**Corneal Angiogenesis: Etiologies, Complications, and Management Corneal Angiogenesis: Etiologies, Complications, and Management**

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http://dx.doi.org/10.5772/66713

#### **Abstract**

A large subset of corneal pathologies involves the formation of new blood vessels, leading to compromised visual acuity. Additionally, neovascularization of the cornea worsens the prognosis of subsequent penetrating keratoplasty, keeping the patient in a vicious circle of poor prognosis. Ocular angiogenesis results from the upregulation of proangiogenic and downregulation of antiangiogenic factors. There is a tremendous need for developing effective measures to prevent and/or treat corneal neovasculariza‐ tion. Topical steroid medication, cautery, argon and yellow dye laser, and fine needle diathermy have all been advocated with varying degrees of success. The process of cor‐ neal neovascularization is primarily mediated by the vascular endothelial growth factor family of proteins, and current therapies are aimed at disrupting the various steps in this pathway. This article aims to review the clinical causes and presentations of corneal neo‐ vascularization caused by different etiologies. Moreover, this chapter reviews different complications caused by corneal neovascularization and summarizes the most relevant treatments available so far.

**Keywords:** cornea, angiogenesis, etiologies, complications, management

## **1. Introduction**

A normal cornea is necessary to protect the eye against structural damage to the deeper ocu‐ lar components as well as to provide a proper anterior refractive surface. Optimal vision and corneal clarity entail an avascular cornea, and maintaining the stromal avascularity is an important feature of the corneal pathophysiology. Corneal vascularization, which is a sign of corneal disease processes than a diagnosis, results from an imbalance between angiogenic and antiangiogenic factors [1]. The angiogenic factors stimulate the proliferation and migra‐ tion of vascular endothelial cells, resulting in the formation of a capillary tube [2, 3]. Corneal

© 2016 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. © 2017 The Author(s). Licensee InTech. This chapter is distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

neovascularization is part of the natural healing processes, which are triggered by exposure of the cornea to trauma or pathogens, and is not necessarily 'harmful.' In the long‐term and under certain circumstances, however, corneal neovascularization can surpass a threshold, invading the cornea, reducing visual acuity, and, in case of lamellar keratoplasty or penetrating kerato‐ plasty, endangering corneal graft survival [4–7]. These complications have prompted clinicians to devise means to shut vessels. Topical steroid medication, cautery, argon and yellow dye laser, and fine needle diathermy (FND) have all been advocated with varying degrees of success. The advent of anti‐vascular endothelial growth factor (VEGF) antibodies has resulted in a surge of interest in using these agents to treat corneal neovascularization. These approaches, however, have a limited clinical efficacy and can result in a multitude of undesirable complications. This chapter aims to review the causes, pathogenesis, and clinical presentations of corneal neovascu‐ larization caused by different etiologies, such as contact lens–induced keratitis, corneal ulcers, and herpes simplex stromal keratitis. Moreover, it reviews different complications caused by corneal neovascularization and summarizes the most relevant treatments available so far.

## **2. Etiologies**

Corneal vascularization occurs as a nonspecific response to different clinical insults. Diseases associated with corneal neovascularization include corneal graft rejection, inflammatory dis‐ orders, chemical burns, contact lens–related hypoxia, stromal ulceration, infectious keratitis, limbal stem cell deficiency, and congenital disease (**Table 1**) [8–10].


**Table 1.** Causes of corneal neovascularization.

Hypoxia related to contact lens wear is a common cause where corneal neovascularization is usually superficial and involves only the corneal periphery [11, 12]. However, if contact lens wear is not discontinued, deep stromal and central corneal invasion can take place.

neovascularization is part of the natural healing processes, which are triggered by exposure of the cornea to trauma or pathogens, and is not necessarily 'harmful.' In the long‐term and under certain circumstances, however, corneal neovascularization can surpass a threshold, invading the cornea, reducing visual acuity, and, in case of lamellar keratoplasty or penetrating kerato‐ plasty, endangering corneal graft survival [4–7]. These complications have prompted clinicians to devise means to shut vessels. Topical steroid medication, cautery, argon and yellow dye laser, and fine needle diathermy (FND) have all been advocated with varying degrees of success. The advent of anti‐vascular endothelial growth factor (VEGF) antibodies has resulted in a surge of interest in using these agents to treat corneal neovascularization. These approaches, however, have a limited clinical efficacy and can result in a multitude of undesirable complications. This chapter aims to review the causes, pathogenesis, and clinical presentations of corneal neovascu‐ larization caused by different etiologies, such as contact lens–induced keratitis, corneal ulcers, and herpes simplex stromal keratitis. Moreover, it reviews different complications caused by corneal neovascularization and summarizes the most relevant treatments available so far.

Corneal vascularization occurs as a nonspecific response to different clinical insults. Diseases associated with corneal neovascularization include corneal graft rejection, inflammatory dis‐ orders, chemical burns, contact lens–related hypoxia, stromal ulceration, infectious keratitis,

> Viral Bacterial Fungal

Mucous membrane pemphigoid

Conjunctival or corneal squamous cell carcinoma

Thermal burn, chemical burn, or other injury

Corneal graft rejection

Atopic conjunctivitis

Rosacea

Papilloma

Ocular surface neoplasia Conjunctival or corneal intraepithelial neoplasia

limbal stem cell deficiency, and congenital disease (**Table 1**) [8–10].

58 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

Hypoxia Contact lens wearing

Inflammatory disorder Stevens‐Johnson syndrome

Loss of limbal barrier function Congenital (e.g., aniridia)

**Table 1.** Causes of corneal neovascularization.

Conjunctival/corneal degeneration Pterygium

**Categories Cause** Infectious keratitis Parasitic

**2. Etiologies**

Infections can result in corneal neovascularization with the patterns of response being different. Herpes simplex virus (HSV) keratitis is likely to cause extensive vascularization and lipid kera‐ topathy, while, in Acanthamoeba keratitis, vascularization tends to develop late in the course of the disease (**Figure 1**). The continued presence of HSV‐DNA and HSV‐immune complexes

**Figure 1.** Acanthamoeba keratitis. Corneal opacity and vascularization (arrows) developed four months after corneal ulcer caused by Acanthamoeba in a contact lens wearer.

contributes to inflammation and angiogenesis in HSV stromal keratitis through increased lev‐ els of matrix metalloproteinase (MMP)‐9 and vascular endothelial growth factor (VEGF) [13, 14]. There is a close link between extent (i.e., superficial or stromal) and location (i.e., central or peripheral) of infections, and the location and extent of corneal neovascularization.

Limbal stem cell deficiency (LSCD) occurs in a variety of ocular pathologies both congenital (e.g., aniridia) and acquired (e.g., contact lens use, drugs, chemical burns, etc.), which lead to partial or total loss of limbal stem cells [15, 16]. Chemical (acidic and alkaline) substances can penetrate and damage the cornea and anterior chamber, with alkali burns being more severe [17]. Conjunctivalization of the cornea with massive neovascularization may develop, lead‐ ing to severe reductions in corneal clarity and visual acuity through the pannus formation on the cornea and an unstable and irregular epithelium [17, 18]. Deep vascularization may develop in the late healing phase following severe chemical burns (**Figure 2**).

Degenerative conditions such as pterygium are associated with corneal neovascularization that usually is accompanied with a fibrovascular pannus located on, rather than in, the corneal stroma. Long‐standing irritation of the ocular surface such as in vernal keratocon‐ junctivitis can lead to aggressive corneal neovascularization (**Figure 3**).

**Figure 2.** Limbal stem cell deficiency after alkali burn. The Figure demonstrates invasion of conjunctival vessels into the cornea (conjunctivalization) along with corneal stromal opacification and vascularization (asterisk).

**Figure 3.** Corneal vascularization (asterisk) in a patient with vernal keratoconjunctivitis.

Ocular surface neoplasia, including papilloma and conjunctival/corneal intraepithelial neopla‐ sia, can cause corneal neovascularization as part of the tumor angiogenic response. Initially, the vessels can be limited to the tumor but eventually invade the entire cornea. Other specific etiologies of corneal neovascularization include persistent corneal edema as in chronic hydrops of keratoconus and bullous keratopathy as well as corneal allograft rejection. Less common causes of corneal neovascularization are corneal foreign bodies and exposure to chemical tox‐ ins including mustard gas, radiation, or sun [19–21]. Intrastromal corneal ring implants, loose sutures, suture knots, and broken sutures seem to provide a stimulus for corneal vascularization

**Figure 4.** Intrastromal corneal ring segment implants complicated by corneal neovascularization. (A) Active young vessels (arrows) emanating from the limbus invade to the site of segment implantation. (B) The vessels have regressed after intrastromal corneal ring segment implants were removed. Partially regressed vessels are present in the inferior cornea (arrow).

(**Figure 4**). The mucus that collects around loose and broken sutures can trap polymorphonu‐ clear cells and microbes inciting localized inflammation/infection, thus attracting vessels.

## **3. Pathogenesis**

Ocular surface neoplasia, including papilloma and conjunctival/corneal intraepithelial neopla‐ sia, can cause corneal neovascularization as part of the tumor angiogenic response. Initially, the vessels can be limited to the tumor but eventually invade the entire cornea. Other specific etiologies of corneal neovascularization include persistent corneal edema as in chronic hydrops of keratoconus and bullous keratopathy as well as corneal allograft rejection. Less common causes of corneal neovascularization are corneal foreign bodies and exposure to chemical tox‐ ins including mustard gas, radiation, or sun [19–21]. Intrastromal corneal ring implants, loose sutures, suture knots, and broken sutures seem to provide a stimulus for corneal vascularization

**Figure 2.** Limbal stem cell deficiency after alkali burn. The Figure demonstrates invasion of conjunctival vessels into the

cornea (conjunctivalization) along with corneal stromal opacification and vascularization (asterisk).

60 Physiologic and Pathologic Angiogenesis - Signaling Mechanisms and Targeted Therapy

**Figure 3.** Corneal vascularization (asterisk) in a patient with vernal keratoconjunctivitis.

The upstream molecular pathway mechanisms resulting in corneal neovascularization differ in the different underlying pathologies. Nonetheless, core molecular pathways governing the processes of corneal hemangiogenesis seem to be shared among various conditions leading to the active stage of corneal neovascularization. The normally avascular cornea may vascularize in circumstances in which a disequilibrium between angiogenic and antiangiogenic stimuli results in a surplus of proangiogenic factors, such as VEGF, basic fibroblast growth factor (bFGF), interleukin‐1 (IL‐1), and MMP, and a deficiency in antiangiogenic agents, such as endostatin, angiostatin, and pigment epithelium‐derived factor (PEDF) [22].

The so‐called VEGF family consists of VEGF‐A, VEGF‐B, VEGF‐C, VEGF‐D, and placental growth factor [23]. VEGF‐A is the most important member of this family, especially relat‐ ing to pathologic hemangiogenesis through VEGF receptor (VEGFR)‐2. VEGF‐C and VEGF‐D can stimulate lymphangiogenesis through VEGFR‐2 and VEGFR‐3, respectively [24, 25]. Macrophages, activated by injury or inflammation, can also produce VEGF‐A, VEGF‐C, and VEGF‐D in corneal stroma [26]. VEGF‐A sustains various steps of hemangiogenesis including vascular endothelial cell proliferation and migration, capillary lumen formation, and pro‐ teolytic activity [1]. The importance of VEGF‐A in corneal neovascularization was exhibited experimentally on animal studies by inhibiting angiogenesis following stromal application of an anti‐VEGF‐A antibody [27].

Platelet‐derived growth factors (PDGFs) are involved in cell division, growth, tissue remodeling, and angiogenesis. Receptors, such as PDGFR‐a and PDGFR‐b, and ligands, such as PDGF‐A and PDGF‐B, can be found in cornea and are associated with corneal neovascularization [28, 29]. Improved understanding of the molecular mechanisms of vascularization has enabled identification of specific factors that suppress angiogenesis to maintain the avascularity of the cornea. Because several molecules are involved in corneal neovascularization, a multipronged approach is desirable.
