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Review Corneal Disorders The Management of Corneal Neovascularisation – Update on New Clinical Data and Recommendations of Treatment Natasha Spiteri, 1 Vito Romano, 2 Matthias Brunner, 3 Bernhard Steger 4 and Stephen B Kaye 5 1. Sydney Hospital and Sydney Eye Hospital, Sydney, Australia; 2. Moorfields Eye Hospital, London, UK; 3. St Paul’s Eye Unit, Royal Liverpool University Hospital, Liverpool, UK; 4. Medical University of Innsbruck, Innsbruck, Austria; 5. Department of Eye and Vision Science, University of Liverpool, Liverpool, UK V ascularisation of the cornea may occur as a sight-threatening response to various insults to the cornea, such as infection, trauma and inflammation, and is a well-recognised risk factor for rejection and subsequent failure of corneal grafts. Various different treatment modalities have been used in the past, with varying levels of success. In this review, we discuss the pathogenesis of corneal neovascularisation, look at recent advances in the assessment of these patients and give an overview of currently available treatment options, both medical and surgical. We also discuss current experimental treatment for corneal neovascularisation, such as gene therapy, which may provide further treatment options in the future. Keywords Corneal neovascularisation, haemangiogenesis, lymphangiogenesis, anterior segment angiography, in vivo confocal microscopy, anti-VEGF, fine-needle diathermy Disclosure: Natasha Spiteri, Matthias Brunner, Bernhard Steger, Vito Romano and Stephen B Kaye have nothing to disclose in relation to this article. No funding was received in the publication of this article. This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. Authorship: All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship of this manuscript, take responsibility for the integrity of the work as a whole, and have given final approval to the version to be published. Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Received: 17 October 2016 Accepted: 6 December 2016 Citation: European Ophthalmic Review, 2016;10(2):86–93 Corresponding Author: Natasha Spiteri, Sydney Hospital and Sydney Eye Hospital Macquarie Street, Sydney NSW 2000, Australia. E: 86 Corneal neovascularisation (CoNV) is a sight-threatening condition caused by new vessel formation from the limbal vascular plexus and marginal corneal arcades and invasion into the cornea in response to inflammation, infection, trauma and hypoxia. 1,2 CoNV may lead to profound visual decline by compromising corneal clarity. Pathologic vessel formation may compromise corneal transparency by blocking and diffracting light, causing lipid and protein exudation and serving as a conduit for inflammatory cells that damage the structural integrity of the cornea leading to scarring (see Figure 1). 3 As one of the main causes of corneal blindness in developed countries and a major risk factor for immune allograft rejection after corneal transplantation, CoNV represents a major health burden to the public. 4 Although the global impact of CoNV is not known, the incidence rate has been estimated to be 1.4 million per year in the United States. 5 Current treatment options of CoNV are limited and prevention of visual loss remains the main challenge for clinicians when facing patients with CoNV. Recent investigations, however, have improved our understanding of the complex mechanisms involved in corneal haem- and lymphangiogenesis and new insights into molecular pathways have opened new doors for potential future treatment strategies. 6 Corneal angiogenic privilege The cornea is a complex sensory organ and its transparency, which presupposes the absence of blood and lymph vessels, is critical for optimal vision. Corneal avascularity is maintained by a highly regulated and delicate balance of naturally occurring pro- and anti-angiogenic factors (angiogenic privilege). Various signaling cascades and molecular mechanisms maintain corneal avascularity under homeostatic conditions. 7 Corneal and limbal epithelial cells have an angiostatic effect on the cornea and limbal epithelial cells further function as a barrier against haem-and lymphangiogenesis. 8,9 It has been demonstrated that different cytokine traps for angiogenic and inflammatory factors are constitutively expressed by the intact corneal epithelium: soluble vascular endothelial growth factor (VEGF)-A receptor-1 (sVEGFR1) acts as a decoy receptor for secreted VEGF and inactivates membrane-bound VEGF-A receptors 1 and 2 by heterodimerisation; 10 VEGFR3 binds and inhibits activation of VEGF-C and VEGF-D which promote lymphangiogenesis; 11 and sVEGFR2 controls the ingrowth of lymphatic vessels. 12 Other inhibitors of angiogenesis found in the corneal epithelium include angiostatin, which plays a role in the maintenance of corneal avascularity after wounding, 13 and pigment epithelium derived factor (PEDF), a serine protease inhibitor responsible for excluding vessels from invading the cornea. 14 Furthermore, the cornea actively counteracts hypoxia-driven upregulation of VEGF by low, if any expression of hypoxia inducible factor (HIF)-1a and by expression of IPAS, an inhibitor of hypoxia-driven HIF-1a-signaling. 14 The corneal epithelial basement membrane (EBM) also plays an important role in regulating angiogenic privilege: Potent anti-angiogenic factors such as endostatin, thrombospondins (TSP-1 and -2), and tissue inhibitor of metalloproteinase-3 are derived from the extracellular matrix component of the EBM. 15–17 Endostatin inhibits the endothelial cell cycle in G1 phase and mitogenic activities of VEGF in vascular endothelial cells by inhibiting binding of VEGF to surface receptors (KDR/Flk-1) and blocking downstream signaling events. 18 TSP-1 inhibits angiogenesis TOU C H ME D ICA L ME D IA