According to the Eye Bank of America Association 2008 Statistical Report, nearly 90% of all grafts performed in the United States for endothelial diseases of the cornea used endothelial keratoplasty, approximating 18,375 of the 41,652 corneal transplants performed in the United States in 2008.1 The rise in endothelial keratoplasty popularity stems from its inherent advantages over penetrating keratoplasty, including avoidance of an open-sky procedure, minimal induced astigmatism, lack of suture-related complications, better tectonic stability, and earlier return of refractive and vision stability. As with any new procedure, new complications can arise and the endothelial keratoplasty learning curve and its potential complications remain in evolution. Although the most common complications of endothelial keratoplasty are early graft dislocation, primary graft failure, and pupil block glaucoma, interface complications may also develop and may include interface haze, debris, epithelial ingrowth, and a potential for interface microbes.1
Herein, we report a rare complication of fungal keratitis that developed within the interface of two cases after Descemet’s stripping automated endothelial keratoplasty (DSAEK) with inclusion of clinical photography, confocal microscopy, and corneal histopathology. To our knowledge, this is the first report of interface keratitis in the absence of a positive donor rim culture and the first to use confocal microscopy as an adjunct to diagnosis.
An 81-year-old man underwent uncomplicated DSAEK for Fuchs corneal dystrophy using precut donor tissue. Preoperative best-corrected visual acuity measured 20/200 in the right eye and 20/40 in the left eye. After descemetorhexis and removal of Descemet’s membrane and endothelium, the clear corneal incision was extended to 5 mm with the keratome. The donor tissue was precut by the eye bank and removed from corneal storage media in the operating room, where the Hanna trephination system (Microtech Inc., Doylestown, PA) was used to trephine the donor tissue, after which the posterior donor portion was carefully peeled from the donor stroma and placed endothelial side down on a bed of viscoelastic. The tissue was inserted by a suture pull-through technique through the 5-mm incision. Three peripheral 1-mm transcorneal vent incisions were made using a 15° blade. A full air bubble was placed to maintain firm intraocular pressure followed by removal of air at the slit lamp 1 hour later to a 40% air fill. Postoperative medications included gatifloxacin 0.3% and prednisolone acetate 1%, each one drop four times daily.
Postoperative examinations on 1 day and at 1 week appeared appropriate. Best-corrected visual acuity at 1 month postoperatively was 20/70 in the right eye with a new small fluffy white opacity in the inferior paracentral interface with a quiet anterior chamber (Fig. 1). The infiltrate was not adjacent to the vent incisions. Confocal microscopy showed refractile bodies in the region of the stromal interface opacity suspicious for fungal elements (Fig. 2). Given the history of a positive donor corneal rim for Candida glabrata on day 3 and the confocal appearance, the patient was given topical amphotericin 0.15% every 2 hours and oral fluconazole 100 mg two times daily. Given the depth of the lesion and lack of response to the medications, an uncomplicated penetrating keratoplasty with intracameral amphotericin (10 mg/0.1 cc) was performed 1 week later. We used a Hanna trephine using an 8.25-mm donor and 8.0-mm host. Histopathologic examination showed a collection of yeast within the interface between the DSAEK lenticule and recipient stroma (Fig. 3). The patient’s condition stabilized with topical amphotericin 0.15%, gatifloxacin 0.3%, and prednisolone acetate 1% with ultimate improvement in best-corrected visual acuity to 20/25 with glasses at 6 months postoperatively.
Figure 1. Case 1. Slit-Lamp Photography Depicting a Fluffy White Infiltrate Within the Interface of the Descemet’s Stripping Endothelial Keratoplasty Graft. (A) A Low Magnification (original Magnification ×10) View at the Slit Lamp. (B) A High Magnification View (original Magnification ×25) at the Slit Lamp.
Figure 2. Confocal Microscopy Depicting Multiple Refractile Bodies (arrows) Suspicious for Fungal Elements in the Region of the Descemet’s Stripping Endothelial Keratoplasty Interface (original Magnification ×40).
Figure 3. Case 1. (A) The Descemet’s Stripping Endothelial Keratoplasty Lenticule Is Separating from the Posterior Surface of the Recipient Cornea. There Is a Focal Accumulation of Yeast on the Anterior Surface of the Lenticule (Periodic Acid-Schiff Stain, Original Magnification ×25). (B) The Yeast Form a Colony on the Anterior Surface of the Lenticule at the Interface (Periodic Acid-Schiff Stain, Original Magnification ×120).
A 76-year-old woman underwent an uncomplicated triple procedure with phacoemulsification, in-the-bag lens implantation, and DSAEK for Fuchs corneal dystrophy. The surgical technique was similar to that described above except a superior limbal incision was used and the donor lenticule was prepared intraoperatively with the Moria ALTK system (Moria, Antony, France) using the Hanna system for trephination of the posterior donor tissue.
Postoperative examinations were unremarkable until week 3, when a small white interface opacity was noted centrally measuring 1 × 1.5 mm without associated edema or apparent inflammation (Fig. 4A). Best-corrected visual acuity was 20/100. The anterior chamber had trace cell and flare. Corneal rim cultures showed no growth at 1 week. Gatifloxacin 0.3% was restarted every 2 hours and prednisolone acetate 1% decreased to two times daily. On the fourth postoperative week, the lesion increased in size with increased anterior chamber cell and flare and associated anterior spread through the recipient stroma. A central epithelial defect was present, affording culture and scrapings. Hourly topical amphotericin 0.15% was added empirically with prednisolone acetate decreased to once a day.
Figure 4. Case 2. (A) Slit-Lamp Microscopy Depicting a Small Interface Opacity in the Early Postoperative Period. (B) Confocal Microscopy Depicting Multiple Refractile Bodies Representing Budding Yeast (arrows) in the Corneal Stroma Consistent with Fungal Elements (original Magnification ×40).
The culture confirmed presence of Candida albicans on Sabouraud agar and oral fluconazole 200 mg two times a day was added to the regimen. A concurrent eyelid and conjunctival culture also confirmed the same pathogen. Confocal microscopy showed suspicious refractile bodies within the interface suspicious for fungal keratitis (Fig. 4B). A penetrating keratoplasty was urgently scheduled to remove the infectious corneal region and was complicated by a suprachoroidal hemorrhage. Histopathologic examination showed an inflammatory infiltrate on the posterior surface of the lenticule and confirmed fungal elements within the recipient lenticule (Fig. 5). Visual acuity remained poor due to retinal complications from the hemorrhage with ultimate development of phthisis bulbi.
Figure 5. Case 2. (A) The Corneal Lenticule Exhibits Disruption of Descemet’s Membrane and an Inflammatory Cell Infiltrate in the Area of Disruption (Periodic Acid-Schiff Stain, Original Magnification ×25). (B) There Are Numerous Fungal Elements (arrows) in the Stroma of the Lenticule (Periodic Acid-Schiff Stain, Original Magnification ×100).
Interface infectious keratitis is a rare complication of endothelial keratoplasty, but one that may potentially create devastating repercussions to the ultimate visual recovery if not recognized and addressed promptly. The entity of fungal interface keratitis typically presents several weeks after endothelial keratoplasty with an asymptomatic white fluffy interface opacity. Although only a few published reports exist on this entity to date, all reports to this point have documented positive donor rim cultures representing the same fungal pathogen ultimately identified in the interface infection. The second case in this report represents the first interface fungal infection to date with negative donor rim cultures. Vision complications after this infectious entity can be severe and devastating, as evidenced by the first reported case in which an enucleation2 was performed and our second case that developed into phthisis bulbi.
As with any infectious entity, the mode of infection remains a critical point for discussion for future identification and prevention. Possible routes of infection include contaminated donor corneal rim inoculation, spread from the recipient ocular surface from inoculation during donor tissue insertion or entry through a vent incision, or an endogenous source.
Donor rim cultures have fallen out of favor for some corneal surgeons in penetrating keratoplasty and endothelial keratoplasty, because some studies have shown a low correlation of donor rim cultures to endophthalmitis after penetrating keratoplasty.3 To the contrary, several reports have demonstrated the importance of donor rim cultures because they have provided early diagnosis and institution of early antifungal treatment.2,4 Unlike with penetrating keratoplasty, the location and depth of infiltrates in the endothelial keratopathy interface make early culture and scraping impossible; thus, a positive donor rim culture may provide rapid identification and drug sensitivities of the potential infectious organism. In fact, the sensitivity and specificity of positive fungal donor rim cultures for post-keratoplasty endophthalmitis have been reported at 100% and 99%, respectively, resulting in a significantly increased risk of developing a fungal endophthalmitis with a culture-positive donor rim compared to a culture-negative donor rim.5
In cases of fungal keratitis in which the donor rim culture is negative, cultures of the conjunctiva and eyelids may provide information on the microbe responsible for the infection (case 2). To our knowledge, our second case represents the first report of a fungal interface infection after DSAEK without a positive donor rim culture for fungi.
Given that interface infections represent a deep posterior stromal infiltrate without access for culture and scraping in the early stages, confocal microscopy can be a useful adjunct to early identification and treatment. Confocal microscopy helped with diagnosis and decision making in both cases described in this report. In cases where a positive donor rim culture is negative for fungi but an interface opacity develops after DSAEK (as in case 2), confocal microscopy can be especially useful to demonstrate suspicion for fungal infection by detecting fungal elements in the area of the recipient stroma/donor stroma interface. However, the accuracy of confocal diagnosis is dependent on observer experience. The sensitivity and specificity of confocal microscopy in microbial keratitis ranges from 28% to 56% and 42% to 84%, respectively.6,7
Management considerations are yet another topic of discussion with this new entity. Given the depth and confined nature of the interface infection, topical antifungal agents will not likely penetrate in time for medical management success. In addition, oral antifungal agents can display either poor or delayed penetration into the ocular tissues; thus, a low threshold for surgical therapy must be present. Although intracorneal antifungal injections may be considered, they carry the risk of creating tissue dislocation from a fluid wave leading to a potential for facilitation of anterior chamber contamination. Early surgical intervention appears to be the best therapeutic regimen with this infectious entity based on these inherent problems. A repeat endothelial keratoplasty has the potential of introducing an infection confined to the interface into the anterior chamber, leading to development of endophthalmitis. Given this risk, a penetrating keratoplasty appears more advantageous because it keeps the infection confined to the interface, significantly lowering the risk of anterior chamber inoculation and resulting fungal endophthalmitis. The earlier timing from diagnosis to penetrating keratoplasty led to a far better outcome in our experience compared to delayed penetrating keratoplasty. The delay in diagnosis and penetrating keratoplasty treatment affords disease progression, leading to increased risk of complications such as choroidal hemorrhage, as in the second case. Treatment should include intraoperative intracameral antifungal agents and topical and oral antifungal agents postoperatively.
Fungal interface keratitis after DSAEK also raises the question of whether adding antifungal agents to the storage media should be considered, especially if increased reports of fungal infection with endothelial keratoplasty occur. Antibiotic agents, including those in corneal storage media, lead to bacterial death in the absence of fungal death, further potentiating fungal growth. In addition, some organisms, such as Candida, have adherence factors that prevent elimination despite donor globe irrigation. Although Ritterband et al. found addition of voriconazole (100 μm/mL) to corneal storage media eliminated culture-positive fungal corneal rims in the absence of donor endothelial cell toxicity, more studies are needed to assess cost-effectiveness, endothelial cell toxicity, duration and effectiveness of antifungal activity, and compatibility with current corneal storage media constituents.8 Underreporting of fungal keratitis complications may remain a hindrance to determining the true prevalence of this complication and alter a proper cost-benefit analysis for antifungal media addition.
Early interface opacities in the setting of DSAEK or any potential endothelial keratoplasty procedure must be considered infectious until proven otherwise. Donor corneal rim cultures, conjunctival/eyelid cultures, and confocal microscopy may provide an early clue to the potential pathogen in cases of infectious interface keratitis. Positive corneal rim cultures for a fungal pathogen must be followed closely and consideration of empiric topical and oral antifungal therapy should be strongly considered. Confocal microscopy may be a useful adjunct to diagnosis of infectious interface fungal infections with a potential for earlier diagnosis and administration of antifungal treatment. It may also help with decision making for therapeutic keratoplasty.