Predicting the Prognosis of Fuchs Endothelial Corneal Dystrophy by Using Scheimpflug Tomography.

PURPOSE: To determine if Scheimpflug tomography pachymetry map and posterior elevation map patterns, central corneal thickness (CCT), and corneal backscatter can predict the prognosis of Fuchs endothelial corneal dystrophy (FECD). DESIGN: Cross-sectional study with follow-up of outcomes. PARTICIPANTS: Ninety-six eyes (56 subjects) with a range of severity of FECD. METHODS: Corneas were graded by cornea specialists according to the area and confluence of guttae and the presence of clinically definite edema. Masked and randomized Scheimpflug imaging pachymetry map and posterior elevation map patterns were assessed by 1 observer for loss of regular isopachs, displacement of the thinnest point of the cornea, and the presence of posterior surface depression. The prognosis of eyes over a 5-year (median) follow-up period was determined based on FECD progression (new onset of clinically definite edema or ≥5% increase in CCT) or intervention by endothelial keratoplasty. Cumulative probabilities of progression and intervention were estimated from survival analyses, with risk factors determined by using Cox proportional hazards models. MAIN OUTCOME MEASURES: Pachymetry map and posterior elevation map patterns, corneal backscatter, and CCT (ultrasonic pachymetry). RESULTS: In univariate analyses, loss of regular isopachs (hazard ratio [HR], 18.00) displacement of the thinnest point (HR, 11.53), focal posterior surface depression (HR, 10.21), and anterior corneal backscatter (HR, 1.22, per 1-grayscale unit increment), were risk factors for progression or intervention (P < 0.001), whereas CCT (HR, 1.30, per 25-µm increment) was not (P = 0.15). In multivariate analyses, loss of regular isopachs (HR, 11.57; P < 0.001) and displacement of the thinnest point (HR, 5.61; P = 0.02) were independent and clinically important risk factors for progression and intervention. The 5-year cumulative risk of disease progression and intervention was 7%, 48%, and 89% when none, 1 or 2, and all 3 pachymetry map and posterior elevation map parameters were present, respectively (P <0.001). The 4-year cumulative risk of disease progression and intervention after uncomplicated cataract surgery was 0%, 50%, and 75% when none, 1 or 2, and all 3 pachymetry map and posterior elevation map parameters were present, respectively (P < 0.001). CONCLUSIONS: Three Scheimpflug tomography pachymetry map and posterior elevation map patterns can predict FECD prognosis independent of CCT. The risk of FECD progression and intervention, including after uncomplicated cataract surgery, increases according to the number of parameters present.

Determining Subclinical Edema in Fuchs Endothelial Corneal Dystrophy: Revised Classification using Scheimpflug Tomography for Preoperative Assessment.

PURPOSE: To determine if Scheimpflug tomography can identify subclinical corneal edema in Fuchs endothelial corneal dystrophy (FECD), and to recommend a new classification of FECD for clinical practice and research. DESIGN: Cross-sectional study with follow-up of outcomes. PARTICIPANTS: Ninety-three eyes from 57 subjects with a range of severity of FECD and 74 eyes from 40 subjects with normal corneas. METHODS: Corneas were clinically assessed for FECD and corneal edema by using slit-lamp biomicroscopy, and categorized as having clinically definite edema (obvious visible edema), being suspicious for subclinical edema (possible corneal thickening without obvious edema on slit-lamp examination), or not having edema (no clinical suspicion of edema). Tomographic pachymetry and elevation maps derived from Scheimpflug images were evaluated by 3 masked observers for specific features believed to be consistent with corneal edema. FECD clinical disease course and outcomes were reviewed from the time of Scheimpflug image acquisition to the last available follow-up. MAIN OUTCOME MEASURES: Presence of tomographic features: (1) loss of parallel isopachs, (2) displacement of the thinnest point of the cornea, and (3) focal posterior corneal surface depression. Clinical outcomes included the change in central corneal thickness (CCT) and vision after endothelial keratoplasty (EK). RESULTS: The 3 specific tomographic features were all present in all FECD corneas with clinically definite edema (n = 15), in ≥81% of FECD corneas suspicious for subclinical edema (n = 16), in ≤42% of FECD corneas deemed not to have edema (n = 62), and in ≤5% of normal corneas (n = 74). Corneas suspicious for subclinical edema that subsequently underwent EK (n = 9) all had at least 2 of the tomographic features present before EK, and improvement in vision, CCT, and tomographic features after EK confirmed the presence of subclinical edema preoperatively. CONCLUSIONS: Subclinical corneal edema in FECD can be detected by Scheimpflug tomography. We recommend classifying FECD corneas as having clinically definite edema (based on slit-lamp examination), subclinical edema (based on tomographic features without clinically definite edema), or no edema (no tomographic or slit-lamp features of edema). This classification is independent of CCT and should be considered when evaluating FECD eyes for cataract surgery or EK.

Patient-Reported Visual Disability in Fuchs' Endothelial Corneal Dystrophy Measured by the Visual Function and Corneal Health Status Instrument.

PURPOSE: Measuring patient-reported visual disability in Fuchs' endothelial corneal dystrophy (FECD) may be helpful in determining when to intervene and for understanding the outcomes of intervention. In this study, we aimed to validate a new patient-reported visual disability questionnaire, the Visual Function and Corneal Health Status (V-FUCHS) instrument, in FECD before and after endothelial keratoplasty (EK). DESIGN: Cross-sectional study with instrument readministration at 6 weeks. PARTICIPANTS: Patients with a range of severity of FECD, including after EK, and patients with healthy corneas. METHODS: The V-FUCHS instrument was developed based on patient interviews, expert consultations, and pretesting. Psychometric methods of classic test theory were applied to estimate reliability and validity, including testing V-FUCHS against Catquest-9SF, a cataract-specific visual disability questionnaire. Ordered polytomous Rasch-based partial credit models and item response theory diagnostics were used to define the response patterns. MAIN OUTCOME MEASURES: Reliability (primary) and validity (secondary). RESULTS: The final instrument was completed by 65% of patients with a range of severity of FECD (n = 41), after undergoing EK for FECD (n = 70), and with healthy corneas (n = 28). Participants were phakic or pseudophakic. Exploratory factor analysis among FECD and patients who underwent EK showed 2 independent factors of visual disability: 7 items related to visual acuity and 8 items related to glare or diurnal variation. Retest reliability was substantial (intraclass correlation coefficient, ≥0.8, both factors). Among all patients, the visual acuity factor was correlated with Catquest-9SF scores (r = 0.65; P < 0.001; n = 96). The glare or diurnal variation factor increased with FECD severity (P < 0.001, n = 69) and was higher in FECD than healthy participants (P < 0.001). Diagnostics revealed that both factors were well calibrated and met Rasch model expectations. CONCLUSIONS: The V-FUCHS instrument is valid and reliable for assessing visual disability in FECD. The instrument allows for standardized, comprehensive, and rapid assessment of disease-specific visual disability and may be useful in clinical practice and research as a patient-reported outcome measure.

Medical and Semi-surgical Treatments for Fuchs Endothelial Corneal Dystrophy.

Unraveling the genetic mechanisms of Fuchs endothelial corneal dystrophy has opened new possibilities for future targeted medical therapy of the disease. Until these possibilities mature, regenerative semi-surgical approaches by cell injection or cell sheet transfer could help expand the donor pool, and possibly enable autologous transplantation. Descemet membrane stripping alone and acellular Descemet membrane transfer are more immediate surgical approaches that could be temporary treatments in some patients, though there is a lack of understanding of the factors that predict success for these procedures. Regardless of approach, clinical trials will be necessary, and clinicians should therefore try to standardize their methods of assessing disease severity and the outcomes of intervention.

RNA toxicity and missplicing in the common eye disease fuchs endothelial corneal dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is an inherited degenerative disease that affects the internal endothelial cell monolayer of the cornea and can result in corneal edema and vision loss in severe cases. FECD affects ∼5% of middle-aged Caucasians in the United States and accounts for >14,000 corneal transplantations annually. Among the several genes and loci associated with FECD, the strongest association is with an intronic (CTG·CAG)n trinucleotide repeat expansion in the TCF4 gene, which is found in the majority of affected patients. Corneal endothelial cells from FECD patients harbor a poly(CUG)n RNA that can be visualized as RNA foci containing this condensed RNA and associated proteins. Similar to myotonic dystrophy type 1, the poly(CUG)n RNA co-localizes with and sequesters the mRNA-splicing factor MBNL1, leading to missplicing of essential MBNL1-regulated mRNAs. Such foci and missplicing are not observed in similar cells from FECD patients who lack the repeat expansion. RNA-Seq splicing data from the corneal endothelia of FECD patients and controls reveal hundreds of differential alternative splicing events. These include events previously characterized in the context of myotonic dystrophy type 1 and epithelial-to-mesenchymal transition, as well as splicing changes in genes related to proposed mechanisms of FECD pathogenesis. We report the first instance of RNA toxicity and missplicing in a common non-neurological/neuromuscular disease associated with a repeat expansion. The FECD patient population with this (CTG·CAG)n trinucleotide repeat expansion exceeds that of the combined number of patients in all other microsatellite expansion disorders.

Descemet Stripping Endothelial Keratoplasty for Fuchs' Endothelial Corneal Dystrophy: Five-Year Results of a Prospective Study.

PURPOSE: To determine 5-year outcomes of Descemet stripping endothelial keratoplasty (DSEK) for Fuchs' endothelial corneal dystrophy (FECD). DESIGN: Prospective cohort study. PARTICIPANTS: Fifty-two eyes of 45 subjects with FECD undergoing primary DSEK. METHODS: Subjects were examined before and at fixed intervals through 60 months after DSEK. At each visit, graft survival was determined by slit-lamp examination; best spectacle-corrected visual acuity (BSCVA) was measured using the electronic Early Treatment Diabetic Retinopathy Study (ETDRS) protocol; total anterior corneal higher-order aberrations (HOAs) were derived from corneal topography; and corneal backscatter, corneal thickness, and endothelial cell density were measured from confocal microscopy images. Corneal thickness also was measured by ultrasonic pachymetry. Changes after DSEK were analyzed using generalized estimating equation models. MAIN OUTCOME MEASURES: Best-corrected visual acuity, HOAs, endothelial cell loss, corneal thickness, and corneal backscatter. RESULTS: Complete 60-month follow-up was possible in 34 eyes. Mean BSCVA±standard deviation improved from 0.45±0.19 logarithm of the minimum angle of resolution (logMAR) (Snellen equivalent, 20/56) before DSEK to 0.09±0.13 logMAR (Snellen equivalent, 20/25) at 5 years (P < 0.001). Between 1 and 5 years, BSCVA improved by 0.06 logMAR (or 3 ETDRS letters; 95% confidence interval, 0.05-0.07 logMAR) per year (P < 0.001), and 56% of eyes were 0.1 logMAR (20/25) or better at 5 years. Graft thickness (approximately 155 µm) and corneal thickness (approximately 700 µm) did not change after surgery. Anterior corneal HOAs and backscatter decreased between 1 and 5 years (P ≤ 0.002). Six grafts failed, of which 4 were primary (iatrogenic); mean endothelial cell loss±standard deviation was 55±15% at 5 years. CONCLUSIONS: Between 1 and 5 years after DSEK, BSCVA continues to improve such that at 5 years, more than half of eyes see better than 20/25 with a mean total corneal thickness of 700 µm. Improvement in vision is accompanied by continued reduction in corneal haze and aberrations, suggesting ongoing remodeling of the cornea after restoration of endothelial function.

MANAGEMENT OF MYCOBACTERIUM CHELONAE ENDOPHTHALMITIS WITH COMPLETE SURGICAL DEBRIDEMENT.

PURPOSE: To report the clinical course and histopathologic findings of two consecutive patients with resolution of Mycobacterium chelonae endophthalmitis and favorable visual outcomes after complete removal of intraocular implants and lens capsular complexes and prolonged sensitivity-guided combination antibiotic therapy. METHODS: Medical records and histopathologic findings were reviewed for two consecutive patients with M. chelonae endophthalmitis. RESULTS: Two consecutive patients with M. chelonae endophthalmitis had prolonged clinical courses with refractory endophthalmitis before complete removal of intraocular implants and lens capsular complexes. One patient had histopathologic evidence of lens remnant-associated acid-fast bacilli. CONCLUSION: Surgical explantation of intraocular implants and lens capsular complexes appears to play an important role in the management of M. chelonae endophthalmitis, which may be closely associated with crystalline lens remnants.

Corneal High-Order Aberrations and Backscatter in Fuchs' Endothelial Corneal Dystrophy.

PURPOSE: Suboptimal visual acuity after endothelial keratoplasty has been attributed to increased anterior corneal high-order aberrations (HOAs). In this study, we determined anterior and posterior corneal HOAs over a range of severity of Fuchs' endothelial corneal dystrophy (FECD). DESIGN: Cross-sectional study. PARTICIPANTS: A total of 108 eyes (62 subjects) with a range of severity of FECD and 71 normal eyes (38 subjects). METHODS: All corneas were examined by using slit-lamp biomicroscopy to determine the severity of FECD versus normality. Fuchs' endothelial corneal dystrophy corneas were categorized as mild, moderate, or advanced according to the area and confluence of guttae and the presence of clinically visible edema. Normal corneas were devoid of any guttae. Wavefront errors from the anterior and posterior corneal surfaces were derived from Scheimpflug images and expressed as Zernike polynomials through the sixth order over a 6-mm diameter optical zone. Backscatter from the anterior 120 µm and posterior 60 µm of the cornea also was measured from Scheimpflug images and was standardized to a fixed scatter source. Variables were compared between FECD and control eyes by using generalized estimating equation models to adjust for age and correlation between fellow eyes. MAIN OUTCOME MEASURES: High-order aberrations, expressed as root mean square of wavefront errors, and backscatter of the anterior and posterior cornea. RESULTS: Total anterior corneal HOAs were increased in moderate (0.61±0.27 µm, mean ± standard deviation; P = 0.01) and advanced (0.66±0.28 µm; P = 0.01) FECD compared with controls (0.47±0.16 µm). Total posterior corneal HOAs were increased in mild (0.22±0.09 µm; P = 0.017), moderate (0.22±0.08 µm; P < 0.001), and advanced (0.23±0.09 µm; P < 0.001) FECD compared with controls (0.16±0.03 µm). Anterior and posterior corneal backscatter were higher for all severities of FECD compared with controls (P ≤ 0.02, anterior; P ≤ 0.001, posterior). CONCLUSIONS: Anterior and posterior corneal HOAs and backscatter are higher than normal even in early stages of FECD. The early onset of HOAs in FECD might contribute to the persistence of HOAs and incomplete visual rehabilitation after endothelial keratoplasty.

Corneal abnormalities early in the course of Fuchs' endothelial dystrophy.

PURPOSE: Corneas with advanced Fuchs' endothelial dystrophy that require endothelial keratoplasty manifest anterior corneal structural and cellular abnormalities that have been associated with visual deficits before and after endothelial keratoplasty. In this study, we determined the onset of these abnormalities in the course of the disease. DESIGN: Cross-sectional study. PARTICIPANTS: Sixty-three eyes (39 subjects) with a range of severity of Fuchs' dystrophy and 25 eyes (13 subjects) with normal corneas. METHODS: All corneas were examined using slit-lamp biomicroscopy, ultrasonic pachymetry, and confocal microscopy. The clinical grade of Fuchs' dystrophy was assessed according to the presence and extent of guttae and clinically evident edema and was categorized as mild (grades 1 and 2), moderate (grades 3 and 4), or advanced (grades 5 and 6). Normal corneas were devoid of any central guttae (grade 0). Corneal backscatter (haze) was measured from the confocal image light intensity profile. Stromal cell density and number and the presence of abnormal subepithelial cells were determined from confocal images. Comparisons between groups were made by using generalized estimating equation models. MAIN OUTCOME MEASURES: Anterior corneal backscatter, stromal cell density and number, presence of subepithelial cells, and central corneal thickness. RESULTS: Anterior corneal backscatter was 18% to 67% higher in eyes with moderate and advanced Fuchs' dystrophy compared with normal eyes (P ≤ 0.003); a similar trend was noted in mild Fuchs' dystrophy eyes compared with normal eyes (P = 0.08). Stromal cell density and the absolute number of stromal cells in the anterior 10% of the stroma were approximately 20% and 27% lower, respectively, in Fuchs' dystrophy (regardless of severity) compared with normal (P < 0.001). Abnormal subepithelial cells were visible in 9%, 19%, and 30% of corneas with mild, moderate, and advanced Fuchs' dystrophy, respectively. Only corneas with advanced Fuchs' dystrophy were thicker than normal (P < 0.001). CONCLUSIONS: Anterior corneal cellular and structural abnormalities begin early in the course of Fuchs' dystrophy, before the onset of clinically evident edema. The chronicity of these changes can explain their incomplete resolution after endothelial keratoplasty, and understanding the onset of these may help to determine the optimal time to intervene to achieve best outcomes.

Vision-related quality of life before and after keratoplasty for Fuchs' endothelial dystrophy.

PURPOSE: To assess vision-related quality of life in Fuchs' dystrophy and changes in vision-related quality of life after 3 types of keratoplasty (penetrating keratoplasty [PK], deep lamellar endothelial keratoplasty [DLEK], and Descemet stripping endothelial keratoplasty [DSEK]). DESIGN: Prospective, observational case series. PARTICIPANTS: Sixty-three subjects with Fuchs' endothelial dystrophy: 12 subjects (12 eyes) received PK, 11 subjects (11 eyes) received DLEK, and 40 subjects (40 eyes) received DSEK. METHODS: Subjects were examined before keratoplasty and at regular intervals through 3 years after keratoplasty. At each examination, vision-related quality of life was assessed using the 25-item National Eye Institute Visual Functioning Questionnaire; best spectacle-corrected and uncorrected visual acuities were measured by using the electronic Early Treatment of Diabetic Retinopathy Study protocol; keratometric cylinder was measured by a manual keratometer. Disability glare was measured with a straylight meter. MAIN OUTCOME MEASURES: Vision-related quality of life composite score. RESULTS: Vision-related quality of life composite score for all eyes with Fuchs' dystrophy before keratoplasty was 72 ± 11 (n = 63) and did not differ between groups (P = 0.88). Vision-related quality of life improved by 6 months (PK, P = 0.008; DLEK, P = 0.03; DSEK, P < 0.001), with continued improvement between 6 months and 3 years after PK (P = 0.01) and DSEK (P = 0.004). At 6 months, the composite score was higher after DSEK than after PK (P = 0.006). At 3 years, there were no differences in composite scores between the 3 treatments (P = 0.33; mean minimum detectable difference, 8 [α = 0.05; ß = 0.20]). After keratoplasty, quality of life was correlated with uncorrected visual acuity at 1 year (r = -0.38; P = 0.001) and at 3 years (r = -0.36; P = 0.02), with disability glare at 3 years (r = -0.41; P = 0.02), and with best-corrected visual acuity at 6 months (r = -0.34; P = 0.03), but not thereafter. CONCLUSIONS: Vision-related quality of life in patients with Fuchs' endothelial dystrophy is significantly impaired but improves after keratoplasty, irrespective of the technique. The improvement is faster after DSEK than after PK, and this might be explained in part by rapid improvement in uncorrected visual acuity after DSEK. This study affirms an advantage of endothelial keratoplasty over PK with respect to patient-reported outcomes.

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.

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.

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.

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.

E2-2 protein and Fuchs's corneal dystrophy.

BACKGROUND: Fuchs's corneal dystrophy (FCD) is a leading cause of corneal transplantation and affects 5% of persons in the United States who are over the age of 40 years. Clinically visible deposits called guttae develop under the corneal endothelium in patients with FCD. A loss of endothelial cells and deposition of an abnormal extracellular matrix are observed microscopically. In advanced disease, the cornea swells and becomes cloudy because the remaining endothelial cells are not sufficient to keep the cornea dehydrated and clear. Although rare genetic variation that contributes to both early-onset and typical late-onset forms of FCD has been identified, to our knowledge, no common variants have been reported. METHODS: We performed a genomewide association study and replicated the most significant observations in a second, independent group of subjects. RESULTS: Alleles in the transcription factor 4 gene (TCF4), encoding a member of the E-protein family (E2-2), were associated with typical FCD (P=2.3x10(-26)). The association increased the odds of having FCD by a factor of 30 for persons with two copies of the disease variants (homozygotes) and discriminated between case subjects and control subjects with about 76% accuracy. At least two regions of the TCF4 locus were associated independently with FCD. Alleles in the gene encoding protein tyrosine phosphatase receptor type G (PTPRG) were associated with FCD (P=4.0x10(-7)), but the association did not reach genomewide significance. CONCLUSIONS: Genetic variation in TCF4 contributes to the development of FCD. (Funded by the National Eye Institute and others.)

Fuchs' endothelial corneal dystrophy: subjective grading versus objective grading based on the central-to-peripheral thickness ratio.

PURPOSE: To assess interobserver agreement between 2 corneal specialists grading Fuchs' dystrophy clinically and to determine if the corneal central-to-peripheral thickness ratio (CPTR) may be an alternative and objective metric of disease severity. DESIGN: Cross-sectional study. PARTICIPANTS: Forty-five eyes (26 subjects) with mild and moderate Fuchs' dystrophy, 73 eyes (60 subjects) with advanced Fuchs' dystrophy, and 267 eyes (142 subjects) with normal corneas. METHODS: Corneas with Fuchs' dystrophy were graded by 2 corneal specialists based on the confluence and area of guttae and the presence or absence of edema. Central corneal thickness (CCT) and peripheral corneal thickness at 4 mm from the center (PCT4) were measured by using scanning-slit pachymetry. The value of CPTR4 was the quotient of CCT and PCT4. MAIN OUTCOME MEASURES: Interobserver agreement for clinical grade and CPTR4. RESULTS: Interobserver agreement for clinical grading of Fuchs' dystrophy was moderate (κ = 0.32; 95% confidence interval, 0.19-0.45). In normal corneas, CCT was not correlated with age (r = -0.10; P = 0.28; n = 267), PCT4 decreased with age (r = -0.33; P<0.001; n = 254), and CPTR4 increased with age (r = 0.59; P<0.001; n = 254). Central corneal thickness was higher in Fuchs' dystrophy (652 ± 61 µm; n = 118) than in normal corneas (559 ± 31 µm; n = 267; P<0.001). Also, PCT4 was higher in Fuchs' dystrophy (650 ± 51 µm; n = 107) than in normal corneas (643 ± 43 µm; n = 254; P<0.001 after adjusting thickness for age). Furthermore, CPTR4 was higher in advanced Fuchs' dystrophy (1.03 ± 0.07; n = 65) than in mild and moderate Fuchs' dystrophy (0.95 ± 0.07; n = 42; age-adjusted P<0.001), which in turn was higher than in normal corneas (0.87 ± 0.05; n = 254; age-adjusted P<0.001). Finally, CPTR4 was highly correlated with clinical grade of Fuchs' dystrophy (r = 0.77; P<0.001; n = 361), was repeatable (median coefficient of variation, 1.3%), and provided excellent discrimination between Fuchs' dystrophy and normal corneas (area under the receiver operator characteristic curve, 0.93). CONCLUSIONS: Agreement between corneal specialists for the subjective and morphologic clinical grading of Fuchs' dystrophy is only moderate. The corneal CPTR is an objective, repeatable, and possibly functional, metric of severity of Fuchs' dystrophy that warrants further investigation to determine its role in monitoring disease progression and predicting the need for keratoplasty.

Genetic variants near TIMP3 and high-density lipoprotein-associated loci influence susceptibility to age-related macular degeneration.

We executed a genome-wide association scan for age-related macular degeneration (AMD) in 2,157 cases and 1,150 controls. Our results validate AMD susceptibility loci near CFH (P < 10(-75)), ARMS2 (P < 10(-59)), C2/CFB (P < 10(-20)), C3 (P < 10(-9)), and CFI (P < 10(-6)). We compared our top findings with the Tufts/Massachusetts General Hospital genome-wide association study of advanced AMD (821 cases, 1,709 controls) and genotyped 30 promising markers in additional individuals (up to 7,749 cases and 4,625 controls). With these data, we identified a susceptibility locus near TIMP3 (overall P = 1.1 x 10(-11)), a metalloproteinase involved in degradation of the extracellular matrix and previously implicated in early-onset maculopathy. In addition, our data revealed strong association signals with alleles at two loci (LIPC, P = 1.3 x 10(-7); CETP, P = 7.4 x 10(-7)) that were previously associated with high-density lipoprotein cholesterol (HDL-c) levels in blood. Consistent with the hypothesis that HDL metabolism is associated with AMD pathogenesis, we also observed association with AMD of HDL-c-associated alleles near LPL (P = 3.0 x 10(-3)) and ABCA1 (P = 5.6 x 10(-4)). Multilocus analysis including all susceptibility loci showed that 329 of 331 individuals (99%) with the highest-risk genotypes were cases, and 85% of these had advanced AMD. Our studies extend the catalog of AMD associated loci, help identify individuals at high risk of disease, and provide clues about underlying cellular pathways that should eventually lead to new therapies.