDR patients in a fellow-eye sham controlled trial. Bevacizumab 1.25 mg was administered at their first session of laser treatment. A total of 87.5% of the bevacizumab-injected eyes and 25% of the sham group eyes showed complete neovascularization regression at week 6 (p < 0.005). At week 16, however, the protective effect of bevacizumab was diminished, and the regression rate in the two groups became identical (25%; p = 1.000). Cho et al. prospectively evaluated 40 eyes with PDR and found that the eyes that received PRP treatment alone had significantly worse VA at 3 months (p = 0.041), whereas the eyes that received PRP plus bevacizumab underwent no significant change in VA. The proportion of eyes that developed VH was also significantly lower in the PRP plus bevacizumab group (p = 0.023) (Cho et al. 2009). Schmidinger suggested that a three monthly bevacizumab retreatment regime might be a valid method to control persistent neovascularization (NV) in PDR patients (Schmidinger et al. 2009), and Arevalo et al. found no safety concerns for both 1.25 and 2.5 mg doses (Arevalo et al. 2009c). Other groups found bevacizumab to be beneficial in PDR patients as well (Jorge et al. 2006; Tonello et al. 2008; Erdol et al. 2010), although some suggested that this procedure may increase the risk of TRD in eyes with fibrous proliferation (Moradian et al. 2008). The use of anti-VEGF agents prior to or in tandem with PRP may prevent DME occurrence secondary to the PRP: Cho et al. (2009) found that in PDR patients undergoing PRP, adjunction of bevacizumab before laser treatment resulted in a significant reduction in CMT at 1 and 3 months compared with PRP alone. In PDR patients with complete PRP undergoing bevacizumab injections for persistent new vessels, a decrease in mean CMT was found after 6 months when compared to baseline (Schmidinger et al. 2009). Bevacizumab was also shown to be effective in PDR patients with VH. Huang et al. administered bevacizumab to 40 patients with VH, followed by PRP when technically possible. A second injection was given after 46 weeks if that VH was not decreased. PPV

was performed if the VH persisted >12 weeks. Vitreous clear-up time was 11.9 weeks in the study group and 18.1 weeks in a historical control group (p = 0.02). The rates of required vitrectomy were 10% in the study group and 45% in the control group (p = 0.01) (Huang et al. 2009). Pegaptanib was also studied for PDR patients in a retrospective analysis of individuals with retinal NV identified from a large trial evaluating pegaptanib for the treatment of DME. Most of the patients with retinal NV who received this drug showed regression by week 36 (Adamis et al. 2006). It would appear that the role of anti-VEGF drugs is important in PDR, but it remains uncertain what should be the exact treatment protocol for these agents. Large prospective studies are needed to determine the exact role of these drugs. Currently, the gold standard for the treatment of PDR remains PRP, while anti-VEGF agents can play a role as an adjunctive therapy in severe or persistent cases. Anti-VEGF Agents in Adjunction to PPV Recent studies demonstrated a few benefits of using anti-VEGF drugs preoperatively for PDR. In most studies, bevacizumab was administered for no longer than 1 week preoperatively, because TRD may occur or progress shortly following the administration of bevacizumab in patients with severe PDR (Arevalo et al. 2008; Moradian et al. 2008). Ahmadieh et al. prospectively evaluated 68 eyes undergoing PPV for the management of PDR complications. Their study patients were randomly assigned to bevacizumab 1.25 mg or sham injections 1 week preoperatively. The incidence of postvitrectomy haemorrhage at 1 week and at 1 month after surgery was significantly lower in the bevacizumab group compared with the control group (p = 0.023 and p = 0.001, respectively) (Ahmadieh et al. 2009). di Lauro et al. (2010) also found that the administration of bevacizumab 1 week preoperatively reduced retinal and iritic NV, thus making surgery easier and safer and improving the anatomical and functional prognosis. Others have also suggested that preoperative bevacizumab facilitates surgery and improves surgical outcomes (Yeh et al. 2009; Rizzo et al. 2008; da et al. 2009; Modarres et al. 2009;Romano et al. 2009a), although intraoperative bevacizumab was not found helpful in preventing the recurrence of VH (Romano et al. 2009b). Oshima et al. (2009) suggested that microincision vitrectomy surgery plus bevacizumab offers comparable anatomical success compared with conventional 20gauge PPV in patients with TRD, with shorter surgical time, fewer intraoperative complications and favourable visual recovery. The results of these studies appear to indicate that the administration of bevacizumab, a few days preoperatively, may provide substantial advantage among patients with PDR. Conclusions

Similar to the revolution in the treatment of AMD with ranibizumab following the MARINA and ANCHOR studies (Brown et al. 2006;Rosenfeld et al. 2006), the recently published results of the DRCR net show promise to revolutionize the treatment of DME patients. There is also growing evidence that anti-VEGF drugs are beneficial among patients with active PDR, including those who are candidates for surgery, although large randomized controlled trials need to be performed to determine when treatment should be initiated, what should be the recommended treatment intervals and when treatment should be withheld. Treatment of diabetic retinopathy with anti-VEGF drugs 1. 2. 3. Michael Waisbourd, Michaella Goldstein, Anat Loewenstein Article first published online: 2 NOV 2010 DOI: 10.1111/j.1755-3768.2010.02010.x 2010 The Authors. Acta Ophthalmologica 2010 Acta Ophthalmologica Scandinavica Foundation Issue

Acta Ophthalmologica Volume 89, Issue 3, pages 203207, May 2011

Corneal Neovascularization
CLINICAL DESCRIPTION: Corneal neovascularization is the in-growth of blood vessels into the avascular corneal tissue secondary to chronic hypoxia, chronic inflammatory disease, trauma or anterior segment pathology including interstitial keratitis, Moorens ulcer formation and Terriens marginal degeneration. (1,2) It can further be divided into superficial and deep, where superficial is more common with contact lens wear and deep is a

result of a chronic inflammatory condition or anterior segment pathology. (3) Due to the various possible causes of corneal neovascularization, it is important to rule out conditions not related to contact lens wear before making a definitive diagnosis. SYMPTOMS: Patients may present with no symptoms or they may notice limbal hyperemia. Upon slit lamp examination, vessels can be seen proliferating anterior to the limbus into the corneal tissue. Additional symptoms may include eye pain, tearing and photophobia, injection, contact lens intolerance after only a few hours of wear and decreased vision these symptoms are seen more in extended wear contact lens patients and will be discussed further below. INCIDENCE: Corneal neovascularization and other signs of corneal hypoxia are mainly seen in soft lens extended wear patients, especially those fit in low Dk/t hydrogel soft lens materials given that other possible causes previously mentioned have been ruled out. (4) In addition to this, corneal neovascularization has been found to occur in patients wearing polymethyl methacrylate (PMMA) or low Dk/t rigid gas permeable materials although this is rare due to the cornea not being completely covered by a gas permeable lens. (3) Vascularization can also occur in patients wearing tight fitting soft hydrogel lenses due to the impingement and compression on the limbal conjunctiva and associated vessels. (5) There appears to be a higher incidence of corneal neovascularization in soft lens extended wear patients as opposed to gas permeable wearers. Fonn et. al conducted a study involving a soft hydrogel lens material and concluded that at least 65% of the subjects showed signs of corneal neovascularization to a certain extent at the conclusion of the study. (6) In gas permeable wearers, localized neovascularization can be seen if there is a poor lens fit causing 3 and 9 oclock staining. Over time, this situation may lead to corneal defects and desiccation that can result in limbal vessel engorgement and epithelial disruption. This is called vascularized limbal keratitis (VLK). (7) ETIOLOGY: The general opinion is that several factors play a role in the development of neovascularization with hypoxia being a front-runner. The different degrees of neovascularization has been neatly summarized by Liesegang (8)

1. Limbal hyperemia: engorgement of existing limbal capillaries and common in soft hydrogel wearing patients. 2. Superficial neovascularization: progression of limbal hyperemia and in-growth of vessels up to 4mm into the cornea. 3. Deep stromal neovascularization: secondary to chronic hypoxia and can lead to the development of an active inflammatory or fibrovascular response with vessels extending past 4mm into the cornea. 4. Intracorneal hemorrhage in severe cases The Role of Oxygen Dk/t measures the oxygen transmissibility of a lens and is a factor of the lens oxygen permeability (Dk) and thickness (t) and is measured by the simple formula Dk/t. Oxygen permeability is further related to the water content of the lens as atmospheric oxygen first dissolves in the tears, moving into the water part of the lens and finally to the cornea. A minimum Dk/t of 25 has been recommended for daily wear lenses and 87 for extended or overnight wear in order to prevent more than 4% corneal swelling which is the amount that occurs in the normal closed eye environment. (9) Other investigators have countered that 3.2% corneal swelling occurs overnight, and using this have concluded that a Dk/t of at least 125 is required to avoid the corneal change. (10) The cornea is avascular and therefore acquires oxygen from the atmosphere. When the cornea is devoid of oxygen, it will under go an 8% increase in corneal thickness over a three hour period (4). When there is no or low amounts of oxygen available for the proper functioning of corneal tissue, the normal aerobic reactions switch over to an anaerobic mechanism producing lactate which accumulates within the tissues along with carbon dioxide. This accumulation produces an acidic pH, thereby causing the influx of water via osmosis subsequently leading to corneal edema and an increase in corneal thickness. (4, 3, 8) Increasing acidosis affects the corneal epithelium and stroma but with negligible effects on the endothelium until the glycogen and adenosine triphosphate energy stores are depleted. This results in the slower functioning of sodium and potassium pumps in the endothelium that normally regulates the amount of water in the cornea thereby causing additional water to be retained within corneal tissues. (8) These reactions set off a chain which can lead to various clinical findings. A closed eye environment or a contact lens can mimic such an environment and can result in the following sequelae: striae, corneal vascularization, microcysts, refractive error change, endothelial changes, decreased corneal sensitivity, depressed metabolic rate, compromised epithelial junction integrity, stromal thinning and increased microbial adherence (8).

(1)

(2) Figure 1 and 2. Previous soft hydrogel multifocal lens wearing patient exhibiting a localized area of neovascularization. This patient was subsequently refit into into a silicone hydrogel material.

Figure 3. Soft hydrogel lens wearing patient exhibiting vascular growth approximately 1mm past the inferior corneal limbus. This patient was subsequently refit into a silicone hydrogel material. MANAGEMENT: A hypoxic corneal environment appears to play a crucial role in the formation of neovascularization in contact lens wearers. New vessels that form are likely to have weak barriers and are prone to leakage of blood constituents such as lipid or cholesterol molecules (3). These substances can acquire an opaque appearance in the clear cornea, therefore deposits close to the visual axis will affect vision. As mentioned previously, corneal neovascularization tends to occur in extended wear of low Dk/t soft hydrogel lens materials. Patients with a high ametropia may also be more prone to neovascular changes due to the increased lens thickness required; for example, aphakic patients or high myopes with a thicker lens periphery. A tight fitting soft lens may also predispose the cornea to neovascular changes due to an increased incidence of limbal vessel engorgement, hypermia and limited tear exchange which may promote the action of angiogenic factors upon limbal vessels (5). Due to the high Dk/t of silicone hydrogel lens materials, corneal vascularization is rarely observed with these lenses (6). The incidence of neovascularization in gas permeable wearers is low due to the newer more oxygen permeable lens materials, the tear pump and the smaller lens diameter. Soft Lens Wearers For daily wear soft hydrogel contact wearers, if limbal hyperemia is present and a tight fitting lens is apparent, the base curve should be changed in order to promote more lens movement. If there is adequate movement with an optimal fit, the lens is not providing the necessary

oxygen to the cornea. Refitting the patient in a silicone hydrogel lens will increase the oxygen to the cornea and decrease the hypoxia. Both limbal hyperemia and corneal vascularization have been found to improve upon refitting with a silicone hydrogel lens. (3, 5,10). In extended soft hydrogel lens wearing patients, because of the inadequate amount of oxygen transmissibility in the lens material, these patients should be refit into a higher Dk/t silicone hydrogel lens material. Available silicone hydrogel lens options are FDA approved for extended wear either up to 6 nights and 7 days, or for 30 days continuous wear; therefore patients should be educated on these options. If there is apparent vessel growth, regression of these vessels will be seen after changing to a higher Dk/t material with a good prognosis for up to 4mm of in-growth. Ghost vessels will remain which have the capacity to fill with blood again if the cornea is subsequently subjected to a similar hypoxic environment. (5, 6) GPs Gas permeable wearers experiencing 3 and 9 staining and evidence of localized neovascular and fibrovascular changes due to a poorly fitting lens should be refit into a design that limits this condition. Recommended methods of preventing 3 and 9 staining and the subsequent neovascularization include the use of wettable fluoro-silicone/acrylate lens materials, improved lens centration, proper edge clearance and adequate corneal lubrication via proper blinking and use of lubricants. (7) In both soft and GP contact lens wear, it is rare that with proper follow-up and annual evaluation, that neovascularization cannot be managed with the aforementioned changes. In extreme cases, with marked neovascularization creeping towards the visual axis and associated fibrovascular areas and lipid deposition all contact lens wear should be discontinued. Close follow-up care every 2 3 months should be initiated to monitor for any possible further detrimental changes and to watch for regression. Afterwards, these patients should be refit into high Dk/t silicone hydrogel or gas permeable lenses. If the opacified areas do not regress and there are areas of scarring and a poor visual outcome, then a corneal transplant may be indicated. (3) Some clinicians advocate the use of a topical steroid in order to suppress active neovascularization. The steroid works to decrease blood vessel permeability and leakage in addition suppressing the recruitment of involved cells. (3) No single cause has been identified as the sole trigger of corneal neovascularization, however it is believed that corneal hypoxia, especially in soft hydrogel extended wear patients, is the main culprit. Patient education plays an important role as many do not understand or are aware of the consequences that can result from lens over-wear or noncompliance to lens wear schedules. Given the multitude of lens options

now available and a more appreciable knowledge of the changes and findings that can be observed, quick diagnosis and management will hopefully prevent any irreversible damage. BEST REFERENCES: Grohe RM and Lebow KA. Vascularized limbal keratitis. ICLC 1989;16(7&8): 197-208. Weissman, BA and Yeung, KK Neovascularization, Corneal, CL-related: Treatment and Medication Nov 21, 2001 http://emedicine.medscape.com/article/1195886-treatment Accessed 02/11/2009 Swarbrick HA. Extended Wear: Physiologic Considerations In: Bennett ES, Weissman BA. eds. Clinical Contact Lens Practice, Philadelphia: Lippincott Williams and Wilkins, 2005:647-675. Liesegang, TJ Physiologic Changes of the Cornea with Contact Lens Wear CLAO Journal 28(1): 12 27, 2002 OTHER REFERENCES: Kanski, JJ. Cornea In: Kanski JJ, Clinical Ophthalmology A Systemic Approach 5th Edition, London: Butterworth-Heinemann, 2003:95 - 143 Efron, N. Contact Lens Complications. London: Butterworth-Heinemann, pp:153 161, 2004 Weissman BA, Yeung KK Neovascularization, Corneal, CL-related: Treatment and Medication Nov 21, 2001 http://emedicine.medscape.com/article/1195886-treatment Accessed 02/11/2009 Swarbrick HA. Extended Wear: Physiologic Considerations In: Bennett ES, Weissman BA. eds. Clinical Contact Lens Practice, Philadelphia: Lippincott Williams and Wilkins, 2005:647-675. Josephson, JJ and Caffery, BF Corneal Neovascularization In: Anterior Segment Complications of Contact Lens Wearers 2nd Edition, ButterworthHeinemann pp:95 106, 2000 Fonn, D, MacDonald KE, Richter, D et al. The Ocular Response to Extended Wear of a High Dk Silicone Hydrogel Contact Lens Clin Exp Optom 85(3):176 182, 2002 Bennett ES, Scheid T. Gas-Permeable Len Problem Solving In: Bennett ES, Henry VA. eds. Clinical Manual of Contact Lenses 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, 2009:183-208. Liesegang, TJ Physiologic Changes of the Cornea with Contact Lens Wear CLAO Journal 28(1): 12 27, 2002

Dumbleton K, Jones, L Extended Wear In Bennett, ES and Henry, VA Clinical Manual of Contact Lenses 3rd Edition, Philadelphia: Lippincott Williams and Wilkins, 2009:410 443 Holden, BA, Mertz, GW Clinical Oxygen Levels to Avoid Corneal Edema for Daily and Extended Wear Contact Lenses Invest Ophthalmol Vis Sci 25(10): 1161 1167, 1984 Fonn, D. and Bruce, A.S. A Review of the Holden-Mertz Criteria for Critical Oxygen Transmission Eye Contact Lens Nov: 31(6): 247 251, 2005

http://www.aocle.org/livingL/cornneo.html 2011 Cornea and Contact Lens Living Library Corneal Neovascularization Authors: Olivia K. Do, O.D. Vinita Allee Henry, O.D., F.A.A.O. Reviewed by: Julie Ott DeKinder, O.D., F.A.A.O. Bruce W. Morgan, O.D., F.A.A.O.

Chen from Taiwan is also assessing the efficacy of subconjunctival bevacizumab and changes in dosing. Designed as an open-label single-group study, patients with neovascularity and lipid keratopathy extending more than 2 mm from the limbus were enrolled. Patients were injected with 1.25 to 2.5 mg of bevacizumab on a monthly basis for 3 months. If corneal neovascularization has not regressed, treatment continues for an additional 3 months. Visual acuity and the extent of lipid infiltrate will be assessed. In Brazil, Nazaralla is conducting a phase IV study assessing the safety and efficacy of subconjunctival bevacizumab in treating corneal neovascularization refractory to other treatments. After a 1.25-mg subconjunctival bevacizumab injection, patients will be followed-up for 2 months; efficacy will be assessed by improvement on anterior segment photographs. Going a step further, Hsiao in Taiwan is comparing topical 1.0% bevacizumab 4 times daily with subconjunctival injection 2.5 mg bevacizumab and monitoring efficacy for 6 months. This will give better insight into the long-term effects of topical and subconjunctival administration of bevacizumab.24 Although anti-VEGF therapy is efficient at preventing corneal neovascularization, there are desirable VEGF functions that bevacizumab may prevent, such as formation of collateral vessels, control of vascular tone, corneal nerve regeneration, and wound healing. It is important to note that long-term neutralization of VEGF may have unintended local or systemic consequences. Delivery models should be explored, because even small doses of anti-VEGF drugs are noted to cause hypertension, proteinuria, and various cardiovascular events. Vascular endothelial growth factors antibodies have a variety of side effects; therefore, patients of childbearing potential or patients with renal disease, with end-stage liver disease, abnormality in anticoagulation, a history of thrombotic event, hypertension, active infectious disease, or a history of glaucoma are contraindicated and have been excluded from the studies described previously.
24. Hsiao CH, principal investigator. Bevacizumab for the treatment of corneal neovascularization. ClinicalTrials.gov identifier NCT00992849. Available at: http://clinicaltrials.gov/ct2/ show/NCT00992849. Accessed September 30, 2010.

Neovascularization can occur with hydrogel and RGP lens wear. Most patients wearing hydrogel lenses on a regular basis have some superficial neovascularization owing to the hypoxia associated with contact lens wear. Contact lenses reduce the amount of oxygen available to the cornea. This effect can be caused by a tightfitting lens, low-Dk lenses,PMMAlenses, or extended wear of conventional hydrogel lenses. Hypoxia can lead to acute or chronic edema. In acute edema, diffuse microcystic epithelial changes can be seen. As the hypoxia advances, the epithelial edema can lead to cell death and desquamation of the stressed epithelial cells.

Patients complain of acute pain, tearing, reduced vision, and photophobia, and cannot tolerate wearing their contact lenses. On examination, conjunctival injection and diffuse superficial punctate staining are seen. Occasionally, epithelial defects can occur.

The symptoms and findings of chronic hypoxia are typically subtler than are those of acute hypoxia. Chronic edema is more common with extended wear, because the low-grade hypoxic stress of continuous wear leads to gradual changes in corneal structure and function [37]. Epithelial microcysts, stromal thickening and striae, endothelial blebs, and, with

persistent hypoxia, neovascularization develop. There is no acute pain, and patients usually have minimally decreased vision. Pachymetry can be performed to evaluate for changes in corneal thickness before it can be diagnosed at the slit lamp.

Suchecki JK, et al 2003:16:47184

Contact lens complications.

Ophthalmol Clin N Am.

The pathogenesis of corneal scarring and vascularization in HSK is uncertain, but it seems to be a complex interaction of various cytokines, chemokines, and growth factors either brought in by inflammatory cells or produced locally in response to HSV-1 infection.14,16,17 It has been suggested that HSV-1 infection disrupts the normal equilibrium between angiogenic and antiangiogenic stimuli, leading to vascularization. The synthesis of potent antiangiogenic factors such as thrombospondin 1 and 2 has been found to be downregulated selectively by HSV-1 infection in human keratocytes.
18 Liu et al, 2012 JS19

MMPs released by leukocytes play vital roles in allowing leukocytes to extravasate and penetrate tissues, a key event in inflammatory disease.
Ciardella et al, 2002

JS 20

Corneal neovascularization, which may follow corneal injury, is a major sight-threatening complication. In general, for neovascularization to occur, invading endothelial cells use proteolytic enzymes to penetrate various barriers, including basement membranes, and cellcell and cellmatrix junctions. Because the basement membrane is composed of collagen IV and laminin and other glycoproteins, 119 and the stromal matrix is mainly composed of collagen I, elastin, and fibronectin,208 an array of enzymes is required to degrade each of these proteins. MMPs and TIMPs have been implicated in the regulation of angiogenesis.47,81,117,217 The process involves the formation of new capillaries from preexisting vessels and is a multistep event. One of the initial steps is the degradation of the blood vessel basement membrane by proteolytic enzymes, including MMPs.12 In this context, vascular endothelial cells from the parent venule are stimulated by various angiogenic factors, such as fibroblast growth factor (FGF) and vascular endothelial growth factor (VEGF), to produce proteolytic MMPs,12 which can then degrade the basal membrane and surrounding extracellular matrix (Fig. 4). Matrix degradation allows the endothelial cells to escape the parent venule and penetrate and migrate into adjacent tissue toward the angiogenic stimulus, where they proliferate and form new capillaries.12,95 In the cornea, there is evidence of increased expression of MMP-2 and VEGF in the limbal region and the corneal stroma during corneal neovascularization. 115 The presence of neutrophil derived MMP-2 may exacerbate corneal angiogenesis together with the associated inflammatory response in the anterior chamber. The inflammatory phase is characterized by an influx of neutrophils and monocytes to the wound site. Immediate local reactions include the release of tissue factors and chemoattractants from the damaged tissues. Damaged vessels induce venous stasis. The leakage of plasma components, including fibrin and acute wound fluid, has been shown to contain high levels of secreted MMP-9. Platelets and leukocytes are rapidly activated and intravascular clotting occurs. Fibrin provides the scaffold of matrix molecules on which cellular migration occurs. The recruitment of neutrophils occurs within a few hours of injury, with lymphocytes and macrophages following soon after. At this stage, MMP-9 stored in macrophage and neutrophil granules is released into the microenvironment. Wong et al, 2002 JS 21

http://emedicine.medscape.com/article/1195886-overview With CL wear, superficial NV is more common than deep stromal vessels. It is speculated that deep stromal NV may reflect a more profound insult (hypoxia) compared to that which generates only superficial NV. Both superficial and deep stromal NV are reported with the use of hydrogel, hard (polymethyl methacrylate [PMMA]), and rigid gas permeable CLs, especially with a history of aphakia, extended wear, poor compliance, and poor follow-up care. [3] Deep stromal NV is serious, possibly leading to loss of optical transparency of the tissue through stromal hemorrhage, scarring, and lipid deposition.

Chan WK, Weissman BA. Corneal pannus associated with contact lens wear. Am J Ophthalmol. May 1996;121(5):540-6. [Medline].

Fine, superficial neovascularization is most commonly seen in contact lens wearers, and also can be associated with blepharitis, superior limbic keratoconjunctivitis, vernal conjunctivitis and many others Pannus or deep stromal neovascularization can be seen in eyes with extended use of contact lens, chronic blepharoconjunctivitis, keratitis, trachoma, toxic chemical injuries, graft rejection and phlyctenulosis.

http://dro.hs.columbia.edu/cornealnv.htm

Superficial vascularization that is acquired may be diffuse, when it is called a pannus, or may be localized, when it is called a fascicle. The pannus variety represents granulation tissue that characteristically separates the epithelium from Bowman's membrane; occasionally it extends into tissue deeper than Bowman's membrane. With trachoma, it affects predominantly the upper portion of the cornea,whereas with exposure keratopathy or bullous keratopathy resulting from longstanding intraocular inflammation it affects predominantly the lower portion of the cornea. Following chemical burns it is particularly apt to be massive and affect the entire cornea. The individual vessels of a pannus are similar to those of the conjunctiva. A relatively small arteriole forms a loop with one large venule or more through a negligibly small capillary bed. The vessels pursue sinuous courses without the sharp angulation characteristic of interstitial vessels. Their method of extension in the cornea is not known but no evidence has been presented to contravene the possibility that they move by simple migration of the loops. In contrast to pannus, fascicular keratitis comprises a sheath of vessels that often includes interstitial as well as superficial vessels. The sheath is directed toward a specific lesion and is particularly common with recurrent herpetic disease; it once was most common with phlyctenularkeratitis. There is nothing distinctive about the histology of superficial vessels in the cornea. The vessels are situated beneath the epithelium and during their active growth they are accompanied by inflammatory cells. Eventually some connective tissue is also formed but this is usually sparse. A pannus in which there is abundant connective tissue suggests that the vascularization was secondary to a membrane, such as that which occurs with long-standing bullous keratopathy, wherein the formation of connective tissue is the primary event.

Deep vascularization in the cornea is only a special case of interstitial vascularization insofar as blood vessels have a particular predilection to persist between the corneal stroma and Descemet's membrane. It is thus that a lamina of vessels is frequently found in the deepest stroma following an interstitial keratitis. There is no other disease entity wherein they occur in this region characteristically and exclusively. Possibly related to deep vascularization are the clear lines and nebulae which are seen in the deep portions of otherwise normal corneas. The explanation for these abnormalities is unknown, but the branching of the clear lines suggested lymphatics to Fuchs 45 who first described them. Others"-10' J7 have assumed they were the sites of deep blood vessels, and it is true that some of these patients have a history compatible with former interstitial or deep keratitis. JS 22

Superficial corneal neovascularization commonly associated with extended-wear contact lens. Note the branching pattern of the newly formed vessels.

Deep stromal vascularization as a response to HZV keratitis.

2003 http://dro.hs.columbia.edu/cornealnv.htm