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 pegatanib sodium, ranibizumab, 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 s. 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.

Reduction of neovascularization has been achieved in rats by the topical instillation of commercially available triamcinolone and doxycycline.

Some evidence exists to suggest that the Angiotensin II receptor blocker drug telmisartan will prevent corneal neovascularization.

Recent treatment developments include topical application of bevacizumab, an anti-VEGF.

CNV is conventionally treated with intravitreal injections of angiogenesis inhibitors (also known as "anti-VEGF" drugs) to control neovascularization and reduce the area of fluid below the retinal pigment epithelium. Angiogenesis inhibitors include pegaptanib, ranibizumab and bevacizumab (known by a variety of trade names, such as Macugen, Avastin or Lucentis). These inhibitors slow or stop the formation of new blood vessels (angiogenesis), typically by binding to or deactivating the transmission of vascular endothelial growth factor ('VEGF'), a signal protein produced by cells to stimulate formation of new blood vessels. The effectiveness of angiogenesis inhibitors has been shown to significantly improve visual prognosis with CNV, the recurrence rate for these neovascular areas remains high.

CNV may also be treated with photodynamic therapy coupled with a photosensitive drug such as verteporfin (Visudyne). The drug is given intravenously. It is then activated in the eye by a laser light. The drug destroys the new blood vessels, and prevents any new vessels forming by forming thrombi.

A meta-analysis found evidence that does not support the use of patching.

Given that episodes tend to occur on awakening and managed by use of good 'wetting agents', approaches to be taken to help prevent episodes include:

- Environmental:

- ensuring that the air is humidified rather than dry, not overheated and without excessive airflow over the face. Also avoiding irritants such as cigarette smoke.

- use of protective glasses especially when gardening or playing with children.

- General personal measures:

- maintaining general hydration levels with adequate fluid intake.

- not sleeping-in late as the cornea tends to dry out the longer the eyelids are closed.

- Pre-bed routine:

- routine use of long-lasting eye ointments applied before going to bed.

- occasional use of the anti-inflammatory eyedrop FML (prescribed by an ophthalmologist or optometrist) before going to bed if the affected eye feels inflamed, dry or gritty

- use of a hyperosmotic (hypertonic) ointment before bed reduces the amount of water in the epithelium, strengthening its structure

- use the pressure patch as mentioned above.

- use surgical tape to keep the eye closed (if Nocturnal Lagophthalmos is a factor)

- Waking options:

- learn to wake with eyes closed and still and keeping artificial tear drops within reach so that they may be squirted under the inner corner of the eyelids if the eyes feel uncomfortable upon waking.

- It has also been suggested that the eyelids should be rubbed gently, or pulled slowly open with your fingers, before trying to open them, or keeping the affected eye closed while "looking" left and right to help spread lubricating tears. If the patient's eyelids feel stuck to the cornea on waking and no intense pain is present, use a fingertip to press firmly on the eyelid to push the eye's natural lubricants onto the affected area. This procedure frees the eyelid from the cornea and prevents tearing of the cornea.

Topical antibiotics may be reasonable.

One review has found that eye drops to numb the surface of the eye such as tetracaine improve pain; however, their safety is unclear. Another review did not find evidence of benefit and concluded there was not enough data on safety.

NSAID eye drops are also useful. A 2000 review found no good evidence to support medications that paralyze the iris. A 2017 review did not find evidence to suggest that topical NSAIDs would significantly reduce pain over standard-of-care treatments, but did find that NSAIDs could be associated with people using fewer pain medications by mouth.

The treatment of corneal perforation depends on the location, severity and the cause of damage

- Tissue adhesive can be used to seal small perforation, but this method cannot be used to treat perforations larger than 1 mm.

- Non infected corneal perforation generally heals when a pressure bandage is used.

- For certain types of corneal perforations, lamellar keratoplasty is used as treatment.

Early diagnosis, targeted treatment according to the severity of the disease, and regular monitoring of patients with neurotrophic keratitis are critical to prevent damage progression and the occurrence of corneal ulcers, especially considering that the deterioration of the condition is often poorly symptomatic.

The purpose of treatment is to prevent the progression of corneal damage and promote healing of the corneal epithelium. The treatment should always be personalized according to the severity of the disease. Conservative treatment is typically the best option.

In stage I, the least serious, treatment consists of the administration of preservative-free artificial tears several times a day in order to lubricate and protect the ocular surface, improving the quality of the epithelium and preventing the possible loss of transparency of the cornea.

In stage II, treatment should be aimed at preventing the development of corneal ulcers and promoting the healing of epithelial lesions. In addition to artificial tears, topical antibiotics may also be prescribed to prevent possible infections. Patients should be monitored very carefully since, being the disease poorly symptomatic, the corneal damage may progress without the patient noticing any worsening of the symptoms. Corneal contact lenses can also be used in this stage of the disease, for their protective action to improve corneal healing.

In the most severe forms (stage III), it is necessary to stop the progression towards corneal perforation: in these cases, a possible surgical treatment option is tarsorrhaphy, i.e. the temporary or permanent closure of the eyelids by means of sutures or botulinum toxin injection. This protects the cornea, although the aesthetic result of these procedures may be difficult to accept for patients. Similarly, a procedure that entails the creation of a conjunctival flap has been shown to be effective in the treatment of chronic corneal ulcers with or without corneal perforation. In addition, another viable therapeutic option is amniotic membrane graft, which has recently been shown to play a role in stimulating corneal epithelium healing and in reducing vascularisation and inflammation of the ocular surface . Other approaches used in severe forms include the administration of autologous serum eye drops.

Research studies have focused on developing novel treatments for neurotrophic keratitis, and several polypeptides, growth factors and neuromediators have been proposed[25]. Studies were conducted on topical treatment with Substance P and IGF-1 (insulin-like growth factor-1), demonstrating an effect on epithelial healing[26]. Nerve Growth Factor (NGF) play a role in the epithelial proliferation and differentiation and in the survival of corneal sensory nerves. Topical treatment with murine NGF showed to promote recovery of epithelial integrity and corneal sensitivity in NK patients[27]. Recently, a recombinant human nerve growth factor eye drop formulation has been developed for clinical use[28].

Cenegermin, a recombinant form of human NGF, has recently been approved in Europe in an eye drop formulation for neurotrophic keratitis.

If caught early, the neovascularization can be reversed with prompt pan retinal photocoagulation (PRP), or injection of anti-VEGF medications with subsequent PRP. The injection blocks the direct effect of VEGF and acts more quickly but will wear off in about 6 weeks. PRP has a slower onset of action but can last permanently. Once the neovascularization has been longstanding, the new vessels recruit fibrous tissue, and as this forms and contracts, the angle can be permanently damaged, and will not respond to treatment. If this occurs, then surgical intervention is required to reduce the pressure (such as a glaucoma drainage implant)

It is important to distinguish between treatment of the underlying inflammation (PIC) and the treatment of CNV.

2-pronged approach:

Treatment is not always necessary and observation may be appropriate for lesions if they are found in non-sight threatening areas (that is not centrally).

Active lesions of PIC can be treated with corticosteroids taken systemically (tablets) or regionally by injections around the eye (periorbital). It has been argued that treating lesions in this way may help minimise the development of CNV.

The treatment of CNV:

Early treatment is required for this complication. There are several possible treatment methods, but none of these treatments appears to be singly effective for the treatment of CNV.

1. Corticosteroids: systemic or intraocular

2. ‘Second line’ immunosuppressants: There is evidence that combined therapies of steroids and second line immunosuppressants may be important.

3. Surgical excision of the affected area in well selected cases.

4. Intravitreal anti-VEGF agents. Examples are bevacizumab (avastin) and ranibizumab. These relatively new drugs are injected into the eye.

5. Photodynamic therapy (PDT): A photosensitive drug is ‘activated’ by strong light. Consideration may be given to combined therapy of PDT and anti VEGF.

6. Laser photocoagulation: This is occasionally used unless the CNV is subfoveal (affecting the central or macular part of the vision). The laser treatment can damage the vision.

The use of the intravitreal anti VEGF agents namely bevacizumab and ranibizumab have been described recently. The current evidence supporting the use of anti-VEGF agents is based on retrospective case studies and could not be described as strong. However, further data from prospective controlled trials are needed before the therapeutic role of anti-VEGF therapy in the uveitis treatment regimen can be fully determined. The anti VEGF agents furthermore have not been shown to have an anti-inflammatory effect.

Thus, treatment of the underlying inflammatory disease should play a central role in the management of uveitic CNV. A two-pronged treatment that focuses on achieving control of inflammation through the use of corticosteroids and/or immunosuppressive agents, while treating

complications that arise despite adequate disease control with intravitreal anti-VEGF agents, may be useful.

Regular monitoring is essential to achieve a good outcome. This is because even if there is no active inflammation, there may still be occult CNV which requires treatment to avoid suffering vision loss.

The visual prognosis of eyes with PIC that do not develop subfoveal CNV is good. If CNV is picked up early and treated appropriately then the visual outcome can also be good. Frequent monitoring is important to ensure a good outcome. Poor vision occurs mostly with subfoveal CNV or if subretinal fibrosis (scarring) has formed.

The above information comes from a Fact sheet produced by the Uveitis Information Group May 2011. It has been factually checked by a member of the charity's Professional Medical Panel.

Treatment options include contact lenses, intrastromal corneal ring segments, corneal collagen cross-linking, or corneal transplant.

When cross-linking is performed only after the cornea becomes distorted, vision remains blurry even though the disease is stabilised. As a result, combining corneal collagen cross-linking with LASIK ('LASIK Xtra') aims to strengthen the cornea at the point of surgery and may be useful in cases where a very thin cornea is expected after the LASIK procedure. This would include cases of high spectacle power and people with thin corneas before surgery. Definitive evidence that the procedure can reduce the risk of corneal ectasia will only become available a number of years later as corneal ectasia, if it happens, usually occurs in the late post-operative period. Some study show that combining LASIK with cross-linking adds refractive stability to hyperopic treatments and may also do the same for very high myopic treatments.

In 2016, the FDA approved the KXL system and two photoenhancers for the treatment of corneal ectasia following refractive surgery.

The effect is normally temporary and after a period of six to eight weeks, the cornea usually returns to its former transparency. The recovery can be aided nonsurgically by bandaging with an osmotic saline solution. Non-steroidal anti-inflammatory topical may be used to reduce the pain and inflammation.

With the eye generally profusely watering, the type of tears being produced have little adhesive property. Water or saline eye drops tend therefore to be ineffective. Rather a 'better quality' of tear is required with higher 'wetting ability' (i.e. greater amount of glycoproteins) and so artificial tears (e.g. viscotears) are applied frequently. Also recommended is Muro 128 5% Ointment (Sodium Chloride Hypertonicity Ophthalmic Ointment, 5%) which is a great relief overnight, it lasts longer than most regular tears and provides protection for those with severe cases.

Nocturnal Lagophthalmos (where one’s eyelids don’t close enough to cover the eye completely during sleep) may be an exacerbating factor, in which case using surgical tape to keep the eye closed at night can help.

Whilst individual episodes may settle within a few hours or days, additional episodes (as the name suggests) will recur at intervals.

Where episodes frequently occur, or there is an underlying disorder, one medical, or three types of surgical curative procedures may be attempted:

use of therapeutic contact lens, controlled puncturing of the surface layer of the eye (Anterior Stromal Puncture) and laser phototherapeutic keratectomy (PTK). These all essentially try to allow the surface epithelium to reestablish with normal binding to the underlying basement membrane, the method chosen depends upon the location & size of the erosion.

Consumption of dark fleshed fish containing dietary omega-3 fatty acids is associated with a decreased incidence of dry eyes syndrome in women. This finding is consistent with postulated biological mechanisms. Early experimental work on omega-3 has shown promising results when used in a topical application or given orally. A randomized, double-masked study published in 2013 to evaluate the effects of a triglyceride of DHA (Omega-3; Brudy Sec 1.5), showed significant results compared to other methods that are being used.

The underlying cause must be treated as soon as possible to stop the disease process. Corticosteroid drop can be used to minimize the scarring on the cornea along with antibiotic cover. However, residual scarring cannot be avoided which can result in long term visual impairment and corneal transplantation is not suitable due to high rejection rate from the corneal vascularization.

Previous long-standing eye infection which possibly during childhood time recalled as being treated with antibiotic and/or hospitalized over long period of time.

Treatment requires careful consideration of angiographic findings when a choroidal neovascular membrane is suspected which is a condition that responds to treatment. A vitreo-retinal specialist (an ophthalmologist specialized in treatment of retinal diseases) should be consulted for proper management of the case.

Presumed ocular histoplasmosis syndrome and age-related macular degeneration (AMD) have been successfully treated with laser, anti-vascular endothelial growth factors and photodynamic therapy. Ophthalmologists are using anti-vascular endothelial growth factors to treat AMD and similar conditions since research indicates that vascular endothelial growth factor (VEGF) is one of the causes for the growth of the abnormal vessels that cause these conditions.

Several other corneal ectatic disorders also cause thinning of the cornea:

- Keratoglobus is a very rare condition that causes corneal thinning primarily at the margins, resulting in a spherical, slightly enlarged eye. It may be genetically related to keratoconus.

- Pellucid marginal degeneration causes thinning of a narrow (1–2 mm) band of the cornea, usually along the inferior corneal margin. It causes irregular astigmatism that, in the early stages of the disease can be corrected by spectacles. Differential diagnosis may be made by slit-lamp examination.

- Posterior keratoconus, a distinct disorder despite its similar name, is a rare abnormality, usually congenital, which causes a nonprogressive thinning of the inner surface of the cornea, while the curvature of the anterior surface remains normal. Usually only a single eye is affected.

- Post-LASIK ectasia is a complication of LASIK eye surgery.

CNV can occur rapidly in individuals with defects in Bruch's membrane, the innermost layer of the choroid. It is also associated with excessive amounts of Vascular endothelial growth factor (VEGF). As well as in wet macular degeneration, CNV can also occur frequently with the rare genetic disease pseudoxanthoma elasticum and rarely with the more common optic disc drusen. CNV has also been associated with extreme myopia or malignant myopic degeneration, where in choroidal neovascularization occurs primarily in the presence of cracks within the retinal (specifically) macular tissue known as lacquer cracks.

Topical ciclosporin (topical ciclosporin A, tCSA) 0.05% ophthalmic emulsion is an immunosuppressant. The drug decreases surface inflammation. In a trial involving 1200 people, Restasis increased tear production in 15% of people, compared to 5% with placebo.

It should not be used while wearing contact lenses, during eye infections or in people with a history of herpes virus infections. Side effects include burning sensation (common), redness, discharge, watery eyes, eye pain, foreign body sensation, itching, stinging, and blurred vision. Long term use of ciclosporin at high doses is associated with an increased risk of cancer.

Cheaper generic alternatives are available in some countries.

The main goals of treatment are to decrease the risk of rebleeding within the eye, corneal blood staining, and atrophy of the optic nerve. Small hyphemas can usually be treated on an outpatient basis. Most treatment plans consist of elevating the head at night, wearing a patch and shield, and controlling any increase in intraocular pressure. Surgery may be necessary for non-resolving hyphemas, or hyphaemas that are associated with high pressure that does not respond to medication. Surgery can be effective for cleaning out the anterior chamber and preventing corneal blood staining.

Elevation of the head of the bed by approximately 45 degrees (so that the hyphema can settle out inferiorly and avoid obstruction of vision, as well as to facilitate resolution). Bedrest may be considered, although evidence suggests that it does not improve outcomes. Wearing of an eye shield at night time (to prevent accidental rubbing of the eyes during sleep, which can precipitate a rebleed). An eye patch should be worn throughout the day to protect the injured eye.

If pain management is necessary, acetaminophen can be used. Aspirin and ibuprofen should be avoided, because they interfere with platelets' ability to form a clot and consequently increase the risk of additional bleeding. Sedation is not usually necessary for patients with hyphema. It is controversial amongst ophthalmologists whether a steroid medication or a dilating eye drop (mydriatic) should be used in treatment of hyphema. Steroids aim to reduce the amount of inflammation, but also cause side effects. Dilating drops aim to increase comfort from the traumatized iris as well as reduce bleeding, but can also cause the pupil to be fixed in a dilated state via posterior synechiae (adhesions).

Aminocaproic or tranexamic acids are often prescribed for hyphema. Although these medications actually cause hyphemas to take longer to clear, they reduce the risk of rebleeding and its associated complications. Tranexamic and aminocaproic acids inhibit the conversion of plasminogen to plasmin, plasmin being the agent of fibrin breakdown in blood clots. Keeping the clots intact allows time for the vessels to heal properly and avert a secondary bleed.

Corneal hydrops might be caused by a tear in the recently discovered Dua's layer, a 15 micron thick layer between the corneal stroma and Descemet’s membrane, Harminder Dua suggests that this finding will affect corneal surgery, including penetrating keratoplasty, and understanding of corneal dystrophies and pathologies, such as acute hydrops.

Corneal collagen cross-linking is a developing treatment which aims to strengthen the cornea, however, according to a 2015 Cochrane review, there is insufficient evidence to determine if it is useful in keratoconus.

In 2016, the US Food and Drug Administration approved riboflavin ophthalmic solution and KXL system for crosslinking based on three 12-month clinical trials.

Non-surgical treatments of FCED may be used to treat symptoms of early disease. Medical management includes topical hypertonic saline, the use of a hairdryer to dehydrate the precorneal tear film, and therapeutic soft contact lenses. Hypertonic saline draws water out of the cornea through osmosis. When using a hairdryer, the patient is instructed to hold it at an arm's length or directed across the face on a cold setting, to dry out the epithelial blisters. This can be done two or three times a day. Definitive treatment, however, (especially with increased corneal edema) is surgical in the form of corneal transplantation. The most common types of surgery for FCED are Descemet's stripping automated endothelial keratoplasty (DSAEK) and Descemet's membrane endothelial keratoplasty (DMEK), which account for over half of corneal transplants in the United States.

More speculative future directions in the treatment of FED include in-vitro expansion of human corneal endothelial cells for transplantation, artificial corneas (keratoprosthesis) and genetic modification. Surgery where the central diseased endothelium is stripped off but not replaced with donor tissue, with subsequent Rho-Associated Kinase (ROCK) inhibition of endothelial cell division may offer a viable medical treatment.

A greater understanding of FED pathophysiology may assist in the future with the development of treatments to prevent progression of disease. Although much progress has been made in the research and treatment of FED, many questions remain to be answered. The exact causes of illness, the prediction of disease progression and delivery of an accurate prognosis, methods of prevention and effective nonsurgical treatment are all the subject of inquiries that necessitate an answer.

Increased attention must be given to research that can address the most basic questions of how the disease develops: what are the biomolecular pathways implicated in disease, and what genetic or environmental factors contribute to its progression? In addition to shaping our understanding of FED, identification of these factors would be essential for the prevention and management of this condition.