Omar, Ahmed F. MD, PhD*,†; Szczotka-Flynn, Loretta B. OD, PhD*; Benetz, Beth Ann MA*; Carcione, Jonathan MD*; Lass, Jonathan H. MD* Abstract National Eye Institute (NEI)–funded randomized controlled trials (RCTs) have significantly shaped the modern landscape of keratoplasty for endothelial disorders. Unlike retrospective studies, RCTs have offered the highest level of clinical evidence and have addressed critical questions related to histocompatibility matching, donor and donor tissue characteristics, donor tissue storage, and operative and postoperative factors supporting postoperative endothelial cell health. These RCTs have in turn directly influenced eye banking and keratoplasty practices. The purpose of this review is to 1) summarize the major findings from all of the NEI-sponsored keratoplasty RCTs, including the Collaborative Corneal Transplantation Studies, the Cornea Donor Study and its ancillary study, the Specular Microscopy Ancillary Study, the Cornea Preservation Time Study, as well as the on-going Diabetes Endothelial Keratoplasty Study and the Descemet Endothelial Thickness Comparison Trial; 2) review select keratoplasty RCTs not supported by the NEI; 3) compare findings from these RCTs with those from the major keratoplasty registries; and 4) discuss promising future directions in keratoplasty and eye banking that would lend themselves for RCTs. Collectively, these RCTs have clarified long-standing controversies, validated emerging practices, and will continue to provide the foundation for future innovation in the surgical management of endothelial diseases. Since the first penetrating keratoplasty (PKP) was performed by Zirm1 in 1905 and the first eye bank in the world was established by Paton in 1944,2 outside of controlled clinical trials, advances in keratoplasty and eye banking have come from pioneer innovators,3–6 single-site technique explorers and refiners,7–9 multicenter exploration and refining technique studies,10–12 and the insights derived from national registry studies.13 From the eye banking standpoint, advances from these studies have resulted in improved donor tissue quality, cost effectiveness, distribution capabilities, and progress in donor tissue processing [eg, lenticule preparation for Descemet stripping automated endothelial keratoplasty (DSAEK) and Descemet membrane endothelial keratoplasty (DMEK)].14 The timeline for the introduction of these keratoplasty procedures are shown in Figure 1. From the keratoplasty standpoint, advances have resulted in improved preoperative diagnostic methods for recipient evaluation that influence procedural selection and graft outcomes, improved operative efficiency and reduction of complications from penetrating keratoplasty (PKP) to DSAEK to DMEK, reduction of postoperative complications (eg, wound issues, infection, graft rejection, late endothelial failure), and improved outcomes (eg, uncorrected and corrected visual acuity, endothelial survival, Scheimpflug tomography parameters and patterns, quality-of-life measures).8 While these advances in keratoplasty and eye banking have been remarkable driven by the work of the innovators, explorers, refiners, and registry studies, their findings can be affected by in some cases by the retrospective and incomplete collection of data, investigator bias, variability in preoperative, operative and postoperative parameters of the donor tissue and graft outcomes, and varying follow-up. To parallel an invited review of “Keratoplasty Registries: Lessons Learned” by Chu et al13 in 2023, this review discusses the highest level of evidence-based medicine, the randomized controlled trial (RCT) in keratoplasty outcomes for endothelial failure conditions. Collectively, RCTs have examined several important questions surrounding keratoplasty and eye banking, complementing the findings of the previously mentioned non-RCT studies and/or providing a more in-depth exploration of the most important factors impacting graft outcomes. METHODS Given the limitations of the scope of this review, RCTs that have examined important questions regarding keratoplasty that were previously or currently supported by the National Eye Institute (NEI) are principally discussed; other RCTs not supported by the NEI are briefly described. Interestingly, all keratoplasty RCTs supported by the NEI have been concerning endothelial failure conditions. Therefore, using a similar approach as Chu et al for the keratoplasty registries review that searched PubMed and Google Scholar databases before April 2021,13 we also conducted a search of PubMed and ClinicalTrials.gov through February 2025 for other RCTs in keratoplasty. The selection of an RCT for this review was defined by a prospective study that consented, enrolled, and assigned participant eyes to one of 2 (or more) arms in a masked manner using a randomization (or minimization) algorithm. We identified RCTs for keratoplasty for endothelial failure conditions by using the keywords keratoplasty or corneal transplant in combination with randomized clinical trial, randomized controlled trial, cornea, and endothelial failure. DISCUSSION The Randomized Controlled Trial Not all evidence provided within clinical research is the same. The first and earliest principle of evidence-based medicine indicated that a hierarchy of evidence exists.15 The principle of a “pyramid of studies,” a framework used in evidence-based medicine to rank different types of research based on their reliability and quality, developed and became well known in the early 1990s as practitioners started to appraise and apply evidence to their clinical practices.15 The pyramid organizes studies from the least to the most reliable: The weakest designs are at the bottom (basic science and case series), followed by case–control and cohort studies in the middle, then RCTs, and at the very top, systematic reviews and meta-analysis. However, rather than consider systematic reviews and meta-analysis as separate study designs, Murad et al15 suggested that they should be chopped off the peak of the pyramid and are instead a lens through which other study evidence is viewed or applied. The RCT has long been considered the “gold standard” for testing interventions, where participants are randomly assigned to treatment arms, including a control, which minimizes bias. Although Murad et al also suggested that methodological limitations of study designs (imprecision, inconsistency, and indirectness) blur the lines of the traditional pyramid, RCTs vetted by unbiased peer review groups, in particular National Institutes of Health (NIH) study sections, undoubtedly are the highest quality and deserve to remain sharply at the top of the evidence hierarchy. Hence, we are particularly reviewing NIH-funded RCTs in keratoplasty. NEI-Sponsored Keratoplasty Randomized Controlled Trials While the RCT is the gold standard for evidence based medicine, since the founding of the NEI in 1968, there have only been 3 RCTs completed related to keratoplasty and eye banking: the Collaborative Corneal Transplantation Studies (CCTS),16 the Cornea Donor Study (CDS)17 and its ancillary study, the Specular Microscopy Ancillary Study (SMAS),18 and the Cornea Preservation Time Study (CPTS).19 A summary of major findings is listed in Table 1. Two NEI-sponsored RCTs are currently being conducted in 2025: the Diabetes Endothelial Keratoplasty Study20 and the Descemet Endothelial Thickness Comparison Trial (DETECT).21,22 Note that all of these studies included participants that required keratoplasty for endothelial failure conditions, which are the most common reason for keratoplasty,23 and to our knowledge, the NEI has never funded a RCT on keratoplasty for other conditions such as keratoconus, ectasias, stromal dystrophies, infections, etc. This review will focus on the primary aims that statistically powered each of these studies and their findings, and other questions regarding impactful questions surrounding keratoplasty and eye banking that were addressed with secondary analyses. CCTS31 Evaluate the impact of HLA matching and systemic cyclosporine on graft survival in high-risk PK. HLA matching did not significantly improve graft survival. Systemic cyclosporine reduced rejection risk but had limiting side effects. CDS and SMAS37,44,51 Assess the effect of donor age on PK graft survival and endothelial cell loss. No significant difference in 5-yr graft survival between donors aged 12–65 vs. 66–75. Slight decrease in survival beyond age 71 at 10 yrs. Significant ECL occurred across all age groups but did not correlate with graft failure. Donor diabetes, cause of death, and retrieval methods had no impact on graft success. CPTS58,62 Investigate the impact of corneal tissue PT on DSAEK outcomes. Corneas preserved up to 11 d demonstrated similar 3-yr graft success as those ≤7 d. Longer PT associated with higher ECL but no difference in survival within the 11-d window. Early graft failure risk increased with donor diabetes and intraoperative complications. DEKS20 Determine the influence of donor diabetes on graft success and endothelial survival following DMEK. Ongoing trial. Designed to determine whether corneas from donors with diabetes have comparable DMEK graft outcomes at 1 year as corneas from donors without diabetes. Will also examine other donor, donor tissue, recipient, operative and postoperative factors impacting DMEK graft outcomes. DETECT21,22 DETECT I: compare ultrathin DSAEK vs. DMEK ± topical ripasudil. DETECT II: compare DMEK vs. DSO+ ripasudil in FECD. Ongoing trial. Designed to define visual and endothelial outcomes of emerging keratoplasty techniques and evaluate Rho-kinase inhibitor therapy. Collaborative Corneal Transplantation Studies The CCTS were designed to evaluate the effect of donor-recipient histocompatibility matching (HLA-A, HLA-B, and HLA-DR antigens) and cross-matching on the graft survival of PKP 3 years after surgery in 457 high-risk patients enrolled between 1989 and 1992.16,24–30 The study enrolled individuals with a history of graft rejection or significant corneal neovascularization, who were at a higher risk of immune-mediated graft failure.29 The subject cohort included predominantly aphakic/pseudophakic corneal edema, while including herpes keratitis, trauma, keratoconus, chemical burn, corneal ulcer, and other cases that had undergone from no previous PKPs to 3 previous PKPs.29 A key finding of the study was that HLA matching did not significantly improve graft survival rates, in contrast to what is observed in solid organ transplantation. This finding suggested that the cornea's unique immune privilege limits the role of HLA compatibility in preventing rejection; hence, routine histocompatibility testing was deemed unnecessary in standard corneal transplantation.31 The study also showed that systemic cyclosporine dosed 5 mg/kg/d and administered orally in divided doses was effective in reducing the risk of graft rejection in high-risk patients. This was given for 6 months postoperatively, and in some patients extended up to 12 months, depending on clinical course and risk of graft rejection. Those who received cyclosporine had a lower incidence of immune-mediated rejection compared with those who did not, particularly in cases with extensive corneal neovascularization. However, cyclosporine systemic side effects, including nephrotoxicity and hypertension limited its long-term use.31 CCTS spurred subsequent RCTs examining topical cyclosporine32 and topical tacrolimus33–35 in lowering the graft rejection risk for these high-risk keratoplasty. The CCTS also examined the impact of donor-recipient ABO blood group compatibility on graft survival. While ABO compatibility was recorded, it was not a criterion for recipient selection. At 3 years post-PKP, graft failure rates were 41% in the ABO-incompatible group compared with 31% in the ABO-compatible group. In addition, failure due to rejection occurred in 30% of ABO-incompatible cases versus 16% in ABO-compatible cases. Although the ABO-compatible group experienced fewer overall graft failures, rejection-related failures, and rejection episodes, these differences did not reach statistical significance.24 The CCTS also evaluated other risk factors for graft failure and rejection.29 Key risk factors identified included younger recipient age, multiple previous grafts, prior anterior segment surgeries, preoperative glaucoma, extensive anterior synechiae, stromal vascularization, chemical burns as the primary diagnosis, and ABO blood group incompatibility. Donor characteristics and corneal storage methods had minimal impact on graft outcomes. The study concluded that even within high-risk groups, the likelihood of graft failure varies significantly, emphasizing the need for individualized risk assessment in keratoplasty planning. The CCTS findings led to paradigm shifts in clinical practice, confirming the limited role of HLA matching and supporting topical corticosteroids as the cornerstone of graft rejection prevention. While systemic immunosuppression is now reserved for select high-graft rejection risk cases36 or keratoprosthesis for multiple failed grafts,37 modern strategies focus on local therapies to control inflammation and newer surgical techniques, such as DMEK, to lower graft rejection risk.8 The CCTS remains one of the most influential trials in keratoplasty, shaping the way high-risk grafts are managed today. Cornea Donor Study and the Specular Microscopy Ancillary Study The CDS was designed to evaluate the effect of donor age on the graft survival of PKPs 5 and 10 years after surgery in 1090 moderate-risk patients with endothelial dysfunction enrolled between 2004 and 2008.17,38–49 The ancillary study of the CDS, the SMAS, evaluated the effect of donor age on endothelial survival in a subgroup of the entire CDS cohort.18,50–53 The initial 5-year results demonstrated no significant difference in graft survival between corneas from donors aged 12 to 65 years and those from donors aged 66 to 75 years.40 However, extended 10-year follow-up indicated a slight decline in success rates for corneas from donors older than 71 years, suggesting that while donor age up to 71 years does not markedly impact graft survival, caution may be warranted with older donors.47 The SMAS reported significant endothelial cell loss (ECL) within the first 5 years post-PKP, with a modest association between increased donor age and greater ECL.54 However, the overall graft survival remained unaffected, indicating that factors beyond endothelial cell density (ECD) contribute to long-term graft success. The CDS also studied various donor factors including cause of death, history of diabetes, and tissue retrieval methods, but did not find any of these to significantly influence 5-year graft survival rates.43 These findings support the current donor eligibility criteria and suggest a larger donor pool can be considered without compromising keratoplasty outcomes. Collectively, these insights from the CDS have refined donor selection processes. The SMAS, conducted as part of the CDS, has provided significant insights into the assessment of donor corneal endothelial cells. The study established robust methods for determining central ECD in a multicenter eye bank setting.18 By implementing standardized certification procedures and addressing intraobserver and inter-observer variability, the central image analysis reading center, the Cornea Image Analysis Reading Center (CIARC, Cleveland, OH), ensured consistent and reliable ECD measurements across participating eye bank and clinical sites. Analysis of 688 donor endothelial images from 23 eye banks revealed that 96% were analyzable, with varying quality grades (6% excellent, 44% good, 47% fair). Notably, 65% of eye bank-determined ECD values were within 10% of CIARC measurements, while 28% were overestimated by more than 10% and 7% were underestimated by the same margin. Factors such as shorter death-to-preservation times, epithelial defects, Descemet membrane folds, lower image quality, and specific analysis methods contributed to these discrepancies.55 These findings highlight the importance of standardized imaging protocols and analysis techniques to improve the accuracy of donor cornea endothelial assessments, which ultimately leads to improved graft survival outcomes. Cornea Preservation Time Study The CPTS was designed to evaluate the effect of donor tissue storage time on both graft and endothelial cell survival of DSAEKs 3 years after surgery in 1330 moderate risk patients with endothelial dysfunction enrolled between 2012 and 2014.19,56–68 The study which was conducted across 40 clinical sites with over 70 surgeons, aimed to determine whether corneas preserved for longer durations (8–14 days) were noninferior to those preserved for shorter periods (≤7 days). The study found that the 3-year success rate for DSAEK was high regardless of preservation time (PT). While it could not be concluded that corneas preserved between 8 and 14 days were noninferior to those preserved for ≤7 days, the difference was minimal when PT was ≤11 days. These findings suggest that corneal tissues can be safely preserved for up to 11 days without significantly affecting graft outcomes.65 The CPTS also investigated the relationship between donor cornea PT and ECL 3 years after DSAEK. The study found that longer PTs were associated with increased ECL. Specifically, corneas stored for 8 to 14 days exhibited a 40% decrease in ECD over 3 years, compared with a 37% decrease for corneas preserved for 0 to 7 days,61 paralleling the graft survival data that showed survival was comparable up to 11 days of donor cornea storage.65 Furthermore, the study investigated various donor, recipient, and operative factors influencing DSAEK graft success.68 Cox proportional hazards regression models were used to assess the association of risk factors with all failures and late failures, whereas logistic regression models were used to assess the association between risk factors and primary donor failure and early failures while including surgeon as a random effect to accommodate the potential correlation in graft success among DSAEKs performed by the same surgeon (“surgeon effect”). The study found that donor diabetes and operative complications were associated with increased risk of failure of the grafts within 8 weeks of surgery. Specifically, tissue from donors with diabetes was associated with a 2.35-fold increased risk for primary donor failure or early failure related to surgical complications. Similarly, operative complications were associated with a 4.21-fold increased risk of primary donor failure or early failure related to surgical complications. In another type of analysis that was performed post hoc, random survival forests confirmed the high predictive factor for failure with operative complications which was exceeded by surgeon and eye bank factors.63 In addition, recipients with pseudophakic or aphakic corneal edema had a 3.59-fold higher risk of late graft failure compared with those with Fuchs endothelial corneal dystrophy (FECD).68 Other factors, such as donor age, preoperative donor ECD, graft diameter, and the use of an injector for graft insertion, showed little variation in graft success.68 Thus, the CPTS confirmed findings from single-site and registry studies13 that the pseudophakic or aphakic corneal edema cases were at a higher risk for late graft failures. CPTS also provided DSAEK surgeons guidance that the prevention of operative complications was most important in reducing graft failures, while donor and donor tissue factors were not important as long as within current EBAA and local medical director guidelines. Diabetes Endothelial Keratoplasty Study The DEKS is an ongoing RCT sponsored by the NEI that is designed to evaluate the effect of diabetes in the donor on both graft and endothelial survival of DMEKs 1 year postoperatively in moderate risk patients with endothelial dysfunction.20 The study has used corneas from 1154 donors for 1421 DMEK procedures on 1097 participants (324 bilateral) at 28 clinical sites enrolled between 2022 and 2024. Initial results are expected in the fall of 2025. The study protocol was written with the assumption that most corneas from diabetic donors would be equivalent to the normal donor pool in graft outcomes and that only donors with severe diabetes may have worse outcomes. Thus, expansion of the donor pool with more diabetic donors could become available for DMEK lenticule preparations. The DEKS could also determine the influence of other donor, donor tissue, recipient and operative and postoperative factors on DMEK outcomes that could provide important information to eye banks and surgeons revealing preventable factors that could lead to a reduction in graft failures with this procedure. Descemet Endothelial Thickness Comparison Trial The DETECT is an ongoing RCT sponsored by the NEI that has 2 arms. DETECT I is designed to evaluate best spectacle-corrected visual acuity and endothelial survival comparing ultrathin DSAEK versus DMEK with or without topical ripasudil 0.4% 12 months postoperatively in 160 moderate risk patients with endothelial dysfunction.21 DETECT II is designed to evaluate the best spectacle–corrected visual acuity (BSCVA) and change in ECD comparing DMEK without topical ripasudil with Descemet stripping only (DSO) with topical ripasudil 0.4% 12 months following surgery in 60 moderate risk patients with FECD.22 Both trials will answer important questions surrounding the best approach for the surgical management of primary endothelial failure conditions and the value of the use of a Rho-kinase inhibitor supporting long-term corneal health and endothelial survival. Other RCTs Examining Keratoplasty Findings Our PubMed database search of the terms “keratoplasty,” “randomized controlled trial,” and “randomized clinical trial” yielded 66 results. We also searched ClinicalTrials.gov using key terms “endothelial” and “keratoplasty” for interventional studies with published data, with an additional 10 results. Studies were then excluded if they were 1) not truly RCTs, 2) from the NEI-funded studies already discussed, 3) evaluated outcomes in keratoconus, ectasia, corneal ulcers, or other nonendothelial dysfunction conditions, or 4) described anterior lamellar keratoplasty techniques. This yielded 23 papers that were reviewed. With the exception of an early clinical trial that evaluated the effect of a viscoelastic, Healon (Johnson & Johnson Vision, Cave Creek, AZ) on graft rejection, ECL, intraocular pressure, and corneal thickness after PKP,69 most of the earliest keratoplasty RCTs from the 1980s and 1990s compared the effects of suture techniques in PKP on resulting astigmatism.70,71 These low-powered studies found conflicting results in post-PKP astigmatism with single running suture versus interrupted plus running sutures. A follow-up trial determined that neither technique offered a statistically significant advantage and that combined interrupted and continuous suture or an adjustable continuous suture yielded similar rates of decreased postoperative astigmatism in the first year postoperatively.72 Additional RCTs concluded that intraoperative suture adjustment during PKP led to more rapid visual recovery and refractive stability than postoperative adjustment.73,74 In 2008, one study compared visual acuity and light scatter outcomes in patients undergoing either deep lamellar endothelial keratoplasty (DLEK) or PKP with equivocal visual acuity outcomes but greater corneal backscatter in DLEK that did not return to baseline through 12 months of follow-up.75 A similar trial 1 year later evaluated higher order aberrations (HOAs) induced by the anterior corneal surface after DLEK versus PKP for patients with corneal edema from FECD, with HOAs elevated in the PKP group without correlation to visual function.76 In the last 15 years, there have been multiple RCTs discussing the impacts of topical and/or subconjunctival medications on high-risk graft survival including cyclosporine A 2%, 0.1% fluorometholone, bevacizumab, and tacrolimus.32–35,77,78 In 2014, Price et al79 compared rates of immunologic rejection episodes and IOP elevation after DMEK in those treated with prednisolone acetate 1% versus fluorometholone 0.1% in months 2 to 12 after surgery. Rejection episodes were rare, and there was no difference in rejection rate between groups, but IOP elevation, defined as IOP ≥24 mm Hg or an increase of ≥10 mm Hg over the baseline preoperative level, was significantly more likely in the prednisolone treatment arm. In 2015, the same authors performed a similar study comparing rates of IOP elevation and graft rejection after DMEK in those maintained on loteprednol etabonate 0.5% gel versus prednisolone acetate 1% solution.80 They found no difference between groups regarding graft rejection, but IOP elevation was again twice as likely in the prednisolone acetate 1% group, favoring the use of loteprednol etabonate 0.5% gel. A prospective, multicenter RCT evaluated the efficacy of topical and subconjunctival bevacizumab on the 52-week endothelial rejection rate after vascularized, high-risk PKP.81 There was no difference in the 52-week graft rejection rate between bevacizumab and placebo groups, although post hoc analyses did show a potential benefit of bevacizumab that may not have been captured in the underpowered study. Other RCTs have evaluated hypothermic storage solutions82–84 and donor lenticule preparation for DSAEK85 on graft outcomes. Most recently, one study evaluated the effect of 2 cornea storage solutions on ECL and graft success 6 months after EK. Donor pairs were stored in either Optisol GS or Life 4°C before DSAEK or DMEK for FECD. Neither central ECL nor the graft clarity at 6 months differed significantly based on the storage solution.84 Another RCT compared precut versus surgeon-prepared donor lenticules for DSAEK and found no difference graft success and mean ECL at 1 year (35% vs. 32%).85 There have also been RCTs in recent years comparing the newer techniques of endothelial keratoplasty (EK). In patients with endothelial dysfunction, femtosecond laser–assisted Descemet stripping endothelial keratoplasty (FS DSEK) was compared with PKP, with both techniques significantly improving straylight and contrast sensitivity compared with preoperative values; best-corrected visual acuity was better in the PKP group.86 DMEK was shown to have less posterior corneal HOAs compared with ultrathin DSAEK (UT-DSAEK) in patients with endothelial failure from either FECD or pseudophakic bullous keratopathy.87 A 2021 study showed that in patients with FECD treated with either microthin DSAEK versus DMEK, patient satisfaction and quality of life-related visual scores were comparable but best-corrected visual acuity was significantly better in the DMEK group at 1 year postoperatively.88 However, the follow-up data on this RCT at the 2-year interval postoperatively showed no significant difference between groups in BSCVA, along with comparable rates of ECL and patient satisfaction.89 Another multicenter RCT on patients with FECD compared visual acuity outcomes, ECD, and complications after DMEK versus UT-DSAEK at 12 months postoperatively.90 No difference was appreciated in BSCVA, contrasting with results from DETECT,21,22 although post hoc analysis in this RCT did show a greater percentage of eyes achieving 20/25 vision or better in the DMEK group (P = 0.02). The DMEK group had a higher rate of adverse events (P = 0.01), and there was no difference in ECD or refractive outcomes. A follow-up study of these patients demonstrated lower posterior corneal HOAs and faster recovery of straylight and contrast sensitivity in those who underwent DMEK compared with UT-DSAEK.91 Finally, the Supine Positioning for Graft Attachment After Descemet Membrane Endothelial Keratoplasty (SUPER-DMEK) trial was conducted to assess whether prolonged supine positioning promoted DMEK graft attachment. Patients with FECD who had undergone DMEK were randomized to either 1 or 5 days of supine head positioning. Results showed no difference in graft detachment rates, as well as a significant increase in frequency of back pain and severity of back pain with the longer duration of supine positioning.92 For these reasons, the authors concluded that prolonged supine positioning was not favorable after DMEK surgery. Registry Studies Compared With NEI-Sponsored RCTs There are 16 keratoplasty registries that have been described in the English literature and have contributed greatly to our knowledge of keratoplasty outcomes and trends.13 Several of these registry studies have evaluated similar questions as the RCTs sponsored by the NEI. HLA matching in the CCTS did not significantly improve survival of the graft in high-risk subjects. This contrasted with findings from the UK transplant registry showing that rejection risk increased with poor matching of HLA class I antigens, and interestingly, that mismatched HLA-DR grafts led to less rejection than grafts with zero HLA-DR mismatch.93 However, the authors concluded that the delay and expense in awaiting matched HLA-DR tissue was likely not justified. Both the Australian corneal graft registry and the CCTS showed that pre-existing glaucoma, corneal neovascularization, and previous graft rejection increased the risk of graft failure. ABO-matched grafts from the CCTS had lower failure and rejection rates, but this was not statistically significant and not evaluated in the registry study.29,94 The UK transplant registry similarly showed pretransplant corneal vascularization as a significant risk factor for subsequent graft failure after PKP for keratoconus, PBK, or corneal infection.95 The question of ECD and donor age which the CDS investigated was also evaluated in the UK transplant registry.96 While the registry study patients all underwent PKP, primarily for FECD or pseudophakic corneal edema, there was no significant effect of donor age or ECD on graft failure. In their study, donor age was stratified into 3 groups (0–60, 61–75, and older than 75 years) and donor ECD was stratified into 3 groups (≤2400, 2401–2600, and >2600 cells/mm2). Donor age up to 90 years and donor ECD to the lower limit of 2200 cell/mm2 did not affect endothelial failure at 5 years post-PKP.96 While the CDS reported on significant ECL within the first 5 years post-PKP, graft survival remained unaffected.43 A study out of the Australian corneal graft registry evaluated the impact of advanced recipient and donor age on the long-term outcome of PKP success.97 This cohort constituted 7741 patients who all underwent PKP, most commonly for bullous keratopathy, keratoconus, or failed graft with the data demonstrating decreased graft survival with increasing recipient age (P < 0.00001). Donor age in this cohort ranged from less than 1 year to 90 years, with a median of 64 years and had no effect on graft survival (P = 0.10). A later study from the registry showed neither donor sex nor age was shown to influence graft survival.98 While the 5-year data from the CDS showed no significant difference in graft survival between corneas from donor age 12 to 65 versus those aged 66 to 75 years, there was a slight decrease in success rate at 10 years for those corneas from donors older than 71 years.40,47 The Ontario corneal recipient registry evaluated more than 300 PKP recipients in the 1980s to determine whether donor age and cause of death impact graft survival.99 Graft survival was not associated with donor age, similar to findings from the CDS.40,43 However, the registry found that those who received grafts from donors who died of heart disease or other natural causes had twice the risk of graft failure compared to those who received grafts from donors who died of injury (P < 0.05).99 This contrasts with findings from the CDS that showed no influence of cause of death on graft survival.40,43 The National Eye Bank Corneal Transplant Registry also evaluated graft failure characteristics in a cohort of 177 transplanted corneas in India with comparable results with the CDS. Age of donor and cause of donor death did not have a significant impact on graft survival (P = 0.54 and P = 0.15, respectively), although their follow-up end point was limited to 1 year after transplant.100 The primary aim of the CPTS was to study the effect of preservation time on graft success, which was also studied by the Eye Bank Association of America adverse reaction registry. They evaluated 147 cases of primary graft failure after PKP.101 One key finding was that compared with controls, cases of graft failure were more likely to occur from donor corneas stored more than 7 days (odds ratio 2.4). These findings differ from the CPTS which demonstrated that grafts preserved for up to 11 days had similar 3-year graft success rates as those preserved ≤7 days, with the caveat that the CPTS only studied DSAEK grafts.65 Strengths and Limitations of the RCT The strengths and limitations of the RCT have been well described in the literature,102–104 by the US Agency of Health care Research and Quality,105 and specifically for ophthalmology.106 The RCT remains the gold standard of medical evidence to assess the effectiveness and safety of therapeutic interventions,103 and in our case, all the donor, donor tissue, recipient, operative and postoperative factors in eye banking, and keratoplasty. These strengths include multi-investigator/site participation, high internal validity, reduced selection and observer bias, standardization of data collection in a highly granular, prospective manner (including before, at the time and after intervention), and if powered appropriately for the primary endpoint, establishment of a causal relationship. However, the limitations include cost, a directed and not necessarily a broader external validity based on clearly defined inclusion and exclusion criteria, the necessity for equipoise for the randomizing parameter in the investigators and participants, not necessarily reflecting the real-world clinical practice thus affecting generalizability, possible shorter follow-up, and variations in surgical technique and experience. All these strengths and limitations are reflected in the NEI-supported RCTs in keratoplasty we have reviewed. However, given the pros and cons of observational studies, including the national keratoplasty registry studies,13 we agree with Fernainy et al104 that the RCT complements the large observational studies to guide the direction of clinical practice, and in our case, important questions in eye banking and keratoplasty. We also agree with Chew106 in her manuscript on the value of RCTs in ophthalmology, that “It is important to remember that we cannot afford to NOT do clinical trials because the results may help to change how we care for our patients with diseases.” The role of cell regenerative therapies for the management of endothelial failure conditions is a new compelling question in the eye banking and corneal surgeon communities.107 Based on the work of Kinoshita's team,108 Aurion Biotech (Seattle, WA; Cambridge, MA, Tokyo, Japan) received approval for neltependocel (Vyznova) in Japan in September 2024 for its anterior chamber injection cell therapy for the treatment of corneal endothelial failure conditions109; initial phase 1/2 trial results have been announced.110 Another biotech company, Emmecell (Menlo Park, CA), incorporates magnetic nanoparticles into cultured corneal endothelial cells for the treatment of corneal endothelial failure conditions. After the cells are injected into the recipient eye, they are pulled toward the posterior cornea with use of a magnetic eye patch111; an initial phase 1 study has shown promising results.112 As the eye banking and corneal surgeon community in the United States await Food and Drug Administration approval of these cell therapies, there will be numerous questions surrounding the novel delivery systems for these cell therapies and how they compare with established procedures for managing endothelial failure conditions (DSAEK, DMEK, DSO) in regard to short-term and long-term best spectacle–corrected acuity, corneal thickness, ECD, and Scheimpflug parameters. These studies will be critical for patient selection for each procedure and with appropriate study design, examine the use of cell therapy as a rescue for failing DSO or EK procedures. The evolution of keratoplasty for endothelial disorders has been significantly influenced by a series of landmark RCTs supported by the NEI. These trials have established from primary analyses the limited role of histocompatibility matching, validated the safety of older donor tissue, and clarified preservation time limits. Secondary analyses have enhanced our understanding that the range of donor and donor tissue characteristics under established EBAA and local medical director guidelines, do not differ in regard to postoperative graft and endothelial survival, while recipient diagnosis, operative complications, and postoperative factors (glaucoma, rejection) are more influential in graft and endothelial survival. Future directions, such as cell-based regenerative strategies,107–112 will require rigorous controlled trial frameworks to evaluate their comparative effectiveness against established surgical procedures. As the field continues to advance, investment in well-designed RCTs will remain essential for evidence-based improvements in surgical techniques, donor tissue management, and long-term graft outcomes in keratoplasty. Divya Srikumaran, MD, provided valuable coordination of the content of this review with her review as senior author on corneal registry studies (Cornea 2023;42:1–11). Keywords: randomized controlled trial; keratoplasty; cornea; endothelium Copyright © 2025 The Author(s). Published by Wolters Kluwer Health, Inc.

Abstract: National Eye Institute (NEI)–funded randomized controlled trials (RCTs) have significantly shaped the modern landscape of keratoplasty for endothelial disorders. Unlike retrospective studies, RCTs have offered the highest level of clinical evidence and have addressed critical questions related to histocompatibility matching, donor and donor tissue characteristics, donor tissue storage, and operative and postoperative factors supporting postoperative endothelial cell health. These RCTs have in turn directly influenced eye banking and keratoplasty practices. The purpose of this review is to 1) summarize the major findings from all of the NEI-sponsored keratoplasty RCTs, including the Collaborative Corneal Transplantation Studies, the Cornea Donor Study and its ancillary study, the Specular Microscopy Ancillary Study, the Cornea Preservation Time Study, as well as the on-going Diabetes Endothelial Keratoplasty Study and the Descemet Endothelial Thickness Comparison Trial; 2) review select keratoplasty RCTs not supported by the NEI; 3) compare findings from these RCTs with those from the major keratoplasty registries; and 4) discuss promising future directions in keratoplasty and eye banking that would lend themselves for RCTs. Collectively, these RCTs have clarified long-standing controversies, validated emerging practices, and will continue to provide the foundation for future innovation in the surgical management of endothelial diseases.

Purpose: The aim of this study was to evaluate the activity of photoactivated 0.1% rose bengal (RB) for in vitro growth inhibition of the most prevalent fungi isolates in infectious keratitis. Methods: Eight corneal clinical isolates were included in the experiments: Fusarium solani complex, Purpureocillium lilacinum, Candida albicans, Candida parapsilosis complex, Exophiala oligosperma, Scedosporium apiospermum complex, Aspergillus niger complex, and Curvularia geniculata. Microorganisms, previously identified by phenotypical methods, were grown and incubated at specific conditions and prepared in suspension for concentration adjustments. The following groups were evaluated in triplicate: group I, no treatment; group II, treated with RB and exposed to the dark for 30 minutes; group III, exposed to green-light light-emitting diode 7.2 mW for 30 minutes (photodynamic therapy [PDT]); and group IV, treated with RB and PDT (RB-PDT). The final work concentration was 104 cells per mL. The RB-PDT was combined with Amphotericin B (AmphoB) to target isolates that were not inhibited by RB-PDT alone. Plates were incubated at specific conditions and photographed after growth for pixel analyses. Results: The growth was inhibited after RB-PDT for F. solani complex, P. lilacinum, C. albicans, C. parapsilosis complex, and E. oligosperma, and not inhibited for S. apiospermum complex, A. niger complex, and C. geniculata, even though combining RB-PDT with AmphoB. Conclusions: RB-PDT presented good activity against five of the tested microorganisms. For the first time, we demonstrated that RB-PDT could inhibit growth of P. lilacinum, C. parapsilosis complex, E. oligosperma, and not inhibit S. apiospermum, A. niger complex, and C. geniculata, even when combined with AmphoB.

No abstract available

Abstract: National Eye Institute (NEI)–funded randomized controlled trials (RCTs) have significantly shaped the modern landscape of keratoplasty for endothelial disorders. Unlike retrospective studies, RCTs have offered the highest level of clinical evidence and have addressed critical questions related to histocompatibility matching, donor and donor tissue characteristics, donor tissue storage, and operative and postoperative factors supporting postoperative endothelial cell health. These RCTs have in turn directly influenced eye banking and keratoplasty practices. The purpose of this review is to 1) summarize the major findings from all of the NEI-sponsored keratoplasty RCTs, including the Collaborative Corneal Transplantation Studies, the Cornea Donor Study and its ancillary study, the Specular Microscopy Ancillary Study, the Cornea Preservation Time Study, as well as the on-going Diabetes Endothelial Keratoplasty Study and the Descemet Endothelial Thickness Comparison Trial; 2) review select keratoplasty RCTs not supported by the NEI; 3) compare findings from these RCTs with those from the major keratoplasty registries; and 4) discuss promising future directions in keratoplasty and eye banking that would lend themselves for RCTs. Collectively, these RCTs have clarified long-standing controversies, validated emerging practices, and will continue to provide the foundation for future innovation in the surgical management of endothelial diseases.

Purpose: The aim of this study was to evaluate the activity of photoactivated 0.1% rose bengal (RB) for in vitro growth inhibition of the most prevalent fungi isolates in infectious keratitis. Methods: Eight corneal clinical isolates were included in the experiments: Fusarium solani complex, Purpureocillium lilacinum, Candida albicans, Candida parapsilosis complex, Exophiala oligosperma, Scedosporium apiospermum complex, Aspergillus niger complex, and Curvularia geniculata. Microorganisms, previously identified by phenotypical methods, were grown and incubated at specific conditions and prepared in suspension for concentration adjustments. The following groups were evaluated in triplicate: group I, no treatment; group II, treated with RB and exposed to the dark for 30 minutes; group III, exposed to green-light light-emitting diode 7.2 mW for 30 minutes (photodynamic therapy [PDT]); and group IV, treated with RB and PDT (RB-PDT). The final work concentration was 104 cells per mL. The RB-PDT was combined with Amphotericin B (AmphoB) to target isolates that were not inhibited by RB-PDT alone. Plates were incubated at specific conditions and photographed after growth for pixel analyses. Results: The growth was inhibited after RB-PDT for F. solani complex, P. lilacinum, C. albicans, C. parapsilosis complex, and E. oligosperma, and not inhibited for S. apiospermum complex, A. niger complex, and C. geniculata, even though combining RB-PDT with AmphoB. Conclusions: RB-PDT presented good activity against five of the tested microorganisms. For the first time, we demonstrated that RB-PDT could inhibit growth of P. lilacinum, C. parapsilosis complex, E. oligosperma, and not inhibit S. apiospermum, A. niger complex, and C. geniculata, even when combined with AmphoB.

No abstract available

Background: Keratoconus is a progressive, degenerative corneal disease that can lead to significant visual impairment. The intrastromal ring segment implantation procedure is effective in reshaping the cornea and improving vision. However, vision does not improve postoperatively in all operated eyes, and the results vary widely among patients, making it challenging to predict postoperative visual gain. Purpose: This study investigated the potential of machine learning in predicting postoperative visual acuity in keratoconus patients undergoing intrastromal ring segment implantation with the aim of enhancing surgical decision-making. Methods: This retrospective study analyzed 120 eyes of 102 patients with keratoconus who underwent ring segment implantation (1 symmetric or asymmetric segment, 150–300 μm thick, 150 degrees, or 160 degrees-arc). Preoperative and postoperative refraction, corneal topography, and tomographic data were collected. Various models were trained to predict postoperative visual acuity improvements. Results: The models demonstrated excellent performance, with XGBoost achieving perfect results in predicting whether vision will improve after surgery (R2 = 1.0, Youden Index = 1.0; all test observations being correctly classified). The CatBoost model achieved an R2 of 0.59 [0.7-line mean absolute error (MAE)] for predicting postoperative visual acuity, an R2 of 0.76 (MAE, 1.08 D) for predicting keratometry, and an R2 of 0.54 (MAE, 0.29) for predicting corneal asphericity. Key features for accurate predictions included preoperative keratometry values (K1, K2, Kmax), corneal asphericity, and visual acuity, whereas segment characteristics featured low importance. Conclusions: This study shows the strong potential of machine learning for selecting candidates for surgery and predicting postoperative visual improvements after ring segment implantation in keratoconus eyes.

Purpose: The purpose of this study was to describe a new technique for rapid extensive dehydration of corneal allogeneic intrastromal ring segments (CAIRSs) using thermal energy conduction to facilitate implantation. Methods: Donor corneas were trephined into annular stromal rings, halved, and placed into a titanium mold with a semicircular recess. The mold was positioned on a sterile polyethylene drape covering a USB-powered cup heater with a tempered glass surface (Tangxi, Guangzhou, China, set to 55°C). Segments were covered with a 1 oz plastic medicine cup (Amsino International, Pomona, CA) for 5 minutes, after which their temperature was monitored using a laser thermometer and found to be 47.5 ± 0.8°C. Resulting segments were rigid and maintained their arc shape, allowing for forceps-only insertion into femtosecond laser-created stromal tunnels. Insertion time (from tunnel creation to segment ironing) was measured through surgical video. Segment dimensions were assessed using optical coherence tomography at 1 week, 1 month, and 3 months. Four dehydrated segments underwent histopathologic analysis. Results: A total of 33 eyes from 29 patients underwent single-segment CAIRS implantation using the thermal dehydration technique. The mean combined insertion and repositioning time was 86 ± 19 seconds. Optical coherence tomography showed segment thickness and width of 498 ± 72 μm and 1119 ± 175 μm at 1 week, and 443 ± 67 μm and 1292 ± 220 μm at 3 months. Histopathology revealed preserved stromal architecture without evidence of thermal damage. Conclusions: Controlled thermal energy conduction significantly reduces CAIRS dehydration time and simplifies insertion, enhancing surgical efficiency while preserving tissue integrity.

Purpose: The aim of this study was to compare the rates of healing, scar formation, and regression of preexisting scars using topical murine hepatocyte growth factor (mHGF), recombinant human deleted HGF (dHGF), murine nerve growth factor (mNGF), and phosphate-buffered saline (PBS). Methods: Mechanical corneal epithelial and stromal injury was induced in C57BL/6 mice. Five groups of mice were studied in each of phase I (wound healing and scar formation) and phase II (regression of preexisting scars). Each group received topical 0.1% mHGF, 0.1% dHGF, 0.2% dHGF, 0.1% mNGF, or PBS. In phase I, animals were dosed 4 times/day (QID) on days 0 to 7. In phase II, a corneal injury was induced, and no treatment was administered for 10 days to allow scar formation. Mice with scars were then dosed QID on days 11 to 21. Ocular assessments included slit-lamp photography (phase I and II) and fluorescein staining (phase I). Results: In phase I, eyes treated with mHGF exhibited significantly faster epithelial healing and decreased scar formation compared with both mNGF-treated and PBS-treated eyes 7 days after treatment. Consistent with that seen in mHGF-treated eyes, 0.1% and 0.2% dHGF-treated eyes each showed significantly faster epithelial healing compared with PBS-treated eyes. Scars formed in dHGF-treated eyes were also significantly smaller than PBS-treated eyes 7 days after treatment. In phase II, both mHGF-treated and dHGF-treated eyes showed a significant decrease in the size of preexisting scars compared with PBS-treated eyes. Conclusions: Topical HGF significantly accelerates corneal wound healing, reduces scar formation, and can reverse preexisting scars.

Purpose: To evaluate the first clinical results of corneal surface reconstruction with the help of a femtosecond laser (FSL)—full FSL-assisted autologous glueless simple limbal epithelial transplantation (Full FSL G-SLET) for unilateral limbal stem cell deficiency. Methods: After chemical eye burns, 3 patients underwent Full FSL G-SLET procedures, including 2 critical laser-assisted steps: harvesting of the 8 autologous limbal micrografts from the healthy eyes and placing them into laser-cut nonpenetrating corneal tunnels performed on the affected eye. Results: The donor eyes recovered very quickly, and 3 to 4 weeks after surgery, a small scar in the limbal area formed with no adverse effects on visual acuity. Three patients had various rates of corneal reepithelization of the recipient eyes: 1 month, 1.5 months, and 4 months postoperatively. Complete corneal epithelialization was achieved in all cases. The epithelial layer was stable for 12 months postoperatively, as confirmed by corneal staining with low-molecular-weight fluorescein and anterior segment optical coherence tomography. Visual acuity improvement was observed in all 3 patients. Conclusions: This is the first report of successful clinical use of FSL for autologous G-SLET surgical procedures when the laser was used not only to create corneal tunnels for autologous limbal micrograft fixation but also for their in vivo harvesting and fragmentation.

Purpose: Conjunctival autografts (CAGs) are the gold standard treatment after pterygium resection, but it is challenging to achieve consistently thin Tenon-free CAGs with manual dissection. We herein report the reproducibility and clinical outcomes of a novel algorithm to produce customizable trapezoidal CAGs using femtosecond laser (femtosecond lasers)-assisted pterygium surgery. Methods: We first tested this algorithm in 4 pig eyes to show reproducibility. We then treated 15 pterygia of 14 patients using this algorithm. After manual pterygium excision, 7-mm x 10-mm preset trapezoidal CAGs were dissected with the Ziemer FEMTO LDV Z8 laser set at a 60 μm depth. The achieved thickness was measured with intraoperative optical coherence tomography, and the achieved area was calculated. Results: For the pig eyes, the average CAG length and width were 9.8 ± 0.1 mm and 7.3 ± 0.04 mm, respectively, with a mean deviation of 7.3% ± 3.2% and 7.5% ± 4.1%, respectively. The mean age of the patients was 56.8 ± 7.3 years. The programmed and achieved CAG areas were 70 mm2 and 72.5 ± 3.9 mm2, respectively, with a mean deviation of 4.7% ± 4.6%. The eventual CAG thickness was 59.5 ± 3.9 μm, with a minimal deviation of 4.4% ± 4.6%. The average time to remove the FSL-prepared CAG to unfold it onto the cornea was 19.9 ± 14.9 seconds. At the postoperative month 3 follow-up, no postoperative complications or recurrences occurred, and all donor CAG sites had completely healed. Conclusions: This novel algorithm using the FEMTO LDV Z8 in Femtosecond Laser–Assisted Pterygium Surgery provides consistent and customizable trapezoid ultrathin CAGs. Longer follow-up and larger cohorts will need to be studied for recurrence and complication rates.

Purpose: The purpose of this study was to report our first clinical experience using topical losartan for the treatment of severe corneal haze after epithelium-off corneal cross-linking (CXL). Methods: A 20-year-old man presented with clinically significant corneal haze in the right eye 1 month following Ultraviolet-A/Riboflavin Epithelium-off Collagen CXL. Haze progressed to a deep stromal scar, and vision was 20/150 with no improvement on refraction, 60 days after CXL. After unsuccessful treatment with topical corticosteroids, the patient elected to start off-label treatment with topical losartan 0.8 mg/mL, administered 6 times per day. Results: After 3 months of initiating topical losartan, the right eye vision improved to preoperative vision of 20/40-1. Corneal haze was significantly reduced as observed on slitlamp examination and on Scheimpflug corneal tomography (Pentacam; OCULUS, Inc. Arlington, WA). Conclusions: Topical losartan, a transforming growth factor-β inhibitor, is a potential treatment in clinically significant corneal haze following epithelium-off corneal CXL. This clinical experience highlights the potential efficacy of topical losartan as a novel therapeutic option in such cases, but further clinical studies are needed.

Purpose: To define a new method for grading severity of keratoconus, the Keratoconus Severity Score (KSS). Methods: A rationale for grading keratoconus severity was developed using common clinical markers plus 2 corneal topographic indices, creating a 0 to 5 severity score. An initial test set of 1012 eyes, including normal eyes, eyes with abnormal corneal and topographic findings but not keratoconus, and eyes with keratoconus having a wide range of severity, was used to determine cutpoints for the KSS. Validation set 1, comprising data from 128 eyes, was assigned a KSS and compared with a clinician's ranking of severity termed the “gold standard” to determine if the scale fairly represented how a clinician would grade disease severity. κ statistics, sensitivity, and specificity were calculated. A program was developed to automate the determination of the score. This was tested against a manual assignment of KSS in 2121 (validation set 2) eyes from the Collaborative Longitudinal Evaluation of Keratoconus (CLEK) Study, as well as normal eyes and abnormal eyes without keratoconus. Ten percent of eyes underwent repeat manual assignment of KSS to determine the variability of manual assignment of a score. Results: From initial assessments, the KSS used 2 corneal topography indices: average corneal power and root mean square (RMS) error for higher-order Zernike terms derived from the first corneal surface wavefront. Clinical signs including Vogt striae, Fleischer rings, and corneal scarring were also included. Last, a manual interpretation of the map pattern was included. Validation set 1 yielded a κ statistic of 0.904, with sensitivities ranging from 0.64 to 1.00 and specificities ranging from 0.93 to 0.98. The sensitivity and specificity for determining nonkeratoconus from keratoconus were both 1.00. Validation set 2 showed κ statistics of 0.94 and 0.95 for right and left eyes, respectively. Test-retest analysis yielded κ statistics of 0.84 and 0.83 for right and left eyes, respectively. Conclusion: A simple and reliable grading system for keratoconus was developed that can be largely automated. Such a grading scheme could be useful in genetic studies for a complex trait such as keratoconus requiring a quantitative measure of disease presence and severity.

Purpose: The aim of this study was to report on the feasibility of setting up a system of corneal transplants at rural outreach centers and report the outcomes of the first 111 cases. Methods: Retrospective analysis of the outcomes of corneal transplantation performed on patients with optical indications between March 2016 and September 2019 at 4 secondary (rural) centers. The centers are a part of a network in the pyramidal model developed by L V Prasad Eye Institute. The graft clarity and best-corrected visual acuity (BCVA) at 1-year follow-up were analyzed. Results: Of the 111 patients, 34.23% underwent penetrating keratoplasty and 65.77% endothelial keratoplasty. The mean age was 59.4 ± 15.0 (range-17–86 years); 47.75% were men and 52.25% were women. The indications for surgery were bullous keratopathy (54.05%), corneal scar/adherent leukoma (23.42%), and repeat grafts (13.51%). At the end of 1 year, 69.37% grafts remained clear. Factors associated with graft failure included poor socioeconomic status and graft infiltrate in both univariate and multivariate analyses. Surgical technique of endothelial keratoplasty was associated with failure on multivariate analysis only. Of the 77 eyes with clear corneal grafts at 1 year, the preoperative mean logMAR BCVA was 1.91 ± 0.06, which improved to 0.90 ± 0.08 postoperatively. Overall, 84.4% had preoperative BCVA of

Purpose: To examine clinical results up to 10 years after Descemet Membrane Endothelial Keratoplasty (DMEK) and Triple-DMEK. Methods: Prospective study including 201 eyes, of which 54 eyes [38 DMEKs and 16 Triple-DMEKs; Fuchs endothelial dystrophy (n = 45), pseudophakic bullous keratopathy (n = 9)] reached the minimum follow-up of 5 years and were followed up for up to 10 years. We evaluated best-corrected visual acuity (BCVA, logarithm of the minimum angle of resolution [logMAR]), endothelial cell density (ECD, cells/mm2), minimal central corneal thickness (CCT, μm), central retinal thickness (μm), rebubbling, graft survival and re-DMEK rate, chamber angle alterations, and incidence of glaucoma. Results: Fifty-four eyes had a 5-year and 37 eyes an 8- to 10-year follow-up. Mean follow-up was 94.4 ± 12.1 months. Best-corrected visual acuity increased from 0.6 ± 0.3 logMAR to 0.1 ± 0.2 logMAR at 6 months (P ≤ 0.001) and was 539 ± 54 μm at long term. Endothelial cell density decreased from 2488 ± 320.9 (donor) to 980.1 ± 437 cells/mm2 with an average ECD loss/year of 4% and did not correlate with BCVA. Central corneal thickness decreased from 596.9 ± 82.2 μm to 498.6 ± 24.3 μm at 12 months (P ≤ 0.001) and remained stable (P = 1.000). Mean rebubbling rate was 0.3 ± 0.5/eye and did not correlate with BCVA. Eight eyes (14.8%) received at least 1 rebubbling. Primary graft failure/rejection rate was 1.5%/0% within the first postoperative year, and secondary graft failure rate was 12.4% at 7 years. Eight eyes (preoperative n = 3, de novo n = 5) had open-angle glaucoma without chamber angle changes (14.8%, P ≤ 0.001). Conclusions: Although ECD decreases continuously in the long-term follow-up, excellent visual acuity can be preserved 10 years after DMEK and Triple-DMEK. The final outcome can be estimated 6 months after surgery.

Purpose: The purpose of this study was to evaluate the safety and efficacy of lotilaner ophthalmic solution, 0.25%, compared with vehicle for the treatment of Demodex blepharitis. Methods: In this prospective, randomized, controlled, double-masked, phase 2b/3 clinical trial, 421 patients with Demodex blepharitis were randomly assigned in a 1:1 ratio to receive either lotilaner ophthalmic solution, 0.25% (study group), or vehicle without lotilaner (control group) bilaterally, twice daily for 43 days. Patients were evaluated at days 8, 15, 22, and 43. Outcome measures were complete collarette cure (collarette grade 0), clinically meaningful collarette cure (grade 0 or 1), mite eradication (0 mites/lash), erythema cure (grade 0), composite cure (grade 0 for collarettes/erythema), and drop comfort. Adverse events were also evaluated. Results: At day 43, the study group achieved a statistically significantly higher proportion of patients with clinically meaningful collarette cure (81.3% vs. 23.0%; P < 0.0001), complete collarette cure (44.0% vs. 7.4%; P < 0.0001), mite eradication (67.9% vs. 17.6%; P < 0.0001), erythema cure (19.1% vs. 6.9%; P = 0.0001), and composite cure (13.9% vs. 1.0%; P < 0.0001) than the control group. Nearly 92.0% of patients rated the study drop as neutral to very comfortable. All ocular adverse events in the study group were mild, with the most common being instillation site pain. Conclusions: Twice-daily treatment with a novel lotilaner ophthalmic solution, 0.25% for 43 days, is safe and effective for the treatment of Demodex blepharitis compared with the vehicle control.

Purpose: Clinical diagnosis of dry eye disease is based on a subjective Ocular Surface Disease Index questionnaire or various objective tests, however, these diagnostic methods have several limitations. Methods: We conducted a comprehensive review of articles discussing various applications of artificial intelligence (AI) models in the diagnosis of the dry eye disease by searching PubMed, Web of Science, Scopus, and Google Scholar databases up to December 2022. We initially extracted 2838 articles, and after removing duplicates and applying inclusion and exclusion criteria based on title and abstract, we selected 47 eligible full-text articles. We ultimately selected 17 articles for the meta-analysis after applying inclusion and exclusion criteria on the full-text articles. We used the Standards for Reporting of Diagnostic Accuracy Studies to evaluate the quality of the methodologies used in the included studies. The performance criteria for measuring the effectiveness of AI models included area under the receiver operating characteristic curve, sensitivity, specificity, and accuracy. We calculated the pooled estimate of accuracy using the random-effects model. Results: The meta-analysis showed that pooled estimate of accuracy was 91.91% (95% confidence interval: 87.46–95.49) for all studies. The mean (±SD) of area under the receiver operating characteristic curve, sensitivity, and specificity were 94.1 (±5.14), 89.58 (±6.13), and 92.62 (±6.61), respectively. Conclusions: This study revealed that AI models are more accurate in diagnosing dry eye disease based on some imaging modalities and suggested that AI models are promising in augmenting dry eye clinics to assist physicians in diagnosis of this ocular surface condition.

Purpose: To evaluate intermediate-term outcomes and complications associated with Ahmed glaucoma valve (AGV) implantation in eyes with type 1 keratoprosthesis (KPro). Methods: We retrospectively reviewed records of 43 eyes of 43 Indian patients with type 1 KPro and AGV from 2009 to 2021 with a minimum of 6-months of follow-up. Five eyes that had AGV before KPro were excluded, leaving 38 eyes for analysis. Primary outcome measure was postoperative complications. Secondary outcome measure was stability of glaucoma, assessed by Humphrey visual fields, intraocular pressure, and best-corrected visual acuity (BCVA). Sight-threatening complications, implant removal, or repeat glaucoma surgery was considered failure. Results: Median age (interquartile range) at AGV implantation was 36.5 (23–49) years, with median post-AGV follow-up of 30.5 (6.5–53) months. Preoperative logarithm of minimal angle of resolution median BCVA was 0.6 (0.4–1). Post-AGV, median intraocular pressure as measured by scleral Schiotz reduced significantly from 30.4 (20.6–30.4) to 13.5(12.2–14.8) mm Hg (P < 0.0001), and the mean number of antiglaucoma medications significantly decreased from 3.4 to 1.7 (P < 0.0001). Mean BCVA (P = 0.24) remained stable. Humphrey visual fields mean deviation progressed from −13.5 dB (−25, −9) to −26 dB (−30, −13) at final follow-up (P = 0.05) and progression occurred in 10 eyes. Seven eyes (18.4%) had postoperative complications needing surgical intervention, including tube block [5 eyes (13.1%)] and tube exposure [2 eyes (5%)]. One failed AGV needed additional glaucoma surgery after 8 years. None had implant extrusion/explanation or endophthalmitis. Conclusions: Ahmed glaucoma valve implantation offered promising results in managing glaucoma in eyes with type 1 KPro, particularly in relatively young Indian population. However, close monitoring for tube-related complications and glaucoma progression is warranted.

Purpose: The purpose of this study was to describe a patient with a primary CD4+ T-cell lymphoproliferative disorder of conjunctiva. Methods: Case report and review of the literature. Results: An 81-year-old man was referred for asymptomatic bilateral conjunctival masses that on biopsy revealed a proliferation of mature CD4+ lymphocytes associated with T-cell receptor γ gene rearrangement. The histopathology and immunophenotypic profile in the absence of disease elsewhere bore resemblance to primary cutaneous CD4+ small/medium T-cell lymphoproliferative disorder. Conclusions: In 2016, the World Health Organization reclassified primary cutaneous CD4+ small/medium T-cell lymphoma to a lymphoproliferative disorder because neither dissemination nor death had been documented. This case displays similarities with the latter but has nonconforming features. Multicentric clonal expansion of T cells do not inevitably indicate lymphoma. Lymphoproliferative disorders that display features of reactive hyperplasia and lymphoma and are not easily classified need to be carefully monitored.

Purpose: To examine clinical results up to 10 years after Descemet Membrane Endothelial Keratoplasty (DMEK) and Triple-DMEK. Methods: Prospective study including 201 eyes, of which 54 eyes [38 DMEKs and 16 Triple-DMEKs; Fuchs endothelial dystrophy (n = 45), pseudophakic bullous keratopathy (n = 9)] reached the minimum follow-up of 5 years and were followed up for up to 10 years. We evaluated best-corrected visual acuity (BCVA, logarithm of the minimum angle of resolution [logMAR]), endothelial cell density (ECD, cells/mm2), minimal central corneal thickness (CCT, μm), central retinal thickness (μm), rebubbling, graft survival and re-DMEK rate, chamber angle alterations, and incidence of glaucoma. Results: Fifty-four eyes had a 5-year and 37 eyes an 8- to 10-year follow-up. Mean follow-up was 94.4 ± 12.1 months. Best-corrected visual acuity increased from 0.6 ± 0.3 logMAR to 0.1 ± 0.2 logMAR at 6 months (P ≤ 0.001) and was 539 ± 54 μm at long term. Endothelial cell density decreased from 2488 ± 320.9 (donor) to 980.1 ± 437 cells/mm2 with an average ECD loss/year of 4% and did not correlate with BCVA. Central corneal thickness decreased from 596.9 ± 82.2 μm to 498.6 ± 24.3 μm at 12 months (P ≤ 0.001) and remained stable (P = 1.000). Mean rebubbling rate was 0.3 ± 0.5/eye and did not correlate with BCVA. Eight eyes (14.8%) received at least 1 rebubbling. Primary graft failure/rejection rate was 1.5%/0% within the first postoperative year, and secondary graft failure rate was 12.4% at 7 years. Eight eyes (preoperative n = 3, de novo n = 5) had open-angle glaucoma without chamber angle changes (14.8%, P ≤ 0.001). Conclusions: Although ECD decreases continuously in the long-term follow-up, excellent visual acuity can be preserved 10 years after DMEK and Triple-DMEK. The final outcome can be estimated 6 months after surgery.

No abstract available

Purpose: Successful antifungal treatment for fungal keratitis does not always result in a good visual outcome. Both infectious and inflammatory components of the disease result in visually significant corneal opacification. We conducted a survey of cornea specialists to elicit expert opinion on the role topical calcineurin inhibitors may play in the management of fungal keratitis. Methods: An online survey was sent to subscribers of several cornea-focused listservs. Descriptive statistics were performed. Results: One hundred thirty-five participants completed the online survey. Approximately 48% of respondents practiced medicine in the United States and 36% in India. About 23% presently “sometimes” prescribe topical calcineurin inhibitors. And 70% never prescribe. When administered adjunctively to topical antifungal drops, 59% of respondents predict 1% to 2% topical cyclosporin would have a clinically significant antiinflammatory effect compared with 33% for the 0.05% to 0.1% cyclosporin dose. About 50% believe the 0.1% tacrolimus dose would have a clinically significant antiinflammatory activity compared with the 0.03% tacrolimus dose. Overall, those surveyed predicted adjunctive topical calcineurin inhibitors could improve final visual acuity by almost one line of vision. Conclusions: Varied opinions exist regarding the role adjunctive topical calcineurin inhibitors can play during a treatment course of fungal keratitis. The overall impression is that these agents may help clinical outcome.

Purpose: To evaluate whether dry eye disease (DED) diagnosis may increase the subsequent risk of developing depression and anxiety. Methods: In this retrospective cohort study, Medicare beneficiaries aged 65 and older with a new diagnosis of DED, no prior history of depression and/or anxiety disorder, and continuous follow-up between 2011 and 2015 were identified from a 5% random sample of nationwide Medicare claims. Beneficiaries included in the DED cohort were matched to a non-DED cohort at a 1:4 ratio using propensity scores based on demographic factors and systemic comorbidities. Crude incidence rates and rate ratios for depression and anxiety were calculated. Multivariable Cox proportional hazards regression model was fit to evaluate the impact of demographic factors and dry eye on the risk of developing these conditions while adjusting for systemic comorbidities. Main Outcome Measures: Longitudinal incidence of depression and anxiety in DED versus non-DED groups. Results: The unadjusted incidence of depression was 30% higher [incidence rate ratio 1.30, 95% confidence interval (CI), 1.24‒1.36] in the DED cohort, and the unadjusted incidence of anxiety was 50% higher (incidence rate ratio 1.50, 95% CI, 1.41–1.58) compared with the non-DED group. The increased susceptibility to depression (adjusted hazard ratio 1.25, 95% CI, 1.19–1.31) and anxiety (adjusted hazard ratio 1.45, 95% CI, 1.37–1.54) because of DED remained significant after adjusting for demographic factors and systemic comorbidities. Conclusions: DED is an independent risk factor for developing depression and anxiety in the elderly.

Purpose: The aim of this study was to compare corneal biomechanics treated with femtosecond laser-assisted in situ keratomileusis (FS-LASIK) and small-incision lenticule extraction (SMILE) for myopia and astigmatism using the new corneal biomechanical parameters of Corvis ST II. Methods: This was a prospective nonrandomized controlled study. Patients treated with FS-LASIK or SMILE between January 2018 and July 2018 were included. Corvis ST II was performed to measure corneal biomechanical parameters, including deformation amplitude ratio 2.0 mm (DA ratio 2.0 mm), integrated inverse radius (Integr Radius), stiffness parameter at first applanation (SP-A1), and Ambrosio relational thickness through the horizontal meridian (ARTh), preoperatively, 1 month postoperatively, and 6 months postoperatively. Pentacam pachymetry was used to assess the reduction in pachymetry. Results: Forty-five eyes underwent FS-LASIK, and 45 eyes underwent SMILE. The new parameters obtained by Corvis ST II between preoperative and postoperative measurements showed significant changes after FS-LASIK or SMILE (all P < 0.001). Postoperative SP-A1 significantly decreased in the 2 groups (108.88 ± 14.47–73.32 ± 13.2 in FS-LASIK and 105.79 ± 17.68–73.91 ± 14.81 in SMILE). Eyes with equal preoperative pachymetry, intraocular pressure, and spherical equivalents showed no significant differences in these new parameters measured using Corvis ST II (all P > 0.05) between the 2 groups. The prediction of the laser platform overestimated the measured pachymetry reduction in the SMILE group (111.93 ± 15.18 μm vs. 87.16 ± 15.47 μm). Conclusions: New corneal biomechanical parameters measured using Corvis ST II showed no significant differences between FS-LASIK and SMILE in eyes with homogeneous preoperative parameters. The laser software platform may have overestimated the actual corneal reduction in the eyes treated with SMILE.