CASE REPORT

Marginal Keratitis After Intravitreal Injection of Ranibizumab Seray Aslan Bayhan, MD, Hasan Ali Bayhan, MD, Mehmet Adam, MD, and Canan Gürdal, MD

Purpose: To report a case of marginal keratitis that developed after intravitreal ranibizumab injection.

Methods: A 56-year-old man with diffuse diabetic macular edema received intravitreal injection of ranibizumab into his right eye. Results: One day after injection, the patient presented with pain, redness, tearing, and discomfort in his right eye. Anterior segment examination of the right eye revealed subconjunctival hemorrhage, 3 corneal subepithelial peripheral infiltrates separated from the limbus by a clear zone, and mild anterior chamber reaction. Examination of the eyelids was remarkable for mild blepharitis. Fungal and bacterial cultures were negative. The condition resolved with topical corticosteroids and antibiotics.

Conclusions: Intravitreal ranibizumab injection may trigger hypersensitivity reaction in the form of marginal keratitis in patients with mild blepharitis. Key Words: intravitreal injection, marginal keratitis, ranibizumab (Cornea 2014;33:1238–1239)

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ntravitreal anti–vascular endothelial growth factor (VEGF) injections have yielded promising results for the treatment of many ophthalmic diseases in recent years. However, most of the patients require multiple injections to achieve or maintain therapeutic effects of these drugs, and complications associated with this therapy have been reported.1 Because of the common use of intravitreal anti-VEGF agents and the potential need for frequent injections, investigation of the complications of these injections is important. In the case presented, treatment of diabetic macular edema with intravitreal ranibizumab (IVR) injection has resulted in consecutive appearance of culture-negative subepithelial peripheral corneal infiltrates. To the best of our knowledge, marginal keratitis after IVR injection has not been previously reported.

CASE REPORT A 56-year-old man was referred to our retina clinic with diffuse macular edema due to diabetic retinopathy. His medical history was significant for 10 years of diabetes mellitus and hypertension. His best-corrected visual acuity was 0.7 in the right eye and 0.6 in the left eye. Intraocular pressure was normal in both eyes. On slit-lamp examination, the corneas were clear, no epithelial defects or infiltrates were determined, and only mild nuclear sclerosis was evident. Treating both eyes with IVR injections was decided. First, 0.5 mg/0.05 mL ranibizumab was injected into the left eye. Follow-up visits were on days 1 and 7. No complications were detected. One week after the first injection, the patient received 0.05 mg/0.05 mL IVR to his right eye under standard aseptic conditions. One day after injection into the right eye, the patient presented with pain, redness, tearing, and discomfort in the injected eye. On examination, visual acuities were 0.7 in both eyes. Slit-lamp biomicroscopy revealed subconjunctival hemorrhage over the injection side, +2 conjunctival vascular injection, 3 corneal subepithelial peripheral infiltrates, and +1 cells in the anterior chamber in the right eye. Corneal infiltrates were creamy white subepithelial infiltrates separated from the limbus by a clear zone, reminiscent of blepharitis induced marginal keratitis (Fig. 1). The patient also had 1+ blepharitis that was disregarded before injection. Dilated fundoscopy was stable, and no vitritis was noticed. Bacterial and fungal cultures were obtained. Gram stain scraping from one of the infiltrates found no bacteria. Because of the peripheral location and appearance of multiple infiltrates, the condition was thought to be noninfectious and decision was made to treat with moxifloxacin eye drops 4 times and dexamethasone eye drops 8 times a day. The patient was recommended to start doxycycline 100 mg orally each day along with lid hygiene instructions. All cultures were negative in both eyes. Over the next few days, there was significant improvement regarding complaints and corneal findings. There was marked improvement of the infiltrates over the next 3 days, and dexamethasone eye drops were tapered to 4 times a day. Infiltrates gradually resolved, and the cornea did not develop any epithelial defect. One month after the IVR injection, slit-lamp examination of each cornea revealed clear corneas with no infiltrates.

DISCUSSION Received for publication June 1, 2014; revision received July 25, 2014; accepted July 26, 2014. Published online ahead of print September15, 2014. From the Department of Ophthalmology, Bozok University Faculty of Medicine, Yozgat, Turkey. The authors have no funding or conflicts of interest to disclose. Reprints: Seray Aslan Bayhan, MD, Department of Ophthalmology, Bozok University Faculty of Medicine, Adnan Menderes Bulvarı, Yozgat 66200, Turkey (e-mail: [email protected]). Copyright © 2014 by Lippincott Williams & Wilkins

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Corneal complications due to anti-VEGF agents during repeated injections include corneal epithelial defects, corneal edema, delayed corneal healing, and limbal insufficiency. However, prospective randomized clinical trials including large series about postoperative corneal complications associated with intravitreal injections are absent, and most of these reported complications belong to small series and case reports.1–3 The most common drug-related side effect of ranibizumab is the development of uveitis.4 Similarly, our patient Cornea  Volume 33, Number 11, November 2014

Cornea  Volume 33, Number 11, November 2014

FIGURE 1. Photograph of the right eye 1 day after intravitreal injection of ranibizumab shows subconjunctival hemorrhage, conjunctival hyperemia, and marginal corneal infiltrates.

had +1 cells in the anterior chamber, also indicative of intraocular inflammation. In this case, our patient with mild blepharitis presented with multiple culture-negative peripheral catarrhal infiltrates of the cornea the day after IVR injection. The location of multiple whitish subepithelial infiltrates was between the 3 and 6 o’clock position in the peripheral cornea and separated from the limbus by a 1- to 2-mm clear zone. The infiltrates resolved with intensive corticosteroid treatment. The clinical findings and response to corticosteroid treatment were compatible with classical marginal keratitis. To the best of our knowledge, there is no reported case of marginal keratitis after IVR injection. Marginal keratitis is a condition thought to result from a hypersensitivity reaction. It is mostly seen in patients with chronic staphylococcal blepharitis.5 The exact mechanism of corneal complications after anti-VEGF injections is unclear. Nevertheless, the corneal epithelium was shown to express VEGF-A. VEGF-A and its receptors are thought to be the basis of these complications.6 During intravitreal injection procedures, there is a possibility of ranibizumab reflux from the intraocular compartment onto the ocular surface. Amount of reflux of anti-VEGF agents is mostly determined by characteristics of the eye including intraocular pressure, scleral thickness, and the degree of liquefaction of vitreous.7 Ranibizumab, which refluxes to the ocular surface, might lead to a hypersensitivity reaction that results in marginal keratitis. Previously, topical eye drops were also shown to cause a hypersensitivity reaction leading to

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Marginal Keratitis After IVR Injection

marginal keratitis.5,8 Colombres et al3 reported that inhibition of VEGF adversely affects corneal physiology and leads to an inflammatory state. In addition, VEGF and its receptors are expressed by neurons and corneal nerves are known to have an important role in protecting the cornea from irritants and help to maintain a healthy ocular surface.9,10 Thus, deterioration of corneal physiology due to the blockage of VEGF activity by ranibizumab, toxic response to the drug or excipients, immune response to the drug or excipients, or rebound inflammation secondary to VEGF suppression might have contributed to the formation of marginal keratitis in our case. However, it should be noted that the development of marginal keratitis the day after injection in this patient with mild blepharitis could be only by coincidence. Preoperative screening is a key factor for successful intravitreal injection. Based on this case, clinicians should be aware of the hypersensitivity reaction in the form of marginal keratitis after injection of ranibizumab in patients with blepharitis or meibomian gland dysfunction even if the condition is mild. Development of sterile corneal infiltrates is an adverse event that might be included in informed consent of patients undergoing IVR injection procedure. REFERENCES 1. Wong LJ, Desai RU, Jain A, et al. Surveillance for potential adverse events associated with the use of intravitreal bevacizumab for retinal and choroidal vascular disease. Retina. 2008;28:1151–1158. 2. Bayar SA, Altinors DD, Kucukerdonmez C, et al. Severe corneal changes following intravitreal injection of bevacizumab. Ocul Immunol Inflamm. 2010;18:268–274. 3. Colombres GA, Gramajo AL, Arrambide MP, et al. Delayed corneal epithelial healing after intravitreal bevacizumab: a clinical and experimental study. J Ophthalmic Vis Res. 2011;6:18–25. 4. Tolentino M. Systemic and ocular safety of intravitreal anti-VEGF therapies for ocular neovascular disease. Surv Ophthalmol. 2011;56:95–113. 5. Taguri AH, Khan MA, Sanders R. Marginal keratitis: an uncommon form of topical dorzolamide allergy. Am J Ophthalmol. 2000;130:120–122. 6. Ambati BK, Nozaki M, Singh N, et al. Corneal avascularity is due to soluble VEGF receptor-1. Nature. 2006;443:993–997. 7. Boon CJ, Crama N, Klevering BJ, et al. Reflux after intravitreal injection of bevacizumab. Ophthalmology. 2008;115:1270. 8. Stern GA, Knapp A. Iatrogenic peripheral corneal disease. Int Ophthalmol Clin. 1986;26:77–89. 9. Nowacka MM, Obuchowicz E. Vascular endothelial growth factor (VEGF) and its role in the central nervous system: a new element in the neurotrophic hypothesis of antidepressant drug action. Neuropeptides. 2012;46:1–10. 10. Wilson SE, Ambrosio R. Laser in situ keratomileusis-induced neurotrophic epitheliopathy. Am J Ophthalmol. 2001;132:405–406.

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Marginal keratitis after intravitreal injection of ranibizumab.

To report a case of marginal keratitis that developed after intravitreal ranibizumab injection...
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