Glaucoma filtration surgery is often augmented with antifibrotics to minimize scar tissue formation and thus increase chances for long-term surgical success.1 Pediatric patients in particular are known to have aggressive healing responses, which places them at greater risk for surgical failure.2 However, the use of antifibrotics in the pediatric population remains controversial with respect to both efficacy and safety. Although studies have shown mitomycin C (MMC) to be more effective than 5-fluorouracil in lowering intraocular pressure, it is also associated with more severe complications.1,3–5 The antifibrotic 5-fluorouracil is thought to be less toxic to the corneal endothelium. We report a case of an infant with primary congenital glaucoma who developed a transient corneal opacity lasting 2 weeks following trabeculectomy revision with adjuvant 5-fluorouracil. We also review the literature on endothelial dysfunction attributed to 5-fluorouracil.
A 3-month-old male infant with bilateral primary congenital glaucoma presented to the University of Maryland Department of Ophthalmology in Baltimore, Maryland, with marked corneal edema 4 days after bleb needling with 5-fluorouracil in the right eye. His previous surgical history in the affected eye included goniotomy and combined trabeculotomy and trabeculectomy, notably without the use of any antifibrotics. The left eye stabilized after initial angle surgery. The patient was otherwise healthy. There was no family history of glaucoma or ocular disease.
The patient underwent bleb needling with suture lysis and subconjunctival injection of 0.25 mL of 50 mg/mL 5-fluorouracil superonasally and away from the superotemporal bleb. On postoperative day 1, the anterior chamber was formed and the cornea was grossly clear with no significant opacity noted. The patient was prescribed prednisolone acetate 1% four times daily with reportedly strong adherence. On postoperative day 4, the patient was noted to have epiphoria, photophobia, and blepharospasm. His parents noticed that the operative eye started to look “cloudy” the day before. His visual acuity was central, steady, and unmaintained in the affected right eye and central, steady, and maintained in the left eye. He demonstrated a preference for the left eye. Intraocular pressure (IOP) in the right eye, measured with Icare tonometry (Icare Finland Oy, Helsinki, Finland), was 23 mm Hg. Anterior segment examination was significant for a focal nasal corneal opacity involving 40% of the cornea in the eye operated on (Figure 1). The opacity was found to involve the endothelium and deep stromal layers on portable slit-lamp examination. There were no tears in Descemet's membrane. The temporal side of the cornea was clear. Anterior chamber examination had appropriate postoperative inflammation. The lens and posterior segment examinations were unremarkable.
Digital photograph of patient's right eye demonstrating substantial nasal corneal clouding on postoperative day 4 after trabeculectomy revision with subconjunctival injection of 5-fluorouracil.
The patient was observed closely over the next 2 weeks and prescribed prednisolone acetate 1% eight times daily, oral acetazolamide taper, and phenylephrine 2.5% in his right eye immediately followed by 2 hours of patching. His IOP improved and remained stable in the mid-teens as measured by Perkins tonometry (Haag Streit, Mason, OH) and Tono-Pen (Reichert Technologies, Depew, NY). There were no signs of infection. This patching regimen with pharmacologic dilation was chosen to prevent amblyopia; the patient's undilated pupil was completely obscured by the corneal clouding but his dilated pupil allowed for a clear view through the temporal cornea. Corneal clarity gradually improved and the clouding completely resolved after 13 days without recurrence (Figure 2).
Digital photograph of patient's right eye with full resolution of corneal clouding noted 13 days later.
The patient subsequently required implantation of a Baerveldt tube shunt (Abbott Medical Optics, Abbott Park, IL) in his right eye. Six months postoperatively, IOP was measured at 12 mm Hg in the affected eye by both Tono-Pen and Perkins tonometry. Notably, his vision was central, steady, and maintained in both eyes with no sign of amblyopia.
Surgical management is the mainstay of treatment for congenital glaucoma.2 Whereas angle surgery is the preferred and most common approach, trabeculectomy is used in patients with refractory congenital glaucoma. The main mechanism of trabeculectomy failure is scarring of the surgical site.3 Filtration surgery in pediatric patients has been associated with lower success rates compared to adult populations due to the rapid healing response and thick Tenon's capsule in children.2 For this reason, antifibrotics are commonly used to augment trabeculectomy in this population.2
In this particular case, the differential diagnosis for corneal clouding after trabeculectomy revision surgery includes infection, elevated IOP, Descemet's membrane tear, and intracorneal drainage of aqueous. Examination effectively ruled out these etiologies. We believe that the corneal clouding was a potential complication of 5-fluorouracil injection.
MMC may be more effective at lowering IOP than 5-fluorouracil, but is believed to have a higher potential for corneal endothelial toxicity. This case report illustrates the potential toxic effect of 5-fluorouracil to the corneal endothelium in pediatric patients with glaucoma. In two separate meta-analyses, Lin et al.1 and De Fendi et al.3 compared the efficacy of 5-fluorouracil and MMC and found intraoperative MMC to be more effective in lowering IOP, although they disagree as to whether 5-fluorouracil is comparable to MMC for overall success rate. MMC is also associated with more severe complications such as hypotony, leakage of ischemic blebs, endophthalmitis, and corneal toxicity.4,5 Clinical studies and case reports documented significant corneal endothelial loss and corneal edema associated with MMC treatment in photorefractive keratectomy, as well as irreversible corneal decompensation following filtration surgery.5 MMC has additionally been shown to cause corneal swelling, transcellular vacuole formation, and intercellular junction effacement in vitro.6 The fact that MMC is considerably more potent than 5-fluorouracil relative to their antifibrotic activity may explain these findings.3 Whereas 5-fluorouracil is known to cause corneal epithelial toxicity,3 only four prior cases of 5-fluorouracil causing endothelial toxicity or stromal opacity in humans7–9 have been reported to our knowledge (Table 1), and only one of these cases was in a child.
Literature Review: Reports of 5-FU Associated With Corneal Endothelial Toxicity
Mazey et al. described two adult cases of corneal edema within 1 day of trabeculectomy bleb needling revision with subconjunctival 5-fluorouracil injection.7 This spontaneously resolved over the course of 3 to 7 weeks. In one of the cases, the patient was also found to have 4+ corneal pleomorphism by specular microscopy of the involved eye at 7 weeks following injection; however, this had completely resolved at 6 months. In another adult patient, Hirji and Griffiths reported snailtrack-like corneal changes thought to signify corneal endothelial cell damage 1 week following bleb needling augmented with 5-fluorouracil.8 This persisted even at 6 months after bleb modulation. Jalil et al. described a 1-week-old infant with congenital glaucoma who developed bilateral corneal stromal scarring after failed combined trabeculotomy and trabeculectomy augmented with 5-fluorouracil,9 although it is unclear whether the corneal scarring was related to the surgery or the adjuvant treatment. Unlike our case, the toxicity in this instance was permanent, requiring multiple diode laser cycloablations in one eye and a glaucoma drainage implant in the other.
This case illustrates the potential toxic effects of 5-fluorouracil to the corneal endothelium. This is an important consideration in pediatric patients with glaucoma undergoing filtration surgeries augmented with antifibrotics because media opacity can potentially cause deprivation amblyopia. Although this patient's corneal clouding entirely resolved within 13 days without any long-term consequences, even short-term visual deprivation at this critical developmental age may result in some degree of amblyopia.10 Surgeons using adjuvant 5-fluorouracil in combination with glaucoma surgery in pediatric patients should consider the potential toxic effects to the corneal endothelium.
- Lin ZJ, Li Y, Cheng JW, Lu XH. Intraoperative mitomycin C versus intraoperative 5-fluorouracil for trabeculectomy: a systematic review and meta-analysis. J Ocul Pharmacol Th. 2012;28:166–173. doi:10.1089/jop.2011.0117 [CrossRef]
- Ehrlich R, Snir M, Lusky M, Weinberger D, Friling R, Gaton DD. Augmented trabeculectomy in paediatric glaucoma. Br J Ophthalmol. 2005;89:165–168. doi:10.1136/bjo.2004.046037 [CrossRef]
- De Fendi LI, Arruda GV, Scott IU, Paula JS. Mitomycin C versus 5-fluorouracil as an adjunctive treatment for trabeculectomy: a meta-analysis of randomized clinical trials. Clin Experiment Ophthalmol. 2013;41:798–806. doi:10.1111/ceo.12097 [CrossRef]
- Fan Gaskin JC, Nguyen DQ, Soon Ang G, O'Connor J, Crowston JG. Wound healing modulation in glaucoma filtration surgery–conventional practices and new perspectives: the role of antifibrotic agents (part I). J Curr Glaucoma Pract. 2014;8:37–45. doi:10.5005/jp-journals-10008-1159 [CrossRef]
- Roh DS, Funderburgh JL. Impact on the corneal endothelium of mitomycin C during photorefractive keratectomy. J Refract Surg. 2009;25:894–897. doi:10.3928/1081597X-20090617-10 [CrossRef]
- McDermott ML, Wang J, Shin DH. Mitomycin and the human corneal endothelium. Arch Ophthalmol. 1994;112:533–537. doi:10.1001/archopht.1994.01090160113030 [CrossRef]
- Mazey BJ, Siegel MJ, Siegel LI, Dunn SP. Corneal endothelial toxic effect secondary to fluorouracil needle bleb revision. Arch Ophthalmol. 1994;112:1411. doi:10.1001/archopht.1994.01090230025011 [CrossRef]
- Hirji N, Griffiths M. Snailtrack corneal changes following subconjunctival injections of 5-fluorouracil. Eye (Lond). 2012;26:1495–1496. doi:10.1038/eye.2012.169 [CrossRef]
- Jalil A, Au L, Khan I, Ashworth J, Lloyd IC, Biswas S. Combined trabeculotomy-trabeculectomy augmented with 5-fluorouracil in paediatric glaucoma. Clin Exp Ophthalmol. 2011;39:207–214. doi:10.1111/j.1442-9071.2010.02444.x [CrossRef]
- Ober M, Beaverson K, Abramson D. Ocular complications. In: Wallace H, Green D, eds. Late Effects of Childhood Cancer. Boca Raton, FL: CRC Press; 2003:39.
Literature Review: Reports of 5-FU Associated With Corneal Endothelial Toxicity
|Author||Patient Age||Surgery||[5-FU] (mg/mL)||Corneal Toxicity||Postoperative Day||Toxicity Duration|
|Mazey et al. (1994)7||52 y||Bleb needling with 5-FU||50||Edema||1||6 moa|
|Mazey et al. (1994)7||68 y||Bleb needling with 5-FU||–||Edema, pleomorphism||0 (2 hours)||6 moa|
|Jalil et al. (2011)9||1 wk||Combined trabeculotomy and trabeculectomy with 5-FU soaked sponges; Peribleb 5-FU injection||25||Stromal scarring||Unspecified||Unspecifiedb|
|Hirji & Griffiths (2012)8||50 y||Bleb needling with 5-FU||–||Snailtracks||7||> 6 mo|
|Fu et al. (2015)||3 mo||Bleb needling with 5-FU||50||Opacity||4||2 wks|