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.].

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.

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.

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.

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.

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.

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.

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.

Micropulse Transscleral Cyclophotocoagulation in Keratoplasty Eyes.

PURPOSE: To assess the outcomes of micropulse transscleral cyclophotocoagulation for intraocular pressure (IOP) control in keratoplasty eyes. METHODS: Outcomes of micropulse laser treatments of postkeratoplasty eyes were retrospectively reviewed. IOP was assessed with applanation tonometry. Keratoplasty survival was calculated with Kaplan-Meier survival analysis. RESULTS: Sixty-one eyes in 57 patients received laser treatment; 31 eyes received 1, 21 received 2, 8 received 3, and 1 received 4 treatments. The median follow-up was 21 months (range, 2-35 months). At baseline, the mean IOP was 28 ± 11 mm Hg. At 1, 3, 6, and 12 months after the last treatment, respectively, the numbers of eyes with IOP data were 58, 50, 46, and 38; the mean IOP was 17 ± 7, 17 ± 8, 18 ± 9, and 15 ± 5 mm Hg; the proportions of eyes with IOP ≤ 15 mm Hg were 40%, 51%, 48%, and 55%; and the proportions with IOP ≤ 12 mm Hg were 21%, 29%, 20% and 29%. Six eyes (10%) received subsequent glaucoma filtration surgery. The mean number of antiglaucoma medications used before the initial treatment was 2.7 (range, 0-4) versus 2.2 (range, 0-4) at last follow-up. At baseline, 7 grafts were decompensated and 5 of 54 clear grafts (9%) had endothelial cell density < 700 cells/mm. Graft survival was 94% at 1 year and 81% at 2 years after the initial laser treatment. CONCLUSIONS: Micropulse transscleral cyclophotocoagulation is a noninvasive alternative to glaucoma filtration surgery for IOP reduction in keratoplasty eyes.

Descemet Membrane Endothelial Keratoplasty for Failed Penetrating Keratoplasty: Visual Outcomes and Graft Survival.

PURPOSE: To evaluate outcomes and graft survival of Descemet membrane endothelial keratoplasty (DMEK) for failed penetrating keratoplasty (PK). METHODS: Ninety-three DMEK procedures performed in 84 eyes of 77 patients with failed PK were retrospectively reviewed. The main outcomes were corrected distance visual acuity and graft survival assessed with Kaplan-Meier survival analysis and proportional hazards modeling taking follow-up into consideration. RESULTS: Sixty-nine eyes had 1 previous failed PK, 13 had 2, 1 had 3, and 1 had 4. Ten eyes had failed Descemet stripping endothelial keratoplasty (DSEK) performed under failed PK. Fourteen cases (15%) had previous glaucoma filtration surgery (9 trabeculectomy alone; 5 trabeculectomy and aqueous shunt). Median follow-up was 21 months (range, 1 month to 7 years). Median Snellen corrected distance visual acuity improved from 20/100 preoperatively (range, 20/30 to count fingers) to 20/30 at 6 months postoperatively (n = 73; range, 20/20-20/200). Rebubbling rates were 53% when the diameter of the DMEK graft was oversized, 27% when same sized, and 33% when undersized relative to that of the previous PK graft. Two grafts (2%) experienced an immunologic rejection episode, and 15 (16%) failed, including 5 primary/early failures and 10 late failures. Previous glaucoma surgery was the only significant risk factor for failure (relative risk, 7.1; 95% confidence interval, 2.1-37.0). The 1-, 2-, and 3-year graft survival rates were 96%, 89%, and 89% without versus 78%, 53%, and 39% with previous glaucoma surgery. CONCLUSIONS: Treatment of failed PK with DMEK produced similar 4-year survival (76%) and better visual outcomes than previously reported with Descemet stripping endothelial keratoplasty or an initial PK regraft.

Corneal Epithelial Remodeling After Standard Epithelium-off Corneal Cross-linking in Keratoconic Eyes.

PURPOSE: To evaluate remodeling of the corneal epithelium after epithelium-off corneal cross-linking (CXL). METHODS: In this prospective single-center study, 93 eyes of 93 patients with progressive keratoconus underwent standard CXL. The maximum keratometry was assessed before and after CXL with Scheimpflug imaging, and the epithelial thickness profile across the central 5 mm of the cornea was assessed with spectral-domain optical coherence tomography anterior segment imaging. RESULTS: The mean patient age was 27 ± 11 years; 76 patients (81%) were male and 17 (19%) were female. Between baseline and 6 months after CXL, the mean corneal maximum keratometry flattened from 58.90 to 57.80 diopters (P < .0001). The mean minimum epithelial thickness increased slightly (from 41 ± 6 to 42 ± 7 µm, P = .12), whereas the mean maximum epithelial thickness decreased slightly (from 65 ± 6 to 64 ± 7 µm, P = .067), reducing the net difference between the minimum and maximum epithelial thickness (from 24 ± 9 to 22 ± 9 µm, P = .0023). The difference between the minimum and maximum epithelial thickness was strongly positively correlated with the maximum keratometry reading at baseline (R2 = 0.38) and at 6 months after CXL (R2 = 0.59). CONCLUSIONS: Epithelium-off CXL resulted in modest regularization of the epithelial thickness profile across the central 5 mm of the cornea at 6 months. This could slightly mask flattening of the underlying stroma. [J Refract Surg. 2018;34(6):408-412.].

Patient satisfaction with epithelium-off corneal crosslinking.

PURPOSE: To assess patient satisfaction with corneal crosslinking (CXL). SETTING: Price Vision Group, Indianapolis, Indiana, USA. DESIGN: Prospective case series. METHODS: Patients treated with the Dresden protocol or accelerated epithelium-off CXL during an 8-year period were invited to participate in an electronic survey. RESULTS: Of the 552 patients who were invited to participate, 448 (80% response rate) completed the electronic survey. The median time from CXL to survey completion was 3.5 years (range 1 to 9 years). The participants were 73% men; 78% had keratoconus, 22% had post-refractive surgical ectasia, and 44% had bilateral treatment. Comparable proportions of those treated with standard and accelerated CXL reported that it halted disease progression (88% versus 87%, respectively, P = .78). A younger treatment age was associated with higher perceived efficacy (P = .0003). The proportion who considered CXL effective was 93% among those with mild keratoconus, 86% with moderate to severe keratoconus, and 78% with post-refractive surgical ectasia (P = .0004). Regarding vision, 41% reported improvement after CXL, 46% noted no change, and 14% perceived continued decline. The mean satisfaction score was 8.8 ± 1.7 (SD) on a scale of 1 (would not recommend CXL) to 10 (definitely would recommend) among those treated for keratoconus and 7.6 ± 2.5 among those treated for ectasia after keratorefractive surgery (P < .0001). Eleven (1.7%) of 644 treated eyes had subsequent keratoplasty. CONCLUSION: Most patients considered CXL effective. The perceived efficacy did not vary significantly as a function of follow-up time (P = .90), suggesting no discernible fading of effect over the 1- to 9-year follow-up.

Intraoperative hyphema in Descemet membrane endothelial keratoplasty alone or combined with phacoemulsification.

PURPOSE: To identify whether intraoperative hyphema from the peripheral iridotomy during Descemet membrane endothelial keratoplasty (DMEK) is associated with anticoagulant or antiplatelet use, age, combined phacoemulsification, or adverse outcomes. SETTING: Price Vision Group, Indianapolis, Indiana, USA. DESIGN: Retrospective case series. METHODS: Data were obtained from consecutive DMEK cases with an intraoperative iridotomy from July 2015 through July 2016. Hyphema was classified as negative or positive (small or large). Associations with possible risk factors and with transplant outcomes were assessed. RESULTS: Of 445 cases, 262 (59%) were negative for hyphema and 183 (41%) were positive. The proportion of patients who used preoperative anticoagulant or antiplatelet medication did not differ significantly with the hyphema classification (negative hyphema 42%, small hyphema 34%, large hyphema 46%) (P = .31). Likewise, recipient age was not a risk factor for hyphema (P = .085). Hyphema was more likely in cases combined with phacoemulsification than in single DMEK procedures (relative risk, 1.5 [95% confidence interval, 1.2-1.9]). Hyphema was not associated with postoperative rebubbling rates (negative hyphema 10.5%, small hyphema 10.3%, large hyphema 8.0%) (P = .33), 6-month endothelial cell loss (mean = 29%, P = .19), or 6-month visual acuity (mean = 20/25 Snellen in all hyphema groups, P = .98). CONCLUSIONS: Preoperative anticoagulant or antiplatelet use was not a significant risk factor for hyphema. The risk for hyphema was increased somewhat when DMEK was combined with cataract surgery. Intraoperative hyphema did not significantly affect the rebubbling rate, endothelial cell loss, or visual acuity outcomes.

NQO1 downregulation potentiates menadione-induced endothelial-mesenchymal transition during rosette formation in Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is a genetic and oxidative stress disorder of post-mitotic human corneal endothelial cells (HCEnCs), which normally exhibit hexagonal shape and form a compact monolayer compatible with normal corneal functioning and clear vision. FECD is associated with increased DNA damage, which in turn leads to HCEnC loss, resulting in the formation rosettes and aberrant extracellular matrix (ECM) deposition in the form of pro-fibrotic guttae. Since the mechanism of ECM deposition in FECD is currently unknown, we aimed to investigate the role of endothelial-mesenchymal transition (EMT) in FECD using a previously established cellular in vitro model that recapitulates the characteristic rosette formation, by employing menadione (MN)-induced oxidative stress. We demonstrate that MN treatment alone, or a combination of MN and TGF-ß1 induces reactive oxygen species (ROS), cell death, and EMT in HCEnCs during rosette formation, resulting in upregulation of EMT- and FECD-associated markers such as Snail1, N-cadherin, ZEB1, and transforming growth factor-beta-induced (TGFßI), respectively. Additionally, FECD ex vivo specimens displayed a loss of organized junctional staining of plasma membrane-bound N-cadherin, with corresponding increase in fibronectin and Snail1 compared to ex vivo controls. Addition of N-acetylcysteine (NAC) downregulated all EMT markers and abolished rosette formation. Loss of NQO1, a metabolizing enzyme of MN, led to greater increase in intracellular ROS levels as well as a significant upregulation of Snail1, fibronectin, and N-cadherin compared to normal cells, indicating that NQO1 regulates Snail1-mediated EMT. This study provides first line evidence that MN-induced oxidative stress leads to EMT in corneal endothelial cells, and the effect of which is further potentiated when redox cycling activity of MN is enhanced by the absence of NQO1. Given that NAC inhibits Snail-mediated EMT, this may be a potential therapeutic intervention for FECD.

Prospective Randomized Trial of Corneal Cross-linking Riboflavin Dosing Frequencies for Treatment of Keratoconus and Corneal Ectasia.

PURPOSE: To investigate whether the riboflavin dosing frequency affects corneal cross-linking efficacy or safety, given that isotonic riboflavin solution is viscous and each installation coats the corneal surface with a film that absorbs some of the incident ultraviolet A light. DESIGN: Prospective, randomized, single-center equivalence trial. PARTICIPANTS: Patients with progressive keratoconus or ectasia after refractive surgery (n = 510). METHODS: One eye per patient was prospectively randomized to 2-minute or 5-minute riboflavin dosing intervals with standard corneal cross-linking (epithelial removal and 30-minute irradiation with 3 mW/cm2 ultraviolet A light). Block randomization resulted in comparable representation of keratoconus and ectasia after refractive surgery in the 2 treatment arms. Treatment equivalence was assessed using the 2 one-sided test. Fellow eyes (n = 207) were treated with 5-minute dosing and considered in the safety analysis. MAIN OUTCOME MEASURES: The primary hypothesis was equivalent change in the topography-derived maximum keratometry value from baseline to 6 months with 2-minute vs. 5-minute dosing. A ±0.75-diopter margin of equivalence for the treatment difference between dosing regimens was considered clinically relevant. Adverse events and changes from baseline to 6 months in corrected distance visual acuity (CDVA), uncorrected distance visual acuity, and minimum corneal thickness were assessed. RESULTS: The mean reduction in maximum keratometry from baseline was equivalent with 2-minute and 5-minute riboflavin dosing intervals at 6 months (0.97 and 0.76 diopters, respectively; 90% confidence interval for treatment difference, -0.23 to 0.66; per-protocol population). With both dosing intervals, the mean improvement in CDVA was 0.07 logarithm of the minimum angle of resolution or 3.5 letters at 6 months. Of the 635 study and fellow eyes examined at 6 months, 134 (21%) gained and 32 (5%) lost 2 or more lines of CDVA. Three eyes (0.4%) developed sterile infiltrates, 1 (0.1%) had delayed epithelial healing with dendrites, and 3 (0.4%) had recurrent epithelial defects. Three eyes (0.4%) were re-treated. CONCLUSIONS: The 2 riboflavin dosing regimens produced equivalent reduction in the maximum keratometry value, with a favorable safety profile.

Immunologic Rejection Episodes After Deep Anterior Lamellar Keratoplasty: Incidence and Risk Factors.

PURPOSE: To assess the rejection episode rate after deep anterior lamellar keratoplasty (DALK) and to identify associated risk factors. METHODS: This retrospective review of 251 primary DALK procedures performed by 14 surgeons at a single center between February 2008 and November 2015 evaluated the rejection episode rate and associated risk factors using Kaplan-Meier survival and proportional hazards analyses, which took the length of follow-up into consideration. RESULTS: Transplant indications were keratoconus or ectasia after laser refractive surgery (n = 170, 68%), corneal opacity (n = 72, 28%), and other anterior corneal disease (n = 9, 4%). The median recipient age was 46 years. The overall rejection episode rate was 14% with 18-month median follow-up and a 7-week median postoperative corticosteroid duration. In univariate analysis, increased risk of rejection episodes was associated with younger recipient age [relative risk (RR): 2.1, 95% confidence interval (CI): 1.4-5.2], African American race (RR: 2.1, 95% CI: 1.1-4.1), and use of manual trephination (compared with the femtosecond laser) for the side-cut incisions (RR: 2.7, 95% CI: 1.4-5.2). In multivariate analysis, the combined effect of patient age and race (P = 0.0012) and the side-cut method (P = 0.021) were each significant risk factors. CONCLUSIONS: This study demonstrates the substantial rate of rejection episodes that can be induced by corneal stroma in DALK and suggests that postoperative topical corticosteroids should be continued longer than the study's 7-week median and that young African Americans need higher-dose, longer-duration topical corticosteroids. The association between the side-cut method and rejection risk merits further investigation.

EK (DLEK, DSEK, DMEK): New Frontier in Cornea Surgery.

Endothelial keratoplasty (EK) has revolutionized treatment of corneal endothelial dysfunction. Compared with penetrating keratoplasty (PK), EK provides faster and more reliable visual rehabilitation while maintaining the eye's structural integrity. The number of EK procedures is growing annually and surpassed PK in the United States in 2012. The most widely used iteration, Descemet stripping endothelial keratoplasty (DSEK), implants healthy donor endothelium, Descemet membrane, and posterior stroma. Descemet membrane endothelial keratoplasty (DMEK) eliminates the donor stromal layer. Although more surgically challenging than DSEK, DMEK provides even faster visual rehabilitation and reduced risk of immunologic rejection, so its use is growing. Potential future alternatives to EK that could help address the unmet demand for donor corneas include removing central guttae and regenerating a central endothelial cell layer from healthy peripheral cells in patients with Fuchs' dystrophy or injecting cultured human corneal endothelial cells to rehabilitate eyes without residual healthy endothelium.