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Purpose: Epithelial keratitis is the most common presentation of ocular infection by herpes simplex virus (HSV). Quantitative assessment of available therapy is needed to guide evidence-based ophthalmology. This study aimed to compare the efficacy of various treatments for dendritic or geographic HSV epithelial keratitis and to evaluate the role of various clinical characteristics on epithelial healing., Methods: Following a systematic review of the literature, information from clinical trials of HSV dendritic or geographic epithelial keratitis was extracted, and the methodological quality of each study was scored. Methods of epithelial cauterization and curettage were grouped as relatively equivalent physicochemical therapy, and solution and ointment formulations of a given topical antiviral agent were combined. The proportion healed with 1 week of therapy, a scheduled follow-up day that approximated the average time of resolution with antiviral therapy, was selected as the primary outcome based on a masked evaluation of maximum treatment differences in published healing curves. The proportion healed at 14 days was recorded as supplemental information. Fixed-effects and random-effects meta-analysis models were used to obtain summary estimates by pooling results from comparative treatment trials. Hypotheses about which prognostic factors might affect epithelial healing during antiviral therapy were developed by multivariate analysis of the Herpetic Eye Disease Study dataset., Results: After excluding 48 duplicate reports, 14 nonrandomized studies, 15 studies with outdated or similar treatments, and 29 trials lacking sufficient data on healing or accessibility, 76 primary reports were identified. These reports involved 4,251 patients allocated to 93 treatment comparisons of dendritic epithelial keratitis in 28 categories and 9 comparisons of geographic epithelial keratitis in 6 categories. For dendritic keratitis, idoxuridine was better than placebo at 7 days (combined odds ratio [OR], 3.59; 95% confidence interval [CI], 1.92-6.70), and at 14 days (OR, 4.17; 95% CI, 1.33-13.04), but pooling was limited by lack of homogeneity and low study quality. Direct comparisons at 1 week of treatment showed that trifluridine or acyclovir was significantly better than idoxuridine (OR, 3.12 and 4.56; 95% CI, 1.55-6.29 and 2.76-7.52, respectively), and indirect comparisons were also consistent with a clinically significant benefit. Vidarabine was not significantly better than idoxuridine in pooled treatment comparisons at 1 week (OR, 1.20; 95% CI, 0.72-2.00) but was better in 2 indirect comparisons (OR, 4.22 and 4.78; 95% CI, 1.69-10.54 and 2.15-10.65, respectively). At 14 days, trifluridine (OR, 6.05; 95% CI, 2.50-14.66), acyclovir (OR, 2.88; 95% CI, 1.39-4.78), and vidarabine (OR, 1.24; 95% CI, 0.65-2.37) were each better than idoxuridine. Trials of geographic epithelial keratitis also suggested that trifluridine, acyclovir, and vidarabine were more effective that idoxuridine. Other topical antiviral agents, such as bromovinyldeoxuridine, ganciclovir, and foscarnet, appeared equivalent to trifluridine or acyclovir. Oral acyclovir was equivalent to topical antiviral therapy and did not hasten healing when used in combination with topical treatment. Antiviral agents did not increase the speed of healing when compared to debridement but reduced the risk of recrudescent epithelial keratitis. The combination of physicochemical treatment with an antiviral agent seemed to be better than either physicochemical or antiviral treatment alone, but the heterogeneous cauterization and curettage techniques and the various treatment combinations limited valid quantitative summary effect measures. The combination of topical interferon with an antiviral agent was significantly better than antiviral therapy at 7 days (OR, 13.49; 95% CI, 7.39-24.61) but not at 14 days (OR, 2.36; 95% CI, 0.82-6.79). Finding apparent heterogeneity for some pooled estimates suggested that dissimilarities in patients, interventions, outcomes, or other logistical aspects of clinical trials occur across studies., Conclusions: The available evidence on the acute treatment of presumed HSV epithelial keratitis demonstrates the effectiveness of antiviral treatment and shows the log-logistic healing curve of treated dendritic epithelial keratitis. Topical trifluridine, acyclovir, and vidarabine were significantly more effective than idoxuridine but similar in relative effectiveness for dendritic epithelial keratitis. Physicochemical methods of removing infected corneal epithelium are effective, but adjunctive virucidal agents are needed to avert recrudescent epithelial keratitis. Whether debridement in combination with antiviral therapy is more beneficial than antiviral chemotherapy alone appears likely but remains inconclusive. The combination of topical interferon with an antiviral agent significantly speeds epithelial healing. Future trials of the acute treatment of HSV epithelial keratitis must aim to achieve adequate statistical power for assessing the primary outcome and should consider the effect of lesion size and other characteristics on treatment response.

A 65-year-old man with recurrent herpetic keratitis underwent corneal transplantation for persistent nonimmunologic graft failure. Histopathologic examination of the corneal button revealed an epithelial dendrite containing Cowdry type A inclusion bodies, moderate stromal edema, and a retrocorneal fibrous membrane. Immunohistochemical studies demonstrated herpes simplex virus antigens in epithelial cells bordering the dendritic defect and in stromal keratocytes. The mean width of corneal epithelium displaying herpes simplex virus-positive epithelial cells on either side of the dendritic defect measured 200 +/- 46 microns. By electron microscopy, herpesvirus particles were identified in epithelial cells lining the dendrite as well as in stromal keratocytes. Infected keratocytes were scattered throughout the stroma but were not observed subjacent to the epithelial dendrite. This study demonstrates that a recurrent epithelial dendrite can be associated with subclinical stromal infection of the graft.

The Herpetic Eye Disease Study (HEDS) includes three double-masked, placebo-controlled clinical trials for potentially blinding herpes simplex virus (HSV) eye infections. One study compares a tapering dosage of topical prednisolone or placebo eye drops for HSV stromal keratitis (HEDS-SKN). Two other trials compare oral acyclovir to placebo capsules for HSV stromal keratitis (HEDS-SKS) or iridocyclitis (HEDS-IRT) in patients on a tapering dosage of topical prednisolone drops. All medications are administered for 10 weeks. Outcome is judged by time to recurrent disease or treatment failure. This paper presents the design, estimated sample size and recruitment as of July 25, 1990.

Four patients with chronic open-angle glaucoma developed a dendriform corneal epithelial lesion. Two were associated with the use of topical betaxolol for 2 months and 6 weeks, and two were related to topical levobunolol. Resolution occurred within 2 weeks of discontinuation of the beta-blocker eyedrop. The distinctive pattern of dendritic epithelial keratopathy associated with these topical medications may be due to epithelial toxicity with subsequent regeneration.

Clinical features of 152 patients with herpetic keratitis after a five-year observation period were analyzed. When compared with dendritic ulceration, geographic ulcers that had been symptomatically present for a longer time were more likely to have been treated with a topical steroid and took longer to heal. After treatment of the corneal ulceration, 40% of the patients experienced a recurrent herpetic ulcer, 25% experienced disciform or irregular stromal keratouveitis, 5% experienced ocular hypertension, and 6% had a decrease in visual acuity caused by corneal scarring. Recurrent ulcerative herpetic keratitis occurred more frequently in men and in patients who entered the study with a history or previous herpetic ulceration.

Blood and tear levels of immunoglobulins against herpes simplex virus (HSV) were examined in 28 patients with dendritic keratitis over a period of 28 days. By means of an indirect micro-immunofluorescent technique blood and tear HSV IgG were detected, but neither circulating HSV IgM nor local HSV IgA were found. Over a four-week interval non-diagnostic fluctuations of HSV IgG occurred in most patients, though seven (25%) developed a rising blood IgG titre. Tear IgG appeared to be an exudate from blood. HSV was isolated from 68% of corneal swabbings and 11% of conjunctival swabbings. This study provides guidelines for laboratory testing in recurrent herpetic keratitis.

Thirty patients with bilateral herpetic keratitis were evaluated, 40% of whom were atopic. Stromal keratitis occurred in 40% of the eyes and recurrent ulceration in 68%. Four patients (5 eyes) developed secondary microbial keratitis. Visual acuity decreased to 6/60 or less because of corneal opacification in 17% of the eyes.

The diagnosis and optimal management of herpes simplex stromal keratitis can be problematic. Clinical features that should be evaluated include the status of the epithelium and the location and type of stromal inflammation. Two principal forms are recognized: nonnecrotizing, or disciform, keratitis and necrotizing keratitis. Both types may coexist and are sometimes accompanied by iridocyclitis and secondary ocular hypertension. Laboratory evaluation is not usually performed, although, lacking a prior history of herpes simplex epithelial keratitis, testing should be considered to seek another cause of stromal inflammation. A topical steroid is generally contraindicated in the presence of herpes simplex epithelial keratitis and has been implicated in prolonging the course of herpetic eye disease. However, judicious topical steroid therapy can be beneficial when used with protective antiviral cover for herpes simplex stromal keratitis without epithelial keratitis. Systemic antiviral therapy may prove to be a valuable adjunctive treatment, and further clinical trials are anticipated.

We treated 25 patients with dendritic keratitis with debridement and 3% acyclovir ointment and another 25 with acyclovir alone. The patients were randomly assigned to the two treatment groups. There were only minimal adverse effects in both groups. The combination of debridement and acyclovir produced a significantly more rapid healing rate than did acyclovir alone. Factors associated with prolonged healing time were duration of symptoms (longer than one week), length of the epithelial defect (greater than 4 mm), proximity of the defect to the corneoscleral limbus (less than 2 mm), and the presence of stromal inflammation.

Sixty patients were treated with either acyclovir 2% ointment or idoxuridine 1% ointment 5 times a day in a stratified randomised double-blind clinical trial. The 2 antiviral agents were equally effective.

Twenty patients with presumptive herpetic iridocyclitis without active corneal inflammation received either topical idoxuridine 0.5% or acyclovir 3% ointment. The uveitis of all ten patients treated with acyclovir resolved within one to eight weeks. Four of ten patients treated with idoxuridine worsened but subsequently responded to topical prednisolone 0.3%. The pathogenesis of herpetic iridocyclitis is discussed with a literature review.