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To assess vision in pseudophakic eyes with Fuchs' endothelial corneal dystrophy (FECD) before the onset of clinically detectable corneal edema.Cross-sectional study.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.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.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.

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).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.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, P0.001), failed graft (HR = 6.4, P0.001), and preoperative medical glaucoma (HR = 7.1, P0.001) or surgical glaucoma (HR = 12.3, P0.001). 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, P0.001) and subsequent glaucoma surgery (HR17.4, P0.001).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.

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.This is a case report and review of relevant literature.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.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.

Fuchs endothelial corneal dystrophy (FECD), a progressive polygenic disease that causes degeneration of the corneal endothelium, is the leading indication for corneal transplantation in the U.S. Characteristically, loss of corneal endothelial cells and formation of degenerative extracellular “guttae” result in failure to maintain appropriate corneal hydration through active ion pumping to counter the passive leakage of aqueous humor. FECD pathogenesis is linked to oxidative stress and environmental exposure to ultraviolet A (UVA), and impaired endogenous response to oxidative stress is common to the disease across multiple genotypes. UV irradiation is also known to cause cellular damage by ferroptosis, a nonapoptotic oxidative cell death resulting from iron-mediated lipid peroxidation. Although a possible role for ferroptosis in FECD has been postulated to account for the increased susceptibility to oxidative damage and lipid peroxidation, this has not been explored systematically. In this study, we investigated the roles of genetic background and UVA exposure in causing lipid membrane damage and endothelial cell degeneration in FECD. We first sought clinical evidence of iron-mediated lipid peroxidation in surgical samples obtained from FECD patients undergoing endothelial keratoplasty, and found increased levels of cytosolic ferrous iron (Fe2+) and evidence of lipid peroxidation were present in end-stage diseased tissues compared with healthy human donor corneas. Next, using immortalized (F35T) and primary cell cultures modeling the TCF4 intronic trinucleotide repeat expansion genotype, we found that alterations in gene and protein expression involved in ferroptosis were conserved in both cell culture and tissue models of FECD disease compared to controls, including elevated levels of the ferroptosis-specific marker transferrin receptor 1. F35T immortalized cells showed significantly higher basal lipid peroxidation than control HCEC-B4G12 cells, indicating higher susceptibility to ferroptosis attributable to genetic background. Then, we tested the impact of physiologically relevant doses of UVA irradiation on F35T cell cultures and found increased cytosolic Fe2+ iron levels indicating a role for ferroptosis in FECD disease progression. Finally, we tested the effects of inhibitory ferroptosis molecules. We found that F35T cells were more prone to RSL3 induced ferroptosis than healthy controls with deferoxamine chelation which indicated increased susceptibility in FECD cells, and cell death could be prevented after experimentally-induced ferroptosis using solubilized antioxidant ubiquinol indicating a role for anti-ferroptosis therapies. This investigation demonstrates that FECD genetic background and UVA exposure contribute to basal and incidental iron-mediated lipid peroxidation and cell death in FECD, and provides the basis for future investigations of ferroptosis-mediated oxidative damage and disease progression in FECD.

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 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.

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 (TCF4 CTG repeat expansions in the FECD corneal endothelium are much longer than those found in leukocytes.

The purpose of this study is to quantify cancer risk in patients with Fuchs endothelial corneal dystrophy (FECD).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.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; P0.001], cutaneous basal cell (OR: 1.42; 95% CI: 1.35-1.49; P0.001), 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; P0.001), ovarian (OR: 1.84; 95% CI: 1.48-2.30; P0.001), 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).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.

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 (

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.

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.

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 two ways: AION within two months and AION within one 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 two 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=0.78). However, the annual incidence rate of pcsAION within one year of surgery (38.9 per 100,000) was significantly higher than the incidence rate of sAION (6.5 per 100,000; p

Purpose: CTG trinucleotide repeat (TNR) expansion is frequently found in transcription factor 4 (TCF4) in Fuchs' endothelial corneal dystrophy (FECD), though the effect of TNR expansion on FECD pathophysiology remains unclear. The purpose of this study was to evaluate the effect of TNR expansion on TCF4 expression in corneal endothelium of patients with FECD. \ud\udMethods: Peripheral blood DNA and Descemet membrane with corneal endothelium were obtained from 203 German patients with FECD. The CTG TNR repeat length in TCF4 was determined by short tandem repeat (STR) assays and Southern blotting using genomic DNA. Genotyping of rs613872 in TCF4 was performed by PCR. TCF4 mRNA levels in corneal endothelium were evaluated by quantitative PCR using three different probes. Control corneal endothelial samples were obtained from 35 non-FECD subjects. \ud\udResults: The STR assay and Southern blotting showed that 162 of the 203 patients with FECD (80%) harbored CTG trinucleotide repeat lengths larger than 50. Quantitative PCR using all three probes demonstrated that TCF4 mRNA is significantly upregulated in the corneal endothelium of patients with FECD, regardless of the presence of TNR expansion. However, the length of the TNR tended to show a positive correlation with TCF4 expression level. No correlation was shown between the genotype of TCF4 SNP, rs613872, and the level of TCF4 expression. \ud\udConclusions: Our findings showed that TCF4 mRNA is upregulated in the corneal endothelium of patients with FECD. Further studies on the effects of TCF4 upregulation on corneal endothelial cell function will aid in understanding the pathophysiology of FECD.

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.Ein Verständnis der genetischen Grundlagen der Fuchs-Endotheldystrophie eröffnet die Möglichkeit zukünftiger gezielter, nicht operativer Therapien. Bis diese Therapien ausgereift sind, könnten neue regenerative therapeutische Ansätze wie die Injektion von Endothelzellen oder der Transfer kultivierter Endothelzellschichten helfen, die Verfügbarkeit von Donorgewebe zu verbessern und vielleicht sogar autologe Transplantationen zu ermöglichen. Eher temporäre operative Ansätze für ausgewählte Patienten sind das alleinige Stripping und der azelluläre Transfer der Descemet-Membran, obgleich unklar ist, welche Patienten am meisten von diesen Verfahren profitieren können. Für alle Behandlungsverfahren werden klinische Studien notwendig sein, weshalb Kliniker anstreben sollten, die Bestimmung des Schweregrads der Fuchs-Endotheldystrophie und der postoperativen Erfolgsparameter zu standardisieren.

The structure of the cornea is vital to its transparency, and dystrophies that disrupt corneal organization are highly heritable. To understand the genetic aetiology of Fuchs endothelial corneal dystrophy (FECD), the most prevalent corneal disorder requiring transplantation, we conducted a genome-wide association study (GWAS) on 1,404 FECD cases and 2,564 controls of European ancestry, followed by replication and meta-analysis, for a total of 2,075 cases and 3,342 controls. We identify three novel loci meeting genome-wide significance (P, Fuchs endothelial corneal dystrophy (FECD) is one of the most common reasons for corneal transplantation, and is known to cluster in families. Here, the authors discover new genetic loci associated with FECD with sex-specific effects and implications for disease mechanism.

Purpose To determine if agreement between subjective interpretations of Scheimpflug tomography maps of corneas with Fuchs endothelial corneal dystrophy (FECD) is affected by daily and hourly changes in corneal edema. Design Reliability analysis. Methods Scheimpflug imaging pachymetry and posterior elevation maps of corneas with a range of severity of FECD were evaluated in a randomized manner for the presence of 3 tomographic features of edema. Agreement between interpretations of 1 masked observer was assessed (percentage, and κ-statistic with 95% confidence interval) for images taken within minutes on the same day, for images taken at a similar time on a different day, and for images taken over the course of a morning. Intra- and interobserver agreement was also assessed. Results Interpretations for individual tomographic features agreed for ≥88% of images (κ ≥ 0.75) taken within minutes on the same day; complete disagreement (ie, disagreement for all 3 tomographic features in an image) occurred in ≤3% of images. Interpretations agreed for ≥77% of images (κ ≥ 0.52) taken at a similar time on a different day; complete disagreement did not occur. Interpretations agreed for ≥81% of images (κ ≥ 0.61) taken over the course of a morning; complete disagreement occurred in ≤6% of images. Intraobserver agreement was ≥93% (κ ≥ 0.83) and interobserver agreement was ≥93% (κ ≥ 0.66); complete disagreement did not occur. Conclusions Subjective interpretation of Scheimpflug images in FECD is highly repeatable for disease classification. Although small variations in interpretations resulted from pathophysiologic changes in corneal hydration and other factors, clinically significant disagreements in interpretation were uncommon and therefore unlikely to affect clinical decision-making.

PReCIS:: Over 10 years in a tertiary care setting, glaucoma drainage devices (GDDs) have not increased as a reason for keratoplasty. PURPOSE The purpose of this study was to determine whether the reasons for keratoplasty have changed between 10 years in a tertiary care setting, with special attention to the rate of GDDs as a reason for keratoplasty. METHODS Patients aged 18 years or above who underwent keratoplasty at Mayo Clinic, Rochester, MN from 2005 to 2006 and 2015 to 2016 were studied. All reasons for keratoplasty performed in the study time period are assessed, including patients who previously had a GDD implanted in the same eye. After analyzing the reasons for keratoplasty, we assess whether the reasons for keratoplasty have changed between 2005 to 2006 and 2015 to 2016 in association with the increasing placement of GDDs. RESULTS The number of keratoplasty procedures performed in the 2 time periods increased by 62% from 163 (2005 to 2006) to 264 (2015 to 2016), whereas GDD placement increased by 164% from 80 GDD (2005 to 2006) to 211 GDD (2015 to 2016). Although the performance of keratoplasty increased between the 2 points in time, the frequency of each cause for keratoplasty did not change significantly. The majority of keratoplasties were performed due to corneal disease, and GDDs made up a small portion of reasons for keratoplasty (2005 to 2006, 4.29%; 2015 to 2016, 5.68%). CONCLUSIONS The frequency of GDDs as a reason for keratoplasty has not changed significantly between 10 years in this tertiary care setting. Patients with GDDs who later required keratoplasty had associated features including multiple surgical procedures and comorbid infection, pseudophakic bullous keratopathy, Fuchs dystrophy, pseudoexfoliation, uveitis, and congenital glaucoma.

PURPOSE: To investigate single nucleotide polymorphisms (SNPs) and trinucleotide repeat (TNR) expansion in the transcription factor 4 (TCF4) gene in a large cohort of German patients with Fuchs endothelial corneal dystrophy (FECD). METHODS: Genomic DNA was obtained from 398 patients with FECD and from 58 non-FECD controls. Thirty-seven previously reported SNPs were evaluated by genotyping. The 398 FECD samples were analyzed for TNR expansions by short tandem repeat (STR) assays and Southern blotting. The possible associations between TNR length and clinical parameters (age, sex, visual acuity, and central corneal thickness) were analyzed in 132 patients. RESULT: The SNPs in COL8A2, TCF8, LOXHD1, and AGBL1 showed no heterogeneity in 36 cases, although SLCA411 showed 3 nonsense mutations. SNPs were detected for TCF4 (rs613872, rs2123392, rs17089887, rs1452787, and rs1348047), but only rs613872 showed a significant association with FECD (P=9.93×10(−12)). Overall, 315/398 (79%) patients harbored TNR lengths >50, while no non-FECD control harbored TNR lengths >50. The TCF4 SNP rs613872 genotype was TT:39 (67%), TG:18 (31%), and GG:1 (2%) in non-FECD controls; TT:39 (47%), TG: 38 (46%), and GG:6 (7%) in FECD cases harboring TNR 50 (P=2.93×10(−25)). No significant association was detected between clinical parameters and TNR length. CONCLUSIONS: Our large German cohort demonstrated a significant association between the risk allele G in rs613872 and FECD, irrespective of TNR expansion, although this risk allele was more frequent in FECD cases with TNR expansion than without.

Amplification of a CAG trinucleotide motif (CTG18.1) within the TCF4 gene has been strongly associated with Fuchs Endothelial Corneal Dystrophy (FECD). Nevertheless, a small minority of clinically unaffected elderly patients who have expanded CTG18.1 sequences have been identified. To test the hypothesis that the CAG expansions in these patients are protected from FECD because they have interruptions within the CAG repeats, we utilized a combination of an amplification-free, long-read sequencing method and a new target-enrichment sequence analysis tool developed by Pacific Biosciences to interrogate the sequence structure of expanded repeats. The sequencing was successful in identifying a previously described interruption within an unexpanded allele and provided sequence data on expanded alleles greater than 2000 bases in length. The data revealed considerable heterogeneity in the size distribution of expanded repeats within each patient. Detailed analysis of the long sequence reads did not reveal any instances of interruptions to the expanded CAG repeats, but did reveal novel variants within the AGG repeats that flank the CAG repeats in two of the five samples from clinically unaffected patients with expansions. This first examination of the sequence structure of CAG repeats in CTG18.1 suggests that factors other than interruptions to the repeat structure account for the absence of disease in some elderly patients with repeat expansions in the TCF4 gene.

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., Highlights • FECD is a common, age-related corneal dystrophy. • The majority of cases are associated with expansion of a CTG repeat (CTG18.1). • FECD is the most common trinucleotide repeat expansion disease in humans. • Evidence supports multiple molecular mechanisms underlying the pathophysiology. • Novel CTG18.1-targeted therapeutics are in development.

Purpose To identify RNA missplicing events in human corneal endothelial tissue isolated from Fuchs' endothelial corneal dystrophy (FECD). Methods Total RNA was isolated and sequenced from corneal endothelial tissue obtained during keratoplasty from 12 patients with FECD and 4 patients undergoing keratoplasty or enucleation for other indications. The length of the trinucleotide repeat (TNR) CTG in the transcription factor 4 (TCF4) gene was determined using leukocyte-derived DNA analyzed by a combination of Southern blotting and Genescan analysis. Commercial statistical software was used to quantify expression of alternatively spliced genes. Validation of selected alternative splicing events was performed by using RT-PCR. Gene sets identified were analyzed for overrepresentation using Web-based analysis system. Results Corneal endothelial tissue from FECD patients containing a CTG TNR expansion sequence in the TCF4 gene revealed widespread changes in mRNA splicing, including a novel splicing event involving FGFR2. Differential splicing of NUMA1, PPFIBP1, MBNL1, and MBNL2 transcripts were identified in all FECD samples containing a TNR expansion. The differentially spliced genes were enriched for products that localize to the cell cortex and bind cytoskeletal and cell adhesion proteins. Conclusions Corneal endothelium from FECD patients harbors a unique signature of mis-splicing events due to CTG TNR expansion in the TCF4 gene, consistent with the hypothesis that RNA toxicity contributes to the pathogenesis of FECD. Changes to the endothelial barrier function, a known event in the development of FECD, was identified as a key biological process influenced by the missplicing events.

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.

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).Cross-sectional study with instrument readministration at 6 weeks.Patients with a range of severity of FECD, including after EK, and patients with healthy corneas.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.Reliability (primary) and validity (secondary).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; P0.001; n = 96). The glare or diurnal variation factor increased with FECD severity (P0.001, 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.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.

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 P 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.

To assess corneal thickness (CT) and correlation with graft outcome after penetrating keratoplasty in the Cornea Donor Study.A total of 887 subjects with a corneal transplant for a moderate-risk condition (principally Fuchs dystrophy or pseudophakic corneal edema) had postoperative CT measurements throughout a 5-year follow-up time. Relationships between baseline (recipient, donor, and operative) factors and CT were explored. Proportional hazards models were used to assess the association between CT and graft failure. Relationship between CT and cell density was assessed with a longitudinal repeated measures model and Spearman correlation estimates.Higher longitudinal CT measurements were associated with the following: diagnosis of pseudophakic or aphakic corneal edema (P0.001), intraocular pressure25 mm Hg during the first postoperative month (P = 0.003), white (non-Hispanic) donor race (P = 0.002), and respiratory causes of donor death (P0.001). Among those without graft failure within the first postoperative year, the 5-year cumulative incidence (± 95% confidence interval) of graft failure was 5% ± 5% in those with a 1-year CT ≤ 500 μm, 5% ± 3% for CT 501 to 550 μm, 7% ± 4% for CT 551 to 600 μm, and 20% ± 11% for CT600 μm. In a multivariate analysis, both 1-year CT and cell density were associated with subsequent graft failure (P = 0.002 and 0.009). CT increase was modestly associated with endothelial cell loss during follow-up (r = -0.29).During the first 5 years after penetrating keratoplasty, CT can serve as a predictor of graft survival. However, CT is not a substitute for cell density measurement because both measures were independently predictive of graft failure.

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 (PCT 4 ) were measured by using scanning-slit pachymetry. The value of CPTR 4 was the quotient of CCT and PCT 4 . Main Outcome Measures Interobserver agreement for clinical grade and CPTR 4 . 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), PCT 4 decreased with age ( r = −0.33; P 4 increased with age ( r = 0.59; P P 4 was higher in Fuchs' dystrophy (650±51 μm; n=107) than in normal corneas (643±43 μm; n=254; P 4 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 P 4 was highly correlated with clinical grade of Fuchs' dystrophy ( r = 0.77; P 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. Financial Disclosure(s) The author(s) have no proprietary or commercial interest in any materials discussed in this article.

To determine corneal sensitivity and evaluate corneal nerves before and after keratoplasty for Fuchs endothelial dystrophy.Central corneal sensitivity, measured by using a Cochet-Bonnet esthesiometer in 69 eyes before and after different keratoplasty procedures for Fuchs dystrophy, was compared with that of 35 age-matched normal corneas. Corneal nerves were qualitatively examined by confocal microscopy in 42 eyes before and after Descemet stripping endothelial keratoplasty (DSEK).Corneal sensitivity in Fuchs dystrophy (4.61 ± 1.42 cm) was lower than that of age-matched controls (5.74 ± 0.48 cm, P0.001). Sensitivity decreased by 1 month after DSEK (2.98 ± 2.01 cm, P0.001), returned to preoperative sensitivity by 24 months (4.50 ± 1.63 cm, n = 33, P = 0.99), but remained lower than controls at 36 months (4.50 ± 1.48 cm, n = 15, P0.001). Sensitivity at 36 months after penetrating keratoplasty (1.46 ± 1.98 cm) remained decreased compared with preoperative sensitivity (P0.001). Subbasal nerves appeared sparse with abnormal branching before and through 36 months after DSEK. Sensitivity was lower in corneas without visible subbasal nerves by confocal microscopy at 12 months after DSEK (P0.005) than in corneas with visible nerves. Stromal nerves were frequently tortuous and formed loops in Fuchs dystrophy, and this appearance persisted in some eyes at 36 months after DSEK.Corneal sensitivity is decreased in Fuchs dystrophy compared with normal and remains subnormal even at 3 years after endothelial keratoplasty. Decreased sensitivity is likely to be related to loss of subbasal nerves and abnormal nerve morphology, which persist after endothelial keratoplasty.

To evaluate the prevalence of musculoskeletal disorders among eye care physicians compared with family medicine physicians.Case control study.Ophthalmologists and optometrists at the University of Iowa and Mayo Clinic (participants) and family medicine physicians at the University of Iowa and Mayo Clinic (controls).An electronic survey was e-mailed to all subjects.The prevalence of musculoskeletal symptoms between eye care providers and family medicine physicians (control group).One hundred eight-six surveys were completed by 94 eye care physicians and 92 family medicine physicians with a response rate of 99% and 80%, respectively. There were no significant differences between the 2 groups with regard to mean age, gender, body mass index, years with current employer, or years in practice. Eye care providers, compared with their family medicine colleagues, reported a higher prevalence of neck (46% vs 21%; P0.01), hand/wrist pain (17% vs 7%; P = 0.03), and lower back pain (26% vs 9%; P0.01). A greater proportion of eye care physicians classified their job as a high-strain job (high demand, low control; 31% vs 20%) and a lower proportion classified their job as an active job (high demand, high control; 24% vs 47%; p = 0.01). Several job factors reported by eye care providers to contribute to musculoskeletal symptoms included performing the same task repeatedly, working in awkward/cramped positions, working in the same position for long periods, and bending/twisting the back (all P0.01).In this survey, the study group, composed of ophthalmologists and optometrists, had a higher prevalence of neck, hand/wrist, and lower back pain compared with family medicine physicians; repetitive tasks, prolonged or awkward/cramped positions, and bending/twisting were contributory factors. Given the ramifications of these findings, future efforts should concentrate on modifications to the eye care providers' work environment to prevent or alleviate musculoskeletal disorders and their personal and socioeconomic burden.

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 = 2.3×10 −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 = 4.0×10 −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.)

Purpose RNA toxicity from CTG trinucleotide repeat (TNR) expansion within noncoding DNA of the transcription factor 4 (TCF4) and DM1 protein kinase (DMPK) genes has been described in Fuchs' endothelial corneal dystrophy (FECD) and myotonic dystrophy, type 1 (DM1), respectively. We prospectively evaluated DM1 patients and their families for phenotypic FECD and report the analysis of CTG expansion in the TCF4 gene and DMPK expression in corneal endothelium. Methods FECD grade was evaluated by slit lamp biomicroscopy in 26 participants from 14 families with DM1. CTG TNR length in TCF4 and DMPK was determined by a combination of Gene Scan and Southern blotting of peripheral blood leukocyte DNA. Results FECD grade was 2 or higher in 5 (36%) of 14 probands, significantly greater than the general population (5%) (P < 0.001). FECD segregated with DM1; six of eight members of the largest family had both FECD and DM1, while the other two family members had neither disease. All DNA samples from 24 subjects, including four FECD-affected probands, were bi-allelic for nonexpanded TNR length in TCF4 (

Purpose The strongest genetic association with Fuchs' endothelial corneal dystrophy (FECD) is the presence of an intronic (CTG·CAG)n trinucleotide repeat (TNR) expansion in the transcription factor 4 (TCF4) gene. Repeat-associated non-ATG (RAN) translation, an unconventional protein translation mechanism that does not require an initiating ATG, has been described in many TNR expansion diseases, including myotonic dystrophy type 1 (DM1). Given the similarities between DM1 and FECD, we wished to determine whether RAN translation occurs in FECD. Methods Antibodies against peptides in the C-terminus of putative RAN translation products from TCF4 were raised and validated by Western blotting and immunofluorescence (IF). CTG·CAG repeats of various lengths in the context of the TCF4 gene were cloned in frame with a 3× FLAG tag and transfected in human cells. IF with antipeptide and anti-FLAG antibodies, as well as cytotoxicity and cell proliferation assays, were performed in these transfected cells. Corneal endothelium derived from patients with FECD was probed with validated antibodies by IF. Results CTG·CAG repeats in the context of the TCF4 gene are transcribed and translated via non-ATG initiation in transfected cells and confer toxicity to an immortalized corneal endothelial cell line. An antipeptide antibody raised against the C-terminus of the TCF4 poly-cysteine frame recognized RAN translation products by IF in cells transfected with CTG·CAG repeats and in FECD corneal endothelium. Conclusions Expanded CTG·CAG repeats in the context of the third intron of TCF4 are transcribed and translated via non-ATG initiation, providing evidence for RAN translation in corneal endothelium of patients with FECD.

OBJECTIVES To describe the use of the Jupiter scleral contact lens (Medlens Innovations, Front Royal, VA or Essilor Contact Lens, Inc., Dallas, TX) in the management of ocular manifestations of chronic graft versus host disease (cGVHD). METHODS This study is a retrospective case series. Five consecutive patients with severe keratoconjunctivitis sicca (KCS) associated with cGVHD that could not be adequately managed with conventional therapy were evaluated for scleral contact lens wear between January and December 2007. All patients were evaluated with lenses from the standard 18.2 mm Jupiter B diagnostic fitting set. If lenses of standard design failed to provide adequate fit, custom lenses were designed. Three outcome measures were evaluated: the patient's ability to tolerate and successfully handle the lenses, improvement in symptoms of KCS, and improvement in visual acuity. RESULTS All 5 patients (10 eyes) were successfully fit with Jupiter scleral lenses. Six eyes of 3 patients were successfully fit with lenses of standard design. Standard parameters were altered to achieve adequate fit in 4 eyes of 2 patients. All patients reported subjective improvements in comfort with Jupiter scleral lenses, and best-corrected vision improved in 7 of the 10 eyes fit within the first several months of contact lens wear. The remaining 3 eyes maintained the visual acuity measured before scleral lens wear (20/20 in 2 eyes, 20/40 in 1 eye). Duration of follow-up ranged from 4 to 14 months. CONCLUSIONS Jupiter scleral lenses can relieve symptoms of KCS and may improve vision in patients with cGVHD.

PURPOSE To describe the first-documented case of histoplasma scleritis in an immunocompetent patient. METHODS Medical and pathological records of the patient described were reviewed. RESULTS A 77-year-old immunocompetent man presented with necrotizing scleritis. Biopsy was consistent with histoplasma species, and culture results confirmed a causative agent of Histoplasma capsulatum. The patient required a long course of treatment, which included topical voriconazole and amphotericin, oral itraconazole and voriconazole, intravenous amphotericin, and periocular voriconazole and amphotericin. After 8 months of treatment, the patient's scleritis resolved, and he maintained good visual acuity. CONCLUSIONS To our knowledge, this is the second report of histoplasma scleritis in the literature and the first report in an immunocompetent patient.

To estimate sex- and age-specific incidence rates of cataract surgery in a defined United States population and evaluate the change in incidence over time.Department of Ophthalmology, Mayo Clinic College of Medicine, Rochester, Minnesota, USA.Rochester Epidemiology Project databases were used to identify all incident cataract surgeries in Olmsted County, Minnesota, residents during the 25-year period from January 1, 1980, through December 31, 2004. Annual incidence rates for each sex and 10-year age group were calculated and adjusted to the 2000 U.S. white population. Change in incidence over time was assessed by fitting generalized linear models assuming a Poisson error structure.During the study period, 10 245 cataract extractions were performed in 7141 residents of all ages. Overall, the age-adjusted cataract surgery incident rate per 100000 residents was 548 (95% confidence interval [CI], 534-561) for women, 462 (95% CI, 447-478) for men, and 511 (95% CI, 501-521) for all residents. The incidence of cataract surgery increased 500% among women and 467% among men during the study period (P.001). Overall, the incidence of cataract surgery was highest in residents 70 years and older (3538 surgeries [95% CI, 3322-3764] per 100,000 residents).This population-based study found a substantial increase in incident cataract surgery among Olmsted County residents during the 25-year study period. The rate of cataract surgery increased in a nearly linear fashion during a period when phacoemulsification replaced extracapsular cataract extraction in the community.

PURPOSE: To report logarithm of the minimum angle of resolution (logMAR) visual outcomes of the Boston Keratoprosthesis Type 1. DESIGN: Prospective, cohort study. METHODS: Pre-, intra-, and postoperative parameters of 300 eyes of 300 patients who underwent implantation of a Boston Keratoprosthesis Type I device between January 2003 and July 2008 by one of 19 surgeons at 18 medical centers were collected. RESULTS: After an average of 17.1 ± 14.8 months, visual acuity improved significantly (p

To determine 5-year outcomes of Descemet stripping endothelial keratoplasty (DSEK) for Fuchs' endothelial corneal dystrophy (FECD).Prospective cohort study.Fifty-two eyes of 45 subjects with FECD undergoing primary DSEK.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.Best-corrected visual acuity, HOAs, endothelial cell loss, corneal thickness, and corneal backscatter.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 (P0.001). 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 (P0.001), 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.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.

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).Cross-sectional study.A total of 108 eyes (62 subjects) with a range of severity of FECD and 71 normal eyes (38 subjects).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.High-order aberrations, expressed as root mean square of wavefront errors, and backscatter of the anterior and posterior cornea.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; P0.001), and advanced (0.23±0.09 μm; P0.001) 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).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.