Functional Approach to IOL Selection in Eyes With Combined Cataract and Keratoconus With an Option for Refractive Lens Exchange.

PURPOSE: To evaluate spherical intraocular lens (IOL) implantation for cataracts in keratoconic eyes followed by optional refractive toric lens exchange to improve uncorrected visual acuity. METHODS: This retrospective study evaluated cataract surgery outcomes in keratoconic eyes. Eyes treated with a spherical IOL targeted for -2.00 diopters (D) either achieved acceptable manifest refraction and desired exchange with a toric IOL (Group 1); achieved satisfactory manifest refraction and chose to use spectacles or contact lenses (Group 2); or did not achieve acceptable refraction and used contact lenses (Group 3). Group 4 had single-stage toric IOL implantation with plano target. Corrected and uncorrected distance visual acuity (CDVA and UDVA) and keratometry were analyzed. RESULTS: Groups 1 to 4 had 18, 23, 18, and 26 eyes, respectively. A staged toric exchange resulted in significantly better (P = .02) UDVA (mean: 0.15 logMAR; 20/25 Snellen) than initial toric IOL implantation (0.24 logMAR; 20/30 Snellen). All toric IOL exchange eyes achieved 20/30 or better CDVA and 94% had 20/40 or better UDVA. Mean manifest cylinder significantly decreased from 3.39 D before lens exchange to 1.10 D postoperatively. CONCLUSIONS: Initial implantation of a spherical IOL in keratoconic eyes allows basing toric calculations on the manifest refraction, which may be more reliable than keratometry measurements in keratoconic eyes. UDVA after staged toric IOL exchange was significantly better than after initial toric IOL implantation. Importantly, by staging use of toric lenses, the authors avoided cases where patients required a rigid contact lens after a toric IOL was implanted. [J Refract Surg. 2024;40(4):e207-e217.].

Long-Term Risk of Steroid-Induced Ocular Hypertension/Glaucoma With Topical Prednisolone Acetate 1% After Descemet Stripping Endothelial Keratoplasty.

PURPOSE: The aim of this study was to assess the long-term risk of steroid-induced ocular hypertension and the need for glaucoma treatment with long-term use of topical prednisolone acetate 1% in patients without preexisting glaucoma. METHODS: We retrospectively reviewed the charts of 211 patients without previous glaucoma, who underwent Descemet stripping endothelial keratoplasty (DSEK) and used topical prednisolone acetate long-term to prevent graft rejection. Dosing was 4 times daily for 4 months and tapered to once daily. The main outcomes were ocular hypertension (defined as intraocular pressure ≥24 mm Hg, or increase of ≥10 mm Hg over baseline) and initiation of glaucoma treatment. RESULTS: The median patient age was 70 years (range: 34-94 years). The indications for DSEK were Fuchs dystrophy (88%), pseudophakic corneal edema (7%), failed DSEK (3%), and failed penetrating keratoplasty (2%). The median follow-up period was 7 years (range, 1-17 years). At 1, 5, and 10 years, the cumulative risks of steroid-induced ocular hypertension were 29%, 41%, and 49%, respectively, and the risks of requiring glaucoma treatment were 11%, 17%, and 25%, respectively. Among 35 eyes treated for glaucoma, 28 (80%) were managed medically and 7 (20%) had filtration surgery. CONCLUSIONS: Long-term use of potent topical corticosteroids, such as prednisolone acetate 1%, entails substantial risk of developing steroid-induced ocular hypertension, so frequent monitoring of intraocular pressure is required. With corneal transplantation, the risk can be mitigated by using techniques with a low inherent risk of rejection, such as Descemet membrane endothelial keratoplasty, whenever possible, to allow earlier reduction of steroid potency.

Innate Immune Cytokine Levels in Eyes With Late Endothelial Keratoplasty Failure.

PURPOSE: The aim of this study was to compare aqueous humor cytokine levels in eyes with an initial endothelial keratoplasty (EK) that cleared and later decompensated versus control eyes. METHODS: In this prospective case-control study, aqueous humor samples were collected under sterile conditions at the start of planned cataract or EK surgery in normal controls (n = 10), Fuchs dystrophy controls with no previous surgery (n = 10) or previous cataract surgery only (n = 10), eyes with Descemet membrane EK (DMEK) endothelial decompensation (n = 5), and eyes with Descemet stripping EK (DSEK) endothelial decompensation (n = 9). Cytokine levels were quantified with the LUNARIS Human 11-Plex Cytokine Kit and compared using the Kruskal-Wallis nonparametric test and post hoc Wilcoxon pairwise 2-sided multiple comparison test. RESULTS: Levels of granulocyte-macrophage colony-stimulating factor, interferon gamma, interleukin (IL)-1ß, IL-2, IL-4, IL-5, IL-10, IL-12p70, and tumor necrosis factorα did not differ significantly between groups. However, IL-6 was significantly increased in DSEK regraft eyes versus controls without previous ocular surgery. IL-8 was significantly increased in eyes with previous cataract or EK surgery versus eyes without previous surgery, and IL-8 was significantly increased in DSEK regraft eyes versus eyes with previous cataract surgery. CONCLUSIONS: The levels of innate immune cytokines IL-6 and IL-8 were elevated in the aqueous humor of eyes with failed DSEK, but not with failed DMEK. The differences between DSEK and DMEK may be related to the lower inherent immunogenicity of DMEK grafts and/or the more advanced stage of some of the DSEK graft failures at the time of diagnosis and treatment.

Case of Progressive Keratoconus With Newly Diagnosed Pellucid Marginal Degeneration After Corneal Cross-Linking.

PURPOSE: The purpose of this study was to document, to our knowledge, the first reported case of keratoconus progression accompanied with newly diagnosed pellucid marginal degeneration after corneal cross-linking (CXL). METHODS: A novel case of further keratoconus progression plus development of pellucid marginal degeneration in the same eye after CXL was documented with supporting evidence from Scheimpflug and optical coherence tomography imaging. RESULTS: A male patient was diagnosed with progressive keratoconus in the left eye and treated with CXL when aged 25 years. Although strongly cautioned not to rub his eyes, he admitted that he continued eye rubbing in association with atopic disease. At a follow-up examination 3.5 years after CXL, progressive keratoconus was detected and pellucid marginal degeneration was newly diagnosed in the left eye. The eye was retreated with CXL. CONCLUSIONS: This case illustrates that progressive keratoconus and pellucid marginal degeneration can occur in the same eye after CXL and demonstrates the deleterious effects that can develop with continued eye rubbing.

Estrogen genotoxicity causes preferential development of Fuchs endothelial corneal dystrophy in females.

Fuchs endothelial corneal dystrophy (FECD) is a genetically complex, age-related, female-predominant disorder characterized by loss of post-mitotic corneal endothelial cells (CEnCs). Ultraviolet-A (UVA) light has been shown to recapitulate the morphological and molecular changes seen in FECD to a greater extent in females than males, by triggering CYP1B1 upregulation in females. Herein, we investigated the mechanism of greater CEnC susceptibility to UVA in females by studying estrogen metabolism in response to UVA in the cornea. Loss of NAD(P)H quinone oxidoreductase 1 (NQO1) resulted in increased production of estrogen metabolites and mitochondrial-DNA adducts, with a higher CEnC loss in Nqo1-/- female compared to wild-type male and female mice. The CYP1B1 inhibitors, trans-2,3',4,5'-tetramethoxystilbene (TMS) and berberine, rescued CEnC loss. Injection of wild-type male mice with estrogen (E2; 17ß-estradiol) increased CEnC loss, followed by increased production of estrogen metabolites and mitochondrial DNA (mtDNA) damage, not seen in E2-treated Cyp1b1-/-male mice. This study demonstrates that the endo-degenerative phenotype is driven by estrogen metabolite-dependent CEnC loss that is exacerbated in the absence of NQO1; thus, explaining the mechanism accounting for the higher incidence of FECD in females. The mitigation of estrogen-adduct production by CYP1B1 inhibitors could serve as a novel therapeutic strategy for FECD.

Initial results of DMEK combined with cataract surgery and implantation of the light-adjustable lens.

PURPOSE: To evaluate the use of light-adjustable intraocular lenses (LALs) to maximize visual acuity (VA) postoperatively in eyes undergoing combined Descemet membrane endothelial keratoplasty (DMEK) and cataract surgery. SETTING: Private practice, tertiary referral center. DESIGN: Retrospective review of initial case series. METHODS: Patients with Fuchs endothelial dystrophy had DMEK combined with phacoemulsification and LAL implantation. Lenses were adjusted based on postoperative manifest refraction and locked-in 3 to 6 months postoperatively. Adjustments to the LAL were started after stabilization of refraction at sequential examinations. Outcomes were uncorrected near and distance VA and manifest refraction 3 to 6 months after locking the lens. RESULTS: A total of 27 eyes in 17 patients with mean age of 65 years (range 53 to 75 years) were included in this study. 6 eyes (22%) had either a near or intermediate target, and 21 eyes (78%) had a distance target. After lock-in, 57% of eyes with a distance target had uncorrected distance VA (UDVA) of 20/20 or better, 90% were 20/25 or better, and 100% were 20/40 or better. After lens lock-in, 100% of eyes had corrected distance VA (CDVA) of 20/20 or better, 86% had postoperative UDVA the same or better than preoperative CDVA, and 100% of eyes had UDVA within 1 line of the preoperative CDVA. In total, 93% of eyes were within 1 diopter (D) of spherical target, and 93% of eyes had ≤0.5 D of refractive cylinder postoperatively. CONCLUSIONS: Combining DMEK with LAL implantation provided significantly better UDVA and refractive outcomes than previously reported data on combined implantation of a standard monofocal lens.

Descemet Membrane Endothelial Keratoplasty: 10-Year Cell Loss and Failure Rate Compared With Descemet Stripping Endothelial Keratoplasty and Penetrating Keratoplasty.

PURPOSE: The aim of this study was to assess long-term endothelial cell loss (ECL) and graft failure with Descemet membrane endothelial keratoplasty (DMEK) and Descemet stripping endothelial keratoplasty (DSEK) versus penetrating keratoplasty (PK) performed for the same indications (primarily Fuchs dystrophy and pseudophakic corneal edema) in the Cornea Donor Study. METHODS: This retrospective study included consecutive primary DMEK (529 recipients, 739 eyes) and DSEK cases (585 recipients, 748 eyes) with 1 or more endothelial cell density (ECD) measurements at 6 months to 16 years. Main outcomes were ECD, longitudinal ECL, and graft failure. RESULTS: Between 6 months and 8 years the ECD declined linearly by approximately 118 cells/mm2/yr after DMEK and 112 cells/mm2/yr after DSEK. Beyond 8 years postoperatively the rate of decline slowed substantially. Selective dropout from graft failure did not significantly affect the ECD trend. At 10 years, median ECL (interquartile range) was 63% (45, 73) with DMEK, 68% (48, 78) with DSEK, and 76% (70, 82) with PK (P = 0.01 DMEK vs. DSEK, P <0.001 DMEK vs. PK, and P < 0.001 DSEK vs. PK). The proportion of surviving grafts with 10-year ECD <500 cells/mm2 was 1.4% with DMEK, 7.3% with DSEK, and 23.9% with PK. The cumulative risk of graft failure between 6 months and 10 years was 5% with DMEK, 11% with DSEK, and 19% with PK (P < 0.001). CONCLUSIONS: Compared with PK and DSEK, DMEK had significantly lower ECL and significantly lower risk of secondary graft failure through 10 years.

Prospective Assessment of Loteprednol Etabonate 0.25% for Prevention of Immunologic Rejection After Descemet Membrane Endothelial Keratoplasty in Eyes With Fuchs Dystrophy.

PURPOSE: The purpose of this study was to assess off-label use of loteprednol etabonate 0.25% ophthalmic suspension for prevention of immunologic rejection after Descemet membrane endothelial keratoplasty (DMEK). METHODS: This prospective, open-label study enrolled 70 eyes of 70 participants without preexisting glaucoma 1 month after DMEK. Participants used topical loteprednol 0.25% 4 times daily for 2 months, tapered by 1 drop/month to once daily use, and continued use through 1 year after DMEK. Main outcomes were rate of intraocular pressure (IOP) elevation (defined as a relative increase of ≥10 mm Hg over the pretransplant IOP) and rate of initial allograft rejection episodes. The results were compared with historical data using the log-rank test. RESULTS: All participants had Fuchs dystrophy, and 40 of 70 (57%) were female. None (0%) experienced an immunologic graft rejection episode, matching the previously reported efficacy of prednisolone acetate 1% suspension and loteprednol 0.5% gel (both 0% incidence). One study eye developed IOP elevation 3 months after DMEK (cumulative risk 1.5%). Compared with historical data, this was similar to the risk with loteprednol 0.5% gel (4%, P = 0.36) and significantly lower than the risk with prednisolone 1% suspension (18%, P = 0.0025). Two participants (3%) complained of instillation site discomfort, consistent with the 5% rate reported on package labeling. CONCLUSIONS: Loteprednol 0.25% suspension, approved for short-term treatment of dry eyes, effectively prevented immunologic rejection episodes with minimal risk of IOP elevation when used from 1 month until 12 months after DMEK in patients without preexisting glaucoma.

Dysregulation of DNA repair genes in Fuchs endothelial corneal dystrophy.

Fuchs Endothelial Corneal Dystrophy (FECD), a late-onset oxidative stress disorder, is the most common cause of corneal endothelial degeneration and is genetically associated with CTG repeat expansion in Transcription Factor 4 (TCF4). We previously reported accumulation of nuclear (nDNA) and mitochondrial (mtDNA) damage in FECD. Specifically, mtDNA damage was a prominent finding in development of disease in the ultraviolet-A (UVA) induced FECD mouse model. We hypothesize that an aberrant DNA repair may contribute to the increased DNA damage seen in FECD. We analyzed differential expression profiles of 84 DNA repair genes by real-time PCR arrays using Human DNA Repair RT-Profiler plates using cDNA extracted from Descemet's membrane-corneal endothelium (DM-CE) obtained from FECD patients with expanded (>40) or non-expanded (<40) intronic CTG repeats in TCF4 gene and from age-matched normal donors. Change in mRNA expression of <0.5- or >2.0-fold in FECD relative to normal was set as cutoff for down- or upregulation. Downregulated mitochondrial genes were further validated using the UVA-based mouse model of FECD. FECD specimens exhibited downregulation of 9 genes and upregulation of 8 genes belonging to the four major DNA repair pathways, namely, base excision repair (BER), nucleotide excision repair (NER), mismatch repair (MMR), and double strand break (DSB) repair, compared to normal donors. MMR gene MSH2 and BER gene POLB were preferentially upregulated in expanded FECD. BER genes LIG3 and NEIL2, DSB repair genes PARP3 and TOP3A, NER gene XPC, and unclassified pathway gene TREX1, were downregulated in both expanded and non-expanded FECD. MtDNA repair genes, Lig3, Neil2, and Top3a, were also downregulated in the UVA-based mouse model of FECD. Our findings identify impaired DNA repair pathways that may play an important role in DNA damage due to oxidative stress as well as genetic predisposition noted in FECD.

Descemet Stripping Endothelial Keratoplasty: Fifteen-Year Outcomes.

PURPOSE: The purpose of this study was to evaluate 15-year outcomes of Descemet stripping endothelial keratoplasty (DSEK). METHODS: We retrospectively reviewed an initial, consecutive series of 350 DSEK cases in 290 patients (mean age 69 years), performed between December 2003 and December 2005 for Fuchs dystrophy (86%), pseudophakic/aphakic bullous keratopathy (10%), or failed penetrating keratoplasty (4%). Outcomes included best spectacle-corrected visual acuity (BSCVA), endothelial cell density (ECD), and graft failure (defined as regraft for any reason or persistent loss of stromal clarity). RESULTS: At 15 years, 46 of 350 DSEK grafts (13%) had failed, 155 (44%) were in patients who died, and 84 of the remaining 149 grafts (56%) were examined. After accounting for loss to follow-up, the probability of graft failure was 7% at 5 years, 16% at 10 years, and 23% at 15 years. The main risk factor for late endothelial failure was preoperative glaucoma (hazard ratio: 4.4 for medically managed and 24 for surgically managed glaucoma). The probability of an immunologic rejection episode was 7% by 1 year, 14% by 10 years, and 17% by 15 years. The median donor ECD decreased from 3030 cells/mm 2 before DSEK to 1973 cells/mm 2 at 6 months (36% loss) and 705 cells/mm 2 at 15 years (78% loss). The median BSCVA, including the eyes with ocular comorbidity, was 20/60 preoperatively, 20/40 at 3 through 12 months, and 20/30 from 2 to 15 years. CONCLUSIONS: DSEK provided excellent long-term visual rehabilitation and graft survival in this early cohort, performed when the technique was still being refined.

Randomized, Double-Masked, Pilot Study of Netarsudil 0.02% Ophthalmic Solution for Treatment of Corneal Edema in Fuchs Dystrophy.

PURPOSE: To evaluate off-label use of netarsudil 0.02% for treatment of corneal edema associated with Fuchs dystrophy. DESIGN: Prospective, randomized clinical trial. METHODS: Twenty-nine subjects with symptomatic Fuchs dystrophy were enrolled and randomized to use netarsudil or placebo eye drops once daily for 3 months. The primary outcomes were the change in central corneal thickness between baseline and 1 month and between baseline and 3 months. Secondary outcomes included change in scotopic corrected distance visual acuity (CDVA) at 3 months and change in scores on a visual disability questionnaire validated for use with Fuchs dystrophy. RESULTS: Compared with use of placebo, use of netarsudil produced significant reduction in central corneal thickness at 1 month (mean difference, -20 µm; 95% confidence interval, -32 to -9 µm) and 3 months (mean difference, -26 µm; 95% confidence interval, -39 to -12 µm) and significant improvement in scotopic CDVA at 3 months (mean difference +1.6 lines; 95% confidence interval, 0.2-3.0 lines). Scores on the visual disability questionnaire did not change significantly in either arm or differ significantly between arms. One subject assigned to netarsudil had baseline epithelial bullae and withdrew from the study because of disabling glare. CONCLUSIONS: Use of netarsudil was associated with reduction of corneal edema and improvement in scotopic CDVA in Fuchs dystrophy patients. Further study is needed to more fully assess patient satisfaction and visual acuity under various lighting conditions and to compare use of netarsudil with other treatment options such as endothelial keratoplasty.

Randomized, Double-Masked Trial of Netarsudil 0.02% Ophthalmic Solution for Prevention of Corticosteroid-Induced Ocular Hypertension.

PURPOSE: To assess whether prophylactic use of netarsudil 0.02% ophthalmic solution reduces the risk of intraocular pressure (IOP) elevation associated with prolonged use of topical corticosteroids to prevent cornea transplantation rejection. DESIGN: Prospective, randomized clinical trial. METHODS: In this study, 120 subjects were randomized to use netarsudil (off-label) or placebo once daily for 9 months after Descemet membrane endothelial keratoplasty, and 71 fellow eyes were enrolled and assigned to the opposite treatment arm. Participants concurrently used topical prednisolone acetate 1% 4× daily for 3 months, 3× daily for a month, twice daily for a month, and once daily for 4 months. The main outcome was IOP elevation (defined as IOP ≥24 mm Hg or an increase of ≥10 mm Hg over baseline) assessed by Kaplan-Meier and proportional hazards analyses, taking loss to follow-up into consideration. RESULTS: Overall, 95 eyes were assigned to netarsudil and 96 to placebo; 15 eyes (16%) were withdrawn early from the netarsudil arm because of ocular irritation. The rate of IOP elevation was 14% with netarsudil and 21% with placebo (relative risk: 0.6; 95% confidence interval: 0.3-1.3; P = .23). IOP was >30 mm Hg in 7.8% assigned to netarsudil versus 7.4% assigned to placebo (P = .84). Median 6-month central endothelial cell loss was 31% versus 29% with netarsudil versus placebo, respectively (P = .49). CONCLUSIONS: Netarsudil did not produce a statistically significant reduction in the risk of steroid-induced IOP elevation after corneal transplantation relative to placebo.

Corneal endothelial dysfunction: Evolving understanding and treatment options.

The cornea is exquisitely designed to protect the eye while transmitting and focusing incoming light. Precise control of corneal hydration by the endothelial cell layer that lines the inner surface of the cornea is required for optimal transparency, and endothelial dysfunction or damage can result in corneal edema and visual impairment. Advances in corneal transplantation now allow selective replacement of dysfunctional corneal endothelium, providing rapid visual rehabilitation. A series of technique improvements have minimized complications and various adaptations allow use even in eyes with complicated anatomy. While selective endothelial keratoplasty sets a very high standard for safety and efficacy, a shortage of donor corneas in many parts of the world restricts access, prompting a search for alternatives. Clinical trials are underway to evaluate the potential for self-recovery after removal of dysfunctional central endothelium in patients with healthy peripheral endothelium. Various approaches to using cultured human corneal endothelial cells are also in clinical trials; these aim to multiply cells from a single donor cornea for use in potentially hundreds of patients. Pre-clinical studies are underway with induced pluripotent stem cells, endothelial stem cell regeneration, gene therapy, anti-sense oligonucleotides, and various biologic/pharmacologic approaches designed to treat, prevent, or retard corneal endothelial dysfunction. The availability of more therapeutic options will hopefully expand access around the world while also allowing treatment to be more precisely tailored to each individual patient.

Endothelial Keratoplasty Update 2020.

ABSTRACT: Endothelial keratoplasty has revolutionized the treatment of corneal endothelial dysfunction and lowered the threshold for treatment by providing rapid visual rehabilitation and setting a high standard for safety and efficacy. Over time, endothelial keratoplasty techniques have evolved toward the use of thinner tissue to optimize visual outcomes; refinements have facilitated donor tissue preparation, handling, and attachment; and adaptations have expanded utilization in eyes with challenging ocular anatomy. Despite early concerns about graft longevity, emerging 10-year endothelial cell loss and graft survival data have been encouraging. A shortage of human donor corneas restricts utilization in many areas of the world and is driving a search for keratoplasty alternatives. Further work is needed to expand the donor supply, minimize impediments to adoption, optimize graft survival, and improve refractive predictability.

Implantation of Presbyopia-Correcting Intraocular Lenses Staged After Descemet Membrane Endothelial Keratoplasty in Patients With Fuchs Dystrophy.

PURPOSE: To assess outcomes of presbyopia-correcting intraocular lens (IOL) implantation after Descemet membrane endothelial keratoplasty (DMEK) in patients with Fuchs endothelial corneal dystrophy. METHODS: This retrospective single-center study evaluated a consecutive series of patients with Fuchs endothelial corneal dystrophy who received presbyopia-correcting IOLs after DMEK. The main outcomes were corrected distance visual acuity, uncorrected distance visual acuity, uncorrected near visual acuity, and refractive error. RESULTS: Fourteen extended depth of focus and 2 bifocal IOLs were implanted in 16 eyes of 8 patients (5 women and 3 men; age, 47-68 years). Fourteen IOLs were spherical and 2 were toric. Postoperatively, the median corrected distance visual acuity was 20/20 (range, 20/15-20/25), the median binocular uncorrected distance visual acuity was 20/25 (range, 20/15-20/25), the median binocular uncorrected near visual acuity was 20/20 (range, 20/20-20/50), and the median manifest spherical equivalent refraction was 0.05 diopters (D) (range, -0.75 to +0.75 D). Implantation of toric extended depth of focus lenses reduced refractive cylinder from 1 and 2.25 D preoperatively to 0 D in both eyes of 1 patient postoperatively. A comparison of biometry measurements taken before and after DMEK showed the median change in average keratometry was 0.26 D with a substantial range of -1.74 to +1.18 D. The median endothelial cell loss was 63 cells/mm (3%) after staged phacoemulsification. CONCLUSIONS: Favorable visual and refractive outcomes were obtained with presbyopia-correcting IOLs in patients with Fuchs dystrophy when the biometry measurements and IOL implantation were staged after DMEK had cleared the guttae and corneal edema.

Loss of NQO1 generates genotoxic estrogen-DNA adducts in Fuchs Endothelial Corneal Dystrophy.

Fuchs Endothelial Corneal Dystrophy (FECD) is an age-related genetically complex disease characterized by increased oxidative DNA damage and progressive degeneration of corneal endothelial cells (HCEnCs). FECD has a greater incidence and advanced phenotype in women, suggesting a possible role of hormones in the sex-driven differences seen in the disease pathogenesis. In this study, catechol estrogen (4-OHE2), the byproduct of estrogen metabolism, induced genotoxic estrogen-DNA adducts formation, macromolecular DNA damage, and apoptotic cell death in HCEnCs; these findings were potentiated by menadione (MN)-mediated reactive oxygen species (ROS). Expression of NQO1, a key enzyme that neutralizes reactive estrogen metabolites, was downregulated in FECD, indicating HCEnC susceptibility to reactive estrogen metabolism in FECD. NQO1 deficiency in vitro exacerbated the estrogen-DNA adduct formation and loss of cell viability, which was rescued by the supplementation of N-acetylcysteine, a ROS scavenger. Notably, overexpression of NQO1 in HCEnCs treated with MN and 4-OHE2 quenched the ROS formation, thereby reducing the DNA damage and endothelial cell loss. This study signifies a pivotal role for NQO1 in mitigating the macromolecular oxidative DNA damage arising from the interplay between intracellular ROS and impaired endogenous estrogen metabolism in post-mitotic ocular tissue cells. A dysfunctional Nrf2-NQO1 axis in FECD renders HCEnCs susceptible to catechol estrogens and estrogen-DNA adducts formation. This novel study highlights the potential role of NQO1-mediated estrogen metabolite genotoxicity in explaining the higher incidence of FECD in females.

Peripheral Reconstructive Lamellar Keratoplasty for Late Ectasia After Penetrating Keratoplasty in Keratoconus Eyes.

PURPOSE: To describe outcomes of customized peripheral anterior lamellar keratoplasty (PALK) for late ectasia of the donor-recipient junction after penetrating keratoplasty (PK) for keratoconus. METHODS: This was a single-center, retrospective review of 33 eyes (28 patients) that developed ectasia restricted to the graft-host junction; 17 eyes underwent PALK using lamellar resections of 8- to 11-mm width starting at the external margin of the previous PK and suturing a same-size donor graft (annular or segmental). Five eyes were excluded from analysis because of postoperative complications unrelated to the technique. RESULTS: The average time between PK and diagnosis of secondary ectasia was 28 years (range 9-49 years). Slit-lamp examination showed localized thinning and elongation of the scar at the graft-host junction with well-defined biomicroscopic limits. Preoperatively, the mean keratometric measures were K1: 44.8 ± 4.8 D and K2: 54.1 ± 4.8 D and postoperatively K1: 47.5 ± 3.5 D and K2: 50.8 ± 2.6 D. The mean improvement in corrected visual acuity was 10 lines, and mean cylinder improved from 9.3 ± 2.1 D to 3.3 ± 1.4 D. All cases showed anatomical and refractive improvement. CONCLUSIONS: With long-term follow-up, late post-PK ectasia becomes an increasing problem. PALK can be a successful surgical option to reinforce the ectatic area while preserving a functional clear PK. By adding donor corneal tissue, PALK restores the ectatic area, improves visual acuity, keratometric values, and astigmatism, and preserves the functional graft while avoiding the higher risks of a larger diameter PK.

Technique for Ensuring Type I Bubble Formation for Pre-Descemet Endothelial Keratoplasty Preparation.

PURPOSE: To describe a technique that ensures the production of a type 1 bubble when preparing pre-Descemet endothelial keratoplasty (PDEK) grafts with a high rate of predictability. METHODS: Donor corneas were placed on a support disc, and a blunt instrument was used to score 360 degrees of the peripheral Descemet membrane and endothelium just inside the trabecular meshwork. Air was injected in several short bursts and several stages with a 30-gauge needle on a 3-mL syringe 2.0 mm away from the limbus to create a type 1 big bubble. The technique was tested by 2 operators (M.S. and A.S.-J.) in 26 human donor corneas, including 12 for possible transplantation, over a 9-month period. Anterior segment optical coherence tomograph (AS-OCT) was performed in 1 case proving a type 1 bubble. RESULTS: A type 1 big bubble was successfully created in 24 of 26 attempted cases (92.3%). The technique was used successfully to obtain PDEK tissue for transplant in 9 eyes. One case was not technically acceptable because of diffuse cell loss (>10%); however, the bubble preparation itself was successful. One case had a mixed bubble because of incomplete scoring, resulting in a Descemet membrane endothelial keratoplasty graft used for transplant. One case failed to form any bubble likely because the scoring was too central. Of a total of 26 cases, 14 cases were for practice. CONCLUSIONS: The Soper technique significantly improved the success rate of creating a type 1 bubble for PDEK preparation.

Activation of PINK1-Parkin-Mediated Mitophagy Degrades Mitochondrial Quality Control Proteins in Fuchs Endothelial Corneal Dystrophy.

Corneal endothelium (CE) is a monolayer of mitochondria-rich cells, critical for maintaining corneal transparency compatible with clear vision. Fuchs endothelial corneal dystrophy (FECD) is a heterogeneous, genetically complex disorder, where oxidative stress plays a key role in the rosette formation during the degenerative loss of CE. Increased mitochondrial fragmentation along with excessive mitophagy activation has been detected in FECD; however, the mechanism of aberrant mitochondrial dynamics in CE cell loss is poorly understood. Here, the role of oxidative stress in mitophagy activation in FECD is investigated. Immunoblotting of FECD ex vivo specimens revealed an accumulation of PINK1 and phospho-Parkin (Ser65) along with loss of total Parkin and total Drp1. Similarly, modeling of rosette formation with menadione (MN), led to phospho-Parkin accumulation in fragmented mitochondria resulting in mitophagy-induced mitochondrial clearance, albeit possibly in a PINK1-independent manner. Loss of PINK1, phospho-Drp1, and total Drp1 was prominent after MN-induced oxidative stress, but not after mitochondrial depolarization by carbonyl cyanide m-chlorophenyl hydrazone. Moreover, MN-induced mitophagy led to degradation of Parkin along with sequestration of Drp1 and PINK1 that was rescued by mitophagy inhibition. This study shows that in FECD, intracellular oxidative stress induces Parkin-mediated mitochondrial fragmentation where endogenous Drp1 and PINK1 are sequestered and degraded by mitophagy during degenerative loss of post-mitotic cells of ocular tissue.