Epithelial downgrowth after Descemet membrane endothelial keratoplasty

Introduction

Endothelial keratoplasty (EK) surgery is a minimally invasive approach and selectively replaces Descemet membrane (DM) and the corneal endothelial cell layers. ¹ Due to the huge benefits of EK compared with penetrating keratoplasty such as faster visual recovery, better functional outcome, reduced risk of graft rejection, and so on, EK became a standard technique to treat corneal endothelial dysfunction.^2,3 This procedure encompasses two techniques: Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK). Differing from DSAEK, DMEK does not require transplantation of an additional thin adherent stromal layer. Only donor-Descemet with endothelium is grafted. Therefore, DMEK is considered to provide better functional results and even lower rejection rates than DSAEK for Fuchs endothelial corneal dystrophy and bullous keratopathy.^4,5

The invasion of epithelial cells into the anterior chamber is a rare but serious complication observed after open globe injury or intraocular surgery with wound fistula, iris incarceration, significant postoperative inflammation or vitreous in the wound. ⁶ In severe cases, these cells can proliferate and downgrowth onto the iris surface, causing corneal decompensation, corectopia, ectropion uveae, or secondary glaucoma. Epithelial downgrowth (ED) was detected from 0.08% to 0.12% after cataract surgery and up to 0.25% after penetrating keratoplasty. ⁷ Regarding endothelial keratoplasty, few cases of epithelial downgrowth were reported after DSAEK in the last decade. With broad use of this technique, however, epithelial downgrowth was recently reported more often and recognized as a complication after DSAEK. Recent studies showed that 15%–20% of failed DSAEK grafts were related to epithelial downgrowth.^8,9 However, to our best knowledge, only one report related to epithelial downgrowth after DMEK has been described so far. ¹⁰ Herein, we present the clinical course and examination findings of a single case with epithelial downgrowth after DMEK surgery and remarkable stability for now 4 years.

Case report

A 73-year-old, healthy woman with Fuchs endothelial dystrophy underwent a penetrating keratoplasty in 2007 and phacoemulsification with intraocular lens (IOL) implantation in 2009 in the right eye (OD), and in 2010 a triple DSAEK procedure in the left eye (OS; all procedures externally). In July 2012, she presented to our department with poor vision in the left eye. Her best spectacle-corrected Snellen’s visual acuity (BSCVA) was 20/20 in OD and 20/50 in OS. The intraocular pressure (IOP) with iCare tonometer (Icare Finland Oy, Vantaa, Finland) was 12 mmHg OS and 15 mmHg OD. Clinical examination of the left eye revealed gentle stromal edema at the center of the transplant and posterior capsular opacity. One year later, her vision dropped to 20/125 due to stromal swelling. The patient was then planned for DMEK with removal of the failed DSAEK graft in December 2013. The standardized DMEK was carried out by an expert DMEK surgeon with more than 3000 DMEK surgeries experience (C.C.) with some modifications to the procedure described previously.^4,11–13 For the DMEK graft preparation, forceps was used to peel off DM from the donor corneoscleral rim followed by trepanation prior to keratoplasty. A 2.5-mm corneal tunnel and 2-mm paracenteses are created at the 12 and 3 o’clock positions, respectively. Under continuous irrigation, a central circular 9-mm Descemetorhexis is performed using an inverted hook (Price Endothelial Keratoplasty Hook; Moria SA, Antony, France). Following Descemetorhexis, a cataract-shooter was used to insert the graft into the anterior chamber (Acritec; Zeiss, Oberkochen, Germany). Then unfolding of the graft lamella was performed by tapping the graft from outside the eye on the cornea. When needed an air bubble was used to move the graft into the correct position. After centering and unfolding of the graft, the anterior chamber was filled nearly completely with 20% SF6 to secure the graft at the recipient’s posterior corneal surface. Always a surgical iridectomy is placed at 6:00 position. Surgical procedure was uneventful, and a bandage contact lens was applied after the surgery. The standard postoperative medication regime after DMEK was applied with topical steroid (Predni-POS 1%; URSAPHARM, Saarbrücken, Germany) every hour for 1 week and then five times a day, ofloxacin (Floxal 3 mg/mL; Bausch & Lomb, Bridgewater, NJ) twice a day, preservative-free artificial tears (Sodium hyaluronate 0.18%, Vislube; TRB Chemedica, München, Germany) every 2 h, and pilocarpine (Pilomann 2%; Dr. Mann Pharma, Berlin, Germany) twice a day for 5 days. One month after the surgery, her BSCVA of the left eye improved to 20/32. Her vision maintained for over 1 year and decreased to 20/40 at the 14-month visit. The IOP measured 10 mmHg. Slit lamp examination revealed stromal edema and keratic precipitates at the center of cornea. Two localized “islands” with a sharp demarcation within the DMEK graft were detected at 12 and 1 o’clock at the endothelium surface. Epithelial pearls were also seen at the lower third of the smaller “island” (Figure 1(a)). Mild inflammatory reaction was seen in the anterior chamber. No evidence of iris involvement was observed. The IOL was in a good position and the posterior pole was unremarkable. Anterior segment optical coherence tomography (AS-OCT) showed a hyperreflective layer to be under the DMEK graft (Figure 1(b)). Given the clinical findings and results of the diagnostic imaging, a diagnosis of epithelial downgrowth with presumed graft rejection was established. Hence, treatment with intensive topical steroids was initiated. Unfortunately, the treatment was unsuccessful, and visual acuity dropped to 20/80. Therefore, repeat DMEK with intracameral fluorouracil (5-FU) was performed in May 2015. First, the rejected DMEK graft was removed and careful scraping and removal of epithelial cells done under viscoelastic coverage of anterior chamber. After repeated irrigation and aspiration of the anterior chamber and no more visible epithelial strands, 0.1 mL 5-FU in a concentration of 200 µg/mL was intracamerally injected toward the area of ED via 27-gauge needle. After 3 min, 5-FU was completely washed out using balanced salt solution. Subsequently, re-DMEK was performed as the same procedure compared with the first one. The removed DMEK graft was submitted for histology examination. This confirmed the diagnosis of conjunctival epithelial downgrowth (Figure 2). The standard DMEK regime was applied as described above. Visual acuity improved from hand movement in the early postoperative period to 20/25 1 month after the surgery. However, at the 2-month visit, sheet-like epithelial downgrowth was detected at 11 o’clock and 1 o’clock which was 3 and 1 mm in length, respectively, and was also in continuity with the superior clear corneal wound (Figure 3). The epithelial downgrowth was limited to the peripheral margin of the DMEK graft and did not affect the visual axis. The center of cornea was clear, the pupil was intact, and no sign of anterior segment inflammation; IOP difference or graft rejection was identified. Therefore, we decided to observe closely without any treatment. Very interestingly, at the current 4-year follow-up, the epithelial downgrowth is stable and localized (Figure 4), her vision increased and remained at 20/20, and pachymetry values are stable at 538 µm.

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Figure 1.

Slit-lamp image (a) and AS-OCT image (b) of epithelial downgrowth prior to re-DMEK. Black arrowhead: epithelial pearls. White arrows: demarcation line. White arrowheads: hyperreflective layer under the graft close to the 12 o’clock tunnel.

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Figure 2.

Histopathology of the removed DMEK graft demonstrating multilayered epithelial cells with goblet cells (black arrow) beneath the graft, suggesting conjunctival origin.

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Figure 3.

Slit-lamp images (a, b) and AS-OCT image (c) of recurrent epithelial downgrowth after DMEK, now stable for 4 years. Epithelial downgrowth in “island” pattern (white arrows) with the accumulation of epithelial pearls (black arrowheads) beneath DMEK tissue (white arrowheads). There is continuity with the superior clear corneal incision (black arrows).

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Figure 4.

AS-OCT images of epithelial downgrowth (white head arrow) 3 months (a) and 4 years (b) after re-DMEK and photo image of the last visit (c) showed the stability of ED for now 4 years.

Discussion

Epithelial downgrowth (ED) is a rare but serious complication of surgery which can threaten patients’ sight. This condition has been reported after many types of intraocular surgeries. Although it has been well investigated after phacoemulsification, penetrating keratoplasty, and DSAEK, to our best knowledge no report has yet been related to DMEK. Here, we present one case with recurrent epithelial downgrowth after DMEK. Several studies have investigated the etiology of epithelial downgrowth and suggested that multiple intraocular surgeries, inadequate or delayed wound closure, tissue incarceration, full-thickness suture tract, prolonged inflammation, corneal vascularization, stripping of or damage to Descemet layer/corneal endothelium, and hypotony as risk factors for ED.^14,15 The history of this patient reveals multiple risk factors for ED, namely, several intraocular surgeries, damage of endothelium, and prolonged course of anterior chamber inflammation. In fact, we cannot rule out that mild ED already occurred after the initial cataract and DSAEK surgery externally and remained unnoticed until after DMEK surgery. The fact that initially the DSAEK graft was relatively clear argues against this however.

ED was classified into three major forms: epithelial pearls, cysts, and sheets. The latter is the most common and aggressive form, and may result in secondary glaucoma or corneal decompensation leading to irreversible loss of vision. ¹⁶ Our patient presented the sheet-like ED with an “islands” pattern and epithelial pearls accumulated within the “islands” (Figures 1(a) and 3(b)). At the beginning, ED appears as translucent membranes with few epithelial pearls. With progression, epithelial pearls gathered and ED ultimately became a homogeneous whitish mass with a sharp demarcation. ¹⁷ Semeraro et al. ¹⁷ proposed three possibilities of ED after DSAEK, specifically the dragging of epithelial cells intracamerally, eccentrically trephined grafts containing full-thickness cornea and the induction of epithelial cells from full-thickness corneal incision. In our patient, recurrence of ED after DMEK was near the clear corneal incision at 12 o’clock, suggesting that this incision was the entry point of epithelial cell invasion. Another possible reason for the recurrence of ED is from the incomplete removal of the previous ED. However, the anterior segment OCT images strengthened the first hypothesis with a connection between two “islands” and corneal incision (Figure 3(c)). The presence of goblet cells indicated the conjunctival origin of the invasive cells (Figure 2). Likewise, Phillips et al. ¹⁸ reported one case of ED after DSAEK with the invasion of conjunctival epithelial cells through clear corneal incision.

Treatment options for ED may vary depending on progression and form of ED. Regarding the sheet form of ED, in cases affecting the vision, many approaches were suggested such as surgical resection with adjunctive cryotherapy and block excision with tectonic grafting.^19,20

Another less aggressive option is antimetabolite therapy using 5-FU. Several previous studies also showed the partial or even complete regression of an epithelial downgrowth after 5-FU intracameral injection.^14,21,22 Notably, our patient was treated by stripping the old graft, intracameral injection of 5-FU, and careful aspiration, followed by a second DMEK. Unfortunately, the ED recurred 2 months after this treatment. Similarly, Itty et al. ²³ reported two of their three cases of ED after DSAEK in which intracameral injection of 5-FU failed to prevent recurrence. In addition, Tomlins et al. ²⁴ reported the failure of antimetabolite therapy to stop the progression of ED after clear corneal cataract extraction even with five injections. Very interestingly, in our case, the recurrent epithelial downgrowth did not progress, with the current follow-up now at 4 years. The ED was localized to the margin of the graft and did not affect vision. The self-limited progression of ED can possibly be explained by the epithelial–endothelial contact inhibition of movement described by Yanoff and Cameron. ²⁵ Indeed, Jaber et al. ²⁶ presented a case of spontaneous regression of sheet-like epithelial downgrowth in the anterior chamber. More recently, Alvarez de Toledo et al. ¹⁰ report one case of ED after DMEK successfully treated with penetrating keratoplasty.

To our best knowledge, we report the second case of ED after DMEK, but the first documented case of self-limited progression of recurrent epithelial downgrowth after DMEK. This suggests that epithelial downgrowth after DMEK even in the recurrence stage may cause less damage than expected. Observation may be an initial option if no sign of progression is observed.