CLINICAL SCIENCE
Prevention and Treatment of Corneal Graft Rejection: Current Practice Patterns of the Cornea Society (2011) Bhairavi Kharod-Dholakia, MD,* J. Bradley Randleman, MD,* Jennifer G. Bromley, MD,* and R. Doyle Stulting, MD, PhD†
Purpose: To analyze current practice patterns in the prevention and treatment of corneal graft rejection for both penetrating keratoplasty (PK) and endothelial keratoplasty (EK) and to compare these patterns with previously reported practices.
Methods: In 2011, an electronic survey was sent to 670 members of the Cornea Society worldwide addressing the routine postoperative management of corneal transplants at different time points, treatment of various manifestations of corneal graft rejection, and preferred surgical techniques. Results: A total of 204 of 670 surveys (30%) were returned and evaluated. All respondents used topical corticosteroids for routine postoperative management and treatment of endothelial graft rejection. Prednisolone was the topical steroid of choice in all clinical scenarios, similar to previous surveys from 1989 to 2004. Use of subconjunctival and systemic steroids increased for many scenarios of probable and definite graft rejection. Routine use of prednisolone decreased by approximately 10% from previous surveys, whereas difluprednate was used in 13% of high-risk eyes during the first 6 months. Dexamethasone, fluorometholone, and loteprednol use remained stable. Adjunctive topical cyclosporine use increased significantly for PK and EK. EK was the preferred technique for endothelial dysfunction, whereas PK and deep anterior lamellar keratoplasty were both used for keratoconus and anterior scars. Most respondents (75%) felt that graft rejection occurs more frequently after PK than after EK. Conclusions: Prednisolone remains the treatment of choice for management and treatment of graft rejection; however, since the introduction of difluprednate, its use has declined slightly since the introduction of difluprednate. Despite perceived differences in rejection rates, there were no differences in prophylactic steroid treatment for PK and EK. Received for publication September 9, 2014; revision received January 21, 2015; accepted January 22, 2015. Published online ahead of print March 26, 2015. From the *Department of Ophthalmology, Emory University, Atlanta, GA; and †Stulting Research Center, Woolfson Eye Institute, Atlanta, GA. Supported in part by an Emory University Department of Ophthalmology unrestricted grant from Research to Prevent Blindness, Inc. The authors have no conflicts of interest to disclose. J. G. Bromley is now in private practice in Savannah, GA. Reprints: Bhairavi Kharod-Dholakia, MD, Department of Ophthalmology, Emory University, 1365 Clifton Rd NE, Atlanta, GA 30322 (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cornea Volume 34, Number 6, June 2015
Key Words: corneal graft rejection, corticosteroid, penetrating keratoplasty, endothelial keratoplasty (Cornea 2015;34:609–614)
G
raft failure from rejection remains the most significant complications of corneal transplantation and is a leading indication for overall corneal transplantation.1–9 There is significant variability among practitioners in prevention and treatment of allograft rejection. Our group developed 2 previous surveys to evaluate practice patterns for members of the Cornea Society (previously the Castroviejo Society) in 19891 and 2004.9 Those studies demonstrated some consistency in practice patterns over time, especially the role of topical prednisolone as primary therapy for prevention and treatment of graft rejection in most situations. However, other practice patterns showed significant changes over time, including a diminishing role for subconjunctival steroids for graft rejection from 1989 to 2004, and increased use of topical cyclosporine and loteprednol in the 2004 survey, 2 agents that were not available at the time of the 1989 survey.9 With the additional years of availability of these agents, the introduction of new topical therapies, including difluprednate, and the advent of endothelial keratoplasty as the procedure of choice for primary endothelial dysfunction and penetrating keratoplasty (PK) failure, Cornea Society members were resurveyed to determine current practice patterns with special focus on how these changes have affected overall practice patterns. The purpose of this study was to determine the current practice patterns of the members of The Cornea Society for the prevention and treatment of corneal graft rejection, including PK and endothelial keratoplasty (EK), and to compare these with past practice patterns reported in previous surveys. This survey also evaluated the utilization of alternative surgical strategies for high-risk corneal transplantation.
MATERIALS AND METHODS A survey was sent worldwide electronically (through surveymonkey.com) to 670 members of the Cornea Society in May 2011. All survey responses were anonymous; however, respondents were asked to provide demographic information, including age and regional location. The first 10 questions in the survey were identical to the past surveys and addressed the preferred treatment strategies for both routine postoperative management and for various presentations of corneal allograft rejection (Table 1). As in www.corneajrnl.com |
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TABLE 1. Steroid Use for Penetrating Keratoplasty Rejection Prevention and Management Percentage of Respondents Using Steroids (1989, 2004), 2011 Question 1. What is your “routine” postoperative immunosuppressive regimen for patients with avascular corneas undergoing keratoplasty for the first time? 2. What is your “routine” postoperative immunosuppressive regimen for patients at high risk for graft failure (vascularized cornea and/or previous graft rejection)? 3. How would you treat a patient with subepithelial infiltrates confined to the graft without corneal edema or other signs of graft rejection in a patient who obviously does not have epidemic keratoconjunctivitis? 4. How would you treat a patient with epithelial rejection line, but no other signs of graft rejection? 5. How would you treat an obvious endothelial rejection line and corneal edema? 6. How would you treat a patient with sudden onset of keratic precipitates and graft edema? 7. How would you treat a patient with the sudden onset of edema, cells in the anterior chamber not previously observed, but no keratic precipitates? 8. How would you treat a patient with new complaints of photophobia, but no change in vision, increase in graft thickness, or inflammatory signs? 9. How would you treat a patient with the sudden onset of corneal edema and decreased acuity, but no signs of inflammation? 10. How would you treat a patient with the gradual onset of corneal edema, but absolutely no signs of inflammation?
Topical (1989, 2004), 2011
Subconjunctival (1989, 2004), 2011
Intravenous, Intramuscular, Orally (1989, 2004), 2011
(100, 100), 100
(43, 48), 76*
(7, 3), 20*
(100, 100), 100
(53, 53), 54
(23, 1), 30*
(93, 96), 97
(7, 3), 35*
(5, 1), 25*
(93, 95), 97
(12, 5), 33*
(7, 3), 45*
(100, 100), 100
(57, 35), 39
(37, 38), 69*
(100, 100), 100
(51, 32), 43
(32, 34), 63*
(100, 100), 100
(40, 21), 42*
(25, 20), 63*
(70, 57), 84*
(3, 0), 22*
(2, 1), 33*
(92, 99), 100
(11, 11), 41*
(7, 14), 44*
(81, 73), 87
(7, 4), 13
(4, 3), 38*
*P , 0.05.
previous surveys, corneal allograft rejection was defined in 3 stages: possible rejection, probable rejection, and definite rejection. Briefly, in previously clear grafts, possible rejection was defined as graft edema without obvious signs of inflammation, probable rejection as corneal edema and inflammation without an endothelial rejection line, and definite rejection as the appearance of corneal edema with an endothelial rejection line.1,9 The survey questions were asked twice for each category, once for penetrating keratoplasty and once for endothelial keratoplasty. Results were collected individually for both PK and EK. The second subset of questions determined the respondent’s utilization of topical steroids in routine and high-risk allografts of patients in phakic, pseudophakic, and aphakic eyes. Based on previous survey responses, treatment regimens included use of topical betamethasone, dexamethasone, difluprednate, fluorometholone, loteprednol, prednisolone (generic), prednisolone (brand), rimexolone, or no topical medication. The respondents were asked about their treatment preferences for penetrating keratoplasty and endothelial keratoplasty separately in 2 different sets of question. The results included separate answers for both PK and EK. This survey included a new third subset of questions to determine potential interest in surgical alternatives to penetrating keratoplasty and surgical treatment strategies for high-risk transplant patients. Respondents were specifically asked about alternative keratoplasty procedures they were currently using or
were planning to use in the future, including Descemet stripping automated endothelial keratoplasty (DSAEK), Descemet membrane endothelial keratoplasty (DMEK), deep anterior lamellar keratoplasty (DALK), and keratoprosthesis (K-Pro). They were also asked about their procedure of choice for a variety of surgical indications, including keratoconus, Fuchs endothelial dystrophy (Fuchs), pseudophakic corneal edema (PCE), anterior stromal scar, multiple failed grafts, severe chemical injury, Stevens–Johnson syndrome (SJS), and ocular cicatricial pemphigoid (OCP). Because these questions were not included in the previous surveys, only the responses were analyzed. Most of the responses were reported using descriptive statistics only. Where appropriate, Student t test and x2 analyses were performed to evaluate differences in responses between surveys, with P , 0.05 considered significant.
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RESULTS A total of 204 of 670 surveys (30%) were returned and evaluated, compared with 137 of 314 (41%) and 111 of 396 (28%) surveys evaluated in 19891 and 2004,9 respectively (P . 0.05).
Demographics of Survey Respondents Most survey respondents were from North America (78.7%), followed by Europe (9.3%), Asia (6.0%), South
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Cornea Volume 34, Number 6, June 2015
America (4%), Australia (1.3%), and the Middle East/Africa (0.7%). The ages of the respondents varied widely, from 30 to more than 70 years, with a relatively even distribution by decade for most respondents from ages 30 to 39 (31%), 40 to 49 (21.9%), and 50 to 59 (30.3%). Most respondents (75%) felt that graft rejection occurs more frequently after PK, 1% felt rejection was more common after EK, and 24% felt there was no difference between rejection rates with the 2 procedures. Treatment strategies for prophylaxis and treatment of rejection were essentially identical for PK and EK for almost all scenarios.
Topical, Subconjunctival, and Oral Steroid Use for Graft Rejection The results of this survey for prevention and treatment of allograft rejection were comparable in most aspects with both previous surveys (Table 1). Topical corticosteroids remained the treatment of choice for routine postoperative management for both penetrating keratoplasty and endothelial keratoplasty. Their use in other clinical situations was similar to that reported in the previous surveys. Most (75% and 68%) respondents used intraoperative subconjunctival corticosteroids for avascular corneas undergoing PK and EK, respectively. Use of subconjunctival and oral/intravenous/ intramuscular steroids for routine postoperative management increased compared with both 1989 and 2004 surveys.
Preferred Topical Steroid: Routine Postoperative Management Prednisolone in brand or generic form remained the preferred treatment for routine management in all scenarios regardless of the risk status or lens status and was used by 55% to 80% of respondents in our survey (Fig. 1). The other most commonly used preparations included dexamethasone, difluprednate, loteprednol, and fluorometholone. Use of
Corneal Graft Management
prednisolone and dexamethasone varied slightly by time, lens status, and risk category, being less common after 6 months than during the first 6 months postoperatively; however, use of difluprednate, loteprednol, and fluorometholone varied more. Difluprednate was used primarily for high-risk eyes, and almost exclusively during the first 6 months. Loteprednol was used most commonly after 6 months, for phakic patients, and low-risk eyes. Fluorometholone was used almost exclusively after 6 months and for low-risk eyes.
Preferred Topical Steroid: Graft Rejection Management Prednisolone was the primary treatment of choice for all manifestations of graft rejection, ranging from 72% to 83%. Dexamethasone was the second most commonly used steroid preparation, with use ranging from 10% to 13% in all clinical scenarios (Table 2). Use of difluprednate varied significantly, depending on the clinical scenario (3%–17%), with highest utilization in eyes with obvious endothelial rejection. Loteprednol and fluorometholone were rarely used for any scenario of graft rejection (,1% for either). There were no differences between responses for PK and EK.
Topical Cyclosporine Use for Graft Rejection Treatment and Prophylaxis Topical cyclosporine was used as adjunctive therapy in 13% to 77% of scenarios for possible, probable, or definite graft rejection (Table 3). Use of topical cyclosporine increased for all clinical scenarios, compared with 2004 (P , 0.05), except for prophylactic management of highrisk grafts (48%), for which utilization was already 48% in 2004. Use of cyclosporine was slightly higher for EK than PK for most clinical scenarios.
FIGURE 1. Preferred topical steroid preparations for first 6 months in low-risk grafts in phakic eyes; after 6 months in low-risk grafts in phakic eyes; first 6 months in high-risk grafts in phakic eyes; after 6 months in high-risk grafts in phakic eyes; first 6 months in low-risk grafts in pseudophakic or aphakic eyes; after 6 months in low-risk grafts in pseudophakic or aphakic eyes; first 6 months in high-risk grafts in pseudophakic or aphakic eyes; after 6 months in high-risk grafts in pseudophakic or aphakic eyes. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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TABLE 2. Preferred Topical Steroid Preparation for Graft Rejection Percentage of Respondents Using Steroids Question
Prednisolone
Dexamethasone
Difluprednate
76
12
6
78
11
6
73 72 75
10 10 11
14 14 10
77
13
3
79
11
7
83
10
3
1. How would you treat a patient with subepithelial infiltrates confined to the graft without corneal edema or other signs of graft rejection in a patient who obviously does not have epidemic keratoconjunctivitis? 2. How would you treat a patient with epithelial rejection line, but no other signs of graft rejection? 3. How would you treat an obvious endothelial rejection line and corneal edema? 4. How would you treat a patient with sudden onset of keratic precipitates and graft edema? 5. How would you treat a patient with the sudden onset of edema, cells in the anterior chamber not previously observed, but no keratic precipitates? 6. How would you treat a patient with new complaints of photophobia, but no change in vision, increase in graft thickness, or inflammatory signs? 7. How would you treat a patient with the sudden onset of corneal edema and decreased acuity, but no signs of inflammation? 8. How would you treat a patient with the gradual onset of corneal edema, but absolutely no signs of inflammation?
Other Systemic Immunosuppressive Use Oral cyclosporine and oral tacrolimus were used in less than 5% of scenarios for graft rejection management.
Alternative Keratoplasty Procedures/ Procedures of Choice The current and projected utilization of procedures other than PK showed that DSEK was the most commonly performed procedure currently, followed by DALK (Fig. 2). There was significant expressed interest in DMEK and DALK, and to a lesser extent K-Pro, for future performance. As expected, the keratoplasty procedure of first choice varied by indication (Fig. 3). Selective keratoplasty was preferred to penetrating keratoplasty for most conditions. DALK was preferred for keratoconus and anterior stromal scars, whereas keratoprosthesis was preferred for very high-risk categories including multiple failed grafts, ocular cicatricial
pemphigoid, Stevens–Johnson syndrome, and severe chemical injuries.
DISCUSSION The results of this survey demonstrate subtle changes in management strategies for the treatment and prevention of corneal transplant rejection over time and evolving surgical technique preferences. The results from this survey combined with the results from 19891 and 20049 provide an opportunity to evaluate the practice patterns of the members of the Cornea Society over time. Changes in medical management from past surveys may be partially explained by newer topical steroid preparations and increased experience with previously “new” preparations. Although prednisolone remained the drug of choice for every scenario, there were significant differences in its use in high-risk grafts during the first 6 months (90% in 2004 vs.
TABLE 3. Topical Cyclosporine Use for Graft Rejection Percentage of Respondents Using Cyclosporine Question
Penetrating Keratoplasty Endothelial Keratoplasty
1. What is your “routine” postoperative immunosuppressive regimen for patients with avascular corneas undergoing keratoplasty for the first time? 2. What is your “routine” postoperative immunosuppressive regimen for patients at high risk for graft failure (vascularized cornea and/or previous graft rejection)? 3. How would you treat an obvious endothelial rejection line and corneal edema? 4. How would you treat a patient with sudden onset of keratic precipitates and graft edema? 5. How would you treat a patient with the sudden onset of edema, cells in the anterior chamber not previously observed, but no keratic precipitates? 6. How would you treat a patient with new complaints of photophobia, but no change in vision, increase in graft thickness, or inflammatory signs? 7. How would you treat a patient with the sudden onset of corneal edema and decreased acuity, but no signs of inflammation? 8. How would you treat a patient with the gradual onset of corneal edema, but absolutely no signs of inflammation?
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13
14
48
40
24 27 23
26 32 30
56
77
29
35
56
4
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Cornea Volume 34, Number 6, June 2015
FIGURE 2. Responses regarding utilization of alternative keratoplasty techniques. DSEK, Descemet stripping endothelial keratoplasty; DMEK, Descemet membrane endothelial keratoplasty; DALK, deep anterior lamellar keratoplasty; K-Pro, keratoprosthesis.
72% this survey, P , 0.05). This most probably corresponds to an increased usage of difluprednate, which was not available in 2004. Difluprednate is a novel, strong synthetic steroid emulsion that has become widely accepted in the treatment of endogenous and postoperative inflammation.12 Interestingly, use of dexamethasone did not seem to be affected. Because responses were not coded by geographic region, we cannot reach definitive conclusions; however, it is possible that regional prescribing patterns explain the probable influence of difluprednate on prednisolone but not dexamethasone utilization. Use of loteprednol increased significantly after 6 months postoperatively. The reason(s) for this change was not captured by our survey, but it may represent increased concern about other steroids’ impact on intraocular pressure.13,14 Decreases in dexamethasone and prednisolone use after 6 months corresponded to increased use of loteprednol and fluorometholone, both of which have less impact on IOP. Usage of subconjunctival steroid preparations was noted to be higher in routine management of low-risk grafts versus high-risk grafts (76% and 54%, respectively). We believe that use of other topical and oral immunosuppressive
FIGURE 3. Keratoplasty procedure of choice by indication. Fuchs, Fuchs endothelial dystrophy; PBK, pseudophakic bullous keratopathy; OCP, ocular cicatricial pemphigoid. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Corneal Graft Management
agents in high-risk grafts is most likely the reason for the lower use of subconjunctival steroid preparations. Since the last survey, endothelial keratoplasty (EK) has become the procedure of choice for endothelial dysfunction for most surgeons. Interestingly, although most respondents (75%) felt that graft rejection occurs much less frequently after EK than PK, there were no differences in rejection prophylaxis or treatment strategies for these 2 procedures. In the 2004 survey, use of topical cyclosporine was evaluated for the first time. Since then, its use has increased manyfold for many graft rejection scenarios except as adjunctive routine management for high-risk grafts, where it was already being used by 48% of respondents in 2004 (Fig. 2). This increased use comes despite recent studies that have shown that topical cyclosporine does not add any advantage to conventional treatment in managing high-risk grafts undergoing graft rejection.15–20 As with the previous surveys, oral immunosuppressive agents, including cyclosporine and tacrolimus, were rarely used for routine graft management, and never used for EK management. Efficacy has been reported for both these agents; however, data are still somewhat limited. In contrast, many physicians continue to use oral corticosteroids in certain graft failure scenarios.9,15–19,21–23 In a survey performed by Price et al24 in 2009, 100% of survey respondents used topical steroid preparations in the routine management of low-risk penetrating keratoplasty; 95% of these respondents used prednisolone acetate 1%. As expected, use of specific keratoplasty techniques has shifted since the last survey. Endothelial keratoplasty, primarily DSEK, is now the procedure of choice for endothelial dysfunction, including Fuchs endothelial dystrophy, pseudophakic corneal edema, and graft failure. Penetrating keratoplasty remains the procedure of choice for keratoconus; however, an equivalent number of respondents reported that DALK was their procedure of choice for keratoconus and a higher number prefer DALK to PK for anterior stromal scars. These results differ from other recent reports on the use of DALK. According to the Eye Bank Association of America (EBAA), 1% of the corneal donor tissue in 2009 was used for anterior lamellar keratoplasty. In 2010 and 2011, 2% and 3%, respectively, of the donor tissue was used for anterior lamellar keratoplasty.25 There is rising interest in newer, selective corneal transplantation procedures, such as DALK and DMEK, with 30% of respondents expressing the desire to begin performing DMEK. Interest in keratoprosthesis usage remains lower than that of other procedures. There are several limitations to these data that require that they be viewed with caution. First, while a 30% survey return rate is relatively good, there is still a significant number of individuals whose practice patterns may not be reflected in this study. Furthermore, as the survey is anonymous, it is difficult to determine if the trends compared between 2004 and 2011 represent changes in a specific individual’s practice over those years or if different individuals responded in those survey years. Most of the responses came from US members; thus, these responses may not accurately represent global practice patterns. Keratoplasty surgical volume was not www.corneajrnl.com |
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Cornea Volume 34, Number 6, June 2015
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directly inquired about and may be another marker to improve interpretation of results. Nevertheless, we believe these results provide a reasonable view of current practice patterns among Cornea Society members. The results of this survey provide insight into practice patterns for the prevention and treatment of corneal graft rejection. Topical prednisolone remains the mainstay for treatment in all scenarios. There were slight shifts in practice patterns over time, with increased use of difluprednate and topical cyclosporine, and significantly increased utilization of endothelial keratoplasty techniques. EK and PK management was similar despite the perception that rejection is less common for endothelial procedures. REFERENCES 1. Rinne JR, Stulting RD. Current practices in the prevention and treatment of corneal graft rejection. Cornea. 1992;11:326–328. 2. Al-Yousuf N, Mavrikakis I, Mavrikakis E, et al. Penetrating keratoplasty: indications over a 10 year period. Br J Ophthalmol. 2004;88:998–1001. 3. Bersudsky V, Blum-Hareuveni T, Rehany U, et al. The profile of repeated corneal transplantation. Ophthalmology. 2001;108:461–469. 4. Cosar CB, Sridhar MS, Cohen EJ, et al. Indications for penetrating keratoplasty and associated procedures, 1996-2000. Cornea. 2002;21: 148–151. 5. Cursiefen C, Kuchle M, Naumann GO. Changing indications for penetrating keratoplasty: histopathology of 1,250 corneal buttons. Cornea. 1998;17:468–470. 6. Maeno A, Naor J, Lee HM, et al. Three decades of corneal transplantation: indications and patient characteristics. Cornea. 2000;19:7–11. 7. Panda A, Vanathi M, Kumar A, et al. Corneal graft rejection. Surv Ophthalmol. 2007;52:375–396. 8. Patel NP, Kim T, Rapuano CJ, et al. Indications for and outcomes of repeat penetrating keratoplasty, 1989–1995. Ophthalmology. 2000;107: 719–724. 9. Randleman JB, Stulting RD. Prevention and treatment of corneal graft rejection: current practice patterns (2004). Cornea. 2006;25:286–290.
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10. Rapuano CJ, Cohen EJ, Brady SE, et al. Indications for and outcomes of repeat penetrating keratoplasty. Am J Ophthalmol. 1990;109:689–695. 11. Stulting RD, Waring GO III, Bridges WZ, et al. Effect of donor epithelium on corneal transplant survival. Ophthalmology. 1988; 95:803–812. 12. Jamal KN, Callanan DG. The role of difluprednate ophthalmic emulsion in clinical practice. Clin Ophthalmol. 2009;3:381–390. 13. Controlled evaluation of loteprednol etabonate and prednisolone acetate in the treatment of acute anterior uveitis. Loteprednol Etabonate US Uveitis Study Group. Am J Ophthalmol. 1999;127:537–544. 14. Novack GD, Howes J, Crockett RS, et al. Change in intraocular pressure during long-term use of loteprednol etabonate. J Glaucoma. 1998;7:266–269. 15. Belin MW, Bouchard CS, Frantz S, et al. Topical cyclosporine in highrisk corneal transplants. Ophthalmology. 1989;96:1144–1150. 16. Cosar CB, Laibson PR, Cohen EJ, et al. Topical cyclosporine in pediatric keratoplasty. Eye Contact Lens. 2003;29:103–107. 17. Hill JC. The use of cyclosporine in high-risk keratoplasty. Am J Ophthalmol. 1989;107:506–510. 18. Inoue K, Amano S, Kimura C, et al. Long-term effects of topical cyclosporine A treatment after penetrating keratoplasty. Jpn J Ophthalmol. 2000;44:302–305. 19. Javadi MA, Feizi S, Karbasian A, et al. Efficacy of topical ciclosporin A for treatment and prevention of graft rejection in corneal grafts with previous rejection episodes. Br J Ophthalmol. 2010;94:1464–1467. 20. Zhao JC, Jin XY. Local therapy of corneal allograft rejection with cyclosporine. Am J Ophthalmol. 1995;119:189–194. 21. Aiken-O’Neill P, Mannis MJ. Summary of corneal transplant activity Eye Bank Association of America. Cornea. 2002;21:1–3. 22. Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the management of high-risk corneal and limbal grafts. Ophthalmology. 2001;108:1838–1844. 23. Koay PY, Lee WH, Figueiredo FC. Opinions on risk factors and management of corneal graft rejection in the United kingdom. Cornea. 2005;24:292–296. 24. Price FW Jr, Price DA, Ngakeng V, et al. Survey of steroid usage patterns during and after low-risk penetrating keratoplasty. Cornea. 2009;28:865–870. 25. Eye Bank Association of America. Eye Banking Statistical report. 2013.
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Prevention and Treatment of Corneal Graft Rejection: Current Practice Patterns of the Cornea Society (2011) Bhairavi Kharod-Dholakia, MD,* J. Bradley Randleman, MD,* Jennifer G. Bromley, MD,* and R. Doyle Stulting, MD, PhD†
Purpose: To analyze current practice patterns in the prevention and treatment of corneal graft rejection for both penetrating keratoplasty (PK) and endothelial keratoplasty (EK) and to compare these patterns with previously reported practices.
Methods: In 2011, an electronic survey was sent to 670 members of the Cornea Society worldwide addressing the routine postoperative management of corneal transplants at different time points, treatment of various manifestations of corneal graft rejection, and preferred surgical techniques. Results: A total of 204 of 670 surveys (30%) were returned and evaluated. All respondents used topical corticosteroids for routine postoperative management and treatment of endothelial graft rejection. Prednisolone was the topical steroid of choice in all clinical scenarios, similar to previous surveys from 1989 to 2004. Use of subconjunctival and systemic steroids increased for many scenarios of probable and definite graft rejection. Routine use of prednisolone decreased by approximately 10% from previous surveys, whereas difluprednate was used in 13% of high-risk eyes during the first 6 months. Dexamethasone, fluorometholone, and loteprednol use remained stable. Adjunctive topical cyclosporine use increased significantly for PK and EK. EK was the preferred technique for endothelial dysfunction, whereas PK and deep anterior lamellar keratoplasty were both used for keratoconus and anterior scars. Most respondents (75%) felt that graft rejection occurs more frequently after PK than after EK. Conclusions: Prednisolone remains the treatment of choice for management and treatment of graft rejection; however, since the introduction of difluprednate, its use has declined slightly since the introduction of difluprednate. Despite perceived differences in rejection rates, there were no differences in prophylactic steroid treatment for PK and EK. Received for publication September 9, 2014; revision received January 21, 2015; accepted January 22, 2015. Published online ahead of print March 26, 2015. From the *Department of Ophthalmology, Emory University, Atlanta, GA; and †Stulting Research Center, Woolfson Eye Institute, Atlanta, GA. Supported in part by an Emory University Department of Ophthalmology unrestricted grant from Research to Prevent Blindness, Inc. The authors have no conflicts of interest to disclose. J. G. Bromley is now in private practice in Savannah, GA. Reprints: Bhairavi Kharod-Dholakia, MD, Department of Ophthalmology, Emory University, 1365 Clifton Rd NE, Atlanta, GA 30322 (e-mail: [email protected]). Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Cornea Volume 34, Number 6, June 2015
Key Words: corneal graft rejection, corticosteroid, penetrating keratoplasty, endothelial keratoplasty (Cornea 2015;34:609–614)
G
raft failure from rejection remains the most significant complications of corneal transplantation and is a leading indication for overall corneal transplantation.1–9 There is significant variability among practitioners in prevention and treatment of allograft rejection. Our group developed 2 previous surveys to evaluate practice patterns for members of the Cornea Society (previously the Castroviejo Society) in 19891 and 2004.9 Those studies demonstrated some consistency in practice patterns over time, especially the role of topical prednisolone as primary therapy for prevention and treatment of graft rejection in most situations. However, other practice patterns showed significant changes over time, including a diminishing role for subconjunctival steroids for graft rejection from 1989 to 2004, and increased use of topical cyclosporine and loteprednol in the 2004 survey, 2 agents that were not available at the time of the 1989 survey.9 With the additional years of availability of these agents, the introduction of new topical therapies, including difluprednate, and the advent of endothelial keratoplasty as the procedure of choice for primary endothelial dysfunction and penetrating keratoplasty (PK) failure, Cornea Society members were resurveyed to determine current practice patterns with special focus on how these changes have affected overall practice patterns. The purpose of this study was to determine the current practice patterns of the members of The Cornea Society for the prevention and treatment of corneal graft rejection, including PK and endothelial keratoplasty (EK), and to compare these with past practice patterns reported in previous surveys. This survey also evaluated the utilization of alternative surgical strategies for high-risk corneal transplantation.
MATERIALS AND METHODS A survey was sent worldwide electronically (through surveymonkey.com) to 670 members of the Cornea Society in May 2011. All survey responses were anonymous; however, respondents were asked to provide demographic information, including age and regional location. The first 10 questions in the survey were identical to the past surveys and addressed the preferred treatment strategies for both routine postoperative management and for various presentations of corneal allograft rejection (Table 1). As in www.corneajrnl.com |
609
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Cornea Volume 34, Number 6, June 2015
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TABLE 1. Steroid Use for Penetrating Keratoplasty Rejection Prevention and Management Percentage of Respondents Using Steroids (1989, 2004), 2011 Question 1. What is your “routine” postoperative immunosuppressive regimen for patients with avascular corneas undergoing keratoplasty for the first time? 2. What is your “routine” postoperative immunosuppressive regimen for patients at high risk for graft failure (vascularized cornea and/or previous graft rejection)? 3. How would you treat a patient with subepithelial infiltrates confined to the graft without corneal edema or other signs of graft rejection in a patient who obviously does not have epidemic keratoconjunctivitis? 4. How would you treat a patient with epithelial rejection line, but no other signs of graft rejection? 5. How would you treat an obvious endothelial rejection line and corneal edema? 6. How would you treat a patient with sudden onset of keratic precipitates and graft edema? 7. How would you treat a patient with the sudden onset of edema, cells in the anterior chamber not previously observed, but no keratic precipitates? 8. How would you treat a patient with new complaints of photophobia, but no change in vision, increase in graft thickness, or inflammatory signs? 9. How would you treat a patient with the sudden onset of corneal edema and decreased acuity, but no signs of inflammation? 10. How would you treat a patient with the gradual onset of corneal edema, but absolutely no signs of inflammation?
Topical (1989, 2004), 2011
Subconjunctival (1989, 2004), 2011
Intravenous, Intramuscular, Orally (1989, 2004), 2011
(100, 100), 100
(43, 48), 76*
(7, 3), 20*
(100, 100), 100
(53, 53), 54
(23, 1), 30*
(93, 96), 97
(7, 3), 35*
(5, 1), 25*
(93, 95), 97
(12, 5), 33*
(7, 3), 45*
(100, 100), 100
(57, 35), 39
(37, 38), 69*
(100, 100), 100
(51, 32), 43
(32, 34), 63*
(100, 100), 100
(40, 21), 42*
(25, 20), 63*
(70, 57), 84*
(3, 0), 22*
(2, 1), 33*
(92, 99), 100
(11, 11), 41*
(7, 14), 44*
(81, 73), 87
(7, 4), 13
(4, 3), 38*
*P , 0.05.
previous surveys, corneal allograft rejection was defined in 3 stages: possible rejection, probable rejection, and definite rejection. Briefly, in previously clear grafts, possible rejection was defined as graft edema without obvious signs of inflammation, probable rejection as corneal edema and inflammation without an endothelial rejection line, and definite rejection as the appearance of corneal edema with an endothelial rejection line.1,9 The survey questions were asked twice for each category, once for penetrating keratoplasty and once for endothelial keratoplasty. Results were collected individually for both PK and EK. The second subset of questions determined the respondent’s utilization of topical steroids in routine and high-risk allografts of patients in phakic, pseudophakic, and aphakic eyes. Based on previous survey responses, treatment regimens included use of topical betamethasone, dexamethasone, difluprednate, fluorometholone, loteprednol, prednisolone (generic), prednisolone (brand), rimexolone, or no topical medication. The respondents were asked about their treatment preferences for penetrating keratoplasty and endothelial keratoplasty separately in 2 different sets of question. The results included separate answers for both PK and EK. This survey included a new third subset of questions to determine potential interest in surgical alternatives to penetrating keratoplasty and surgical treatment strategies for high-risk transplant patients. Respondents were specifically asked about alternative keratoplasty procedures they were currently using or
were planning to use in the future, including Descemet stripping automated endothelial keratoplasty (DSAEK), Descemet membrane endothelial keratoplasty (DMEK), deep anterior lamellar keratoplasty (DALK), and keratoprosthesis (K-Pro). They were also asked about their procedure of choice for a variety of surgical indications, including keratoconus, Fuchs endothelial dystrophy (Fuchs), pseudophakic corneal edema (PCE), anterior stromal scar, multiple failed grafts, severe chemical injury, Stevens–Johnson syndrome (SJS), and ocular cicatricial pemphigoid (OCP). Because these questions were not included in the previous surveys, only the responses were analyzed. Most of the responses were reported using descriptive statistics only. Where appropriate, Student t test and x2 analyses were performed to evaluate differences in responses between surveys, with P , 0.05 considered significant.
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RESULTS A total of 204 of 670 surveys (30%) were returned and evaluated, compared with 137 of 314 (41%) and 111 of 396 (28%) surveys evaluated in 19891 and 2004,9 respectively (P . 0.05).
Demographics of Survey Respondents Most survey respondents were from North America (78.7%), followed by Europe (9.3%), Asia (6.0%), South
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Cornea Volume 34, Number 6, June 2015
America (4%), Australia (1.3%), and the Middle East/Africa (0.7%). The ages of the respondents varied widely, from 30 to more than 70 years, with a relatively even distribution by decade for most respondents from ages 30 to 39 (31%), 40 to 49 (21.9%), and 50 to 59 (30.3%). Most respondents (75%) felt that graft rejection occurs more frequently after PK, 1% felt rejection was more common after EK, and 24% felt there was no difference between rejection rates with the 2 procedures. Treatment strategies for prophylaxis and treatment of rejection were essentially identical for PK and EK for almost all scenarios.
Topical, Subconjunctival, and Oral Steroid Use for Graft Rejection The results of this survey for prevention and treatment of allograft rejection were comparable in most aspects with both previous surveys (Table 1). Topical corticosteroids remained the treatment of choice for routine postoperative management for both penetrating keratoplasty and endothelial keratoplasty. Their use in other clinical situations was similar to that reported in the previous surveys. Most (75% and 68%) respondents used intraoperative subconjunctival corticosteroids for avascular corneas undergoing PK and EK, respectively. Use of subconjunctival and oral/intravenous/ intramuscular steroids for routine postoperative management increased compared with both 1989 and 2004 surveys.
Preferred Topical Steroid: Routine Postoperative Management Prednisolone in brand or generic form remained the preferred treatment for routine management in all scenarios regardless of the risk status or lens status and was used by 55% to 80% of respondents in our survey (Fig. 1). The other most commonly used preparations included dexamethasone, difluprednate, loteprednol, and fluorometholone. Use of
Corneal Graft Management
prednisolone and dexamethasone varied slightly by time, lens status, and risk category, being less common after 6 months than during the first 6 months postoperatively; however, use of difluprednate, loteprednol, and fluorometholone varied more. Difluprednate was used primarily for high-risk eyes, and almost exclusively during the first 6 months. Loteprednol was used most commonly after 6 months, for phakic patients, and low-risk eyes. Fluorometholone was used almost exclusively after 6 months and for low-risk eyes.
Preferred Topical Steroid: Graft Rejection Management Prednisolone was the primary treatment of choice for all manifestations of graft rejection, ranging from 72% to 83%. Dexamethasone was the second most commonly used steroid preparation, with use ranging from 10% to 13% in all clinical scenarios (Table 2). Use of difluprednate varied significantly, depending on the clinical scenario (3%–17%), with highest utilization in eyes with obvious endothelial rejection. Loteprednol and fluorometholone were rarely used for any scenario of graft rejection (,1% for either). There were no differences between responses for PK and EK.
Topical Cyclosporine Use for Graft Rejection Treatment and Prophylaxis Topical cyclosporine was used as adjunctive therapy in 13% to 77% of scenarios for possible, probable, or definite graft rejection (Table 3). Use of topical cyclosporine increased for all clinical scenarios, compared with 2004 (P , 0.05), except for prophylactic management of highrisk grafts (48%), for which utilization was already 48% in 2004. Use of cyclosporine was slightly higher for EK than PK for most clinical scenarios.
FIGURE 1. Preferred topical steroid preparations for first 6 months in low-risk grafts in phakic eyes; after 6 months in low-risk grafts in phakic eyes; first 6 months in high-risk grafts in phakic eyes; after 6 months in high-risk grafts in phakic eyes; first 6 months in low-risk grafts in pseudophakic or aphakic eyes; after 6 months in low-risk grafts in pseudophakic or aphakic eyes; first 6 months in high-risk grafts in pseudophakic or aphakic eyes; after 6 months in high-risk grafts in pseudophakic or aphakic eyes. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
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Kharod-Dholakia et al
TABLE 2. Preferred Topical Steroid Preparation for Graft Rejection Percentage of Respondents Using Steroids Question
Prednisolone
Dexamethasone
Difluprednate
76
12
6
78
11
6
73 72 75
10 10 11
14 14 10
77
13
3
79
11
7
83
10
3
1. How would you treat a patient with subepithelial infiltrates confined to the graft without corneal edema or other signs of graft rejection in a patient who obviously does not have epidemic keratoconjunctivitis? 2. How would you treat a patient with epithelial rejection line, but no other signs of graft rejection? 3. How would you treat an obvious endothelial rejection line and corneal edema? 4. How would you treat a patient with sudden onset of keratic precipitates and graft edema? 5. How would you treat a patient with the sudden onset of edema, cells in the anterior chamber not previously observed, but no keratic precipitates? 6. How would you treat a patient with new complaints of photophobia, but no change in vision, increase in graft thickness, or inflammatory signs? 7. How would you treat a patient with the sudden onset of corneal edema and decreased acuity, but no signs of inflammation? 8. How would you treat a patient with the gradual onset of corneal edema, but absolutely no signs of inflammation?
Other Systemic Immunosuppressive Use Oral cyclosporine and oral tacrolimus were used in less than 5% of scenarios for graft rejection management.
Alternative Keratoplasty Procedures/ Procedures of Choice The current and projected utilization of procedures other than PK showed that DSEK was the most commonly performed procedure currently, followed by DALK (Fig. 2). There was significant expressed interest in DMEK and DALK, and to a lesser extent K-Pro, for future performance. As expected, the keratoplasty procedure of first choice varied by indication (Fig. 3). Selective keratoplasty was preferred to penetrating keratoplasty for most conditions. DALK was preferred for keratoconus and anterior stromal scars, whereas keratoprosthesis was preferred for very high-risk categories including multiple failed grafts, ocular cicatricial
pemphigoid, Stevens–Johnson syndrome, and severe chemical injuries.
DISCUSSION The results of this survey demonstrate subtle changes in management strategies for the treatment and prevention of corneal transplant rejection over time and evolving surgical technique preferences. The results from this survey combined with the results from 19891 and 20049 provide an opportunity to evaluate the practice patterns of the members of the Cornea Society over time. Changes in medical management from past surveys may be partially explained by newer topical steroid preparations and increased experience with previously “new” preparations. Although prednisolone remained the drug of choice for every scenario, there were significant differences in its use in high-risk grafts during the first 6 months (90% in 2004 vs.
TABLE 3. Topical Cyclosporine Use for Graft Rejection Percentage of Respondents Using Cyclosporine Question
Penetrating Keratoplasty Endothelial Keratoplasty
1. What is your “routine” postoperative immunosuppressive regimen for patients with avascular corneas undergoing keratoplasty for the first time? 2. What is your “routine” postoperative immunosuppressive regimen for patients at high risk for graft failure (vascularized cornea and/or previous graft rejection)? 3. How would you treat an obvious endothelial rejection line and corneal edema? 4. How would you treat a patient with sudden onset of keratic precipitates and graft edema? 5. How would you treat a patient with the sudden onset of edema, cells in the anterior chamber not previously observed, but no keratic precipitates? 6. How would you treat a patient with new complaints of photophobia, but no change in vision, increase in graft thickness, or inflammatory signs? 7. How would you treat a patient with the sudden onset of corneal edema and decreased acuity, but no signs of inflammation? 8. How would you treat a patient with the gradual onset of corneal edema, but absolutely no signs of inflammation?
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13
14
48
40
24 27 23
26 32 30
56
77
29
35
56
4
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Cornea Volume 34, Number 6, June 2015
FIGURE 2. Responses regarding utilization of alternative keratoplasty techniques. DSEK, Descemet stripping endothelial keratoplasty; DMEK, Descemet membrane endothelial keratoplasty; DALK, deep anterior lamellar keratoplasty; K-Pro, keratoprosthesis.
72% this survey, P , 0.05). This most probably corresponds to an increased usage of difluprednate, which was not available in 2004. Difluprednate is a novel, strong synthetic steroid emulsion that has become widely accepted in the treatment of endogenous and postoperative inflammation.12 Interestingly, use of dexamethasone did not seem to be affected. Because responses were not coded by geographic region, we cannot reach definitive conclusions; however, it is possible that regional prescribing patterns explain the probable influence of difluprednate on prednisolone but not dexamethasone utilization. Use of loteprednol increased significantly after 6 months postoperatively. The reason(s) for this change was not captured by our survey, but it may represent increased concern about other steroids’ impact on intraocular pressure.13,14 Decreases in dexamethasone and prednisolone use after 6 months corresponded to increased use of loteprednol and fluorometholone, both of which have less impact on IOP. Usage of subconjunctival steroid preparations was noted to be higher in routine management of low-risk grafts versus high-risk grafts (76% and 54%, respectively). We believe that use of other topical and oral immunosuppressive
FIGURE 3. Keratoplasty procedure of choice by indication. Fuchs, Fuchs endothelial dystrophy; PBK, pseudophakic bullous keratopathy; OCP, ocular cicatricial pemphigoid. Copyright © 2015 Wolters Kluwer Health, Inc. All rights reserved.
Corneal Graft Management
agents in high-risk grafts is most likely the reason for the lower use of subconjunctival steroid preparations. Since the last survey, endothelial keratoplasty (EK) has become the procedure of choice for endothelial dysfunction for most surgeons. Interestingly, although most respondents (75%) felt that graft rejection occurs much less frequently after EK than PK, there were no differences in rejection prophylaxis or treatment strategies for these 2 procedures. In the 2004 survey, use of topical cyclosporine was evaluated for the first time. Since then, its use has increased manyfold for many graft rejection scenarios except as adjunctive routine management for high-risk grafts, where it was already being used by 48% of respondents in 2004 (Fig. 2). This increased use comes despite recent studies that have shown that topical cyclosporine does not add any advantage to conventional treatment in managing high-risk grafts undergoing graft rejection.15–20 As with the previous surveys, oral immunosuppressive agents, including cyclosporine and tacrolimus, were rarely used for routine graft management, and never used for EK management. Efficacy has been reported for both these agents; however, data are still somewhat limited. In contrast, many physicians continue to use oral corticosteroids in certain graft failure scenarios.9,15–19,21–23 In a survey performed by Price et al24 in 2009, 100% of survey respondents used topical steroid preparations in the routine management of low-risk penetrating keratoplasty; 95% of these respondents used prednisolone acetate 1%. As expected, use of specific keratoplasty techniques has shifted since the last survey. Endothelial keratoplasty, primarily DSEK, is now the procedure of choice for endothelial dysfunction, including Fuchs endothelial dystrophy, pseudophakic corneal edema, and graft failure. Penetrating keratoplasty remains the procedure of choice for keratoconus; however, an equivalent number of respondents reported that DALK was their procedure of choice for keratoconus and a higher number prefer DALK to PK for anterior stromal scars. These results differ from other recent reports on the use of DALK. According to the Eye Bank Association of America (EBAA), 1% of the corneal donor tissue in 2009 was used for anterior lamellar keratoplasty. In 2010 and 2011, 2% and 3%, respectively, of the donor tissue was used for anterior lamellar keratoplasty.25 There is rising interest in newer, selective corneal transplantation procedures, such as DALK and DMEK, with 30% of respondents expressing the desire to begin performing DMEK. Interest in keratoprosthesis usage remains lower than that of other procedures. There are several limitations to these data that require that they be viewed with caution. First, while a 30% survey return rate is relatively good, there is still a significant number of individuals whose practice patterns may not be reflected in this study. Furthermore, as the survey is anonymous, it is difficult to determine if the trends compared between 2004 and 2011 represent changes in a specific individual’s practice over those years or if different individuals responded in those survey years. Most of the responses came from US members; thus, these responses may not accurately represent global practice patterns. Keratoplasty surgical volume was not www.corneajrnl.com |
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Cornea Volume 34, Number 6, June 2015
Kharod-Dholakia et al
directly inquired about and may be another marker to improve interpretation of results. Nevertheless, we believe these results provide a reasonable view of current practice patterns among Cornea Society members. The results of this survey provide insight into practice patterns for the prevention and treatment of corneal graft rejection. Topical prednisolone remains the mainstay for treatment in all scenarios. There were slight shifts in practice patterns over time, with increased use of difluprednate and topical cyclosporine, and significantly increased utilization of endothelial keratoplasty techniques. EK and PK management was similar despite the perception that rejection is less common for endothelial procedures. REFERENCES 1. Rinne JR, Stulting RD. Current practices in the prevention and treatment of corneal graft rejection. Cornea. 1992;11:326–328. 2. Al-Yousuf N, Mavrikakis I, Mavrikakis E, et al. Penetrating keratoplasty: indications over a 10 year period. Br J Ophthalmol. 2004;88:998–1001. 3. Bersudsky V, Blum-Hareuveni T, Rehany U, et al. The profile of repeated corneal transplantation. Ophthalmology. 2001;108:461–469. 4. Cosar CB, Sridhar MS, Cohen EJ, et al. Indications for penetrating keratoplasty and associated procedures, 1996-2000. Cornea. 2002;21: 148–151. 5. Cursiefen C, Kuchle M, Naumann GO. Changing indications for penetrating keratoplasty: histopathology of 1,250 corneal buttons. Cornea. 1998;17:468–470. 6. Maeno A, Naor J, Lee HM, et al. Three decades of corneal transplantation: indications and patient characteristics. Cornea. 2000;19:7–11. 7. Panda A, Vanathi M, Kumar A, et al. Corneal graft rejection. Surv Ophthalmol. 2007;52:375–396. 8. Patel NP, Kim T, Rapuano CJ, et al. Indications for and outcomes of repeat penetrating keratoplasty, 1989–1995. Ophthalmology. 2000;107: 719–724. 9. Randleman JB, Stulting RD. Prevention and treatment of corneal graft rejection: current practice patterns (2004). Cornea. 2006;25:286–290.
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10. Rapuano CJ, Cohen EJ, Brady SE, et al. Indications for and outcomes of repeat penetrating keratoplasty. Am J Ophthalmol. 1990;109:689–695. 11. Stulting RD, Waring GO III, Bridges WZ, et al. Effect of donor epithelium on corneal transplant survival. Ophthalmology. 1988; 95:803–812. 12. Jamal KN, Callanan DG. The role of difluprednate ophthalmic emulsion in clinical practice. Clin Ophthalmol. 2009;3:381–390. 13. Controlled evaluation of loteprednol etabonate and prednisolone acetate in the treatment of acute anterior uveitis. Loteprednol Etabonate US Uveitis Study Group. Am J Ophthalmol. 1999;127:537–544. 14. Novack GD, Howes J, Crockett RS, et al. Change in intraocular pressure during long-term use of loteprednol etabonate. J Glaucoma. 1998;7:266–269. 15. Belin MW, Bouchard CS, Frantz S, et al. Topical cyclosporine in highrisk corneal transplants. Ophthalmology. 1989;96:1144–1150. 16. Cosar CB, Laibson PR, Cohen EJ, et al. Topical cyclosporine in pediatric keratoplasty. Eye Contact Lens. 2003;29:103–107. 17. Hill JC. The use of cyclosporine in high-risk keratoplasty. Am J Ophthalmol. 1989;107:506–510. 18. Inoue K, Amano S, Kimura C, et al. Long-term effects of topical cyclosporine A treatment after penetrating keratoplasty. Jpn J Ophthalmol. 2000;44:302–305. 19. Javadi MA, Feizi S, Karbasian A, et al. Efficacy of topical ciclosporin A for treatment and prevention of graft rejection in corneal grafts with previous rejection episodes. Br J Ophthalmol. 2010;94:1464–1467. 20. Zhao JC, Jin XY. Local therapy of corneal allograft rejection with cyclosporine. Am J Ophthalmol. 1995;119:189–194. 21. Aiken-O’Neill P, Mannis MJ. Summary of corneal transplant activity Eye Bank Association of America. Cornea. 2002;21:1–3. 22. Sloper CM, Powell RJ, Dua HS. Tacrolimus (FK506) in the management of high-risk corneal and limbal grafts. Ophthalmology. 2001;108:1838–1844. 23. Koay PY, Lee WH, Figueiredo FC. Opinions on risk factors and management of corneal graft rejection in the United kingdom. Cornea. 2005;24:292–296. 24. Price FW Jr, Price DA, Ngakeng V, et al. Survey of steroid usage patterns during and after low-risk penetrating keratoplasty. Cornea. 2009;28:865–870. 25. Eye Bank Association of America. Eye Banking Statistical report. 2013.
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