Endothelial Corneal Dystrophy Research Articles

Transcription factor 4 promotes increased corneal endothelial cellular migration by altering microtubules in Fuchs endothelial corneal dystrophy

Fuchs endothelial corneal dystrophy (FECD) is a complex corneal disease characterized by the progressive decline and morphological changes of corneal endothelial cells (CECs) that leads to corneal edema and vision loss. The most common mutation in FECD is an intronic CTG repeat expansion in transcription factor 4 (TCF4) that leads to its altered expression. Corneal endothelial wound healing occurs primarily through cell enlargement and migration, and FECD CECs have been shown to display increased migration speeds. In this study, we aim to determine whether TCF4 can promote cellular migration in FECD CECs. We generated stable CEC lines derived from FECD patients that overexpressed different TCF4 isoforms and investigated epithelial-to-mesenchymal (EMT) expression, morphological analysis and cellular migration speeds. We found that full length TCF4-B isoform overexpression promotes cellular migration in FECD CECs in an EMT-independent manner. RNA-sequencing identified several pathways including the negative regulation of microtubules, with TUBB4A (tubulin beta 4A class IVa) as the top upregulated gene. TUBB4A expression was increased in FECD ex vivo specimens, and there was altered expression of cytoskeleton proteins, tubulin and actin, compared to normal healthy donor ex vivo specimens. Additionally, there was increased acetylation and detyrosination of microtubules in FECD supporting that microtubule stability is altered in FECD and could promote cellular migration. Future studies could be aimed at investigating if targeting the cytoskeleton and microtubules would have therapeutic potential for FECD by promoting cellular migration and regeneration.

Retinal Detachment Rates After Uncomplicated DMEK Versus Cataract Surgery Combined (Triple-)DMEK.

To evaluate the rate of and risk factors for rhegmatogenous retinal detachment (RRD) after Descemet membrane endothelial keratoplasty (DMEK) either alone or in combination with cataract surgery. Retrospective analysis of prospective database. Consecutive eyes with Fuchs endothelial corneal dystrophy (FECD) that received DMEK surgery with a minimum follow-up of 1 year between July 2011 and January 2021 at the Department of Ophthalmology at the University of Cologne were analyzed. Exclusion criteria were complicated history including repeat DMEK within 1-year, previous retinal or glaucoma surgery, complicated phacoemulsification, congenital cataract, history of trauma. From 3858 consecutive DMEKs, 1961 patients were identified suitable for analysis. 846 (43.1%) were pseudophakic DMEK, 91 (4.6%) phakic DMEK and 1,024 (52.2%) combined with cataract surgery. RRD occurred in 13 eyes (12 patients). Within two years after DMEK RRD occurred in 0.49% and 0.47% after DMEK and DMEK with cataract surgery, respectively. Mean age of 59.24 ± 8.42 years with subsequent RRD was significantly lower than overall 68.81 ± 9.89 years (t-test two-tailed; p < 0.001). The spherical equivalent was -4.69 ± 3.98 D (range -9.00 to 0.5) in RRD after pseudophakic DMEK compared to -2.79 ± 3.54 D (range -7.5 to 0.75) in combined procedures. Re-bubbling had no influence on RRD rate. DMEK alone or in combination with cataract surgery showed similar postoperative RRD rates in the first two years, generally in the range of pseudophakic RRDs. Risk factors such as myopia and younger age could be identified. Re-bubbling has no influence on RRD rates.

Characterization of a Novel Mouse Model for Fuchs Endothelial Corneal Dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is a progressive blinding disorder, characterized by increased corneal endothelial excrescences (guttae), corneal endothelial cell loss, and edema. These symptoms are hypothesized to be caused by changes in the extracellular matrix (ECM) and mitochondrial dysfunction in the corneal endothelium. Despite this clinical and biological relevance, a comprehensive animal model that recapitulates all the major disease characteristics is currently unavailable. In this study, we develop such a model to improve our understanding of the signaling pathways involved in the FECD progression and develop strategies for early intervention. To generate a comprehensive FECD model, we generated a double mutant mouse bearing tamoxifen-inducible knockdown of Slc4a11 and the Col8a2 (Q455K) mutation. We performed optical coherence tomography (OCT) and in vivo confocal microscopy using the Heidelberg Retinal Tomography 3 - Rostock Cornea module (HRT3-RCM) on the mice at 5 weeks of age before tamoxifen feeding to establish baseline values for corneal thickness, endothelial cell density, and test for the presence of guttae. We measured these parameters again post-tamoxifen treatment at 16 weeks of age. We collected corneas at 16 weeks to perform histopathology, immunofluorescence staining for tight junctions, adherens junctions, and oxidative stress. We evaluated endothelial pump function using a lactate assay. The double mutant tamoxifen-fed animals showed the presence of guttae, and displayed increased corneal thickness and decreased endothelial cell density. Endothelial cells showed altered morphology with disrupted adherens junctions and elevated reactive oxygen species (ROS). Finally, we found that stromal lactate concentrations were elevated in the double mutant mice, indicative of compromised endothelial pump function. Overall, this mouse model recapitulates all the important phenotypic features associated with FECD.

Expression and Impact of Fibronectin, Tenascin-C, Osteopontin, and Type XIV Collagen in Fuchs Endothelial Corneal Dystrophy.

Fuchs endothelial corneal dystrophy (FECD) is characterized by Descemet's membrane (DM) abnormalities, namely an increased thickness and a progressive appearance of guttae and fibrillar membranes. The goal of this study was to identify abnormal extracellular matrix (ECM) proteins expressed in FECD DMs and to evaluate their impact on cell adhesion and migration. Gene expression profiles from in vitro (GSE112039) and ex vivo (GSE74123) healthy and FECD corneal endothelial cells were analyzed to identify deregulated matrisome genes. Healthy and end-stage FECD DMs were fixed and analyzed for guttae size and height. Immunostaining of fibronectin, tenascin-C, osteopontin, and type XIV collagen was performed on ex vivo specimens, as well as on tissue-engineered corneal endothelium reconstructed using healthy and FECD cells. An analysis of ECM protein expression according to guttae and fibrillar membrane was performed using immunofluorescent staining and phase contrast microscopy. Finally, cell adhesion was evaluated on fibronectin, tenascin-C, and osteopontin, and cell migration was studied on fibronectin and tenascin-C. SPP1 (osteopontin), FN1 (fibronectin), and TNC (tenascin-C) genes were upregulated in FECD ex vivo cells, and SSP1 was upregulated in both in vitro and ex vivo FECD conditions. Osteopontin, fibronectin, tenascin-C, and type XIV collagen were expressed in FECD specimens, with differences in their location. Corneal endothelial cell adhesion was not significantly affected by fibronectin or tenascin-C but was decreased by osteopontin. The combination of fibronectin and tenascin-C significantly increased cell migration. This study highlights new abnormal ECM components in FECD, suggests a certain chronology in their deposition, and demonstrates their impact on cell behavior.

Retropupillary Iris-fixated versus Sutured Scleral-fixated Intraocular Lenses.

Aim: To compare the anatomical and functional results and patient satisfaction following retropupillary implantation of Artisan Aphakia iris-fixated intraocular lens (rAAIF) and sutured scleral fixated intraocular lens (SFIOL). Subjects and methods: We presented a prospective double-arm non-blinded study. Forty-one eyes with acquired aphakia, no age-related macular degeneration, no previous keratoplasty, no combined procedures, no AC reaction (cells, fibrin), normal intraocular pressure, no history of endothelial corneal dystrophy in relatives or fellow eye were included. Indications, complications, corrected distance visual acuity (CDVA), endothelial cell density (ECD), and patient satisfaction score were assessed. Results: Retropupillary AAIF was implanted in 21 (51.22%) eyes and SFIOL in 20 (48.78%) eyes. The most common indication was complicated cataract surgery in 18 cases (43.90%), followed by trauma in 16 (39.02%), and spontaneous dislocation in 7 (17.07%). No difference between rAAIF and SFIOL in terms of sex, laterality (χ=0.13, p=0.72), indications (χ=0.78, p=0.68), previous ocular history, and comorbidities was observed. The complications and the visual outcomes at 6 months postoperatively were similar between the two groups (p=0.95 and p=0.321, respectively). The ECD loss in the two groups was also similar (p=0.89). The patient satisfaction score was 58.67±8.80 in the rAAIF and 56.69±11.50 in the SFIOL group, which was statistically similar (p=0.764). Conclusion: Retropupillary AAIF and SFIOL showed similar results concerning visual acuity, endothelial cell loss, and patient satisfaction. Careful preoperative individual assessment is required to have optimal results with either technique. Abbreviations: AAIF = Artisan Aphakia iris-fixated intraocular lens, rAAIF = retropupillary Artisan Aphakia iris-fixated intraocular lens, CDVA = corrected distance visual acuity, ECD = endothelial cell density, IOL = intraocular lens, SD = standard deviation, SFIOL = scleral fixated intraocular lens.

Deep learning for detection of Fuchs endothelial dystrophy from widefield specular microscopy imaging: a pilotstudy

BackgroundTo describe the diagnostic performance of a deep learning (DL) algorithm in detecting Fuchs endothelial corneal dystrophy (FECD) based on specular microscopy (SM) and to reliably detect widefield peripheral SM images with an endothelial cell density (ECD) > 1000 cells/mm2.MethodsFive hundred and forty-seven subjects had SM imaging performed for the central cornea endothelium. One hundred and seventy-three images had FECD, while 602 images had other diagnoses. Using fivefold cross-validation on the dataset containing 775 central SM images combined with ECD, coefficient of variation (CV) and hexagonal endothelial cell ratio (HEX), the first DL model was trained to discriminate FECD from other images and was further tested on an external set of 180 images. In eyes with FECD, a separate DL model was trained with 753 central/paracentral SM images to detect SM with ECD > 1000 cells/mm2 and tested on 557 peripheral SM images. Area under curve (AUC), sensitivity and specificity were evaluated.ResultsThe first model achieved an AUC of 0.96 with 0.91 sensitivity and 0.91 specificity in detecting FECD from other images. With an external validation set, the model achieved an AUC of 0.77, with a sensitivity of 0.69 and specificity of 0.68 in differentiating FECD from other diagnoses. The second model achieved an AUC of 0.88 with 0.79 sensitivity and 0.78 specificity in detecting peripheral SM images with ECD > 1000 cells/mm2.ConclusionsOur pilot study developed a DL model that could reliably detect FECD from other SM images and identify widefield SM images with ECD > 1000 cells/mm2 in eyes with FECD. This could be the foundation for future DL models to track progression of eyes with FECD and identify candidates suitable for therapies such as Descemet stripping only.

Applications of Imaging Technologies in Fuchs Endothelial Corneal Dystrophy: A Narrative Literature Review.

Fuchs endothelial corneal dystrophy (FECD) is a complex genetic disorder characterized by the slow and progressive degeneration of corneal endothelial cells. Thus, it may result in corneal endothelial decompensation and irreversible corneal edema. Moreover, FECD is associated with alterations in all corneal layers, such as thickening of the Descemet membrane, stromal scarring, subepithelial fibrosis, and the formation of epithelial bullae. Hence, anterior segment imaging devices that enable precise measurement of functional and anatomical changes in the cornea are essential for the management of FECD. In this review, the authors will introduce studies on the application of various imaging modalities, such as anterior segment optical coherence tomography, Scheimpflug corneal tomography, specular microscopy, in vitro confocal microscopy, and retroillumination photography, in the diagnosis and monitoring of FECD and discuss the results of these studies. The application of novel technologies, including image processing technology and artificial intelligence, that are expected to further enhance the accuracy, precision, and speed of the imaging technologies will also be discussed.

Comparative Analysis of Tomographic Indicators Forecasting Decompensation in Fuchs Endothelial Corneal Dystrophy.

To compare the performance of 3 commercially available tomographers (the Pentacam Scheimpflug camera, the swept-source optical coherence tomography Casia, and the blue light slit-scanning tomographer Precisio) in the identification of patterns associated with Fuchs endothelial corneal dystrophy (FECD) decompensation. This was a clinic-based cross-sectional imaging study. Pachymetry maps and posterior surface elevation maps were acquired with the 3 devices from 61 eyes affected by FECD. The maps were graded according to the evidence of tomographic patterns predictive of FECD decompensation (loss of parallel isopachs, displacement of the thinnest point, and focal posterior depression) by 2 blind cornea specialists. The loss of parallel isopachs was significantly less frequently evident in Pentacam pachymetry maps [8%, 95% confidence interval (CI) (3%, 18%)] compared with both the Casia [31%, 95% CI (20%, 44%), P = 0.01] and Precisio devices [24%, 95% CI (15%, 37%), P = 0.05]. The displacement of the thinnest point was graded as most evident in a significantly higher proportion of Precisio pachymetry maps [43%, 95% CI (31%, 55%)] compared with both the Pentacam [13%, 95% CI (6%, 24%), P = 0.001] and Casia devices [21%, 95% CI (12%, 33%), P = 0.03]. There were no significant differences in the identification of focal posterior depression on posterior elevation maps across the 3 devices. Identification of patterns predictive of FECD prognosis on pachymetry and posterior elevation maps is possible with different devices. However, their evidence varies across tomographers, and the results from different devices are not interchangeable.

A Review of the Management of Fuchs Endothelial Corneal Dystrophy

Fuchs Endothelial Corneal Dystrophy leads to progressive visual deterioration that may cause acutely painful episodes. Medical management  has been limited to prescribing hyperosmotic agents. The advancement in therapeutic and surgical management has led to earlier intervention, better visual prognosis, and improved quality of life for patients affected by FECD. Optometrists play a role in the management of this condition’s diagnosis, treatment, and postsurgical care.

Differences in Guttae Ultramorphology in Relation to Visual Function in Fuchs Endothelial Corneal Dystrophy.

The purpose of this study was to investigate the differences in guttae ultramorphology and their relation to visual function in eyes with Fuchs endothelial corneal dystrophy (FECD). Thirty FECD eyes without ocular comorbidities were included. Visual functional parameters (best-corrected visual acuity with high-contrast and low-contrast letters and contrast sensitivity/LogCS) and corneal morphology measured with Scheimpflug tomography (Pentacam) were assessed. The surgically removed Descemet membranes were examined by light and transmission electron microscopy. Preoperative mean best-corrected visual acuity (logarithm of the minimum angle of resolution) was 0.52 ± 0.18, LogCS 0.96 ± 0.21 and central corneal thickness 640 ± 55 μm. All eyes had signs of subclinical corneal edema in Scheimpflug tomography; clinically visible corneal edema was present in 40% of eyes. Histological findings included a posterior fibrillar zone (PFZ) in 10 specimens (33%) and abnormal collagen depositions in Descemet membranes in 14 specimens (47%). Guttae buried within the PFZ were present only in eyes with clinically visible edema (n = 4, 13%). There was no difference in visual function results and tomography parameters between eyes with and without PFZ or between protruding guttae and guttae embedded in a PFZ, respectively. Guttae morphology and density were not correlated with visual functional parameters. Guttae buried in a PFZ occurred only in eyes with clinically manifest edema, and thereby, they are an ultramorphological sign for advanced FECD. Subclinical edema was present in all eyes and might be more relevant for quality of vision than guttae ultramorphology.

Absence of the Klotho Function Causes Cornea Degeneration with Specific Features Resembling Fuchs Endothelial Corneal Dystrophy and Bullous Keratopathy.

The Klotho loss-of-function mutation is known to cause accelerated senescence in many organs, but its effects on the cornea have not been published. The present study aims to investigate the effects of the Klotho null mutation on cornea degeneration and to characterize the pathological features. Mouse corneas of Klotho homozygous, heterozygous, and wild-type mice at 8 weeks of age for both genders were subject to pathological and immunohistological examinations. The results show an irregular topography on the corneal surface with a Klotho null mutation. Histological examinations revealed a reduced corneal epithelial cell density, endothelial cell-shedding, and decreased cornea stromal layer thickness in the absence of the Klotho function. Furthermore, guttae formation and the desquamation of wing cells were significantly increased, which was comparable to the characteristics of Fuchs endothelial corneal dystrophy and bullous keratopathy. The mechanism analysis showed multi-fold abnormalities, including oxidative stress-induced cornea epithelium apoptosis and inflammation, extracellular matrix remodeling in the stroma, and a disruption of epithelial repair, presumably through the epithelial-mesenchymal transition. In conclusion, cornea degeneration was observed in the Klotho loss-of-function mutant mice. These pathological features support the use of Klotho mutant mice for investigating age-related cornea anomalies, including Fuchs endothelial corneal dystrophy, bullous keratopathy, and dry eye diseases.

Long noncoding RNA ZFAS1: A novel anti-apoptotic target in Fuchs endothelial corneal dystrophy

Fuchs endothelial corneal dystrophy (FECD) is the leading cause of endothelial keratoplasty without efficacious drug treatment. Recent studies have emphasized the involvement of epigenetic regulation in FECD development. Long non-coding RNAs (lncRNAs) are recognized as crucial epigenetic regulators in diverse cellular processes and ocular diseases. In this study, we revealed the expression patterns of lncRNAs using high-throughput sequencing technology in FECD mouse model, and identified 979 significantly dysregulated lncRNAs. By comparing the data from FECD human cell model, we obtained a series of homologous lncRNAs with similar expression patterns, and revealed that these homologous lncRNAs were enriched in FECD related biological functions, with apoptosis (mmu04210) showing the highest enrichment score. In addition, we investigated the role of lncRNA zinc finger antisense 1 (ZFAS1) in apoptotic process. This study would broaden our understanding of epigenetic regulation in FECD development, and provide potential anti-apoptotic targets for FECD therapy.

Fuchs endothelial corneal dystrophy: an updated review.

The present review will summarize FECD-associated genes and pathophysiology, diagnosis, current therapeutic approaches, and future treatment perspectives. Literature review. Fuchs' endothelial corneal dystrophy (FECD) is the most common bilateral corneal dystrophy and accounts for one-third of all corneal transplants performed in the US. FECD is caused by a combination of genetic and non-heritable factors, and there are two types: early-onset FECD, which affects individuals from an early age and is usually more severe, and late-onset FECD, which is more common and typically manifests around the age of 40. The hallmark findings of FECD include progressive loss of corneal endothelial cells and the formation of focal excrescences (guttae) on the Descemet membrane. These pathophysiological changes result in progressive endothelial dysfunction, leading to a decrease in visual acuity and blindness in later stages. The present review will summarize FECD-associated genes and pathophysiology, diagnosis, current therapeutic approaches, and future treatment perspectives. With the characterization and understanding of FECD-related genes and ongoing research into regenerative therapies for corneal endothelium, we can hope to see more significant improvements in the future in the management and care of the disease.

Assessing Fuchs Corneal Endothelial Dystrophy Using Artificial Intelligence–Derived Morphometric Parameters From Specular Microscopy Images

Purpose: The aim of this study was to evaluate the efficacy of artificial intelligence–derived morphometric parameters in characterizing Fuchs corneal endothelial dystrophy (FECD) from specular microscopy images. Methods: This cross-sectional study recruited patients diagnosed with FECD, who underwent ophthalmologic evaluations, including slit-lamp examinations and corneal endothelial assessments using specular microscopy. The modified Krachmer grading scale was used for clinical FECD classification. The images were processed using a convolutional neural network for segmentation and morphometric parameter estimation, including effective endothelial cell density, guttae area ratio, coefficient of variation of size, and hexagonality. A mixed-effects model was used to assess relationships between the FECD clinical classification and measured parameters. Results: Of 52 patients (104 eyes) recruited, 76 eyes were analyzed because of the exclusion of 26 eyes for poor quality retroillumination photographs. The study revealed significant discrepancies between artificial intelligence–based and built-in microscope software cell density measurements (1322 ± 489 cells/mm2 vs. 2216 ± 509 cells/mm2, P &lt; 0.001). In the central region, guttae area ratio showed the strongest correlation with modified Krachmer grades (0.60, P &lt; 0.001). In peripheral areas, only guttae area ratio in the inferior region exhibited a marginally significant positive correlation (0.29, P &lt; 0.05). Conclusions: This study confirms the utility of CNNs for precise FECD evaluation through specular microscopy. Guttae area ratio emerges as a compelling morphometric parameter aligning closely with modified Krachmer clinical grading. These findings set the stage for future large-scale studies, with potential applications in the assessment of irreversible corneal edema risk after phacoemulsification in FECD patients, as well as in monitoring novel FECD therapies.

Enhanced Monofocal Intraocular Lenses in Fuchs' Endothelial Dystrophy Patients: Results from Triple Descemet Membrane Endothelial Keratoplasty Procedure.

Descemet membrane endothelial keratoplasty (DMEK) is currently regarded as the most effective surgical procedure for addressing Fuchs Endothelial Corneal Dystrophy (FECD), frequently performed in conjunction with cataract surgery. In this retrospective study, we present a comparison of visual performance, clinical outcomes, and optical quality between two types of monofocal Intraocular Lenses (IOLs): one standard and one enhanced intermediate vision model, implanted in patients who underwent combined phacoemulsification and DMEK surgery. This single center comparative retrospective study was conducted at the Eye Clinic of the University of Florence (Italy) and included a total of 48 eyes of 48 patients affected by FECD and cataract. All patients underwent combined DMEK with phacoemulsification procedures. The patients' data were analyzed and divided into two groups: one group (standard group) consisted of 24 eyes that underwent phaco-DMEK with implantation of a monofocal IOL, and the second group (enhanced monofocal group) included 24 eyes that underwent phaco-DMEK with implantation of an enhanced monofocal IOL. In both groups, the following monocular visual outcomes were evaluated 6 months after surgery: Uncorrected Distance Visual Acuity (UDVA) and Best-Corrected Distance Visual Acuity (BCDVA) at 4 mts; Uncorrected Intermediate Visual Acuity (UIVA), Distance-Corrected Intermediate Visual Acuity (DCIVA) at 66 cm; Uncorrected Near Visual Acuity (UNVA) and Best Corrected Near Visual Acuity (BCNVA). Monocular defocus curves were also assessed. Furthermore, optical quality in terms of Contrast Sensitivity (CS) in photopic conditions, Higher-Order Aberrations (HOAs) at a pupil size of 5 mm. Modulation Transfer Function (MTF), Objective Scatter Index (OSI), and Strehl ratio, were also analyzed. A Patient-Reported Spectacle Independence Questionnaire was revised to evaluate spectacle independence outcomes. the two groups did not exhibit statistically significant differences in terms of UDVA, BCDVA, UNVA and BCNVA, photopic CS, HOAs, OSI, Strehl ratio, and MTF. However, in the phaco-DMEK enhanced monofocal IOL group, significantly better results were observed in terms of UIVA and DCIVA as well as a different defocus curve profile at 1.50 D, providing better defocus results at intermediate distance compared with the ZCB00 IOL. In our study, we found that enhanced monofocal lens performed favorable visual outcomes, even in cases of FECD, compared to standard monofocal IOLs. Comparable optical quality observed in the Eyhance group could allow surgeons to consider these lenses as a viable option for selected patients with FECD.

Fuch's Endothelial Corneal Dystrophy in Cataract Patients Is Associated with Elevated Levels of Inflammatory Chemokines, but Not Growth Factors, in the Aqueous Humor.

The study investigated a profile of chemokines and growth factors in the aqueous humor (AH) of eyes with Fuch's endothelial corneal dystrophy (FECD) and cataracts in comparison with cataract patients as a control group. A total of 52 AH samples (26 FECD + cataract and 26 cataract/control) were collected before cataract surgery. None of the patients had any clinically apparent inflammation at the time of AH collection. The AH levels of MCP-1 (CCL2), MIP-1α (CCL3), MIP-1β(CCL4), RANTES (CCL5), eotaxin (CCL11), IP-10 (CXCL10), FGF basic, G-CSF, GM-CSF, PDGF-bb, and VEGF were compared between the groups. The analyses were performed using the Bio-Plex 200 System from Bio-Rad. Among the studied parameters, the AH levels of RANTES, eotaxin, and IP-10 significantly increased in the FECD + cataract eyes, compared with the cataract controls (p < 0.05). Elevated levels of the RANTES, Eotaxin, and IP-10 indicate more intense inflammation in the eyes of patients in the FECD + cataract group. Moreover, these factors exhibit potential as predictive biomarkers for early detection of FECD in cataract patients. The discovery of elevated concentrations of biochemical markers in a patient, who has not yet received a clinical diagnosis, may suggest the need for heightened observation of the other eye to monitor the potential development of FECD.

Predicting Long-Term Endothelial Cell Loss after Preloaded Descemet Membrane Endothelial Keratoplasty in Fuchs’ Endothelial Corneal Dystrophy: A Mathematical Model

(1) Background: This study offers a biexponential model to estimate corneal endothelial cell decay (ECD) following preloaded “endothelium-in” Descemet membrane endothelial keratoplasty (DMEK) in Fuchs’ endothelial corneal dystrophy (FECD) patients; (2) Methods: A total of 65 eyes undergoing DMEK alone or combined with cataract surgery were evaluated. The follow-up period was divided into an early phase (first 6 months) and a late phase (up to 36 months). Endothelial cell count (ECC) and endothelial cell loss (ECL) were analyzed; (3) Results: The half time of the ECD was 3.03 months for the early phase and 131.50 months for the late phase. The predicted time-lapse interval to reach 500 cells/mm2 was 218 months (18.17 years), while the time-lapse interval to reach 250 cells/mm2 was 349 months (29.08 years). There was no statistically significant difference between the ECL in DMEK combined with cataract extraction and DMEK alone at 24 months (p ≥ 0.20). At the late phase, long-term ECL prediction revealed a lower ECC half time in patients undergoing DMEK combined with cataract surgery (98.05 months) than DMEK alone (250.32 months); (4) Conclusions: Based on the mathematical modeling, a predicted average half-life of a DMEK graft could reach 18 years in FECD. Moreover, combining cataract extraction with DMEK could result in excessive ECL in the long term.

Comparison of Scheimpflug and Anterior Segment Optical Coherence Tomography Imaging Parameters for Japanese Patients With Fuchs Endothelial Corneal Dystrophy With and Without TCF4 Repeat Expansions.

The aim of this study was to investigate the association between cytosine-thymine-guanine trinucleotide repeat (TNR) expansion in TCF4 and the clinical phenotypes of corneal densitometry or anterior segment morphology in Fuchs endothelial corneal dystrophy. This retrospective cross-sectional study included 150 eyes from 75 Japanese consecutive patients with Fuchs endothelial corneal dystrophy. Cytosine-thymine-guanine repeat expansion of leukocyte-derived genomic DNA was analyzed through fragment analysis using polymerase chain reaction and triplet repeat primed polymerase chain reaction. Scheimpflug-based densitometry and anterior segment optical coherence tomography were applied. Corneal densitometry, and corneal and anterior segment morphology parameters were compared between patients with and without TNR expansion of 50 or more (expansion and nonexpansion groups, respectively) using a mixed model. The average age of the patients was 66.8 ± 13.0 years, and the modified Krachmer grading scale was 1, 2, 3, 4, 5, and 6 for 7, 32, 28, 51, 6, and 18 eyes, respectively. Sixteen patients (21%) exhibited ≥50 TNR expansion. No significant differences in sex, age, history of keratoplasty, modified Krachmer grade, and corneal densitometry in either diameter or depth were observed between the 2 groups. No significant differences in anterior segment morphology, including the anterior chamber depth and anterior chamber angle width parameters, were observed using a univariate mixed model, except for central corneal thickness (P = 0.047). However, according to the multivariate mixed model, repeat expansion was not significantly associated with central corneal thickness (P = 0.27). No significant differences in clinical phenotypes were found between Japanese patients having Fuchs endothelial corneal dystrophy with and without TNR expansion.

Investigation of the functional impact of CHED- and FECD4-associated SLC4A11 mutations in human corneal endothelial cells.

Mutations in the solute linked carrier family 4 member 11 (SLC4A11) gene are associated with congenital hereditary endothelial dystrophy (CHED) and Fuchs corneal endothelial dystrophy type 4 (FECD4), both characterized by corneal endothelial cell (CEnC) dysfunction and/or cell loss leading to corneal edema and visual impairment. In this study, we characterize the impact of CHED-/FECD4-associated SLC4A11 mutations on CEnC function and SLC4A11 protein localization by generating and comparing human CEnC (hCEnC) lines expressing wild type SLC4A11 (SLC4A11WT) or mutant SLC4A11 harboring CHED-/FECD4-associated SLC4A11 mutations (SLC4A11MU). SLC4A11WT and SLC4A11MU hCEnC lines were generated to express either SLC4A11 variant 2 (V2WT and V2MU) or variant 3 (V3WT and V3MU), the two major variants expressed in ex vivo hCEnC. Functional assays were performed to assess cell barrier, proliferation, viability, migration, and NH3-induced membrane conductance. We demonstrate SLC4A11-/- and SLC4A11MU hCEnC lines exhibited increased migration rates, altered proliferation and decreased cell viability compared to SLC4A11WT hCEnC. Additionally, SLC4A11-/- hCEnC demonstrated decreased cell-substrate adhesion and membrane capacitances compared to SLC4A11WT hCEnC. Induction with 10mM NH4Cl led SLC4A11WT hCEnC to depolarize; conversely, SLC4A11-/- hCEnC hyperpolarized and the majority of SLC4A11MU hCEnC either hyperpolarized or had minimal membrane potential changes following NH4Cl induction. Immunostaining of primary hCEnC and SLC4A11WT hCEnC lines for SLC4A11 demonstrated predominately plasma membrane staining with poor or partial colocalization with mitochondrial marker COX4 within a subset of punctate subcellular structures. Overall, our findings suggest CHED-associated SLC4A11 mutations likely lead to hCEnC dysfunction, and ultimately CHED, by interfering with cell migration, proliferation, viability, membrane conductance, barrier function, and/or cell surface localization of the SLC4A11 protein in hCEnC. Additionally, based on their similar subcellular localization and exhibiting similar cell functional profiles, protein isoforms encoded by SLC4A11 variant 2 and variant 3 likely have highly overlapping functional roles in hCEnC.

Comparison of Pre- and Post-DMEK Keratometry and Total Keratometry Values for IOL Power Calculations in Eyes Undergoing Triple DMEK

Purpose To evaluate prediction accuracy of pre- and post-DMEK keratometry (K) and total keratometry (TK) values for IOL power calculations in Fuchs endothelial corneal dystrophy (FECD) eyes undergoing DMEK with cataract surgery (triple DMEK). Methods Retrospective cross-sectional multicenter study of 55 FECD eyes (44 patients) that underwent triple DMEK between 2019 and 2022 between two centers in USA and Europe. Swept-source optical coherence tomography biometry (IOLMaster 700) was used for pre- and post-DMEK measurements. K and TK values were used for power calculations with ten formulae (Barrett Universal II (BUII), Castrop, Cooke K6, EVO 2.0, Haigis, Hoffer Q, Hoffer QST, Holladay I, Kane, and SRK/T). Mean error, mean absolute error (MAE), standard deviation, and percentage of eyes within ±0.50/±1.00 diopters (D) were calculated. Studied formulae were additionally adjusted using a method published previously (IOLup1D Method), which increases the IOL power by 1D. While both eyes from the same patient were considered for descriptive statistics, we restricted to one eye per individual (44 eyes for statistical comparisons. Results MAEs for all formulae were lower for post-DMEK K and TK than pre-DMEK K and TK by an average of 0.24 and 0.47 D, respectively. The lowest MAE was 0.49 D for Kane using post-DMEK TK, and the highest MAE was 1.05 D for BUII using pre-DMEK TK. Most IOLup1D formulae had lower MAEs than pre-DMEK K and TK formulae. Conclusions The IOLup1D Method should be used instead of pre-DMEK K and TK values for triple DMEK in FECD eyes. Using post-DMEK TK values for cataract surgery after DMEK provides better refractive accuracy than any of the three studied methods used for triple DMEK procedures.