Risk factors for herpes simplex virus epithelial keratitis recurring during treatment of stromal keratitis or iridocyclitis. Herpetic Eye Disease Study Group.

AIMS: Possible risk factors were evaluated for herpes simplex virus (HSV) epithelial keratitis in patients with stromal keratouveitis. METHODS: The study population included 260 patients who had active stromal keratitis and/or iridocyclitis without epithelial disease and who were enrolled in one of three clinical trials of the Herpetic Eye Disease Study. Study treatment involved a 10 week course of topical placebo, topical prednisolone phosphate, or topical prednisolone phosphate with oral acyclovir. All groups received topical trifluridine four times daily for 3 weeks then twice daily for another 7 weeks. Patients were examined for HSV epithelial keratitis for 16 weeks. RESULTS: Dendritic or geographic epithelial keratitis occurred in 12 (4.6%) study patients. Adverse effects attributable to trifluridine prophylaxis were acute allergic blepharoconjunctivitis in 10 (3.8%) study patients and corneal epithelial erosions in 11 (4.2%) study patients. No significant difference in the occurrence of HSV epithelial keratitis was found among the study treatment groups: one (2.0%) of 49 topical placebo treated patients, nine (6.5%) of 138 patients treated with topical corticosteroids without acyclovir, and two (2.7%) of 73 patients treated with topical corticosteroids and oral acyclovir. Univariate exponential models suggested that patients with a history of previous HSV epithelial keratitis and non-white patients were more likely to develop HSV epithelial keratitis during treatment of stromal keratouveitis. CONCLUSION: Individuals with prior HSV epithelial keratitis and certain ethnic groups may have a higher rate of recurrent epithelial keratitis during the acute treatment of HSV stromal keratouveitis.     

Oral acyclovir for the management of herpes simplex virus keratitis in children

PURPOSE: To evaluate the use of oral acyclovir in pediatric patients with herpes simplex virus (HSV) keratitis. DESIGN: Retrospective noncomparative case series. PARTICIPANTS: Seven pediatric patients seen at the University of Minnesota Hospitals and Clinics with herpes simplex virus (HSV) infectious epithelial keratitis between January 1992 and October 1998. Patient ages ranged from 6 weeks to 5 years at time of presentation with a median of 1.7 and mean of 1.9 years. INTERVENTION: All patients received oral acyclovir; six of seven patients also received topical antiviral medications. Three of seven patients had topical antiviral therapy fail before being placed on oral acyclovir, and the remaining four patients were placed on oral acyclovir primarily. RESULTS: All patients showed resolution of HSV infectious epithelial keratitis. Three patients have been maintained on prophylactic dosage of oral acyclovir because of recurrent disease or because they have been chronically treated with topical corticosteroids for immune stromal keratitis. All patients tolerated acyclovir well, and there were no adverse reactions. CONCLUSIONS: Oral acyclovir is useful in treating HSV infectious epithelial keratitis in pediatric patients. It is beneficial in treating infectious epithelial keratitis and prophylactically either while treating with topical corticosteroids for immune stromal keratitis or for preventing recurrent infectious epithelial keratitis.     

Herpes simplex virus keratitis after laser in situ keratomileusis

PURPOSE: To report two cases of herpes simplex virus (HSV) keratitis after laser in situ keratomileusis (LASIK). METHODS: Interventional small case series. Two patients underwent uneventful LASIK. History of herpes labialis in one patient and herpetic eye disease > 10 years prior to intervention in the other patient was reported. Both patients developed stromal herpetic keratitis 6 weeks and 2 years after the procedure, respectively. RESULTS: Treatment consisting of topical steroid drops and topical and systemic antiviral therapy was administered. Recurrences of the herpetic keratitis were seen after tapering of the topical steroids; four and three recurrences were observed, respectively. Final visual acuity was > 6/9 in both cases. CONCLUSIONS: Herpetic keratitis after LASIK is an uncommon, possibly under-reported, entity. Even patients without history of herpetic eye disease can present with this complication. Oral antiviral prophylaxis may be appropriate when performing LASIK on patients with a history of ocular or systemic HSV infection.     

Treatment of HSV-1 stromal keratitis with topical cyclosporin A: a pilot study

· Background: In stromal keratitis induced by herpes simplex virus (HSV) the host’s immune response contributes to corneal scarring and neovascularization. The purpose of this study was to analyze the efficacy of topically applied cyclosporin A (CsA) in patients with HSV keratitis. · Methods: The authors performed a prospective pilot study in patients with HSV stromal keratitis (n=18). Eyes were treated with CsA eyedrops and acyclovir ointment. The drugs were tapered off gradually. Visual acuity, slit-lamp appearance, intraocular pressure and corneal sensitivity were evaluated monthly (follow-up 5.2±0.28 months, mean±SEM. · Results: Keratitis resolved with CsA treatment in 10 of 14 patients with non-necrotizing keratitis and in 2 of 4 with necrotizing keratitis. As CsA was used topically, the corticosteroids could be withdrawn in all patients with non-necrotizing keratitis and in 1 of 3 with necrotizing keratitis. Under CsA therapy, persistent or progressive inflammation was noted in 6 of the 18 patients. These 6 patients with keratitis improved only with combined CsA/corticosteroids. Corneal ulcers healed in 4 patients with topical CsA, and corneal neovascularization improved in a further 8. Except for toxic epitheliopathy, no further CsA complications were noted. · Conclusions: The findings in this pilot study suggest that HSV stromal keratitis can be treated successfully with CsA eyedrops, especially in non-necrotizing disease. CsA may be particularly helpful in the presence of steroid glaucoma, herpetic corneal ulcers, and to taper off topical corticosteroids. Additional use of acyclovir may aid in suppressing the recurrence of epithelial HSV keratitis. A randomized study should be performed to evaluate the role of topical CsA in more detail. Received: 23 April 1998 Revised version received: 12 August 1998 Accepted: 14 September 1998     

Effects of topical unoprostone and latanoprost on acute and recurrent herpetic keratitis in the rabbit

PURPOSE: To determine the effect of the topical ocular hypotensive drug, isopropyl unoprostone, a docosanoid molecule with very weak prostaglandin activity, on herpes keratitis in the rabbit eye. METHODS: For acute disease, rabbit corneas inoculated with the corticosteroid-sensitive F(MP)E strain of herpes simplex virus type 1 were treated with various combinations of 0.12% isopropyl unoprostone, latanoprost, trifluridine, benzalkonium chloride 0.02%, dexamethasone sodium phosphate, ketorolac tromethamine, or saline solution beginning 1 day after infection. Severity of keratitis was evaluated in a masked manner. For recurrent disease, rabbit corneas infected with McKrae strain herpes simplex virus type 1 were treated with unoprostone or saline solution on postinfection days 25 to 42, and the presence or absence of lesions was recorded. RESULTS: Eyes treated with unoprostone showed significantly less severe disease than saline-treated or latanoprost-treated eyes during acute infection. Unoprostone-treated and saline-treated eyes showed no significant difference in the frequency of recurrent lesions. Eyes treated with latanoprost and/or dexamethasone, separately or in combination, showed increased severity of acute herpes simplex virus keratitis, whereas benzalkonium chloride 0.02%--treated eyes showed no significant difference, compared with saline treatment. Trifluridine resulted in rapid healing. CONCLUSIONS: Unoprostone did not increase the severity or recurrence rate of herpes simplex virus keratitis. Unoprostone requires twice-a-day administration, compared with once-a-day for latanoprost, and unoprostone lowers intraocular pressure less than latanoprost. Nevertheless, unoprostone's superior safety profile may make its use advantageous. Benzalkonium chloride alone did not make the keratitis worse.     

Clinical efficacy of oral and topical acyclovir in herpes simplex virus stromal necrotizing keratitis

Purpose:To evaluate the efficacy of systemic and topical antiviral therapy in the treatment of active herpes simplex virus (HSV) necrotizing stromal keratitis (NSK).Design:Prospective interventional case series.Methodology:Patients with a diagnosis of HSV NSK based on history and clinical findings were enrolled in the study. A standard protocol was used for microbiologic investigations. Ten weeks regime of systemic acyclovir and 2 weeks of topical acyclovir was given. Complete ophthalmic examination was performed at every visit. Outcome measures were a reduction in the area of infiltration and improvement in visual acuity.Results:Fifteen patients were enrolled in the study. The mean age of presentation was 51.53 years. The duration of symptoms at presentation ranged from 2 to 8 weeks. HSV1 DNA polymerase chain reaction was positive in 70% cases of those tested. Area of infiltration at trial entry and at the end of 2 weeks of antiviral treatment reduced significantly (P = 0.007). All patients showed a complete resolution of keratitis at the end of study.Conclusion:Topical and systemic acyclovir for treatment of NSK facilitates healing of ulceration. Topical steroids after initial antiviral therapy are safe and decreases inflammation and improve visual recovery. Early initiation of therapy has better outcomes as compared to late presentations.     

Diagnosis and management of herpes simplex stromal keratitis

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.     

Oral Acyclovir in the Management of Herpes Simplex Ocular Infections

Acyclovir, an oral antiviral agent that inhibits viral DNA replication, was used to treat 27 patients (16 males, 11 females) (mean age, 50 years) with vision-threatening herpes simplex virus (HSV) infections. Twenty patients had active stromal keratitis or keratouveitis, four had controlled nonnecrotizing stromal keratitis but could not taper topical medications, and four eczema patients with previous HSV infections had intraocular surgery (1 of these patients also is included in the 20 with active stromal keratitis). All 20 patients with active stromal keratitis or keratouveitis improved on acyclovir, all four patients using acyclovir postoperatively were disease-free while on the drug, but only two of the four patients using acyclovir to assist tapering topical medications were successful. There has been only one recurrence during a cumulative 194 months while on acyclovir. Thirteen patients have remained on acyclovir, and three who stopped acyclovir had prompt recurrences. Acyclovir seems to be a promising adjunct antiviral agent for the treatment of recalcitrant epithelial, stromal, or uveal disease secondary to HSV.     

Topical cyclosporine A 0.5% as a possible new treatment for superior limbic keratoconjunctivitis

PURPOSE: To report the early success of the use of topical cyclosporine A 0.5% drops to treat Theodore's superior limbic keratoconjunctivitis (SLK). DESIGN: A retrospective noncomparative case series. PARTICIPANTS: Five patients diagnosed with SLK. INTERVENTION: All five patients were treated with topical cyclosporine A 0.5% drops as primary or adjunctive therapy after treatment failure in some of prednisolone acetate 1% drops and topical silver nitrate 0.5% application. Topical cyclosporine A 0.5% drops were used four times a day in both eyes. MAIN OUTCOME MEASURES: Resolution of symptoms (foreign body sensation and irritation) and signs (rose bengal staining, tarsal papillary reaction, and injection). RESULTS: All five patients had long-term (6 months to 3 years) improvement of irritation and foreign body sensation, as well as improvement of injection and filamentary keratitis. Aside from burning on instillation, there were no complications related to this therapy. CONCLUSIONS: Topical cyclosporine A 0.5% is helpful as primary or adjunctive therapy for SLK. It may also be used as a maintenance drug to prevent recurrence. Further study may delineate the specific role and treatment parameters for the use of topical cyclosporine A 0.5% in the treatment of SLK.     

Reactivation of herpes simplex virus keratitis after initiating bimatoprost treatment for glaucoma

PURPOSE: To report a case of herpes simplex virus reactivation after starting bimatoprost treatment for glaucoma. DESIGN: Interventional case report. METHODS: A 66-year-old woman had a herpes simplex keratouveitis reactivation that occurred within 1 month after starting bimatoprost. The herpes simplex had been inactive for more than 10 years. RESULTS: Bimatoprost and prednisolone acetate 0.12% were discontinued; oral acyclovir, ofloxacin, and betaxolol 0.25% were initiated. Two weeks later, prednisolone acetate 1% was added. The reactivation resolved, and 1 month later, the best corrected visual acuity improved to 20/40. CONCLUSION: Caution should be used in prescribing bimatoprost for patients with a history of herpes simplex virus keratitis.     

Topical tacrolimus ointment for treatment of refractory anterior segment inflammatory disorders

PURPOSE: To report 4 cases of patients treated with topical tacrolimus ointment 0.03% for ocular inflammatory conditions refractory to traditional treatment. METHODS: Four patients were treated topically with tacrolimus 0.03% ointment twice daily: 2 patients with blepharokeratoconjunctivitis, 1 patient with severe atopic keratoconjunctivitis, and 1 patient with chronic follicular conjunctivitis. RESULTS: Three patients had a dramatic improvement of their ocular condition as early as 2 weeks after starting tacrolimus ointment. One patient developed a herpes simplex virus dendrite after 1 week of tacrolimus use. CONCLUSION: Tacrolimus ointment appears to be an effective alternative for certain ocular inflammatory conditions refractory to traditional treatments. There may be an increased risk of herpes simplex virus keratitis associated with topical use. Our results support previous literature of patients benefiting from topical tacrolimus use.     

Prophylactic perioperative antiviral therapy for LASIK in patients with inactive herpetic keratitis

PURPOSE: To report the outcome of LASIK in patients with inactive herpetic keratitis in which perioperative antiviral prophylaxis was used to prevent the recurrence of ocular herpes. METHODS: We report an uncontrolled series of five patients with inactive herpetic keratitis for at least 1 year before surgery in whom LASIK was successfully performed. All patients showed normal topography, pachymetry, and corneal sensitivity with no central corneal scarring. Perioperative prophylaxis was used in each case with oral valacyclovir and topical acyclovir ointment. RESULTS: None of the eyes developed reactivation of herpetic keratitis during follow-up. CONCLUSIONS: This study suggests that perioperative antiviral prophylaxis may protect the cornea from herpes simplex virus reactivation after LASIK.     

Erythema multiforme after use of topical sulfacetamide

An 8-year-old boy developed erythema multiforme major after topical administration of sodium sulfacetamide for conjunctivitis. He had received systemic treatment with trimethoprim-sulfamethoxazole four months previously without evidence of drug allergy. There was no history of recent exposure to other drugs or evidence of herpes simplex or Mycoplasma infection. After 12 days of treatment with erythromycin ointment, 1% prednisolone eyedrops, systemic prednisone, and intravenous nafcillin, the patient's condition improved dramatically. A slit-lamp examination showed only superficial punctate keratitis. Two months later his visual acuity had improved from 20/200 bilaterally to R.E.: 20/40 and L.E.: 20/30.     

Effect of topical cyclosporin A on herpetic stromal keratitis in a mouse model

PURPOSE: To study the effect of topical cyclosporin A on herpetic stromal keratitis (HSK) in a mouse model. METHODS: The corneas of BALB/c mice were infected with herpes simplex type 1 virus. The mice were divided into 4 groups according to topical treatment methods: vehicle solution, 0.01% cyclosporin A, 0.1% cyclosporin A, and 1% cyclosporin A. The severity of stromal keratitis was graded clinically at 3, 7, 10, and 14 days after treatment. Histologic and immunohistochemical examinations were performed to analyze infiltrating inflammatory cells and T lymphocytes at 14 days after treatment. Flow cytometry was performed to count CD4 T cells at 14 days after treatment. RESULTS: On day 3 after treatment, there were no significant differences in mean severity scores of HSK between the vehicle and cyclosporin A-treated groups. On days 7, 10, and 14, the severity scores in the groups treated with 0.1% or 1% cyclosporin A decreased significantly compared with the vehicle group (P < 0.05). However, the scores in the group treated with 0.01% cyclosporin A did not change up to 14 days after treatment. By histologic and immunohistochemical analysis, a significant decrease in the total number of inflammatory cells and T lymphocytes was detected in the groups treated with 0.1% or 1% cyclosporin A. Flow cytometry also showed similar findings. CONCLUSIONS: Topical cyclosporin A effectively reduces stromal haze and inflammation in experimental HSK, and cyclosporin A eyedrops with a >0.1% concentration can be used for the treatment of HSK.     

Efficacy of topical cyclosporine 0.05% in the treatment of dry eye associated with graft versus host disease

PURPOSE: To assess the efficacy of topical cyclosporine 0.05% (Restasis) in patients with dry eye associated with graft versus host disease after stem cell transplantation. METHODS: After completing a 3-month run-in period of using only artificial tears to control dry eye symptoms in both eyes, patients who failed to achieve adequate relief (n = 8) were instructed to instill topical cyclosporine twice a day. Visual acuity, slit-lamp appearance, and intraocular pressure were evaluated every 2 weeks for a minimum of 3 months. In addition, Schirmer basal secretion tests, noninvasive fluorescein breakup time, and tear lysozyme were also performed. Patients were also given a dry eye questionnaire regarding symptoms of burning, tearing, and blurred vision. RESULTS: Dry eye signs improved significantly with cyclosporine treatment in 7 of 8 patients. Cyclosporine provided statistically significant improvements in Schirmer basal secretion scores (P = 0.003), tear breakup time (P = 0.002), and tear lysozyme levels (P = 0.033) after 3 months of treatment. CONCLUSION: The findings in this prospective study suggest that dry eye associated with graft versus host disease can be effectively treated with topical cyclosporine, especially in patients unresponsive to other treatment modalities. These findings should be further evaluated in large-scale, controlled clinical trials.     

Herpes simplex keratitis after ophthalmic surgery

PURPOSE: We report 6 cases of herpes simplex keratitis after ophthalmic surgery, in eyes without clinical history of herpes simplex keratitis. CASES: These cases comprised 6 patients examined at our hospital between April 1992 and November 2001. Past operations were keratoplasty in 5 eyes and cataract surgery in 1 eye. Clinical findings and predisposing factors were evaluated retrospectively. The period between herpetic epithelial keratitis onset and ophthalmic surgery ranged from 1.5 to 79 months. Predisposing factors included corticosteroid therapy and operative wound. The herpetic epithelial lesions were dendritic ulcers in 2 eyes, geographic ulcer in 1 eye, and atypical epithelial lesions in 3 eyes; in all cases, herpes simplex virus (HSV)-DNA was detected by polymerase chain reaction (PCR) in tear fluid. All herpetic epithelial lesions healed with oral and topical acyclovir. CONCLUSIONS: When corticosteroids are used following ophthalmic surgery, physicians should be alert to the possibility of herpetic epithelial keratitis, even in patients with no clinical history of herpes simplex keratitis. PCR detection in tear fluid is helpful in diagnosing this disease.     

Recurrent herpetic keratitis during topical acyclovir application.

Dendritic herpetic keratitis developed in a 49-year-old patient during topical acyclovir treatment. A positive herpes simplex culture was obtained. After acyclovir was replaced by trifluorothymidine and interferon, the dendritic lesion disappeared and herpes simplex culture became negative. Six months later a carcinoma of the larynx was diagnosed. The acyclovir-resistant herpetic keratitis may be associated with the carcinoma because resistant herpes simplex virus strains are predominantly described in patients suffering from immune deficiency.     

Efficacy of (E)-5-(2-bromovinyl)-2′-deoxyuridine in the topical treatment of herpes simplex keratitis

BVDU [(E)-5-(2-bromovinyl)-2-deoxyuridine] has a potent and selective activity against herpes simplex (type 1) in both cell culture systems and animal models. The efficacy of topical BVDU treatment (0.1% eye drops) has been evaluated in 37 patients with different forms of herpes simplex keratitis. Of these patients, 35 were followed for 2–9 months (average 6.5 months). Most of the patients had first been treated with topical IDU (idoxuridine) or ara-A (adenine arabinoside), albeit unsuccessfully, before BVDU treatment was started. Upon BVDU treatment, dendritic corneal ulcers healed in 7.8 days (on average) and the geographic corneal ulcers in 10.8 days. BVDU also exerted a pronounced healing effect on stromal keratitis, whether it was used alone or in combination with topical corticosteroids. No early recurrences were observed. Late recurrences were seen in four patients who again responded quickly to BVDU treatment. No toxic side effects, whether local or systemic, were noted in any of the patients treated with BVDU. These results establish the efficacy of BVDU in the local treatment of herpetic keratitis in man.     

Geldanamycin is effective in the treatment of herpes simplex virus epithelial keratitis in a rabbit model

Background: To evaluate the efficacy of geldanamycin eye drops against herpes simplex virus epithelial keratitis in a rabbit model. Methods: New Zealand white rabbits were randomized into four groups and infected with herpes simplex virus type 1; geldanamycin topical eye drops was initiated 24 h after the infection and maintained for 12 consecutive days. Four groups of rabbits received 5 µg/mL geldanamycin, 10 µg/mL geldanamycin, 0.1% acyclovir and escipient (a kind of artificial tears), respectively. The severity of herpes simplex virus type 1 epithelial keratitis was measured by slit‐lamp and scored for statistics analysis. The virus shedding in eye swabs was isolated, and tissue culture infective dose (TCID₅₀) was determined. Results: Geldanamycin (10 µg/mL) treatment reduced significantly the severity of herpes simplex virus type 1 epithelial keratitis than the other three groups. Geldanamycin (5 µg/mL) was as effective as acyclovir (0.1%) treatment. The effect of geldanamycin against herpes simplex virus type 1 epithelial keratitis correlated with accelerated clearance of virus of the rabbits. Conclusion: Geldanamycin is a promising treatment option against herpes simplex virus type 1 epithelial keratitis. Geldanamycin (10 µg/mL) is better than acyclovir and geldanamycin (5 µg/mL) in the rabbit model. The optimal concentration of this drug in human is still to be determined.     

Bilateral herpetic keratoconjunctivitis

PURPOSE: To review the clinical characteristics and visual outcomes of patients with bilateral herpetic keratitis. DESIGN: Retrospective, noncomparative, observational case series. PATIENTS AND METHODS: A retrospective review of medical records of 544 patients with herpes simplex virus (HSV) eye disease treated between January 1996 and September 2001 was performed at the Department of Ophthalmology, University of Minnesota. Seven patients (1.3%) with bilateral herpetic keratoconjunctivitis were identified. RESULTS: In these seven patients, the age at the initial onset of corneal disease ranged from 7 weeks to 46 years, with a median of 18 years and a mean of 19.3 years. Five patients had systemic atopy, and two patients had severe ocular rosacea. Systemic immune disorders were noted in two patients. Recurrent blepharoconjunctivitis was noted in 8 eyes (57%), epithelial keratitis in 12 eyes (85.7%), stromal keratitis in 9 eyes (64.3%), necrotizing stromal keratitis in 5 eyes (35.7%), and progressive endotheliitis in 2 eyes (14.2%). Corneal complications included opacification, neovascularization, and corneal thinning or perforation. Penetrating keratoplasty was performed in 1 eye, in which endophthalmitis subsequently developed and which required enucleation. Four patients with continued use of oral antiviral prophylaxis (acyclovir 400 mg twice daily) since September 1999 showed significant decreases in recurrence. The average remission in these four patients was 1.7 years. The visual acuity at the last follow-up was 20/40 or worse in 6 eyes (42.8%). CONCLUSIONS: In contrast to unilateral HSV keratitis, our patients with bilateral herpetic corneal infections had underlying atopy or immune deviations and evinced more protracted clinical courses. Long-term prophylactic antiviral treatment has reduced the incidence of recurrence in this group of patients.