Epithelial downgrowth represents a migration of corneal or conjunctival epithelial tissue into the eye, potentially causing significant ocular morbidity. Epithelial downgrowth is a rare complication of ophthalmic surgery or penetrating ocular trauma. It is seen most commonly following cataract surgery, but other associated surgical procedures include penetrating keratoplasty, trabeculectomy, glaucoma drainage implantation, transcorneal sutures and pterygium excision. Typically, it manifests as a sheet of tissue but sometimes appears as a cyst or as cells floating in the anterior chamber.
Historically, epithelial downgrowth was encountered more commonly than it is today; in fact, 20 percent of enucleations after cataract extraction in the early part of the 20th century were related to epithelial downgrowth. Recent estimates suggest that epithelial downgrowth occurs in less than 0.1 percent of cataract surgeries, including intra- and extracapsular surgeries. The incidence has further decreased from there thanks to current emphasis on phacoemulsification and better corneal wound construction. During the past quarter century, the incidence has significantly decreased mainly due to technological advances in ophthalmic surgery.
Although rare, epithelial downgrowth is an important entity to recognize, as its sequelae can lead to significant ocular morbity and blindness. The treatment of epithelial downgrowth has been associated with limited success, but recently there have been some advances.
Epithelial downgrowth is typically detected six to 11 months after the initial surgery or trauma, but it can be seen as early as two weeks and as late as 10 years following the inciting event. Epithelium must gain entry into the eye, as it does not develop de novo within the eye by metaplasia.
Several hypotheses exist about its etiology. The three main theories include 1) implantation of epithelial cells within the eye by trauma or surgical manipulation, 2) incorporation of a conjunctival flap of tissue through a traumatic or surgical wound and 3) delayed closure of a corneal or scleral wound. Experimentally, simple implantation of epithelial tissue within the eye has failed to produce the typical downgrowth pattern. The third mechanism is generally accepted to be the most likely, with migrating epithelial cells gaining entry through a persistent open wound.
Epithelial downgrowth usually represents a diagnostic challenge, and a high index of suspicion is required. Therefore, understanding the presenting signs and symptoms is critical.
The most common presenting sign is a retrocorneal membrane, which is found in 45 percent of patients. This characteristic membrane appears as a grayish deposit on the endothelium. It has been noted to grow circumferentially and then centrally. Epithelium can also grow over the iris, causing pupil irregularities or distortion of the normal stromal surface.
Laser photocoagulation is one technique that has helped to identify the borders of the intraocular epithelial membrane on the iris surface. In areas of the iris covered by the epithelial cells, the laser photocoagulation causes a fluffy whitening of the epithelial membrane, not seen on normal iris tissue. Specular microscopy also has been used for the detection of the advancing edge of epithelium on the corneal endothelium. Slit-lamp examination may show evidence of other presenting signs, including iris incarceration, vitreous wick or a positive Seidel test.
Complications associated with epithelial downgrowth include pupillary block, secondary glaucoma, iridocyclitis, corneal edema, corneal decompensation, loss of vision and intractable pain. Glaucoma is present in more than half of cases at presentation, with epithelial downgrowth over the angle, peripheral anterior synechiae and trabecular meshwork all potentially playing a role. The angle structure is partially or totally involved in 87 percent of enucleated eyes with epithelial downgrowth.1
Irradiation was first used to treat epithelial downgrowth in the early part of the 20th century. It had a poor success rate and a variety of postoperative radiation-related complications. More recent treatment modalities involve surgical scraping, peeling, alcohol treatment, cryotherapy and wide excision of epithelial proliferation with ablative therapy to adjacent structures in order to eliminate residual cells.
More conservative therapies are commonly associated with treatment of epithelial cysts with well-defined boundaries. Treatment of these cysts include aspiration of the cystic fluid with or without cauterization, aspiration and diathermy, aspiration and iridectomy, aspiration and injection of sclerosing agents or alcohol, direct electrocautery and photocoagulation.
Unfortunately, all these modalities for epithelial downgrowth are associated with a high failure rate. Failures associated with treatment are related to difficulty identifying the borders of the lesion and the destructive nature of the surgical procedures.
In one study, more than 50 percent of epithelial downgrowth cases treated surgically with most of the techniques described above eventually resulted in enucleation, and eyes that did not have surgical therapy had an even higher enucleation rate.1 Despite the poor surgical outcomes, aggressive management offered a better prognosis than the natural progression of the disease. Another study showed that after surgical treatment of epithelial downgrowth, the eye often continues to have problems with corneal edema, glaucoma, hypotony, vitreous haze and possible retinal detachment. Some of these postoperative complications ultimately lead to phthisis and enucleation. Only 27.5 percent of eyes in that study were considered to have a good result based on visual acuity and the lack of complications.2
A Nonexcisional Approach to Treatment
More recently, 5-fluorouracil, a pyrimidine-analog antimetabolite that inhibits cellular proliferation, has been used as an alternative treatment for epithelial downgrowth. The antimetabolite has been used widely in ophthalmology for conjunctival neoplasia, pterygium and trabeculectomy because of its ability to inhibit cellular proliferation, fibrosis and excessive scarring. And it can be used in a wide range of cases from epithelial cysts to extensive epithelial downgrowth for which excision is not feasible or would lead to hypotony and phthisis.
After a pars plana core vitrectomy and air-fluid exchange, the pupil is pharmacologically constricted with acetylcholine (Miochol). Then, 500 mg of undiluted 5-fluorouracil in a total of 0.2 cc volume is injected with a 30-gauge blunt-tip cannula into the anterior chamber. Postoperatively, the patient maintains face-down positioning such that the drug is localized and concentrated in the area of epithelial downgrowth while the posterior segment remains filled with filtered air. Repeat injections of 5-fluorouracil may be performed postoperatively to re-treat the residual area of epithelial downgrowth.
This nonexcisional approach eliminates the need for extensive surgical dissection using viscoelastic or viscoelastic and 5-fluorouracil mixture, which is often associated with difficulty in identifying the true border and the extent of the epithelial incursion.3 It also helps to avoid damage related to the surgery, such as iatrogenic trauma to the endothelium or bleeding from the iris or the ciliary body.
This technique is capable of treating small or extensive lesions of intraocular epithelial cells and of safely eliminating any recurrence months after the injection. Owing to the selective inhibition of the 5-fluorouracil on actively dividing cells, there is no apparent damage to other intraocular structures, as evidenced by the resolution of cornea edema and the resolution of secondary glaucoma. The safety of needling and subconjunctival injection of 5-fluorouracil can be seen clinically in humans with the repeated injection of the bleb after trabeculectomy at a much higher concentration of the drug. More direct evidence of this safety profile comes from animal studies testing repeated intraocular injection and sustained-release intraocular devices of 5-fluorouracil. These demonstrated no damage to the intraocular structures, including endothelium, ciliary body and the retina.1,4
Epithelial downgrowth is a rare complication of intraocular surgery and penetrating trauma. Because of its rarity, it poses a diagnostic challenge. But it is important to recognize epithelial downgrowth, given its potentially blinding sequelae. Epithelial downgrowth most commonly is secondary to a persistent leaky wound, which may allow conjunctival or corneal epithelium to grow over normal intraocular tissue, including the corneal endothelium, iris and angle structures, or even the retina in aphakic patients. This can lead to corneal edema and difficult-to-control glaucoma. A novel approach using 5-fluorouracil without surgical debridement can be used to treat this condition.
1 Weiner, M. J. et al. Br J Ophthalmol
2 Maumenee, A. E. et al. Am J Ophthalmol
3 Shaikh, A. A. et al. Arch Ophthalmol
4 Lattanzio, F. A. et al. J Ocul Pharmacol Ther
___________________________ Dr. Seth is an ophthalmology resident. Dr. Huang is an assistant professor of ophthalmology. Both are at Yale University. Dr. Foster is a professor of ophthalmology at the Massachusetts Eye Research and Surgery Institute in Cambridge, Mass. The authors report no related financial interests.