Corneal neovascularization (CNV) is the in-growth of new blood vessels from the pericorneal plexus into avascular corneal tissue as a result of oxygen deprivation. Maintaining avascularity of the corneal stroma is an important aspect of corneal pathophysiology as it is required for corneal transparency and optimal vision. A decrease in corneal transparency causes visual acuity deterioration. Corneal tissue is avascular in nature and the presence of vascularization, which can be deep or superficial, is always pathologically related. Corneal neovascularization is a sight-threatening condition that can be caused by inflammation related to infection, chemical injury,

autoimmune In immunology, autoimmunity is the system of immune responses of an organism against its own healthy cells, tissues and other normal body constituents. Any disease resulting from this type of immune response is termed an "autoimmune disease". ...

conditions, immune

hypersensitivity Hypersensitivity (also called hypersensitivity reaction or intolerance) refers to undesirable reactions produced by the normal immune system, including allergies and autoimmunity. They are usually referred to as an over-reaction of the immune ...

, post- corneal transplantation, and traumatic conditions among other ocular pathologies. Common causes of CNV within the cornea include

trachoma Trachoma is an infectious disease caused by bacterium '' Chlamydia trachomatis''. The infection causes a roughening of the inner surface of the eyelids. This roughening can lead to pain in the eyes, breakdown of the outer surface or cornea of ...

, corneal ulcers, phylctenular keratoconjunctivitis
rosacea keratitis

interstitial keratitis Interstitial keratitis (IK) is corneal scarring due to chronic inflammation of the corneal stroma. Interstitial means space between cells i.e. corneal stroma which lies between the epithelium and the endothelium. Keratitis means corneal inflammati ...

sclerosing keratitis

chemical burns A chemical burn occurs when living tissue is exposed to a corrosive substance (such as a strong acid, base or oxidizer) or a cytotoxic agent (such as mustard gas, lewisite or arsine). Chemical burns follow standard burn classification and may cau ...

, and wearing contact lenses for over-extended periods of time. Superficial presentations of CNV are usually associated with contact lens wear, while deep presentations may be caused by chronic inflammatory and anterior segment ocular diseases. Corneal neovascularization has become more common worldwide with an estimated incidence rate of 1.4 million cases per year, according to a 1998 study by the Massachusetts Eye and Ear Infirmary. The same study found that the tissue from twenty percent of corneas examined during corneal transplantations had some degree of neovascularization, negatively impacting the prognosis for individuals undergoing keratoplasty procedures.

Presentation

Complications

In advanced stages, corneal neovascularization can threaten eyesight, which is why routine (annual) eye exams are recommended for contact lens patients.

Causes

CNV causes may be congenital in nature, such as with Aniridia, or acquired. Frequently, inflammatory, infectious, degenerative, traumatic or iatrogenic (e.g. contact lenses) conditions can be responsible for acquired CNV. Some major acquired inflammatory conditions include

graft rejection Transplant rejection occurs when transplanted tissue is rejected by the recipient's immune system, which destroys the transplanted tissue. Transplant rejection can be lessened by determining the molecular similitude between donor and recipient a ...

following keratoplasty, graft or host diseases of the new tissue
atopic conjunctivitis

rosacea Rosacea is a long-term skin condition that typically affects the face. It results in redness, pimples, swelling, and small and superficial dilated blood vessels. Often, the nose, cheeks, forehead, and chin are most involved. A red, enlarg ...

, ocular pemphigoid, Lyell's syndrome, and Steven's Johnson syndrome. Infections responsible for CNV range from bacterial (

chlamydia Chlamydia, or more specifically a chlamydia infection, is a sexually transmitted infection caused by the bacterium '' Chlamydia trachomatis''. Most people who are infected have no symptoms. When symptoms do appear they may occur only several we ...

, syphilis, pseduomonas), viral (

herpes simplex Herpes simplex is a viral infection caused by the herpes simplex virus. Infections are categorized based on the part of the body infected. Oral herpes involves the face or mouth. It may result in small blisters in groups often called col ...

herpes zoster Shingles, also known as zoster or herpes zoster, is a viral disease characterized by a painful skin rash with blisters in a localized area. Typically the rash occurs in a single, wide mark either on the left or right side of the body or face. ...

viruses), fungal ( candida, asperigillus,

fusarium ''Fusarium'' is a large genus of filamentous fungi, part of a group often referred to as hyphomycetes, widely distributed in soil and associated with plants. Most species are harmless saprobes, and are relatively abundant members of the soil mi ...

), to parasitic ( onchocerca volvolus) infection. Degenerative diseases such as pterygiums an
terrien's marginal degeneration
may also be responsible. Traumatic causes of CNV include

ulceration An ulcer is a discontinuity or break in a bodily membrane that impedes normal function of the affected organ. According to Robbins's pathology, "ulcer is the breach of the continuity of skin, epithelium or mucous membrane caused by sloughing o ...

alkali burns
an
stem cell deficiency
One of the most common causes of corneal neovascularization is iatrogenic pathology from extended contact lens wear. This is especially likely with lenses made with older hydrogel materials such as HEMA (

2-hydroxyethyl methacrylate Hydroxyethylmethacrylate (also known as glycol methyacrylate) is the organic compound with the chemical formula . It is a colorless viscous liquid that readily polymerizes. Hydroxyethylmethacrylate is a monomer that is used to make various polymer ...

) for both daily and extended wear. Such older hydrogel materials have a relatively low oxygen transmissibility so the cornea becomes starved of oxygen; this leads to the ingress of blood capillaries into the clear cornea, in an attempt to provide more oxygen to the affected area. Older estimates cite 128,000 to 470,000 cases of lens-induced CNV each year, but this may be decreasing due to the increasing popularity of daily disposable lenses. The risk for CNV is elevated in certain instances for patients following penetrating keratoplasty without active inflammation or epithelial defects. For example, the condition is more likely to occur in those with active blepharitis, those who receive sutured knots in their host stromas, and those with a large recipient area.

Pathogenesis

The in-growth of new blood vessels is mediated by the

upregulation In the biological context of organisms' production of gene products, downregulation is the process by which a cell decreases the quantity of a cellular component, such as RNA or protein, in response to an external stimulus. The complementary proc ...

of angiogenic

cytokine Cytokines are a broad and loose category of small proteins (~5–25 kDa) important in cell signaling. Cytokines are peptides and cannot cross the lipid bilayer of cells to enter the cytoplasm. Cytokines have been shown to be involved in autocrin ...

s. The enzyme

metalloproteinase A metalloproteinase, or metalloprotease, is any protease enzyme whose catalytic mechanism involves a metal. An example is ADAM12 which plays a significant role in the fusion of muscle cells during embryo development, in a process known as myo ...

degrades the cornea's basement membrane and extracellular matrix, whil
proteolytic enzymes
allow vascular epithelial cells to enter the stromal layer of the cornea. When ocular inflammation occurs, corneal

epithelial Epithelium or epithelial tissue is one of the four basic types of animal tissue, along with connective tissue, muscle tissue and nervous tissue. It is a thin, continuous, protective layer of compactly packed cells with a little intercell ...

and

endothelial The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vessel ...

cells, macrophages and certain inflammatory cells produce angiogenic growth factors, namely

vascular endothelial growth factor Vascular endothelial growth factor (VEGF, ), originally known as vascular permeability factor (VPF), is a signal protein produced by many cells that stimulates the formation of blood vessels. To be specific, VEGF is a sub-family of growth factors, ...

(VEGF) and

fibroblast growth factor Fibroblast growth factors (FGF) are a family of cell signalling proteins produced by macrophages; they are involved in a wide variety of processes, most notably as crucial elements for normal development in animal cells. Any irregularities in their ...

s. VEGF paves the way for new blood vessel formation by upregulating matrix metalloproteinases production by endothelial cells in the limbal vascular plexus.

Treatment

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. For contact lenses related hypoxia, ceasing the use of contact lenses is the first step until corneal neovascularization is addressed by a physician. Modern rigid gas permeable and silicon hydrogel contact lenses have a much higher level of oxygen transmissibility, making them effective alternatives to help prevent corneal neovascularization.

Topical A topical medication is a medication that is applied to a particular place on or in the body. Most often topical medication means application to body surfaces such as the skin or mucous membranes to treat ailments via a large range of classes ...

administration of steroids and non-steroid anti-inflammatory drugs are first-line treatment for individuals with CNV. The administration of steroids can increase the risk of infection,

glaucoma Glaucoma is a group of eye diseases that result in damage to the optic nerve (or retina) and cause vision loss. The most common type is open-angle (wide angle, chronic simple) glaucoma, in which the drainage angle for fluid within the eye rem ...

cataract A cataract is a cloudy area in the lens of the eye that leads to a decrease in vision. Cataracts often develop slowly and can affect one or both eyes. Symptoms may include faded colors, blurry or double vision, halos around light, trouble ...

recurrence. The anti-inflammatory drugs, however, increase the risk of

corneal ulcer Corneal ulcer is an inflammatory or, more seriously, infective condition of the cornea involving disruption of its epithelial layer with involvement of the corneal stroma. It is a common condition in humans particularly in the tropics and the a ...

ation and melting. Since VEGF plays an important role in

vasculogenesis Vasculogenesis is the process of blood vessel formation, occurring by a '' de novo'' production of endothelial cells. It is sometimes paired with angiogenesis, as the first stage of the formation of the vascular network, closely followed by ang ...

and pathologic neovascularization associated with eye diseases, a potential treatment for CNV is to inhibit VEGF activity by competing the binding of VEGF with specific neutralizing anti-VEGF antibody. VEGF inhibitors include pegatanib sodium,

ranibizumab Ranibizumab, sold under the brand name Lucentis among others, is a monoclonal antibody fragment ( Fab) created from the same parent mouse antibody as bevacizumab. It is an anti-angiogenic that is approved to treat the "wet" type of age-related ...

, and off-label bevacizumab are currently used for treatment of various retinal disease. Anti-VEGF antibodies such as the application of ranibizumab or bevacizumab have has been shown to reduce corneal neovascularization. Both ranibizumab and bevacizumab uses the same mechanism and inhibits all iso-forms of VEGF. The significant reduction in invasion of in-growth blood vessels in terms of neovascular area and vessel caliber suggests that treatment with ranibizumab induces thinning of the blood vessels, however, there's no significant change of the blood vessel's length. Using anti-VEGF antibodies to treat CNV has some limitations such as it is not a cure and may require repeated treatments to maintain positive effects over time. Topical and/or subconjunctival administration of bevaicizumab or ranibizumab have demonstrated short-term safety and efficacy, however long term effects have not been documented. Anti-VEGF therapy is currently an experimental treatment. If the cornea is inflamed via corneal neovascularization, the suppression of enzymes can block CNV by compromising with corneal structural integrity. Corneal neovascularization can be suppressed with a combination of orally administration of doxycycline and with topical corticosteroid. Surgical Options Invasive solutions for corneal neovascularization are reserved when the medical therapies do not provide the desired results. Invading blood tissues and ablating tissues in the cornea can be obstructed by the use of laser treatments such as Argon and Nd:YAG lasers. Irradiation and/or damages to adjacent tissues caused by the procedure can result in corneal

hemorrhage Bleeding, hemorrhage, haemorrhage or blood loss, is blood escaping from the circulatory system from damaged blood vessels. Bleeding can occur internally, or externally either through a natural opening such as the mouth, nose, ear, urethra, v ...

and corneal thinning. Obstruction of the blood vessels can be unsuccessful due to the depth, size, and, high blood flow rate of the vessels. In conjunction, thermal damage from the lasers can trigger inflammatory response which can exaggerate the neovascularization. An effective treatment is

photodynamic therapy Photodynamic therapy (PDT) is a form of phototherapy involving light and a photosensitizing chemical substance, used in conjunction with molecular oxygen to elicit cell death (phototoxicity). PDT is popularly used in treating acne. It is used cl ...

, however, this treatment has limited clinical acceptance due to high costs and many potential complications involved that are also related to laser ablation. Complications can include irradiation from previously injected photosensitive dye inducing apoptosis and necrosis of the

endothelium The endothelium is a single layer of squamous endothelial cells that line the interior surface of blood vessels and lymphatic vessels. The endothelium forms an interface between circulating blood or lymph in the lumen and the rest of the vesse ...

and basement membrane. Diathermy and

cautery Cauterization (or cauterisation, or cautery) is a medical practice or technique of burning a part of a body to remove or close off a part of it. It destroys some tissue in an attempt to mitigate bleeding and damage, remove an undesired growth, or ...

is a treatment where an electrolysis needle is inserted into the feeder vessels in the limbus. The vessels are obstructed by a coagulating current through the use of unipolar diathermy unit or by thermal cautery.

Research

Reduction of neovascularization has been achieved in rats by the topical instillation of commercially available

triamcinolone Triamcinolone is a glucocorticoid used to treat certain skin diseases, allergies, and rheumatic disorders among others. It is also used to prevent worsening of asthma and COPD. It can be taken in various ways including by mouth, injection i ...

and doxycycline. Some evidence exists to suggest that the Angiotensin II receptor blocker drug

telmisartan Telmisartan, sold under the brand name Micardis among others, is a medication used to treat high blood pressure, heart failure, and diabetic kidney disease. It is a reasonable initial treatment for high blood pressure. It is taken by mouth ...

will prevent corneal neovascularization. Recent treatment developments include topical application of bevacizumab, an anti-VEGF.

References

External links

{{Eye pathology Disorders of sclera and cornea