Bilateral Herpetic Keratitis After Bilateral Intravitreal Bevacizumab for Exudative Macular Degeneration

CASE REPORT

Angeline M. Derham, MD,* Eric Chen, MD,* Vatinee Y. Bunya, MD,† and Ronan E. O’Malley, MD*

report a case of bilateral herpes simplex virus (HSV) Purpose: To report a case of bilateral herpetic epithelial keratitis epithelial keratitis in a patient with exudative AMD after after bilateral intravitreal bevacizumab injections for the treatment of bilateral intravitreal injections of bevacizumab. exudative age-related macular degeneration. Methods: A 66-year-old man with diabetes and an extensive CASE REPORT history of bilateral anti-vascular endothelial growth factor treatments A 66-year-old white man with well-controlled type II for exudative age-related macular degeneration received an intra- diabetes mellitus was diagnosed 7 years before presentation with vitreal bevacizumab injection in the right eye and triple therapy exudative AMD in his right eye and treatment was initiated with (bevacizumab, photodynamic therapy, and triamcinolone acetonide) pegaptanib intravitreal injections. Medical and ocular histories in the left eye. After 4 days, he presented with pain, photophobia, were otherwise unremarkable, including no history of ocular HSV tearing, and decreased vision in both eyes. Slit-lamp examination infection. Three years later, he also developed exudative macular revealed bilateral dendritic epithelial lesions with terminal bulbs, and degeneration in his left eye. Over the subsequent 4 years, he he was diagnosed with bilateral herpes simplex epithelial keratitis. received numerous intravitreal injections of triamcinolone and anti- vascular endothelial growth factor agents, as well as PDT, in both Results: The patient was treated with ganciclovir ophthalmic eyes without any complications. ointment and oral acyclovir with resolution of signs and symptoms. The patient then received his 14th bevacizumab injection in the right eye and a triple therapy treatment of bevacizumab, full- Conclusions: To our knowledge, this is the first documented fluence PDT, and intravitreal triamcinolone in the left eye on the account of bilateral herpetic epithelial keratitis after bilateral intra- same day. After 4 days, he presented with pain in the right eye and vitreal bevacizumab injections. photophobia in both eyes associated with tearing and decreased vision. His visual acuity had declined from 20/100 in the right eye to Key Words: age-related macular degeneration, bevacizumab, 20/300 and from 20/60 in the left eye to 20/70. Intraocular pressures diabetes mellitus, herpes simplex epithelial keratitis, intravitreal were 17 mm Hg in both eyes. Slit-lamp examination with fluorescein injection staining revealed arborizing dendritic epithelial lesions with terminal bulbs consistent with what is classically seen with HSV epithelial (Cornea 2017;36:878–879) keratitis (Fig. 1). The corneal stroma was clear, and there was no inflammation in the anterior chamber or posterior segment. On further questioning, the patient reported a history of periodic mouth xudative age-related macular degeneration (AMD) is sores, including some active lesions at the time of the previous Ea leading cause of vision loss, and the current standard intravitreal injections. of care often involves intravitreal anti-vascular endothelial The patient was diagnosed with bilateral HSV epithelial growth factor injections, including the off-label use of keratitis and treated with ganciclovir ophthalmic ointment 5 times a day in both eyes and 400 mg oral acyclovir twice a day. After 1 bevacizumab.1 Serious sight-threatening complications from fl month, all symptoms had resolved and both corneas were clear intravitreal injection are rare but can include in ammation, without evidence of scarring. Since then, the patient has under- elevated intraocular pressure, cataract, retinal detachment, and gone 5 monthly intravitreal bevacizumab injections in both eyes endophthalmitis.2 There have been several reports of epithe- with stable vision of 20/100 in the right eye and 20/40 in the left lial herpetic keratitis after both intravitreal3,4 and sub- with no recurrence of HSV keratitis or other complications in Tenon5,6 injections of triamcinolone acetonide, as well as either eye. recurrence after verteporfin photodynamic therapy (PDT).7 However, there has only been 1 report of unilateral epithelial herpetic keratitis after intravitreal bevacizumab injection.8 We DISCUSSION HSV-1 can infrequently result in ocular involvement. Primary infection commonly occurs in childhood but is Received for publication February 14, 2017; revision received March 5, 2017; accepted March 7, 2017. Published online ahead of print May 09, 2017. largely asymptomatic. Latency can develop in the neurons From the *Retina Consultants of Houston, Houston, TX; and †Blanton Eye of cranial nerve ganglia, and autopsy studies have found HSV Institute, Houston Methodist Hospital & Weill Cornell Medical College, DNA in over 90% of trigeminal ganglia.9 Multiple stressors Houston, TX. have been implicated in herpetic activation including aging, The authors have no funding or conflicts of interest to disclose. Reprints: Eric Chen, MD, Retina Consultants of Houston, 6560 Fannin St, immunosuppressive disease, or stress. Such stressors may Suite 750, Houston, TX 77030 (e-mail: [email protected]). reduce the body’s cell-mediated virus-specific immune Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved. response. Recurrent ocular herpes can present as epithelial

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Copyright Ó 2017 Wolters Kluwer Health, Inc. Unauthorized reproduction of this article is prohibited. Cornea Volume 36, Number 7, July 2017 Bilateral Herpetic Epithelial Keratitis

FIGURE 1. Slit-lamp photography of both eyes under white light (top row) and cobalt blue filter after fluorescein staining (bottom row) shows arborizing dendritic epithelial lesions with terminal bulbs. keratitis in either eye; however, bilateral keratitis is rare and is treatment should be considered in the setting of concurrent often seen only in the setting of immunosuppression.10 immunosuppressive disease. Accounts of herpetic keratitis after intravitreal and sub-Tenon triamcinolone injection implicate the role of the injection procedure itself and local corticosteroid-induced REFERENCES immunosuppression in inducing viral reactivation.3–6 1. Dadgostar H, Waheed N. The evolving role of vascular endothelial Although 1 unilateral case has been reported describing growth factor inhibitors in the treatment of neovascular age-related 8 macular degeneration. Eye (Lond). 2008;22:761–767. herpetic keratitis after intravitreal bevacizumab injection, 2. Sampat KM, Garg SJ. Complications of intravitreal injections. Curr Opin to our knowledge, our case is the first report of bilateral Ophthalmol. 2010;21:178–183. HSV keratitis after intravitreal bevacizumab injections. 3. Gulkilik G, Demirci G, Ozdamar AM, et al. A case of herpetic keratitis Many possible factors may have contributed to this rare after intravitreal triamcinolone injection. Cornea. 2007;26:1000–1001. complication. The presence of long-standing diabetes mellitus 4. Shtein RM, Stahl RM, Saxe SJ, et al. Herpes simplex keratitis after intravitreal triamcinolone acetonide. Cornea. 2007;26:641–642. in our patient and in all cited cases of herpetic keratitis after – 5. Hashizume K, Nabeshima T, Fujiwara T, et al. A case of herpetic triamcinolone or bevacizumab injections3 6 suggests that epithelial keratitis after triamcinolone acetonide subtenon injection. neuronal stress in the trigeminal ganglion could be promoted Cornea. 2009;28:463–464. by diabetic microvascular disease.11 Poor diabetic control 6. Inoue H, Suzuki T, Joko T, et al. A case of herpetic keratitis after subconjunctival triamcinolone acetonide injection. Case Rep Ophthal- compounded by physical stressors, the injection itself and/or mol. 2014;5:277–280. the PDT light source, could have triggered the incident. 7. Yoon KC, Im SK, Park HY. Recurrent herpes simplex keratitis after Furthermore, the periodic occurrence of mouth sores experi- verteporfin photodynamic therapy for corneal neovascularization. enced by our patient, including around the time of injection, Cornea. 2010;29:465–467. adds the possibility of active local infection as a risk for HSV- 8. Khalili MR, Mehdizadeh M, Mehryar M. Herpetic epithelial keratitis after intravitreal injection of bevacizumab (avastin). Cornea. 2009;28: 1 ocular reactivation. 360–361. This case of bilateral herpetic keratitis after bilateral 9. Mitchell BM, Bloom DC, Cohrs RJ, et al. Herpes simplex virus-1 intravitreal bevacizumab injections suggests that many exter- and varicella-zoster virus latency in ganglia. JNeurovirol.2003;9: nal and internal factors may contribute to an individual’s risk 194–204. 10. Liesegang TJ. Herpes simplex virus epidemiology and ocular impor- of corneal herpetic reactivation. Therefore, in the presence of tance. Cornea. 2001;20:1–13. active oral ulcers of suspected herpetic origin, close follow- 11. Kaiserman I, Kaiserman N, Nakar S, et al. Herpetic eye disease in up after intravitreal injections and prophylactic antiviral diabetic patients. Ophthalmology. 2005;112:2184–2188.