TCF4 trinucleotide repeat expansions and UV irradiation increase susceptibility to ferroptosis in Fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD), the leading indication for corneal transplantation in the U.S., causes loss of corneal endothelial cells (CECs) and corneal edema leading to vision loss. FECD pathogenesis is linked to impaired response to oxidative stress and environmental ultraviolet A (UVA) exposure. Although UVA is known to cause nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation, ferroptosis has not been characterized in FECD. We investigated the roles of genetic background and UVA exposure in causing CEC degeneration in FECD. Using ungenotyped FECD patient surgical samples, we found increased levels of cytosolic ferrous iron (Fe2+) and lipid peroxidation in end-stage diseased tissues compared with healthy controls. Using primary and immortalized cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found altered gene and protein expression involved in ferroptosis compared to controls including elevated levels of Fe2+, basal lipid peroxidation, and the ferroptosis-specific marker transferrin receptor 1. Increased cytosolic Fe2+ levels were detected after physiologically relevant doses of UVA exposure, indicating a role for ferroptosis in FECD disease progression. Cultured cells were more prone to ferroptosis induced by RSL3 and UVA than controls, indicating ferroptosis susceptibility is increased by both FECD genetic background and UVA. Finally, cell death was preventable after RSL3 induced ferroptosis using solubilized ubiquinol, indicating a role for anti-ferroptosis therapies in FECD. This investigation demonstrates that genetic background and UVA exposure contribute to iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated disease progression in FECD.

Anatomic Characteristics of Eyes With Fuchs Endothelial Corneal Dystrophy.

PURPOSE: The purpose of this study was to evaluate and compare the anatomic characteristics of eyes with Fuchs endothelial corneal dystrophy (FECD) with eyes without FECD. METHODS: This study was a retrospective chart review performed at an academic medical center. Patients with FECD were identified through a search of the electronic medical records. Eligible patients underwent Scheimpflug imaging and optical biometry and were compared with age and sex-matched control subjects who underwent similar testing in preparation for cataract surgery. Several measurements of the cornea, anterior chamber, and eyes were evaluated using multivariable linear regression models and multivariable logistic regression models. RESULTS: A total of 404 eyes (202 eyes with FECD and 202 control eyes) were included in this study. Compared with controls, eyes with FECD had shallower AC depths, lower AC volumes, and narrower angles. Conversely, the spherical equivalent before cataract surgery, corneal pachymetry, and corneal volume were higher in eyes with FECD. On Scheimpflug imaging analysis, these anatomical differences were present in FECD eyes with and without corneal edema. After adjusting for sex, these differences remained statistically significant. Shorter axial length was found to be statistically significant in male eyes but not in female eyes with FECD. CONCLUSIONS: This study reports new ocular characteristics in FECD eyes with and without edema. Optical biometry and Scheimpflug imaging established that the anatomic findings in eyes with FECD were not simply due to the larger volume of an edematous cornea but rather unique to eyes with FECD. These findings will provide reliable, normative data for future studies examining surgical, medical, and anatomical factors in FECD.

Corneal Backscatter, Pachymetric Indices, and Ectasia Indices for the Assessment of Fuchs Endothelial Corneal Dystrophy.

PURPOSE: To determine whether corneal backscatter, pachymetric indices, and ectasia indices derived from Scheimpflug tomography can identify Fuchs endothelial corneal dystrophy (FECD) corneas with abnormal tomography, the relationships between these parameters and tomographic edema in FECD, and if these parameters help predict improvement in central corneal thickness (CCT) after Descemet membrane endothelial keratoplasty (DMEK). METHODS: Tomography maps of 132 eyes of 80 subjects with FECD were analyzed to determine how backscatter, pachymetric, and ectasia parameters compared with the instrument's normative database and if any predicted tomographic edema. Tomography maps from a separate group undergoing DMEK were split into derivation (48 eyes of 39 subjects) and validation (45 eyes of 41 subjects) subgroups to derive a predictive model of improvement in CCT after DMEK. Backscatter, pachymetric, and ectasia parameters were incorporated to determine if the model could be enhanced. RESULTS: Among all ectasia, pachymetric, and backscatter parameters, at best only 65% of FECD corneas with definite tomographic edema could be identified based on the instrument's normative database. Among all parameters individually, the highest sensitivity for detecting tomographic edema was 77%. Anterior and mid-corneal backscatter featured in a model predicting improvement in CCT after DMEK with high performance in derivation (R2 = 0.79; 95% confidence interval, 0.65-0.87) and validation (R2 = 0.72; 95% confidence interval, 0.52-0.83) subgroups. CONCLUSIONS: The Scheimpflug camera software program could not reliably detect abnormal tomography in FECD from corneal backscatter, pachymetric indices, or ectasia indices. Corneal backscatter contributes to, but does not enhance, a predictive model of improvement in CCT after DMEK.

Appropriateness of Ophthalmology Recommendations From an Online Chat-Based Artificial Intelligence Model.

Objective: To determine the appropriateness of ophthalmology recommendations from an online chat-based artificial intelligence model to ophthalmology questions. Patients and Methods: Cross-sectional qualitative study from April 1, 2023, to April 30, 2023. A total of 192 questions were generated spanning all ophthalmic subspecialties. Each question was posed to a large language model (LLM) 3 times. The responses were graded by appropriate subspecialists as appropriate, inappropriate, or unreliable in 2 grading contexts. The first grading context was if the information was presented on a patient information site. The second was an LLM-generated draft response to patient queries sent by the electronic medical record (EMR). Appropriate was defined as accurate and specific enough to serve as a surrogate for physician-approved information. Main outcome measure was percentage of appropriate responses per subspecialty. Results: For patient information site-related questions, the LLM provided an overall average of 79% appropriate responses. Variable rates of average appropriateness were observed across ophthalmic subspecialties for patient information site information ranging from 56% to 100%: cataract or refractive (92%), cornea (56%), glaucoma (72%), neuro-ophthalmology (67%), oculoplastic or orbital surgery (80%), ocular oncology (100%), pediatrics (89%), vitreoretinal diseases (86%), and uveitis (65%). For draft responses to patient questions via EMR, the LLM provided an overall average of 74% appropriate responses and varied by subspecialty: cataract or refractive (85%), cornea (54%), glaucoma (77%), neuro-ophthalmology (63%), oculoplastic or orbital surgery (62%), ocular oncology (90%), pediatrics (94%), vitreoretinal diseases (88%), and uveitis (55%). Stratifying grades across health information categories (disease and condition, risk and prevention, surgery-related, and treatment and management) showed notable but insignificant variations, with disease and condition often rated highest (72% and 69%) for appropriateness and surgery-related (55% and 51%) lowest, in both contexts. Conclusion: This LLM reported mostly appropriate responses across multiple ophthalmology subspecialties in the context of both patient information sites and EMR-related responses to patient questions. Current LLM offerings require optimization and improvement before widespread clinical use.

Baseline Participant Characteristics at Enrollment in the Zoster Eye Disease Study.

PURPOSE: The Zoster Eye Disease Study (ZEDS) is the first randomized clinical trial to study the efficacy of long-term (1 year) suppressive valacyclovir treatment on herpes zoster ophthalmicus (HZO) outcomes. This article details the baseline characteristics of participants. SETTING: The study was set at 95 participating clinical centers in 33 states, Canada, and New Zealand. STUDY POPULATION: Immunocompetent adults with a history of a characteristic HZO unilateral rash and documentation of an episode of active dendriform epithelial keratitis, stromal keratitis, endothelial keratitis, or iritis within the preceding year, enrolled in ZEDS from November 2017 to January 2023. INTERVENTION: Participants were randomized to double-masked oral valacyclovir 1 gm daily versus placebo for 1 year of treatment and followed for 18 months. RESULTS: Five hundred twenty-seven participants were enrolled across 4 strata according to age at HZO onset (younger or older than 60 years) and duration of HZO at enrollment (less or greater than 6 months), with an even distribution of men and women and a median age of 60 years. More participants with recent (57%, 300/527) than chronic HZO and younger than 60 years at HZO onset (54%, 286/527) were enrolled. Most participants were treated acutely with a recommended antiviral regimen (91%, 480/527) and had not been vaccinated against zoster (79%, 418/527). CONCLUSIONS: The broad ZEDS study population enhances the likelihood that ZEDS will provide generalizable high-quality evidence regarding the efficacy and safety of suppressive valacyclovir for HZO immunocompetent adults and whether it should become standard of care. TRIAL REGISTRATION: ClinicalTrials.gov Identifier: NCT03134196.

Suture Fixation to Reduce Graft Detachment in Descemet Stripping Endothelial Keratoplasty.

PURPOSE: The aim of this study was to report the outcomes of graft fixation using interrupted, full-thickness sutures on graft detachment after Descemet stripping endothelial keratoplasty (DSEK). METHODS: All DSEK procedures performed at Mayo Clinic, Rochester, MN, from 2015 through 2022 were retrospectively reviewed. Risk factors for graft detachment were defined as previous incisional glaucoma surgery, previous penetrating keratoplasty, or absence of the normal lens-capsule barrier. Cases were categorized into sutured, high-risk grafts; unsutured, high-risk grafts; and unsutured, low-risk grafts. The primary outcome was graft detachment, and secondary outcomes were early graft failure and graft clarity at 12 months after surgery. RESULTS: Demographics between the high-risk groups were similar for sex and age at the time of surgery. Graft detachment occurred in 4 of 97 sutured, high-risk eyes (4.1%) and 24 of 119 unsutured high-risk eyes (20.2%) ( P = 0.002). In comparison, graft detachment occurred in 18 of 181 unsutured low-risk eyes (9.9%). The incidence of early graft failure was 2.1%, 5.0%, and 3.3% and late graft failure by 12 months was 9.8%, 12.8%, and 4.2%, respectively. CONCLUSIONS: In eyes with high-risk factors for graft detachment, suture fixation of the graft in DSEK decreased graft detachment to a rate at least as low as that in low-risk eyes.

Graft Survival, Graft Rejection, and Glaucoma in a Consecutive Series of Descemet Stripping Endothelial Keratoplasty.

PURPOSE: The goal of this study was to compare outcomes of Descemet stripping endothelial keratoplasty (DSEK) in eyes with glaucoma and abnormal anatomy to eyes with Fuchs endothelial corneal dystrophy (FECD). METHODS: In a retrospective interventional series of all cases of DSEK between April 1, 2006, and November 30, 2015, recipient diagnosis, preoperative glaucoma status, concurrent surgical procedures, and graft outcomes were recorded. Graft survival, risk of rejection, and subsequent glaucoma surgery were estimated by using Kaplan-Meier analysis with risk factors determined by proportional hazard models. RESULTS: Of 703 DSEKs in 666 eyes (509 subjects), the main recipient diagnoses were FECD (n = 496), pseudophakic corneal edema (n = 112), and failed graft (n = 83). Glaucoma was present in 150 cases before DSEK. Overall graft survival was 85%, 75%, and 71% at 5, 10, and 12 years, respectively, and for FECD without glaucoma was 95%, 89%, and 87% at 5, 10, and 12 years, respectively. Independent risk factors for graft failure included recipient diagnoses of pseudophakic corneal edema (HR = 8.3, P < 0.001), failed graft (HR = 6.4, P < 0.001), and preoperative medical glaucoma (HR = 7.1, P < 0.001) or surgical glaucoma (HR = 12.3, P < 0.001). Preoperative glaucoma treated by previous surgery resulted in graft survival of 28% at 10 years. Preoperative glaucoma was associated with an increased risk of graft rejection (HR = 6.8, P < 0.001) and subsequent glaucoma surgery (HR > 17.4, P < 0.001). CONCLUSIONS: Preoperative glaucoma increases the risk of graft failure, graft rejection, and needing subsequent glaucoma surgery in the first decade after DSEK. With previous glaucoma surgery, DSEK graft survival was more favorable compared with published reports of Descemet membrane endothelial keratoplasty.

Predicting Corneal Improvement after Descemet Membrane Endothelial Keratoplasty for Fuchs Endothelial Corneal Dystrophy.

Purpose: To develop a model to predict corneal improvement after Descemet membrane endothelial keratoplasty (DMEK) for Fuchs endothelial corneal dystrophy (FECD) from Scheimpflug tomography. Design: Cross-sectional study. Participants: Forty-eight eyes (derivation group) and 45 eyes (validation group) with a range of severity of FECD undergoing DMEK. Methods: Scheimpflug images were obtained before and after DMEK. Before DMEK, pachymetry map and posterior elevation map patterns were quantified by a special image analysis program measuring tomographic features of edema (loss of regular isopachs, displacement of the thinnest point of the cornea, posterior surface depression). Image-derived novel parameters were combined with instrument-derived parameters, and the relative influences of parameters associated with the change in central corneal thickness (CCT) after DMEK in the derivation group were determined by using a gradient boosting machine learning model. The parameters with highest relative influence were then fit in a linear regression model. The derived model was applied to the validation group. Correlations and agreement were assessed between predicted and observed changes in CCT. Main Outcome Measures: Predictive power (R 2) and mean difference between predicted and observed change in CCT. Results: The gradient boosting machine model identified 4 novel parameters of isopach circularity and eccentricity and 1 instrument-derived parameter (posterior surface radius); preoperative CCT was a poor predictor. In the derivation group, the model strongly predicted the change in CCT after DMEK (R 2 = 0.80; 95% confidence interval [CI], 0.71-0.89) and the mean difference between predicted and observed change was, by definition, 0 µm. When the same 5 parameters were fit to the validation group, the model performed very highly (R 2 = 0.89; 95% CI, 0.84-0.94). When the coefficient estimates from the derivation model were used to predict the change in CCT in the validation group, the predictive power was also high (R 2 = 0.78; 95% CI, 0.68-0.88), and the mean difference was 4 µm (predicted minus observed). Conclusions: Scheimpflug tomography maps of corneas with FECD can predict the improvement in CCT after DMEK, independent of preoperative corneal thickness measurement. The model could be applied in clinical practice or for clinical research of FECD.

Oleander-Associated Keratitis and Uveitis.

PURPOSE: Oleander is a poisonous plant with extensively documented systemic side effects; however, oleander's ophthalmic side effects have not been detailed in the literature. We report a case of oleander-associated keratitis with subsequent corneal edema and anterior uveitis. METHODS: This is a case report and review of relevant literature. RESULTS: A 58-year-old woman presented with large corneal epithelial defect after being struck in the eye with an oleander leaf. Despite treatment with topical moxifloxacin, she developed severe corneal edema and anterior uveitis. A diagnosis of oleander-associated ocular inflammation with secondary corneal edema was made, given the temporal relationship, and treatment was initiated with topical prednisolone and cyclopentolate. However, the corneal edema and inflammation continued to progress until oral prednisone and topical difluprednate were initiated. Visual acuity, anterior uveitis, and corneal edema significantly improved with aggressive immunomodulation. Follow-up at 1 month confirmed complete recovery of symptoms, corneal edema and anterior uveitis. CONCLUSIONS: Severe corneal edema and anterior uveitis can be associated with oleander exposure. Aggressive treatment with oral and topical steroids may be required without persistent sequelae at the 5-month follow-up. Ophthalmologists should consider this inflammatory reaction if patients experience ocular exposure to oleander.

Cancer Risk in Patients With Fuchs Endothelial Corneal Dystrophy.

PURPOSE: The purpose of this study is to quantify cancer risk in patients with Fuchs endothelial corneal dystrophy (FECD). METHODS: Using the 2014 to 2016 Medicare Limited 5% Data Sets-Carrier Line File, US Medicare fee-for-service beneficiaries (aged 65 years or older) with FECD and cancer were identified through International Classification of Diseases , ninth and 10th Revision diagnostic codes from January 1, 2014, to December 31, 2016. The main outcome measures were odds ratios (ORs) of cancer at various anatomic locations in patients with versus without FECD. RESULTS: Of the 1,462,740 Medicare beneficiaries, 15,534 patients (1.1%) had an International Classification of Disease code for FECD. Compared with US Medicare beneficiaries without FECD, patients with FECD were at increased risk for the following malignancies: breast [OR: 1.32; 95% confidence interval (CI): 1.22-1.43; P < 0.001], cutaneous basal cell (OR: 1.42; 95% CI: 1.35-1.49; P < 0.001), cutaneous melanoma (OR: 1.20; 95% CI: 1.03-1.40; P = 0.02), cutaneous squamous cell (OR: 1.45; 95% CI: 1.38-1.53; P < 0.001), ovarian (OR: 1.84; 95% CI: 1.48-2.30; P < 0.001), and thyroid (OR: 1.32; 95% CI: 1.04-1.68; P = 0.02). By contrast, FECD cases were at lower odds of having lung (OR: 0.81; 95% CI: 0.71-0.93; P = 0.003) and prostate cancer diagnoses (OR: 0.88; 95% CI: 0.81-0.96; P = 0.002). CONCLUSIONS: Patients with FECD aged 65 years or older may be at increased risk for cancer at several anatomic locations. Follow-up studies are needed to further explore the association of FECD and malignancy, elucidate potential disease mechanisms, and identify genetic and/or environmental risk factors.

Intraocular plasmacytoma: A case of iris involvement and a review of the literature.

Purpose: Describe a case of intraocular plasmacytoma in a patient with multiple myeloma successfully treated with photon irradiation. Observations: A 61-year-old man with a history of relapsing/refractory multiple myeloma and left frontal bone plasmacytoma treated with monthly belantamab mafodotin salvage chemotherapy developed bilateral treatment-related corneal keratopathy. An iris mass was incidentally noted in the right eye during a follow-up examination. The mass was amelanotic with diffuse intrinsic vasculature involving the pupillary margin from 1:30 to 10:30. Fundus examination showed an irregularly shaped amelanotic superotemporal scleral lesion in the right eye and two smaller amelanotic scleral lesions in the left eye. Given known systemic multiple myeloma and history of left frontal bone plasmacytoma, a presumed diagnosis of iris and scleral plasmacytoma was made. Due to rapid progression of the iris plasmacytoma despite systemic chemotherapy, the patient was treated with 20 Gy photon irradiation to the anterior and posterior segments of both eyes. One month after photon irradiation, there was complete regression of the iris plasmacytoma, and the scleral lesions in both eyes also appeared to be regressing despite systemic progression of multiple myeloma. Conclusions and importance: Intraocular plasmacytoma is rare and can occur in isolation but typically occurs as a manifestation of systemic multiple myeloma. Intraocular plasmacytoma can be successfully treated with photon irradiation in patients with multiple myeloma who progress on systemic chemotherapy.

Visual Function in Pseudophakic Eyes with Fuchs' Endothelial Corneal Dystrophy.

PURPOSE: To assess vision in pseudophakic eyes with Fuchs' endothelial corneal dystrophy (FECD) before the onset of clinically detectable corneal edema. DESIGN: Cross-sectional study. METHODS: Sixty-one otherwise healthy pseudophakic eyes of 38 subjects with FECD (without clinically detectable edema) and 17 otherwise healthy pseudophakic eyes of 9 subjects with normal corneas. Subjects underwent clinical examination to determine the morphologic distribution of guttae (severity grading). Standardized best-corrected high-contract and low-contrast (photopic and mesopic) visual acuity (HCVA, LCVA) and straylight were measured. Scheimpflug tomography posterior elevation and pachymetry maps were interpreted for 3 tomographic features of subclinical edema: loss of regular isopachs, displacement of the thinnest point of the cornea, and presence of posterior surface depression. RESULTS: In FECD without tomographic features of edema (ie, normal tomography patterns), HCVA, LCVA, and straylight did not differ from that of eyes with normal corneas (P ≥ .09); these eyes encompassed the full range of severity grading of guttae. In FECD with all 3 tomographic features of edema, the same parameters were worse compared with eyes with normal corneas (P ≤ .02). In FECD with 1 or 2 tomographic abnormalities, mesopic LCVA (P = .04) and straylight (P = .003) were worse compared with eyes with normal corneas. CONCLUSIONS: Impairment of vision was associated with the presence of tomographic edema in eyes with FECD. When tomography patterns were normal in FECD (ie, guttae were present without tomographic edema), visual acuity and straylight were normal, and therefore corneal surgical intervention would not typically be indicated to improve vision.

Honeycomb Epithelial Edema Associated With Rho Kinase Inhibition: A Case Series and Review of the Literature.

ABSTRACT: The Rho kinase inhibitor netarsudil is a recently approved therapeutic option for the management of increased intraocular pressure in the United States. Although phase 3 clinical trials noted corneal changes related to the medication-namely, nonvisually-significant corneal verticillata-descriptions of a unique form of cystic epithelial edema began to surface as netarsudil (and its sister drug ripasudil, approved in Japan) gained widespread use. This series adds 3 new cases and reviews the current literature on this unique side effect.

Comparison of TCF4 repeat expansion length in corneal endothelium and leukocytes of patients with Fuchs endothelial corneal dystrophy.

Expansion of CTG trinucleotide repeats (TNR) in the transcription factor 4 (TCF4) gene is highly associated with Fuchs Endothelial Corneal Dystrophy (FECD). Due to limitations in the availability of DNA from diseased corneal endothelium, sizing of CTG repeats in FECD patients has typically been determined using DNA samples isolated from peripheral blood leukocytes. However, it is non-feasible to extract enough DNA from surgically isolated FECD corneal endothelial tissue to determine repeat length based on current technology. To circumvent this issue, total RNA was isolated from FECD corneal endothelium and sequenced using long-read sequencing. Southern blotting of DNA samples isolated from primary cultures of corneal endothelium from these same affected individuals was also assessed. Both long read sequencing and Southern blot analysis showed significantly longer CTG TNR expansion (>1000 repeats) in the corneal endothelium from FECD patients than those characterized in leukocytes from the same individuals (<90 repeats). Our findings suggest that the TCF4 CTG repeat expansions in the FECD corneal endothelium are much longer than those found in leukocytes.

Characterization of a dual media system for culturing primary normal and Fuchs endothelial corneal dystrophy (FECD) endothelial cells.

Primary cultures of human corneal endothelial cells (HCECs) are an important model system for studying the pathophysiology of corneal endothelium. The purpose of this study was to identify and validate an optimal primary culture model of normal and Fuchs endothelial corneal dystrophy (FECD) endothelial cells by comparing cell morphology and marker expression under different media conditions to in vivo donor tissues. Primary and immortalized HCECs, isolated from normal and FECD donors, were cultured in proliferation media (Joyce, M4, Bartakova) alone or sequentially with maturation media (F99, Stabilization 1, M5). CD56, CD73 and CD166 expressions were quantified in confluent and matured cell lines by flow cytometry. HCECs that were allowed to proliferate in Joyce's medium followed by maturation in low-mitogen containing media yielded cells with similar morphology to corneal endothelial tissues. Elevated expression of CD56 and CD166 and low expression of CD73 correlated with regular, hexagonal-like HCEC morphology. CD56:CD73 > 2.5 was most consistent with normal HCEC morphology and mimicked corneal endothelial tissue. Immortalization of normal HCECs by hTERT transduction showed morphology and CD56:CD73 ratios similar to parental cell lines. HCECs established from FECD donors showed reduced CD56:CD73 ratios compared to normal HCECs which coincided with reduced uniformity and regularity of cell monolayers. Overall, a dual media system with Joyce's medium for proliferation and a low-mitogen media for maturation, provided normal cultures with regular, hexagonal-like cell morphologies consistent with corneal endothelial cells in vivo. CD56:CD73 expression ratio >2.5 was predictive of in vivo-like cellular morphology.

Relationship of Body Mass Index With Fuchs Endothelial Corneal Dystrophy Severity and TCF4 CTG18.1 Trinucleotide Repeat Expansion.

PURPOSE: To investigate the association of body mass index (BMI) with Fuchs endothelial corneal dystrophy (FECD) severity and TCF4 CTG18.1 expansion. METHODS: A total of 343 patients with FECD were enrolled from the Mayo Clinic. FECD severity was graded by slit-lamp biomicroscopy. BMI values were obtained from the electronic medical records. DNA extracted from leukocytes was analyzed for CTG18.1 expansion length, with ≥40 repeats considered expanded. Wilcoxon signed-rank tests were used to compare FECD grade and CTG18.1 expansion length in patients by BMI (<25, ≥25 to <30, and ≥30 kg/m2). FECD grade was regressed on age, sex, BMI, and CTG18.1 expansion and, separately, BMI on CTG18.1 expansion. Models were investigated for effect modification by age and sex with an interaction term of P < 0.05 considered statistically significant. RESULTS: When examining the association between BMI and FECD, there was a significant interaction between BMI and sex (P for interaction = 0.004). When controlling for age and CTG18.1 expansion, a positive association was observed between BMI and FECD grade in women, but not in men. In addition, BMI was not associated with CTG18.1 expansion when controlling for age and sex. CONCLUSIONS: BMI was positively associated with FECD severity among women but not men. There was no significant association between BMI and CTG18.1 expansion. These findings suggest that increased BMI is potentially a modifiable risk factor for FECD disease progression among women.

Disease Expression and Familial Transmission of Fuchs Endothelial Corneal Dystrophy With and Without CTG18.1 Expansion.

Purpose: To characterize inheritance, penetrance, and trinucleotide repeat expansion stability in Fuchs endothelial corneal dystrophy (FECD). Methods: One thousand unrelated and related subjects with and without FECD were prospectively recruited. CTG18.1 repeat length (CTG18.1L) was determined via short tandem repeat assay and Southern blotting of leukocyte DNA. Multivariable logistic regression and generalized estimating equation models were employed. Results: There were 546 unrelated FECD cases (67.6% female; 70 ± 10 years) and 235 controls (63.8% female; 73 ± 8 years; all ≥ 50 years). CTG18.1 expansion (CTG18.1exp+) was observed in 424 (77.7%) cases and 18 (7.7%) controls (P = 2.48 × 10-44). CTG18.1 expansion was associated with FECD severity (P = 5.62 × 10-7). The family arm of the study included 331 members from 112 FECD-affected families; 87 families were CTG18.1exp+. Autosomal dominant inheritance with variable expression of FECD was observed, regardless of expansion status. FECD penetrance of CTG18.1 expansion increased with age, ranging from 44.4% in the youngest (19-46 years) to 86.2% in the oldest (64-91 years) age quartiles. Among 62 parent-offspring transmissions of CTG18.1exp+, 48 (77.4%) had a change in CTG18.1L ≤ 10 repeats, and eight (12.9%) were ≥50 repeats, including five large expansions (∼1000-2000 repeats) that contracted. Among 44 offspring who did not inherit the CTG18.1exp+ allele, eight (18.2%) exhibited FECD. Conclusions: CTG18.1 expansion was highly associated with FECD but demonstrated incomplete penetrance. CTG18.1L instability occurred in a minority of parent-offspring transmissions, with large expansions exhibiting contraction. The observation of FECD without CTG18.1 expansion among family members in CTG18.1exp+ families highlights the complexity of the relationship between the FECD phenotype and CTG18.1 expansion.

A Population-Based Study of Anterior Ischemic Optic Neuropathy Following Cataract Surgery.

PURPOSE: To determine if there is an increased incidence rate of post-cataract surgery (pcs) anterior ischemic optic neuropathy (AION) compared to spontaneous AION (sAION). DESIGN: Retrospective, population-based cohort. METHODS: Patients diagnosed with AION from January 1, 1990, through December 31, 2016, while residing in Olmsted County, Minnesota. Patients with cataract surgery preceding AION were included in the pcsAION cohort defined in 2 ways: AION within 2 months and AION within 1 year of cataract surgery. The incidence rates of pcsAION and sAION were compared using Poisson regression models. RESULTS: During the study period, 102 residents developed AION. The median age was 65 years (range, 40-90 years), 44 (43.1%) were female. Twenty of 102 (19.6%) patients had previous cataract surgery, of which 2 and 9 developed AION within 2 months and 1 year of surgery, respectively. The annual incidence rate of pcsAION within 2 months of surgery (8.6 per 100,000) was not significantly greater than the annual incidence rate of sAION (6.9 per 100,000; P = .78). However, the annual incidence rate of pcsAION within 1 year of surgery (38.9 per 100,000) was significantly higher than the incidence rate of sAION (6.5 per 100,000; P < .001). CONCLUSION: The incidence of AION is increased in the first year after cataract surgery, but not in the early (i.e., 2 months) postoperative period.

TCF4-mediated Fuchs endothelial corneal dystrophy: Insights into a common trinucleotide repeat-associated disease.

Fuchs endothelial corneal dystrophy (FECD) is a common cause for heritable visual loss in the elderly. Since the first description of an association between FECD and common polymorphisms situated within the transcription factor 4 (TCF4) gene, genetic and molecular studies have implicated an intronic CTG trinucleotide repeat (CTG18.1) expansion as a causal variant in the majority of FECD patients. To date, several non-mutually exclusive mechanisms have been proposed that drive and/or exacerbate the onset of disease. These mechanisms include (i) TCF4 dysregulation; (ii) toxic gain-of-function from TCF4 repeat-containing RNA; (iii) toxic gain-of-function from repeat-associated non-AUG dependent (RAN) translation; and (iv) somatic instability of CTG18.1. However, the relative contribution of these proposed mechanisms in disease pathogenesis is currently unknown. In this review, we summarise research implicating the repeat expansion in disease pathogenesis, define the phenotype-genotype correlations between FECD and CTG18.1 expansion, and provide an update on research tools that are available to study FECD as a trinucleotide repeat expansion disease. Furthermore, ongoing international research efforts to develop novel CTG18.1 expansion-mediated FECD therapeutics are highlighted and we provide a forward-thinking perspective on key unanswered questions that remain in the field.