Introduction and Background
The cornea remains transparent for many reasons. But the reason it is important to understand what is happening in a "blue eye" is that in a normal cornea, the collagen fibrils that make up the corneal stroma are uniformly spaced in a configuration that allows visible light to go through. While other tissues in the body have higher water contents, the cornea is only 78% water. This allows the collagen fibrils to maintain their optimal spacing. When excess water enters the cornea, it increases the space between the corneal fibrils, causing a wavelength-dependent decrease in light transmission through the cornea. This wavelength-dependent decrease is why the cornea not only turns cloudy when it is edematous, but it acquires a blueish hue as well.
As the cornea is surrounded by water (the tear film in front and the aqueous humor behind), the cornea must work very hard to regulate the water levels within its stroma. The outermost cells of the corneal epithelium have tight junctions between them. These junctions completely encircle each cell, and there is an anastomosis of the lipid bilayer so that the entire surface of the cornea is one large hydrophobic membrane. This keeps tears from hydrating the cornea.
Keeping the aqueous humor from entering the stroma is slightly more difficult since the fluid inside is under pressure. Additionally, the endothelial cells that line the posterior aspect of the cornea have leaky tight junctions between them. This allows aqueous humor to constantly percolate into the corneal stroma. To counter this, the endothelial cells constantly pump fluid against a pressure gradient out of the corneal stroma and back into the anterior chamber. Since this requires a lot of energy, endothelial cells are very active metabolically.
The endothelial cells contribute a lot more to maintaining dehydration of the cornea than do the epithelial cells. In fact, if the cornea is immersed in fluid and all the epithelium is removed, the cornea will only swell to twice its size. However, if the endothelium is removed, the cornea will swell to 5 times its size.
Knowing this, determining what is causing corneal edema becomes a simple exercise in determining what is damaging either the epithelium or the endothelium.
Common Causes of Corneal Edema
Corneal ulcers will allow the tear film to come in contact with the stroma. However, corneal ulcers do not typically involve the entire surface of the cornea, and, because the epithelium contributes significantly less to corneal dehydration than does the endothelium, rarely does the amount of edema present with simple ulcers become severe enough to cause significant opacity or to impart a "blue eye" appearance. A corneal ulcer can be diagnosed by applying fluorescein stain. Fluorescein stain will be taken up by the cornea in areas that are lacking epithelium.
As the intraocular pressure within the eye increases, water moves into the cornea at faster and faster rates. At the same time, as the intraocular pressure increases, the energy necessary for the endothelial cells to pump fluid back into the anterior chamber increases. Typically, at around 35–45 mm Hg, the endothelial cells cannot pump fluid out fast enough to keep up with the amount of water leaking into the cornea, resulting in the cornea taking on water and turning cloudy and blue. Glaucoma is diagnosed by measuring the intraocular pressure. Pressures higher than 25 mm Hg are typically associated with glaucoma. As glaucoma is a blinding disease and the damage is dependent on the amount of time the eye is glaucomatous, the nature of the glaucoma should be investigated at once (primary or secondary), and treatment to decrease the intraocular pressure should be started immediately. Because glaucoma can present with corneal edema, any dog presenting with a blue eye should be treated as an emergency until glaucoma can be ruled out.
Inflammation of the uvea leads to the release of inflammatory mediators into the aqueous humor. The aqueous humor is the main source of nutrients for the endothelial cells. These inflammatory mediators and inflammatory products lead to an increase in the permeability of the endothelial cells as well as an impairment of the pumping mechanisms responsible for removing fluid from the stroma. Anterior uveitis is diagnosed by examining the aqueous humor and detecting aqueous humor flare, cells, or blood. The most common cause of uveitis in dogs and cats is idiopathic. Other common causes of uveitis include tickborne diseases (ehrlichiosis, Rocky Mountain spotted fever), fungal diseases (blastomycosis, cryptococcosis, histoplasmosis), neoplastic (lymphosarcoma, intraocular tumors), and protozoal, or algal diseases. Because of the possibility of these systemic diseases causing uveitis, every animal with uveitis should have a systemic workup to try to rule out these causes.
Natural infection with canine adenovirus type I leads to a type III hypersensitivity reaction resulting in uveal inflammation as well as destruction of endothelial cells. This also occurs, although at a much lower rate, with vaccination. Currently, vaccines use canine adenovirus type II antigens to protect against infectious canine hepatitis. This decreases the incidence of edema to less than 1%. Diagnosis is based on a history of infectious canine hepatitis, recent vaccination, and lack of other causes of corneal edema.
Anterior Lens Luxation
Luxation of the lens into the anterior chamber can cause corneal edema by two mechanisms. Firstly, the lens can cause mechanical damage to the endothelial cells. Typically, this results in a focal area of corneal edema just around the area where the anterior lens capsule is touching the back of the cornea. Secondly, anterior lens luxations can result in secondary glaucoma. This will cause corneal edema as described under the glaucoma section. An anterior lens luxation is diagnosed by seeing the lens in the anterior chamber. Elevated intraocular pressure due to an anterior lens luxation constitutes a surgical emergency if vision is to be maintained.
There are several drugs that have been associated with the development of corneal edema due to corneal endothelial damage. These include chlorpromazine, lortalamine, and tocainide, among others.
Intraocular surgery, chronic uveitis, chronic anterior lens luxations, or old age can lead to the death of corneal endothelial cells. The remaining endothelial cells can compensate to a certain point. However, when this threshold is reached, corneal edema occurs.
Certain dog breeds (most notably Boston Terriers, Chihuahuas, and Dachshunds) have congenital defects that lead to early endothelial cell death. Typically these dogs will exhibit localized corneal edema in the dorsal temporal quadrant of the cornea that then spreads to the entire cornea. Dogs are usually middle aged at the time of onset. Endothelial dystrophy is diagnosed by excluding all other causes of corneal edema in a dog of the appropriate age and breed.
Treatment of Corneal Edema
If there is an underlying cause such as glaucoma, uveitis, corneal ulceration, or a lens luxation, it should be treated. Unless there has been extensive damage to the endothelium, once the underlying cause is removed, the edema will resolve.
In cases of endothelial degeneration or dystrophy, there is no treatment that will reliably decrease the edema and regain corneal clarity. The corneal transplants performed in humans for these conditions are currently not highly successful in dogs and cats. Therefore, treatment is aimed at decreasing discomfort associated with endothelial dysfunction. The major complication associated with corneal edema is the formation of bullae that then rupture, leaving a corneal ulcer.
Topical Hypertonic Saline (5%)
Besides treating the ulcers symptomatically when they occur, a medical therapy that may help decrease the number of bullae and the subsequent ulceration associated with them, is the frequent application of hypertonic saline solution or ointment. It may not be tolerated by some dogs due to its stinging sensation on instillation.
Thermokeratoplasty has been shown to decrease the number of ulcerations associated with bullous keratopathy. A low temperature ophthalmic cautery probe is used to make many pinpoint anterior stromal scars. These scars, theoretically, decrease the number of bullae that are able to form. This procedure does not improve the corneal clarity, and its only goal is to decrease the rate of ulceration.
Corneal edema has a characteristic appearance and is caused by a specific set of differentials: corneal ulceration, glaucoma, anterior lens luxation, anterior uveitis, or endothelial cell loss. Some of these differentials will cause blindness if not treated immediately and appropriately. Therefore, dogs with corneal edema should be handled as an emergency which could result in permanent vision loss until glaucoma or a lens luxation can be ruled out. Treatment of endothelial cell insufficiency is aimed at maintaining a comfortable eye and decreasing the incidence of ulcer formation.