Epithelial keratitis

PM Hughes, AK Mitra. (1993). Effect of acylation on the ocular disposition of acyclovir. II Corneal permeability and anti-HSV 1 activity of 2 -esters in rabbit epithelial keratitis. J Ocular Pharmacol 9 299-309. 

The answer is b. (Hardman, p 1203.) Trifluridine inhibits viral activity in HSV types 1 and 2, CMV, vaccinia, and perhaps adenovirus. It acts as a viral DNA synthesis inhibitor by irreversibly blocking thymidylate synthetase. Trifluridine triphosphate is a competitive inhibitor of thymidine triphosphate accumulation into DNA It is used in the treatment of primary keratoconjunctivitis and recurrent epithelial keratitis caused by HSV 1 and 2. 

Primary keratoconjunctivitis and recurrent epithelial keratitis caused by herpes simplex virus types 1 and 2. 

Epithelial keratitis that has not responded clinically to topical idoxuridine, or when ocular toxicity or hypersensitivity to idoxuridine has occurred. In a smaller number of patients resistant to topical vidarabine, trifluridine was also effective. 

Efficacy In other conditions The clinical efficacy in the treatment of stromal keratitis and uveitis caused by herpes simplex or ophthalmic infections caused by vaccinia virus and adenovirus, or in the prophylaxis of herpes simplex virus keratoconjunctivitis and epithelial keratitis has not been established by well-controlled clinical trials. Not effective against bacterial, fungal, or chlamydial infections of the cornea or trophic lesions. 

Trifluridine (trifluorothymidine) is a fluorinated pyrimidine nucleoside that inhibits viral DNA synthesis in HSV-1, HSV-2, CMV, vaccinia, and some adenoviruses. It is phosphorylated intracellularly by host cell enzymes, and then competes with thymidine triphosphate for incorporation by the viral DNA polymerase (Figure 49-3). Incorporation of trifluridine triphosphate into both viral and host DNA prevents its systemic use. Application of a 1% solution is effective in treating keratoconjunctivitis and recurrent epithelial keratitis due to HSV-1 or HSV-2. Cutaneous application of trifluridine solution, alone or in combination with interferon alfo, has been used successfully in the treatment of acyclovir-resistant HSV infections. 

The development of latanoprost-induced corneal dendritiform epitheliopathy has been reported. These lesions resemble those of herpes simplex virus epithelial keratitis, but, in contrast to herpes simplex virus disease, the pseudodendrites associated with latanoprost promptly disappear on discontinuation of drug therapy. Coincident with discontinuation of latanoprost, patients can be treated with preservative-free artificial tears with or without topical antibiotics. 

When treating HSV epithelial keratitis, there is no benefit achieved by adding oral acyclovir to treatment with trifluridine to prevent the development of herpes stromal keratitis or iritis. 

Oral acyclovir may be as effective as topical acyclovir in the treatment of HSV epithelial keratitis. 

The treatment of HSV epithelial keratitis with oral acyclovir has not been studied by the Herpetic Eye Disease Study, but there is some evidence to suggest that oral acyclovir may be as effective as topical acyclovir. The clinical management of HSV in immunocompromised patients differs from that of immimocompetent patients because the immimocompromised experience more frequent and more severe infections. 

Herpetic Eye Disease Smdy Group l.A controlled trial of oral acyclovir for the prevention of stromal keratitis or iritis in patients with herpes simplex vims epithelial keratitis. Arch Ophthalmol 1997 115 703-712. 

Associated toxic epithelial keratitis should respond to blepharitis treatment. Topical steroids are generally not required imless the cornea is significantly involved or a phlyctenule is present. In this case prednisolone 0.12% used two or three times a day for a few days may be used. Combination steroid-antibiotic ointments, such as tobramycin-dexamethasone or the topical combination drop tobramycin-loteprednol, may prove to be useful for those patients complaining of excessive itching and burning. Steroids control the hypersensitivity component that is often present and reduce the congestion and irritation that often provoke the patient to rub the eye and aggravate the blepharitis. 

Herpetic Eye Disease Study Group. Oral acyclovir for herpes simplex virus eye disease effect on prevention of epithelial keratitis and stromal keratitis. Arch Ophthalmol 2000 118 1030-1036. 

In its early stages trachoma presents as a chronic follicular conjunctivitis with a predilection for the superior tarsal and bulbar conjunctiva. Over time, the conjunctival reaction becomes papillary in nature and, with the inflammatory infiltration that occurs, the follicular character of the infection can become obscured. Patients experience symptoms of photophobia, tearing, and mucoid or mucopurulent discharge. Limbal edema and superior bulbar conjunctival hyperemia also may occur. Conjunctival follicles that form at the limbus are characteristic of severe trachoma. Primary corneal involvement often includes superior epithelial keratitis and superficial superior pannus formation. A wide variety of corneal infiltrates... 

The conjunctivitis and symptoms last 7 to 16 days, with a mean between 8.6 and 10 days. A diffuse superficial epithelial keratitis usually develops in the first week and may be cansed by proliferation of live virus within the corneal epithelium. In approximately 1 week this fine keratitis progresses to become deeper, positively staining, slightly elevated focal epithelial lesions. These epithelial lesions fede slowly, usually disappearing by 4 weeks. 

Corneal involvement in the form of epithelial keratitis or dendrites occurs in up to 63% of initial clinical HSV infections.These tend to be small, late in onset, and transitory, lasting only 1 to 3 days. Stromal disciform keratitis, which manifests as a round area of stromal edema with an overlying intact epithelium, is much less frequent in... 

Disciform or stromal keratitis may develop beneath a dendrite in recurrent HSK, can occur months after the initial episode, or may develop without a history of epithelial keratitis or blepharoconjunctivitis. The 5- to 7-mm disc-shaped area of edema in the corneal stroma can cause folds in Descemet s membrane. Disciform keratitis occurs in approximately 20% to 48% of patients with recurrent HSK. 

TSPK is a chronic epithelial keratitis of unknown etiology, suggested to be due to chronic subclinical viral infection in the deep layers of the basal epithelium. Support for this theory includes the protracted coruse of this condition, its tendency to recur, the lack of effect by antibiotics on its clinical course, and lack of bacterial isolation from eyes affected by the condition. The clinical presentation of corneal mononuclear cell infiltrates, the rapid resolution of these infiltrates with topical steroids, and their rapid reappearance if topical steroids are stopped too quickly support the possibility that the primary presentation is a typical immunologic response. 

When Thygeson described this condition in 1961, he noted that the disease was chronic, bilateral, and had a long duration with exacerbations and remissions. Also noted was the typical pimctate epithelial keratitis that showed no response to antibiotics or epithelial debridement, a rapid response to very low doses of steroids, and eventual healing without scars. These features, with few variations, are still characteristic of the disease today. Although the disease is bilateral in most patients, there are reports of unilateral cases and cases with marked asymmetry between the two eyes. 

Trifluridinc is approved in the United Stales for the treatment of primary kcratoconjunclivilis and recurrent epithelial keratitis due to HSV types I and 2. Topical irifluridine shows some efficacy in patients with acyclovir-rcsislunl HSV cutaneous infections. Trifluridinc solutions are heal sensitive and require tefrigeralion. 

Trifluridine, an antiviral agent (1 drop of 1% solution onto the cornea), is nsed every 2 honrs while awake until the corneal nicer has reepithelialized completely. Trifluridine is indicated for primary keratoconjnnctivitis and recurrent epithelial keratitis dne to herpes simplex virus types 1 and 2. In addition, it is nsed for epithelial keratitis that has not responded clinically to topical idoxnridine, or when ocular toxicity or hypersensitivity to idoxnridine has occurred. 

Vidarabine, an antiviral agent (10 to 15 mg/kg/day for 5 to 10 days), is indicated in the treatment of herpes simplex virus encephalitis, neonatal herpes simplex virus infections, and herpes zoster in immunosuppressed patients. In addition, vidarabine (ophthalmic ointment 3% vidarabine monohydrate [equivalent to 2.8% vidarabine]) is indicated in the treatment of acute keratoconjunctivitis and recurrent epithelial keratitis due to herpes simplex virus types 1 and 2, or superficial keratitis caused by herpes simplex virus that has not responded to topical idoxuridine or when toxic or hypersensitivity reactions to idoxuridine have occurred. 

Trifluridine is FDA approved for treatment of primary keratoconjunctivitis and recurrent epithelial keratitis owing to HSV types 1 and 2. Topical trifluridine is more active than idoxuridine and comparable with vidarabine in HSV ocular infections. Adverse reactions include discomfort on instillation and palpebral edema. Hypersensitivity reactions, irritation, and keratopathy are uncommon. Topical trifluridine also is effective in some patients with acyclovir-resistant HSV cutaneous infections. 

Trifluorothymidine, because of its greater solubility in water, is active against HSV-1 and HSV-2. It also is useful in treating infections caused by human CMV and VZV infections (Table 43.3). The advantage of use of this agent over idoxuridine is its high topical efficacy in the cure of primary keratoconjunctivitis and recurrent epithelial keratitis. It also is useful for difficult cases of herpetic iritis and established stromal keratitis. 

Vidarabine is used mainly in human HSV-1 and HSV-2 encephalitis, decreasing the mortality rate from 70 to 30%. Whitley et al. (57) reported that early vidarabine therapy is helpful in controlling complications of localized or disseminated herpes zoster in immunocompromised patients. Vidarabine also is useful in neonatal herpes labialis or genitalis, vaccinia virus, adenovirus, RNA viruses, papovavirus, CMV, and smallpox virus infections. Given the efficacy of vidarabine in certain viral infections, the U.S. FDA approved a 3% ointment for the treatment of herpes simplex keratoconjunctivitis and recurrent epithelial keratitis, and a 2% IV injection for the treatment of herpes simplex encephalitis and herpes zoster infections (Table 43.3). A topical ophthalmic preparation of vidarabine is useful in herpes simplex keratitis but shows little promise in herpes simplex labialis or genitalis. The monophosphate esters of vidarabine are more water-soluble and can be used in smaller volumes and even intramuscularly. These esters are under clinical investigation for the treatment of hepatitis B, systemic and cutaneous herpes simplex, and herpes zoster virus infections in immunocompromised patients. 

Trifluridine 202 is an antiviral drug for topical treatment of epithelial keratitis caused by herpes simplex virus. It is a modified form of deoxyuridine and similar to be... 

Amphotericin B is also used as a topical agent in the treatment of mycoses but to a lesser extent than is nystatin [409]. Amphotericin B has been used successfully to treat epithelial keratitis due to Rhodotorula sp. [473] and fungal endopthalmitis [474],... 

Herpetic epithelial keratitis has been reported after intravitreal bevacizumab injection [7 ]. 

Khalili MR, Mehdizadeh M, Mehryar M. Herpetic epithelial keratitis after intravitreal injection of bevacizumab (Avastin). Cornea 2009 28(3) 360-1. 

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