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Case Reports and Small Case Series
August 2000

Corneal Melting Associated With Use of Topical Nonsteroidal Anti-inflammatory Drugs After Ocular Surgery

Arch Ophthalmol. 2000;118(8):1129-1132. doi:

Nonsteroidal anti-inflammatory drugs (NSAIDs) are used widely for systemic control of acute or chronic pain and inflammation. Topical NSAIDs have been used to effectively alleviate ocular inflammation after cataract removal and argon laser trabeculoplasty and to treat cystoid macular edema. They have also been used for pain control after radial keratotomy and excimer laser photorefractive keratectomy. Additional indications include allergic conjunctivitis and the prevention of miosis during cataract surgery. Despite the increased topical use of this class of drug after ocular surgery, corneal complications due to NSAID use have been uncommon. Reported complications include superficial punctate keratitis,1 subepithelial infiltrates,2 stromal infiltrates,3 immune rings,3 and persistent epithelial defects.4 In August 1999, severe complications associated with topical NSAID use, including corneal melting, were reported by members of the American Society of Cataract and Refractive Surgery (ASCRS) responding to a survey and distributed in letters from ASCRS to members and nonmembers. We report 5 cases of corneal melting associated with the use of topical NSAIDs after ocular surgery referred to our service over a past 4-month period (Table 1). Four of the cases progressed to corneal perforation. Three eyes required tissue glue, 2 required a patch graft, and 1 required a penetrating keratoplasty. Of the 2 eyes for which cultures were obtained, 1 was positive for bacteria. We conclude that topical NSAID use after ocular surgery in healthy patients should be used with caution due to the potential of corneal melting.

Summary of Cases*
Summary of Cases*
Report of Cases
Case 1

A 76-year-old woman was referred for evaluation of a corneal ulcer in her left eye. She had undergone uncomplicated cataract surgery 3 months previously. By history, 2 weeks prior to her visit, she had developed a painful red eye and was prescribed diclofenac sodium (Falcon Ophthalmics, Inc, Fort Worth, Tex), 4 times daily, and artificial tears, as needed, by a local ophthalmologist. On examination, visual acuity was 20/25 OD and 20/50 OS. A 4 × 4-mm epithelial defect and corneal infiltrate associated with 80% tissue loss was noted in the inferior temporal cornea. She had fibrin, 4+ cells, and a hypopyon in the anterior chamber. Corneal cultures were performed, and she was treated with topical fortified cefazolin (50 mg/mL) and tobramycin sulfate (15 mg/mL) every hour alternating around the clock. Diclofenac therapy was discontinued. Cultures were positive for group B streptococcus. Despite treatment, microbial keratitis was complicated by corneal perforation and required cyanoacrylate tissue adhesive 8 days later. Six weeks after diclofenac therapy was discontinued, the corneal sensitivity measured by Cochet-Bonnet esthesiometry was normal (60 mm OD and 55 mm OS). The basal Schirmer tear secretion test result was 2 mm OD and 5 mm OS. Her visual acuity was 20/400 OS, and the tissue adhesive and bandage soft contact lens were in place. Repeated basal Schirmer tear secretion test results 3 months later were 10 mm OD and 15 mm OS.

Case 2

A 66-year-old woman was referred for evaluation of a corneal ulcer in her left eye. She had undergone uncomplicated cataract surgery 4 weeks previously, and was taking apraclonidine hydrochloride and diclofenac (Voltaren; Ciba Vision Ophthalmic, Atlanta, Ga) 4 times daily. She had a history of foreign body sensation, red eye, and photophobia beginning a few days after the surgery. She also noted a burning sensation on installation of the diclofenac drops. She called the surgeon's staff and was told to refrigerate the drops to minimize the burning. Examination disclosed visual acuity to be 20/40 OD and 20/100 OS. A 2 × 4-mm epithelial defect with 50% tissue loss was noted in the inferior cornea. There were rare cells in the anterior chamber and mild stromal infiltration. The ulcer appeared neurotrophic. Diclofenac use was discontinued and she was treated with ciprofloxacin hydrochloride drops every hour and bacitracin ointment every 2 hours to cover possible infection and promote epithelial healing. The ulcer resolved over 2 weeks with mild residual stromal thinning and superficial scarring. The visual acuity was 20/40 OS. Basal Schirmer tear secretion test results were 12 mm OD and 8 mm OS, and the corneal sensitivity measured by Cochet-Bonnet esthesiometry was normal (55 mm OD and 50 mm OS).

Case 3

A 77-year-old white man was referred to the Cornea Service for evaluation of a peripheral corneal perforation in his left eye. He had undergone uncomplicated cataract surgery 2½ weeks prior to his visit and had normal follow-up examination results 1 week previously. He had been taking topical tobramycin-dexamethasone drops and diclofenac drops (Voltaren) 4 times daily since surgery. On examination visual acuity was hand motions in the left eye. Slitlamp examination revealed a perforated corneal ulcer measuring 3.2 × 2.0 mm near the 11-o'clock position. The anterior chamber was flat. The Seidel test result was trace positive because a plug of iris was incarcerated in the perforation. Corneal sensitivity was severely diminished on the left eye. It measured 1 mm in the left eye by Cochet-Bonnet esthesiometer compared with 60 mm in the right eye. The patient was treated with tissue adhesive, a bandage soft contact lens, topical ofloxacin, and intravenous cefazolin (1 g every 8 hours). One week later, his vision improved to finger counting. The tissue adhesive was in place, and the anterior chamber was deep. However, 2 weeks after the placement of tissue adhesive, he underwent a corneal patch graft for a recurrent leak and a flat anterior chamber. Two weeks after the corneal patch graft, basal Schirmer tear secretion test results were 5 mm OD and 9 mm OS. The corneal sensitivities measured by Cochet-Bonnet esthesiometry were 60 mm OD and 35 mm OS.

Case 4

A 71-year-old white man was referred for evaluation of sclerokeratitis in his left eye. He had undergone cataract surgery 10 days previously and was receiving diclofenac (Falcon Ophthalmics, Inc) 4 times daily, and 1% prednisolone acetate 6 times per day since surgery. He had a 3-day history of mild hyperemia and discomfort and a 1-day history of decreased vision in his left eye. Examination showed a 4.5 × 12.0-mm epithelial defect and diffuse infiltrate in the area of his cataract wound superiorly at the limbus with 90% tissue loss. His visual acuity was 20/400. The anterior chamber was deep with fibrin and 4+ cells (Figure 1, A). Cultures were performed, and he was admitted to the hospital and given fortified tobramycin (15 mg/mL) and cefazolin (50 mg/mL) every hour alternating around the clock, and aqueous suppressants. The next day he progressed to corneal perforation with iris prolapse. A corneoscleral patch graft was performed. Cultures were negative and no organisms were identified in the corneal button (Figure 1, B). Three months after patch penetrating keratoplasty, his visual acuity was 20/200 OS (Figure 1, C). At that time basal Schirmer tear secretion test results were 12 mm OD and 30 mm OS, and the corneal sensitivity measured by Cochet-Bonnet esthesiometry was normal (60 mm OD and 55 mm OS).

Figure 1.
Case 4. A, Slitlamp examination shows a 4.5 × 12.0-mm defect superiorly at the limbus with diffuse infiltrate and 90% tissue loss. B, Arrow in photomicrographs denotes loss of epithelium, Bowman layer, and anterior stroma in area of bland ulceration (hematoxylin-eosin, original magnification ×25). Inset shows paucity of inflammatory cells in ulcer bed (hematoxylin-eosin, original magnification ×100). C, Three months after patch penetrating keratoplasty, there is a clear graft and deep anterior chamber.

Case 4. A, Slitlamp examination shows a 4.5 × 12.0-mm defect superiorly at the limbus with diffuse infiltrate and 90% tissue loss. B, Arrow in photomicrographs denotes loss of epithelium, Bowman layer, and anterior stroma in area of bland ulceration (hematoxylin-eosin, original magnification ×25). Inset shows paucity of inflammatory cells in ulcer bed (hematoxylin-eosin, original magnification ×100). C, Three months after patch penetrating keratoplasty, there is a clear graft and deep anterior chamber.

Case 5

A 79-year-old white man was referred to the Cornea Service for evaluation of a descemetocele in the left eye. He had undergone argon laser trabeculoplasty in his left eye 5 weeks previously for chronic open-angle glaucoma. His visual acuities were 20/30 OD and 20/40 OS. Postoperatively he was instructed to use 1% prednisolone acetate 4 times daily for 3 days. Results of a follow-up examination 1 week after argon laser trabeculoplasty were unremarkable. Three weeks after laser surgery he returned with a red eye and was noted to have anterior chamber inflammation. Diclofenac (Falcon Ophthalmics, Inc), 4 times daily, was added to his regimen of glaucoma medications (brimonidine tartrate, dorzolamide hydrochloride, timolol maleate, and latanoprost). Five weeks after argon laser trabeculoplasty, the patient presented with hyperemia, pain, photophobia, and decreased vision in the left eye. His visual acuity in the left eye was finger counting. A 2.5 × 2.0-mm epithelial defect with 99% tissue loss and a descemetocele were noted inferocentrally. There was fibrin and 4+ flare in the anterior chamber. The ulcer appeared sterile (Figure 2, A). Corneal sensitivities measured by Cochet-Bonnet esthesiometry were 50 mm OD and 35 mm OS. Basal Schirmer tear secretion test results were 5 mm OD and 15 mm OS. Tissue adhesive and a bandage soft contact lens were applied over the melt. One week later the contact lens had torn and moved and the tissue adhesive had dislodged. Both the epithelial defect and the descemetocele had enlarged. The ulceration was weakly Seidel positive (Figure 2, B). He underwent therapeutic penetrating keratoplasty the next day. Two weeks later basal Schirmer tear secretion test results were 9 mm OD and 8 mm OS, and corneal sensitivities measured by Cochet-Bonnet esthesiometry were 60 mm OD and 45 mm OS.

Figure 2.
Case 5. A, Photograph 5 weeks after argon laser trabeculoplasty shows a 2.5 × 2.0-mm epithelial defect with 99% tissue loss and descemetocele inferocentrally. B, The descemetocele was Seidel positive.

Case 5. A, Photograph 5 weeks after argon laser trabeculoplasty shows a 2.5 × 2.0-mm epithelial defect with 99% tissue loss and descemetocele inferocentrally. B, The descemetocele was Seidel positive.

Comment

Diclofenac is an anti-inflammatory drug that inhibits cyclo-oxygenase activity and decreases the synthesis of prostaglandins. Prostaglandins contribute to postoperative inflammation and pain. Topical diclofenac has also been used to minimize postsurgical pain. Four drops of the NSAIDs ketorolac and diclofenac instilled over 20 minutes have been shown to significantly decrease normal corneal sensation.5,6 Although decreased corneal sensation was confirmed in only 2 of our patients at time of presentation and was not tested in the other 3, hypesthesia may be why our patients reported little pain and delayed seeking medical attention. All our patients used diclofenac. Seitz et al7 reported that repeated instillation of diclofenac had more pronounced and longer lasting effects on corneal sensitivity than ketorolac. This finding may have predisposed our patients to the severe complication of corneal melting. In all our patients corneal sensitivity was in the normal range after the NSAIDs were discontinued.

Topical NSAIDs are used frequently. NSAIDs, especially diclofenac, are used for the treatment of cystoid macular edema for up to 3 months. Topical indomethacin has been used for inflamed pterygia and pinguecula.8 Ketorolac (Acular; Allergan, Irvine, Calif) is effective in relieving ocular itching caused by seasonal allergic conjunctivitis. Surprisingly, despite the frequent use of topical NSAIDs, there have been few reports of corneal complications.

In addition to reducing pain, NSAIDs have been shown to affect corneal epithelial healing. Topical diclofenac retards epithelial healing to a significantly greater extent than dexamethasone.9 Topical diclofenac has been associated with persistent epithelial defects in patients after undergoing penetrating keratoplasty.4 In addition to the patients described in this report, we have treated 2 other patients who developed acute corneal surface breakdown when given topical NSAIDs for cystoid macular edema. One had severe ocular surface disease due to dry eyes associated with graft-vs-host disease and the other had neurotrophic keratitis following a cerebral vascular accident. The first patient was treated with topical ketorolac and the second with diclofenac.

Three of our patients had corneal melts that were located inferiorly consistent with neurotrophic ulcers. These patients had a normal lid position and lid closure and no evidence of exposure. The melt in the other 2 patients was located superiorly at the limbus near the phacoemulsification entrance wound. The corneal and scleral melting in our patients resembled that seen in patients who have an underlying collagen vascular disease. None of our patients was known to have collagen vascular disease. One patient had borderline diabetes.

In our small series of 5 cases, both generic and brand-name diclofenac were used. Two patients used brand-name Voltaren and the other 3 patients used generic diclofenac (Falcon Ophthalmics, generic company of Alcon). This distribution contrasts with a recent letter from the ASCRS indicating that a preponderance of cases occurred with generic diclofenac.

Patients receiving topical diclofenac after ocular surgery, especially cataract surgery, should be monitored closely. The frequency of administration and duration of treatment should be minimized, and as-needed use should be discouraged. A history of ocular surface disease associated with an increased risk of corneal melting is a relative contraindication for topical NSAID use, but patients without any such history may also develop severe complications.

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Article Information

The authors have no proprietary interest in the development or marketing of the drugs mentioned. The authors have no financial interest in any of the products mentioned herein.

Corresponding author: Elisabeth Cohen, MD, Cornea Service, Wills Eye Hospital, 900 Walnut St, Philadelphia, PA 19107 (e-mail: ejcohen@hslc.org).

References
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