Corneal Neovascularization

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Article initiated by:

Marianna Kavalaraki MD, Msc

All contributors:

Vatinee Y. Bunya, MD, MSCE, Colleen Halfpenny, M.D., Sumayya Ahmad, MD, Marianna Kavalaraki MD, Msc, Alexander Black, MD

Assigned editor:

Minh T Nguyen, MD

Review:

Assigned status Up to Date

 by Sumayya Ahmad, MD on December 30, 2025.

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Contributing Editors:	add

Disease Entity

Corneal neovascularization is a sight-threatening condition in which ocular pathology causes ingression of new blood vessels into the normally avascular cornea. This can be caused by many different pathologies, both acute and chronic, including infection, inflammation, chemical injury, ischemia, mechanical disruption of the normal ocular surface, autoimmune disease, immune hypersensitivity, post-corneal transplantation, traumatic conditions, and hypoxia from contact lens over-wear, among other ocular pathologies.

Disease, Etiology, and Risk Factors

Corneal neovascularization (NV) is a pathologic condition of the cornea which affects over 1.4 million people per year. NV is 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. NV is typically described in terms of its anatomical relation to the cornea. It is most commonly superficial or within the corneal stroma. It can be described as focal, regional, or diffuse. NV is caused by a disruption of the balance between pro-angiogenic and anti-angiogenic factors that normally preserves limbal blood flow while maintaining corneal transparency. Immature new blood vessels may lead to lipid exudation, persistent inflammation, and scarring, thus threatening visual acuity the blood vessels or their sequelae involve the visual axis. In advanced stages, ingrown blood vessels become mature and recalcitrant to regression despite treatment of the underlying condition, even causing conjunctivalization of the cornea. These mature vessels can be permanently vision-reducing and require surgical intervention. In patients with corneal grafts, NV may contribute to rejection. Treatment of NV is often aimed at treating the underlying cause, and when possible, preventing NV from developing.

Pathophysiology

Corneal neovascularization is a nonspecific response to different clinical insults, rather than a diagnosis. It 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 pro-angiogenic and anti-angiogenic 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 up-regulation of proteolytic and angiogenic cytokines. One of the well recognized classes of destructive enzymes in this inflammatory cascade are metalloproteinases (MMP), which degrade collagens, liberate inflammatory cytokines, and assist in further release of pro-angiogenic factors such as vascular endothelial growth factor (VEGF). Ultimately, this inflammatory cascade and subsequent proteolysis degrades the cornea's basement membrane and extracellular matrix, allowing vascular epithelial cells to enter the stromal layer of the cornea and proliferate.

When ocular inflammation occurs, corneal epithelial and endothelial cells, macrophages and certain inflammatory cells produce angiogenic growth factors such as VEGF, fibroblast growth factor (FGF), platelet derived growth factors (PDGF), and angiopoetins (Ang). These factors work in concert to pave the way for new blood vessel formation by up-regulating MMP production by endothelial cells in the limbal vascular plexus, however, they also offer different targets for highly selective biologic treatments which are being studied widely in ophthalmology in retinal and corneal conditions.

Limbal stem cell deficiency (LSCD) can also cause corneal neovascularization. LSCD is a consequence of limbal stem cell dysfunction, which results in apoptosis and reduced ability to regenerate normal epithelial cells, and loss of the normal cellular barrier which helps prevent angiogenesis on the clear cornea.

Diagnosis

The diagnosis is made by clinical examination at the slit lamp, in which blood vessels extend from the corneal limbus into the stroma of the clear corneal surface. New blood vessels may vary in quantity and configuration. They may demonstrate a fine, reticular pattern, appear engorged and reactive in the acute setting, or be dense, mature, and chronic appearing with an underlying corneal haze and lipid exudation.

Management

General treatment

The treatment of corneal neovascularization is challenging. A variety of off-label treatment approaches, such as topical treatments, anti-VEGF injections and laser/ phototherapy, have been shown to produce varying degrees of effectiveness. The main therapeutic aims of these treatments are to induce vessel regression and/or inhibit new vessel growth.

Medical therapy

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. ,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 PDGF, 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.

Doxycycline: A widely utilized medication in various corneal inflammatory pathologies due to inhibition of matrix metalloproteases (MMP), doxycycline has also demonstrated efficacy as a topical and oral medication in cases of corneal neovascularization in animal models. This is thought to occur through MMP inhibitory activity and modulation of the PI3K/Akt-eNOS pathway.

Surgery

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.

Mitomycin C Intravascular Chemoembolization (MICE) Procedure - Introduced in 2022 by Mimouni and Ouano, MICE involves intravascular injection of 0.01 to 0.05cc of 0.4mg/mL mitomycin C using a 33 to 34 gauge-needle, per the initial study. The goal of MICE is targeted chemoembolization of the neovascular vessel and subsequent resolution of visually significant lipid keratopathy. The injection should be performed within the largest bore vessel possible and is targeted anterograde at the the peripheral clear cornea. Long term safety data for MICE is not yet available, however early case series and preliminary safety studies have demonstrated a reasonable safety and efficacy profile .

Keratoprosthesis - Newer technologies such as keratoprosthesis (KPro) offer a new avenue of surgical treatment for corneal blindness. While penetrating keratoplasty is a successful treatment for many causes of corneal blindness, certain conditions such as neovascularization, dry ocular surface, and recurrent inflammatory and infectious conditions are unique challenges for maintaining a clear corneal window after keratoplasty. KPro is indicated in the setting of failed corneal transplant, or in situations where the likelihood of donor graft failure is high. The different types of KPro have their own advantages and disadvantages, which can be further explored here (Boston) and here (Osteo-Odonto).