Corneal neovascularization | |
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Blood vessels in the cornea | |
Specialty | Ophthalmology |
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. [1] Maintaining avascularity of the corneal stroma is an important aspect of healthy corneal physiology 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. [2]
Corneal neovascularization is a sight-threatening condition that can be caused by inflammation related to infection, chemical injury, autoimmune conditions, immune hypersensitivity, post-corneal transplantation, and traumatic conditions among other ocular pathologies. Common causes of CNV within the cornea include trachoma, corneal ulcers, phlyctenular keratoconjunctivitis, rosacea keratitis, interstitial keratitis, sclerosing keratitis, chemical burns, and wearing contact lenses for over-extended periods of time. [3] 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. [4]
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. [1]
In advanced stages, corneal neovascularization can threaten eyesight, which is why routine (annual) eye exams are recommended for contact lens patients. [4]
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. [1]
Some major acquired inflammatory conditions include graft rejection following keratoplasty, graft or host diseases of the new tissue, atopic conjunctivitis, rosacea, ocular pemphigoid, Lyell's syndrome, and Stevens–Johnson syndrome. [3]
Infections responsible for CNV range from the bacterial (chlamydia, syphilis, pseudomonas) and viral (e.g., herpes simplex & herpes zoster viruses) to the fungal (candida, aspergillus, fusarium) and parasitic (onchocerca volvolus). [1]
Degenerative diseases such as pterygiums and Terrien's marginal degeneration may also be responsible. [1]
Traumatic causes of CNV include ulceration, alkali burns, and stem cell deficiency. [1]
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) 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. [5]
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. [1]
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. [4]
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 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, cataracts, herpes simplex recurrence. The anti-inflammatory drugs, however, increase the risk of corneal ulceration and melting.
Since VEGF plays an important role in vasculogenesis 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 pegaptanib sodium, ranibizumab, and off-label bevacizumab are currently used for treatment of various retinal disease. [6] 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. [6] 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. [6] 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 bevacizumab or ranibizumab have demonstrated short-term safety and efficacy, [4] 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. [7] Irradiation and/or damages to adjacent tissues caused by the procedure can result in corneal hemorrhage 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, 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 and basement membrane.
Diathermy and cautery 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. [7]
Reduction of neovascularization has been achieved in rats by the topical instillation of commercially available triamcinolone and doxycycline. [8]
Some evidence exists to suggest that the Angiotensin II receptor blocker drug telmisartan will prevent corneal neovascularization. [2]
Recent treatment developments include topical application of bevacizumab, an anti-VEGF. [9]
The cornea is the transparent front part of the eye that covers the iris, pupil, and anterior chamber. Along with the anterior chamber and lens, the cornea refracts light, accounting for approximately two-thirds of the eye's total optical power. In humans, the refractive power of the cornea is approximately 43 dioptres. The cornea can be reshaped by surgical procedures such as LASIK.
Keratitis is a condition in which the eye's cornea, the clear dome on the front surface of the eye, becomes inflamed. The condition is often marked by moderate to intense pain and usually involves any of the following symptoms: pain, impaired eyesight, photophobia, red eye and a 'gritty' sensation. Diagnosis of infectious keratitis is usually made clinically based on the signs and symptoms as well as eye examination, but corneal scrapings may be obtained and evaluated using microbiological culture or other testing to identify the causative pathogen.
The corneal endothelium is a single layer of endothelial cells on the inner surface of the cornea. It faces the chamber formed between the cornea and the iris.
A red eye is an eye that appears red due to illness or injury. It is usually injection and prominence of the superficial blood vessels of the conjunctiva, which may be caused by disorders of these or adjacent structures. Conjunctivitis and subconjunctival hemorrhage are two of the less serious but more common causes.
Corneal transplantation, also known as corneal grafting, is a surgical procedure where a damaged or diseased cornea is replaced by donated corneal tissue. When the entire cornea is replaced it is known as penetrating keratoplasty and when only part of the cornea is replaced it is known as lamellar keratoplasty. Keratoplasty simply means surgery to the cornea. The graft is taken from a recently deceased individual with no known diseases or other factors that may affect the chance of survival of the donated tissue or the health of the recipient.
A scleral lens, also known as a scleral contact lens, is a large contact lens that rests on the sclera and creates a tear-filled vault over the cornea. Scleral lenses are designed to treat a variety of eye conditions, many of which do not respond to other forms of treatment.
A corneal ulcer, or ulcerative keratitis, is an inflammatory condition of the cornea involving loss of its outer layer. It is very common in dogs and is sometimes seen in cats. In veterinary medicine, the term corneal ulcer is a generic name for any condition involving the loss of the outer layer of the cornea, and as such is used to describe conditions with both inflammatory and traumatic causes.
Neovascularization is the natural formation of new blood vessels, usually in the form of functional microvascular networks, capable of perfusion by red blood cells, that form to serve as collateral circulation in response to local poor perfusion or ischemia.
Acanthamoeba keratitis (AK) is a rare disease in which amoebae of the genus Acanthamoeba invade the clear portion of the front (cornea) of the eye. It affects roughly 100 people in the United States each year. Acanthamoeba are protozoa found nearly ubiquitously in soil and water and can cause infections of the skin, eyes, and central nervous system.
Intravitreal administration is a route of administration of a drug, or other substance, in which the substance is delivered into the vitreous humor of the eye. "Intravitreal" literally means "inside an eye". Intravitreal injections were first introduced in 1911 when Ohm gave an injection of air into the vitreous humor to repair a detached retina. In the mid-1940s, intravitreal injections became a standard way to administer drugs to treat endophthalmitis and cytomegalovirus retinitis.
Rubeosis iridis is a medical condition of the iris of the eye in which new abnormal blood vessels are found on the surface of the iris.
Corneal ulcer, also called keratitis, 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 in farming. In developing countries, children afflicted by vitamin A deficiency are at high risk for corneal ulcer and may become blind in both eyes persisting throughout life. In ophthalmology, a corneal ulcer usually refers to having an infection, while the term corneal abrasion refers more to a scratch injury.
Choroidal neovascularization (CNV) is the creation of new blood vessels in the choroid layer of the eye. Choroidal neovascularization is a common cause of neovascular degenerative maculopathy commonly exacerbated by extreme myopia, malignant myopic degeneration, or age-related developments.
Herpetic simplex keratitis is a form of keratitis caused by recurrent herpes simplex virus (HSV) infection in the cornea.
Punctate inner choroiditis (PIC) is an inflammatory choroiditis which occurs mainly in young women. Symptoms include blurred vision and scotomata. Yellow lesions are mainly present in the posterior pole and are between 100 and 300 micrometres in size. PIC is one of the so-called White Dot Syndromes. PIC has only been recognised as a distinct condition as recently as 1984 when Watzke identified 10 patients who appeared to make up a distinct group within the White Dot Syndromes.
Aganirsen is a 25 mer DNA antisense oligonucleotide therapeutic inhibiting insulin receptor substrate-1 (IRS-1), which is being investigated as a topical treatment for ocular neovascularization. Aganirsen is a candidate for the treatment of ocular neovascularization in patients with front of the eye (cornea) or back of the eye (retinal) diseases, including progressive corneal neovascularization in patients with infectious keratitis and wet age related macular degeneration (AMD).
Mooren's ulcer is a rare idiopathic ocular disorder that may lead to blindness due to progressive destruction of the peripheral cornea. Although the etiology of Mooren's ulcer is poorly understood, recent evidence suggests that the pathogenesis of this disease appears to be the result of an autoimmune process directed against molecules expressed in the corneal stroma.
Neurotrophic keratitis (NK) is a degenerative disease of the cornea caused by damage of the trigeminal nerve, which results in impairment of corneal sensitivity, spontaneous corneal epithelium breakdown, poor corneal healing and development of corneal ulceration, melting and perforation. This is because, in addition to the primary sensory role, the nerve also plays a role maintaining the integrity of the cornea by supplying it with trophic factors and regulating tissue metabolism.
Exposure keratopathy is medical condition affecting the cornea of eyes. It can lead to corneal ulceration and permanent loss of vision due to corneal opacity.
Peripheral Ulcerative Keratitis (PUK) is a group of destructive inflammatory diseases involving the peripheral cornea in human eyes. The symptoms of PUK include pain, redness of the eyeball, photophobia, and decreased vision accompanied by distinctive signs of crescent-shaped damage of the cornea. The causes of this disease are broad, ranging from injuries, contamination of contact lenses, to association with other systemic conditions. PUK is associated with different ocular and systemic diseases. Mooren's ulcer is a common form of PUK. The majority of PUK is mediated by local or systemic immunological processes, which can lead to inflammation and eventually tissue damage. Standard PUK diagnostic test involves reviewing the medical history and a completing physical examinations. Two major treatments are the use of medications such as corticosteroids or other immunosuppressive agents and surgical resection of the conjunctiva. The prognosis of PUK is unclear with one study providing potential complications. PUK is a rare condition with an estimated incidence of 3 per million annually.
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