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Epithelial Downgrowth: A New Option for an

Old Adversary
Written 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
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This article is from May 2008 and may contain outdated material.
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.

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
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

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 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 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.
___________________________
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.
___________________________
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.