Epithelial downgrowth is a rare, but vision-threatening, complication of penetrating ocular trauma or intraocular surgery. In this disease, epithelial cells enter the anterior chamber and proliferate into intraocular structures. Stratified squamous epithelium is not normally present in the interior of the eye but can grow into nearly any intraocular structure. Epithelialization can appear in three forms: pearls, cysts, and sheets. The sheet-like, diffuse form is the most common and most aggressive and more frequently leads to complications like secondary glaucoma. The cystic form, on the other hand, has a more benign course. The natural course of epithelial downgrowth, however, leads to extensive epithelial invasion resulting in inflammation, secondary glaucoma, hemorrhage, and ultimately permanent vision loss or loss of the eye.
This article presents a brief overview of the etiology, pathophysiology, and risk factors for epithelial downgrowth with a broader discussion of the many diagnostic and therapeutic options, along with the advantages and disadvantages of each. Of note, the terms epithelial downgrowth and epithelial ingrowth are sometimes used interchangeably in the literature. However, this article will not discuss epithelial ingrowth that occurs after procedures such as LASIK where there is ingrowth of epithelium into the corneal flap interface.
Epithelial downgrowth should also be distinguished from fibrous downgrowth. These two conditions are quite similar in terms of etiology, risk factors, and complications and are often managed the same way. However, there are subtle but important differences between the two that will be further discussed in the “Differential Diagnosis” section.
Epithelial invasion was first described in 1832 by Dr. William Mackenzie as a semitransparent cyst in the anterior chamber of a patient after a perforating intraocular injury. Since then, epithelial downgrowth has mostly been reported following ocular trauma and cataract surgery, though it has been associated with other procedures such as penetrating keratoplasty, pterygium excision, aspiration of aqueous, and retinal detachment surgery. Although modern surgical techniques have reduced the risk, epithelial downgrowth has been reported after clear cornea phacoemulsification, DSAEK, DMEK, glaucoma implant surgery, and type 1 Boston keratoprosthesis (KPro).
Intracapsular and extracapsular cataract surgery have been reported in the literature as the most common cause of epithelial downgrowth with an average reported incidence of 0.076% to 0.12%, but with ranges from 0% to 1.1%. The incidence of this condition after penetrating keratoplasty has been reported as 0.25%. Most cases of epithelial downgrowth present within the first year following intraocular surgery, but there have been reports of cases presenting decades after surgery or trauma.
Epithelial downgrowth occurs when non-keratinized epithelial cells are introduced through a traumatic or surgical wound and proliferate in the inner structures of the eye. Proposed pathophysiologic mechanisms include implantation of the epithelium, the introduction of a conjunctival flap into a wound, or delayed closure of a wound. These cells can come from the conjunctiva or cornea and grow over the cornea, iris, trabecular meshwork, ciliary body, and crystalline, artificial lens, and retina.
Risk factors potentially allowing for epithelial entry and proliferation include multiple intraocular surgeries, delayed wound healing, gaping wound edges, wound fistulas, iris or vitreous incarceration, and full-thickness sutures. Also, damaged or denuded endothelium may pose a risk for epithelial migration secondary to loss of contact inhibition. This invasion of epithelium leads to an inflammatory reaction and tissue damage.
Patients with epithelial downgrowth will usually present within a year of the inciting event with a variety of symptoms, including decreasing visual acuity, redness, pain, tearing, and photophobia. The sheet-like form more commonly presents with marked inflammation and pain. These findings are nonspecific, however, making the clinical diagnosis of epithelial downgrowth challenging. Slit-lamp examination classically reveals a translucent growth with a scalloped, advancing margin on the posterior surface of the cornea or anterior iris, or a cyst emanating from a wound site. Gonioscopy may reveal epithelium covering the iris and angle, often resulting in glaucoma. However, intraocular pressure is variable and is normal in many cases due to the presence of a fistula.
Many diagnostic tools for detecting epithelial downgrowth have been reported in the literature. Certain modalities may be more useful when specific risk factors or anatomical involvement are suspected. For example, Seidel testing may be useful in identifying fistulas, which are a commonly cited risk factor for epithelial downgrowth. For suspected iris involvement, argon laser photocoagulation (100-200 micrometers, 0.1 to 0.2 s, 100 to 200 mW) can be useful in detecting epithelium. Normal iris usually turns dark upon photocoagulation, but the presence of epithelial cells will produce a pathognomonic fluffy white reaction. This method, again, is only useful in diagnosing iris involvement. Cytology can be performed from an anterior chamber aspirate if free-floating cells are present. Papanicolaou staining may reveal cells of epithelial origin.
Specular microscopy, a noninvasive diagnostic test, reveals a pattern consisting of a sharply defined border between endothelium and epithelial downgrowth. When adjusted to focus on a deeper plane, the microscope will also show a pattern of interlacing borders representing the cell margins of the epithelium. However, this test may be ineffective in the presence of corneal edema.
Confocal microscopy is another diagnostic tool. This non-invasive modality allows the observer to image living tissue at higher resolutions than specular microscopy and is less affected by corneal edema. Visualization of round, hyperreflective nuclei is characteristic of epithelial cell invasion. Confocal microscopy can also help distinguish between fibrous and epithelial downgrowth in the presence of a retrocorneal membrane and may be able to detect changes in the appearance of epithelium after treatment, which could be useful in following the clinical course of epithelial downgrowth. Confocal microscopy may even be more sensitive than light microscopy in detecting residual epithelial downgrowth.
Anterior segment optical coherence tomography (AS-OCT) is another noninvasive imaging modality that has been shown to aid in the diagnosis of epithelial downgrowth after DSAEK and penetrating keratoplasty. Epithelial downgrowth will appear as a hyperreflective layer.
A histopathologic analysis is the gold standard to confirm epithelial downgrowth. Diagnosis is based on the classic finding of one to three layers of stratified, non-keratinized squamous epithelium on the posterior cornea and anterior iris; however, any intraocular structure can be involved. The source of the epithelium may also be distinguished. If the epithelium contains goblet cells, this indicates conjunctival rather than corneal origin. Immunohistochemistry may also be used, but the evidence is limited. Cornea and conjunctival cells can be located by the expression of AE1/AE3, which are anti-cytokeratin antibodies found in almost all epithelia. However, corneal endothelium may also express cytokeratins, making it difficult to distinguish between attenuated squamous epithelium and a single layer of corneal endothelium using this method alone.
Historically, many therapeutic modalities have been used to treat epithelial downgrowth. These include surgical interventions such as iridectomy, vitrectomy, cautery, penetrating keratoplasty, cryotherapy, photocoagulation, and mechanical debridement. Medical treatments historically include radiation, alcohol, steroids, and antibiotics. Many of these are no longer used due to complications or high recurrence rates. Regardless, the management of epithelial downgrowth depends on the extent of the involvement and whether it is the cystic or the diffuse, sheet-like form. Often, aggressive surgical management is required; however, some of the more conservative approaches listed below may be used alone or in conjunction with others.
Cryotherapy, for example, can be used to eliminate epithelium if localized to the posterior cornea, drainage angle, or ciliary body. This approach can be combined with other surgical techniques such as penetrating keratoplasty (PKP), fistula resection, or Descemet's membrane endothelial keratoplasty (DMEK) to restore clarity and vision. While cryotherapy typically spares other intraocular structures, different rates of success have been reported, and endothelial loss should be anticipated, possibly necessitating corneal transplantation at a later date.
Transcorneal photocoagulation with an argon laser is typically used for the cystic form of epithelial downgrowth, but in rare cases, has shown effectiveness in treating the diffuse form. This procedure is less invasive than cryotherapy, leading to less inflammation. However, several disadvantages exist, including the need for multiple sessions and a rise in intraocular pressure, caused by the release of cyst contents, subsequently blocking the trabecular meshwork. Applying photocoagulation to the posterior surface of the iris or in the angle can also be technically difficult. Endoscopic photocoagulation with a diode laser has been shown to allow for better visualization and precision and thus complete treatment, especially in the setting of corneal opacification. However, all forms of photocoagulation reportedly risk rupturing the cyst, potentially leading to the development of the diffuse, sheet-like form.
Intracameral injection of antimetabolites such as 5-fluorouracil (5-FU) and Mitomycin-C (MMC) have also been reported as potentially effective treatments for epithelial downgrowth. These injections offer an alternative to more aggressive surgical management. The pyrimidine analog 5-FU inhibits cell proliferation and may alter the appearance of epithelial cells on histopathology. Reported dosages range from 40 to 1000 mcg in single or sequential doses. One protocol described an initial injection of 1000 mcg/0.1mL of 5-FU combined with 0.1 mL viscoelastic, followed three weeks later by another injection of 5-FU at 500 mcg/0.1mL with 0.1mL of viscoelastic. This sequential dose pattern was designed to eradicate rapidly proliferating cells with the first injection. The second injection targets cells in the rest phase that may have proliferated after the drug had cleared. This is similar to a protocol used by Lai and Haller, where 500 mcg of 5-FU was injected into the anterior chamber after a fluid-gas exchange, followed by a second injection of 500 mcg two weeks later without gas. Intraocular injections offer several potential advantages over subconjunctival injections, including the ability to use smaller doses with decreased risk of toxic side effects to the cornea. These injections completely resolve epithelial downgrowth in some cases, but complications include epithelial defect and corneal decompensation.
Mitomycin C (MMC) is a DNA cross-linking antineoplastic agent which also inhibits RNA and protein synthesis. It has been hypothesized that applying MMC in the cystic form of epithelial downgrowth damages the epithelial cells that secrete cyst fluid, leading to regression of the cyst. Yu et al. described a protocol beginning with aspirating an epithelial cyst with a 30-gauge needle followed by injection of MMC at a concentration of 0.0002mg/mL into the drained cyst. However, MMC can have devastating effects if it leaks into the anterior chamber, so this procedure must be performed with caution.
Lambert et al. reported a case of recurrent epithelial downgrowth refractory to membrane peeling, endolaser photocoagulation, and 5-FU injection that was treated successfully with intravitreal methotrexate (400 mcg/0.1mL). The protocol was derived from the treatment of intraocular lymphoma. The first injection was performed with an additional membrane peel and endolaser treatment, followed by injections weekly for 4 weeks, and then every other week for a total of 12 injections.
More aggressive surgical procedures for epithelial downgrowth vary greatly in technique and rates of success and depend on the location and structures affected. In some situations, epithelial cysts can be treated more conservatively, which may be recommended in children to preserve intraocular structures and manage amblyopia. One such technique consists of the viscodissection of the cyst with the aspiration of cyst contents and photocoagulation. Again, these procedures still run the risk of recurrence or converting a cyst into the diffuse form. Therefore, complete excision of cysts along with affected intraocular structures with full-thickness corneoscleral grafting may provide the most definitive surgical management. While the diffuse, sheet-like form may be effectively treated conservatively in rare cases with photocoagulation or epithelial membrane peeling, a more aggressive surgical approach is also usually necessary. Surgical removal of the cystic form is more likely to be successful due to implanted cells being circumscribed within the cyst. These approaches seek to completely remove the epithelium and the intraocular structures involved but run the risk of collateral damage to ocular structures.
To prevent epithelial downgrowth, a meticulous approximation of wound edges and attention to incisions intraoperatively and postoperatively are crucial. Wound leaks should also be evaluated and repaired when applicable.
Fibrovascular Downgrowth vs. Epithelial Downgrowth
The term retrocorneal membrane can encompass both epithelial downgrowth and fibrous downgrowth. Both can be a result of trauma or intraocular surgery; for example, fibrous downgrowth has been reported after cataract surgery, rigid Schreck anterior chamber lens implantation, intraocular telescope implantation, and traumatic corneoscleral wound dehiscence. Risk factors appear to be similar, including prolonged inflammation, wound dehiscence, and delayed wound closure. Symptoms in each are nonspecific, and both appear as a translucent retrocorneal membrane. Complications of fibrous downgrowth are like that of epithelial downgrowth, including glaucoma. However, there are a few distinctions. The membrane in fibrous downgrowth may be vascular and is predominately fibrous instead of cellular. Fibrous downgrowth is also more common than epithelial downgrowth and tends to progress more slowly. There are few adjunctive tests to confirm the presence of fibrous downgrowth, although there are reports that immunohistochemical positive staining for α-smooth muscle actin can help sway the diagnosis towards fibrous downgrowth. However, management mainly appears to be similar between epithelial and fibrous downgrowth with the use of photocoagulation, surgical excision, and intracameral metabolites. Bevacizumab has been suggested as a unique treatment for fibrous downgrowth. Mansour reports using combined intracorneal (0.05 mL; 1.25 mg) and subconjunctival (0.1 mL; 2.5 mg) injections of bevacizumab in a patient to halt vascularization within the fibrous membrane to reduce intraocular bleeding. Intracorneal and subconjunctival routes of injection were chosen instead of intracameral due to the presence of glaucoma and intravitreal silicone oil.
Pseudophakic Bullous Keratopathy vs. Epithelial Downgrowth
Pseudophakic bullous keratopathy (PBK) is the development of irreversible corneal edema after cataract surgery and postoperative inflammation. This corneal edema occurs due to the loss of corneal endothelium secondary to surgical trauma. PBK can clinically resemble epithelial downgrowth with a reduction in visual acuity, tearing, and pain. However, signs of PBK include stromal edema and sub-epithelial bullae. Epithelial downgrowth should be considered in patients undergoing penetrating keratoplasty for presumed diagnoses of PBK, and these may be distinguished immunohistochemically with the presence of anti-cytokeratin antibodies in epithelial downgrowth.
Epithelial Downgrowth vs. Secondary Endothelial Proliferation
Secondary endothelization usually arises from ischemia and can also present after multiple intraocular surgeries. The endothelial cells can proliferate in the angle and anterior surface of the iris. This can be considered a precursor to rubeosis iridis (neovascularization of the iris), which can lead to neovascular glaucoma, a form of secondary glaucoma. Clinically, this can appear as neovascularization of the iris. Histologically, this can be differentiated from epithelial downgrowth by a lack of stratification.
Visual outcome after a diagnosis of epithelial downgrowth is generally poor due to recurrence, refractory glaucoma, and corneal decompensation. Prognosis tends to be worse in the diffuse, sheet-like form because it is more difficult to identify and requires more extensive surgical procedures. Many cases have historically ended in enucleation, most commonly due to severe secondary glaucoma. In one retrospective study from 1953 to 1983, enucleation occurred in 52% of patients treated with surgery and 95% of those without surgery.
In a series of 52 patients from 1980-1996 treated with en bloc excision and corneoscleral grafting, the mean visual acuity at the final follow-up visit was 20/100 in the cystic-type cases and 20/200 in the diffuse-type cases. In this study, there were no reported cases of recurrence or enucleation. While many cases require early and aggressive intervention to prevent permanent vision loss, there are rare case reports of epithelial downgrowth spontaneously regressing.
Complications include chronic inflammation, secondary glaucoma, corneal decompensation, and in severe cases, phthisis bulbi. Glaucoma is common with the diffuse sheet-like form and may occur due to blockage of the trabecular meshwork by the epithelium directly or by mucin from conjunctival goblet cells. Inflammation can also lead to peripheral anterior synechiae and trabeculitis, worsening aqueous drainage. This secondary glaucoma is often refractory to medical management and is a major cause of irreversible vision loss in epithelial downgrowth. Management usually centers around combining topical intraocular pressure-lowering medications with a glaucoma drainage device and possibly cryoablation procedures. Epithelium can also progress to the posterior chamber in the setting of aphakia, lens luxation, trauma, or scleral buckle insertion. This can lead to proliferation onto the inner retina causing tractional retinal detachment and epiretinal membranes.
The patient should be informed of the treatment options for epithelial downgrowth, and that recurrence is common. Patients should also be educated that depending on the extent of disease, the goal of treatment may not be to completely restore visual acuity and function, but rather to achieve stability and comfort. If surgery is pursued, the patient should be encouraged to follow postoperative safety measures to improve outcomes.
Epithelial downgrowth is a rare, but vision-threatening, complication of penetrating ocular trauma or intraocular surgery.
Epithelial downgrowth ranges in the severity of presentation but can include decreasing visual acuity, redness, pain, tearing, and photophobia.
A thorough history and physical examination, in addition to supplemental studies like imaging and histopathology, is crucial to diagnose epithelial downgrowth accurately.
Treatment options depend on the extent of involvement and growth pattern and vary from conservative measures to surgical excision with corneoscleral transplantation.
Epithelial downgrowth is a rare pathology, but clinicians should be able to identify it promptly to minimize severe complications. Managing epithelial downgrowth requires a team of medical professionals. Physicians, eye care specialists, nurses, technicians, and medical assistants should be thorough when performing the history and physical, paying particular attention to previous intraocular surgeries or trauma. The clinician should be aware of relevant testing to expedite the diagnosis of epithelial downgrowth, as it is progressive and carries a poor prognosis. The patient should be adequately informed on the diagnosis, treatment options, and complications.
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