Feline corneal diseases: herpesvirus and more (Proceedings)

Herpesvirus Infections - Overview

Ocular disease due to feline herpesvirus (FHV) is common. It is estimated that 80% of cats are latently infected with the virus, and approximately 40% of these cats will suffer recrudescent infection in later life. These estimates are based on data that is several decades old, and the actual percentages may be higher. FHV affects cats of all ages, but the initial (or primary) infection usually occurs in neonatal and adolescent cats. Symptoms include bilateral conjunctivitis, respiratory disease, and fever. Most cats recover from the primary infection in 7-10 days without specific antiviral treatment, but neonatal cats are more likely to suffer serious corneal and conjunctival scarring. Recrudescent infection can be unilateral or bilateral and with or without respiratory signs. Unilateral conjunctivitis or ulcerative keratitis in the absence of respiratory signs is common in adult cats with recrudescent infection. Stress appears to be an important factor in precipitating FHV. "Stressful" events may include topical or systemic corticosteroids, concurrent systemic disease, anesthesia, hospitalization, acquisition of a new cat, or extended owner absences (e.g., vacation). Other conditions that may be associated with FHV include non-ulcerative (or stromal) keratitis, conjunctival and corneal scarring (symblepharon), corneal sequestrum, eosinophilic keratitis, keratoconjunctivitis sicca (KCS), blocked nasolacrimal duct, and possibly uveitis. The remainder of this discussion will focus on corneal diseases.

Herpesvirus Keratitis

FHV keratitis can be ulcerative or non-ulcerative, but the ulcerative form is most common and is due to direct cytopathic effects of the virus. The non-ulcerative form (stromal keratitis) is primarily immune-mediated, occurs in response to viral antigen, and is characterized histologically by lymphocytic infiltrates. Corneal ulcers are most often superficial and irregular or geographic (map-like). However, faint linear to tree-branching ulcers, or dendritic ulcers, are considered pathognomonic of FHV. Dendritic ulcers can be detected with fluorescein stain using magnification and a cobalt blue light, but they may be easier to detect using rose Bengal stain. Ulcers resulting from especially virulent strains of FHV, or secondarily infected with bacteria, can quickly deteriorate. Conjunctival graft or corneo-conjunctival transposition surgery may be required for a deep stromal ulcer or descemetocele. Any cat with a corneal ulcer of undetermined cause should be promptly treated with an antiviral agent.

The non-ulcerative or stromal keratitis is characterized by circumcorneal to diffuse stromal opacity and blood vessels. Because the stromal keratitis is immune-mediated, improvement may occur with judicious application of topical steroids. However, topical steroids should be used only if the cornea is negative to fluorescein stain and if prior antiviral treatments have been ineffective. Then, they should only be used in conjunction with an antiviral agent. Caution is advised when contemplating steroid use in a cat with suspected FHV, and frequent examinations (at least initially) are prudent if they are used.

Diagnostic tests such as immunofluorescent antibody (IFA) and polymerase chain reaction (PCR) to detect FHV can be performed on samples obtained by conjunctival or corneal scraping. However, the incidence of false-negative test results is significant. Furthermore, normal cats with no evidence of ocular disease can be positive for FHV. The diagnostic value of such testing is therefore questionable, and the author rarely performs these tests. However, conjunctival or corneal scrapings for cytologic examination can be useful to eliminate other disease conditions from consideration (e.g., eosinophilic keratitis). If a cat has ocular disease consistent with FHV and has not received antiviral treatment, the best approach is to initiate such treatment.

Antiviral Agents

The most commonly used antiviral agents are the nucleoside analogues. They exert their antiviral effects primarily by DNA substitution, thereby inhibiting viral replication. In one study, the in vitro efficacy of several nucleoside analogues against FHV was compared and indicated trifluridine > idoxuridine > vidarabine > acyclovir. There is no in vivo study to corroborate these results. Vidarabine (Vira-A) is no longer commonly used. Trifluridine (Viroptic) is available as a 1% ophthalmic solution, but it is expensive, must be refrigerated, and is not tolerated by many cats. Idoxuridine 0.1% solution (formerly Herplex) is the author's first choice for topical treatment, but it is no longer commercially available and must be compounded. Most cats tolerate this drug well, and it is considerably less expensive than trifluridine. Either drug can be formulated as an ointment. Refrigeration of idoxuridine is recommended for antibacterial purposes but is not required for stability of the drug. Trifluridine and idoxuridine solutions should be applied q.4-6h. for initial treatment and the frequency tapered as the eye improves. Gradual reduction in treatments is advised (e.g., q.i.d. for one week, t.i.d. for one week, etc.). Idoxuridine is a safe drug, and cats prone to recurrent infection can be maintained on once or twice daily treatments. More recently, topical cidofovir 0.5% solution has been shown effective against FHV when used b.i.d. Cidofovir must be compounded and is expensive, and except for more convenient twice-daily administration, it has not been shown to be more effective than other available treatments. Famciclovir (Famvir) is available for oral use. Recent studies have shown it to be a safe drug and tolerated at much higher doses (i.e., 90 mg/kg t.i.d) than required for clinical improvement. Most ophthalmologists administer only 62.5 mg per cat, once or twice daily, depending on the severity of infection. The safety of long-term administration has not been evaluated, nor has is safety in kittens. The author has safely administered famciclovir to adult cats for several weeks at a time with no adverse effects. It is available as a 125 mg or 250 mg tablet.

Interferon is a naturally synthesized cytokine that has both antiviral and immunomodulating effects. It is non-species specific in its action, so human interferon can, theoretically, be used to treat feline infections. Interferon has been used in cats primarily to treat retroviral infections. Prior studies have shown it is absorbed poorly after oral administration, and detectable serum levels are not achieved. Topical interferon administration is effective for ocular herpetic infections in other species, and interferon is active against FHV in vitro. Veterinary ophthalmologists have used interferon orally and topically with varying opinions as to its efficacy. The same preparation of human alpha-interferon (Roferon, Hoffman LaRoche Inc., Nutley, NJ) can be used topically or orally. When given orally, it is administered at 10-30 IU daily for seven days on, then seven days off, etc., until the clinical condition improves. Interferon appears to be safe when administered orally to cats. Since the oral preparation is made in saline, the same preparation can be safely applied to the eye up to q.i.d. Interferon is typically made in a large quantity and then frozen in small aliquots until ready for use. It is reportedly stable for years when frozen and for months when refrigerated. It can be easily obtained from a compounding pharmacist.

L-lysine is an amino acid that has demonstrated antiviral activity against FHV both in vitro and in vivo. Arginine is an amino acid that is essential for the replication of herpesvirus, and L-lysine competes with arginine utilization by the virus. L-lysine may be substituted for arginine during synthesis of viral proteins thereby acting as an antimetabolite, it may compete with arginine for transport across cell membranes, and it induces arginase, then enzyme responsible for degradation of arginine. L-Lysine alone is unlikely to resolve a serious herpesvirus infection, but it may be a useful adjunct to other treatments. It may reduce the severity and duration of symptoms during active infection and may reduce the tendency for recurrent infections. L-lysine appears safe and can be administered as a daily oral supplement. It is available as a powder or gel (Viralys), as a paste (Enisyl-F), and as a soft chew treat (Vetri-Lysine Plus, Optixcare). The recommended dose is 250 mg b.i.d., but it can be administered at 500 mg b.i.d. in larger cats or those with severe infections. The higher dose is not advised in adolescent cats or kittens.

Eosinophilic Keratitis (or Proliferative Keratitis)

Eosinophilic keratitis (EOK) is an inflammatory condition of undetermined cause. It has been suggested to be a manifestation of the eosinophilic granuloma complex (e.g., rodent ulcer, etc.), but this has not been proven. The clinical appearance is that of corneal vessels in one or more quadrants with focal to large areas (or plaques) of inflammatory cells that appear as pinkish-white, or all white, thickened lesions. EOK can occur in one or both eyes, but unilateral involvement is most common. It occurs in cats of all ages with no proven breed predisposition, though it tends to occur more often in young to middle aged, neutered male, cats. The differential diagnosis should include FHV keratitis, neoplasia, and mycotic infection, but the latter two conditions are extremely rare. FHV usually causes an ulcerative keratitis, whereas EOK is more often non-ulcerative. Fluorescein staining of affected eyes often reveals faint stain retention over inflammatory lesions, but affected cornea is usually thicker rather than thinner as would be expected for a herpetic ulcer. Also, cats with FHV keratitis are typically more uncomfortable than a cat with EOK. The diagnosis is easily confirmed by corneal (or conjunctival) cytology. Cytologic findings usually reveal a predominance of eosinophils and occasional mast cells, whereas corneal histology (e.g., after keratectomy) may reveal more lymphocytes and plasma cells. Eosinophils and mast cells are not a feature of normal cornea, and the presence of even one eosinophil on cytologic examination is considered significant.

EOK is a disease to be controlled rather than cured. Recurrence is common, so the goal should be to find the lowest level of treatment necessary for control. This can sometimes be achieved with as little as one or twice weekly topical treatments after the initial inflammation is resolved. Topical corticosteroids are the primary treatment in most instances, and 1% prednisolone and 0.1% dexamethasone acetate preparations are preferred. Steroids drops should be applied 3-4 times daily in initial treatment, and the frequency is gradually reduced as the condition improves.

Concurrent FHV infection can complicate treatment, especially if topical steroids are used.

Studies indicate that 50% of cats with EOK can be positive by immunofluorescent antibody testing to FHV, and up to 76% can be positive by PCR. The significance of a positive FHV status is not clear, as another study showed that 30% of normal cats were positive for FHV. Given the uncertain relationship between FHV and EOK, and the fact that affected eyes can be fluorescein positive with both conditions, empiric antiviral treatment should be considered in the initial treatment of EOK. The author routinely uses topical idoxuridine concurrent with topical steroid treatments, usually at the same frequency. As the eye improves and one can be more confident that herpesvirus is not a factor, the antiviral drop can be discontinued. Methylprednisolone acetate (Depo Medrol) may be an effective alternative to topical steroid treatment. Systemic steroids have less potential to cause corneal complications compared with topical steroids (e.g., delayed corneal healing, collagenase activity, etc.). A single intramuscular injection of 20 mg Depo Medrol is often effective, and idoxuridine can be dispensed for topical treatment. Affected eyes are usually improved in one or two weeks, at which time the injection can be repeated, or topical steroids can be started for maintenance.

Additional treatment options include topical cyclosporine (and possibly tacrolimus) and oral megestrol acetate. One study showed that topical 1.5% cyclosporine solution is effective in almost 90% of EOK cases, but blepharitis occurred in 6% of the cases. In another study of eosinophilic conjunctivitis (a similar but distinct entity), 25% of cases were irritated by 0.2% cyclosporine ointment (Optimmune). Cyclosporine can be safely used in the presence of non-infected corneal ulcers, but there is potential for it to exacerbate FHV infection in a manner similar to steroids. Even so, cyclosporine provides another treatment option.

Oral megestrol acetate is an effective treatment, but the client must be cautioned about its potential adverse effects. This drug is available as a 5 mg (Ovaban) or 20 mg (Megace) tablet. For the average 10 lb or heavier cat, a typical dose regimen is 5 mg p.o. once daily for 5-7 days, then 5 mg every other day for two weeks, then 5 mg once weekly for two weeks, then 5 mg once or twice monthly for maintenance. The lowest effective dose of megestrol should be used for maintenance. Megestrol is not FDA approved for use in cats and should only be used in neutered males or spayed females. Potential complications include diabetes mellitus, metritis, mammary neoplasia, pyometra, weight gain, and behavioral changes. In the author's experience, serious side effects are uncommon. If diabetes occurs, it is usually transient and resolves when the drug is discontinued. Prospective patients should be selected carefully, and it may be best to limit megestrol treatment to those cases where topical treatments are either ineffective or deemed too risky. A biochemical profile is advised prior to treatment to assess glucose and liver enzymes. Caution is advised in older cats where the risk for diabetes may be greater.

Corneal Sequestrum

Corneal sequestrum is a condition unique to the cat. The exact cause is undetermined, but predisposing factors include corneal ulcers (usually chronic), lagophthalmos, entropion, and tear film abnormalities. Because most feline corneal ulcers are the result of FHV infection, it is not surprising that FHV has been isolated from sequestra. Toxoplasma gondii has also been detected in sequestra removed by keratectomy. In a study of nine cases, 33% of sequestra were positive for FHV by PCR, and 33% were positive for T. gondii. The significance of these findings is unclear. There is also a well-recognized breed predisposition for Persians, Himalayans, and Siamese cats, but any breed can be affected. Sequestra can be unilateral or bilateral. They appear as an amber, brown, or black plaque, of the central or paracentral cornea, but can occasionally occur in the peripheral cornea. There is usually concurrent corneal ulceration, vascularization, ocular drainage, and varying degrees of patient discomfort. Recent ultrastructural studies indicate the dark material to be consistent with melanin granules. Histologically, sequestra are characterized by degenerate collagen, ulceration, and a variable degree of inflammation. Blood vessels often extend to the lesion but do not infiltrate the sequestrum, and the corneal vascularization is similar to a foreign body response. Sequestra appear to represent an abnormal healing response and are probably preceded by corneal ulceration in most instances. The clinical appearance can be considered pathognomonic because corneal pigmentation (or pigmentary keratitis) is rare in the cat, and epibulbar melanoma occurs at the periphery (or limbus).

Medical management may be acceptable, but surgery is the most expeditious way to resolve the problem. For cats that are especially painful and for which the pain cannot be resolved with medical treatment, surgery is mandatory. A topical antibiotic is appropriate, and an antiviral drop (e.g., idoxuridine) should be considered for aforementioned reasons. Ocular lubricants can be helpful, and mucinomimetic agents containing hyaluronate or carbomer are recommended. Topical interferon has been reported to decrease corneal discoloration in some cases. Oral analgesic (buprenorphine) or analgesic/anti-inflammatory treatment (e.g., Metacam) may be indicated for initial treatment. Medical management alone is acceptable for pets that are comfortable and for which the eye is minimally inflamed. Some sequestra will ultimately slough from the corneal surface, but months are usually required before this occurs. It is also possible for a sequestrum to migrate deeper in the cornea, and globe rupture occurs in a small percentage of cases. The sequestrum can usually be removed by lamellar keratectomy, but it is extends deeply, a conjunctival pedicle graft or corneoconjunctival transposition may be required. Sequestra can recur after surgical removal, and it is important to advise clients accordingly. The literature suggests there is no difference in recurrence rate in pets that have had a graft procedure versus those who have not after removal by keratectomy. However, this is contrary to the author's experience, and I have seen sequestra recur within two weeks of keratectomy surgery alone. It is this author's opinion that a graft procedure is indicated in most instances.

Bullous Keratopathy

This is an uncommon condition characterized by profound and sometimes rapid onset of corneal edema with bullae formation and protrusion. Bullae can rupture resulting in corneal ulcers, and collagenase activity (or melting) with rapid stromal destruction and globe rupture are possible. Treatment should include topical antiviral drops (on the assumption of underlying FHV), and 5% sodium chloride drops or ointment to reduce edema (if tolerated by the cat). Topical autologous serum may be indicated to prevent melting (e.g., 1-2 hours in initial treatment). Temporary tarsorrhaphy or a nictitans flap can be helpful to provide structural support to the distorted cornea. The prognosis must be guarded, and graft surgery or enucleation is sometimes necessary.

Miscellaneous Conditions

Corneal dystrophy, degeneration, and neoplasia are uncommon conditions in cats. Of these, lipid corneal degeneration, corneal dermoid, and limbal melanomas are most common, and they are managed similar to the same conditions in dogs (refer to Canine corneal diseases).