What Is Wrong With My Patient’s Cornea? Nonulcerative Keratitis in Veterinary Medicine

Keratitis is defined simply as an inflammation of the cornea. Keratitis may be caused by a number of disease conditions, including infection (bacterial, fungal, viral, parasitic, or protozoal), desiccation due to decreased tear production or excessive exposure, immune-mediated conditions, or trauma. Many types of keratitis can progress to ulceration of the cornea, but many are nonulcerative.

Keratitis cases can be confusing because many types of keratitis look similar. However, they can easily be distinguished with diagnostic testing. An accurate diagnosis is important as treatment of keratitis varies widely depending on the cause. Veterinary nurses can be immensely helpful in performing diagnostic tests in these patients.

This article reviews the clinical signs, diagnostic tests, classic appearance, and treatment for the most common nonulcerative keratitides in dogs, cats, and horses.

Corneal Anatomy and Physiology

A healthy cornea consists of 4 layers: the epithelium, the stroma, Descemet’s membrane, and the endothelium (FIGURE 1). Together, they are less than 1 mm thick, with the average canine cornea measuring 0.62 mm; the normal feline cornea, 0.74 mm; and the central equine cornea, 0.85 mm thick.^1,2 For reference, a dime is 1.35 mm thick.

Figure 1. The 4 layers of a healthy cornea: epithelium, stroma, Descemet’s membrane, and endothelium. Alexander_P/shutterstock.com; Alila Medical Media/shutterstock.com

The corneal epithelium is made of 5 to 7 layers of stratified, nonkeratinized squamous cells that can regenerate when injured. Corneal epithelium provides a barrier to chemicals, water, and microbes. The epithelium is hydrophobic (water-repelling); therefore, fluorescein stain does not adhere to it.

Beneath the epithelium lies the stroma, which is composed of fine, evenly spaced collagen fibers. The stroma is avascular and produces growth factors, extracellular matrix components, and kinases that are essential for corneal development and homeostasis. Unlike the epithelium, the stroma’s hydrophilic (water-absorbing) character allows fluorescein stain to adhere to it when there is a break in the epithelium. This identifies a corneal ulceration.

Descemet’s membrane is the basement membrane of the posterior epithelium. It is composed of collagen fibers and is made by the endothelial cells that lie below it. Descemet’s membrane also repels fluorescein stain. An ulcer that is completely through the stroma but has not perforated the cornea is called a descemetocele. (Breaks in Descemet’s membrane caused by stretching of the globe due to glaucoma are called Haab’s striae.) Descemetoceles are often described as “halos” or “donuts,” as the stroma on the sides of the ulcer take up stain and the deep center does not.

The deepest layer of the cornea, the endothelium, is a single cell layer thick and cannot regenerate. Sodium–potassium pumps in the endothelium are responsible for keeping excess fluid out of the cornea.

The cornea should remain clear and free of blood vessels and pigmentation. Anything that causes the cornea to become opaque is indicative of corneal disease.

Diagnostic Tests and Normal Values

Schirmer Tear Test and Fluorescein Stain

The first diagnostic test that should be performed on a patient with keratitis (unless the cornea is noticeably fragile) is a Schirmer tear test (STT). To perform this test:

• Bend the strips at the notch while they are still in the package.
• Open the package at the end opposite to the rounded end, which will be placed inside the lower eyelid.
• If there is a large amount of mucus in the conjunctival sac, gently remove it with gauze, but do not rinse, as this may artificially elevate the tear measurement.
• Place the rounded end of the strip inside the lower eyelid and leave it there for 60 seconds.
• At 60 seconds, remove the strip and read the distance the wetness (tears) has traveled.

A normal STT result in dogs is a distance greater than 15 mm/min.³ Opinions on normal STT results in cats and horses vary. One study reported the normal STT result for cats to be 11 to 13 mm/min.⁴ Another study that evaluated normal STT results in horses and ponies concluded that the distance should be greater than 35 mm/min.⁵

The second recommended diagnostic test in patients with suspected keratitis is applying fluorescein stain to check for an ulcer. Commercial fluorescein stain strips can be purchased from many distributors. To perform this test:

• Open the stain strip package at the end opposite to the end of the strip containing the stain.
• Apply a few drops of eye wash or saline to the portion of the strip containing the stain.
• Gently touch the moist end of the strip to the conjunctiva, taking care not to touch the strip directly to the cornea. Drops of stain may also be allowed to fall from the strip onto the cornea.

The examiner should then examine the cornea with a cobalt blue light in a dimly lit room. If there is excess stain on the cornea, rinsing will make it easier to determine if there is uptake. In patients with nonulcerative keratitis, the result of this test should be negative (i.e., no stain uptake).

Cytology

Cytologic sampling of corneal lesions is easy to perform and provides a wealth of information. However, it should be noted that cytology is not typically performed in nonulcerative keratitis cases. It is only useful for certain types of nonulcerative keratitis (e.g., eosinophilic keratitis, stromal abscess).⁶

Three main instruments can be used for collecting corneal cells: a Kimura spatula, the blunt end of a scalpel blade, or a cytology brush. The safest, most accurate instrument is a cytology brush. These are nonlinting, nonabsorbent, fiber-tipped brushes commonly used in human dental offices. After proparacaine (a topical anesthetic) has been applied to the cornea, the fiber tip of the brush is rolled back and forth over the lesion and then rolled onto a microslide. After the slide has been allowed to dry, it is stained in a commercial Romanowsky stain variant and examined under a microscope.⁷

Noncornified epithelial cells, lymphocytes, and neutrophils are normal cytology findings in corneal samples. The presence of any other cells is considered abnormal.⁸

Types of Nonulcerative Keratitis

Pigmentary Keratitis

Pigmentary keratitis is a chronic corneal irritation leading to melanin deposition in the cornea. Pugs are the most commonly represented breed; however, any brachycephalic breed is predisposed to this condition.⁹ In fawn pugs, pigment is often deposited on the cornea without any discernible cause. Pigmentary keratitis is not painful, but it can cause functional blindness if it progresses to cover the entirety of the cornea. Corneal pigment can often go unnoticed by owners, especially if the patient has dark-colored irises. An STT and fluorescein staining should be performed on any eye with pigment on the cornea.

Treatment options vary depending on the cause of the pigmentation and the opinion of the attending ophthalmologist. If there is a chronic physical irritant that can be removed, such as a nasal fold, trichiasis, entropion, or distichia, the recommendation would be to remove the irritant. If the pigment is due to chronic exposure, surgery can be performed to narrow the eyelid opening.

Medical treatment can include topical cyclosporine or tacrolimus to prevent further pigment deposition and possibly decrease the current pigmentation. However, most of these cases maintain the pigmentation that they have at the time of diagnosis.¹⁰

Keratoconjunctivitis Sicca

The tear film plays a particularly important role in maintaining corneal health and clarity. It helps keep a smooth ocular surface, trap bacteria, lubricate the cornea, and hydrate the conjunctiva. A significant decrease in tear production leads to corneal inflammation due to decreased nutrient supply to the epithelium and chronic desiccation. Corneal inflammation due to desiccation, or keratoconjunctivitis sicca (KCS), can result in dense scarring that causes functional blindness (FIGURE 2).

Figure 2. Dog with keratoconjunctivitis sicca. The cornea is dull and pigmented, and blood vessels are present.

An early sign of KCS is a dull, lackluster cornea. If the condition persists, the conjunctiva becomes inflamed, leading to a thick mucoid discharge that can become purulent if a secondary infection occurs. It is therefore important to perform an STT in patients that present with what appears to be primary conjunctivitis to diagnose KCS at an early stage.

As the disease progresses and the cornea endures more damage, corneal vascularization and pigmentation are noted. The patient may also present with corneal ulcers that can lead to further corneal scarring and complications, including secondary bacterial keratitis, descemetocele, and corneal perforation. Therefore, it is also important to check for ulcers with fluorescein stain in these patients.

Medical treatment of KCS consists of tear stimulants and tear replacements. Cyclosporine and tacrolimus are the current tear stimulants of choice.¹¹ These 2 drugs also have immunosuppressive properties to combat the secondary neovascularization and pigmentation that accompany KCS. Artificial tear ointment or nighttime dry-eye lubricants are recommended for use between doses of tear stimulants.

If medical treatment is not possible or the patient does not respond to medication, a surgical procedure, parotid duct transposition, can be performed. This procedure relocates the parotid duct of the salivary gland to the conjunctival sac so that the patient salivates on their cornea. This procedure has potential complications; therefore, all other medical options should be exhausted before it is performed.

Eosinophilic Keratitis

Eosinophilic keratitis (EK) is a condition affecting cats and horses that has become more prevalent in the last 20 years.¹² The clinical appearance is similar in both species: a white, “chunky,” raised lesion on 1 or both corneas (FIGURE 3). It may be confused with squamous cell carcinoma (SCC), especially in horses.

Figure 3. Cat with dorsolateral eosinophilic keratitis. White eosinophilic plaques and blood vessels are present, and the cornea is opaque.

The lesion usually appears under the third eyelid or in the ventral cornea in horses and is dorsolateral in cats. The patient may be mildly to moderately uncomfortable and may have mild conjunctival hyperemia. In horses, EK can also involve the conjunctiva and third eyelid, again making it easily confused with SCC. It may also present as a superficial yellow infiltrate at the limbus.

EK is diagnosed by finding eosinophils in a cytology sample of the lesion. Even just 1 eosinophil on the slide confirms the diagnosis of EK. Obtaining a cytology sample of the lesion is particularly important to distinguish between EK, SCC, and a stromal abscess. Patients with EK should have the cornea stained to be sure there is no corneal ulcer, particularly before and during treatment with topical steroids.

EK can be treated with topical medications. Topical steroids are often used to initially control the condition quickly. Topical cyclosporine has also been used for its immune-modulating effect. Results vary, but adverse effects are minimal.¹³

Topical megestrol acetate has been shown to have success at controlling the lesions in cats without the significant side effects of systemic megestrol acetate.¹⁴ Megestrol acetate is a synthetic progestin that has the same physiologic effects as natural progesterone. Megestrol acetate was originally used in cats to postpone and prevent estrus. It was noticed that it also cleared up eosinophilic granuloma complex; therefore, it was tested as an EK treatment in cats. Systemic adverse effects of systemic megestrol acetate include the development of mammary gland tumors and diabetes mellitus; therefore, a study between Purdue University and Angell Animal Medical Center investigated the use of a topical formulation. It found that a compounded 0.5% solution resulted in the resolution of the EK and no systemic adverse effects.¹⁴

The author could not find any reports of using megestrol acetate to treat EK in horses. Medical therapy with steroids or immune modulators has been successful. Surgical removal of the lesions has also been reported.¹⁵

Exposure Keratitis

As with pigmentary keratitis, exposure keratitis involves corneal pigmentation resulting from melanin deposition due to chronic exposure of the cornea. The sequelae are similar to those of pigmentary keratitis.

These patients should have an STT and fluorescein stain performed. Exposure keratitis may be a diagnosis of exclusion and based on owner history and conformation of the patient’s head. If the patient has normal tears, does not have mechanical irritation, does not blink fully, and/or has exophthalmic or buphthalmic eye(s), it most likely has exposure keratitis.

Topical lubrication is the prescribed medical therapy. Cyclosporine or tacrolimus can be used to see if the pigmentation will improve. A medial canthoplasty (permanently decreasing the palpebral opening at the medial canthus) is a surgical option that can be performed in young patients with breed-related exophthalmos (e.g., Shih Tzus, pugs). The goal of this procedure is to prevent secondary inflammation by reducing the corneal exposure. As exophthalmic breeds are also predisposed to proptosis, the surgery can also decrease the chances of globe displacement.

Herpes Keratitis

Cats with keratitis should be assumed to have herpes until proven otherwise. Feline herpesvirus is extremely common and extremely contagious. More than 90% of cats carry herpesvirus.¹⁶ Once infected, the cat is infected for life and any amount of stress can cause a flare-up. Although many cats present with corneal ulcers, they can have nonulcerative keratitis as well.

A cat with a herpes flare-up will most likely present with epiphora and blepharospasm. The conjunctiva will likely be swollen and hyperemic, also known as chemosis. The cornea should be fluorescein stained to check for ulcers. A conjunctival and/or corneal cytology sample may also be collected to rule out EK or primary bacterial conjunctivitis.

After several or chronic persistent flare-ups of herpesvirus, the cornea can have chronic changes, including neovascularization, inflammatory cell infiltration, pigment, and scarring. Other nonulcerative corneal changes due to herpesvirus include symblepharon, sequestrum formation, and calcific band keratopathy.

Definitive diagnosis requires polymerase chain reaction or virus isolation testing. An educated assumption can be made from history, clinical signs, and response to treatment. As noted, assumption of herpesvirus should be standard for cats with keratitis.

Treatment of feline herpes keratitis can be challenging at best. The goal of treatment is to manage the clinical signs rather than to treat the disease. There are multiple antiviral choices, both topical and systemic. Topical cidofovir has been shown to significantly decrease ocular herpesvirus shedding.¹⁷ Cats have variable responses to these types of medications; therefore, what works for one cat may not work for the next. Owner compliance with giving the medications as well as decreasing environmental stress is very important.

Acute Bullous Keratopathy

Bullous keratopathy is a common nonulcerative (or ulcerative) keratitis in cats. Bullous keratopathy appears as a giant, fluid-filled bubble in the cornea (FIGURE 4). These cases should be stained with fluorescein to be sure that there is no ulcer. Treatment for bullous keratopathy is typically a third eyelid flap or temporary tarsorrhaphy to put pressure on the cornea. Sometimes, these cases present with ulceration and require conjunctival grafting surgery. Topical antibiotics should also be part of the treatment plan.¹⁸

Figure 4. Cat with bullous keratopathy. Corneal edema is present, making the cornea dome shaped.

Stromal Abscess

Stromal abscesses can happen in any species but are most often seen in horses. Stromal abscesses in horses are most commonly caused by fungus but can be bacterial or even sterile. Fungal hyphae have been found in up to 70% of surgical biopsy samples.¹⁹

Horses with stromal abscesses are painful or are reported as being painful on and off. Generally, the history is of an eye with a healed corneal ulcer that suddenly became painful again and still has a corneal opacity. The eye will have a focal white to yellow cellular infiltrate. Fluorescein stain will be negative because the epithelium has healed the initial injury.

A corneal cytology sample should be obtained for culture. Because the epithelium is intact, it may be unrewarding. A deeper sample can be collected by performing a superficial keratectomy with standing sedation, local blocks, and topical anesthetic. This procedure also gives topical medications a greater chance of reaching the abscess.

Surgical treatment is often recommended. Multiple surgical techniques are used, but they all involve opening the abscess and placing one of several grafts. Medical treatment is necessary regardless of surgery. If a cytology sample and/or culture cannot be obtained, a broad-spectrum antibiotic should be used. Both topical and systemic antibiotics are appropriate. Topical medications should be able to penetrate the intact epithelium. Depending on the local climate, systemic and topical antifungals may also be indicated. Topical atropine to relieve ciliary spasm and systemic nonsteroidal anti-inflammatory drugs are commonly recommended to increase comfort and alleviate secondary uveitis.²⁰ Intralesional injections of voriconazole have also been reported to have success.²¹ Subconjunctival injections of amphotericin B can be given in addition to other topical and systemic medications.²²

Immune-Mediated Keratitis

Immune-mediated keratitis (IMMK) describes any noninfectious, nonulcerative, presumed immune-inflammatory corneal disease. The following are included in the IMMK group.

Pannus

Pannus, or chronic superficial keratitis, is an IMMK seen primarily in German shepherds. Other breeds reported to develop pannus include border collies, greyhounds, and other shepherd breeds. Pannus is thought to be related to ultraviolet (UV) radiation. It is generally not a painful condition.

Pannus begins as vessels or a red/pink plaque that usually starts laterally and progresses toward the center of the cornea (FIGURE 5). Pigmentation of the cornea tends to accompany the plaque. Left untreated, the vascularization and pigmentation can cause functional blindness.

Figure 5. Dog with early pannus. Blood vessels and opacity are visible at the lateral aspect of the cornea.

As with the other keratitides, an STT and fluorescein stain should be performed during the ophthalmic examination. Diagnosis is based on clinical presentation and signalment.

The treatment of choice is topical steroids or topical immunosuppressants.²³ If the condition is caught early, treatment can be started with cyclosporine. If it has significantly progressed, steroids are often necessary to quickly improve the lesions before switching to cyclosporine for long-term maintenance. There is no cure, and the goal of treatment is to maintain the dog on the lowest number of drops that maintains control and reduces flare-ups. UV-protective goggles are also recommended for dogs that are often outside or live at higher elevations, if the dog will tolerate wearing them. One retrospective study showed that living at a higher altitude significantly increased the risk of developing pannus.²⁴

Superficial Punctate Keratitis

Superficial punctate keratitis (SPK) is a less common condition almost exclusively found in dachshunds. Dogs usually present with ocular discomfort, blepharospasm, and epiphora. SPK is primarily bilateral.

On close examination of the cornea, diffuse, multiple opacities that may or may not be ulcerated are seen. Therefore, it is important to fluorescein stain the cornea. If left untreated, the cornea becomes diffusely opaque and possibly pigmented. Diagnosis is made based on signalment and clinical signs. Treatment is generally topical steroids if there is no ulceration. Some doctors treat this condition with cyclosporine instead of steroids so that if the cornea does become ulcerated, it will not complicate the healing.²⁵

Immune-Mediated Keratitis in Dogs

IMMK lesions in dogs resemble corneal dystrophy or corneal degeneration. They are round to oval and white to gray in color. When examined under magnification, multiple clusters of corneal infiltrates are seen. An STT and fluorescein stain should be performed. The treatment of choice is immunosuppressants, with 0.03% tacrolimus having been shown to have better effect than 0.2% cyclosporine.²⁶

Immune-Mediated Keratitis in Horses

IMMK is a common finding in horses with nonulcerative corneal disease and discomfort. It is categorized depending on where in the cornea the lesions are found. The cornea will have variable opacity and vascularization (FIGURE 6). These eyes should be fluorescein stained to look for corneal ulceration before and during treatment.

Figure 6. Horse with immune-mediated keratitis. Blood vessels and edema are present medially.

Treatment differs based on the location of the lesions; however, most cases are treated with a topical immunosuppressant. Because continued treatment is difficult, if the eye responds to cyclosporine, subconjunctival cyclosporine implants that slowly release the medication can be surgically placed.²⁷ These implants work best for horses with superficial and endothelial IMMK. The cyclosporine implants are reported to be effective for 12 to 18 months.²⁷

Summary

Nonulcerative keratitides can easily be misdiagnosed as they can look very similar. All patients should have a complete ophthalmic examination with STT, fluorescein stain, and detailed examination of the cornea for subtle changes like vascularization, opacity, pigmentation, bullae, or dullness. Early detection of keratitis can change the outcome of treatment. The veterinary nurse plays an integral role in the ophthalmic examination, from obtaining a thorough history to performing diagnostic tests.