Epithelial Downgrowth: A New Option for an Old Adversary

By Rajeev K. Seth, MD, C. Stephen Foster, MD, and John J. Huang, MD

Edited by Ingrid U. Scott, MD, MPH, and Sharon Fekrat, MD
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.

Pathogenesis/Mechanism

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.

1 Weiner, M. J. et al. Br J Ophthalmol 1989;73:6–11.

2 Maumenee, A. E. et al. Am J Ophthalmol 1970;69:598–603.
3 Shaikh, A. A. et al. Arch Ophthalmol 2002;120(10):1396–1398.
4 Lattanzio, F. A. et al. J Ocul Pharmacol Ther 2005;21(3):223–235.
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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 interest
Complications

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
intractabe 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

Treatment

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 sability 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 µg 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

Summary

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.
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