Epithelial Downgrowth

Etiology

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.[4] 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.[5][6] Although modern surgical techniques have reduced the risk, epithelial downgrowth has been reported after clear cornea phacoemulsification[2], Descemet's stripping automated endothelial keratoplasty (DSAEK),[7] Descemet's membrane endothelial keratoplasty (DMEK),[1] glaucoma implant surgery,[8] and type 1 Boston keratoprosthesis (KPro).[9]

Epidemiology

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%,[5] but with ranges from 0% to 1.1%.[10] The incidence of this condition after penetrating keratoplasty has been reported as 0.25%.[11] 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.[5][12][13]

Pathophysiology

Epithelial downgrowth occurs when nonkeratinized 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.[14] These cells can come from the conjunctiva or cornea and grow over the cornea, iris, trabecular meshwork, ciliary body, 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.[2][5] Additionally, damaged or denuded endothelium may pose a risk for epithelial migration secondary to loss of contact inhibition.[15] This invasion of epithelium leads to an inflammatory reaction and tissue damage.

History and Physical

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.[5][16] The sheet-like form more commonly presents with marked inflammation and pain.[2] These findings are nonspecific, 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.[17] Gonioscopy may reveal epithelium covering the iris and angle, often resulting in glaucoma.[3] However, intraocular pressure is variable and is normal in many cases due to the presence of a fistula.[18]

Evaluation

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 help identify fistulas, which are commonly cited risk factors for epithelial downgrowth.[5] For suspected iris involvement, argon laser photocoagulation (100-200 micrometers, 0.1 to 0.2 s, 100 to 200 mW) can detect epithelium.[19] A normal iris usually turns dark upon photocoagulation, but the presence of epithelial cells will produce a pathognomonic fluffy white reaction.[8] This method is only helpful 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.[20] 

Specular Microscopy

This noninvasive diagnostic test reveals a pattern consisting of a sharply defined border between endothelium and epithelial downgrowth.[3] 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.[3] However, this test may be ineffective in the presence of corneal edema.[21]

Confocal Microscopy

This noninvasive modality allows the observer to image living tissue at higher resolutions than specular microscopy and is less affected by corneal edema.[21] 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. It may be able to detect changes in the appearance of epithelium after treatment, which could be helpful in following the clinical course of epithelial downgrowth. Confocal microscopy may be more sensitive than light microscopy in detecting residual epithelial downgrowth.[21]

Anterior Segment Optical Coherence Tomography 

Anterior segment optical coherence tomography (AS-OCT) is another noninvasive imaging modality that has been shown to aid in diagnosing epithelial downgrowth after DSAEK and penetrating keratoplasty.[22][23] Epithelial downgrowth will appear as a hyperreflective layer.

Histopathologic Analysis 

Histopathologic analysis is the gold standard to confirm epithelial downgrowth. Diagnosis is based on the classic finding of 1 to 3 layers of stratified, nonkeratinized squamous epithelium on the posterior cornea and anterior iris; however, any intraocular structure can be involved.[5] The source of the epithelium may also be distinguished. If the epithelium contains goblet cells, this indicates conjunctival rather than corneal origin.[16] 

Immunohistochemistry

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 anticytokeratin antibodies found in almost all epithelia.[20] 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.[16]

Treatment / Management

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.[2] 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. Aggressive surgical management is often required; however, some of the more conservative approaches listed below may be used alone or in conjunction with others.(B3)

Cryotherapy

Cryotherapy can be used to eliminate epithelium if localized to the posterior cornea, drainage angle, or ciliary body.[19] This approach can be combined with other surgical techniques, such as penetrating keratoplasty (PKP), fistula resection, or DMEK, to restore clarity and vision.[2][24] Although cryotherapy typically spares other intraocular structures, different success rates have been reported, and endothelial loss should be anticipated, possibly necessitating corneal transplantation later.[2](B3)

Transcorneal Photocoagulation

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.[25] 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.[26] Applying photocoagulation to the posterior surface of the iris or in the angle can also be technically difficult.[2] 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.[27][28] However, all forms of photocoagulation reportedly risk rupturing the cyst, potentially leading to the development of the diffuse, sheet-like form.(B3)

Intracameral Injections

Intracameral injections of antimetabolites such as 5-fluorouracil (5-FU) and Mitomycin-C (MMC) have also been reported as potentially effective treatments for epithelial downgrowth.[28][29][30] 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.[21] Reported dosages range from 40 to 1000 mcg in single or sequential doses.[29][30] One protocol described an initial injection of 1000 mcg/0.1mL of 5-FU combined with 0.1 mL viscoelastic, followed 3 weeks later by another injection of 5-FU at 500 mcg/0.1mL with 0.1mL of viscoelastic.[30] (B3)

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 in which 500 mcg of 5-FU was injected into the anterior chamber after a fluid-gas exchange, followed by a second injection of 500 mcg 2 weeks later without gas.[31] (B3)

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.[32] In some cases, these injections completely resolve epithelial downgrowth, but complications include epithelial defect and corneal decompensation.[29][30](B3)

MMC

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.[26] Yu et al described a protocol beginning with aspirating an epithelial cyst with a 30-gauge needle followed by an injection of MMC at a concentration of 0.0002 mg/mL into the drained cyst.[26] However, MMC can have devastating effects if it leaks into the anterior chamber, so this procedure must be performed with caution.(B3)

Intravitreal Methotrexate 

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).[33] 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.

Surgical Procedures

More aggressive surgical procedures for epithelial downgrowth vary greatly in technique and success rates 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.[34] 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.[17][35][36] (B2)

Although 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.[25][37][25] 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.(B3)

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.

Differential Diagnosis

Fibrovascular 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,[38] rigid Schreck anterior chamber lens implantation,[39] intraocular telescope implantation,[40] and traumatic corneoscleral wound dehiscence.[41] Risk factors appear similar, including prolonged inflammation, wound dehiscence, and delayed wound closure. Symptoms in each are nonspecific, and both appear as translucent retrocorneal membranes.

Complications of fibrous downgrowth are like that of epithelial downgrowth, including glaucoma.[42] However, there are a few distinctions. The membrane in fibrous downgrowth may be vascular and is predominately fibrous instead of cellular.[14][19] 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. However, there are reports that immunohistochemical positive staining for α-smooth muscle actin can help sway the diagnosis toward fibrous downgrowth.[43] 

Management mainly appears to be similar between epithelial and fibrous downgrowth using 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.[14] Intracorneal and subconjunctival routes of injection were chosen instead of intracameral due to the presence of glaucoma and intravitreal silicone oil.

Pseudophakic Bullous Keratopathy 

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 reduced visual acuity, tearing, and pain. However, signs of PBK include stromal edema and subepithelial 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 anticytokeratin antibodies in epithelial downgrowth.[20]

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.[16]

Prognosis

Visual outcome after a diagnosis of epithelial downgrowth is generally poor due to recurrence, refractory glaucoma, and corneal decompensation.[15] Prognosis tends to be worse in the diffuse, sheet-like form because it is more difficult to identify and requires more extensive surgical procedures.[2] Many cases have historically ended in enucleation, most commonly due to severe secondary glaucoma.[5] In one retrospective study from 1953 to 1983, enucleation occurred in 52% of patients treated with surgery and 95% of those without surgery.[5] 

In a series of 52 patients from 1980 to 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.[44] In this study, there were no reported cases of recurrence or enucleation. Although many cases require early and aggressive intervention to prevent permanent vision loss, there are rare case reports of epithelial downgrowth spontaneously regressing.[45]

Complications

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.[42] 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.[9] This can lead to proliferation onto the inner retina, causing tractional retinal detachment and epiretinal membranes.[46]