Corneal neovascularization is a sight-threatening condition that introduces vascular pathology into the normally avascular cornea. This can be caused by inflammation related to infection, chemical injury, autoimmune conditions, immune hypersensitivity, post-corneal transplantation, and traumatic conditions, among other ocular pathologies.
Disease, Etiology, and Risk Factors
Corneal neovascularization (NV) is a pathologic condition of the cornea, characterized by the formation and extension of new vascular capillaries within and into the previously avascular corneal regions, extending from the limbus into the superficial or deep areas of the cornea. It is caused by a disruption of the balance between angiogenic and antiangiogenic factors that preserves corneal transparency. Immature new blood vessels may lead to lipid exudation, persistent inflammation, and scarring, thus threatening corneal transparency and visual acuity. Advanced stages, in which ingrown blood vessels reach the visual axis, can become permanently vision-threatening and, in patients with corneal grafts, may contribute to rejection.
Corneal neovascularization, which is a nonspecific response to different clinical insults, rather than a diagnosis, develops in a wide variety of corneal pathologies including congenital diseases, contact lens-related hypoxia, inflammatory disorders, chemical burns, limbal stem cell deficiency, allergy, trauma, infectious keratitis, autoimmune diseases, and corneal graft rejection. These pathologies lead to a disequilibrium between proangiogenic and antiangiogenic factors that can result in the proliferation and migration of vascular endothelial cells into the corneal stroma.
The in-growth of new blood vessels is mediated by the upregulation of angiogenic cytokines. The enzyme metalloproteinase degrades the cornea's basement membrane and extracellular matrix, while proteolytic enzymes allow vascular epithelial cells to enter the stromal layer of the cornea.
When ocular inflammation occurs, corneal epithelial and endothelial cells, macrophages and certain inflammatory cells produce angiogenic growth factors, namely vascular endothelial growth factor (VEGF) and fibroblast growth factors. VEGF paves the way for new blood vessel formation by upregulating matrix metalloproteinases production by endothelial cells in the limbal vascular plexus.
The diagnosis is made by clinical examination at the slit lamp, in which blood vessels cross the corneal limbus.
The treatment of corneal neovascularization is challenging. However, a variety of off-lab treatment approaches, such as topical treatments, anti-VEGF injections and laser/ phototherapy, have been shown to produce varying degrees of effectiveness, . The main therapeutic aim of these treatments is to initiate anti-angiogenesis and inhibit the neoangiogenesis at early stages, whereas the other treatment modality aims to achieve angio-regression by inducing reversion of immature vessels.
Treatments for corneal neovascularization are predominately off-lab with a multitude of complications as a result. The desired results from medical therapy may not always occur, ergo an invasive procedure may be needed to prevent further decrease in corneal avascularity.
Topical treatments for corneal neovascularization include steroids and anti-VEGF agents are currently the mainstay initial treatment for corneal neovascularization.
Topical steroids : Cortisone, dexamethasone and prednisolone have all been shown to produce an antiangiogenic effect and hence inhibit corneal neovascularization.  However, some studies suggest that steroids do not inhibit the development of post-chemical induced corneal neovascularization, whilst recent research suggests positive outcomes in suppressing angiogenesis when applied directly after or before corneal injury in other scenarios. Steroids are thought to work by inhibiting cell chemotaxis and by inhibiting pro-inflammatory cytokines like interleukin-1 and -6, as well as by also causing lymphocyte death and inhibiting vascular dilation, which all amounts to their antiangiogenic effect. The use of steroids (such as cortisone) in conjunction with heparin and cyclodextrins causes a greater antiangiogenic effect, leading to the development of ‘angiostatic steroids’, which are thought to modulate collagen metabolism that can completely disintegrate the basement membrane of the blood vessels. Heparin modulates the expression of anti-angiogenic and pro-angiogenic factors. However, steroids have a considerable side effect profile with negative associations such as glaucoma and increased infection susceptibility due to their immune suppressive effect.
Anti-VEGF therapy: Pro-angiogenic factors include VEGF, FGF and PDG, with VEGF having a crucial role in inflammatory corneal neovascularization. The cornea has ‘angiogenic privilege’ , meaning it has a balance between pro-angiogenic and anti-angiogenic factors, therefore selectively targeting these angiogenic growth factors is desirable over steroids due to their side effect profile and more selective action. Anti-VEGF drugs work by inhibiting VEGF which prevents new blood vessel formation through down regulation of endothelial cell proliferation. Bevacizumab has been shown to have an immediate inhibitory effect on corneal neovascularization and inflammation, but with very short-lived effects; therefore, early treatment with bevacizumab inhibits corneal neovascularization but late treatment does not . Anti-VEGF treatment is important during active vessel growth which is characterized by the presence of immature blood vessels relying on pro-angiogenic factors for proliferation. This is in line with the findings by Lin that anti-VEGF treatment (bevacizumab) is effective when used in early treatment of patients with corneal neovascularization. Anti-VEGF treatment can have undesirable effects, including suppression of wound healing, limbal stem cell deficiency, corneal nerve dysregulation and can systemically cause hypertension and cardiovascular disease. Krizova showed that the use of bevacizumab is effective and very safe in treating active corneal neovascularization whether applied topically or given as a subconjunctival injection. However, they also show that bevacizumab does not have the same effect on mature corneal neovascularization and this treatment does not cure the disorder.
Invasive solutions for the treatment of corneal neovascularization, including several laser and surgical procedures, are reserved for patients in whom medical therapies have failed to produce the desired results.
- Laser Ablation : Corneal argon laser or Nd: YAG laser photocoagulation may be used to occlude invading blood vessels by coagulating blood vessels and ablating tissue. An argon or Nd: YAG laser beam normally passes through the clear cornea, however, when there are many vessels present, the hemoglobin absorbs the argon energy allowing corneal vessels to coagulate, which causes reversal of the corneal neovascularization. Studies have shown its efficacy in regression of corneal neovascularization. Laser photocoagulation can also be efficiently employed for the treatment of corneal vascularization in cases of graft rejection and lipid keratopathy. Careful attention must be paid to avoid excessive irradiation and damage to adjacent tissues, as complications such as corneal hemorrhage and corneal thinning may develop. Occlusion of afferent vessels is often unsuccessful because of vessel depth, size, and high blood flow rates. Paradoxically, thermal damage may trigger an inflammatory response, exacerbating neovascularization. Failure due to vessel lumen reopening is common, and new shunt vessels may form.
- Photodynamic therapy involves a photosensitizing compound, light and oxygen. Irradiation of a previously injected photosensitive dye causes a reaction that produces and releases reactive oxygen species in the vessel lumen, inducing apoptosis and necrosis of the endothelium and basement membrane, thus destroying the surrounding neovascular tissue and reversing corneal neovascularization. The highly specific tissue damage, combined with the resulting thrombogenic response, seals off the vessel. Photodynamic therapy has proven to be a safe and highly efficient therapeutic approach; however, it is a very costly method of treatment as well as time consuming. Although it is effective, photodynamic therapy has limited clinical acceptance due to high costs and potential complications related to laser irradiation and generation of reactive oxygen species.
- Diathermy and cautery. A fine needle may be inserted into feeder vessels at the limbus. Vessels are occluded either by application of a coagulating current through a unipolar diathermy unit or by thermal cautery using an electrolysis needle. Although initial studies found these techniques to be safe and effective, additional data from multi-institutional studies are required. This may also result in limbal stem cell deficiency due to ablation of the stem cells in the limbus.
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