Serious Complications of Topical Mitomycin,C after Pterygium Surgery Roy S. Rubinfeld, MD,l,2 Roswell R. Pfister, MD, 3 Raymond M. Stein, MD, 4 C. Stephen Foster, MD,s Neil F. Martin, MD,l,2,6 Samuel Stoleru, MD,z,6 Audrey R. Talley, MD/ Mark G. Speaker, MD, PhD8 Background: The use of topical mitomycin (mitomycin-C) as a medical adjunct to pterygium and glaucoma surgery is increasing. Methods: The authors report on a series of 10 patients who experienced serious, vision-threatening complications associated with the use of this drug after pterygium surgery. Results: Complications included severe secondary glaucoma (4 patients), corneal edema (3 patients), corneal perforation (1 patient), corectopia (2 patients), iritis (8 patients), sudden onset mature cataract (2 patients), scleral calcification (1 patient) and incapacitating photophobia and pain (8 patients). Two patients required penetrating keratoplasties and a third required three lamellar keratoplasties. Another patient underwent four additional surgeries including a conjunctival Z-plasty, scleral patch grafting, and conjunctival autografting before his intractable pain and photophobia resolved 15 months after the original surgery. Because of these complications, 6 patients required a total of 20 return visits to the operating room after their original pterygium surgery. In 5 eyes, visual acuity remained at 20/200 or less. Three of the six patients with the most severe complications had concomitant chronic external diseases (rosacea [3 patients], ichthyosis [1 patient], keratitis sicca [1 patient]). Conclusion: The authors urge extreme caution in the use of mitomycin. If mitomycin is used, the lowest possible concentration should be applied for the shortest time period in an effort to avoid these complications. A prospective multicenter study of the ophthalmic use of this medication is needed. Ophthalmology 1992;99:1647-1654 Originally received: April 2, 1992. Revision accepted: June 5, 1992. Center for Sight/Georgetown University Medical Center, Washington. Department of Ophthalmology, Washington Hospital Center, Washington. I

2

Eye Research Laboratories, Brookwood Medical Center, Birmingham. Department of Ophthalmology, University of Toronto, Toronto, Ontario. S Massachusetts Eye & Ear Infirmary, Boston. 3

4

6 Department of Ophthalmology, George Washington University Medical Center, Washington. 7

8

Department of Ophthalmology, Washington University, St. Louis. Cornea Service, New York Eye and Ear Infirmary, New York.

Presented at the American Academy of Ophthalmology Annual Meeting, Dallas, November 1992. Supported in part by an unrestricted grant from Research to Prevent Blindness, Inc, New York, New York. The authors have no proprietary interest in any medications or products described herein. Reprint requests to Roy S. Rubinfeld, MD, 5454 Wisconsin Ave, Suite 950, Chevy Chase, MD 20815.

Although many surgical approaches to pterygia have been developed, the optimal choice for surgical treatment of this common lesion remains controversial. Simple excision of pterygia results in an unacceptably high incidence of recurrence. Scleral ulceration, cataract, and infection may complicate the use of postoperative beta-irradiation. J The technical difficulties associated with conjunctival grafting have limited its general acceptance, 2 although recent modifications of this procedure may overcome these problems. 3 The use of topical mitomycin (mitomycin-C) to prevent recurrence after pterygium surgery is increasing since its introduction by Kunitomo and Mori 4 in Japan, and its subsequent popularization in the United States by Singh and associates. 5 In these and other reports, the recurrence rate is 0 % to II %.4-9 There have been very few reports of mitomycin treatment complications in the Western literature. 7 ,8,JO For these reasons, mitomycin has appeared to be a favorable alternative to other approaches. We report lO vision-threatening complications associated with the use of topical mitomycin after pterygium

1647

Ophthalmology

Volume 99, Number 11, November 1992

surgery. These cases suggest that certain pre-existing conditions and/or a high cumulative dosage might increase the risk of corneal or scleral ulceration. This knowledge should prove useful in predicting which patients might be likely to have such a complication and how much mitomycin is safe to use.

Case· Reports Case 1. A 67 -year-old white man with ichthyosis underwent pterygium excision ofthe right eye using a bare sclera technique with cauterization of bleeding vessels. Topical mitomycin treatment was initiated on postoperative day I, consisting of 0.02% mitomycin 4 times daily for I week and then twice daily for 3 weeks. For 12 months, the patient experienced constant discomfort. A conjunctival defect was unresponsive to ocular lubricants, topical steroids, and patching. He was referred to a corneal specialist (RSR) for further treatment. He was found to be blepharospastic and in severe pain. Acne rosacea, Meibomian gland dysfunction, and facial skin scaling were present. Visual acuity in the right eye was 20/100. A 6 X 4 mm avascular epithelial defect was found on the nasal portion of the right eye, involving the sclera and adjacent cornea (Fig 1). Corneal edema encircled the epithelial defect, and in one area the sclera was thinned to leave only 40% of its normal thickness remaining. No anterior segment signs characteristic of ichthyosis were present. He was treated with cycloplegics, collagen shields, and patching, with no significant improvement in the epithelial defect. The patient's pain remained severe and intractable. A conjunctival peritomy with closure of the conjunctival defect and autograft of conjunctival and limbal epithelium from the patient's fellow eye were performed. Postoperatively, the epithelial defect resolved until 3 weeks later, when the conjunctiva retracted and the original large epithelial defect recurred. One month after the initial conjunctival graft, a hypopyon developed with severe corneal thinning and infiltrate in the base of the corneal epithelial

defect. Cultures grew Staphylococcus epidermidis . Cyanoacrylate tissue adhesive and a bandage lens were applied to avert impending perforation. Topical Ciprofloxacin drops were started. Five weeks after the original peritomy and conjunctival autograft, the cyanoacrylate was removed, a patch of eye bank sclera was sewn into the bed, and a large conjunctival autograft from the fellow eye was sutured over the graft. A conjunctival Z-plasty and peritomy were performed in an effort to swing a viable flap of vascularized conjunctiva over the eye bank sclera. Postoperatively, the patient felt much improved, and the autograft was vascularized and viable (Fig 2). Three weeks later, the conjunctiva retracted, exposing bare sclera. The conjunctival flap was then undermined and reapproximated with silk sutures. Further retraction and cheese wiring of the silk sutures (Fig 3) necessitated a repeat conjunctival autograft from the other eye. Results of a full systemic evaluation, with special reference to collagen vascular disease including complete blood count, erythrocyte sedimentation rate, antinuclear antibody, hepatitis B antigen, C3, C4, CH 50, chest x-ray, and cryoglobulin screen were within normal limits. Graft retraction prompted a fourth conjunctival autograft 15 months after the original pterygium surgery because of recurrence of the conjunctival defect and intractable pain. Immunofluorescent examination of biopsied conjunctiva showed no evidence of cicatricial pemphigoid. Four months after this final procedure and 19 months after the original pterygium excision, pain and scleral ulceration have resolved, but visual acuity has remained counting fingers with a clear cornea because of severe macular edema. Nonstaining avascular areas of conjunctiva and sclera still persist. Case 2. A 44-year-old Hispanic man underwent bare sclera pterygium excision of the right eye, followed by postoperative instillation of 0.04% mitomycin drops 4 times daily. Topical mitomycin use apparently extended several weeks beyond the 2-week period prescribed by his surgeon because of poor compliance. A nonhealing chronic epithelial defect appeared in the medial cornea and a large contiguous area of medial sclera where the excision had been performed (Fig 4). The epithelial defects did not respond to patching and antibiotics; 2 months later, a

) Top left, Figure 1. Slit-lamp photograph of patient 1 shows a 6 X 4 mm white, avascular ulceration. Top right, Figure 2. Slit-lamp photograph of the same patient after scleral patch graft, repeat conjunctival autograft, and conjunctival transposition shows vascularizing conjunctival transplant and no epithelial defect. Second row left, Figure 3. Slit-lamp photograph of the same patient shows cheese wiring of silk sutures, which had been placed to reappose the conjunctiva after retraction of the second conjunctival autograft. Second row right, Figure 4. Slit-lamp photograph of patient 2 shows a 7 X 6 mm nonhealing medial epithelial defect involving the sclera and contiguous cornea. Arrows show limits of fluorescein staining of the epithelial defect. Third row left, Figure 5. Higher magnification slit-lamp photograph shows corneal stromal edema; 50% stromal thinning is visible (arrow). Third row right, Figure 6. Slit-lamp photograph of patient 2, 1 month after penetrating keratoplasty, anterior vitrectomy, and intraocular lens implantation. Notice the fluorescein staining of the recurrent epithelial defect, which involves medial sclera and host and donor corneal epithelium (arrows). Bottom left, Figure 7. Slit-lamp photograph of patient 4 shows 90% scleral thinning in the bed from which the pterygium was excised. This photograph was taken approximately 1 year after the original pterygium surgery and 9 weeks after a conjunctival transposition. The choroid is visible through the severe scleral thinning. Bottom right, Figure 8. Slit-lamp photograph of patient 5, 3 weeks after pterygium surgery. Notice the white, porcelainized de-epithelialized area of scleral melting. Peaking of the pupil toward the scleral ulceration is visible, as is corneal edema.

1648

1649

Ophthalmology Volume 99, Number 11, November 1992 hypermature cataract and phacomorphic glaucoma developed in the operated eye. An extracapsular cataract extraction was complicated by vitreous loss. Postoperatively, photophobia, chronic blepharospasm, and pain prompted referral to corneal surgeons (NFM, RSR). Best-corrected visual acuity in the right eye was counting fingers. Results of external examination showed severe acne scars of the face and body and bilateral blepharitis with marked Meibomian gland dysfunction. A 7 X 6 mm inferomedial corneal epithelial defect was present. A contiguous staining conjunctival and scleral defect extended approximately 6 mm onto the sclera. There was marked corneal stromal edema and, in one area, the stroma was thinned to approximately 50% of its normal thickness (Fig 5). The patient was treated with patching, collagen shields, topical unpreserved lubricants, and oral tetracycline, 250 mg 4 times daily. His intractable pain and epithelial defects did not respond to several weeks of this conservative treatment. Four months after the initial pterygium surgery, a penetrating keratoplasty, conjunctivoplasty, anterior vitrectomy, and anterior chamber intraocular lens implantation were performed. Postoperatively, the eye was hypotonous, and peripheral choroidal elevations were noted, although no wound leak was present. One week later, a small epithelial defect in the area of the medial limbus developed as the conjunctiva tore loose. This defect enlarged, and the eye became painful again 1 month after keratoplasty (Fig 6). A conjunctival autograft from the left eye was used to cover the epithelial defect on the right medial limbus. His postoperative course was then uneventful for 2 months, until an allograft reaction and elevated intraocular pressure developed, responding to hourly topical prednisolone acetate and levobunolol 0.5% twice daily. He continues to have frequent rejection episodes, but he has been free of pain, and visual acuity has remained at 20/200 for 7 months. Case 3. A 50-year-old black woman had a recurrent pterygium excised from the right eye by a corneal surgeon (CSF) using a bare sclera technique. Her prescribed postoperative medications were 0.04% mitomycin drops 4 times daily for 14 days, Bacitracin-polymyxin-B ointment twice daily for 1 week, and 1% prednisolone acetate 4 times daily for 1 week. The patient failed to return for her first postoperative visit, but instead returned 21 days later with severe pain in her right eye, photophobia, and a throbbing headache. The visual acuity was 20/50. Diffuse 2+ conjunctival injection and a 1+ iritis were present. Conjunctival and scleral avascularity was noted in the operative site, and a conjunctival epithelial defect and superficial punctate keratopathy also were present. The mitomycin drops and bacitracin-polymyxin-B ointment were stopped and the topical 1% prednisone acetate was continued. One week later, the patient was somewhat more comfortable, but the conjunctival epithelial defect and the corneal superficial punctate keratopathy persisted. The findings were essentially the same in follow-up 3 weeks later, although the conjunctival epithelial defect had healed. Four months after surgery, the globe was finally white and quiet and the patient free of pain. The cornea was clear and compact, and, although avascular in appearance (porcelainized), the surgical site was well healed and without evidence of scleral thinning or pterygium recurrence. Case 4. A 50-year-old white man presented with a history of progressive growth of a right pterygium. He had had no previous ocular surgery and uncorrected visual acuity was 20/20 bilaterally. There was a nasal pterygium extending 3 mm onto the cornea in the right eye. The left eye showed a nasal pterygium that had advanced 1 mm onto the cornea. The remainder of the eye examination was unremarkable.

1650

Excision of the right pterygium was performed by a corneal surgeon (RMS) along with a superficial keratectomy. Gentamicin ointment was instilled and the eye was patched for 24 hours. On the first postoperative day, the patient was started on mitomycin 0.04% 4 times daily for 2 weeks, prednisolone acetate 3 times daily for 6 weeks, and gentamicin every day for 1 week. The epithelium healed within 3 days. Five months later, he presented for follow-up, completely asymptomatic, at which point a 2 X 2 mm epithelial defect of the sclera was detected associated with 10% thinning. He was managed with a lubricating ointment and patching initially at bedtime, and then throughout the day. One month later, the epithelial defect had healed completely. He was instructed to use artificial tears three times daily and as required. Follow-up examinations were unremarkable until 4 months thereafter, when the epithelium had broken down again, overlying a 2.0 X 2.5 mm scleral bed. A conjunctival transposition was performed to cover the avascular scleral bed. He was treated with tobramycin and dexamethasone 3 times daily for 2 weeks. The eye appeared to be healing well until 9 weeks later, when the conjunctiva had pulled away from the scleral bed and 90% thinning was observed (Fig 7). He was experiencing no discomfort and visual acuity had not changed from 20/20. There were no signs of neurotrophic keratitis. One week later (13 months after the original pterygium surgery), a 4 X 4 mm scleral patch graft using a fresh donor eye was performed along with a conjunctival and Tenon's transposition. One year postoperatively, the eye has healed well without recurrent inflammation. Case 5. A 41-year-old Hispanic woman underwent a primary pterygium excision of the right eye and was treated with mitomycin 0.02% topical solution in the right eye 4 times daily for 3 days after surgery. The procedure involved a bare sclera technique with minimal cautery. The patient experienced severe irritation and was noted to have blepharoptosis and blepharospasm 3 days after surgery. She was treated with topical prednisolone and aminoglycoside drops without relief. She was referred to a corneal specialist (MGS) 3 weeks after surgery with visual acuity of 20/70. The entire bed ofthe pterygium excision was ulcerated and porcelain white (Fig 8). A diagnosis of scleral melting was made. The remaining conjunctiva was injected and without discharge. The nasal cornea adjacent to the involved sclera was edematous with Descemet's folds extending centrally. Pigmented keratitic precipitates were noted on the central corneal endothelium. A trace cellular reaction was noted in the anterior chamber. The pupil was noted to be peaked in the direction of the involved sclera. At 5 weeks after surgery, a bandage contact lens was placed, which resulted in relief of the patient's symptoms and slow reepithelialization ofthe involved sclera over a period of 4 months. At 5 months after surgery, a small epithelial defect remained. At 8 months after surgery, best-corrected visual acuity was 20/ 200. The patient was then lost to follow-up. Case 6. A 65-year-old white man had a history of pterygium surgery in both eyes 20 years ago. Recurrence of the pterygia caused him to undergo a repeat excision in the left eye with a bare sclera technique followed by postoperative instillation of 0.04% mitomycin drops 4 times daily and prednisolone acetate 1% 4 times daily. After treatment for 3 weeks, a persistent epithelial defect developed in the cornea and adjacent sclera where the pterygium had been excised. All medication was discontinued and the eye was patched. Some improvement was noted, but a secondary iritis soon developed. After treatment of the iritis with cyclopentolate 1% and prednisolone acetate 1%, the epithelial defect again enlarged 5 weeks after surgery with visual acuity of 20/40 in the left eye.

Rubinfeld et al . Topical Mitomycin-C after Pterygium Surgery Despite patching and bandage soft contact lenses, the corneal ulceration was relentless, and a conjunctival flap was performed 8 weeks after surgery. Two weeks later, a 2 X 4 mm perforation occurred with 90% surrounding thinning in a 5 X 6 mm area. This was repaired with an onlay lamellar keratoplasty. Pilocarpine 2% 4 times daily and dexamethasone 0.1 % drops 4 times daily were instituted. One week later, the anterior chamber was formed, but an epithelial defect was present over one third of the graft. Best-corrected visual acuity was counting fingers at 3 feet. Two weeks later, visual acuity was counting fingers at 1 foot. The left eye was irritated, and an epithelial defect was noted on the bulging graft. The pilocarpine and dexamethasone were discontinued and petrolatum ointment four times daily was begun. Two weeks later, visual acuity had improved to 20/80, but there was still a 50% epithelial defect on the graft. Over the next 10 weeks, visual acuity decreased to less than 20/400, the sutures began to loosen, and progressive thinning of the cornea led to a second perforation (Fig 9). He was referred to a second corneal surgeon (RRP), who performed a repeat lamellar keratoplasty patch graft. One week after the graft was performed, visual acuity was counting fingers. Sjogren syndrome was diagnosed on the basis of dry eye and rheumatoid arthritis. Acne rosacea also was present. Closure of all puncta and placement of a bandage lens relieved the pain in the patient's left eye until 2 weeks later when the pain returned and visual acuity decreased to hand motions at 3 feet. Infiltration and ulceration of the graft occurred with negative cultures, and the patient was started on cyclophosphamide 50 mg twice daily with homatropine twice daily and soft bandage lenses. After 1 week, there was subjective improvement; however, the epithelial defect and necrosis in the graft was unchanged. The patient was noncompliant in keeping his follow-up appointments and in the use of cyclophosphamide. The second transplant ultimately ulcerated severely and required a repeat lamellar keratoplasty. On systemic cyclophosphamide treatment, the patient's new transplant epithelialized and has been stable for 9 months. Case 7. A 51-year-old Hispanic man underwent excision of primary nasal and temporal pterygia of the left eye using a bare scleral technique. Medical and ophthalmic histories were unremarkable. Postoperative medications included mitomycin 0.04% and neomycin-dexamethasone-polymyxin-B drops 4 times daily for 3 days, then twice daily for an additional 4 days. Three weeks after surgery, the patient experienced pain and severe photophobia. Epithelial defects were seen overlying the areas of pterygium excision. He was treated with cycloplegics, lubricating ointments, and pressure patching, which resulted in reepithelialization and symptomatic relief. Five months later, he presented with severe pain, photophobia, and decreased vision. Best-corrected visual acuity was 20/60 (preoperative visual acuity was 20/20). A 3 X 4 mm conjunctival epithelial defect was present nasally, with 20% scleral thinning, and a 5 X 6 mm defect was seen temporally, with up to 60% thinning. Intraocular pressure had increased to 28 mmHg and a 2+ flare and cell reaction was present. Cycloplegics, erythromycin ointment, pressure patching, and timolol 0.5% were used topically, and oral ibuprofen 600 mg was given 3 times daily to decrease the severe pain. The intraocular pressure continued to increase to 32 mmHg 2 days later. Systemic scleritis work-up and cultures were unremarkable. A tapering dose of oral prednisone starting at 80 mg 4 times daily was instituted, along with dexamethasone ointment 5 times daily, and acetazolamide was used to assist with management of the intraocular pressure. One week later, visual acuity had improved to 20/40, and the epithelial defects were slightly smaller (Figs 10 and 11). One

month later, visual acuity had improved to 20/25 and the intraocular pressure was 16 mmHg. The nasal conjunctival defect had re-epithelialized, and the temporal defect measured 2 X 4 mm, with 30% scleral thinning. Conjunctival transposition surgery was performed because of the scleral thinning. The graft retracted somewhat, and a calcified scleral plaque developed, which was surrounded by mild chronic conjunctival inflammation. Case 8. A 38-year-old white female model presented with a nasal pterygium extending 2 mm onto the cornea of the right eye. Because the pterygium interfered with contact lens wear, she underwent surgical excision of the pterygium and a superficial keratectomy using a bare sclera technique by a corneal surgeon (RMS). Postoperative medications included mitomycin 0.04% 4 times daily for 2 weeks, prednisolone acetate 1% 3 times daily for 6 weeks, and gentamicin drops every day for 1 week. The postoperative course was unremarkable until the patient presented 7 months later with irritation and redness of the right eye. A 1 X 2 mm conjunctival epithelial defect was seen overlying the sclera. The epithelial defect resolved after nightly patching for 1 month. Two months later, the epithelial defect recurred and the patching was restarted. She did not keep her follow-up appointment and returned 3 months later with a larger epithelial defect associated with 50% scleral thinning. A conjunctival and Tenon's transposition was performed 15 months after her original pterygium surgery. The graft retracted and the epithelial defect recurred. Patching the eye every night and tobramycin and dexamethasone three times daily did not heal the epithelial defect. Conjunctival autograft surgery was performed, and the patient has done well postoperatively. Case 9. A 43-year-old man underwent primary excision of a nasal pterygium in his left eye using a bare scleral technique. His ocular and medical histories were unremarkable. Mitomycin 0.04% and dexamethasone-neomycin-polymyxin-B drops were used 4 times daily for 3 days and then twice daily for 3 additional days. The patient did well until 4 months after surgery, when he presented with severe pain and photophobia in his left eye. A 2 X 1 mm conjunctival epithelial defect was present, with 20% scleral thinning and ulceration. There was a 1+ anterior chamber reaction. The patient was treated with cycloplegics, lubricating ointment, and pressure patching, and he gradually became more comfortable over the next 10 days (Fig 12). One month later, the epithelial defect had finally resolved after treatment with artificial tears and bland lubricating ointment. Another month after this, however, the epithelial defect and the pterygium have recurred. Case 10. A 61-year-old Hispanic woman underwent primary pterygium surgery of her right eye using a bare sclera technique. Mitomycin 0.04% and dexamethasone-neomycin-polymyxin-B drops were used 4 times daily for 1 week, and then twice daily for an additional 7 days. The patient did not keep follow-up appointments and returned 3 weeks later. She had continued to use the mitomycin four times daily and experienced decreased visual acuity, severe pain, and photophobia. Visual acuity was 20/100 (preoperative visual acuity was 20/25). Results of slit-lamp examination showed 2+ corneal edema and conjunctival injection, marked pigmented keratic precipitates, and a 3 X 4 mm corneal epithelial defect. Intraocular pressure was 20 mmHg and the patient's cup-to-disc ratio was recorded as 0.35 in both eyes. Mitomycin use was discontinued, and she was treated with erythromycin ointment, cycloplegics, pressure patching, and pain medication. Three months later, the epithelial defect was unchanged, with 20% scleral thinning. A conjunctival autograft was performed.

1651

Ophthalmology Volume 99, Number 11, November 1992

Top left, Figure 9. Slit-lamp photograph of patient 6 shows corneal perforation 6 months after his original pterygium surgery. This patient is status post conjunctival flap surgery and a subsequent o~ay lamellar keratoplasty. This photograph shows the patient's second perforation after pterygium surgery and, mitomycin treatment. Top right, Figure 10. Slit-lamp photograph of patient 7 shows nasal epithelial defect and avascular scleral ulceration 6 months after original pterygium surgery. Bottom left, Figure 11. Slit-lamp photograph of same patient taken at the same time as Figure 12 shows temporal epithelial defect and more severe scleral thinning. Bottom right, Figure 12. Slit-lamp photograph of patient 9 shows epithelial defect and vascular scleral ulceration (open arrow) and corneal edema (closed arrow) 4 months after pterygium excision.

One month later, visual acuity was 20/300 and a corneal epithelial defect developed temporal to the edge of the conjunctival graft with 20% stromal thinning. Intraocular pressure was 26 mmHg,and the patient was treated with topical betablockers, lubricating ointments, and pressure patching. One month later, the cornea had re-epithelialized, but the intraocular pressure remained elevated at 30 mmHg despite the use of oral acetazolamide and topical timolol. A dense cataract developed rapidly, and visual acuity decreased to hand motions. An extracapsular cataract extraction, trabeculectomy, and implantation of a posterior chamber lens were performed. One month after surgery, recurrent corneal epithelial defects developed in the area of previous thinning. Thinning to one half of normal corneal thickness and stromal scarring occurred in this area and extended to involve the central visual axis despite 6 weeks of treatment with lubricating ointments, pressure patching, and bandage lenses. Visual acuity decreased to bare hand motions

1652

and intraocular pressure remained near 30 mmHg despite maximum medical therapy. A penetrating keratoplasty was performed and the patient's glaucoma remained uncontrolled with pressures greater than 40 mmHg. A YAG cyclodestructive procedure transiently decreased the pressure. This procedure was repeated as the pressure increased again. Nine months after this second YAG procedure, the graft was clear and the anterior segment was quiet. Visual acuity remained at hand motions because of end-stage glaucoma.

Discussion Encouraged by excellent results, low recurrence rates, and few reports of complications in the Western literature, the

Rubin/eld et al . Topical Mitomycin-C after Pterygium Surgery use of topical mitomycin is becoming significantly more popular in the pharmacologic armamentarium of ophthalmology. Mitomycin is now being used not only as an adjunct in the surgical treatment of pterygia but also in glaucoma surgeryl1 and as a modulator of corneal wound healing after excimer laser refractive surgery.12 In North America, the use of mitomycin in the treatment of pterygia has been believed to avoid the risk of serious complications. In the Japanese literature, however, there have been reports of scleral ulceration,t3-ls necrotizing scleritis, 13-1S perforation 13,16 iridocyclitis 13-1S cataract IS infection 13,14 glaucoma,15,16 scleral calcification, 14-16 ~nd loss of the eye. IS In the Western literature, only rare, less serious cases of symblephara8 and scleral ulceration 7,8,17,18 and calcification 10 have been reported. This current series constitutes, to our knowledge, the first report in the Western literature of severe visual loss and serious complications caused by mitomycin. Mitomycin is an extremely toxic, noncell cycle-specific alkylating agent. 19 Alkylating agents such as mitomycin form covalent linkages with guanine residues in DNA. This class of drugs is therefore referred to as "radiomimetic" in that their mode of action mimics that of ionizing radiation. 2o Indeed, the complications of beta-irradiation treatment after pterygium surgery are known to include scleral ulceration, infection, and cataract. 1 The systemic use of mitomycin in cancer therapy is severely limited by its toxicity and rapid metabolism by the liver. It is currently used only for the treatment of hypoxic tumor cells of the bladder by topical intravesicular instillation and in treating unresponsive adenocarcinomas in combination with other agents. Systemic mitomycin causes a marked late and often unpredictable toxicity against all three formed blood elements in addition to a major toxic effect on stem cells. 19- 21 We hypothesize that this toxic effect on stem cells, particularly vascular endothelial cells and limbal pleuripotent stem cells, might explain some of the long-term effects of mitomycin. Of note is how remarkably avascular (porcelainized) the scleral beds generally remain after pterygium excision and mitomycin treatment. These areas may well remain avascular permanently. In fact, there is evidence that a single application of mitomycin at the time of filtering surgery may have a lifelong effect on fibroblast activity, conjunctival healing, and the success of filtration surgery.ll,22 Also, in quantitative studies on cultured rabbit fibroblasts, mitomycin-induced inhibition of proliferation became irreversible at higher doses or after longer treatment times. 23 The irritation, photophobia, delay in epithelial healing, and avascularity of the sclera and cornea seen in a significant number of mitomycin-treated patients testify to the ocular toxicity of this medication. Singh and associates S found the 0.1 % concentration of mitomycin to be more irritating than a concentration of 0.04%. Recent research has shown that microgram amounts of mitomycin injected into rabbit eyes causes permanent hypotony, irreversible corneal edema, and loss of most of these eyes. In contrast, similar amounts of injected 5-fluorouracil produced dramatically less corneal endothelial

and other intraocular damage (Stein, RM, personal communication). Other authors also have demonstrated intracameral24 and intravitreal2s mitomycin in rabbits to be extremely destructive. Because of concerns regarding mitomycin toxicity, Hayasaka and associates7.8 have suggested decreasing the postoperative dose from 0.04% 4 times daily for 10 days to 0.02% twice daily for 5 days. These investigators evaluated the efficacy and safety of this lower dose and found it to be more than adequate. There is, however, some controversy in this area. S,17,18 A common element among 9 of the 10 patients in our series is a relatively large cumulative dose of mitomycin. This is consistent with the known pharmacology of mitomycin, specifically that its toxicity increases dramatically with increasing cumulative dose. 19 Also, there are certain conditions that might predispose to corneal or scleral ulceration after pterygium surgery. Pterygium excision with or without topical steroids can lead to corneal ulceration and perforation in Sjogren syndrome. 26 In the current series, one patient had dry eye syndrome and three had acne rosacea blepharitis, a disease causing corneal infiltrates, ulceration, and vascularization in a significant percentage of patients. One patient also carried the diagnosis of ichthyosis. It is probable that mitomycin further inhibits wound healing in these susceptible patients, thereby triggering a prolonged and unresponsive ulcerative process. Some of these processes might be immunologic in nature. The systemic use of mitomycin is associated with a syndrome of microangiopathic hemolytic anemia and thrombocytopenia. This toxic drug effect is likely immune-mediated. 21 Several facts lend support to the concept of an immunologic mechanism in at least some of our cases as well. Intact epithelium and sclera were seen to ulcerate late postoperatively in our cases 4, 7, 8, and 9. The epithelial defects did not respond quickly to patching, suggesting a more complex process than simple epithelial sloughing. A similar but less serious case also has been reported. 18 Also, early reports of mitomycin-induced scleral ulceration 13, 14 described this process as relentlessly progressive in nature, similar to the scleromalacia seen in scleritis, a disease known to be immune-mediated. Finally, in case 6, the patient's clinical course correlated with his compliance in the use of cyclophosphamide, an immunosuppressive drug. The delayed, insidious conjunctival defect and scleral melting seen in four of our cases is particularly worrisome. These patients had uneventful postoperative courses with intact epithelium until several months after surgery. The lesions in some of these patients healed, only to decompensate again months after surgery. These patients may constitute the first reported cases of an expanding pool of patients in whom similar delayed, serious complications may occur. Based on the findings of this study, the following recommendations are made. Patients with conditions predisposing to ulceration or poor wound healing such as Sjogren syndrome, severe keratoconjunctivitis sicca, acne rosacea, atopic keratoconjunctivitis, or herpes keratitis should be excluded from mitomycin therapy. The use of

1653

Ophthalmology

Volume 99, Number 11, November 1992

mitomycin also should likely be restricted to cases involving aggressive or severe pterygia only, if this drug is to be used at all. Indeed, we urge caution in deciding to operate on any pterygium; a cavalier attitude toward this surgery is not appropriate. It also should be noted that conjunctival grafts are a highly successful alternative to the use of mitomycin especially in recurrent pterygia. 3 If a decision is made to use mitomycin, it should be used as a 0.02% (or less concentrated) topical solution, either as a single application at the time of surgery or instilled twice daily for 5 days7.8 or fewer. Dispensing a low concentration of mitomycin in small aliquots with the bottles marked "no refills" may help to assure better patient compliance and limit some potential dangers associated with the use of this drug. Patients should be followed closely and the mitomycin drops should be confiscated after the intended course is completed. Concomitant postoperative use of antibiotics known to cause conjunctival toxicity may exacerbate healing problems or ulceration. 27 Damage to the sclera by episcleral excision or cautery should be avoided. 13,16,17 Patients on mitomycin treatment should be monitored closely for severe ischemia of the operative site, evidence of failure of epithelial healing or ulceration. Lamellar or penetrating keratoplasty may be necessary to replace significant tissue lost. Scleral patch grafts also may be needed. 14 The use of topical corticosteroids and/or systemic agents like cyclophosphamide should be considered. When ulceration develops, transposition of a conjunctival bucket handle from the opposite side may encourage revascularization and thereby arrest ulceration. This report raises serious questions regarding dosage and patient selection criteria in the ophthalmic use of mitomycin-Co In vitro and in vivo dose-response curves should be established for this medication. The carcinogenic potential of this agent also should be carefully evaluated. A multicenter prospective study of the use of mitomycin-C after pterygium excision is needed to evaluate the benefits and risks of this drug. We also suggest careful observation, reporting, and tabulation of these and other similar complications. All ophthalmologists should be aware of the potential for patient misuse of mitomycinC and the possibility of idiosyncratic reactions resulting in vision-threatening complications.

References 1. Tarr KH, Constable IJ. Late complications of pterygium treatment. Br J Ophthalmol 1980;64:496-505. 2. Vastine DW, Stewart WB, Schwab IR. Reconstruction at the periocular mucous membrane by autologous conjunctival transplantation. Ophthalmology 1982;89: 1072-81. 3. Shaw EL. A modified technique for conjunctival transplant. CLAO J 1992;18: 112-16. 4. Kunitomo N, Mori S. Studies on the pterygium. Part IV. A treatment of the pterygium by mitomycin C instillation. Nippon Ganka Gakkai Zasshi 1963;67:601-7. 5. Singh G, Wilson MR, Foster CS. Mitomycin eye drops as treatment for pt_erygium. Ophthalmology 1988;95:813-21.

1654

6. Dash RG, Boparai MS. Pterygium-evaluation of management (primary & recurrent). Indian J Ophthalmol 1986;34: 7-10. 7. Hayasaka S, Noda S, Yamamoto Y, Setogawa T. Postoperative instillation oflow-dose mitomycin C in the treatment of primary pterygia. Am J OphthalmoI1988;106:715-18. 8. Hayasaka S, Noda S, Yamamoto Y, Setogawa T. Postoperative instillation of mitomycin C in the treatment of recurrent pterygium. Ophthalmic Surg 1989;20:580-3. 9. Chayakul V. Prevention of recurrent pterygium by Mitomycin-C. Fortschr Ophthalmol 1987;84:422-4. 10. Dunn JP, Seamone CD, Ostler HB, et al. Development of scleral ulceration and calcification after pterygium excision and mitomycin therapy [letter]. Am J OphthalmoI1991;112: 343-4. 11. Palmer SS. Mitomycin as adjunct chemotherapy with trabeculectomy. Ophthalmology 1991 ;98:317 -21. 12. Talamo JH, Gollamudi S, Green WR, et al. Modulation of corneal wound healing after excimer laser keratomileusis using topical mitomycin C and steroids. Arch Ophthalmol 1991;109:1141-6. 13. Fukamachi Y, Hikita N. Ocular complication following pterygium operation and instillation of mitomycin C. Folia Ophthalmol Jpn 1981;32:197-201. 14. Yamanouchi U, Takaku I, Tsuda N, et al. Scleromalacia presumably due to mitomycin C instillation after pterygium excision. Jpn J Clin Ophthalmol 1979;33: 139-44. 15. Yamanouchi U. A case of scleral calcification due to mitomycin C instillation after pterygium operation. Folia Ophthalmol Jpn 1978;29:1221-5. 16. Yamanouchi U, Mishima K. Eye lesions due to mitomycin C instillation after pterygium operation. Folia Ophthalmol Jpn 1967;18:854-61. 17. Singh G. Postoperative instillation oflow-dose mitomycin C in the treatment of primary pterygium [letter]. Am J Ophthalmol 1989; 107:570-1. 18. Hayasaka S, Noda S, Yamamoto Y, Setogawa T. Reply, 571. To: Singh G. Postoperative instillation oflow-dose mitomycin C in the treatment of primary pterygium [letter]. Am J Ophthalmol 1989;107:570. 19. Gilman AG, Rall TW, Nies AS, Taylor P, eds. Goodman and Gilman's The Pharmacological Basis of Therapeutics, 8th ed. New York: Pergamon Press 1990;1247-8. 20. Bowman WC, Rand MJ, eds. Textbook of Pharmacology, 2nd ed. Oxford: Blackwell, 1980;3:14-5. 21. Craig CR, Stitzel RE, eds. Modern Pharmacology, 3rd ed. Boston: Little, Brown, 1990;807. 22. Bergstrom TJ, Wilkinson WS, Skuta GL, et al. The effects of subconjunctival mitomycin-C on glaucoma filtration surgery in rabbits. Arch OphthalmoI1991;109:1725-30. 23. Yamamoto T, Varani J, Soong HK, Lichter PRo Effects of 5-fluorouracil and mitomycin C on cultured rabbit subconjunctival fibroblasts. Ophthalmology 1990;97: 1204-10. 24. Derrick RJ, Pasquale L, Quigley HA, Jampel H. Potential toxicity of mitomycin C [letter]. Arch OphthalmoI1991;109: 1635. 25. Peyman GA, Greenberg BS, Fishman GA, et al. Evaluation of toxicity of intravitreal antineoplastic drugs. Ophthalmic Surg 1984;15:411-13. 26. Pfister RR, Murphy GE. Corneal ulceration and perforation associated with Sjogren's syndrome. Arch Ophthalmol 1980;98:89-94. 27. Davison CR, Tuft SJ, Dart JKG. Conjunctival necrosis after administration of topical fortified aminoglycosides. Am J Ophthalmol 1991; 111 :690-3.