Development of Herpes Simplex Virus Infectious Epithelial Keratitis During Oral Acyclovir Therapy and Response to Topical Antivirals

CASE REPORT

Stuart B. Carter, MD, and Elisabeth J. Cohen, MD

clinician experience and preference. Here we present 3 cases Purpose: To describe 3 cases of herpes simplex virus (HSV) of HSV blepharoconjunctivitis that progressed to corneal vesicular blepharitis that progressed to infectious epithelial keratitis epithelial keratitis despite receiving treatment doses of oral despite treatment with oral acyclovir, but responded to topical acyclovir, and subsequently resolved with the addition of antiviral therapy. topical antiviral therapy. Methods: Retrospective review of a small case series. Results: One adult and 2 children presented with unilateral HSV MATERIALS AND METHODS vesicular blepharitis without evidence of corneal involvement. Each We retrospectively reviewed the medical records of 3 patient was placed on a therapeutic dose of oral acyclovir. While patients who presented to the New York University Ophthal- taking oral antiviral therapy, the patients developed HSV infectious mology Service with a diagnosis of HSV vesicular blepharitis epithelial keratitis, which was treated with trifluridine 1% solution 9 and subsequently developed HSV infectious epithelial kera- times daily in the adult and ganciclovir 0.15% ophthalmic gel 5 titis while on oral antiviral therapy. This case series is exempt times daily in the 2 children. All 3 cases showed resolution of from review by the New York University School of Medicine epithelial keratitis within 3 to 10 days after initiation of topical Institutional Review Board. antiviral treatment while oral acyclovir was continued. Conclusions: Oral antiviral therapy alone may not adequately RESULTS prevent progression of infectious ocular HSV blepharoconjunctivitis. Topical antiviral therapy appeared to enable resolution of HSV Case 1 epithelial keratitis that arose during oral acyclovir treatment. A 25-year-old female presented to the eye clinic with 1 day of painful vesicular rash on her left upper and lower Key Words: herpes simplex virus, infectious epithelial keratitis, eyelids. She complained of redness and tearing in the left eye, blepharitis, antiviral medication but denied any change in vision. Her past medical history was (Cornea 2016;35:692–695) significant for eczema and asthma, and she had experienced a mild exacerbation of facial eczema 3 days prior for which she had not sought treatment. She denied any recent use of erpes simplex virus (HSV) ocular disease may present topical or oral steroids, only using an albuterol inhaler Hwith a variety of anterior segment manifestations includ- occasionally as needed. She had a history of prior episodes ing blepharoconjunctivitis, epithelial keratitis, stromal kerati- of oral cold sores, but denied any previous history of ocular tis, endothelial keratitis, and iritis.1,2 Both topical and oral infections or similar lesions around the eyes. Vision was antiviral agents have shown efficacy in the treatment of HSV found to be 20/20 in OD and 20/25 in OS at distance with epithelial infections. Randomized controlled trials such as the spectacle correction. Slit lamp examination revealed crops of Herpetic Eye Disease Study (HEDS) have refined the clear vesicles along the left medial upper and lower eyelids, treatment of HSV keratitis over the past 20 years.3–5 Specific approaching the lid margins, with scattered ruptured vesicles. treatment for HSV blepharoconjunctivitis is often based on The eyelids were bilaterally erythematous and scaly. There was mild conjunctival injection of the left eye, but no follicles Received for publication December 7, 2015; revision received January 13, or staining on the palpebral or bulbar conjunctiva. The left 2016; accepted January 14, 2016. Published online ahead of print March cornea was clear without fluorescein staining. There was no 18, 2016. anterior chamber reaction, and intraocular pressure (IOP) and From the Department of Ophthalmology, New York University (NYU) School of Medicine, NYU Langone Medical Center, New York, NY. dilated fundus examination were within normal limits. Funded, in part, by the Liesegang Research Fund to publish the figure in Examination of the right eye revealed no abnormalities. The color. patient was administered oral acyclovir 400 mg 5 times daily, The authors have no conflicts of interest to disclose. bacitracin ophthalmic ointment to the left eye and lids 3 times Reprints: Stuart B. Carter, MD, Department of Ophthalmology, New York fi University School of Medicine, 462 First Avenue, NBV 5N 18 (Bellevue daily, and arti cial tears as needed. Hospital Building), New York, NY 10016 (e-mail: [email protected]). The patient was seen in clinic 3 days later with Copyright © 2016 Wolters Kluwer Health, Inc. All rights reserved. improvement in symptoms and reported compliance with

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Copyright Ó 2016 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Cornea Volume 35, Number 5, May 2016 Herpes Simplex Virus Epithelial Keratitis her medications. Examination revealed resolving vesicular good compliance. She denied any medical or ocular history, lesions of the left eyelids, trace conjunctival injection, and but had a history of oral cold sores. On examination in the clear corneal examination without fluorescein staining. The emergency room, the patient’s vision was 20/40 OD and 20/ patient was continued on oral acyclovir. The next day, the 20 OS without correction at near. The right upper lid was patient reported acute worsening of symptoms and increased edematous with a few erosive epidermal lesions without pain and foreign body sensation in the left eye with decreased evidence of marginal involvement. There was moderate vision. She presented for evaluation 2 days later, and vision conjunctival injection. Corneal examination revealed a prob- had decreased to 20/100 OS. Slit lamp examination revealed able geographic central epithelial lesion with multiple discrete multiple dendritic lesions of the central cornea without corneal dendrites nasally without stromal involvement (Fig. stromal involvement (Fig. 1A). The anterior chamber was 1B). There was no anterior chamber reaction, and the IOP and quiet and the IOP was normal. Trifluridine 1% ophthalmic dilated fundus examination were within normal limits. The solution 9 times daily and cyclopentolate 1% ophthalmic left eye was unremarkable. solution 3 times daily were added to the regimen for treatment The patient was administered ganciclovir 0.15% oph- of HSV infectious epithelial keratitis. thalmic gel 5 times daily to the right eye and continued on On follow-up examination the next day, the dendritic oral acyclovir and topical tobramycin ointment. On follow-up lesions of the cornea had decreased in size. After 4 days of examination 3 days later, the patient’s symptoms had trifluridine treatment, there were only trace epithelial defects completely resolved. Vision improved to 20/15 OU at remaining. The patient reported minimal pain, and cyclo- distance without correction and the right eyelid lesions had pentolate was discontinued. After 10 days of topical treat- healed. Corneal examination revealed trace residual superfi- ment, the dendritic lesions had completely resolved with faint cial punctate keratopathy in the right eye and no evidence of residual central superficial punctate keratopathy and underly- stromal disease or uveitis. Ganciclovir gel was then tapered to ing subepithelial haze. After 15 days of treatment, trifluridine 3 times daily for 1 week and the patient was instructed to was decreased to 5 times daily and stopped completely 2 complete a 14-day course of oral acyclovir. weeks later. The patient completed a 20-day course of oral acyclovir at 400 mg 5 times daily. Fluorometholone 0.1% ophthalmic solution was initiated 4 times daily during the Case 3 third week of treatment for residual subepithelial haze, which An 8-year-old male presented to the clinic with a 1-day resolved over the next month. At 7 weeks after initiation of history of a vesicular rash of the right upper and lower topical antiviral therapy, vision had recovered to 20/20 OS eyelids. His parents denied any redness, tearing, or changes in with correction. Fluorometholone was then tapered over vision. He had no past medical or ocular history, recent 3 weeks. illnesses, or history of cold sores. On examination, vision was 20/30 OU at distance without correction. Slit lamp examination revealed multiple vesicles on the right central upper and Case 2 lower eyelids with surrounding edema. The conjunctiva was A 16-year-old female presented to the emergency room white and quiet. The cornea was clear without fluorescein with a 2-day history of right eye redness, blurry vision, and staining. There was no anterior chamber reaction, and the IOP pain. She had a painful vesicular rash of her right upper eyelid and dilated fundus examination were within normal limits. 5 days before presentation, without any ocular symptoms or The left eye was unremarkable. The patient was administered changes in vision. She saw her pediatrician who began oral acyclovir elixir 300 mg 3 times daily (30 mg$kg21$d21; treatment with tobramycin 0.3% ophthalmic ointment to the patient weight = 30 kg) and bacitracin ophthalmic ointment to right eyelids and oral acyclovir 400 mg 5 times daily with the right eyelids 3 times daily.

FIGURE 1. A, Slit lamp photograph of the left eye in case 1 with fluorescein stain under cobalt blue filter demonstrating appearance of multiple dendritic corneal lesions consistent with HSV epithelial keratitis. The lesions developed 4 days after initiation of oral acyclovir. B, Slit lamp photograph of the right eye in case 2 with fluorescein stain under cobalt blue filter demonstrating probable central geographic corneal epithelial lesion with multiple distinct dendritic lesions peripherally, consistent with herpes simplex virus epithelial keratitis. The lesions developed 3 days after initiation of oral acyclovir.

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The patient presented 3 days later with acute redness, recurrences, and are used as prophylaxis.3,12 Oral valacyclovir tearing, and pain in the right eye. His parents reported good has improved bioavailability owing to gastrointestinal absorp- medication compliance. On slit lamp examination, the right tion compared with acyclovir. eyelid lesions had improved; however, the patient was Although acyclovir-resistant HSV has been described, found to have multiple discrete dendritic lesions of the right prevalence in immunocompetent hosts is estimated to be cornea on fluorescein staining without evidence of stromal ,1% with almost all resistance secondary to mutations in involvement. There was no anterior chamber reaction and thymidine kinase.13 Thymidine kinase mutations also confer IOP was normal. Ganciclovir 0.15% ophthalmic gel 5 times resistance to valacyclovir and ganciclovir, however, not daily was added to the patient’s regimen. On follow-up trifluridine.1 Although it is possible, but unlikely, that examinations 1 day and again 1 week later, the corneal acyclovir resistance played a role in the case of the adult epithelial lesions healed steadily and vision recovered to 20/ patient, the rapid response to topical ganciclovir in the 2 25 OU. Ganciclovir gel was then tapered to 3 times daily for pediatric patients makes acyclovir resistance even less likely 1 week and the patient completed a 14-day course of in those cases. oral acyclovir. There is little evidence to support the use of 2 antiviral agents, oral and topical, in the treatment of ocular HSV.14 The HEDS placed patients with HSV epithelial keratitis on topical DISCUSSION trifluridine treatment alone versus the addition of oral We present 3 cases of HSV vesicular blepharitis who acyclovir 400 mg 5 times daily to investigate the effect on had no evidence of corneal disease and developed HSV development of stromal or endothelial keratitis.15 There was infectious epithelial keratitis within 3 to 4 days while no benefit to the addition of oral acyclovir for these outcomes, receiving treatment with oral acyclovir. These cases each and the study additionally noted that there was no difference responded favorably to the addition of topical antiviral in the rate of epithelial healing in these groups as well. In our treatment [trifluridine 1% solution (case 1) or ganciclovir case series, however, the addition of topical therapy to oral 0.15% gel (cases 2 and 3)] with resolution of corneal therapy resulted in immediate improvement and eventual epithelial lesions within 3 to 10 days. While cases 1 and 2 resolution of epithelial keratitis that developed despite oral had a history of oral cold sores, and had recurrent HSV antiviral treatment. infection, case 3 did not have a history of prior cold sores and A small case series found a similar effect in herpes presented with extensive vesicular blepharitis, which may zoster ophthalmicus.16 In 4 patients who developed corneal represent primary HSV infection. Of note, 2 of the 3 patients epithelial dendriform keratitis despite administration of oral in this series were children, who are known to be at risk for valacyclovir, treatment with ganciclovir 0.15% gel resulted severe ocular HSV disease manifestations, recurrences, and in healing. detrimental visual outcomes such as corneal scarring and Our results suggest that oral antiviral treatment may not amblyopia.6,7 Additionally, the adult patient had a history of prevent progression of HSV blepharoconjunctivitis to infec- atopy, which has also been associated with more severe and tious epithelial keratitis, and that addition of topical antiviral recurrent HSV disease.8,9 These cases demonstrate the therapy may be more effective than oral therapy alone. The potential for ocular HSV infectious disease progression occurrence of HSV infectious epithelial keratitis in patients despite treatment with oral antiviral therapy. on therapeutic dosages of oral antivirals was unexpected, and Although treatment of HSV keratitis was advanced by it is important to be aware of this possibility and follow-up the HEDS,3–5 there is still uncertainty regarding best treatment patients closely, especially if new symptoms develop. practices in cases that present with epithelial keratitis. Topical trifluridine 1% solution and ganciclovir 0.15% gel are REFERENCES approved by the Food and Drug Administration for HSV epithelial keratitis. Oral antivirals are not approved by the 1. White ML, Chodosh J. Herpes Simplex Virus Keratitis: A Treatment Guideline. AAO Compendium of Evidence-Based Eye Care; 2014. 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