Trends in Indications and Techniques of Corneal Transplantation from 1999 through 2015 at a Tertiary Referral Center in Athens, Greece

Introduction During the past decade, novel techniques of corneal transplantation allowing faster and better restoration of vision have emerged. The present cohort study describes a shift of indications and techniques that has occurred in the field of corneal transplantation over a 17-year period in Greece. Methods All patients undergoing keratoplasty between January 1999 and December 2015 at an academic tertiary referral center in Athens, Greece, were retrospectively reviewed. The annual incidence of keratoplasty indications and techniques was recorded and analyzed. Results A total of 1382 keratoplasty procedures were included. Leading indications were bullous keratopathy (BK) (37.5%), followed by allograft rejection (17.7%), corneal scar (12%), keratoconus (KC) (10.3%), and Fuchs endothelial dystrophy (FED) (8.8%). A decreasing trend was observed for KC (P=0.009) and an increasing trend for BK (P=0.003) and FED (P=0.001). In 2015, the incidence of penetrating keratoplasty (PK) had decreased from 100% (1999 to 2009) to 21.4%; for cases with isolated pathology of the corneal endothelium, DSAEK was the preferred technique (59.8%), while the respective rate of DMEK was 18.8%. Conclusion Herein, we observed an increasing trend of endothelial pathology among keratoplasty indications as well as a major shift in preferred techniques due to a wide adoption of the new EK procedures.


Introduction
Keratoplasty is one of the most common and successful allotransplantations in humans and the only treatment of several corneal pathologies. Since the first successful corneal transplantation by Zirm in 1906 [1], penetrating keratoplasty (PK) was the gold standard. Over the past decade, however, advancements in the field of corneal transplantation changed the preferred practice patterns of corneal surgeons. e more or less selective transplantation of corneal endothelium evolved since the introduction of posterior lamellar keratoplasty in 1998 [2] to safer and more targeted techniques, for example, Descemet (automated) stripping endothelial keratoplasty (DS(A)EK) [3] and Descemet membrane endothelial keratoplasty (DMEK) [4,5]. Moreover, advancements in the field of keratoconus surgery that may delay or even arrest disease progression, that is, corneal crosslinking (CXL), have reduced the need for keratoplasty [6].
Indeed, recent reports describe both an increase of endothelial pathology and a shift from PK to lamellar keratoplasty techniques [7][8][9]. However, only limited data on the implementation of DMEK among keratoplasty procedures are available [8,9]. Purpose of the current paper is therefore to report trends in indications and techniques in a cohort where both DMEK and DSAEK were implemented.

Materials and Methods
e records of all corneal transplantations conducted between 1999 through 2015 at a referral center in a large hospital in Athens, Greece (First Department of Ophthalmology, National and Kapodistrian University, Athens, and Ophthalmology Department, General Hospital "G. Gennimatas") were reviewed.
All procedures were performed by 3 surgeons in total. e number of surgeons operating during each calendar year varied from 1 to 3. e present research adhered to the tenets of the Declaration of Helsinki. Due to the observational and retrospective character of the study, IRB approval was not required.

Data Collection.
Indications were grouped according to the following criteria: (1) "Bullous keratopathy" (BK) included all cases of corneal endothelial decompensation except for cases of Fuchs endothelial dystrophy and failed corneal grafts. (2) "Regraft" included cases of repeat keratoplasty due to graft failure.

Statistical Analysis.
All data were collected with Excel software (version 14, Microsoft Corp.). Descriptive and inferential data analysis was performed with SPSS software (version 17.0, SPSS Inc.). Numerical data are presented as mean ± standard deviation. Evolution of recipient age, gender, and surgical indication were assessed using linear regression analysis. e x 2 test was used where appropriate. A P value less than 0.05 was considered statistically significant.

3.1.
Demographics. e present retrospective cohort study includes 1382 eyes undergoing corneal transplantation at a single tertiary referral center with a nationwide patient pool. While the majority of donor tissue (79.4%) was imported from eye banks outside Greece, the rest was retrieved from local multiorgan donors.
Univariate linear regression analysis of the annual incidence for each indication revealed a significant increase of endothelial    pathologies, that is, BK (r 2 � 0.47, P � 0.003) and FED (r 2 � 0.55, P � 0.001) and a significant decrease in corneal scar (r 2 � 0.72, P < 0.001) and KC (r 2 � 0.38, P � 0.009). All other indications did not show significant fluctuations (univariate linear regression analysis) (Figure 4).

Techniques.
PK was the only technique applied until 2009, when DSAEK was introduced, starting with 8.9% (2009) and reaching 59.9% (2015) ( Figure 5). DMEK was introduced in July 2013 reaching 11.8% in the first (half ) year, peaking with 41.5% in the second year, and decreasing to 18.8% in the third year of its implementation ( Figure 5). By the final year of the study, EK was the preferred treatment for BK (89.8% EK versus 11.2% PK) and the only treatment for FED ( Figure 6).

Discussion
e present study reports trends in keratoplasty indications and techniques from 1999 through 2015 at an academic tertiary referral center in Athens, Greece. As part of this study, the implementation of new endothelial keratoplasty techniques (DMEK and DSAEK) in a large keratoplasty cohort was evaluated. e leading indication herein was BK (37.7%), being in accordance with a previous Greek multicenter study reporting aphakic/pseudophakic corneal edema (29.1%), keratoconus (26%), and regraft (11.9%) as main indications [10]. e increase of corneal endothelial pathology (BK and FED) among indications may be explained by the early and successful adoption of DSAEK and DMEK in our cohort (Figure 4).

Journal of Ophthalmology
On the other hand, KC demonstrated a significant decrease over time that may relate to the introduction of CXL as well as advancements in optical rehabilitation, for example, scleral contact lenses or intracorneal ring segments.
Compared to the global introduction of new lamellar techniques [7], the present cohort keeps up with advancements in endothelial keratoplasty.
us, although it took three years for EK (DSAEK) to surpass PK, both EK techniques (DSAEK and DMEK) were successfully implemented, with EK accounting for 78.6% of the total keratoplasty procedures performed during the final year of our study ( Figure 5). is is in agreement with other studies reporting similar trends in keratoplasty techniques [7][8][9]. With regard to endothelial pathology, EK procedures have almost completely replaced PK, ranging between 88.9% for BK and 100% for FED cases ( Figure 6). is rapid shift in surgeons' preferences from PK to EK techniques in the treatment of endothelial pathology can easily be explained by several advantages of EK, for example, smaller incisions, fewer or no sutures, and no open sky surgery. e main advantage of EK however is faster and better visual rehabilitation and lower risk for immunologic rejection [8,11,12].
Another notable observation is the smooth implementation of DMEK accounting for 36% of EK procedures during the last 3 years of the study, as opposed to a peak rate of 11% for 2014, as recently reported by the Eye Bank Association of America [7].
In conclusion, keratoplasty indications showed remarkable trends over the past 17 years. ese changes relate to the introduction of endothelial keratoplasty as well as to new treatment alternatives for KC other than keratoplasty. Respectively, a considerable shift of keratoplasty techniques from PK to DSAEK and DMEK in the treatment of endothelial disorders is evident. Finally, despite being a challenging procedure, DMEK was successfully implemented in our center.  Figure 6: Column chart depicting keratoplasty techniques applied for endothelial pathology, that is, BK (a), FED (b), and regrafts (c). Note that, in the last 3-6 years of the observation period, PK has been replaced to a variable extent by endothelial keratoplasty, that is, DSAEK and DMEK. 6 Journal of Ophthalmology